The gap in Research and Innovation (R&I) performance, which persists despite considerable investments from the European Structural and Investment Funds (ESIF) in the lower-performing regions of the EU, is an issue with major socio-economic and political consequences. In Health R&I the gap has a profound impact on distribution of funding from the EU Framework Programmes as well as on hindering the EU-wide impact of R&I on health and quality of life. With A4L_ACTIONS, we aim to address roots of this situation in the lower-performing Central and Eastern Europe (CEE) by improving culture, governance, recognition and innovation potential of the health research-performing institutions. Our goal is to increase their attractiveness for collaborations with advanced Europe and create spill-over effects in the whole region. As the Alliance4Life, we are an established network of progressive health research institutions in CEE and a source of successfully piloted good practice. By building upon our results and impact achieved so far, we will convert our recommendations and strategies into actions as follows: - Culture fostering excellence: piloting peer-evaluation and assessment of institutional practice as a strategic management tool, professionalizing research administration; - Recognition and trust towards CEE: attracting advanced partners to identified pockets of excellence, supporting scientific ideas originating in CEE, initiating new international projects and collaborations with industry; - Career policy nurturing talent: training and networking next generation of leaders, upgrading institutional career systems; - Impact on innovation: raising the competences of Technology Transfer specialists, creating industry relations platform linking academia and industry; - Spill-over effects: sharing, inspiring, communicating with stakeholders and policy makers; using the established networks to gain advice, new collaborations and EU-wide impact.

Depression is a common and serious comorbidity of cardiovascular disease (CVD) affecting one in three patients, among which women earlier and more frequently. Depression increases the risk for CVD development, acute events and mortality by >2 fold, independently of traditional risk factors, and constitutes an enormous socioeconomic burden in terms of morbidity, mortality and healthcare costs. Still, the patients at risk, disease trajectories and causative mechanisms involved remain unknown. TO_AITION addresses the hypothesis that immune-metabolic dysregulation, occurring as a result of genetic, lifestyle and environmental risk factors ‘training’ innate immunity, drives low grade systemic inflammation leading to the development of CVD-depression comorbidity. It integrates basic (cell models, immune-metabolic mechanisms, myeloid cell reprogramming), preclinical (animal models, CRISPR genome editing) and clinical (longitudinal cohorts with comprehensive existing data) research, in order to characterise immune-metabolic mechanisms driving CVD-depression comorbidity. Both hypothesis and data-driven strategies will be employed to address causality, focusing on genetic, epigenetic, transcriptional, metabolic and other disturbances leading to the development of comorbidity. Drug-drug interactions and their effects on causative mechanisms and disease trajectories will also be determined. Pathways identified will be evaluated in cell-based and animal models to prove their causal role and obtain mechanistic insight. Finally, new risk models will be developed, and relevant regulatory, cost-effectiveness and feasibility issues addressed. Effective patient-oriented awareness actions, dissemination, exploitation and management activities are also provisioned. TO_AITION will therefore rationally change our current understanding of the causative mechanisms driving CVD-depression comorbidity, unravelling patients’ complexity and improving their diagnosis, monitoring and management.