Financing and Reimbursement of Approved Advanced Therapies in Several European Countries

Advanced medicinal products; Financing government; Health technology assessmentMedicamentos avanzados; Financiación del gobierno; Evaluación de tecnologías sanitariasMedicaments avançats; Finançament del govern; Avaluació de tecnologies sanitàriesObjectives The uncertainty in the cost-benefit of advanced therapy medicinal products (ATMPs) is a current challenge for their reimbursement in health systems. This study aimed to provide a comparative analysis of the National Health Authorities (NHAs) reimbursement recommendations issued in different European countries. Methods The NHA reimbursement recommendations for the approved ATMPs were compared among 8 European Union (EU) Countries (EU8: Ireland, England/Wales, Scotland, The Netherlands, France, Germany, Spain, and Italy). The search was carried out until December 31, 2021. Results A total of 19 approved ATMPs and 76 appraisal reports were analyzed. The majority of the ATMPs were reimbursed, although with uncertainty in added therapeutic value. No relationship between the type of the European Medicines Agency approval and reimbursement was found. Managed entry agreements, such as payment by results, were necessary to ensure market access. The main issue during the evaluation was to base the cost-effectiveness analyses on assumptions because of the limited long-term data. The estimated incremental cost-effectiveness ratio among countries reveals high variability. Overall, the median time to NHA recommendation for the EU8 is in the range of 9 to 17 months. Conclusions Transparent, harmonized, and systematic assessments across the EU NHAs in terms of cost-effectiveness, added therapeutic value, and grade of innovativeness are needed. This could lead to a more aligned access, increasing the EU market attractiveness and raising public fairness in terms of patient access and pricing

Severe Accident Investigations for VVER-Reactors including Radiological Impact and Quantification of Uncertainties

Sicherheitsbedenken hinsichtlich der Minderung potenzieller Auswirkungen einer möglichen Freisetzung von Source Term (ST) auf die Bevölkerung und die Umwelt werden nach den Folgen des Unfalls von Tschernobyl und Fukushima verstärkt. Studien zu schweren Unfällen werden von Aufsichtsbehörden unter Verwendung deterministischer und integraler Tools durchgeführt, um den Unfallverlauf und ST vorherzusagen sowie die radiologischen Auswirkungen einer solchen Freisetzung zu bewerten, um Notfallmanagementpläne zu entwickeln und Notfallteams mit der bestmöglichen, zuverlässigen und zuverlässigen Unterstützung zu unterstützen schnelle Auskunft. In dieser Dissertation wird eine Plattform des integralen Schwere-Unfall-Tools ASTECAtmosphären dispersions- und Entscheidungsunterstützungssystem JRODOs verwendet, um den Transport und die Freisetzung des ST während eines schweren Unfalls sowie die möglichen Folgen eines solchen ST-Inventars für die Umwelt vorherzusagen, ausgehend von der Berechnung des Spaltproduktinventars unter Verwendung von KORIGEN in VVER-1000. Außerdem werden die Unsicherheitsquantifizierung und Sensitivitätsanalyse (U&S) mit dem KATUSA-Tool durchgeführt. Mit diesem Ziel werden physikalische Modelle des ASTEC-Codes zur Simulation der Schiffsphase eines schweren Unfalls validiert, indem eine VVER-ähnliche Geometrie von QUENCH-12-Experimentdaten verwendet wird. Die Vorhersagen des ASTEC-Codes werden mit Versuchsergebnissen verglichen, und physikalische Modelle, die die wichtigsten Schlüsselphänomene des Unfallverlaufs wie Oxidation, Wärmeübertragung und Wachstum von Oxidablagerungen beschreiben, sind gut geeignet, um den Unfallverlauf zu demonstrieren. Obwohl das Wasserstofferzeugungsprofil vollständig von ASTEC erfasst wird, sind die Modelle in der Lage, eine ähnliche Wasserstoffmenge bis zur Abschreckphase vorherzusagen. Die Unterschätzung der Wasserstoffproduktion während der Abschreckphase wird durch fehlende thermische Eigenschaften von VVERverwandtem Material verursacht. Das umfangreiche Modell von VVER-1000 wird von ASTEC modelliert, einschließlich aller primären und sekundären Kreislaufkomponenten, Sicherheitsräume und aktiven und passiven Sicherheitssysteme nach der Validierung, um den Verlauf schwerer Unfallszenarien und die Freisetzung von FPs in die Umwelt simulieren zu können. Risikorelevante Szenarien, die zu Kernschäden und ST-Freisetzung führen, werden ermittelt und Large Break Loss of Coolant Accident (LBLOCA) auf Cold- und Hot-Leg zeitgleich mit Station Blackout (SBO) bis zum Reißen der Kavität simuliert. Nach der ASTEC-Simulation wird eine JRODOS-Analyse für ausgewählte Standorte mit ausgewählter Jahreszeit durchgeführt, um die Ausbreitung des radiologischen Inventars in die Umwelt zu beobachten. Schließlich wird das KATUSA-Tool verwendet, um Unsicherheiten zu quantifizieren und die empfindlichsten Variablen innerhalb der ausgewählten Parameter zu bestimmen. Nach den Ergebnissen der genannten schweren Unfallfolgen lassen sich folgende Befunde auflisten: • Die erzeugte Wasserstoffmasse beträgt etwa 790 kg, wenn sich die Unterbrechung auf dem kalten Abschnitt befindet. Die höhere Wasserstoffmasse, 1270 kg, entsteht im Bruchfall auf dem heißen Strang aufgrund des langsameren Fortschreitens des schweren Unfalls. • Die an die Umgebung abgegebene Aktivität beträgt etwa 1.2x1018 Bq am Ende der Simulation im Fall von LBLOCA auf der kalten Strecke. Die Retentionswerte sind aufgrund der Retention an den Wänden von Dampferzeugern signifikant hoch. • Im Gegensatz dazu werden 7.0x1018 Bq Aktivität freigesetzt, wenn sich der Bruch auf dem heißen Bein befindet, da der Weg zum Containment deutlich kürzer ist als der eine Bruch auf dem Fall des kalten Beins. • Die JRODOS-Analyse zeigt, dass die Kontamination etwa 22.9 MBq/km2 erreicht, was zu einer jährlichen effektiven Dosis von 1.38x103 mSv für einen Erwachsenen aus allen Pfaden mit der vorhergesagten ST für den Fall von LBLOCA auf kaltem Bein führt. • Höhere ST-Vorhersage im Fall von LBLOCA auf Hot Leg-Ergebnissen mit 11.5 GBq/km2 Aerosolablagerung und 1.75x105 mSv jährlicher effektiver Dosis für einen Erwachsenen. • Die durchgeführte KATUSA-Analyse zeigt, dass die maximale Dosisvorhersage etwa 2.9x1018 Bq für kalte Beinbrüche und 1.30x1019 Bq für heiße Beinbrüche beträgt. In beiden Fällen ist der Formfaktor relativ zur Stokes-Geschwindigkeit der dominierende Faktor für die Ergebnisse, dass die Änderung das gravitative Absetzen von Aerosolen beeinflusst. • Schließlich beträgt der Unterschied bei der Kontamination mit Cs-137-Isotopen etwa 3.2 MBq/km2 für das Kaltbeinbruchszenario, während dieser Unterschied im Falle eines Heißbeinbruchs etwa 0.5 TBq/km2beträgt, basierend auf der radiologischen Auswirkungsanalyse unter Verwendung Beste-Schätzung- und Schlimmsten-Fall-ST-Lagerbestände. Die Ergebnisse der Arbeit und der ASTEC-JRODOS-KATUSA-Plattform sind unerlässlich, um genaue, zuverlässige und schnelle Informationen über den Verlauf eines schweren Unfalls, mögliche radiologische Folgen und den Bereich der radiologischen Ausbreitung für jeden nuklearen Standort, jedes Unfallszenario und jede meteorologische Bedingung zu erhalten an die Aufsichtsbehörden und Teams für frühzeitige Reaktion, um Pläne für schwere Unfälle sowie effektive und effiziente Reaktionen auf die Unfälle zu entwickeln. Außerdem erweitert diese Dissertation die Fähigkeit, Folgen eines schweren Unfalls von der Einleitung des Ereignisses bis zur Ausbreitung von ST zu bewerten

MIM publication series volume 3. Standard directory record structure for organizations, individuals and their research interests

In this manual a standard directory record structure is proposed, for use in the preparation of databases of organizations, individuals and their research interests. The structure is designed to be, as far as is possible, independent of the software used. However it is anticipated that the main use will be with the Unesco Mini-micro CDS/ISIS software. Provision is made for additional fields for local needs

Beyond 'anti-smacking': Challenging violence and coercion in parent-child relations

This paper reviews contradictions between the increasing recognition that smacking is unnecessary and dangerous and its continuing prevalence and acceptability. Two underlying causes for this paradox are considered: the cultural system that constructs children as human becomings rather than human beings, and the power system that guarantees „parents‟ rights‟ over children‟s human rights. We highlight the lack of critical engagement with these issues by the anti-smacking lobby and outline the beginnings of an alternative approach

MEDIEAL ETHICS: Research Themes and Intellectual Base

The objective of this paper is to reflect the intellectual structure of the research field in medical ethics. Central research themes of both citing and cited doiuments were found to focus on issues concerning autonomy, ethics education, principles of ethics, medical research and life-death decisions. An additional number of themes with delimited foci were also identified. On the basis of the findings it was concluded that the objective of describing the intellectual structure of medical ethics was notreachedin terms of completenessT. he data consistedo f 477 bibliographic descriptionso f publications of Jourhal of Medical Ethics fuomthe period I993-2OOL and the bibiiometric methods used were cocitation analysis and bibliographic coupling. Additional bibliometric applications identified and extracted documents in the sample with a citation relationship to the same and analysed the co-occurrence of descriptor terms. General statistical techniques applied were multidimensional scaling and cluster analysis. Keywords: Bibliometrics; bibliogrtphic coupling; citation analysis; cocitation analysis ; medicai ethic

Survey of Health Effects among Residents Adjacent to a National Priority List Site in Ssouthwest Virginia.

The Saltville Waste Disposal Site is a National Priority List site used during the 77- year operation (1895–1972) of an electrolytic chlorine and caustic soda plant. A cross-sectional study was conducted to determine disease prevalence among Saltville Medical Center (SMC) patients. Diseases associated with chronic exposures to mercury, arsenic, and lead were reviewed in patient records and these data were analyzed. Ratios of illness observed at the SMC were compared to health studies of similar environmental exposures and disease prevalence among residents of neighboring communities. Prevalence ratios were calculated for residents and non-residents of Saltville who were SMC patients. Saltville residence accounted for a higher risk of developing the targeted diseases (odds ratio=1.68, 95% confidence interval (1.54, 1.82)). Increased risk was among patients aged 31-45 years; with a history of smoking; and family history of the same disease

Contribution of infrastructure to the township's sustainable development in Southwest China

Townships in Southwest China are usually located in mountainous regions, which are abundant in natural and cultural landscape resources. There are additional requirements for the township’s sustainable development in these areas. However, insufficient infrastructures, due to limited resources, constrain the sustainable development of these townships. Sustainable contribution of infrastructure (SCOI) in this study is defined as the performance of infrastructure as a contribution to the coordinated development among economic, social, and environmental dimensions of township’s sustainable development. It is necessary to assess these infrastructures according to SCOI and provide choices for investment to maximize resource utilization. Therefore, an assessing model of SCOI with 26 general indicators was developed, which covers five most urgently needed infrastructures of these townships in Southwest China, including road transport, sewage treatment, waste disposal, water supply, and gas. In this model, quantitative and qualitative methods are combined to acquire different SCOI of each infrastructure. The result of the SCOI would be an important reference for infrastructure investment. A case study of Jiansheng Town, that is located in the Dadukou district of Chongqing, demonstrates the applicability of the model. It shows the assessing model of SCOI is efficient to identify the most valuable infrastructure that is appropriate for investment with the goal of township’s sustainable development. This study can provide insights for infrastructure investment and management in townships or areas

Decoding malaria T-cell responses using adaptive immune receptor repertoire sequencing

Malaria continues to be a serious public health problem in many parts of the world, and progress in reducing the global malaria burden has stalled in recent years. Despite decades of research, current vaccine candidates have low efficacy, and major challenges in achieving long-lasting immune-mediated elimination of malaria remain. This is in part due to a lack of knowledge regarding how both clinical and anti-parasite immunity develops during a malaria infection. Epidemiologically, immunity to severe clinical disease develops after only a limited number of infections, whilst anti-parasite immunity requires years of repeat exposure. T-cells are known key functional mediators of the developing immune response during a first Plasmodium infection, undergoing extensive activation and splenic expansion during the acute phase. However aberrant T-cell responses have also been implicated in the pathogenesis of severe disease. The clonality and clonal composition of the T-cell response during a first malaria infection, and how this varies following repeat exposure, has not previously been described. Here, I have used T-cell receptor repertoire sequencing as a novel tool to address this knowledge gap. Firstly, I sequenced the splenic CD4+ T-cell receptor repertoires generated over the time-course of a murine P. chabaudi infection. Profiling the response using bulk TCRb repertoire sequencing, single-cell RNA-seq, and analyses of independent RNA-seq data, I determined that following a first infection - within a highly polyclonal expansion - murine T-effector repertoires are consistently dominated by a specific TCRb signature. This conserved T-cell response was consistently a hallmark of a first infection, but not expanded upon re-challenge. Determining the host or parasite factors driving this conserved response may uncover novel immune targets for malaria therapeutic purposes. Secondly, to resolve if similar dynamics occur in human P. falciparum infections, I sequenced the peripheral TCRb repertoires generated longitudinally over the time-course of a controlled human malaria infection model, including following re-challenge. No clonally expanded or conserved populations were evident in response to either a first or second P. falciparum infection. However, non-specific recruitment of established T-cell clones from the peripheral circulation was evident, a dynamic repeated in homologous re-challenge infections. Understanding the consequences of this non-specific trafficking, and whether or not it shapes an individual’s response to a Plasmodium infection, warrants further investigation. Overall, the results presented here demonstrate the utility of TCR repertoire sequencing when applied to antigenically complex infections and provide novel insights that deepen our understanding of the multifaceted immune response elicited by the parasite. Findings also set up a myriad of future research directions to address the question of how immune-mediated protection against malaria is achieved

Characteristics of female users of the female sterilization contraceptive method

Introduction: Female sterilization is a permanent contraceptive method, whose choice represents a transcendental decision in a woman's life, influenced by her context, and her personal qualities. Objective: To describe the characteristics of women users of the female sterilization contraceptive method. Methods: Descriptive study based on the Demographic and Family Health Survey of 2021. From the databases, 2 306 women between 20 and 49 years of age were selected as users of female sterilization, in which the sociodemographic, reproductive and method-specific characteristics were analyzed. Unweighted and weighted counts with 95% confidence intervals. Results: Regarding sociodemographic characteristics, 51% were aged 40 to 49 years, 87.9% were urban, 42.8% had secondary education and 11.4% were very poor. Regarding the reproductive profile, 61.7% have 3 to 4 children, 3.7% have been visited by health personnel to discuss family planning and 29.2% have a history of abortion. Regarding the characteristics related to the method, 5.7% were not informed that they could not have more children and 19.9% had had an abortion 2 to 3 years before. Conclusion: Most of the women are adults, well-educated and live in urban areas. In addition, they have 3 or more children and know that they cannot have more children after female sterilization