Anterior cingulate cortex is one of the largest riddles in cognitive neuroscience and presents a major challenge to mental health research. ACC dysfunction contributes to a wide spectrum of psychiatric and neurological disorders but no one knows what it actually does. Although more than a thousand papers are published about it each year, attempts to identify its function have been confounded by the fact that a multiplicity of tasks and events activate ACC, as if it were involved in everything. Recently, I proposed a theory that reconciles many of the complexities surrounding ACC. This holds that ACC selects and motivates high-level, temporally extended behaviors according to principles of hierarchical reinforcement learning. For example, on this view ACC would be responsible for initiating and sustaining a run up a steep mountain. I have instantiated this theory in two computational models that make explicit the theory's assumptions, while yielding testable predictions. In this project I will integrate the two computational models into a unified, biologically-realistic model of ACC function, which will be evaluated using mathematical techniques from non-linear dynamical systems analysis. I will then systematically test the unified model in a series of experiments involving functional magnetic resonance imaging, electroencephalography and psychopharmacology, in both healthy human subjects and patients. The establishment of a complete, formal account of ACC will fill an important gap in the cognitive neuroscience of cognitive control and decision making, strongly impact clinical practice, and be important for artificial intelligence and robotics research, which draws inspiration from brain-based mechanisms for cognitive control. The computational modelling work will also link high level, abstract processes associated with hierarchical reinforcement learning with low level cellular mechanisms, enabling the theory to be tested in animal models.

Context/background:About 5% of the European population report symptoms for which the doctor cannot find a medical cause that sufficiently explains their symptoms, even after adequate medical examinations. These Medically Unexplained Symptoms (MUS) are f.e. chronic fatigue, dizziness, abdominal discomfort, chronic lower back pain or non-cardiac chest pain. MUS represent 30-40% of the caseload of doctors and are one of the most expensive diagnostic categories in Europe. MUS consultations are perceived by many doctors as very difficult, especially when patients are from different ethnic minorities, have invalidating symptoms without underlying pathology and face substantial functional impairment. MUS and intercultural doctor-patient communication (IC) don't get enough attention in undergraduate and postgraduate medical teaching in European countries despite the weight of the problem in healthcare. Hence most doctors feel incompetent to define with their patients a shared problem definition and are easily triggered to perform more additional medical investigations than guidelines suggest, while patients often feel misunderstood. Crucial challenges in MUS intercultural doctor-patient communication are dealing with differences in perspectives, values and beliefs about illness. Objectives:To better prepare European doctors for their daily clinical encounters with ethnic minority MUS patients the MUSIC project had 5 objectives:- developing a competency profile on patient-centered communication on MUS and IC, - synthesizing expertise on MUS and IC into accessible information for medical students, residents and faculties, - developing blended training for teachers on MUS and IC,- developing blended training for medical students on MUS and IC,- developing a blended Small Private Online Course (SPOC) for residents aimed at patient-centered communication on MUS and IC.Number and type of participants:- Teachers: 55 medical teachers have been trained through an online course and in person on patient-centered communication on MUS & IC.- Medical students:460 Bachelor students and 782 Master students in Medicine have received education on MUS & IC.- Residents: 106 residents were trained by the renewed Blended Learning on MUS & IC.Description of undertaken activities:5 Intellectual Outputs were realized and 3 Multiplier Events were organized. Monthly online meetings were held by the partnership to monitor the progress of activities. Additionally 8 Transnational Project Meetings were held to facilitate the interaction with stakeholders and deepen the cooperation as partners.Results attained:- a competency profile focused on MUS and intercultural communication on four levels (Ba, Ma students, residents and teacher).- an online platform with validated and qualified information, resources and practical tools on MUS and intercultural communication for medical students, residents and teachers, - a blended Teacher Programme on MUS and Intercultural doctor-patient communication accredited for Continuing Medical Education - a training programme on MUS and Intercultural Communication for Bachelor students- a blended Training programme on MUS and Intercultural Communication for Master students - a SPOC on MUS and Intercultural Communication for residents, - a narrative review in Journal Medical & Clinical Research, titled 'Perceptions and attitudes of health care givers and patients on MUS: a narrative review with focus on cultural diversity and migrants'.- Manuscript titled 'Education on MUS: a systematic review with a focus on cultural diversity and migrants' is submitted in 2021 to Journal Medical Education Online, under review.- implementation and dissemination of the developed training programmes has been accomplished by the staff of the MUSIC partnership in the curricula of the medical faculties. In some of the modules migrant training actors or patients take part in the education. - the article 'Epidemiology and organisation of care in MUS: a systematic review with a focus on cultural diversity and migrants' has been published in the International Journal of Clinical Practice, 2021. Impact attained:Students (Ba/Ma), teachers and residents have gained more know how, skills and a better understanding and attitude how to deal with complex consultations on migrant patients with MUS.The participating organisations improved their education for students, residents and teachers, and contributed to better health care for MUS patients from minority groups. Longer term benefits:An improved healthcare for MUS patients from minority groups, less costs due to more effective consultations with ethnic minority MUS patients and less unnecessary referrals, reinforcement of efficient healthcare networks focused on migrant patients with MUS and a better cooperation between primary and secondary care in the region as well as between mental health care and somatic care concerning ethnic minority MUS patients.

Allogeneic stem cell transplantation (HSCT) is a curative treatment for a variety of diseases. Viral infections such as Cytomegalovirus (CMV), Epstein-Barr-virus (EBV) and Adenovirus (AdV) are major unsolved problems for patients receiving allogeneic HSCT. Refractory viral infections post-HSCT are rare, life-threatening conditions due to the deficient T-cell response post-SCT and lacking effective treatment options. Protective T-cell immunity could be restored by means of a procedure known as adoptive T-cell transfer. Although cellular immunotherapy is considered a major recent breakthrough in medicine, none of the cellular treatment approaches has yet become a standard treatment. The reason for this limited translation into daily clinical practice is the lack of controlled, prospective clinical trials investigating efficacy of immunotherapy. The objective of TRACE is to bring adoptive T-cell transfer into clinical routine as a life-saving, curative and safe treatment for refractory viral infection post-HSCT. TRACE is a multi-national clinical trial to prove efficacy and safety of adoptive T-cell transfer in immune-compromized individuals. For the first time, this trial will show that a unique individualized immunotherapy could be included into evidence based clinical routine in rare diseases. Regulatory and structural hurdles will be overcome by standardized GMP-procedures. It will be a major milestone in the development of medicine and health economics to bring such a unique personalized treatment approach into a clinical efficacy trial. The consortium provide excellence in immunotherapy through partners from basic, clinical and industrial research and GMP facilities, with proven qualification and expertise in the field of HSCT, GMP manufacturing and adoptive T-cell transfer. It will bring medicine towards physiological self-protection of the human body instead of cost-intensive toxic agents and will thereby improve survival and quality of life.

Despite the availability of flu vaccines for decades, influenza is still an important disease in both developing and developed countries with 500,000 casualties annually and many more people affected. From a global health perspective, the lack of effectivity, availability, affordability, and accessibility of flu vaccines significantly limits our ability to respond to the seasonal flu every year and in the event of a pandemic. Currently, a low vaccine effectivity of 40% implies that 60% of vaccinated people are not sufficiently protected, with low confidence further contributing to limited uptake/immunization. Within INDIGO, public and private R&D organizations in India, EU and US collaborate on the development of two novel influenza vaccine concepts that meet the requirements of global vaccination, aiming to achieve less non-responders, lower costs, and better accessibility: 1) TETRA-LITE, an affordable seasonal flu vaccine with high efficacy at low cost and possible exploitation within a few years after completion of the project; and 2) PANDEMIC-PLUS, a further improved flu vaccine concept dealing with technological shortcomings and challenges of wide-spread use. The first approach combines a low dose of a commercial, inactivated, seasonal flu vaccine with a novel, potent adjuvant CMS (LVA). The adjuvant was tested in humans for the first time within the INDIGO project and was proven safe and well tolerated. When combined with just one-fifth of the standard flu vaccine dose, CMS induced immune responses comparable to full-dose vaccines without adjuvants. This suggests significant potential for antigen sparing, which could lead to more cost-effective vaccine production. The second approach builds on three innovations: 1) a novel recombinant HA with increased immunogenicity, 2) novel adjuvants, and 3) an easy, needle-free delivery by intradermal patches. Contra-productive parts of HA have been removed to increase the immunogenicity of influenza epitopes. The adjuvants further stimulate protective immunity and immunological memory. The use of intradermal patches opens possibilities for self-administration, which will improve vaccine uptake in developing as well as developed countries. These plans differ in complexity and timelines but can all contribute to delivering next-generation flu vaccines for the globe.