Whereas the pandemic due do Covid-19 continues to spread, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Severe Acute Respiratory Distress Syndrome in 30% of patients with a 30%-60% mortality rate for those requiring hospitalization in an intensive care unit. The main physio-pathological hallmark is an acute pulmonary inflammation. Currently, there is no treatment. Mesenchymal stem cells (MSC) feature several attractive characteristics: ease of procurement, high proliferation potential, capacity to home to inflammatory sites, anti-inflammatory, anti-fibrotic and immunomodulatory properties. If all MSC share several characteristics regardless of the tissue source, the highest productions of bioactive molecules and the strongest immunomodulatory properties are yielded by those from the Wharton’s jelly of the umbilical cord. An additional advantage is that they can be scaled-up to generate banks of cryofrozen and thus readily available products. These cells have already been tested in several clinical trials with an excellent safety record. The objective of this project is to treat intubated-ventilated patients presenting with a SARS-CoV2-related Acute Respiratory Distress Syndrome (ARDS) of less than 96 hours by three intravenous infusions of umbilical cord Wharton’s jelly-derived mesenchymal stromal cells (UC-MSC) one every other day (duration of the treatment: one week). The primary endpoint is the PaO2/FiO2 ratio at day 7. The evolution of several inflammatory markers, T regulatory lymphocytes and donor-specific antibodies will also be monitored. The trial will include 60 patients, of whom 20 will be cell-treated while the remaining 40 patients will be injected with a placebo solution in addition to the standard of care. Given the pathophysiology of SARS-CoV2, it is thus sound to hypothesize that the intravenous administration of UC-MSC during the initial phase of ARDS could control inflammation, accelerate its recovery with improved oxygenation, reduced mechanical ventilation and ventilation weaning time and therefore reduced length of stay in intensive care. The feasibility of the project is supported by the expertise of the Méary Cell and Gene Therapy Center, which is approved for the production of Advanced Therapy Medicinal Products and has already successfully prepared the first batches of cells, as well as by the involvement of a cardiac surgery team which will leverage its experience with stem cells for the treatment of heart failure to make it relevant to the Stroma-Cov-2 project.

With the increased terrorist threat, there is a renewed interest in emergency inter-organizations coordination, and in particular between medical and non-medical first responders teams in extreme contexts, notably in multiple terror attacks. We are currently facing a growth in crisis complexity, due to multiple factors that need further investigation. As a consequence, organizations need to change their responses. They tend to increase the number of plans, while trying to preserve some agility for the first responders. The effectiveness of the response heavily relies on the preparation and coordination of the first responders, e.g. the various emergency medical groups, police services, fire brigades. Within this perspective, the project’s objective is twofold. First, it ambitions to advance knowledge on coordination, sensemaking and learning in extreme contexts. Second, it aims at improving the emergency responses in terms of coordination, training and the learning processes related to the management of extreme crises. The project will study the coordination of first responders teams (mainly medical emergency groups, police units and fire brigades) in extreme settings and their coordination with second responders (in particular hospitals departments). In this attempt, the project will: - Assess the impact of the increasing complexity in extreme situations on the coordination and decision-making of first responders; - Determine the conditions of effective coordination by identifying the success and failure factors in the organization and coordination of responders to extreme crisis; - Propose new organizational forms of coordination, recruitment, training and learning modalities.

No treatment for traumatic brain injury (TBI) patients has yet provided prolonged neurorestorative effects. Sustained TBI-induced neuroinflammation (NI) is associated with poor outcomes and a growing body of evidence suggests a link between NI and post-TBI neurodegenerative disorders (ND). Thus, modulation of NI offers a promising therapeutic window for interventions aimed at improving the prognosis of TBI. In this context immunomodulation (IM) via mesenchymal stromal cell (MSC)-based therapies have been investigated in various animal models of brain injury and are currently investigated in human to treat various ND through NI modulation but not yet in the specific setting of TBI. These data shown good safety record. In this human multi-centre double-arm double-blind placebo randomized study, we hypothesize that iterative IV injection of Wharton's jelly of the umbilical cord (WJ-UC-MSC) prevents NI and brain lesions exacerbation through IM and thus improve neuroclinical status. We will include 68 patients with severe TBI (Glasgow score<12 within the 48 first hours, brain lesion on CT scan, need for intracranial pressure monitoring) unresponsive to verbal commands 5 days after sedation discontinuation. They will be randomized to receive either 3 injections 1 week apart of WJ-UC-MSC or placebo. Primary outcome will be NI quantified by [18F]-DPA-714 signal intensity measured by dynamic quantitative PET-MRI at 6 months. A clinical evaluation will be performed at 6 and 12 months. We also plan to study early immune response to WJ-UC-MSC using deep immunophenotyping (flow cytometry analysis), next generation sequencing and digital PCR, on blood samples performed between first and second injection. Finally, we will seek for predictive biomarkers by studying transcriptomic and epigenomic peripheral blood mononuclear cells phenotype, on blood samples performed before first and third injections and at 6 months, in order to implement post-TBI personalized medicine.