ENDOSIM is a research project in the field of predictive simulation and computer-aided medical interventions (CAMI). It focuses on the treatment of aortic aneurisms and valvular stenoses. In a previous ANR TecSan project (ANGIOVISION, ended in February 2013), the partners of the ENDOSIM project have developed operative assistance tools using augmented angio-navigation for the treatment of abdominal aortic aneurysms (AAA). The results demonstrated, on more than 20 patients, the accuracy of the patient-specific simulation approach. Based on these developments and results, the team aims to move forward and tackle the problem of predictive planning, in order to maximize the accuracy and reliability of two complex endovascular procedures: • the implantation of fenestrated stent-grafts for the treatment of thoraco-abdominal aneurysms, • the endovascular implantation of cardiac valves for the treatment of aortic stenoses. For these two minimally invasive procedures, atheromatous plaques are sources of numerous, unsolved so far, difficulties among which: navigability issues in the vicinity of the lesions, risk of plaque rupture due to ancillary contacts, complexity for positioning the device on the lesion site, brittleness of the vasculature, crushing of the native valves… These issues currently constitute a major obstacle for a more massive use of endovascular techniques. The goal of ENDOSIM is to develop the first predictive endovascular surgery planning software in the world. This will lead to optimize the pre-operative planning and to secure per-operative navigation, through the following points: • tool navigability estimation from the patient’s imaging data, • improvement of the pre-operative device sizing reliability, • pre-operative prediction of the device positioning and per-operative visualization, • decision-making help for patient eligibility and device selection. In order to reach these objectives, the novel approach featured in ENDOSIM relies upon the joint use of image analysis techniques and biomechanical numerical simulation techniques, both being patient-specific and predictive. The scientific breakthroughs of ENDOSIM comprise mainly accurate and predictive patient-specific simulations of the endovascular ancillary insertion and device deployment. These simulations will be based on pre-operative imaging data and validated using per- and post-operative data on a group of atheromatous patients. The prediction of the risk of surgery-induced injury at the atheromatous sites is also very original. The numerical simulations developed through the project will be systematically enhanced and validated thanks to 3D imaging data obtained on real patients with the per-operative multi-incidence equipment of the TherA-Image platform. From a clinical point of view, the benefits of the ENDOSIM project will relate to securing the surgical planning thanks to simulations based on pre-operative data and improved positioning accuracy thanks augmented navigation tools. This should allow a more massive use of endovascular treatments and hence make the most of these minimally invasive procedures for the patients. From the industrial point of view, ENDOSIM will lead Therenva® (French leader in endovascular surgery software) to market the first predictive endovascular planning software solution. This will also be complemented by a visualization system for per-operative assistance. The close partnership with Ansys® (worldwide leader in numerical simulation) will promote a widespread adoption of Therenva® software solutions by endovascular device companies, as a first step, and by the worldwide clinical community as a second step.

Context: Assessed by WHO as a pandemic on March 11, COVID-19 is caused by the SARS-CoV-2 coronavirus. The spectrum of its manifestations is strikingly broad and extends from mild disease (resembling an ordinary bout of flu or even asymptomatic) to pneumonia. The latter cases convey a high risk of evolution towards acute respiratory distress syndrome (ARDS), eventually fatal when worsening with cytokine storm and multiple organ failure or with superinfection and sepsis. In the absence of overt variations of the virus itself, its interactions with the host immune system are likely crucial. Clinical features of patients with severe forms of COVID-19 were reported, but immunological description of biomarkers for exacerbation and mortality vs recovery remains superficial. Globally decreased white blood cells, notably T-cells, suggest that CoV-2 might trigger or exploit an immune defect. This could correspond to gaps in immune cell subpopulations, kinetics of activation or repertoires. Immune failure would then be responsible for exacerbations and a poor outcome in intensive care unit (ICU) patients. Our objective is to characterize the kinetics of the immune response and of immune dysregulation in ARDS patients. In addition to studying severe ARDS patients, an inverse image of immune repertoires should appear in healed up patients, after they have reached an undetectable viral load and acquired protective antibodies (Abs). Humoral immunity mediated by specific anti-viral Abs was a key factor for recovery from SARS-CoV-1 infection, and this is also expected for CoV-2, making the Ig repertoire also of special interest for its inclusion of anti-viral neutralizing Abs (nAbs). Altogether, there is thus an urgent need for high-resolution characterization of the anti-CoV-2 immune response, correlating the dynamics of immune activation, cytokine production and immune repertoires with clinical evolution. In addition to providing biomarkers for prognosis evaluation and for monitoring innovative treatments, this will also participate to the urgent quest of as many possible mAb candidates for immunotherapy. Methods: In this prospective study, we will include 3 groups of 25 adult inpatients matched for age and sex from Rennes University Hospital. We will first concentrate on comparing either i) ICU patients with ARDS and laboratory-confirmed COVID-19, ii) COVID-19 patients without ARDS or undergoing rapid favorable evolution after their admission in the ICU, or iii) control ARDS patients without COVID-19. Clinical and laboratory data, including high-resolution immunomonitoring and serial samples for CoV-2 detection will be collected for all patients. Parameters collected will include complete analysis of blood lymphoid and myeloid subpopulations by Flow cytometry (FCM) and Mass cytometry (CyTOF), blood levels of inflammatory and regulatory cytokines, TCR and Ig repertoire evaluation by RepSeq, single-cell evaluation of gene expression. Specifically on blood samples from a fourth group of Covid-19 patients having recovered, presence of serum nAbs will be evaluated and EBV-transformed cell lines producing specific anti-CoV-2 mAbs will be grown and selected for the highest possible affinity and neutralizing ability. The project will thus pursue two complementary objectives, first determining biomarkers through high resolution immunomonitoring of critically ill patients without preexisting immune defect, hereby characterizing the breaches appearing in their immune defenses along COVID-19, and oppositely characterizing in healed-up patients potent nAbs the most representative of anti-CoV-2 immunity. Our ICU is used to research on sepsis, our labs are expert in biobanking, high-resolution immunomonitoring and immune repertoire studies. They are also fully operational during the COVID-19 outbreak within EFS and hospital premises despite the current confinement. This altogether warrants the unique feasibility and timeliness of the project.

In the context of the growing interest in data-sharing in medicine, this project aims 1/ to perform systematic re-analyses of Randomised Controlled Trials (RCTs) in order to assess their reproducibility and 2/ to develop a tool to identify transparent and reproducible scientific practices. We will critically appraise all initiatives for data-sharing in medicine and identify all platforms that enable RCT data to be shared. A random sample of 62 RCTs will be selected and re-analysed. The results of these re-analyses will be compared with the results of the original analyses. The same method will be applied for all new drugs submitted to the European Medicine Agency in order to replicate results and to provide practical information for drug regulation. The impact of certain contextual factors on reproducibility will be explored. A scale for scoring the sharing and reproducibility of useful data will be developed. France is involved in the G7 initiative calling for open practices in Science. This project will provide empirical data on these practices and their usefulness.