61Cu/67Cu theranostic pair production, chemical separation and radiolabeling

Historical relations between physics and medicine accelerated with the discovery of X-ray radiation and shortly thereafter with the discovery of radioactivity in the 19th century. At present, the term medical physics refers to physicists whose work is mainly concerned with medical applications of radiation. One of the most prominent applications of physics and chemistry in the medical field is nuclear medicine. Nuclear medicine can be defined as the medical specialization that uses radionuclides to investigate organ metabolism and to provide diagnosis and therapeutic interventions. The origin of nuclear medicine and radiopharmaceutical chemistry was started with the fundamental research started by George De Hevesy, and the first cyclotron was built by Ernest Orlando Lawrence in 1930. About 95% of the radiopharmaceuticals are employed in nuclear medicine for diagnosis, while the rest are used for therapy. A radiopharmaceutical consists of two components: a radionuclide and a pharmaceutical compound. First, a pharmaceutical compound is chosen that preferentially targets a given receptor or other cellular targets, then an appropriate radionuclide is attached to it for diagnosis or therapy. According to the available data at the International Atomic Energy Agency (IAEA), 134 countries use nuclear medicine facilities and equipment. Due to the rising prevalence of NCDs (Non-Communicable Diseases), the availability of new tracers, and the high demand for early and accurate diagnoses, NCD are expected to be the fastest-growing segment in nuclear medicine. There is an increasing demand for a personalized medicine approach in this era with scientific and technological developments. Several factors have resulted in the growth of personalized medicine, such as advances in molecular biology, a better understanding of processes, and more excellent knowledge of individual diseases' mechanisms. Theranostics, which is a combination of therapy and diagnosis, has introduced a new chapter in the field of nuclear medicine for providing personalized treatment to the patient. Among the different radioisotopes, Cu offers several radioisotopes potentially appropriate for use in nuclear medicine. One of the most promising pairs is 61Cu/67Cu that could be applied in theranostic applications. However, its optimized production and its availability in large quantity have been among the main challenges in nuclear medicine and constitute our inspiration to start this Ph.D. study. This thesis was performed in the framework of the Sinergia project “PHOtonuclear Reactions (PHOR): Breakthrough Research in Radionuclides for Theranostics” funded by Swiss National Science Foundation (SNSF). This enterprise is based on a collaboration among the Department of Chemistry, Biochemistry, and Pharmacy (DCBP) and the Laboratory of High Energy Physics (LHEP) of the University of Bern, and the Federal Institute of Metrology (METAS). This thesis is structured in 5 chapters: The first chapter introduces and deals with the basics of radiopharmaceutical chemistry and different production methods. In addition, the first chapter presents an introduction of nuclear medicine and its applications in diagnosis and therapy, along with introducing different radionuclide production facilities such as cyclotron, reactor, and electron accelerators. Chapter two focuses on the investigation of 61Cu and 67Cu production through different nuclear reactions and finally production of 61Cu by irradiation of 64Zn using a proton cyclotron at SWAN Isotopen AG at Inselspital Bern and production of 67Cu via irradiations of 68Zn with Bremsstrahlung generated by a 22 MeV Microtron at METAS. Chapter three introduces a novel method based on an evaporation technique for the efficient separation of Cu from the irradiated Zn targets, followed by a liquid chemical separation using extraction chromatography. To achieve this, an automated system (using a Modular-Lab PharmTracer system) was developed and installed in the framework of this thesis. With this automated system, Cu was completely separated and purified from the irradiated Zn targets. Moreover, in chapter three, radiolabeling of Cu with DOTA peptide was investigated. In chapter four, as a part of this study, the production of further potentially suitable radionuclides for medical applications such as 167Tm, 165Er, and 135La were investigated. Chapter five gives a summary of all processes that were considered and employed in this Ph.D. thesis and provides an outlook for further studies in the near future

Left Ventricular Pseudoaneurysm as a Complication of Myocardial Infarction; A Case Series and Review of the Literature

Introduction: Pseudoaneurysm may occur as a rare complication of myocardial infarction (MI) when a hemorrhagic process is covered by adherence of the visceral or parietal pericardium or of both, preventing the formation of cardiac tamponade. Pseudoaneurysm is prone to rupture because they are not easy to diagnose. Case presentation: Here, we report three cases of left ventricular pseudo-aneurysm (LVP) that all were related to MI. Two patients were managed conservatively, one of them was lost to follow-up, and the other one expired one month later. One patient underwent surgery, but he expired during post-operation period. Conclusions: High mortality rate of LVP emphasizes the importance of looking for it in cardiac evaluation of patients with history of MI. Due to available non-invasive modalities, the ability to differentiate LVP from other cardiac pathologies is improving. Still, the most recommended management of LVP is early surgery

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Związek między nadzorem korporacyjnym a kosztem kapitału własnego

The strategic planning of firms is highly dependent on capital investment, and corporate governance practices in firms play a critical role in seeking to invest with a risk reduction. Two emerging stock markets, India (NSE) and Pakistan (PSX), are selected to investigate the links of costs of equity capital with corporate governance. Therefore, the study's primary aim is to find out the relationship between corporate governance and cost of equity capital and the ways that can be helpful for firms to reduce risk. Data are collected from 260 firms in the chemical and pharmaceutical industries from 2011 to 2020. Dimensions used to measure the corporate governance index include committees’ existence, size and composition of board, ownership structure, and CEO duality. The pooled OLS (fixed effect) regression model has been applied to estimate the coefficient regarding data collected from companies. Study results presented a comparison of firms with strong and weak corporate governance and concluded a higher cost of equity capital for the firms with weak corporate governance compared to others. Using PEG ratio to estimate the cost of equity model is regarded as most suitable for developed countries and is currently deployed in the current study. The study's major contribution is using cross-country data to conduct a preliminary investigation on the relationship between the costs of equity capital with corporate governance. The study findings are highly significant for developing and strengthening the corporate governance structure in companies and providing protection to shareholders' interests. The current paper has presented managerial implications and suggestions for policymakers and shareholders that, in return, are likely to boost assurance in the market.Planowanie strategiczne firm jest w dużym stopniu uzależnione od inwestycji kapitałowych, a praktyki nadzoru korporacyjnego w firmach odgrywają kluczową rolę w dążeniu do inwestowania przy ograniczeniu ryzyka. Dwa wschodzące rynki giełdowe, Indie (NSE) i Pakistan (PSX), zostały wybrane do zbadania powiązań kosztów kapitału własnego z ładem korporacyjnym. Dlatego też głównym celem badania jest poznanie związku między nadzorem korporacyjnym a kosztem kapitału własnego oraz sposobów, które mogą być pomocne firmom w ograniczaniu ryzyka. Dane zbierane są od 260 firm z branży chemicznej i farmaceutycznej w latach 2011-2020. Wymiary stosowane do pomiaru wskaźnika nadzoru korporacyjnego obejmują istnienie komitetów, wielkość i skład zarządu, strukturę własności oraz dualism CEO . Do oszacowania współczynnika dotyczącego danych zebranych od firm zastosowano model regresji puli OLS (fixed effect). Wyniki badania pozwoliły na porównanie firm o silnym i słabym nadzorze korporacyjnym i wskazują na wyższy koszt kapitału własnego dla firm o słabym ładzie korporacyjnym w porównaniu z innymi. Wykorzystanie wskaźnika PEG do oszacowania kosztu kapitału własnego jest uważane za najbardziej odpowiednie dla krajów rozwiniętych i jest stosowana w niniejszym badaniu. Głównym wkładem badania jest wykorzystanie danych z różnych krajów do przeprowadzenia wstępnego badania relacji pomiędzy kosztami kapitału własnego a nadzorem korporacyjnym. Wyniki badań mają duże znaczenie dla rozwoju i wzmocnienia struktury ładu korporacyjnego w spółkach oraz zapewnienia ochrony interesów akcjonariuszy. W obecnym artykule przedstawiono implikacje zarządcze i sugestie dla decydentów i akcjonariuszy, które w zamian mogą zwiększyć pewność na rynku

The need for culture sensitive diagnostic procedures

Objective We examine the procedural validity of a standardized instrument for the diagnosis of psychotic disorders in Morocco. Method Twenty-nine patients from Casablanca, Morocco, with a psychotic or mood disorder were examined using the Comprehensive Assessment of Symptoms and History (CASH) an adapted version using cultural formulation to make the instrument more culturally sensitive (CASH-CS). Chance corrected agreement was calculated between diagnoses based on these two versions of CASH and independent clinical diagnoses according to local psychiatrists. Results Agreement for traditional CASH versus clinical diagnosis and for CASH versus CASH-CS was low (kappa = -0.19; SD 0.16 and kappa = 0.21; SD 0.16, respectively). De CASH-CS, showed good agreement with clinical diagnosis (kappa = 0.79; SD 0.11). Conclusion Standardized instruments for the assessment of psychosis such as the CASH may be liable to cultural misinterpretations. This may be relevant to the interpretation of the high incidence rates of schizophrenia among immigrants. Significant outcomes Agreement between a culturally naive version of a standardized diagnostic instrument for the assessment of psychosis and clinical diagnosis by Moroccan psychiatrists is poor. Adding additional probes and decision rules based on cultural formulation improves agreement with clinical diagnosis significantly. Limitations The study was conducted in a small sample. Both versions of CASH were administered by the same interviewer in a single interview session

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background Accurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundAccurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios. MethodsTo estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline. FindingsDuring the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction. InterpretationFertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world. FundingBill & Melinda Gates Foundation

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundAccurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios.MethodsTo estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline.FindingsDuring the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction.InterpretationFertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world.</p