Journal articles on the topic 'With a concentration on the last thirty years in particular . During the time'

For most of the literary historians, the time period between the 1880s and 1920s have generally been accepted as the climax years of the notion of literary travelling not only in Europe but also in England. This type of journeying fashion is seen in the literary works of many English writers such as Charles Dickens, Thomas Hardy, Arthur Conan Doyle and many others. Literary travel can be considered as roaming of places of literary interest for pleasure where the traveller could experience and re-memory of birthplaces, homes, haunts and even graves of the prominent literary figures. Visiting places related with the particular writers or books coincides with bicycle condensed years of the last quarter of the nineteenth century (fin de siècle) in England. In addition to the above writers, Elizabeth Robins Pennell and Joseph Pennell are two different kind of travellers and their published account namely Our Sentimental Journey through France and Italy is worth scrutinizing. Both as American citizens, the Elizabeth Robins and Joseph Pennells decided to move to England in 1884, where they carried on their artistic and literary engagements for nearly thirty years, and the couple regularly had the chance to travel to Europe and brought their cultural baggage there on their tricycles. Joseph Pennell was born in Philadelphia, and he was an acclaimed lithographer of his time. After graduating from Pennsylvania Academy of Fine Arts, Joseph worked on the illustrations of travel articles and books for American publishers for a while. Through the mutual connection and overlapping of these two fin de siècle trends (literary travel and cycle travel) and the above-mentioned text of the Pennells’, this paper argues that the sentimental preconception of cycling complicates the experience of travelling for the above-mentioned couple as they tried to imitate Laurence Sterne, well-known writer of novels and travel accounts. For this respect, some supportive quotations will be given from the Pennells’ text in which they both lack to illustrate their sentimental mood in times and in other times, successfully show their joy enthusiasm in their pedalling with their tricycles. Thus, the foremost aim of this paper is to elaborate on Pennells’ text claiming their intertextual allusions on their former model Laurence Sterne.

The role of the brain in the somatic development, as well as in the establishment of the different variables of the life history pattern in vertebrates has been largely debated. Moreover, during the last thirty years, dental development has been used as a good proxy to infer different aspects of the life history in hominins, primarily due to the correlation that exists between age at first molar eruption and brain size in the order Primates. We review these questions using what is known about brain growth and maturation, dental development and life history pattern, mainly in Homo sapiens and Pan troglodytes. It has been assumed that the brain represents the pace-maker of our development. However, we consider that our particular phenotype is the result of a hierarchical genetic program modulated by epigenetic and environmental factors. The particular bauplan of any kind of organisms (e.g. primates) may explain the high correlation observed between different variables of its life history pattern, brain size or dental development. However, the correlation of these variables seems to be less reliable when dealing with low-rank taxonomical categories (i.e., species). We suggest that, while there is likely some relationship between the rate of somatic development and tooth development, our brain size and maturation (and, by extension, those of other species of the genus Homo) have derived towards a particular trajectory, with a unique pattern of prenatal and postnatal time and rate of growth and, particularly, with remarkable slow brain maturation. We suggest that extremely slow brain maturation could be a very recent acquisition of the last H. sapiens populations. Furthermore, our review of the literature suggests caution in drawing conclusions about aspects of the life history of the hominins from the information we can obtain from dental development in fossil specimens.

Lahore, the home of 11 million people, is one of the most polluted cities in the world. Pollution causes deaths, birth defects, and years of life lost. This study’s real-time data analysis of the air quality index (AQI) showed that air pollution remained “unhealthy for everyone” for 54% of the time, and “unhealthy for sensitive groups” for 88% of the time, during the last three years (June 2019–September 2021). The air quality index (AQI) value in Lahore reached 175 µg/m3 in 2021. This alarmingly hazardous air situation was analyzed by selecting fourteen sites based on the provenance of industrialization and tailpipe emissions. An analysis of remote sensing data for these sites was performed, in addition to field surveys, to identify the relationship between pollutant concentration and on-ground current practices. The key primary and secondary air pollutants selected for analysis were carbon monoxide (CO), nitrogen dioxide (NO2), sulphur dioxide (SO2), aerosol optical depth (AOD), methane (CH4), and formaldehyde (HCHO). The assessment was carried out for the study period of July 2018 to April 2021. The real-time AQI was plotted against each pollutant’s monthly concentration, which showed a significant positive correlation of AQI with SO2, NO2, and CO. A plotting of the percentage contribution of each pollutant with its emission sources highlighted the main pollutant to take action to reduce, as a priority on those particular sites. The pollutant hotspot within each economic activity was also determined. Assessments showed that the AQI value was higher on weekends than on weekdays. These findings can help to develop smart adaptation action plans for immediate implementation, to dilute the current environmental risks in the city.

Abstract: The paper reviews the climatic changes that took place during the Quaternary, in particular those of the Holocene, including the historical time. The role of carbon dioxide, as a greenhouse gas, is emphasized since it is an important factor influencing the global climate. During the last century, a non-negligible increase in the atmospheric concentration of CO2 brought about a rise in global temperature attributed by many scientists to a man-made cause and labeled “anthropogenic global warming “. It is claimed that a rapid (even exponential) increase in the content of man-made greenhouse gases (of which CO2 is the most important) in the atmosphere may have grave consequences for human society, such as a rise in the see level, desertification processes on a large scale, with ensuing water shortages, biological mass extinctions, many more violent meteorological phenomena, etc. A large group of scientists claimed that mathematical-statistical models predicted extremely alarming worldwide events and proceeded to popularize such consequences of global warming, emphasizing their catastrophic impact upon planet Earth and, especially, upon human society. Strong measures to counteract these man-made climatic changes were recommended. Against such alarmist point of view other scientists advocated more research, since climate and its variations represent the most complex natural phenomenon. They questioned many conclusions of the adepts of global warming, conclusions drawn from the climate-statistical models (Global Circulation Models). This paper agrees with the skeptical scientists and advocates that more research is necessary before reaching a definitive conclusion, that it is indeed only mankind which is responsible for the present and future climate change and that the so-called science of anthropogenic climate change is settled and no more doubts should be expressed. In particular, the role and accuracy of mathematical models and the influence of climate feedbacks need much more research to confirm or negate the process of global anthropogenic warming. It is concluded that skepticism is a healthy scientific position and that alarmist and confrontational view points are not helpful in an ongoing discussion and, thus, a moderate and reasonable approach is recommended.

The Corona learnt a lot of lessons to humans and also introduced sophisticated digital world to complete all the duties digitally. Employees are integral to the process of digital transformation, which is a great asset for established organizations. This research advances our knowledge of how workers in the education industry interpret the digital transition. The complexity of organizational change the primary focus of this research is digital transformation. Despite their broad support for digital transformation, teachers' perspectives vary over time about a variety of particular problems encountered along the employee change journey, according to the research. Adopting a social exchange lens in digital transformation knowledge is crucial because it represents a significant structural shift that might lead to the failure of well-designed transformation processes. This is where the stress, human values, and technological values come in. Sharing and departmental cooperation are implications for the education and service sectors. Common emotional responses to change are fear, uncertainty, and worry. Teachers might not be able to articulate how they are feelings or they may not want to say it to leadership. Over the last 200 years, the workplace has changed constantly due to new technology and more globalisation. Additionally, since analytical and creative tasks are becoming more and more important, flexibility is required. Productivity in these professions is supported by the availability of quiet places and adaptable spatial designs given that workers in these positions often need quiet and concentration.

Abstract. Elevated surface chlorophyll-a (chl-a) concentration ([chl-a]), an index of phytoplankton biomass, has been previously observed and documented by remote sensing in the waters to the southwest of Sable Island (SI) on the Scotian Shelf in eastern Canada. Here, we present an analysis of this phenomenon using a 21-year time series of satellite-derived [chl-a], paired with information on the particle backscattering coefficient at 443 nm (bbp(443), a proxy for particle suspension) and the detritus/gelbstoff absorption coefficient at 443 nm (adg(443), a proxy to differentiate water masses and presence of dissolved organic matter) in an attempt to explain some possible mechanisms that lead to the increase in surface biomass in the surroundings of SI. We compared the seasonal cycle, 8 d climatology and seasonal trends of surface waters near SI to two control regions located both upstream and downstream of the island, away from terrigenous inputs. Application of the self-organising map (SOM) approach to the time series of satellite-derived [chl-a] over the Scotian Shelf revealed the annual spatio-temporal patterns around SI and, in particular, persistently high phytoplankton biomass during winter and spring in the leeward side of SI, a phenomenon that was not observed in the control boxes. In the vicinity of SI, a significant increase in [chl-a] and adg(443) during the winter months occurred at a rate twice that of the ones observed in the control boxes, while no significant trends were found for the other seasons. In addition to the increase in [chl-a] and adg(443) within the plume southwest of SI, the surface area of the plume itself expanded by a factor of 5 over the last 21 years. While the island mass effect (IME) explained the enhanced biomass around SI, we hypothesised that the large increase in [chl-a] over the last 21 years was partly due to an injection of nutrients by the island's grey seal colony, which has increased by 200 % during the same period. This contribution of nutrients from seals may sustain high phytoplankton biomass at a time of year when it is usually low following the fall bloom. A conceptual model was developed to estimate the standing stock of chl-a that can be sustained by the release of nitrogen (N) by seals. Comparison between satellite observations and model simulations showed a good temporal agreement between the increased abundance of seal on SI during the breeding season and the phytoplankton biomass increase during the winter. We found that about 20 % of chl-a standing stock increase over the last 21 years could be due to seal N fertilisation, the remaining being explained by climate forcing and oceanographic processes. Although without in situ measurements for ground truthing, the satellite data analysis provided evidence of the impact of marine mammals on lower trophic levels through a fertilisation mechanism that is coupled with the IME with potential implications for conservation and fisheries.

Objective: In competitive sports, too small or too large loads lead to poor sports results. Situation of overload are particularly dangerous to the body, which may lead to overtraining. In this work, the literature on the possibility of assessing training loads with the use of leptin concentration measurement in men and women practicing rowing was analysed. Materials and methods: A systematic review was performed using the Scopus, Pubmed and Google Scholar databases between 1995-2020. After an initial analysis of 56 articles and taking the analysed topics into account, 25 articles were included in this review. As part of the review, data for 75 rowers were analysed. The usefulness of leptin - a hormone produced by adipose tissue - as a marker of training loads in several sports disciplines, with particular emphasis on rowing, was evaluated. Within this context, the role of leptin may be to control these loads due to its relatively high sensitivity in response to increases in training intensity or volume. The presented general characteristics of rowing and the physiological basis of exercise are the background for considerations on the possibility of using leptin as a burden marker in this discipline. Results: Due to the fact that the concentration of leptin correlates with the content of adipose tissue and BMI (Body Mass Index), its changes may inform about training loads directly related to the amount of energy expenditure. A review of the literature from the last 25 years, i.e. from the moment when this hormone was discovered, allowed to formulate the thesis that leptin may be a marker of training loads, however, determining its concentration makes sense when the same factors that may affect its secretion are taken into account each time. Conclusions: Training in rowing, that involves high training loads, causes significant changes in blood leptin levels. Training periods with high exercise load, associated with a significant increase in energy expenditure, lead to a decrease in resting leptin concentration, while periods with less load increase it. The main factor determining changes in leptin concentration during training is the amount of energy expenditure, which in the case of rowing involving very large muscle groups, is very high. Although the amount of energy expenditure in training, leading to a decrease in leptin concentration is difficult to determine, the energy expenditure cannot be less than 800 kcal in a single training unit.

Abstract. Volcanic eruptions are among the most jeopardizing natural events due to their potential impacts on life, assets, and the environment. In particular, atmospheric dispersal of volcanic tephra and aerosols during explosive eruptions poses a serious threat to life and has significant consequences for infrastructures and global aviation safety. The volcanic island of Jan Mayen, located in the North Atlantic under trans-continental air traffic routes, is considered the northernmost active volcanic area in the world with at least five eruptive periods recorded during the last 200 years. However, quantitative hazard assessments on the possible consequences for the air traffic of a future ash-forming eruption at Jan Mayen are nonexistent. This study presents the first comprehensive long-term volcanic hazard assessment for the volcanic island of Jan Mayen in terms of ash dispersal and concentration at different flight levels. In order to delve into the characterization and modeling of that potential impact, a probabilistic approach based on merging a large number of numerical simulations is adopted, varying the volcano's eruption source parameters (ESPs) and meteorological scenario. Each ESP value is randomly sampled following a continuous probability density function (PDF) based on the Jan Mayen geological record. Over 20 years of meteorological data is considered in order to explore the natural variability associated with weather conditions and is used to run thousands of simulations of the ash dispersal model FALL3D on a 2 km resolution grid. The simulated scenarios are combined to produce probability maps of airborne ash concentration, arrival time, and persistence of unfavorable conditions at flight levels 50 and 250 (FL050 and FL250). The resulting maps can serve as an aid during the development of civil protection strategies, to decision-makers and aviation stakeholders, in assessing and preventing the potential impact of a future ash-rich eruption at Jan Mayen.

Objective The management of acute coronary syndrome (ACS) has evolved dramatically over the last 50 years. Currently, management includes a multidisciplinary approach potentially including catheter-based therapy, surgery, or purely medical management. Where surgical therapy is indicated, data regarding long-term outcomes are limited. In particular, little data exist regarding on-pump (conventional coronary artery bypass grafting, cCABG) versus off-pump (OPCABG) outcomes for this group. Methods A retrospective review of prospectively collected data was undertaken. Patients undergoing isolated CABG from January 2000 to December 2011 with ACS were identified (n = 271); non-ACS patients (n = 854) were established as a control. Data were analyzed with a χ2 or a t test, where appropriate. Survival was compared using Kaplan-Meier analysis and Cox proportional hazards model. Results Thirty-day mortality between the ACS and the control groups was similar; however, long-term mortality was worse for the ACS group ( P = 0.032; median follow-up, 5.5 years). Length of stay and composite morbidity were higher in the ACS group ( P < 0.01). Subgroup analysis of ACS patients (OPCABG vs cCABG) demonstrated worse preoperative comorbidities in the OPCABG group, but similar 30-day and long-term mortality. However, the cCABG group had higher rates of reoperation ( P = 0.034) and longer length of stay ( P = 0.017) and operative time ( P < 0.0001). Cox proportional hazards model was applied. Risk factors for the non-ACS cohort included age, diabetes, OPCABG, and ACS ( P < 0.05). Among the ACS cohort, only age remained a statistically significant factor ( P < 0.0001). Conclusions ACS appears to negatively impact long-term, but not short-term, mortality. Within the ACS group, OPCABG compares favorably to cCABG in the long-term and also improves short-term morbidity.

Abstract. After 2003's summer heat wave, Electricité de France created a global plan called "heat wave-dryness". In this context, the present study tries to estimate high river temperatures for the next decades, taking into account climatic and anthropogenic evolutions. To do it, a specific methodology based on Extreme Value Theory (EVT) is applied. In particular, a trend analysis of water temperature data is done and included in EVT used. The studied river temperatures consist of mean daily temperatures for 27 years measured near the French power plants (between 1977 and 2003), with four series for the Rhône river, four for the Loire river and a few for other rivers. There are also three series of mean daily temperatures computed by a numerical model. For each series, we have applied statistical extreme value modelling. Because of thermal inertia, the Generalized Extreme Value (GEV) distribution is corrected by the medium cluster length, which represents thermal inertia of water during extremely hot events. The μ and σ parameters of the GEV distributions are taken as polynomial or continuous piecewise linear functions of time. The best functions for μ and σ parameters are chosen using Akaike criterion based on likelihood and some physical checking. For all series, the trend is positive for μ and not significant for σ, over the last 27 years. However, we cannot assign this evolution only to the climatic change for the Rhône river because the river temperature is the resultant of several causes: hydraulic or atmospheric, natural or related to the human activity. For the other rivers, the trend for μ could be assigned to the climatic change more clearly. Furthermore, the sample is too short to provide reliable return levels estimations for return periods exceeding thirty years. Still, quantitative return levels could be compared with physical models for example.

The paper reviews the climatic changes that took place during the Quaternary, in articular those of the Holocene, including the historical time. The role of carbon dioxide, as a greenhouse gas, is emphasized since it is an important factor influencing the global climate. During the last century, a non-negligible increase in the atmospheric concentration of CO2 brought about a rise in global temperature attributed by many scientists to a man-made cause and labeled “anthropogenic global warming “. It is claimed that a rapid (even exponential) increase in the content of man-made greenhouse gases (of which CO2 is the most important) in the atmosphere may have grave consequences for human society, such as a rise in the see level, desertification processes on a large scale, with ensuing water shortages, biological mass extinctions, many more violent  eteorological phenomena, etc. A large group of scientists claimed that mathematical-statistical models predicted extremely alarming worldwide events and proceeded to popularize such consequences of global warming, emphasizing their catastrophic impact upon planet Earth and, especially, upon human society. Strong easures to counteract these man-made climatic changes were recommended. Against such alarmist point of view other scientists advocated more research, since climate and its variations represent the most complex natural phenomenon. They questioned many conclusions of the adepts of global warming, conclusions drawn from the climate-statistical models (Global Circulation Models). This paper agrees with the skeptical scientists and advocates that more research is necessary before reaching a definitive conclusion, that it is indeed only mankind which is responsible for the present and future climate change and that the o-called science of anthropogenic climate change is settled and no more doubts should be expressed. In particular, the role and accuracy of mathematical models and the influence of climate feedbacks need much more research to confirm or negate the process of global anthropogenic warming. It is concluded that skepticism is a healthy scientific position and that alarmist and confrontational iew points are not helpful in an ongoing discussion and, thus, a moderate and reasonable approach is recommended.

Despite the effort done by member states during the last decade, failure in the implementation of the Ambient Air Quality Directive is being continuously registered in many European cities for different air pollutants. One of the biggest concerns in Bulgaria is the exceeded PM10 concentration in the ambient air, measured in all six air quality zones during the winter period. This has induced numerous activities (at the national and European level) focused on the following issues: identification of the level of exceedance of the air quality norms for PM10; the general emission sources; the most prominent omissions and discrepancies in the legislative framework; the level of implementation of the prescribed measures and many others. However, the PM10 exceedance is still of a significant concern in at least 28 municipalities in Bulgaria. Thus, the present work introduces a brief report on the current state of the problem in the country. For that purpose, benchmarking analyses was applied for obtaining the range of discrepancies and the tendencies of the PM10 concentrations, monitored in the ambient air at the affected municipalities. The investigation was carried out using merely officially reported and freely accessible data and covered a relatively short period of time of six years. The latest national and European environmental reports present data confirming the primary role of residential heating and transport during the winter period as well as at the occurrence of particular atmospheric conditions.

During the last 30 years, the World Health Organization (WHO) reported a gradual increase in the number of patients with cardiovascular disease (CVD), not only in developed but also in developing countries. In particular, acute myocardial infarction (AMI) is one of the severe CVDs because of the high death rate, damage to the body, and various complications. During these harmful effects, rapid diagnosis of AMI is key for saving patients with CVD in an emergency. The prompt diagnosis and proper treatment of patients with AMI are important to increase the survival rate of these patients. To treat patients with AMI quickly, detection of a CVD biomarker at an ultra-low concentration is essential. Cardiac troponins (cTNs), cardiac myoglobin (cMB), and creatine kinase MB are typical biomarkers for AMI detection. An increase in the levels of those biomarkers in blood implies damage to cardiomyocytes and thus is related to AMI progression. In particular, cTNs are regarded as a gold standard biomarker for AMI diagnosis. The conventional TN detection system for detection of AMI requires long measurement time and is labor-intensive and tedious. Therefore, the demand for sensitive and selective TN detection techniques is increasing at present. To meet this demand, several approaches and methods have been applied to develop a TN detection system based on a nanostructure. In the present review, the authors reviewed recent advances in TN biosensors with a focus on four detection systems: (1) An electrochemical (EC) TN nanobiosensor, (2) field effect transistor (FET)-based TN nanobiosensor, (3) surface plasmon resonance (SPR)-based TN nanobiosensor and (4) surface enhanced Raman spectroscopy (SERS)-based TN nanobiosensor.

SynopsisThis chapter sets out to give a historical overview of the African rain forest from its origins, towards the end of the Cretaceous period. The areas around the Gulf of Guinea, in particular from Ivory Coast to Nigeria and especially Cameroon, Gabon and Congo, appear to have been already occupied at this time by wet tropical forest formations mainly composed of Angiosperms which were then becoming established. In the course of the Tertiary period the combined effect of the equator being situated further north than now and the development of the Antarctic ice cap favoured the development of wet tropical conditions over a large part of North Africa which in turn led to the extension of tropical forest to various sites on the shores of the Tethys Sea. There were probably at this time common taxa and similar vegetation patterns stretching from the Gulf of Guinea to the Tethys Sea.Towards the end of the Tertiary, the equator reached its present position and the northern hemisphere ice caps appeared, and these phenomena resulted in the disappearance of the forest formations spread across the north of Africa, and the concentration of these formations near the equatorial zone around the Gulf of Guinea and in the Congo–Zaïre basin. From 800 000 years ago onwards the marked glacial variations at middle and high latitudes in both hemispheres, with a periodicity of about 100 000 years determined by the orbital variations of the earth around the sun, lowered temperatures in equatorial areas and brought arid climates at times of maximum glacial extension. The most arid periods resulted in the fragmentation of the forest cover, and the forest biotopes and their biodiversity were preserved in a series of refugia. The lowering of temperatures also resulted in the extension of montane flora to low altitudes, with migration of montane flora and fauna between main mountain ranges. These compounded phenomena of isolation and migration, probably involving genie exchange, must have resulted in numerous speciation phenomena. Subsequently, such montane flora or fauna became isolated on mountain areas during periods of maximum warming, in the last instance in the course of the Holocene, when a vast forest cover became re-established from Guinea westwards, and to the East as far as the Lake Victoria area. The phases of maximum fragmentation, which appear to have been connected with only the coldest periods – in the last instance during the second part of isotopic stages 6 (fromc.160 to 130 000 years) and 2 (fromc.24 to 12000 years BP) – relate to less than 10% of the last 800 000 years, and the phases of maximum forest extension would likewise appear to be less than 10% of the period. The remaining 80–90% of the time relates to ‘intermediate situations’ which varied from period to period, and these intermediate extension situations seem to have been the norm over the larger part of the Quaternary, rather than the present situation which is closer to a situation of maximum extension.

This is a summary of the main CO2 results obtained from the Vostok core which have been presented in two papers recently published (Barnola and others 1987; Genthon and others 1987).Previous results of ice-core analysis have already provided valuable information on atmospheric CO2 variations associated with anthropogenic activities (Neftel and others 1985, Raynaud and Barnola 1985[a], Pearman and others 1986) and with climatic variations back to about 40 ka ago (Delmas and others 1980, Neftel and others 1982, Raynaud and Barnola 1985[b]). The Antarctic Vostok ice core provides a unique opportunity for extending the ice record of atmospheric CO2 variations over the last glacial–interglacial cycle back to the end of the penultimate ice age, about 160 ka ago.CO2 measurements were made at 66 different depth levels on the air enclosed in the 2083 m long core taken at Vostok Station. The air was extracted by crushing the ice, under vacuum, in a cold-room, and analysed by gas chromatography (Barnola and others 1983). The selected sampling corresponds to a time resolution between two neighbouring levels which range approximately from 2000 to 4500 years. The ages quoted in this abstract are based on the Vostok ice chronology given by Lorius and others (1985) and take into account the fact that the air is trapped in the firn well after snow deposition (between about 2500 and 4300 years after precipitation in the case of Vostok). The CO2 variations observed are compared directly with the changes in Antarctic temperature as depicted by the stable-isotope record of the Vostok ice (Jouzel and others 1988, this volume).Furthermore, a CO2-orbital forcing-climate interaction is suggested by spectral analysis of the CO2 and temperature profiles, which both show a concentration of variance around orbital frequencies. The temperature profile is clearly dominated by a 40 ka period (which can be related to the obliquity frequency) (Jouzel and others 1988, this volume), whereas the CO2 record exhibits a well-defined 21 ka peak (which can be related to the precession frequencies) and only a weak and doubtful 40 ka peak. To check the relative influence of CO2 and orbital forcings on the temperature at Vostok, we modelled the temperature signal deduced from the stable-isotope record of the ice as a response to CO2, Northern Hemisphere ice volume and local insolation forcings. The results indicate that more than 90% of the temperature variance can be explained by these three kinds of forcing and that the contribution of the CO2 radiative effect associated with an amplification factor (which should reflect the long-term feed-back mechanisms) lies between 27 and 85% of the explained variance. This approach stresses the important role that CO2 may generally have played in determining the Earth’s climate during the late Pleistocene.The most obvious feature of the Vostok CO2 record lies in its high correlation (r2 = 0.79) with the climatic record. The results obtained show high CO2 concentrations during warm periods (mean CO2 values of 263 ppm volume for the Holocene and 272 ppm volume for the last interglacial period) and low concentrations (between about 240 and 190 ppm volume) over glacial periods. Within the last glaciation, the CO2 concentrations are higher during the first part (mean CO2 value of 230 ppm volume between about 110–65 ka B.P.) than during the second part (203 ppm volume between 65–15 ka B.P.); the second part also indicates that climatic conditions were colder.Our results point to some limitation on the possible mechanisms driving the atmospheric CO2 variations and, in particular, the influence of some oceanic areas or of changes in sea-level (see, for example, Broecker and Peng 1986). The weak 41 ka cycle (this cycle seems to be a characteristic of the spectra of the proxy data for high latitudes) in our CO2 record suggests that high latitudes may not have a major influence on CO2 variations. Furthermore, the phase relationship between CO2 and the temperature variations indicates that at the beginning of the two deglaciations around 145ka B.P. and 15ka B.P., taking into account the time resolution of our profile, the CO2 increases roughly in phase with the Vostok temperature. As surface-temperature changes around Antarctica are expected to lead to changes in sea-level (see, for instance, CLIMAP Project Members 1984), our results suggest that the CO2 increase cannot lag the increase in sea-level and thus that this parameter cannot initiate the CO2 variation recorded at the beginning of those two deglaciations. Nevertheless, this does not rule out influence of variations in sea-level on atmospheric CO2 for other periods of interest, in particular during the last interglacial–glacial transition, where the CO2 lags the Vostok temperature.

This is a summary of the main CO2 results obtained from the Vostok core which have been presented in two papers recently published (Barnola and others 1987; Genthon and others 1987). Previous results of ice-core analysis have already provided valuable information on atmospheric CO2 variations associated with anthropogenic activities (Neftel and others 1985, Raynaud and Barnola 1985[a], Pearman and others 1986) and with climatic variations back to about 40 ka ago (Delmas and others 1980, Neftel and others 1982, Raynaud and Barnola 1985[b]). The Antarctic Vostok ice core provides a unique opportunity for extending the ice record of atmospheric CO2 variations over the last glacial–interglacial cycle back to the end of the penultimate ice age, about 160 ka ago. CO2 measurements were made at 66 different depth levels on the air enclosed in the 2083 m long core taken at Vostok Station. The air was extracted by crushing the ice, under vacuum, in a cold-room, and analysed by gas chromatography (Barnola and others 1983). The selected sampling corresponds to a time resolution between two neighbouring levels which range approximately from 2000 to 4500 years. The ages quoted in this abstract are based on the Vostok ice chronology given by Lorius and others (1985) and take into account the fact that the air is trapped in the firn well after snow deposition (between about 2500 and 4300 years after precipitation in the case of Vostok). The CO2 variations observed are compared directly with the changes in Antarctic temperature as depicted by the stable-isotope record of the Vostok ice (Jouzel and others 1988, this volume). Furthermore, a CO2-orbital forcing-climate interaction is suggested by spectral analysis of the CO2 and temperature profiles, which both show a concentration of variance around orbital frequencies. The temperature profile is clearly dominated by a 40 ka period (which can be related to the obliquity frequency) (Jouzel and others 1988, this volume), whereas the CO2 record exhibits a well-defined 21 ka peak (which can be related to the precession frequencies) and only a weak and doubtful 40 ka peak. To check the relative influence of CO2 and orbital forcings on the temperature at Vostok, we modelled the temperature signal deduced from the stable-isotope record of the ice as a response to CO2, Northern Hemisphere ice volume and local insolation forcings. The results indicate that more than 90% of the temperature variance can be explained by these three kinds of forcing and that the contribution of the CO2 radiative effect associated with an amplification factor (which should reflect the long-term feed-back mechanisms) lies between 27 and 85% of the explained variance. This approach stresses the important role that CO2 may generally have played in determining the Earth’s climate during the late Pleistocene. The most obvious feature of the Vostok CO2 record lies in its high correlation (r2 = 0.79) with the climatic record. The results obtained show high CO2 concentrations during warm periods (mean CO2 values of 263 ppm volume for the Holocene and 272 ppm volume for the last interglacial period) and low concentrations (between about 240 and 190 ppm volume) over glacial periods. Within the last glaciation, the CO2 concentrations are higher during the first part (mean CO2 value of 230 ppm volume between about 110–65 ka B.P.) than during the second part (203 ppm volume between 65–15 ka B.P.); the second part also indicates that climatic conditions were colder. Our results point to some limitation on the possible mechanisms driving the atmospheric CO2 variations and, in particular, the influence of some oceanic areas or of changes in sea-level (see, for example, Broecker and Peng 1986). The weak 41 ka cycle (this cycle seems to be a characteristic of the spectra of the proxy data for high latitudes) in our CO2 record suggests that high latitudes may not have a major influence on CO2 variations. Furthermore, the phase relationship between CO2 and the temperature variations indicates that at the beginning of the two deglaciations around 145ka B.P. and 15ka B.P., taking into account the time resolution of our profile, the CO2 increases roughly in phase with the Vostok temperature. As surface-temperature changes around Antarctica are expected to lead to changes in sea-level (see, for instance, CLIMAP Project Members 1984), our results suggest that the CO2 increase cannot lag the increase in sea-level and thus that this parameter cannot initiate the CO2 variation recorded at the beginning of those two deglaciations. Nevertheless, this does not rule out influence of variations in sea-level on atmospheric CO2 for other periods of interest, in particular during the last interglacial–glacial transition, where the CO2 lags the Vostok temperature.

Background: Ramadan is the holy month in which all Muslims abstain from eating and drinking from sunrise to sunset. The impact of Ramadan fasting on the oral cavity and saliva needs more attention because of the important function of saliva in the protection of the mouth. Objective: To determine the impact of Ramadan fasting on salivary uric acid, flow rate, and pH among Iraqi male dental students. Patients and Methods: The subject population consisted of thirty healthy male dental students (College of Dentistry/University of Baghdad) with an age range of 20–23 years who intended to fast the whole of Ramadan (1443 Hijri calendar). Saliva samples were obtained from all dental students one week prior to the start of Ramadan, the last week of Ramadan, and one month after the end of Ramadan. The salivary flow rate was calculated, and the salivary pH was measured using a digital pH meter. Then a saliva sample was analyzed to detect the concentration of uric acid by using the spectrophotometer. Results: The data analysis for this study revealed that the salivary flow rate decreased from baseline to Ramadan and then increased again after one month of Ramadan with significant differences (p<0.05). While salivary uric acid increased continuously with significant differences from baseline to Ramadan and after one month of Ramadan fasting (p<0.05), on the other hand, salivary pH showed no significant differences (p > 0.05) among the three time periods of the study. Conclusion: Saliva was affected by Ramadan fasting through a decrease in salivary flow rate during fasting and a return to normal salivary flow rate after the end of Ramadan. In addition, uric acid, which acts as a salivary antioxidant, shows an increase during Ramadan fasting.

Background: Ramadan is the holy month in which all Muslims abstain from eating and drinking from sunrise to sunset. The impact of Ramadan fasting on the oral cavity and saliva needs more attention because of the important function of saliva in the protection of the mouth. Objective: To determine the impact of Ramadan fasting on salivary uric acid, flow rate, and pH among Iraqi male dental students. Patients and Methods: The subject population consisted of thirty healthy male dental students (College of Dentistry/University of Baghdad) with an age range of 20–23 years who intended to fast the whole of Ramadan (1443 Hijri calendar). Saliva samples were obtained from all dental students one week prior to the start of Ramadan, the last week of Ramadan, and one month after the end of Ramadan. The salivary flow rate was calculated, and the salivary pH was measured using a digital pH meter. Then a saliva sample was analyzed to detect the concentration of uric acid by using the spectrophotometer. Results: The data analysis for this study revealed that the salivary flow rate decreased from baseline to Ramadan and then increased again after one month of Ramadan with significant differences (p<0.05). While salivary uric acid increased continuously with significant differences from baseline to Ramadan and after one month of Ramadan fasting (p<0.05), on the other hand, salivary pH showed no significant differences (p > 0.05) among the three time periods of the study. Conclusion: Saliva was affected by Ramadan fasting through a decrease in salivary flow rate during fasting and a return to normal salivary flow rate after the end of Ramadan. In addition, uric acid, which acts as a salivary antioxidant, shows an increase during Ramadan fasting. Keywords: Ramadan fasting, salivary flow rate, salivary pH, uric acid

Abstract. Fast-growing speleothems allow for the reconstruction of palaeoclimate down to a seasonal scale. Additionally, annual lamination in some of these speleothems yields highly accurate age models for these palaeoclimate records, making these speleothems valuable archives for terrestrial climate. In this study, an annually laminated stalagmite from the Han-sur-Lesse cave (Belgium) is used to study the expression of the seasonal cycle in northwestern Europe during the Little Ice Age. More specifically, two historical 12-year-long growth periods (ca. 1593–1605 CE and 1635–1646 CE) and one modern growth period (1960–2010 CE) are analysed on a sub-annual scale for their stable-isotope ratios (δ13C and δ18O) and trace-element (Mg, Sr, Ba, Zn, Y, Pb, U) contents. Seasonal variability in these proxies is confirmed with frequency analysis. Zn, Y and Pb show distinct annual peaks in all three investigated periods related to annual flushing of the soil during winter. A strong seasonal in-phase relationship between Mg, Sr and Ba in the modern growth period reflects a substantial influence of enhanced prior calcite precipitation (PCP). In particular, PCP occurs during summers when recharge of the epikarst is low. This is also evidenced by earlier observations of increased δ13C values during summer. In the 17th century intervals, there is a distinct antiphase relationship between Mg, Sr and Ba, suggesting that processes other than PCP, i.e. varying degrees of incongruent dissolution of dolomite, eventually related to changes in soil activity and/or land-use change are more dominant. The processes controlling seasonal variations in Mg, Sr and Ba in the speleothem appear to change between the 17th century and 1960–2010 CE. The Zn, Y, Pb, and U concentration profiles; stable-isotope ratios; and morphology of the speleothem laminae all point towards increased seasonal amplitude in cave hydrology. Higher seasonal peaks in soil-derived elements (e.g. Zn and Y) and lower concentrations of host-rock-derived elements (e.g. Mg, Sr, Ba) point towards lower residence times in the epikarst and higher flushing rates during the 17th century. These observations reflect an increase in water excess above the cave and recharge of the epikarst, due to a combination of lower summer temperatures and increased winter precipitation during the 17th century. This study indicates that the transfer function controlling Mg, Sr and Ba seasonal variability varies over time. Which process is dominant – either PCP, soil activity or dolomite dissolution – is clearly climate driven and can itself be used as a palaeoenvironment proxy.

Abstract The author evaluates his own data on the food of the Eurasian eagle-owl (Bubo bubo) in Slovakia using material he collected between 1975 and 2020. A total of 105,543 food items were identified in 254 samples taken at 136 localities. Mammals had the highest representation (Mammalia, 65 species, 58.4%), and the species composition of birds was diverse (Aves, minimally 140 species, 8.5%), but the common frog (Rana temporaria, 32.0%), from the lower vertebrates, is represented more abundantly. Invertebrates (Evertebrata, 0.1%) occurred in food residues only occasionally. The bulk of the samples were collected from eagle-owl nests. The samples were divided into three time periods (A–C), which differ in the manner of human land-use management: A up to the 1950s, with a smaller area of field plots and more extensive grazing in the uplands; B from the 1950s to the 1980s, during the Socialist period, with the concentration of agricultural production in large units; C the last 30 years, 1990 to 2020, with the gradual break-up of collective land management. The first period (A) is characterised by a strong dominance of frogs, particularly the European brown frog R. temporaria (44.6%), and a large share of small mammal species of the family Muridae (genera Apodemus and Mus). During the time of Socialism (B), eagle-owls adapted to hunting larger species of mammals and birds, and the share of frogs in their food fell by half (R. temporaria, 23.3%). With the decline in livestock production after 1990 (period C), the species diversity of birds increased: aquatic species and raptors in particular are on the rise. Successive overgrowth of pastures in the submontane zone is reducing the hunting territories of eagle-owls. The dominance of the common vole (Microtus arvalis) in their diet has gradually increased from period A (26.8%) to period C (37.3%). Data from eleven areas around Slovakia are evaluated separately for the three time periods. In period A, the highest proportion of frogs was in the Liptov region (R. temporaria, 68.2%), when eagle-owls nested deeper in the mountains. The proportion of frogs decreased towards lower areas, and in the Ponitrie (Nitra river basin) it was only 10.8%. At the same time, the share of M. arvalis and larger prey increased. A similar trend of increasing shares of larger prey towards lower locations also applied during the Socialist period (B). In the last 30 years (C), frogs in the higher river basins have given way to European water voles Arvicola amphibius and M. arvalis. In association with the progressive overgrowth of pastures, forest species such as the yellow-necked mouse (Apodemus flavicollis) and bank vole (Myodes glareolus) are increasingly prevalent, as are the white-breasted hedgehog (Erinaceus roumanicus) and various thrushes (Turdus sp.).

To start with the obvious: journals come into being for specific reasons. And if one regards the most influential titles born during the last thirty years or so, it seems that one of the principal motivating factors has been interventionist – an attempt to kick-start a particular subdiscipline, or to promote a hitherto neglected or insufficiently examined field. Thus Music Analysis (Basil Blackwell, 1982) sought to place on a fully professional footing a subdiscipline which, whilst recognized in North America (as Music Theory), was at that time underdeveloped in the UK, while 19th Century Music (University of California Press, 1977) sought ‘to stimulate and focus work on what has for too long been American musicology’s lost century’. There is, however, little need to stimulate the study of twentieth-century music(s): if one includes (as we believe one must) popular music, jazz, film music, and twentieth-century developments in traditional musics, as well as ‘art’ or ‘classical’ music, activity in the field is burgeoning at an impressive rate. What is needed, rather, is a dedicated forum. Earlier journals specializing in twentieth-century music (such as Contact and Perspectives of New Music) tended to act as voices for particular constructions of the field. Established generalist journals have frequently found a place for twentieth-century classical music, and more recently (following the trajectory of musicology in general) have begun to widen their scope to include the discussion of popular, film, and traditional music. But as the first three meetings of the Biennial International Conference on Twentieth-Century Music have shown (the third, held in Nottingham, UK, in June 2003, is reviewed in these pages), forums dedicated to the whole range of twentieth-century music promote a synergy and crossfertilization that will inevitably escape generalist journals or those confined to one corner of the field. twentieth-century music aims to provide such a forum; and not the least of our hopes is that, through the contiguity of divergent topics in each issue, the journal will stimulate the creation of new perspectives by encouraging contact with areas and approaches that we might not, as individual scholars, otherwise think to engage with.

The main retrospective-geographical (historical) stages of ponds formation in the Volyn Region are considered – initial, early (manufactory), industrial and modern (agrarian, post-industrial). In order to analyse conditions and functioning of the region’s pond farms we used topographic maps for four historical periods: Commonwealth of Poland historical atlas (scale 1 : 300,000, early ХІХ century), Russian Empire (scale 1 : 126,000, 1875), Polish (scale 1 : 100,000, 1924-1933) and Soviet maps (scale 1 : 100,000, 1977-1992). They reflect the trend of changes in the parameters and functioning of the existing ponds in the Volyn Region over the last 220 years. Landscape-hydrological systems were selected for geospatial analysis of location features of the ponds and water mills within the Volyn Region. Overall, 19 individual landscape-hydrological systems were established. An exponential increase in the number of ponds in early and industrial stages was identified, considering some decreases in particular historical periods. The number of ponds in the region varied from 76 (in the 1970s) to 625 units (1970-80s). A clear, almost linear, increase in ponds total area was observed. During the studied historical period, the area of ponds increased from 1,553.7 to 4,242.4 ha. The highest concentration of pond farms is specific to the landscape-hydrological systems of the Volyn Highland, especially to the Stir-III sub-basins (29.9 % of the total count in the region), Luga-III and Goryn-III. At the same time, a gradual decrease in the average area of a pond – from 20.44 (in the 70s of the XIX century) to 6.28 ha (70-80 years of the XX century) was shown. The considerable number of ponds in the rural areas of the Volyn Region is an important factor in the creation of new work places, recreation areas, diversification of agricultural products and feed base.

The origins of criminology as a separate and independent field of scientific research are usually linked to the emergence of the so called positive school of criminology in the second half of the nineteenth century and with the name of its leading representative Cesare Lombroso. Undoubtedly since that time criminological thought went through a long and substantial evolution which produced a variety of new concepts and theories. As a result of this one could assume that contemporary criminology has very little in common with the ideas of its founders. Despite this, there is growing conviction in the literature that the heritage of Lombroso and Italian positivism still influences significantly contemporary criminological theory. Of course, the essence of this influence lies not in the details of Lombroso’s anthropological ideas which were proven wrong long ago, but in certain quetions asked by him and his school and methods adopted to answer them. Those questions and methods were strictly connected with and resulted from the particular ideas about human society and social world, as well as with the ideas regarding the role, functions and methods of scientific research which prevailed in the social sciences in the second half of the previous century which are commonly referred to as positivism. It justifies the designation as positivist criminology of almost all criminological thought and research since the times of Lombroso up to the late 1950’s. Positivist criminology is ditinguished first of all by its naturalism, e.g. an assumption that all methodological principles developed in sciences apply equally to social sciences which do not possess any substantial methodical peculiarities. It means also that the main task of scientific research is to discover and formulate causal laws and the assumption of objectivity and value neutrality of science and the scientist. The basic question of such criminology based on the deterministic concept of social world and human behaviour was an etiological one: why do certain people commit crimes while others don’t? It means that the main task of positivist criminology is the search for the causes of crime. Another important feature of positivist criminology is the consensual model of the social order it usually assumes. Such a model implies that the entire social order and the very existence of human society result from the sharing of certain values and norms by the large majority of the members of such society. According to this view, also, criminal law represents an example of such consensus and its norms are subject to widespread acceptance. Criminals represent some unique category of misfits or outsiders somehow different from all other „normal” people, a category which refuses to submit to social consensus. A final result of this way of thinking leads to the conclusion that the explanation of a crime and finding its causes requires concentration on the individual who behaves criminally. Because of this, positivist criminology is a science having as its subject the criminal and his behaviour. Pure accumulation of knowledge was never the sole purpose of criminological research. Positivist criminology tried always to be also an applied science, providing scientific grounds for lawmaking and law enforcement. Results of criminological research, data about the criminal and his behaviour should help to change him: rehabilitate, resocialize, correct or heal. In other words, the main purpose of positivist criminology was to provide scientific methods of bringing known misfits and outsiders back the social consensus they left. This feature of positivist criminology is usually referred to in literature as correctionalism. The above reconstruction of the main features of positivist criminology probably corresponds better to European criminology, which was in fact for many years dominated by the ,,lombrosian myth”. One can doubt however whether American criminology may also be described in such terms. The problem is that, because of its clear sociological orientation, American criminology is regarded rather as a heritage of A. Quetelet, A. Guerry or E. Durkheim and not of Lombroso. Usually it perceived crime as a social phenomenon and not as an individual pathology. But it is equally true that such classical American theories of crime causation as the differential association theory or anomie theory focus their attention on the individual criminal as well. What distinguishes those theories from the European tradition is the conviction that the criminal and his special features are products of an environment. However, in both cases criminals are treated as somehow a different kind of people. All this has important practical implications. The individual approach to crime casuation implies that the proper aim of any correctional influences is the criminal himself. The sociological approach claims that there is also no sense in correcting or changing the criminal unless we do something about the environment which produced him. The natural consequence of such an approach is the preference for social reform and social policy over criminal law as instruments of fighting the crime problem. The former is assigned only a secondary role. This is probably one of the main reasons for a certain uneasiness and mistrust towards the sociological approach which may be observed criminologists with a legal background; it is considered too abstract and detached from the everyday problems of the criminal justice system as well as too difficult and complicated to implement. Two new criminological currents emerged during last thirty years which remain in opposition towards positivism. The first one, called antinaturalistic criminology, was born during the sixties. It rejected the positivist concept of social science, asked new and different questions and tried to answer them using different methods. The decisive role in launching this new approach was played by the labelling approach, Its main contribution constituted rejection of the old etiological question and its substitution with the „reactive” one, a question regarding origins and development of the societal reaction to criminal or dewiant behaviour. This meant also an abandonment of positivist methodology of searching for casual laws and a turn towards the methods of humanistic sociology, including understanding, empathy and other similar qualitative methods. According to this trend the main task of the criminological enterprise is to create a sociology law and other forms of social control. Antinaturalistic criminology also adopted an unequivocally pluralistic model of society. Crime and deviance ceased to be perceived as something necessarily pathological. Instead, an attempt was undertaken to treat those phenomena as the result of natural diversity of human beings. To support this stance the labelling approach provided a variety of research on deviant subcultures conducted from what may be called ,,ethnographic positions”, which also denounced the negative effects of punitive social control. The final result was growing scepticism towards the agencies of official social control and such ideas as for example radical nonintervention. The next development can be attributed to radical and critical criminology. These trends assume that social conflict is the main feature of social order and try to understand criminal law and the criminal justice system as the result and manifestation of such conflict. This means that criminalisation processes, e.g. lawmaking and law enforcement, should be explained primarily in terms of political and economic power. Certain groups, because of their access to power, are able to enforce their own values and norms against the will of other groups which may not share them. All this means an unequivocally negative evaluation of the mechanism of social control in contemporary societies which are considered oppressive and unjust. An alternative vision of the society is proposed, a society where facts of human diversity are not subject to the power to criminalize. The way such vision should be implemented are very different and may be placed on the broad continuum from the orthodox Marxism-Leninism and belief in ideal socialism to the humanistic utopias of contemporary abolitionists. Such visions are accompanied by very strong opposition to traditional, mainstream criminology which is accused of being totally and uncritically apologetic and subservient towards the state and institutions of power. According to this view, positivist criminology under the disguise of scientific neutrality and objectivity, in fact legitimizes the existing political and moral order and serves the interests of the privileged groups in society. As a result a new attitude of moral and political commitment is proposed. Science, according to these postulates should be definitely partisan. Such an attitude should break the monopoly of positivist criminology in creating social consciousness about crime and deviance and show the broad audience that alternative are possible. In sum, one can say that the main subject of interest for traditional, positivist criminology constituted always the criminal and that the main problem was to root out his criminal propensities. For antinaturalistic criminology the main problem is the system of social control which requires fundamental change. During the seventies another criminological current emerged, known as neoclassicism, which criticized traditional, positivist criminology from quite different angles. This current, which remains primarily an American phenomenon, constitutes, first of all, opposition against the traditional, in the United States, domination of the sociological approach to the crime problem. Representatives of neoclassical criminology are troubled first of all by the above mentioned unclear practical implications of these theories for the criminal justice system. They are, namely, very difficult to translate into the language of policy actions. Moreover, proposed remedies against crime usually remain beyond the reach of traditional measures which the criminal justice system has at its disposal. As a result the turn towards the tradition of the European classical school of criminal law is proposed and enriched by recent achievements of behavioristic psychology and the economic theory of bohaviour. The essence of this approach constitutes the concept of free will and the assumption that criminals are quite normal human individuals making only false decisions. The fact that human behaviour is always guided by the desire to maximize gains and minimize loses makes this behaviour susceptible to external manipulation. The easiest way to influence human decisions is to create a high enough barrier of costs which should eliminate undesired decisions. Criminal law should play a key role in creating such a barrier and preventing criminal behaviour. Moreover, the barrier of costs provided by criminal law constitutes practically the only factor easily accessible to manipulation by any democratic and liberal government. Other ways of influencing crime rates are usually too costly or too difficult to implement. The basic task of criminology is to provide the necessary empirical data on the functioning of criminal law and the criminal justice system, which should be than used to formulate the most effective policies. All three criminological currents discussed above were usually treated as mutually exclusive and competitive paradigms. Today, when the heat of the discussions of the sixties and seventies diminished, there is a good chance to have a less emotional analysis of recent developments in criminology. Probably it will be possible now to come to the conclusion that the emergence during last 150 years of the three distinct paradigms in theoretical criminology may be comprehended not only in terms of consecutive scientific revolutions. Probably it may be also interpreted as the evolutionary process of the cumulation of knowledge about crime. During this process points of view and focuses’ changed as every paradigm considered different aspects of criminal phenomena as being most important and worth of researching. But all three may be considered, at least to a certain extent, complementary ones.

The response to strenuous exercise was investigated by reactive oxygen species (ROS) production, oxidative damage, thiol redox status, and inflammation assessments in 32 enrolled triathlon athletes (41.9±7.9 yrs) during Ironman® (IR), or half Ironman® (HIR) competition. In biological samples, inflammatory cytokines, aminothiols (glutathione (GSH), homocysteine (Hcy), cysteine (Cys), and cysteinylglycine (CysGly)), creatinine and neopterin, oxidative stress (OxS) biomarkers (protein carbonyl (PC), thiobarbituric acid-reactive substances (TBARS)), and ROS were assessed. Thirteen HIR and fourteen IR athletes finished the race. Postrace, ROS (HIR +20%; IR +28%; p<0.0001), TBARS (HIR +57%; IR +101%), PC (HIR +101%; IR +130%) and urinary neopterin (HIR +19%, IR +27%) significantly (range p<0.05-0.0001) increased. Moreover, HIR showed an increase in total Cys +28%, while IR showed total aminothiols, Cys, Hcy, CysGly, and GSH increase by +48, +30, +58, and +158%, respectively (range p<0.05-0.0001). ROS production was significantly correlated with TBARS and PC (R2=0.38 and R2=0.40; p<0.0001) and aminothiols levels (range R2=0.17-0.47; range p<0.01-0.0001). In particular, ROS was directly correlated with the athletes’ age (R2=0.19; p<0.05), with ultraendurance years of training (R2=0.18; p<0.05) and the days/week training activity (R2=0.16; p<0.05). Finally, the days/week training activity (hours/in the last 2 weeks) was found inversely correlated with the IL-6 postrace (R2=‐0.21; p<0.01). A strenuous performance, the Ironman® distance triathlon competition, alters the oxidant/antioxidant balance through a great OxS response that is directly correlated to the inflammatory parameters; furthermore, the obtained data suggest that an appropriate training time has to be selected in order to achieve the lowest ROS production and IL-6 concentration at the same time.

Introduction. The prerequisites and the first steps towards the development of cimbalom performance in Kharkiv universities are shown in the historical aspect. The necessity of training the qualified specialists for teaching high-level musicians is revealed and the direction of development of the pedagogical process is justified. Objectives is to highlight the role of the class of cymbals KhNUА in the context of the formation and development of the Kharkiv cimbalom school since the last third of XX – early XXI centuries. Results and Discussion. Different sides of the development of the cymbal class of the Department of Folk Instruments of Ukraine of the I. Kotlyarevsky Kharkiv National University of Arts (KhNUA). The research and methodological principles, features of work on the original repertoire and fruitful cooperation with Kharkiv composers, forms of instrumental, performing professional training, participation in methodological seminars, practical classes in advanced training courses, concerts, festivals, competitions, conferences and projects of various levels are considered. Lists of students-laureates of competitions and names of all significant concert projects are given. Attention is drawn to the pedagogical sphere of activity as an integral part of creative work in music schools, as well as in higher educational institutions of the arts. This allows us to speak of the Kharkiv cimbalom school as of independent creative subject, which is distinguished by the originality of the repertoire, the search for new forms of expression, the use of non-traditional techniques of playing the instrument. According to the register, Kharkiv cimbalom school is the youngest, but at the same time one of the most progressive performing schools in Ukraine. Conclusions. It is shown that for thirty years of existence of the cimbalom class of KhNUA the idea of professional training at three educational levels – from music school to institution of higher education has been successfully realized. Many laureates of international, all-Ukrainian and regional competitions, festivals, graduates of the class are brought up. The high level of instrumental, performing, professional training is distinguished. At the same time, the development of the academic direction in performance on folk instruments, in particular on cimbalom, has significantly broaden the boundaries of the traditional folk instrumental genre. It is shown that the formation of the cymbal class in KhNUA during the 30 years of its existence completed the formation of the Kharkiv cimbalom school, and its future will be improved and filled with new victories and ideas at a new, more advanced level.

The article presents and rethinks the attempts to establish a Polish-Ukrainian dialogue in The Second Polish Republic between the First and Second World Wars. The strategic partnership between Poland and Ukraine has been maintained for the last thirty years. The state of this bilateral relations remains one of the determining factors of regional stability, especially in the context of deterring external threats. The long and contradictory history of Polish-Ukrainian relations is not only the subject of emotional scientific discussions, but also plays the role of a factor that contributes to the growth of ideological and political confrontation, while influencing the current policy of both countries. Interethnic relations in The Second Polish Republic continue to be interpreted differently by Polish and Ukrainian historians. In view of this, the search for and rethinking the facts of attempts to establish a Polish-Ukrainian dialogue between the First and Second World Wars is becoming especially relevant today. It is concluded that during the years of domination in Western Ukraine, the Polish authorities have failed to develop a comprehensive program to resolve the “Ukrainian question”, instead trying to break the resistance of Ukrainian by force. In general, the entire national policy of the Polish state of the interwar period was characterized by uncertainty, half-hearted decisions and unjust and cruel discriminatory measures against Ukrainians. On the Ukrainian side, the constructive dialogue was also complicated by the propaganda of radical forces, which proclaimed that there was no need to seek a compromise with the Poles, and characterized any attempts at understanding as national treason. National extremism on both sides led to further aggravation of relations, which erupted, in particular, the Volyn tragedy of 1943. As a result, it led to the radicalization of the Ukrainian national movement, the weakening of the Polish state, and subsequently cost both nations numerous casualties as a result of the violent suppression of the national development of Ukrainians and Poles that lasted for decades. At the same time, there are many examples of Polish-Ukrainian cooperation of intellectual elites of the interwar period, which not only observed and stated, but also took practical steps in this direction

Abstract An internal tandem duplication (ITD) or a point mutation of the FLT3 is detected in about one third of MDS patients at the time of clinical progression, but very few studies have determined whether these mutations are already present on clinical diagnosis. A high FLT3 expression is caused by both these as well as by other still undefined mutations. Therefore, we have decided to analyse the expression of the FLT3 gene by RT-PCR on clinical diagnosis and during disease outcome in twenty-six MDS patients. Our study was aimed at determining whether a high FLT3 expression was correlated with any peculiar clinico-haematological parameter, clinical evolution to AML and response to treatment. Fourteen patients were males and twelve females; their median age was 60 years (range 36–76). According to FAB classification seven patients were classified as refractory anemia with ringed sideroblasts (RARS), fourteen as RA and five as refractory anemia with excess of blasts (RAEB). Conventional cytogenetic studies discovered a normal karyotype in twenty patients, a del(20q) in three, a del(5q) in two and a del(12p) in one. Blast cell percentage was 0–5% in twenty patients, 6–10% in four and 11–20% in two. According to IPSS fifteen patients were considered low-risk, eight intermediate-1 risk and three as intermediate-2 risk. FLT3 expression was evaluated through a relative real-time quantification approach which used SybrGreen I as DNA binding fluorescent dye. Total RNA from mononuclear cells from a patient, who harboured an ITD of the FLT3 gene and presented a high expression of the gene, was serially diluted in order to obtain a standard curve for real-time quantification. FLT3 expression was determined by the ΔΔCt method. FLT3 levels were normalized to ABL and calibrated on a normal sample. At the onset of the disease twenty-three patients showed a FLT3 expression similar to that of the normal control, while three (one RA and two RAEB) presented a two-four fold increase. In these last patients no correlation with any particular clinico-haematological feature was noted. Nine of the twenty-six patients progressed in AML after a median time of thirty-one months (range 8–86). Three of them had already presented an increased FLT3 expression on clinical diagnosis. Considering the remaining six patients, a three-seventeen fold increase of FLT3 expression was observed in two patients and a normal FLT3 expression in the other four. Time from MDS to AML evolution was 8,22,29,33,39 months for patients with a high FLT3 expression and 31,40,42 and 86 months for those with a normal FLT3 expression. Three of the five patients with a high FLT3 expression were given different courses of intensive chemotherapy. One of them, who never responded to chemotherapy, maintained a constantly high FLT3 expression, the other two, who achieved complete remission, showed a normalization of FLT3 expression. However both of these two responsive patients again presented a six-eight fold increase of FLT3 expression on relapse. In conclusion, a high FLT3 expression i) may be observed on clinical diagnosis in about 11,5% of MDS patients, ii) does not associate with any peculiar clinico-haematological finding, iii) frequently appears at the time of AML evolution since it was detected in two of our six patients who showed a normal FLT3 expression on clinical diagnosis but a high expression on relapse.

Abstract Abstract 4080 The introduction of new targeted therapeutics agents together with stem cell transplantation have led to a remarkable evolution in the management of Multiple Myeloma (MM) over the last 15 years. Osteolytic disease is the major complication of MM that may lead to devastating skeletal-related events. Up to 90% of the MM patients develop osteolytic lesions during the course of their disease and 70% of patients are affected at some stage with painful progressive vertebral compression fractures (VCFs). Patients with myeloma are living a lot longer and it is thus especially important to maximally treat osteolytic bone disease and in particular, painful VCFs of the spine that cause substantial morbidity, compromised quality of life and increased healthcare costs. Balloon Kyphoplasty is a minimally invasive procedure which has purported benefits of relieving pain and restoring function in patients who are poor candidates or should not undergo invasive procedures. Despite increasing evidence on the use of this procedure, the indications, timing, efficacy, safety and their role in the treatment algorithm of myeloma spinal disease are yet to be defined. We report a retrospective analysis on the outcome of the use of Balloon Kyphoplasty in 103 MM patients with VCFs confirmed by MRI who were treated at the Royal National Orthopaedic Hospital between January 2007 and July 2012. Pending on the level of the fracture, patients were fitted with brace, were receiving monthly bisphosphonates and the majority required high dose opioid pain relief and had restricted mobility. Main indications for the interventional management of the VCFs were severe persistent pain, spinal instability, neurological symptoms, level of fracture and associated high risk for severe kyphosis. All patients had peri-procedure prophylactic antibiotic cover according to the local protocol and their chemotherapy withheld for 10 days. Quantitative outcome measures including the Roland –Morris Disability and Visual Analog Scales (graded 0–10) for pain at rest and pain with activity were assessed prior to the procedure 6 hours post and during the monthly follow up at the MM clinic. In addition, qualitative measures of clinical outcome, pain and mobility improvement, opioid pain relief use were monitored. The median follow up was 3.2 years ranging from 6 weeks to 6.8 years. Fifty-two were male patients, the median age at the time of the procedure was 67 years (41–89) and ECOG performance status was ≥3 in 41% of the patients. Fifty-four patients underwent the procedure at diagnosis within a median time from diagnosis to kyphoplasty of 10 weeks (1 week – 8 months). The time of the procedure was depended on patient's presentation symptoms and signs, chemotherapy, MRI findings and co morbidities. Thirty-four patients were treated with kyphoplasty at the time of disease relapse or progression and 15 patients had the procedure early at diagnosis and later at relapse. Five frail elderly patients unsuitable for general anaesthesia had the procedure performed under local anaesthetic and sedation. A total of 197 painful VCFs were treated. A single vertebral level was treated in 48 patients, with two levels treated simultaneously in 32 patients and three or more levels in 23 patients. All patients tolerated the procedure well. Accidental finding of asymptomatic cement PE was found in one patient. Eight-two percent of the patients had rapid pain relief, became independent of pain relief and their mobility and functionality were markedly improved within a median time of 5 weeks (4 days to 3.5 months). For 32% of the patients mobility improved gradually in view of additional problems with steroid induced myopathy. In conclusion these data suggest that kyphoplasty is a safe procedure for the management of VCFs in MM and results to early and sustained pain relief and functional improvement. Prospective studies are warranted to further define indications and timing of cement augmentation, the number of levels and the role on preventing spinal deformity in MM spinal disease. Disclosures: Molloy: Medtronic Spine & Biologics: Honoraria, Speakers Bureau.

Abstract Introduction: The PK profile of carfilzomib is well characterized in patients with multiple myeloma. However, during clinical development of carfilzomib, patients with moderate to severe hepatic impairment (HI) were excluded from initial clinical studies. To support carfilzomib dose recommendations for patients with baseline HI, this study evaluated PK and safety of carfilzomib in patients with varying degrees of HI and relapsed or progressive advanced malignancies. Methods: This open-label, single-arm, phase 1 study evaluated adult patients with normal (Norm) hepatic function or, mild, moderate (Mod), severe HI receiving carfilzomib infusion on days (D) 1-2, 8-9, 15 and 16 in 28-D cycles (C). Dose was escalated from 20 mg/m2 on C1 D1-D2 to 27 mg/m2 on D8 of C1 and if tolerated, further to 56 mg/m2 on D1 of C2. Norm hepatic function defined as bilirubin and aspartate aminotransferase (AST) levels </=upper limit of normal (ULN). HI defined as mild: bilirubin >1-1.5 x ULN, or AST >ULN but with bilirubin </=ULN; Mod: bilirubin >1.5-3 x ULN with any AST; or severe: bilirubin >3 x ULN and any AST. The primary objective was to assess the effect of HI on area under the curve (AUC) from time 0 to the last concentration measured (AUC0-last) and from time 0 extrapolated to infinity (AUC0-inf) of carfilzomib. Secondary objectives included evaluation of carfilzomib maximum plasma concentration (Cmax), time to maximum concentration (Tmax), clearance (CL), terminal half-life (T1/2), volume of distribution at steady state (Vss), mean residence time (MRT), and safety and tolerability, as well as PK parameters for carfilzomib's major metabolites. Plasma for analysis of PK parameters were collected on C1D16 for carfilzomib 27 mg/m2 and on C2D1 for the 56 mg/m2 dose. PK parameters were evaluated using a non-compartmental approach. The carfilzomib PK in HI patients was compared with Norm patients using summary statistics and analysis of variance. Due to enrollment challenges and lack of demonstrable efficacy with carfilzomib monotherapy, enrollment of severe HI patient (mostly advanced solid tumors) was discontinued. Results: 11 Norm, 17 Mild, 14 Mod, and 4 severe patients were enrolled; 61% male, mean age 62 years. Of these patients, 10 Norm, 14 Mild, 9 Mod, and 0 severe HI patients were PK evaluable. Following carfilzomib 27 and 56 mg/m2, considerable PK variability was seen within each of the treatment groups, with an overlapping exposure observed between groups (Table 1). Median Tmax ranged from 0.29 to 0.48 hour with peak concentrations of carfilzomib most often observed at 15 minutes after start or immediately before the end of infusion. Thereafter, concentrations of carfilzomib declined rapidly with a mean T1/2 of approximately 0.5 to 0.7 hour in all patient groups. A dose-dependent increase in mean AUC and Cmax of carfilzomib was observed between 27 mg/m2 and 56 mg/m2 in all 3 patient groups (Table 1); however, there was no consistent trend of increasing exposure (AUC0-last, AUC0-inf, and Cmax) with increasing severity of HI (Table 1 and 2). The mean AUC of the most abundant metabolite, PR-389/M14 was similar across all groups. A mean increase of approximately 60%-80% was observed for M15 and M16 AUC0-last, AUC0-inf and Cmax in patients with Mod HI vs Norm patients. These metabolites have no known biological activity. Median duration of exposure was 6 (Norm), 4.3 (Mild), 2.3 (Mod), and 0.8 (severe) wks. Thirty-five (76%) patients had grade >/=3 adverse events (AEs) including 15 patients with treatment-related grade >/=3 AEs. Grade >/=3 increased blood bilirubin (22%; Mod HI patients only), anemia (15%), fatigue (15%), and increased alanine aminotransferase (9%; Mod HI patients only) occurred in >3 patients. Conclusions: No marked differences in exposures (AUC and Cmax) were observed between Norm patients and mild/Mod HI patients following carfilzomib doses of 27 and 56 mg/m2.No consistent trend in carfilzomib exposure related to HI severity was seen. With the exception of the increased frequency of AEs consistent with hepatic function abnormalities, the observed AE profile in this study was consistent with the known safety profile of carfilzomib. HI did not appear to substantially increase severity of AEs; however, the number of patients was limited. Based on the results in this study, no carfilzomib dose adjustment appears to be warranted in patients with relapsed or progressive advanced malignancies and mild or Mod HI. Disclosures Anthony: Spectrum Pharmaceuticals: Speakers Bureau; Paradigm Diagnostics: Consultancy. De Vos:European Organization for Research and Treatment of Cancer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dutch Working Group Neuro-Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; University Medical Center Utrecht: Employment. White:Amgen: Employment. Schupp:Amgen Inc.: Employment, Equity Ownership. Ou:Amgen: Employment, Equity Ownership.

Background and rationale: Bosutinib is a second generation tyrosine kinase inhibitor (TKI), which has been indicated in Italy in the second line of CML treatment, since 2014. Thanks to its safety profile, bosutinib is frequently chosen as an advanced line of treatment in fragile patients. We collected retrospective data from patients treated with bosutinib in any line of TKI therapy, in order to study the role that this drug has in real-life, compared to clinical trials in terms of treatment line, dosage, toxicity and efficacy. Patients and methods: We collected data from65 chronic phase CML patients treated with bosutinib between 2015-08-18 and 2023-04-27, followed at 12 Haematology centers in Sicily and Calabria. Of these patients, 42 (64.6%) were male, and had a median follow-up of 29 months (range 1-96). Mean age at diagnosis was 62, and mean age at bosutinib start was 67. Median therapies prior bosutinib treatment was 2. Fourtyfour patients (67.7%) had cardiovascular comorbidities (CV) at diagnosis: 37 patients (55%) had at least one cardiovascular risk factor: in particular, arterial hypertension in 31 patients (70.4%), dyslipidaemia in 10 patients (22.7%), diabetes mellitus in 14 patients (31.8%), obesity (grade 3) in 2 patients (4.5%); 7 patients (10.7%) had already experienced an acute cardiovascular or cerebrovascular event. Finally, only 12 patients (18.4%) had no comorbidity at diagnosis. Mean age at the start of bosutinib for CV-risk patients was 70 years. Among 44 patients with CV risk before starting bosutinib, 38 patients were still alive (86.4%) at last follow-up. Fifteen patients with CV risk discontinued bosutinib (34%), while none presented new CV events during treatment. In terms of efficacy, however, in patients with CV risk, the median molecular response, at the last follow-up, is MR2. Results: Thirty-eight patients (58.5%) discontinued bosutinib, while 27 (41.5%) were still on treatment at the time of the last follow-up. Of the 38 patients who discontinued bosutinib, 5 discontinued due to resistance (13.8%) and 19 due to intolerance (50%). Of these 19 intolerant patients, only 1 patient discontinued bosutinib due to CV event (heart failure) and only 1 patient discontinued due to gastrointestinal toxicity (grade 3 diarrhea). Most reported toxicities were as follows: Skin Toxicity 3 pt 5%Perpheral edema 2 pt 3%Hepatototoxicity 2 pt 3% In the efficacy evaluation, early-suspenders (bosutinib treatment duration < 6 months) were, therefore, cut out, 55 patients (84.6%) were evaluated in this sub-analysis, 34 (61.8%) male and 21 (38.2%) female. Median age in this subanalysis is 67 years. Bosutinib was second-line treatment in 35 cases (63.6%), third-line therapy in 15 cases (27.3%), fourth-line therapy in 4 cases (7.3%). Overall, 35 patients assumed bosutinib as a second-line TKI: 22 of them were from the 1L-imatinib group (62.9%), while 13 were from the 2nd generation TKI-1L group (37.1%). Of the 22 1L-imatinib and 2L-bosutinib patients, 56.1% reached MR3 or deeper during bosutinib treatment and 38.1% reached MR4.5 or deeper. Of the 13 patients in 1L-2genTKI 2L-bosutinib group, 61.5% reached at least MR3, while 15.4% reached MR4.5 or MR5. Drop-out rate was similar between the two groups. Conclusion Bosutinib revealed to be safe in patients with CML in 2 nd and further lines of treatment, especially in terms of cardiotoxicity, even in subjects with a high CV risk at treatment initiation. Furthermore, our data revealed as most patients are currently treated with a lower dose of bosutinib than standard (median dosage 302 vs 500 mg a day), obtaining good response rates in 2 nd and further lines. Subsequent eventual dose increase is evaluated on the basis of the molecular response.

Abstract Objectives: Romiplostim (RMP) is a thrombopoietin mimetic protein that increases platelet production. RMP has already been approved in numerous countries for treatment of immune thrombocytopenia. However, the efficacy of RMP in aplastic anemia (AA) is still unclear. Therefore, we conducted this study to determine an optimal initial dose of RMP for the treatment of patients with AA refractory to immunosuppressive therapy (IST). We also evaluated the efficacy and safety of a 52-week treatment. Methods: This study was a multicenter, randomized, open-label, parallel, comparative, dose-finding study in South Korea (NCT02094417). The subjects enrolled were patients with AA refractory to prior IST. The eligible patients were randomized to four treatment groups (1, 3, 6, or 10 μg/kg), and subcutaneously administered RMP once weekly for 8 weeks. After the 8-week treatment, the dose of RMP was adjusted from 1 to 20 μg/kg to maintain their platelet response. Patients who did not achieve a platelet response after the 8-week treatment with 20 μg/kg were withdrawn from the study. Platelet response was defined as 1) absolute increase of ≥20×109/L above baseline or 2) increase ≥10×109/L and by at least 100% from baseline. The bone marrow and cytogenetic analysis were performed prior to enrollment and every 6 months after treatment. The planned data collection was suspended after treatment week 52 in the middle of the trial. Total treatment period is 156 weeks (3 years). Results: A total of 35 subjects were randomized into one of four treatment groups. The platelet count, hemoglobin concentration and absolute neutrophil count at baseline were similar between all treatment groups. The median age and time since last therapy with anti-thymocyte globlin (ATG) were 49 (28-76) years and 92 (7-267) months, respectively. Thirty-three patients completed the initial 8-week treatment while 18 completed the 52-week treatment. The primary endpoint, which was the platelet response rate after 8 weeks was 0% (0/7 subjects), 0% (0/7 subjects), 33.3% (3/9 subjects) and 70.0% (7/10 subjects) at 1, 3, 6 and 10 µg/kg, respectively, and it was dose-dependent. By treatment week 8, the platelet, erythroid and neutrophil responses to 10 µg/kg at any time were 100.0% (10/10 subjects), 30.0% (3/10 subjects), and 60.0% (6/10 subjects), respectively. The bi-lineage responses at 10 µg/kg were the highest among all treatment groups. By treatment week 52, 33.3% (11/33 subjects) achieved the tri-lineage response at least once, and 45.5% (15/33 subjects) went off their platelet transfusion at least once. No dose-dependent adverse events (AEs) or dose-dependent drug-related AEs occurred during the 52-week treatment. Common AEs were upper respiratory tract infection, fatigue, transfusion reaction, myalgia, and dyspepsia. None of the patients developed clonal evolution or cytogenetic abnormalities. Finally, no neutralizing antibody was detected in any patient during the 52-week treatment. Conclusion: These results demonstrate that RMP was effective and safe for patients with AA that was refractory to IST by 1 year. Based on the efficacy and safety results of the initial 8-week treatment, we recommend 10 μg/kg as an optimal initial dose for AA. Further clinical studies of RMP to confirm its efficacy in patients with AA are currently ongoing (NCT02773290). Disclosures Jang: Kyowa Hakko Kirin Co., Ltd.: Research Funding.

Este artículo ofrece un análisis del proceso de consolidación de las
 Tecnologías de la Información y la Comunicación (TIC) como una parte esencial
 de las políticas de modernización administrativa que se han llevado a cabo dentro
 de la Administración General del Estado (AGE) desde la aprobación de la Constitución
 Española de 1978. En concreto, se pretende mostrar que las TIC se han convertido
 en uno de los principales agentes de innovación dentro del sector público
 español a lo largo de los treinta últimos años de historia administrativa. Al mismo
 tiempo, el estudio de la AGE pone de manifi esto que los antecedentes de la actual
 difusión de la eAdministración, sobre todo, unidos a la informatización administrativa,
 resultan decisivos para comprender algunas de las prioridades y limitaciones
 más recientes de las dinámicas asociadas a la explotación de las nuevas TIC e
 Internet en el sector público. En concreto, los primeros pasos de la institucionalización
 tecnológica dentro de la AGE determinaron en no poca medida algunas de
 las posteriores orientaciones de la estrategia de eAdministración, y con ello, las
 políticas de modernización administrativa. Por consiguiente, este artículo subraya
 la relevancia de las instituciones y del análisis institucional para caracterizar las
 políticas de modernización administrativa, en general, y la difusión de la eAdministración,
 en particular Artikulu honek Informazioaren eta Komunikazioaren Teknologiak
 (IKT) sendotzeko prozesua aztertzen du, Estatuko Administrazio Orokorrak (EAO),
 1978ko Espainiako Konstituzioa onartu zenetik, Administrazioa modernizatzeko
 egin dituen politiken funtsezko parte den aldetik.
 Zehazki, demostratu nahi du, azken hogeita hamar urteetan, IKTak berrikuntzako
 eragile nagusietariko bat bilakatu direla sektore publiko espainolaren barruan. Estatuko
 Administrazio Orokorraren azterketak agerian uzten du, era berean, eAdministrazioaren
 oraingo hedapenaren aurrekariak, batez ere administrazioaren informatizazioarekin
 bat, erabakigarri bilakatu direla IKT berriak eta Internet ustiatzearekin
 lotutako dinamika berrienen zenbait lehentasun eta muga ulertzeko. Zehazkiago,
 EAOren barruan instituzionalizazio teknologikoaren aurreneko urratsek fi nkatu zuten,
 hein handi batean, eAdministrazioak ondoren izan duen estrategiaren zenbait
 orientazio, eta, horrekin batera, administrazioa modernizatzeko politika ere bai. Horrenbestez,
 artikulu honek azpimarratzen du zer-nolako garrantzia duten erakundeek
 eta erakunde-azterketak, oro har, Administrazioa modernizatzeko politiken ezaugarriak
 ezartzeko, eta, bereziki, eAdministrazioa zabaltzeko. This article assesses the diffusion of Information and Communication
 Technologies (ICTs) within the administrative modernization policies undertaken
 at Administración General del Estado (AGE) level of government since
 the Spanish Constitution of 1978. Particularly, this articles shows that ICTs have become a relevant agent for innovation during the last thirty years in the Spanish
 public sector. At the same time, the study of the AGE corroborates how important
 is the analysis about the fi rst origins of eGovernment, above all, regarding to informatization
 processes and its consequences. Also, it provides insights on priorities
 and limitations of more recent public policies to boost ICT and the Internet in
 public administration. In particular, fi rst steps of AGE¿s technological institutionalization
 shaped both orientations and contents of later eGovernment strategies, and
 in so doing, administrative modernization policies. In sum, this article pinpoints
 the relevance of institutions and institutional analysis to understand administrative
 reform policies, in general, as well as the diffusion of eGovernment, in particular.

Abstract Thirty-six adult patients aged between 20 and 60 years (median age: 44) with BCR-ABL+ ALL were prospectively monitored by Q-RT-PCR between December 2001 to November 2005. All patients were treated according to the GIMEMA LAL 0201/A protocol, in which Imatinib alone, was administered as post-consolidation therapy, in responding patients after high-dose induction and consolidation treatment, at the dosage of 400 mg x 2 daily for at least six months and continued on the basis of the opinion of physicians. Twenty-three (64%) were p190+ and 13 (36%) p210+. At presentation, the median BCR-ABL/ABL ratio was 1.33 (range 0.23 to 7.8). Before Imatinib, all patients were in 1st CR (34 after the first induction and consolidation course; 2 after a salvage treatment). At this time point, the median reduction from baseline in BCR-ABL transcripts, calculated for each individual patients, was 2.1 log (range: 0 to 6.1). In particular, 18 of the 36 cases showing a log reduction of the BCR-ABL/ABL ratio > 2.1 (p190=14 cases; p210 = 4 cases) were considered as good responders to the antecedent chemotherapies, whereas 18 cases (p190=9; p210=9 cases) showing a log reduction ≤2.1 were considered as bad responders. The median reduction from baseline in BCR-ABL levels was 2.49 log (range: 0.00–6.1) and 1.45 log ( range: 0.19–5.34) in p190 and p210 positive cases, respectively (p=.16). During Imatinib treatment, 10 (56%) of the 18 poor responders patients presented a relapse of disease versus 5 (28%) ( 3 =BM; 2=CNS) of the 18 good responders.At last follow-up 16 patients were in first CR; of these patients, only 4 were allo-transplanted (2 good, 2 bad responders), therefore 12 (9 good, 3 bad responders) persisted in first CR maintained by Imatinib alone after a median follow-up of 24 months (range: 7–48). At 24 months, the cumulative incidence of relapse was 29% vs 44% for good and bad responders (p=.034), respectively, whereas, the DFS and OS rates were 65% vs 33% ( p=.0032) and 76% vs 32% (p=.0056) for good and poor responder patients, respectively. Monitoring of MRD was prospectively evaluated at the starting of Imatinib therapy and afterwards at the 3rd, 5th and 6th month. At these time points, the median BCR-BCR/ABL ratio were 0.015, −0.006, −0.008 and −0.009, respectively. In addition to the classification as good/ bad responders, the current variation of BCR-ABL ratio (used as time-dependent covariate in a Cox model), was associated with an increase of the hazard of failure (hazard ratio of an increase by 2 log of the BCR-ABL levels compared to a constant ratio equal to 2.1). In conclusion, Imatinib mesylate is a highly effective post-consolidation treatment for adult Ph+ ALL patients. However, the clinical outcome after Imatinib was significantly affected by the level of molecular response evaluated before the starting of Imatinib, resulting excellent for the good responders but remaining dismal for patients who responded poorly to the initial chemotherapy.

B a c k g r o u n d . According to the genre characteristics, the article is a form of publicizing analytical conclusions from the experience of research in the field of the philosophical Chinese studies at the National Academy of Sciences of Ukraine from 1991 to the present day. The material for understanding was supplied from the environment of scientific professional activity of prominent figures of Ukrainian philosophical Sinology from the H. Skovoroda Institute of Philosophy of the NAS of Ukraine and the A. Krymskyi Institute of Oriental Studies of the NAS of Ukraine. The scientific achievements of academic Sinologists, who are leading researchers of Chinese philosophical education, science and culture from the archaic to modern times, are highlighted. They are, namely: V. Kiktenko, V. Pyrohiv, V. Hamianin, S. Kapranov, Y. Hobova and A. Usyk. M e t h o d s . The article uses an analytical approach based on the study of historical and philosophical sources. The methodological basis of the research is the main methods of historical and philosophical science: problem-categorical analysis, socio-cultural analysis and biographical analysis. At the same time, the methods of situational and contextual analysis of scientific texts are applied. R e s u l t s . Four conditional thematic vectors of the progress of academic philosophical Sinology in modern Ukraine are classified, namely the study of: 1. the history of ancient Chinese philosophy, especially Confucianism; 2. the history of Chinese philosophy in the 19th – early 21st centuries; 3) the history of Ukrainian Sinology in the 18th – early 21st centuries; 4. the history of modern foreign Sinology. The director of the A. Krymskyi Institute of Oriental Studies of the NAS of Ukraine and the head of the Ukrainian Association of Sinologists V. Kiktenko very effectively studies all these vectors, especially the last three of them. His colleagues at the institute V. Pyrohiv, V. Hamianin and Y. Hobova mainly research the first of these vectors, and primarily the history of Confucianism. Employees of the H. Skovoroda Institute of Philosophy of the NAS of Ukraine S. Kapranov and A. Usyk are also focused scientific attention on the history of Confucianism, in particular, the second of them studies social ethics and anthropology of Confucius. C o n c l u s i o n s . As a result it was established that modern domestic philosophical academic Sinology is a qualitatively new and innovative direction of Oriental studies in independent Ukraine. This discipline was formed as a result of the two-century progress of Ukrainian Chinese studies from the era of Hetmanshina until now. V. Kiktenko and his colleagues have made a significant and already internationally recognized contribution to the study of both the classical philosophical schools of Ancient China and their ideological heirs, in particular, the leaders of the PRC and the CCP from Deng Xiaoping to Xi Jinping during these thirty years. V. Kiktenko also laid the foundations for the study both of the history of Ukrainian Chinese studies and of modern foreign, primarily Western European and North American, Sinology.

In the circumstances when human life is intensively affected by many harmful environmental factors resulting from large-scale disasters of different origins and types, the issues of population training in emergency preparedness and response as well as public safety culture development in general are of great importance. According to the State Emergency Service of Ukraine, in 2018 168 people were killed and 839 were injured because of emergencies. In comparison with the same last year period, there is a steady death toll increase despite the fact that the total number of emergencies in Ukraine has decreased in contrast to the previous period. In addition, rescuers have considered fire safety and hygiene violations along with low-level control over the epidemic prevention measures implementation as main causes of natural and man-made emergencies in the country during recent years.
 Such state of affairs may indicate that very often the loss of life during emergency results from the lack of knowledge and failure to comply with the recommendations on life safety, and that the existing system of civil protection training is not able to cover all segments of the population. In addition, the complex technogenic and environmental, and military and political situations significantly increases the risk of dangerous incidents occurrence with casualties. Thus, modernization of knowledge dissemination system on the civil protection and life safety issues among the population are of particular relevance.
 The problem of mobile technologies for educational purposes is analyzed by the Ukrainian and foreign researchers, namely: V. Bykov, A. Struk, S. Smerikov, D. Kigan, A. Andreeva, etc. At the same time, the analysis of scientific and methodological literature and online sources shows that the problem of the use of mobile training for raising public awareness on civil protection issues has not been considered as a separate research subject before.
 The purpose of the article is to determine the peculiarities of the mobile technologies used for population emergency preparedness, as well as to present the developed social mobile application “SES Alphabet” and the prospects of its usage for population training.
 Under the rapid civilizational development of humanity, there will always be the possibility of various natural and manmade threats, and a certain part of the population will suffer from dangerous factors of the external environment. Therefore, the issue of citizen’s safety competence development and the culture of society safety in general will always remain urgent. According to the Ukrainian Constitution, human life and health, its protection against the impact of harmful man-made, natural, environmental and social factors are the highest social values, for which a unified state system of civil protection was created. One of the system’s components is the preparing of the population to behave properly under the conditions of potential emergencies.
 Taking into account the fact that the main task of public policy in the civil protection field is emergency prevention, preparing people to act under special circumstances is an effective form of prophylaxis, first and foremost, of human casualties caused by disasters. The basics of human behavior in extreme situations are formed because of constant training, which provides an adequate level of preparedness in case of emergency. Therefore, the training of the population on civil protection issues should be standardized and widespread.
 There is a natural question about effective tools for such training. In our opinion, it is possible to solve this problem by developing a suitable mobile application. Using of mobile devices for outreach activities on civil protection issues with the civilians and promotion of a safety culture in society have wide prospects because it addresses the major problem of accessibility and rapid provision of the adapted, easy-to-read educational information material. Mobile learning offers great opportunities for self-education of the population because the application allows you to remotely study in the field of life safety regardless of place and time. The high concentration and multimedia of the training material make it possible to focus on the main points, while the user-friendly interface allows you to navigate the vast array of civil protection information material very quickly.
 Considering the opportunities and advantages, mobile education, in our opinion, in the long run can be the most effective outreach activity for the population on socially significant issues, in particular informing citizens about emergency response. The use of mobile devices will create the conditions for accessible, inclusive and continuous education of the population on civil protection issues.
 International experience in the mobile applications in civil protection systems used to inform the public about emergency demonstrates the effectiveness of the mobile technologies in achieving the key tasks in the field of civil protection, namely the protection of life and health of citizens. The mobile application will provide useful and easy-to-read information about emergency procedures, which will help to avoid loss of human lives among the affected population.

Abstract Echocardiography studies have reported that approximately 30% of screened adult patients with sickle cell disease (SCD) have pulmonary hypertension (PH) defined as systolic pulmonary artery pressures of ≥ 35 mm Hg or regurgitant jet velocity value (TRV) of ≥ 2.5 m/sec. PH is increasingly observed in SCD and thalassemia. B-type natriuretic peptide (BNP) and the putatively inactive amino-terminal fragment of proBNP (NT-proBNP) are produced by the cleavage of proBNP, which is secreted from the ventricles during pressure strain. The serum concentration of NT-proBNP is considered as one of the strongest independent predictors for survival in patients with left ventricular dysfunction. The aim of this study was to evaluate the prevalence of PH in correlation with hemolytic findings and NT-proBNP levels in 73 patients with HbS/beta-thalassemia (HbS/β-thal; thal 0: 44 pts and thal +: 29 pts). The presence of PH was evaluated by using Doppler echocardiography and applying the modified Bernoulli equation (pulmonary artery systolic pressure=4V2 +right atrial pressure). Exclusion criteria of this study include: evidence of left ventricular failure, vaso-occlussive crisis during the last 15 days, atrial fibrillation or ventricular tachycardia, mitral value regurtitation (MVR) >2/4+ or mitral value stenosis, and severe pericardial perfusion. In all pts we measured Hb, leukocyte, platelet, and reticulocyte counts, LDH, bilirubin, ferritin, creatinine, and Hb F. NT-proBNP levels were evaluated using an electrochemiluminescence immunoassay (Roche Diagnostics GmbH, Mannheim, Germany). Thirty-six patients (49%) were on hydroxyurea administration for a median time of 9 years. Nineteen patients (26%) had PH and experienced mild symptoms, such as fatigue or dyspnea on slight exertion. The administration of hydroxyurea did not affect the presence of PH. Patients with PH had elevated values of NT-pro BNP, reticulocyte counts and serum ferritin and a borderline increase of HbF compared with non PH patients (table). Even patients without PH had elevated concentrations of NT-proBNP compared with 20 controls of similar age and gender (mean±SD for controls: 48.1±22.1 pg/mL; p<0.0001). The results of this ongoing study have shown that the frequency of PH in our cohort of HbS/beta-thal patients is similar with that observed in patients with SCD. Serum NT-proBNP is a strong indicator of PH in this cohort of hemoglobinopathy patients. Furthermore, the correlation between PH with reticulocyte counts and ferritin suggests that the degree of hemolysis and iron overload is implicated in the pathogenesis of PH in HbS/beta-thal. Parameter Patients with PH (n=19) Patients without PH (n=54) p-value Age (median; range) 40 ± 10.4 38 ± 12.6 Gender (n) 11M/8F 17M/37F On hydroxyurea (n) 12 (33.3%) 24 (66.6%) 0.23 NT-proBNP (pg/mL; mean ± SD) 486.8 ± 126.8 261.7 ± 139.6 <0.01 Hb (g/dL; mean ± SD) 9.0 ± 1.5 8.9 ± 1.6 0.31 Retics (x1000/mm3) (mean ± SD) 239 ± 88 170 ± 61 0.01 LDH (U/L; mean ± SD) 779.6 ± 378.1 780.7 ± 352.9 0.76 Bilirubin (mg/dL; mean ± SD) 2.3 ± 1.8 2.4 ± 1.6 0.51 Creatinine (mg/dL; mean ± SD) 0.8 ± 0.1 0.8 ± 0.3 0.37 Ferritin (μg/L; mean ± SD) 1204.5 ± 1159.7 508.7 ± 599.1 0.02 HbF (%) 16.2 ± 8.0 13.5 ± 10.1 0.07

Abstract. Processes occurring in the tropical upper troposphere and lower stratosphere (UT/LS) are of importance for the global climate, for the stratospheric dynamics and air chemistry, and they influence the global distribution of water vapour, trace gases and aerosols. The mechanisms underlying cloud formation and variability in the UT/LS are of scientific concern as these still are not adequately described and quantified by numerical models. Part of the reasons for this is the scarcity of detailed in-situ measurements in particular from the Tropical Transition Layer (TTL) within the UT/LS. In this contribution we provide measurements of particle number densities and the amounts of non-volatile particles in the submicron size range present in the UT/LS over Southern Brazil, West Africa, and Northern Australia. The data were collected in-situ on board of the Russian high altitude research aircraft M-55 "Geophysica" using the specialised COPAS (COndensation PArticle counting System) instrument during the TROCCINOX (Araçatuba, Brazil, February 2005), the SCOUT-O3 (Darwin, Australia, December 2005), and SCOUT-AMMA (Ouagadougou, Burkina Faso, August 2006) campaigns. The vertical profiles obtained are compared to those from previous measurements from the NASA DC-8 and NASA WB-57F over Costa Rica and other tropical locations between 1999 and 2007. The number density of the submicron particles as function of altitude was found to be remarkably constant (even back to 1987) over the tropical UT/LS altitude band such that a parameterisation suitable for models can be extracted from the measurements. At altitudes corresponding to potential temperatures above 430 K a slight increase of the number densities from 2005/2006 results from the data in comparison to the 1987 to 2007 measurements. The origins of this increase are unknown. By contrast the data from Northern hemispheric mid latitudes do not exhibit such an increase between 1999 and 2006. Vertical profiles of the non-volatile fraction of the submicron particles were also measured by a COPAS channel and are presented here. The resulting profiles of the non-volatile number density fraction show a pronounced maximum of 50% in the tropical TTL over Australia and West Africa. Below and above this fraction is much lower attaining values of 10% and smaller. In the lower stratosphere the fine particles mostly consist of sulphuric acid which is reflected in the low numbers of non-volatile residues measured by COPAS. Without detailed chemical composition measurements the reason for the increase of non-volatile particle fractions cannot yet be given. The long distance transfer flights to Brazil, Australia and West-Africa were executed during a time window of 17 months within a period of relative volcanic quiescence. Thus the data measured during these transfers represent a "snapshot picture" documenting the status of a significant part of the global UT/LS aerosol (with sizes below 1 μm) at low concentration levels 15 years after the last major (i.e., the 1991 Mount Pinatubo) eruption. The corresponding latitudinal distributions of the measured particle number densities are also presented in this paper in order to provide input on the UT/LS background aerosol for modelling purposes.

Abstract. High-resolution paleoclimate records from tropical continental settings are greatly needed to advance understanding of global climate dynamics. The International Continental Scientific Drilling Program (ICDP) project DeepCHALLA recovered a 214.8 m long sediment sequence from Lake Chala, a deep and permanently stratified (meromictic) crater lake in eastern equatorial Africa, covering the past ca. 250 000 years (250 kyr) of continuous lacustrine deposition since the earliest phase of lake-basin development. Lipid biomarker analyses on the sediments of Lake Chala can provide quantitative records of past variation in temperature and moisture balance from this poorly documented region. However, the degree to which climate proxies derived from aquatically produced biomarkers are affected by aspects of lake developmental history is rarely considered, even though it may critically influence their ability to consistently register a particular climate variable through time. Modern-system studies of Lake Chala revealed crucial information about the mechanisms underpinning relationships between proxies based on isoprenoid (iso-) and branched (br-) glycerol dialkyl glycerol tetraethers (GDGTs) and the targeted climate variables, but the persistence of these relationships in the past remains unclear. Here we assess the reliability of long-term climate signals registered in the sediments of Lake Chala by comparing downcore variations in GDGT distributions with major phases in lake-system evolution as reflected by independent proxies of lake depth, mixing regime and nutrient dynamics: seismic reflection data, lithology and fossil diatom assemblages. Together, these records suggest that during early lake history (before ca. 180–200 ka) the distinct mixing-related depth zones with which specific GDGT producers are associated in the modern-day lake were not yet formed, likely due to more open lake hydrology and absence of chemical water-column stratification. Consequently absolute GDGT concentrations dating to this period are relatively low, proxies sensitive to water-column stratification (e.g., branched versus isoprenoid tetraether (BIT) index) display highly irregular temporal variability, and correlations between proxies are dissimilar to expectations based on modern-system understanding. A sequence of lake-system changes between ca. 180–200 and ca. 80 ka first established and then strengthened the chemical density gradient, promoting meromictic conditions despite the overall decrease in lake depth due to the basin gradually being filled up with sediments. From ca. 180 ka onward some GDGTs and derived proxies (e.g., crenarchaeol concentration, BIT index and IR6Me) display strong ∼ 23 kyr periodicity, likely reflecting the predominantly precession-driven insolation forcing of Quaternary climate variability in low-latitude regions. Our results suggest that GDGT-based temperature and moisture-balance proxies in Lake Chala sediments reflect the climate history of eastern equatorial Africa from at least ca. 160 ka onwards, i.e., covering the complete last glacial–interglacial cycle and the penultimate glacial maximum. This work confirms the potential of lacustrine GDGTs for elucidating the climate history of tropical regions at Quaternary timescales, provided they are applied to suitably high-quality sediment archives. Additionally, their interpretation should incorporate a broader understanding of the extent to which lake-system evolution limits the extrapolation back in time of proxy-climate relationships established in the modern system.

Zusammenfassung: Der Beitrag von Institutionen-Vielfalt im Finanzsektor zu nachhaltigem Wachstum und Finanzstabilität – insbesondere die Rolle effektiver lokaler Bankstrukturen – wird nicht selten unterschätzt, sei es im Rahmen der Entwicklungszusammenarbeit oder in der strukturpolitischen Diskussion in den hochentwickelten Volkswirtschaften. Dabei kommen in jüngster Zeit mehr und mehr Untersuchungen zu dem Ergebnis, dass Finanzinstitute mit einem Geschäftsmodell, welches die Pflege langfristig angelegter Geschäftsbeziehungen zu breiten Bevölkerungsschichten und zu mittelständischen Unternehmen vor Ort in den Mittelpunkt stellt, in der Tat einen positiven Einfluss auf Wirtschaftsentwicklung und Stabilität ausüben. Diese Untersuchungen reichen von Studien über Faktoren, die inklusive Finanzstrukturen in Entwicklungsländern vorantreiben helfen, bis hin zu vergleichenden Analysen der Geschäftsergebnisse unterschiedlicher Bankengruppen in Folge der globalen Finanzkrise. Diese Forschungsergebnisse werden überdies auch bestätigt, wenn man die spezifischen Erfolgsfaktoren hinter der mehr als 200-jährigen Geschichte des deutschen Sparkassen- und Genossenschaftsbankwesens einmal genauer unter die Lupe nimmt. Zu solchen Faktoren gehören unter anderem: Die Konzentration ihrer Aktivitäten auf eine geographisch begrenzte Region bei gleichzeitiger Zusammenarbeit in einem „Verbund“ (das heißt in einem Netzwerk autonomer Institute); die Förderung des Sparens und eine Fokussierung auf das Einlagengeschäft, und last but not least, ein Mandat, sich für das wirtschaftliche und soziale Wohl der Region einzusetzen, und zwar auf der Basis von nachhaltiger Ertragskraft und finanzieller Solidität anstatt enger Ausrichtung auf kurzfristige Profitmaximierung. Ähnliche Erfolgsfaktoren finden sich auch in einer Reihe von Entwicklungsländern im Zusammenhang mit dem Aufbau eines heimischen Finanzinstitutionengefüges und damit einhergehenden dezidierten Anstrengungen zur Förderung von Mikrofinanzinstituten und lokal verankerten Banken, deren Angebot an Finanzdienstleistungen nicht zuletzt auf die Bedürfnisse der ärmeren Bevölkerungsschichten ausgerichtet ist. Summary: The contribution of institutionally diversified financial sectors to more sustainable growth and financial stability—in particular the role of effective local banking structures—is not always fully appreciated, whether in the context of development cooperation or in policy discussions in the advanced economies. At the same time, a growing number of studies—ranging from analyses of the drivers of financial inclusion in developing countries to assessments of various banking groups’ performance during and after the global financial crisis (GFS)—find that financial institutions whose business models focus on local economies, retail and relationship banking do, indeed, have a positive impact on economic development, growth and financial stability. Those findings are also supported by a closer examination of the factors, which contributed to the successful evolution of the German savings banks and cooperative banks over a period of more than 200 years. These factors include: the concentration of their banking activities on a limited geographical region while working as a network of cooperating autonomous institutions; the prioritization of savings mobilization; a mandate to serve the economic and social wellbeing of the local region, while remaining profitable and financially viable over the long run, rather than narrowly focusing on profit maximization. Similar success factors can also be observed in the context of financial institution building and the deliberate promotion of locally oriented and people-focused microfinance and banking institutions in several developing economies.

Abstract Myelodysplastic syndrome (MDS) is mainly a disease of elderly population. Chronic cytopenias, especially anemia, frailty comorbidities, and age may alter the physical status significantly. Only a few proportions of patients can achieve long-term cure. In particular, but not limited to patients with low risk MDS; palliative/supportive care is the mainstay of the treatment. Erythropoietin-stimulating agents (ESAs) and red blood cell transfusions are the treatment options for patients suffering from anemia. Except one study, ESA-responders had a better quality of life (QoL) in three studies. Hematologic improvements should be assesses by patient-reported outcomes (PROs) as well as objective measures. Validated PROs those were used to assess QOL in patients with MDS included Functional Assessment of Cancer Therapy- Anemia (FACT-An) and European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC-QLQ C30) questionnaires and a MDS-specific questionnaire, QoL-E. All patients with MDS were screened. Patients with low-risk MDS were included in the study. One physician completed FACT-An, Hematopoietic Stem Cell Transplantation-Comorbidity Index (HCT-CI), and G8 frailty questionnaires in all patients. Demographic data were collected from patients' chart records. A total of 66 patients were screened. Fourteen patients were excluded due to high-risk MDS or indefinite diagnosis. In one patient, informed consent could not be obtained. Finally, 51 patients were included in the study. Median age was 66 years old (interquartile range [IQR]: 55-77). Twenty-one out of 51 patients (41.2%) were male. Most prevalent MDS subtype was MDS-refractory anemia (47%). All patients had very-low/low (86.3%) or intermediate-risk (13.7%) MDS according to age-adjusted IPSS-R (IPSS-RA). Median time from the diagnosis of MDS was 113 (IQR: 53-170) weeks. Twenty-eight patients (54.9%) were transfusion-dependent. Ten patients had a high transfusion burden, which was defined as transfusion requirement ≥4 units (U) over 8 weeks. Median transfusion duration was 112 (IQR: 31-173) weeks for transfusion-dependent patients. Median red blood cell transfusion during eight weeks was 1.5 (IQR: 0-4.5) U. Median hemoglobin concentration was 10.0 (7.9-11.3) g/dL for all patients. A total of nineteen patients (37.3%) were ESA-user/responder. Most of the patients (80.4%) had a low (<11 years) education level. Thirty-eight (74.5%) patients were living with their parents or partners. A half of the patients had an ECOG performance status ≤2. Sixty per cent were frail and 39% had significant (≥2) comorbidities. In univariate analyses, older age (β: -0.740, 95% CI: -1.138; -0.341, p<0.001), higher transfusion burden (β: -7.235, 95% CI: -14.279; -0.190, p=0.044), intermediate risk IPSS-RA (β: -8.113, 95% CI: -15.715; -0.511, p=0.037), lower educational status (β: -19.625, 95% CI: -32.565; -6.684, p=0.004), lower ECOG performance status (≥2) (β: -14.385, 95% CI: -24.805; -3.964, p=0.008), frailty (β: -13.740, 95% CI: -24.518; -2.962, p=0.014), and being ESA-user/responder (β: -15.431, 95% CI: -26.141; -4.722, p=0.006) were associated with worse FACT-An total scores. Multivariate analyses revealed that age (β: -0.738, %95 GA: -1.101; -0.374, p<0.001) and being ESA-user/responder (β: 15.368, %95 GA: 6.040; 24.697, p=0.002) were the only independent predictors of QoL in patients with low-risk MDS (Table 1, figure 1). Model stability was tested in 5000 bootstrap replicates of dataset. Age and being ESA-user/responder were included in 40.6% and 38.2% of all models (Table 1). These data indicates that age and ESA use are independent parameters of QoL in low-risk MDS. Impact of ESA use on QoL is independent from the hemoglobin level. Disclosures No relevant conflicts of interest to declare.

Background: SAR442257 (SAR'257) is a trispecific antibody that targets CD38, CD3 and CD28. Simultaneous CD3 and CD28 binding triggers T cell co-signaling, and additional CD38 recognition directs the T cells to CD38+ cancer cells such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This is a first-in-human phase 1 study investigating the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of SAR'257 in patients (pts) with refractory and relapsed (rr) MM and rrNHL. Methods: This is a multicenter, international, open-label, dose-escalation study (NCT04401020) of SAR'257 in pts with rrMM refractory to standard-of-care (SOC) options, including anti-CD38 monoclonal antibodies, and in pts rrNHL without any SOC options. SAR'257 was administered intravenously with lead-in doses (Day 1−5) in the first week, followed by twice weekly (BIW) or once weekly (QW) dosing; 11 target dose levels (TDLs) in pts with rrMM (9 TDLs: 0.06-11 µg/kg BIW; 2 TDLs: 18-27 µg/kg QW), and 2 TDLs in pts with rrNHL (2 µg/kg BIW and 4 µg/kg QW). Results: As of February 19, 2024, 47 pts (rrMM, n=40; rrNHL, n=7) received SAR'257. The median ages (years) were 64 (rrMM; range: 40−84) and 70 (rrNHL; range: 18−75). The median number of prior lines was 5 (range: 3−12) for rrMM and 5 (range: 2−7) for rrNHL cohort. In rrMM cohort, all (100%) pts had prior exposure to an anti-CD38 monoclonal antibody (MAb) and were refractory to anti-CD38 and in rrNHL cohort all were anti-CD38 naïve. The median time from last anti-CD38 dose was 2.7 (range: 1−65) months for rrMM cohort. Safety analysis revealed that 68% (n=32) pts had treatment-emergent adverse events (TEAEs; 26 pts in rrMM and 6 pts in rrNHL); 21.3% pts (n=10) Grade (G) ≥3 TEAEs (7 in rrMM and 3 in rrNHL). Cytokine release syndrome (CRS) was the most common TEAE, occurring in 52.5% of rrMM pts across all TDLs (n=21; G≥3 in 1 pt from 11 µg/kg BIW TDL) and in 57.1% of rrNHL pts (n=4; no G≥3) at the two TDLs tested. Repetitive CRS episodes (>1 episode) were more frequent at higher TDLs. Infusion-related reactions (IRRs; any G) were observed in 22.5% pts with rrMM (n=9; no G≥3) and in 28.5% pts with rrNHL (n=2; G≥3 in 1 pt). Epstein-Barr virus (EBV) infection/reactivation was reported in 17.5% (n=7; G≥3 in 4 pts) and 28.6% (n=2; no G≥3) pts with rrMM and rrNHL respectively. Further, 15% (n=6, G≥3 in 2 pts) from rrMM and 14.3% (n=1; G2 CMV reactivation) pts from rrNHL cohort reported cytomegalovirus (CMV) infection/reactivation. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported (G4) in the rrNHL cohort. Four dose-limiting toxicities (DLTs) were observed in the rrMM cohort [1 at 4 µg/kg BIW (G3 hepatotoxicity); 1 at 11 µg/kg BIW (G5 CRS−EBV reactivation; and 2 at 27 µg/kg QW (G3 CMV infection reactivation and G3 febrile neutropenia in same pt)]. Three DLTs were observed in the rrNHL cohort (2 at 2 µg/kg BIW [G4 neutropenia and G4 thrombocytopenia; same pt] and 1 at 4 µg/kg QW [ICANS G4]). For pts with rrMM, the maximum plasma concentration of SAR'257 reached within or above the theoretical efficacious range (0.1−1nM; extrapolated from ex vivo models), starting at 8 µg/kg BIW and 18 µg/kg QW in the first treatment cycle. As of July 08, 2024, the overall response rate (ORR), defined as partial response (PR) or better, was 5% (n=2) in the rrMM cohort: 1 pt exhibited stringent complete response (duration of response [DOR]=8.1 months, on-going) and 1 showed a complete response (CR) at 27 µg/kg QW TDL. In rrNHL cohort, the ORR was 14.3%, 1 pt achieved PR (DOR=7.1 months) at 2 µg/kg BIW TDL. The disease control rate (stable disease or better for >8 weeks) was 60% (n=24) and 28.6% (n=2) in the rrMM and rrNHL cohorts respectively. For both cohorts exploratory biomarker analysis revealed that: (1) SAR'257 treatment activated peripheral blood T cells and reduced regulatory T cell numbers and CD4/CD8 ratio; (2) CD38 expression on plasma cells positively corelated with time since the last anti-CD38 MAb dose; (3) Among the pts experiencing CRS, the peak values of cytokines (Interleukin (IL)-6, IL-8, and C-reactive protein) were significantly higher during the first cycle in comparison to subsequent cycles. Conclusion: This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation.

THE SURVEYS Two consecutive alcohol consumption surveys were carried out in Poland in 1980 and 1985. In both of them quota samples of population 16 years of age and over were used, and the sizes of the samples were 1972 and 1808 respectively. The surveys were sponsored by the Institute of Psychiatry and Neurology which is responsible for funding research on a broad range of topics related to alcohol, its effects, use and misuse. The fieldwork was carried our by specially trained interviewers of the Centre for Public Opinion Survey and Programme studies of the state Committee for Radio and TV in Warsaw, a well established public opinion poll institute working already for more than 30 years. The majority of items included in the questionnaires used in each survey were identical, only some were altered, dropped entirely, or substituted for by other formulations. The preliminary part of both questionnaires concerned the relations of the respondents with other people. This was followed by a group of several questions related to the last drinking occasion: place and company of drinking, kind and amount of alcohol consumed, and the reason for drinking. In the 1985 survey more detailed information on the last occasion of drinking was collected, viz. separate questions were asked in relation to the last occasion of consumption of spirits and that of the consumption of wine, as well as on the duration of these occasions. The persons who had not consumed alcohol during the twelve months preceding the interview were asked whether they had ever drunk before, and what the reasons were for their being teetotallers. All the respondents were requested to tell about their pleasant and unpleasant experiences with alcohol, and whether alcohol helped them or caused trouble in some situations listed in the questionnaire, and pertaining to their social and professional life. Apart from that, the respondents were asked to express their approval or disapproval of several statements concerning good and bad consequences of drinking. In this part of the questionnaire, in the 1985 survey several alterations were introduced in comparison with the former survey. What remained unchanged in the questions were those on being victimized during the last twelve months while drunk, or by a drunk person. The questions on drinking in excess or more often than desired, or binge drinking-asked in the 1980 survey - were replaced in the 1985 survey by questions forming the CAGE questionnaire. Other questions asked in both surveys concerned the consumption of moonshine alcohol and drinking at work. The concluding part of the questionnaires was designed to obtain information on the respondents age, sex, education, place of residence, kind of work, etc. In the above surveys, the-last-occasion approach was applied in order to estimate the size and the pattern of alcohol intake by the respondents. This approach is adopted in the majority of Polish alcohol consumption surveys, following the example of a Finnish researcher P. Kuusi. Both surveys were carried out in mid-September, i.e. after-summer holidays, during a normal working month, without any important religious or national festivities, which would have changed to some extent the ordinary drinking practices. THE BEVERAGES During the years 1980-1985, the size of the apparent consumption of alcoholic beverages changed considerably. According to the official data derived from the statistics on sales of commodities, in 1980 the per capita consumption amounted to 8.4 litres of pure alcohol, of which 71 per cent was drunk in spirits,15 per cent- in wine, and 14 per cent -in beer. The 1985 figures were: 6,8 litres, 67, 15 and 18 per cent respectively. It looks as if the total consumption decreased substantially (by 19 per cent), but the structure of beverages consumed remained fairly stable. However , according to the opinion shared by the majority of specialists on the subject, the drop in the officially recorded consumption was associated with a marked increase in moonshine alcohol, which resulted in raising the total consumption to at least the 1980 level. The results of the survey seem to support this assertion. The per capita self-reported consumption of alt alcoholic beverages amounted to 5.6 and 5,9 litres of pure alcohol in 1980, and 1985 respectively. Thus, instead of the 1985 drop, a slight increase occurred (by 5 per cent). Moreover, while. the self-reported consumption of the majority of the beverages remained stable a large increase was noted in the home-made beverages: the illegally distilled moonshine alcohol (spirits) and the legally made fruit wine. The consumption of moonshine spirits was in 1985 higher than that in 1980 by 130 per cent and the consumption of fruit wine was higher by 60 per cent. In1985,one-scventh of all alcoholic beverages consumed were home-made, while in 1980 - only one-thirteenth. As a result, the share of spirits in the total amount of alcohol consumed – whether legally or illegally distilled in 1985 exceeded the 71 per cent level of 1980. Between the years 1980 and 1985 the proportion of consumers of fruit wine and spirits within the population remained stable, and that of other beverages increased. In particular, the number of those who drank moonshine spirits doubled. With the exception of fruit wine drunk in 1985 by nearly one-third of men as well as women 16 years of age and over, other beverages were consumed by far more men than women. This was particularly the case as regards beer which was drunk by 70 per cent of men and only 20 per cent of women, and moonshine spirits which were drunk by 30 per cent of men and 11 per cent of women. Spirits, which in Poland means mostly vodka, were consumed by 85 per cent of men and 62 per cent of women, and wine by 46 and 39 per cent respectively. FREQUENCY AND AMOUNT The-last-occasion approach adopted in the surveys consists not only in asking the respondents of how much and of how long ago they had drunk for the last time each of, the alcoholic beverages enumerated in the questionnaire, but also in assuming that the occasions reported were typical for the ways the respondents drank. Frequency of drinking depends heavily, among other things, on the kind of' beverage. In the Polish culture, wine is the less frequently drunk alcoholic beverage. Two-thirds of its consumers drink it at most once a month, and half of all its consumers - at most once every three months. Home-made fruit wine is being drunk even less often. Only one in five or six wine consumers drink it once a week or more often. The consumers of spirits seem to be divided into two distinct groups, one formed by occasional drinkers (at most once a month) and the other by frequent drinkers (several times a month or even several times a week). The first group consists of one-third, and the other one of more than half of all spirits drinkers. One in five of them drinks spirits several times a week. Most evenly distrributed on the frequency scale of drinking were the consumers of beer. Nearly as many drank it every day, every week, every month or every three months. Similar picture emerges in respect of the amount drunk on one occasion. Regardless of the beverage, most consumers drink small quantities only. But there are also heavy drinkers who consume on one occasion at least a quarter of a litre of spirits, one litre of wine or more than one litre of beer. Those drinkers constituted one in five of spirits' consumers, even one in two of moonshine spirits consumers, and one in five of wine or beer consumers, less heavy drinkers are only among home-made fruit wine drinkers (one in ten). The information concerning the frequency of drinking and the amount of alcohol consumed makes it possible to separate four patterns of drinking: heavy and frequent, heavy and infrequent, moderate and frequent, moderate and infrequent. Among consumers of different beverages, the group of persons drinking moderately and infrequently was the most numerous particularly as regards the consumers of wine, and smaller degree the consumers of spirits and moonshine spirits, and to the smallest degree-the consumers of beer. Also the group of persons drinking heavily and infrequently were relatively numerous, apart from consumers of beer, among whom the second most numerous group was that of persons drinking moderately and frequently. Every fourth or fifth consumer of beer, every seventh consumer of home-made frit wine drank much and frequently. As regards persons, who drank any two of the above-mentioned beverages, a convergence of their drinking parents could be noticed which consisted in the following regularity: if one of the beverages was consumed according to one of the patterns, the other beverage was generally also consumed according to the same pattern. The above results were very similar in both surveys. However, in the 1985survey, a slight shift towards greater concentration of consumption could be noticed. One of the effects of drinking alcohol, and for some consumers probably also one of the aims of drinking, is to get drunk. Using the information from the 1985 survey on such factors as the kind and amount of beverages consumed, the duration of the drinking occasion, and the sex and weight of the respondent, the blood alcohol concentration was estimated for every drinking occasion reported. In about one quarter of drinking occasion this estimate could not be done due to the lack of some of the necessary data, most often that of the weight of the respondents. Only one in every five events of drinking spirits and one in three events of drinking wine have not caused a rise in blood alcohol concentration above the physiological level of 0,2 per mille. Getting drunk, i. e. overstepping the blood alcohol concentration of 1.5 per mille, occurred in 13 per cent of incidents of drinking spirits, 7 per cent of drinking wine, and 5 per cent of drinking home-made fruit wine. If related to the total number of drinking occasion of the above beverages this means that in Poland every day about 600 thousand persons would get drunk. Persons getting drunk were significantly more numerous among men than women, and as far as men are concerned among young (up to 40 years of age), less educated, blue-collar workers describing themselves as non-believers or non-worshiping believers. Among women only those who felt to be better off than average would drink significantly more often than others. DRINKING OCCASION One of the characteristic features of drinking alcohol in Poland is using the existing occasions or inventing them. Alcohol happens to be drunk in order to celebrate such events as family festivities (like name-days or birthdays), religious ceremonies (like baptism, confirmation or - in particular - wedding), national holidays, government ceremonies (like opening a factory, a museum'' new railway station or a bridge), other happy events (tike winning a match by a favourite soccer team, passing important examinati.ons by the son or daughter, their entrance to the high school or the university). Drinking occasion may be called for while looking for some comfort caused by losing a march by a favourite soccer team a set-back at work, or misfortune in personal matters. Alcohol is served and drunk in order to show hospitality, to emphasize the importance of a guest or an unusual, lofty, or particular character of the meeting, etc. This list could be easily extended, but it does not seen necessary as its aim is only to show that drinking alcoholic beverages - probably with the exception of beer only – is perceived as an event calling for special justification. This justification should not be equated with causes of drinking, deeply rooted and often not understood and realized clearly by the person in question. Therefore, the justification for drinking provides an insight not so much into the reasons of drinking as into its cultural context. Using the information on the kind and amount of alcohol drunk, on the place of drinking, character of the occasion, and, in the 1985 survey, also on the duration of the drinking incidence, three main types of spirits and wine consumption occasions were distinguished: a family celebration, a friendly social meeting, and a drinking-for-purpose event. The family celebration comprised nearly half of all drinking occasions described in the replies of the respondents. These occasions lasted longer than others, namely about 4 to 5 hours, with many persons taking part, the amount of alcohol drunk was smaller by half than the average amount and in more than 90 per cent of cases they took place in private quarters. The friends-meeting social type of drinking occasions were less numerous, they comprised about one-third of the total number of the last occasions reported. Half of them occurred in friends appartments, one-fourth on the respondents flats, and one in seven in a bar or restaurant. The meeting lasted about 2-3 hours, and the amount of spirits or wine drunk was somewhat larger than the average. Most often 4 to 5 persons took part in these encounters. One in five of the last occasions described by the respondents was of the drinking-for-purpose type. The most often stated justification for such a drinking occasion was that ,,it just happened this way" or ,,without any special reason, and the second in the row was that the drinking tock place in order to handle some business which made it necessary to have a drink’’. These occasions lasted usually l-2 hours and the company consisted of about 3-4 persons. Most often the meeting took place in a bar or a restaurant at work; relatively rarely in private appartments, and occasionally in a park or another commonly frequented place. Persons drinking on these type of occasions consumed twice as much alcohol as the average. The types and characteristics of drinking occasions did not change between 1980 and 1985; only few exceptions were noted, such as those with more alcohol drunk in private apartments and less in bars and restaurants. The same types of drinking occasions were fund in respect of consumption of spirits and wine, only home-made fruit wine did not seem to be drunk ,,for purpose’’ DRINKING AT WORK One of the special features of drinking practices in Poland is the consumption of alcohol at work. It takes place against the provisions of the labour law and in some circumstances also against criminal law. Every few years the authorities launch a campaign against drinking at work only to learn that it brings about temporary results. In order to understand the reasons for limited effects of such endeavours a closer look at a socialist enterprise is necessary' fn a state-controlled economy, a socialist enterprise is not. only a place where employees provide work in order to produce some commodities or services. One of the Polish leading sociologists described such an enterprise as a combination of an industrial plant, an office, and charity. Its peculiar social life stems from all the above factors, and it is only against this background that an appraisal of the data on drinking at work can be made. The 1980 survey revealed that two of every three respondents employed in the state-owned enterprises and offices had in the course of the last year prior to the interview drunk alcohol while at work. The results of the 1985 survey were markedly different since the affirmative answers to the question of drinking at work was given by one in every two such respondents. On the assumption of the last occasion approach an attempt was made at amount of drinking events at work. The numbers of such events in1980 and 1985 were 14.6 and 7.3 per one employee respectively. It seems to be a marked decrease, but is has to be seen whether it will be a lasting one. Drinking at work seems to be very common also in another respect. When looping at the characteristics of the consumer of alcohol at work they correspond closely to the characteristics of all drinking persons. The justification for drinking at work is very similar to that described above, only the family celebration and friends-meeting social types seen to merge into one. In 1980 nearly half, and in 1985 one-third the persons who drank at work did it while celebrating name-days or birthdays. One in five of those who drank at work did it ,,with no special reason" or because alcohol was offered by somebody, which corresponds to the drinking-for-purpose type. ALCOHOL DEPENDENCE Alcohol dependence is a very complex concept and it is debatable whether tackling it in a survey research can produce conclusive results. In the 1985 survey it was approached by means of one of the questionnaires used by medical practitioners. After reviewing several of such questionnaires, like MAST, SMAST, CAGE, MALT, Reich, the CAGE questionnaire was selected as the most suitable, among other things, because of its brevity. A common feature of all the above instruments is that they are in fact screening tests, and their aim is to spot out in a pool of patients those who might have an alcohol problem. These patients are referred afterwards to a qualified specialist for a proper examination and diagnosis. The use of such a questionnaire in a survey conducted in a general population is an extention of its application far beyond the limits of its original design, because in such a situation it is expected to provide a final ,,diagnosis" instead of pointing to persons suspected of being addicted to alcohol. In the circumstances both the sensitivity and specificity of the questionnaire become of utmost importance. The low specificity of the CAGE questionnaire makes it impossible to estimate- within the known limits of errors - the size of the group of alcohol dependent persons in the general population because a number of persons likely to be classified on its basis as being alcohol dependent in fact are not dependent. The size of the latter (i. e. those incorrectly classified as alcohol dependent) is partly a function of the size of the group of the alcohol dependent in the general population. The percentage of respondents who in the 1985 survey said ,,yes" to al1 the four questions of the CAGE questionnaire was 4.4, to three questions - 11.8, to two questions - I2.1, and to one question - 15.1. The results of the previous applications of the CAGE test show that four ,,yes" answers to the questionnaire questions were given only by alcohol dependent persons, and no such answers were given by persons not dependent. Hence it can be assumed that in the cases of all four ,,yes" answers one deals with alcohol dependent persons, without fear of making a serious error. As to the persons who gave three ,,yes" answers) one can assume among them a higher cumulation of alcohol dependent persons, and as regards those who said ,ryes" to two questions it can be hypothesised that there are few such persons among them. On the basis of the results obtained, the probable number of persons in 1985 in Poland in the age group of 16 years and over, who were alcohol dependent, has been estimated as somewhat higher than number of persons who said ,,yes’’ to all the four questions in the CAGE questionnaire, i. e. approximately 1,500 000, the error limits of this estimate, unfortunately, cannot be specified. The persons who gave a higher number of ,,yes’’ answers to the test questions drank largel quantities of alcohol. More answers of this kond were given by men, middle-aged persons and elderly (but not old), living in villages, not well-off, non-worshipping believers and non-believers. THE ABSTAINERS AND TEETOTALLERS Abstainers are referred to here as those who do not drink a particular alcoholic beverage, and teetotalers as those who according to themselves do not drink alcohol at all (1980 survey) or who did not consume alcohol during the last twelve months prior to the interview. Only 25 per cent of the respondents abstained from drinking spirits, about 25 per cent-from wine, 58 per cent (in 1980)and 50 per cent (in 1985)-from beer, 70 per cent (in 1980) and 64 per cent (in1985)-from home-made fruit wine, and 89 per cent (in 1980) and 79 per cent (in 1985)-from moonshine spirits. The were 14.8 per cent teetotalers in 1980 and 16.1 per cent in 1985, however, the difference in those percentages is statistically insignificant. In general population the fraction of teetotalers is probably a few points higher because in both the 1980 and 1985 samples the persons aged 16-19 and 60 and more, namely those among whom the non-drinkers are most numerous, were underrepresented. Less than half of the teetotalers never drank alcohol and the share of those who stopped drinking increased between the years 1980 and 1985. This result would have looked promising were it not for the reasons for not drinking given by the respondents. Most often old age, poor health, lack of money, and similar justification were offered, and only one in seven non-drinking alcohol respondent mentioned that drinking alcohol would interfere with his studies or work, or against his beliefs or cherished values. Also the social characteristics of teetotalers give reason for worry: among these overrepresented are very young and elderly, women, poorly educated, blue-collar workers, poor-in general those who belong to the lower social strata of the population. To be a teetotaler in Poland is unenviable.

Metallomics is an emerging area of the omics disciplines that has grown enormously since its conception as an academic discipline in 2004. This discipline integrates research related to biometals, along with other disciplines such as genomics, proteomics, metabolomics, and bioinorganic chemistry. It is defined as the study of the metallome, the interactions and functional connections of metal ions or species with genes, proteins, metabolites, and other biomolecules in biological systems. The study of the metallome of a species can provide information on the distribution of an element between cellular compartments, on the coordination environment in which a biomolecule is incorporated, or on the concentration of individual metal species present. In this regard, it plays a very important role in providing integrated information that connects metallomics with other omics disciplines.1,2 The term ‘metallomics’ was pronounced for the first time in June 2002 during the Tokushima Seminar on Chemical Engineering held in Tokushima, Japan, where the development of this new omics discipline was suggested, which was closely influenced by the progress of Analytical Atomic Spectrometry, in particular by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES). Since the mid-1970s, ICP-MS and ICP-AES techniques have been positioned as highly sensitive analytical tools with excellent possibilities for simultaneous quantification of multiple elements. Nowadays, it is possible to carry out analyses of basically all the elements in any type of sample using one of these two techniques. Likewise, the use of several other techniques for metallomic studies has been reported, such as Electrothermal Atomic Absorption Spectrometry (ETAAS), Microwave Plasma Atomic Emission Spectrometry (MP-AES), Laser Induced Plasma Spectroscopy (LIBS), and Energy Dispersive X-Ray Fluorescence Spectrometry (EDXRF), among others.2 A very useful bioanalytical study, within the field of metallomics, is the cellular uptake assay of potential metallodrugs. Using an adequate analytical technique, the metallic center of a given metallodrug can be monitored, and thus the fraction capable of entering a certain type of cell can be evaluated. Likewise, the distribution at the subcellular level and the association of the studied metallodrug with biomacromolecules of interest may be studied. In this context, our research group has been working on the optimization and validation of different bioanalytical methods for monitoring potential metallodrugs with activity against Trypanosoma cruzi, a protozoan parasite that causes Chagas disease, which is a pressing health problem in high-poverty areas of Latin America.3 A large number of metallic compounds with anti-Trypanosoma cruzi activity have been synthesized by our group, using as a strategy the coordination of metal ions or organometallic centers of pharmacological importance with bioactive organic ligands that have proven activity against Trypanosoma cruzi. Binding to metal can modify properties such as the solubility, lipophilicity, stability, and electronic and transport properties of the organic ligand, generating compounds that may be more active and/or less toxic. These metallic compounds can act by affecting two or more targets in the parasite: the ligand itself and others resulting from the presence of the metal. The biological properties of the metal–bioactive ligand compound will depend on the nature of the metallic center and the bioactive ligand, the presence of other ligands, and, fundamentally, its physicochemical-structural properties. In this regard, our group has focused its attention on the rational design of antiparasitic metallic compounds based on the relationships between chemical structure, physicochemical properties, and biological activity. This research line has led to important contributions that have been transferred to the scientific field, showing the vital importance of cellular uptake metallomic studies to understand the fate of potential metallodrugs and elucidate targets and mechanisms of action. In this context, the potential as an antitrypanosomal agent of a new rhenium(I) tricarbonyl compound with the formula fac-[Re(I)(CO)3(tmp)(CTZ)](PF6), where CTZ = clotrimazole and tmp = 3,4,7,8-tetramethyl-1,10-phenanthroline, was recently evaluated. It showed very good activity against the epimastigote form of Trypanosoma cruzi, with IC50 values (half maximal inhibitory concentration) in the low micromolar range. For this task, a new bioanalytical method based on the MP-AES technique was developed and validated.3 This technique has reemerged in the last few years with several improvements and can be considered as a good strategy for the determination of highly refractory elements such as rhenium. The method was applied to the determination of the percentage of rhenium taken up by the parasites and the association of the compound with the main biomacromolecules: soluble proteins, insoluble fraction, DNA, and RNA. The results of the metallomic study showed a low percentage of total rhenium taken up by the parasites, around 1 %, and a preferential accumulation in the soluble protein fraction, around 83 %. Also, the low localization of the compound in the DNA and RNA fractions, less than 1 %, made it possible to discard these biomolecules as the main targets of action. The developed method turned out to be an economical and efficient alternative for metallomic studies of potential rhenium metallodrugs, applied for the first time for the analysis of this particular element.3 In order to deepen in the localization of the compound taken up in the whole parasite, confocal Raman microscopy was performed.4 However, the main bands of the rhenium(I) tricarbonyl compound showed a strong overlap with signals coming from lipids, proteins, and DNA from the parasite, and due to the low concentration assayed, signals associated with ν(CO) could not be detected. Notwithstanding that, the overlap found by confocal Raman spectroscopy gave us a clue to the actual location of the compound inside the parasite, constituting an interesting indirect metallomic tool.4 Similar bulk studies were previously carried out by our research group using the ETAAS technique. For this task, novel bioanalytical methods were developed and validated, which were successfully applied to study the cellular uptake of potential palladium, platinum, and vanadium metallodrugs against Trypanosoma cruzi.5,6 This example of interdisciplinary work highlights the importance of developing and validating bioanalytical methods such as metallomic strategies to carry out cellular uptake studies, in order to assess the fate and possible targets and mechanisms of action of potential metallodrugs. Likewise, they promote the key role of Bioanalytical Chemistry in supporting Medicinal Inorganic Chemistry during the development of new potential metallodrugs, in the search for answers to important Public Health issues.