Framework Of Research Program Research Articles

The Association between Long-Term DDT or DDE Exposures and an Altered Sperm Epigenome-a Cross-Sectional Study of Greenlandic Inuit and South African VhaVenda Men.

The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the Arctic, where its endocrine disrupting metabolite, -dichlorodiphenyldichloroethylene (-DDE) accumulates in marine mammals and fish. DDT and -DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come via the heritable sperm epigenome. The objective of this study was to assess the sperm epigenome in relation to -DDE serum levels between geographically diverse populations. In the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men and selected 50 paired blood serum and semen samples, and 47 Greenlandic Inuit blood and semen paired samples were selected from a total of 193 samples from the biobank of the INUENDO cohort, an EU Fifth Framework Programme Research and Development project. Sample selection was based on obtaining a range of -DDE serum levels (). We assessed the sperm epigenome in relation to serum -DDE levels using MethylC-Capture-sequencing (MCC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. Differences in DNAme and H3K4me3 enrichment were identified at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with sperm DNAme and H3K4me3 that differed between exposure groups was predicted to persist in the preimplantation embryo and to be associated with embryonic gene expression. These findings suggest that DDT and -DDE exposure impacts the sperm epigenome in a dose-response-like manner and may negatively impact the health of future generations through epigenetic mechanisms. Confounding factors, such as other environmental exposures, genetic diversity, and selection bias, cannot be ruled out. https://doi.org/10.1289/EHP12013.

3.D. Round table: Cancer Epidemiology and Prevention: which opportunities from the EU Cancer Mission?

Abstract While Europe accounts for a tenth of the world's population, it holds a quarter of the world's cancer cases. In the current scenario that see an increase in the proportion of elderly population in the EU, lives lost to cancer in the EU are set to increase by more than 24% by 2035, making it the leading cause of death in the EU. The overall economic impact of cancer in Europe is estimated to exceed €100 billion annually. Moreover, the COVID-19 pandemic has severely impacted cancer care, disrupting prevention and treatment, delaying diagnosis and vaccination, and affecting access to medicines. Since the pandemic began, the number of cancer diagnoses has decreased, foreshadowing a future increase in cases. In response to such challenges, the Europe's Beating Cancer Plan (EBPC) published in 2021 reflects a political commitment to leave no stone unturned to take action against cancer. In the EBPC, there is a renewed commitment to invest in cancer prevention, treatment and care that recognises the growing challenges, and opportunities to overcome them, including the developments in cancer care. In order to implement the EBPC the European Commission will use all the related funding instruments of the Horizon Europe Framework Programme for Research and Innovation (2021-2027) and it will be constantly guided from the experts of the Mission Board of Cancer. By establishing specific goals together with funding, the EU ensures the involvement of the Member States in tackling risk factors that are common to most non-communicable diseases. Simultaneously, there is a clear step towards health equity by collecting data stratified by equity-relevant attributes such as education or income. On another level, the focus on cancer might trigger new effective outcome-based payment models for personalised medicine, as well as better collection of data needed for a value-based approach on the effectiveness of health care. In the round table the panellists will discuss the opportunities and challenges of the EBCP implementation with the President of the Cancer Mission Board Walter Ricciardi, by addressing the epidemiological scenario of cancer disease in Europe and the related economic burden (Joao Vasco Santos), the role of the Comprehensive Cancer Control Networks and related Joint Action (Tit Albreht), and the readiness of the health services (Johan Hansen). Key messages • The implementation of the Europe's Beating Cancer Plan requires coordinated efforts among stakeholders with a clear leadership from Public Health Professionals. • Many externalities can be achieved through the EBCP as cancer has same determinants of most of the non-communicable diseases. Speakers/Panelists Walter Ricciardi Catholic University of the Sacred Heart Rome, Rome, Italy Tit Albreht National Institute of Public Health, Ljubljana, Slovenia João Vasco Santos EUPHA-ECO Johan Hansen EUPHA-HSR

Copernicus for urban resilience in Europe

The urban community faces a significant obstacle in effectively utilising Earth Observation (EO) intelligence, particularly the Copernicus EO program of the European Union, to address the multifaceted aspects of urban sustainability and bolster urban resilience in the face of climate change challenges. In this context, here we present the efforts of the CURE project, which received funding under the European Union’s Horizon 2020 Research and Innovation Framework Programme, to leverage the Copernicus Core Services (CCS) in supporting urban resilience. CURE provides spatially disaggregated environmental intelligence at a local scale, demonstrating that CCS can facilitate urban planning and management strategies to improve the resilience of cities. With a strong emphasis on stakeholder engagement, CURE has identified eleven cross-cutting applications between CCS that correspond to the major dimensions of urban sustainability and align with user needs. These applications have been integrated into a cloud-based platform known as DIAS (Data and Information Access Services), which is capable of delivering reliable, usable and relevant intelligence to support the development of downstream services towards enhancing resilience planning of cities throughout Europe.

Morocco and Tunisia on the Shores of Mare Nostrum: Positive Differentiation Across the Mediterranean and Segmentation in the European Union Research Policy

The European Research Area and Framework Programme 7 represents a conducive means for positive differentiation beyond the borders of the EU. The article aims to identify the ERA’s differentiated integration and segmentation swatches by concentrating on the closely-tied neighbouring countries of Morocco and Tunisia. The thematic distinction of the Mediterranean represents positive differentiation that surpasses EU territory. It occurs based on the thematic priorities co-decided by key EU institutions and articulated by the European Commission in annual work programmes. Segmentation in research across the Mediterranean area is a centrally-steered process incentivised by the European Commission through open calls for project applications. Process tracing allows for even more nuanced thematic steering patterns to be explored. A content analysis of open calls with a specific focus on the annual work programmes demonstrates the important role played by the fact that Morocco and Tunisia correspond to the country category of “(African) Mediterranean Partner Countries”. This geographical position offers preferential treatment to participate in several project applications explicitly inviting geographical focus on the Mediterranean area and/or partnerships with a Mediterranean membership.

Security knowledges: circulation, control, and responsible research and innovation in EU border management

ABSTRACT The knowledge emerging from research funded by the European Union (EU) through its Framework Programmes for Research and Innovation and other funding streams is significantly shaped by different forms of epistemic control exerted by the EU itself. Through the promotion of industry-research-policy cooperation in EU-funded research, and in light of the growing importance attached to ‘impact,’ this knowledge will often contribute to bureaucratic decisions taken by the European Commission, Frontex, the EU Agency for the Operational Management of Large-Scale IT Systems (eu-LISA), and other agencies tasked with border security and control. The circular dynamics surrounding knowledge production, from the calls for proposals to the results of the research, are intrinsically political and contribute to exposing the limits of the EU-promoted principle of Responsible Research and Innovation. Additionally, and due to the centrality of EU funding in the research outlook in contemporary Europe, these processes raise wider questions about the sociology of the academic fields that this article relates to: critical border studies, critical security studies, and science and technology studies. How can we interpret the interplays between the EU’s policies fostering development and integration of border security technologies, on the one hand, and the Union’s broader principles for free and open research and innovation? Through the use of autoethnographic vignettes, and mediated by an expanded Foucauldian understanding of circulation as a technology of control with performative effects, the article sheds light on the dynamics surrounding knowledge production in the field of border technologies in an EU context.

Spatial Heterogeneity in the Distribution of European Research and Development Funds and its Effects on Territorial Cohesion

The latest research and development (R&D) framework programmes of the European Union (EU), “Horizon 2020” and “Horizon Europe”, have significantly increased the resources available to promote science and innovation in Europe. However, the strong competitiveness of the research teams and their search for excellence may cause inequality in the spatial distribution of investment effort in R&D. The aim of this paper is to analyse the geographic distribution of R&D spending in the EU. A greater concentration of funds is observed in the most advanced and dynamic economies, capable of promoting more competitive research teams and projects. Through an empirical analysis, estimated by a spatial convergence model, it is found that EU R&D funds are preventing cross-regional convergence in Europe by driving growth mainly in wealthier regions. Based on these results, it seems relevant to consider spatial correction mechanisms for the distribution of R&D resources so that they achieve greater territorial cohesion in Europe.

Clustering networked funded European research activities through rank-size laws.

This paper treats a well-established public evaluation problem, which is the analysis of the funded research projects. We specifically deal with the collection of the research actions funded by the European Union over the 7th Framework Programme for Research and Technological Development and Horizon 2020. The reference period is 2007-2020. The study is developed through three methodological steps. First, we consider the networked scientific institutions by stating a link between two organizations when they are partners in the same funded project. In doing so, we build yearly complex networks. We compute four nodal centrality measures with relevant, informative content for each of them. Second, we implement a rank-size procedure on each network and each centrality measure by testing four meaningful classes of parametric curves to fit the ranked data. At the end of such a step, we derive the best fit curve and the calibrated parameters. Third, we perform a clustering procedure based on the best-fit curves of the ranked data for identifying regularities and deviations among years of research and scientific institutions. The joint employment of the three methodological approaches allows a clear view of the research activity in Europe in recent years.

Adaptation of a Scientific Decision Support System to the Productive Sector—A Case Study: MOPECO Irrigation Scheduling Model for Annual Crops

Despite the great number of models developed in research projects, only a small percentage have been successfully transferred to the productive sector. The PRIMA programme supported by Horizon 2020, the European Union Framework Programme for Research and Innovation, aims to reverse this situation. The SUPROMED project funded by PRIMA sought to develop an online platform composed of several models adapted to the requirements of end users for increasing the economic and environmental sustainability of Mediterranean agricultural systems. MOPECO, in its research version, was designed to maximize the profitability of irrigated farms in water-scarce regions. A simplified version of this model (MOPECO irrigation scheduling) was included in the SUPROMED platform for improving irrigation efficiency, providing farmers with a useful irrigation scheduling software. This paper shows the approach to adapt and transfer MOPECO to the productive sector. The tool was validated in three different demosite areas across the Mediterranean, involving local stakeholders in the design, validation, and dissemination of the software. The simplified tool reached similar or higher yields than farmers using less water. Thus, the average water saved was around 16%, while the average yield increased around 10% in the plots located in the three demosites of the project (Eastern Mancha in Spain, Bekaa valley in Lebanon, and Sidi Bouzid in Tunisia). This fact decreased the water footprint and increased the profitability of farms. The high applicability of the tool has generated interest among many technicians, farmers, and advisory enterprises. Furthermore, regional and national governmental extension services have shown interest in spreading the use of the tool across their territories, validating the methodology used for adapting and transferring a scientific model to the productive sector.

Social labs as good practice for transdisciplinary engagement processes in research and innovation

This article discusses a ‘Social Lab process’ applied in the field of research and innovation as good practice for transdisciplinary processes, and elaborates upon the structure and dynamics of these processes. It sheds light on how engagement processes could be set up for a more inclusive and participant-friendly atmosphere, allowing for meaningful and sustainable outcomes. Supported by data from a qualitative analysis of 19 Social Lab experiences according to the thematic programmes of the European Commission Horizon 2020 research framework programme, this article outlines requirements that need to be taken into account when implementing a transdisciplinary process in a Social Lab. Based on the concept of transdisciplinary research and the experience of this one-and-a-half-year process, the elements of participatory approaches required for successful implementation of a Social Lab, starting with inviting participants to develop small implementation projects (pilot activities) are described. The qualitative analysis of the process documentations highlights the importance of a clear definition of the framework and purpose of the process. Concrete assignments of the lab teams and roles, and the implementation of pilot activities, further proved crucial for successful and sustainable results. On this basis, recommendations for a fruitful participatory process are formulated.

A relations-based evaluation framework to support collaborative research and innovation (R&I) networks

The majority of the projects funded under the European Research Framework Programme (FP) require a collaborative effort in order to tackle complex societal challenges. The underlying assumption is that collaborative networks boost research productivity and the attainment of the goals set out by the European Commission's agenda. In general, the production of scientific knowledge increasingly takes place within networks and consortia with a wide diversity and interlinkages of disciplines, expertise, backgrounds and approaches. This relational dimension has become even more important in the Horizon Europe FP, which has moved from a project-focused to a mission-oriented approach whereby a portfolio of projects is managed in coordination in order to stimulate cross-learning and experimentation. Starting from key concepts and theories of evaluation research, including ten years of experience for the Italian National Research Council (CNR) team as an internal evaluator, we are proposing a new approach, namely a Relations-based Evaluation (RE) approach, that analyses, assesses and builds relationships, both internal and external, with the ultimate aim of supporting collaborative research and innovation (R&I) projects. The framework originated within the context of EU projects and deals with the specific case of consortia funded under the EU FPs. However, it could be easily applied to other types of research consortia and project networks with similar features.

The role of stakeholder involvement in EU research and innovation policy: a case study of Technology Platform Organics

This paper analyses the importance that participatory approaches may play in shaping the innovation policy in the context of the EU research framework programme. The paper reports case study research on the role of “TP Organics”, a European Technology Platform (ETP) that supports research and innovation in organic farming in the EU. The case study is based on data concerning the relevance of resources pertaining to organic farming in the EU’s most recent framework programmes for research and development (FP7 and Horizon 2020). We use process tracing to analyse the causal effects of the participatory approach used by TP Organics in defining policies and promoting funding for the organic sector. Data concerning textual content analysis on research calls and budget disaggregation for EU research funding are used to test the hypothesis that the engagement of stakeholders provides substantial effects in terms of the number of research projects explicitly oriented to organic farming and the amount of research funding made available. Results refer to the outcomes of a structured testing sequence for the key hypotheses supporting the causal model. They show that the impact of TP Organics relies on its successful multi-stakeholder participatory processes, which have improved the relevance of research themes related to organic farming and have ultimately yielded an increase in financed research projects and financial contributions to research on organic farming in the EU. Conclusions provide some theoretical generalisations on the importance of stakeholder engagement in successfully lobbying for research policy.

Oral minocycline plus rifampicin versus oral linezolid for complicated skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus: the AIDA open label, randomized, controlled Phase 4 trial

The need for oral, cost-effective treatment for complicated skin and skin structure infections (cSSSIs) due to methicillin-resistant Staphylococcus aureus (MRSA) was addressed by the non-inferiority comparisons of oral minocycline plus rifampicin with linezolid. In the AIDA multicenter, open label, randomized, controlled clinical trial, hospitalized adults with cSSSI and documented MRSA were randomly assigned at a 2:1 ratio to either oral 600mg rifampicin qd plus 100mg minocycline bid or oral 600mg linezolid bid for 10 days. The primary endpoint was the clinical cure rate in the clinically evaluable (CE) population at the test-of-cure visit (14 days). Non-inferiority was confirmed if the lower confidence limit (CI) did not fall below the accepted error margin of 15%. The study is registered with EudraCT number 2014-001276-56. 123 patients recruited between November 2014 and January 2017 were randomly assigned to treatment (81 patients to minocycline plus rifampicin and 42 patients to linezolid). Cure rates were 78.% (46/59, 90% CI 67.3-86.5) and 68.6% (24/35, 90% CI 53.4-81.3), respectively (P=0.337). The percent difference in cure rates was 9.4% (90% CI-7.2 to 26.8%). Minocycline plus rifampicin combination was deemed non-inferior to linezolid as the lower CI was-7.2% i.e. smaller than the accepted error margin of-15%. Although statistically not significant, the overall rate of adverse events was higher in the linezolid group (47.6%, 20/42 versus 38.3%, 31/81). Oral minocycline plus rifampicin was non-inferior to oral linezolid treatment providing alternative oral treatment for cSSSI. The EU Seventh Research Framework Programme.

Stop re-inventing the wheel: or how ELSA and RRI can align

ABSTRACT Ethical, Legal and Social Aspects (ELSA) originated in the 4th European Research Framework Programme (1994) and responsible research and innovation (RRI) from the EC research agenda in 2010. ELSA has received renewed attention in European funding schemes and research. This raises the question of how these two approaches to social responsibility relate to one another and if there is the possibility to align. There is a need to evaluate the relationship/overlap between ELSA and RRI because there is a possibility that new ELSA research will reinvent the wheel if it does not engage with the body of literature already present in RRI research. This provides unneeded extra bureaucracy, reformulations of research agendas, extra investment, and an overabundance of frameworks to implement, and ELSA research does not take advantage of the body of research developed in RRI. This paper evaluates how ELSA and RRI diverge, are complementary, and can be aligned.

A Review of Project Management Practices in EU-funded Horizon2020 Projects

The current global economy is extremely competitive and it requires an efficient funding of public projects, especially when it comes to research and development. Project Management (PM) practices are intended to increase such an efficiency. The objective of this work is to explore the usage of PM methodologies and practices in projects funded by the European Union as part of the “Horizon2020” research framework program from 2014 to 2020. To this end, this research uses of a survey-based data retrieval to investigate the level of perceived PM maturity in Horizon 2020 projects. The results show that Project Managers involved in Horizon 2020 projects hold a high level of PM maturity, especially in the areas of cost management, communication and stakeholders management thus confirming that PM standards, which are imposed by the EU commission as a binding process, are effectively enforced. In conclusion, this work extends the results to provide useful feedback, suggestions, and opportunities for improvement to be implemented in future programs.

Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative

Tracking progress and providing timely evidence is a fundamental step forward for countries to remain aligned with the targets set by WHO to eliminate cervical cancer as a public health problem (ie, to reduce the incidence of the disease below a threshold of 4 cases per 100 000 women-years). We aimed to assess the extent of global inequalities in cervical cancer incidence and mortality, based on The Global Cancer Observatory (GLOBOCAN) 2020 estimates, including geographical and socioeconomic development, and temporal aspects. For this analysis, we used the GLOBOCAN 2020 database to estimate the age-specific and age-standardised incidence and mortality rates of cervical cancer per 100 000 women-years for 185 countries or territories aggregated across the 20 UN-defined world regions, and by four-tier levels of the Human Development Index (HDI). Time trends (1988-2017) in incidence were extracted from the Cancer Incidence in Five Continents (CI5) plus database. Mortality estimates were obtained using the most recent national vital registration data from WHO. Globally in 2020, there were an estimated 604 127 cervical cancer cases and 341 831 deaths, with a corresponding age-standardised incidence of 13·3 cases per 100 000 women-years (95% CI 13·3-13·3) and mortality rate of 7·2 deaths per 100 000 women-years (95% CI 7·2-7·3). Cervical cancer incidence ranged from 2·2 (1·9-2·4) in Iraq to 84·6 (74·8-94·3) in Eswatini. Mortality rates ranged from 1·0 (0·8-1·2) in Switzerland to 55·7 (47·7-63·7) in Eswatini. Age-standardised incidence was highest in Malawi (67·9 [95% CI 65·7 -70·1]) and Zambia (65·5 [63·0-67·9]) in Africa, Bolivia (36·6 [35·0-38·2]) and Paraguay (34·1 [32·1-36·1]) in Latin America, Maldives (24·5 [17·0-32·0]) and Indonesia (24·4 [24·2-24·7]) in Asia, and Fiji (29·8 [24·7-35·0]) and Papua New Guinea (29·2 [27·3-31·0]) in Melanesia. A clear socioeconomic gradient exists in cervical cancer, with decreasing rates as HDI increased. Incidence was three times higher in countries with low HDI than countries with very high HDI, whereas mortality rates were six times higher in low HDI countries versus very high HDI countries. In 2020 estimates, a general decline in incidence was observed in most countries of the world with representative trend data, with incidence becoming stable at relatively low levels around 2005 in several high-income countries. By contrast, in the same period incidence increased in some countries in eastern Africa and eastern Europe. We observed different patterns of age-specific incidence between countries with well developed population-based screening and treatment services (eg, Sweden, Australia, and the UK) and countries with insufficient and opportunistic services (eg, Colombia, India, and Uganda). The burden of cervical cancer remains high in many parts of the world, and in most countries, the incidence and mortality of the disease remain much higher than the threshold set by the WHO initiative on cervical cancer elimination. We identified substantial geographical and socioeconomic inequalities in cervical cancer globally, with a clear gradient of increasing rates for countries with lower levels of human development. Our study provides timely evidence and impetus for future strategies that prioritise and accelerate progress towards the WHO elimination targets and, in so doing, address the marked variations in the global cervical cancer landscape today. French Institut National du Cancer, Horizon 2020 Framework Programme for Research and Innovation of the European Commission; and EU4Health Programme.

Challenges of ubiquitous and wearable solutions to address active ageing in the Andalusian community

Active ageing is a multidimensional process for achieving the potential quality of life and meaning in the life cycle. In the context of the Andalusian region in Spain, where the majority of the population is over 60 years old and lives in rural areas, it has become a key challenge. That is why the European projects within the Framework Programme for Research and Innovation, such as Pharaon - Pilots for Active and Healthy Ageing, promote technologies adapted by and for our elders. In the case of the Andalusian pilot, part of this project, we have selected a social network adapted to them, enabling them to communicate with the community at home and share their experiences. In addition, to improve their physical fitness, a device to count active minutes and steps is included, which provides users and caregivers with a visible and objective metric of daily health status. The technology has been evaluated following a well-defined methodology, which is described in this work to promote the deployment of technology in large-scale pilots. A specific architecture (Information System for Active Ageing in Andalusia - ISA3) and the components evaluated within a common ecosystem (Pharaon Project) are presented.

План за джендър равенство в научните изследвания – ново изискване на Рамковата програма „Хоризонт Европа“

In the research sphere, gender equality is among the core values, criteria and principles for building the new European Research Area. The European Union is constantly concerned with putting this principle into practice by ensuring equal opportunities for women and men and eliminating existing imbalances and distinctions. To this end, a new requirement is introduced for submitting validated gender equality plans in organisations applying for projects under the current Horizon Europe Framework Programme for Research and Innovation covering 2021-2027. This study aims to: (a) outline the fulfilment of this criterion for participation in the programme by academic institutions in Bulgaria; (b) assess the conformity of the planned areas of intervention with the current state of gender differences in research in Bulgaria; (c) raise the awareness and sensitivity of academic staff to this issue given current European regulations.

Social sciences and humanities research funded under the European Union Sixth Framework Programme (2002–2006): a long-term assessment of projects, acknowledgements and publications

The Framework Programmes for Research and Technological Development are funding programmes created by the European Union to support and foster research. This study aims to describe the features and assess the performance of Social Sciences and Humanities research projects funded under the Sixth Framework Programme that was active between 2002 and 2006. The results show that most funded projects were in the fields of economics and political sciences, in line with the use of the Framework Programme to enhance economic development and the integration process in Europe. Research teams showed a high level of collaboration with an average of 7.8 countries and 10.8 institutions involved in each project. However, the large size and diversity of consortia did not translate into a large number of co-authored scholarly journal articles. The results show that research funds in the Social Sciences and Humanities may have long-term effects, with some outputs acknowledging funding being published more than a decade after the end of the project. Qualitative analysis of the acknowledgements in the articles revealed four types of support: direct funding; utilisation of results from former funded projects as the basis for further research; involvement in conferences and networks resulting from funded projects; and utilisation of datasets or other products resulting from former funded projects. The study also illustrates the difficulties in retrieving the outputs resulting from funded projects since the funding information in Scopus is heterogeneous and not standardised. As a result, the type of assessment conducted in this project is time-consuming and requires a significant amount of manpower to clean and standardise the data. Nevertheless, the procedure could be applied to analyse the performance of subsequent European Framework Programmes in building a European Research Area in the Social Sciences and Humanities.

Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial

Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies. EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667. Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]). Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma. The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Widespread exposure to Crimean-Congo haemorrhagic fever in Uganda might be driven by transmission from Rhipicephalus ticks: Evidence from cross-sectional and modelling studies

Crimean-Congo haemorrhagic fever (CCHF) is a widespread tick-borne viral infection, present across Africa and Eurasia, which might pose a cryptic public health problem in Uganda. We aimed to understand the magnitude and distribution of CCHF risk in humans, livestock and ticks across Uganda by synthesising epidemiological (cross-sectional) and ecological (modelling) studies. We conducted a cross-sectional study at three urban abattoirs receiving cattle from across Uganda. We sampled humans (n=478), livestock (n=419) and ticks (n=1065) and used commercially-available kits to detect human and livestock CCHF virus (CCHFV) antibodies and antigen in tick pools. We developed boosted regression tree models to evaluate the correlates and geographical distribution of expected tick and wildlife hosts, and of human CCHF exposures, drawing on continent-wide data. The cross-sectional study found CCHFV IgG/IgM seroprevalence in humans of 10·3% (7·8-13·3), with antibody detection positively associated with reported history of tick bite (age-adjusted odds ratio=2·09 (1·09-3·98)). Cattle had a seroprevalence of 69·7% (65·1-73·4). Only one Hyalomma tick (CCHFV-negative) was found. However, CCHFV antigen was detected in Rhipicephalus (5·9% of 304 pools) and Amblyomma (2·9% of 34 pools) species. Modelling predicted high human CCHF risk across much of Uganda, low environmental suitability for Hyalomma, and high suitability for Rhipicephalus and Amblyomma. Our epidemiological and ecological studies provide complementary evidence that CCHF exposure risk is widespread across Uganda. We challenge the idea that Hyalomma ticks are consistently the principal reservoir and vector for CCHFV, and postulate that Rhipicephalus might be important for CCHFV transmission in Uganda, due to high frequency of infected ticks and predicted environmental suitability. UCL Global Challenges Research Fund (GCRF) and Pan-African Network on Emerging and Re-Emerging Infections (PANDORA-ID-NET) funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) under the EU Horizon 2020 Framework Programme for Research and Innovation.