Framework Programme Research Articles

Dengue viremia kinetics and effects on platelet count and clinical outcomes: An analysis of 2340 patients from Vietnam.

Viremia is a critical factor in understanding the pathogenesis of dengue infection, but limited data exist on viremia kinetics. This study aimed to investigate the kinetics of viremia and its effects on subsequent platelet count, severe dengue, and plasma leakage. We pooled data from three studies conducted in Vietnam between 2000 and 2016, involving 2340 dengue patients with daily viremia measurements and platelet counts after symptom onset. Viremia kinetics were assessed using a random effects model that accounted for left-censored data. The effects of viremia on subsequent platelet count and clinical outcomes were examined using a landmark approach with a random effects model and logistic regression model with generalized estimating equations, respectively. The rate of viremia decline was derived from the model of viremia kinetics. Its effect on the clinical outcomes was assessed by logistic regression models. Viremia levels rapidly decreased following symptom onset, with variations observed depending on the infecting serotype. DENV-1 exhibited the highest mean viremia levels during the first 5-6 days, while DENV-4 demonstrated the shortest clearance time. Higher viremia levels were associated with decreased subsequent platelet counts from day 6 onwards. Elevated viremia levels on each illness day increased the risk of developing severe dengue and plasma leakage. However, the effect size decreased with later illness days. A more rapid decline in viremia is associated with a reduced risk of the clinical outcomes. This study provides comprehensive insights into viremia kinetics and its effect on subsequent platelet count and clinical outcomes in dengue patients. Our findings underscore the importance of measuring viremia levels during the early febrile phase for dengue studies and support the use of viremia kinetics as outcome for phase-2 dengue therapeutic trials. Wellcome Trust and European Union Seventh Framework Programme.

HYDROGEN POWER AND NOT ONLY: "PRO" AND "CONTRA"

The increase in global temperature caused by global climate warming is considered. Open data on Ukraine’s energy strategy until 2050, in particular on the production and use of natural gas and hydrogen, are provided. The results of the energy efficiency of the production of primary energy resources are presented, including main renewable energy sources. The relevance of the problem of production and use of hydrogen as a significant renewable source of reducing greenhouse emissions and increasing energy security is presented. The indicators and their critical indicators for the stability and stability of the terrestrial system of the socio-ecological state of the planet Earth are presented — the so-called planetary boundaries of sustainability, it is emphasized that not only climate change, but also the extinction of biodiversity is critical for life. In response to the latter, the main points of the Kunming-Montreal UN Global Framework Program until 2030 in the field of biodiversity are outlined, the main goal of which is to return the biosphere to recovery. Based on this year’s materials of the International Energy Agency, we will generally consider the global state of hydrogen issues from the point of view of the strategy for the development of production, distribution and final use of renewable hydrogen. Some environmental and energy characteristics of electrolytic hydrogen production are presented. Recommendations for the prospects of hydrogen use are given. Bibl. 34, Fig. 7, Tab. 2.

National Research and Innovation Policy the Case of Greece: A Benchmarking Exercise to Assist Evidence-Based Policies on Research, Innovation, and Technological Entrepreneurship

Greece has made considerable effort to develop and implement a concise research and innovation policy during the last decades aiming at a knowledge-intensive economy. New legal frameworks and funding schemes are introduced, funding increased, but evaluation of impact is implemented marginally. The landscape in the early 2020ies has little in common with that in the late 1970ies. The active participation of Greece to the European Union’s framework programs and the European institutions’ prioritization of research and innovation increased the impetus for the policy makers at national level and for an informed policy in this field. Nevertheless, the data are relentless in the demonstration of the effectiveness of the policies. Despite the efforts deployed, Greece continues to lag most European countries, pairing mostly with its neighbors. This proves a strong need for improvement of the efficiency and effectiveness of the policies. It shows that politicians and policy makers are ill prepared to face the new challenges in global competitiveness. Greece is not the only case in this position.

PROJECT ARCHETYPES OF THE EUROPEAN RESEARCH AREA: EXPLORING THE OCCASIONAL ENGAGEMENT PATTERNS OF THE EUROPEAN SOUTHERN NEIGHBOURHOOD

This paper examines the project-based pattern of European Southern Neighbourhood engagement in the European Research Area. Thereby, this study informs about the role of the European Research Area in advancing EU objectives and ambitions in the enduringly salient European Neighbourhood Policy context. The research question that drives this study is: What project archetypes’ pattern denotes the European Southern Neighbourhood’s participation in the pan-European space intended to facilitate the free flow of talent and ideas? The guiding hypothesis anticipates that the prevailing archetype corresponds to an encounter lasting for one project, and prolonged engagement throughout several consecutive projects is a rarity. This enquiry into the relationality weaved by research collaboration formulates four archetypes. The main empirical material employed to model and study the four archetypes is semi-structured interviews with Europe-based project managers. Insights offered by the leading figures of projects funded by Framework Programme 7 and Horizon 2020 reveal how multilateral research-driven ties contribute to post-Westphalian external action aspirations. Devised analytic narratives attest to the performances of the EU science diplomacy, for example, in the form of technoscientific gifts as well as sharing and jointly developing kn/own/ables. Expert experiences of co-developing research-intensive solutions with Morocco- and Tunisia-based colleagues to address the most pressing challenges faced by the EU and its Southern neighbours are resourceful. They offer new insights into the patterned routines that support the implementation of such supranationally steered governance frameworks as the European Research Area, including its external action and science diplomacy dimensions. Almost half of the studied projects correspond to the archetype with one EU-funded project interaction. This confirms the rather sporadic or ad hoc relational ties of the European Southern Neighbourhood to the European Research Area, facilitated by various Europe-based competence centres.

Anhedonia as a Potential Transdiagnostic Phenotype With Immune-Related Changes in Recent-Onset Mental Health Disorders

BackgroundChronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes, reflecting a potential transdiagnostic dimension. Previous investigations have focused on distinct illness categories in people with enduring illness, but few have explored inflammatory changes. We sought to identify an inflammatory signal and the associated brain function underlying anhedonia among young people with recent-onset psychosis and recent-onset depression. MethodsResting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from 108 (mean [SD] age = 26.2 [6.2] years; female = 50) participants with recent-onset psychosis (n = 53) and recent-onset depression (n = 55) from the European Union/Seventh Framework Programme–funded PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Time series were extracted using the Schaefer atlas, defining 100 cortical regions of interest. Using advanced multimodal machine learning, an inflammatory marker model and a functional connectivity model were developed to classify participants into an anhedonic group or a normal hedonic group. ResultsA repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic recent-onset psychosis/recent-onset depression groups with a balanced accuracy of 63.9% and an area under the curve of 0.61. The functional connectivity model produced a balanced accuracy of 55.2% and an area under the curve of 0.57. Anhedonic group assignment was driven by higher levels of interleukin 6, S100B, and interleukin 1 receptor antagonist and lower levels of interferon gamma, in addition to connectivity within the precuneus and posterior cingulate. ConclusionsWe identified a potential transdiagnostic anhedonic subtype that was accounted for by an inflammatory profile and functional connectivity. Results have implications for anhedonia as an emerging transdiagnostic target across emerging mental disorders.

HiPSC-derived cardiomyocyte cultivation and measurement of electrophysiological properties on gelatine/glucose/polypyrrole scaffold

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Horizon 2020 Framework Programme (H2020) under Grant agreements No. 953138 (EMAPS-Cardio) Purpose Cardiotoxicity is one of the main side effects limiting development of new medicines and resulting in withdrawal of drugs from the market. There are different mechanisms of drug-induced cardiotoxicity, including arrhythmia, disruption of mitochondria function, apoptosis, altered growth factor signalling [1]. Heart on a chip model for drug testing seems attractive approach to evaluate the possible cardiotoxic effects on cell biological, but mostly electrophysiological properties. Our aim was to create a 3D system with a biocompatible scaffold, coated with a conductive layer, suitable for culturing and maturation of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) and compatible with electrophysiology parameter measurement techniques. Methods Elastic scaffold was fabricated by electrospinning of gelatin-glucose microfibers followed by the vapor-phase and electrochemical deposition of conductive polymer polypyrrole (PPy) to create electroconductive layer. hiPSC-CMs at different maturation levels (at 6 vs 14 weeks) were used to test biocompatibility of the scaffold. To increase cell attachment, scaffold was treated with 0.1 M HCl and coated with Geltrex. Cells were stained with fluorescent dyes (Calcein AM, DAPI). Electrophysiological properties were analysed using intracellular calcium imaging (Cal520) and action potential recordings with sharp electrodes. HiPSC-CMs on coverslips were used as a 2D control. Results Calcein AM staining showed that high number of hiPSC-CMs attached to gelatine/glucose/PPy scaffold proving that the scaffold is biocompatible and cells remain viable even after long term incubation (> 2 weeks). HiPSC-CMs at lower maturity (6 weeks) had better attachment properties to it, indicating that more mature cardiomyocytes (14 weeks) gradually lose their capacity to attach to PPy surface. Intracellular calcium imaging showed that both types of cells generated synchronous spontaneous calcium oscillations on gelatine/glucose/PPy scaffolds. Action potential recordings in 3D were similar to those in 2D, and confirmed differences in hiPSC-CMs maturation levels – at lower maturation level hiPSC-CMs had lower upstroke velocity as compared to more matured hiPSC-CMs. Conclusions Gelatine/glucose/PPy scaffold is biocompatible for hiPSC-CMs cultivation, and suitable for evaluation of cardiomyocyte electrophysiological properties. Such electromechanoactive scaffold can be further employed for development of heart-on-a-chip model.

Placental structural adaptation to maternal physical activity and sedentary behavior: findings of the DALI lifestyle study.

Are maternal levels of moderate-to-vigorous physical activity (MVPA) and sedentary time (ST) in obese pregnant women associated with placental structural adaptations for facilitating oxygen delivery to the fetus? Higher maternal MVPA and ST are associated with a higher density of villi, a proxy measure of placental surface area for oxygen delivery to the fetus, without further added placental vessels. Physical activity during pregnancy intermittently reduces uterine blood flow, potentially limiting placental and fetal oxygen supply. The placenta can mount several adaptive responses, including enlargement of the surface area of villi and/or feto-placental vessels to accommodate fetal needs. Early research on the morphology and growth of the placenta with exercise interventions has shown inconsistencies and is lacking, particularly in non-lean pregnant women. This study is a secondary longitudinal analysis of the vitamin D and lifestyle intervention for gestational diabetes prevention (DALI) randomized controlled trial. The prospective study was conducted between 2012 and 2015 in nine European countries at 11 different sites. In this analysis, 92 pregnant women with a BMI ≥ 29 kg/m2 were combined into one cohort. MVPA and percentage of time spent sedentary (% ST) were measured with accelerometers during gestation. Placental sections were immunostained for endothelial cell-specific CD34. Artificial intelligence (AI)-based stereology assessed villous density, number, and cross-sectional area of vessels on whole-slide images and in selected regions comprising peripheral villi only, where the majority of vascular adaptations occur. Expression of pro- and anti-angiogenic factors was quantified using molecular counting analysis. In multivariable regression, higher levels of maternal MVPA (min/day) were associated with a higher density of villi in both whole-slide images (beta 0.12; 95% CI 0.05, 0.2) and selected regions (0.17; CI 0.07, 0.26). Unexpectedly, ST was also positively associated with density of villi (0.23; CI 0.04, 0.43). MVPA and ST were not associated with vessel count/mm2 villous area, vessel area, or pro- and anti-angiogenic factor mRNA expression. All estimates and statistical significance of the sensitivity analyses excluding smokers, women who developed gestational diabetes or pre-eclampsia and/or pregnancy-induced hypertension were similar in the main analysis. The placenta is a complex organ undergoing dynamic changes. While various adjustments were made to account for different maternal contributing factors, in addition to the outcome measures, various other factors could impact oxygen delivery to the fetus. For the first time, we evaluated the association between placental structures quantified using an AI-based approach with objectively measured physical activity and ST at multiple time points in pregnant women with obesity. The observed adaptations contribute to the advancement of our understanding of the hemodynamics and adaptations of the placental unit in response to MVPA and ST. However, our results might not be generalizable to lean pregnant women. The DALI project has received funding from the European Community's 7th Framework Program (FP7/2007-2013) under grant agreement no. 242187. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare. ISRCTN70595832.

Beyond materialist green transitions: sketching a vitalist approach for evaluating R&I policy towards deep green transformation

ABSTRACT Situated within the growing literature on green alternatives to research and innovation-led green transition approaches, this paper sketches the contours of an emerging transition policy evaluation matrix aiming at going beyond contemporary (new) materialist concerns. To do so, I introduce a vitalist focus on life and establishing all connectedness as a long-term normative goal of just and deep global development policy. For this purpose, I draw from key insights from the recent interim evaluation of the European Framework program ‘Horizon Europe’, as well as non-Western and indigenous and feminist approaches to environmental justice to argue for overcoming an exclusive materialist and individualist preoccupation with green transition as it has been characteristic hitherto. Building on the requirement of a theory of change for encompassing well-being that includes a shifted yet assessable notion of being, I describe the non-linear sequence of green transition phases transcending materialist approaches to shifted energy supply and large-scale decarbonization to include an imaginary of a connected biocentric humanity with a just vitalist concern for life and well-being.

OFFICE BP MEASUREMENT USING CONICAL CUFFS IN OBESE CHILDREN AND ADOLESCENTS

Objective: Findings from adult studies suggest that tronco-conical cuffs should be used for accurate blood pressure (BP) measurement in obese individuals with large arm circumference (AC). The aim of the present study was to examine differences in office blood pressure (BP) levels using conical cuffs compared to standard-shaped cylindrical cuffs in obese children and adolescents. Design and method: We performed an observational study enrolling 37 obese children and adolescents consequently recruited from the outpatient clinics of the Obesity Unit at General University Hospital Consortium of Valencia. The device used for the office BP measurements was OMRON HBP-1320 (HBP-1320-E). Middle AC was measured in all participants and the appropriate cuff size was selected among five sizes of conical and three sizes of regular cylindrical cuffs. Results: Mean participants’ age was 11.8±2.5 years, mean BMI was 28.8±3.4 kg/m2, BMI z-score was 2.1 ± 0.3, and mean AC was 30.0±3.6 cm. There was no statistical significance in BP levels measured by cylindrical compared to conical cuffs (mean difference cylindrical-conical cuff was -0.22±6.55 mmHg for SBP, -0.02±0.81 for SBP z-score, -0.70±4.95 mmHg for DBP, and -0.06±0.44 for DBP z-score). The analysis was repeated after excluding participants aged <9 years old, retrieving similar results. A significant positive association was found between the measurements obtained by cylindrical and conical cuffs in both mean and z-score SBP and DBP values (p <0.001). Bland-Altman analysis showed good agreement, with 94.6% of the values for all BP parameters, lying between the limits of agreement. No proportional bias was detected (p >0.05). Conclusions: The use of conical cuffs resulted in similar office BP levels in obese children and adolescents suggesting no advantage in enhancing tolerability and accuracy of office BP measurement in these patients. Although conical cuffs may be considered an alternative for office BP measurements in obese children, their reliability should be confirmed in larger populations and different settings. Acknowledgments: This abstract is based on the work of the COST Action HyperChildNET (CA19115), with the support of COST (European Cooperation in Science and Technology) and the Horizon 2020 Framework Program of the European Union.

Determining directions for improving the legal regulation of technology transfer forms

The object of this study is the existing regulatory approaches to determining the forms of technology transfer in the legal systems of economically developed countries of the world, international treaties, and agreements. During the research and generalization of existing concepts, it was established that they are not unified and differ significantly from each other. It has been proven that this does not meet the needs of technology transfer participants and significantly destabilizes the technology transfer process. The expediency of improving the existing normative concept of determining the forms of technology transfer by fixing their single list has been substantiated. Recommendations on the list of the main forms of technology transfer have been formed based on a systematic analysis of legal acts that determine the peculiarities of the essence of technology. A classification of the main forms of technology transfer was proposed. Four main forms of technology transfer were identified as the transfer of rights to technology during its creation, within the framework of joint cooperation, within the framework of cooperation based on corporate and/or proprietary commercial principles. The expediency of dividing each form of transfer into separate subtypes was also substantiated. The need to make changes to the provisions of such international treaties and agreements as the World Trade Organization Agreements, the Recommendations of the World Organization for the Protection of Intellectual Property, the Oslo Guidelines, the UNCTAD Recommendations, and the framework program "Horizon Europe" has been proven. The study is aimed at forming general theoretical foundations for improving the essence of regulatory techniques for identifying forms of technology transfer. The research results could be used in the formation of international normative acts, recommendations of international institutions, acts of national legislation, and serve as a basis for further scientific research into these issues

Tackling adversity through innovation: A pilot study exploring VR as a tool to identify and diagnose depression

AbstractIntroduction The final aim of the EXPERIENCE project is to enable individuals to record and share extended-personal realities in Virtual Reality (VR) - which entails the consideration of a person’s neurophysiological, psychological, and cognitive states. One prospective application is using this technology to aid in assessing symptoms of affective disorders.ObjectivesThe objective is to test the ability of a pre-designed VR environment to differentiate between individuals with depressive symptoms and healthy controls (HCs) via machine learning algorithms.Methods Conducted as a pilot study in Italy, we recruited 100 volunteers, comprising 50 HCs and 50 individuals with moderate depressive symptoms assessed via the PHQ-9. Through a 40–60-minute VR engagement, comprehensive data on cognitive (inc. cognitive flexibility, sustained attention, working memory, processing speed), behavioral (exploration, attentional bias), and physiological (heart-rate variability, skin conductance) variables was collected. Subsequently, an explainable artificial intelligence model (xAI) was trained on data from 80% of the sample and tested on the remaining 20% in terms of accuracy for between-group classification.ResultsFollowing an iterative process that considered both the importance assigned to each variable in the different models and the theoretical relevance of these variables to depression the final model achieved an average accuracy of 71% (with individual trials ranging from 64.5% to 77.1%). Key predictors included exploratory behaviors and heart-rate variability during both exploration and cognitive tasks.ConclusionsThese results are comparable, however remain below the levels of accuracy achieved based on fMRI and DTI data alone (around 80%). Nonetheless, the EXPERIENCE system, slated for refinement beyond this pilot phase, shows potential in integrating multimodal data for evaluating affective disorder symptoms, aiming for a more objective screening and diagnostic approach at a lower cost.AcknowledgementThe EXPERIENCE project is funded by the European Commission H2020 Framework Program, Grant No. 101017727.Disclosure of InterestNone Declared

Safety and immunogenicity of the co-administered Na-APR-1 and Na-GST-1 hookworm vaccines in school-aged children in Gabon: a randomised, controlled, observer-blind, phase 1, dose-escalation trial

A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant Na-GST-1 and catalytically inactive Na-APR-1 (Na-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area. This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered Na-GST-1 on Alhydrogel plus Na-APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 μg, 30 μg, and 100 μg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with ClinicalTrials.gov, NCT02839161, and is completed. Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 μg of the co-administered antigens (n=8 for each injection schedule), 30 μg (n=8 for each schedule), 100 μg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti-Na-APR-1(M74) and anti-Na-GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for Na-APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for Na-GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for Na-APR-1[M74] and Na-GST-1, respectively). Co-administration of recombinant Na-APR-1(M74) and Na-GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas. European Union Seventh Framework Programme.

The collaborative framework for the management of tuberculosis and type 2 diabetes syndemic in low- and middle-income countries: a rapid review

IntroductionGiven the absence of international guidelines on the joint management and control of tuberculosis (TB) and type 2 diabetes mellitus (T2D), the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (The Union) launched in 2011 a policy framework to address the growing syndemic burden of TB-T2D. This review aimed at mapping the available evidence on the implementation of the Union-WHO Framework, explicitly, or bi-directional TB-T2D health programs as an initiative for co-management in patients in low- and middle-income countries (LMIC).MethodsA rapid review was performed based on a systematic search in PubMed and Web of Science electronic databases for peer-reviewed articles on The Union-WHO Framework and bi-directional interventions of TB and T2D in LMIC. The search was restricted to English language articles and from 01/08/2011 to 20/05/2022.ResultsA total of 24 articles from 16 LMIC met the inclusion criteria. Four described the implementation of The Union-WHO Framework and 20 on the bi-directional interventions of TB and T2D. Bi-directional activities were found valuable, feasible and effective following the Union-WHO recommendations. Limited knowledge and awareness on TB-T2D comorbidity was identified as one of the barriers to ensure a functional and effective integration of services.ConclusionsThis review revealed that it is valuable, feasible and effective to implement bi-directional TB and T2D activities (screening and management) according to the Union-WHO Framework recommendations, especially in countries that face TB-T2D syndemic. Additionally, it was apparent that gaps still exist in research aimed at providing evidence of costs to implement collaborative activities. There is need for TB and T2D services integration that should be done through the well-stablished TB programme. This integration of two vertical programmes, could ensure patient-centeredness, continuum of care and ultimately contribute for health systems strengthening.

Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial

No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.

Regional and sectoral variations in the ability to attract funding from the European Union’s Seventh Framework Program and Horizon 2020

The funding from the European Union’s Framework Programs for Research and Innovation (EU FPs) is skewed across European countries and institutions. The goal of this article is to deepen our understanding of this skewness by incorporating a regional (NUTS-2) and a sectoral (higher education sector and private sector) perspective when studying the ability to attract 71.6 billion euros of research funding distributed by the EU Framework Programs between 2007 and 2020, and to explore how it changed from FP7 to Horizon 2020. We explore the ability to attract grant funding per unit of R&D personnel, and how it is affected by a region’s volume of research personnel, R&D investments, research intensity, level of development, and mediated by the amount of funding requested. In the private sector, we find that several Southern European regions are highly capable of attracting funding, primarily through a high proposal intensity, e.g., large amounts of funding requested. In the higher education sector, regions in the so-called “blue banana” are particularly able to attract funding, due to high levels of R&D investments, strong research intensity, and a high amount of funding requested. From FP7 to Horizon 2020, we observe increasing divergence in the ability to attract funding in the private sector, in favor of peripheral regions, which aligns with the aims of the European Commission's cohesion policy.

Research priorities and considerations for nutrition research: methods of sex and gender analysis for biomedical and nutrition research.

For some 20 years, science funding bodies have been asking for the integration of sex- and gender-related factors into the content of research and innovation. The rationale for those requirements has been the accumulated evidence that sex and gender are important determinants of health and disease. The European Commission (EC) has been the first, since 2002, to seriously ask for the integration of sex and gender into research and innovation in the context of their multi-annual framework programmes. When introduced, this condition was not immediately applauded by the research community, who perhaps lacked training in methods for the integration of sex- and gender-related factors. The EC Expert Group on Gendered Innovations sought to fill this gap. This review describes the work of this international collaborative project which has resulted in the development of general and field-specific methods for sex and gender analysis and 38 case studies for various research domains (science, health and medicine, environment, engineering) to illustrate how, by applying methods of sex and gender analysis, new knowledge could be created. Since 2010, science funding bodies in Canada, the USA and several EU member states have followed the example of the EC issuing similar conditions. Although the effects of nutritional patterns on a range of (physiological and health) outcomes may differ for men and women, sex and gender analyses are rarely conducted in nutrition research. In this review, we provide examples of how gender is connected to dietary intake, and how advancing gender analysis may inform gender-sensitive policies and dietary recommendations.

Less-advanced regions in EU innovation networks: Could nanotechnology represent a possible trigger for path upgrading?

This paper examines whether nanotechnology projects funded under the European Union (EU) Framework Programmes (FPs) are a possible trigger for path upgrading (i.e., infusion of new technologies in existing traditional sectors) in less-advanced regions. First, the adoption of cluster analysis and a set of key indicators (i.e., technological intensity, scientific excellence, human capital, and research and development expenditure) allowed us to distinguish between 79 more-advanced and 127 less-advanced EU regions. Subsequently, through social network analysis and nonparametric testing we were able to demonstrate how the less-advanced EU regions (average degree centrality: 40.5) play a marginal role compared with the more-advanced ones (average degree centrality: 98.5) in the nanotechnology network created within Horizon 2020-i.e., the EU programming cycle implemented in the 2014-2020 period. Despite this, we observed that a few less-advanced regions (33 out of 127) were able to score higher than the EU median in terms of participation in the targeted nanotechnology network, thus benefiting from relevant knowledge flows potentially leading to re-industrialization processes. The adoption of qualitative comparative analysis allowed us to determine which combinations of key innovation, scientific and socioeconomic factors could facilitate such beneficial interregional interactions and related knowledge exchange in these types of regions (i.e., primarily what we defined as "relative innovativeness," excellence in nanotechnology research and a comparatively high level of gross domestic product per capita). Our empirical results provided some clear policy implications. For instance, the necessity to I) remove the barriers impeding a more balanced participation to promote a widespread renewal of traditional industries in less-advanced regions and II) implement coordinated EU and domestic actions designed to encourage the involvement of the great majority of the less-advanced regions, which remain marginal in the periodically launched FPs.

Efficacy of three benznidazole dosing strategies for adults living with chronic Chagas disease (MULTIBENZ): an international, randomised, double-blind, phase 2b trial

BackgroundTreatment with benznidazole for chronic Chagas disease is associated with low cure rates and substantial toxicity. We aimed to compare the parasitological efficacy and safety of 3 different benznidazole regimens in adult patients with chronic Chagas disease. MethodsThe MULTIBENZ trial was an international, randomised, double-blind, phase 2b trial performed in Argentina, Brazil, Colombia, and Spain. We included participants aged 18 years and older diagnosed with Chagas disease with two different serological tests and detectable T cruzi DNA by qPCR in blood. Previously treated people, pregnant women, and people with severe cardiac forms were excluded. Participants were randomly assigned 1:1:1, using a balanced block randomisation scheme stratified by country, to receive benznidazole at three different doses: 300 mg/day for 60 days (control group), 150 mg/day for 60 days (low dose group), or 400 mg/day for 15 days (short treatment group). The primary outcome was the proportion of patients with a sustained parasitological negativity by qPCR during a follow-up period of 12 months. The primary safety outcome was the proportion of people who permanently discontinued the treatment. Both primary efficacy analysis and primary safety analysis were done in the intention-to-treat population. The trial is registered with EudraCT, 2016-003789-21, and ClinicalTrials.gov, NCT03191162, and is completed. FindingsFrom April 20, 2017, to Sept 20, 2020, 245 people were enrolled, and 234 were randomly assigned: 78 to the control group, 77 to the low dose group, and 79 to the short treatment group. Sustained parasitological negativity was observed in 42 (54%) of 78 participants in the control group, 47 (61%) of 77 in the low dose group, and 46 (58%) of 79 in the short treatment group. Odds ratios were 1·41 (95% CI 0·69–2·88; p=0·34) when comparing the low dose and control groups and 1·23 (0·61–2·50; p=0·55) when comparing short treatment and control groups. 177 participants (76%) had an adverse event: 62 (79%) in the control group, 56 (73%) in the low dose group, and 59 (77%) in the short treatment group. However, discontinuations were less frequent in the short treatment group compared with the control group (2 [2%] vs 11 [14%]; OR 0·20, 95% CI 0·04–0·95; p=0·044). InterpretationParticipants had a similar parasitological responses. However, reducing the usual treatment from 8 weeks to 2 weeks might maintain the same response while facilitating adherence and increasing treatment coverage. These findings should be confirmed in a phase 3 clinical trial. FundingEuropean Community's 7th Framework Programme.

The role of City Climate Networks in Promoting Citizen Participation in Municipalities: A Critical Multi-Case Analysis

BackgroundAt the COP21, cities were recognised as key actors in combatting climate change. In supporting cities, climate city networks such as transnational climate networks (TCNs) and national climate networks (NCNs) have emerged to enable cities in building capacities and formulating climate policy whilst also encouraging citizen engagement and participation in public decision-making. This paper addresses the question whether and how TCN or NCN membership enables municipalities to implement citizen participation in public decision-making. Six propositions are presented addressing: presumed influence of TCN membership on citizen participation, organization of citizen participation, initiator capacity, goal setting, involvement of stakeholders, participatory methods used, and planning processes. A multi-case study research design is used to verify these propositions, comprising of four medium-sized cities in the Netherlands and three in Belgium.ResultsResults of the analysis of four cities in The Netherlands show that municipalities having membership to climate city networks only to a low extent empower citizen participation via local climate agendas. Citizen participation emerges rather bottom-up via local initiatives or capacity building via EU framework programs—outside TCNs or NCNs—that better suit financial needs and provide more immediate benefits to municipalities. None of the six propositions were confirmed. A more positive image resulted from the Belgian cases that moderately confirmed four out of six propositions (i.e., organizing citizen participation, goal setting, selection of methods, and planning), and featured indirect empowerment via externally funded implementation projects following firm integration of participation in local climate policy through TCN influence.ConclusionsIn terms of citizen participation selected municipalities in the Netherlands having TCN and/or NCN membership only to a small extent differ from those not having membership. This is partly due to poor implementation of TCNs and NCNs—with Covenant of Mayors and ‘Klimaatverbond’ lacking support structure and capacity—having lost importance during the past years. However, there is reason to believe that context makes a difference as revealed by the cases from Belgium, which revealed more positive results.

Ethics reviews in the European Union. Implications for the governance of scientific research in times of data science and Artificial Intelligence

ABSTRACT This article builds on discussions on peer review in science and the role of ethics in the governance of technologies to achieve a two-fold goal. First, it shows the process of co-production of the European Commission’s (EC’s) standardised ‘ethics appraisal process’ with the development of the EC’s Framework Programmes (FPs), by looking at the standardisation of the process and the mutual shaping of data protection law and risk-based discourses around Artificial Intelligence. Second, it investigates the political and epistemic implications arising from this process for the EU governance of scientific research regarding (1) sponsorship of science and technology by the EU and (2) how many limitations or constraints researchers have in practice when carrying out their research. After sketching the origins of the ethics appraisal process and its co-production with data protection law and risk-based jargon, the article outlines the implications for the governance of scientific research and draws recommendations.