Protein-carbohydrate (PC) interactions play a key role in various biological processes. In particular, PC interactions govern infected erythrocyte (IE) adhesion on placental cells during placental malaria (PM) leading to severe pathological conditions. Experimental description of PC interfaces remains very challenging. The main goal of SugarPred is the development of structure- and sequence-based carbohydrate binding site prediction tools through implementation of the most recent machine learning approaches on the basis of the available structural data. We will apply the developed tools to VAR2CSA, the protein responsible for IE adhesion during PM, and will verify our predictions in direct experiment. This interdisciplinary approach will allow identification of VAR2CSA sugar-binding residues, and thus fill an important knowledge gap currently limiting the improvement of PM vaccines. A set of machine learning tools for the carbohydrate binding site prediction will be made available to the scientific community.

Despite a significant decrease in number of Plasmodium falciparum-related deaths in recent years, malaria remains a major public health problem. Resistance of parasites to anti-malarial drugs could soon lead to a resurgence of the disease and calls for the need of developing new interventional strategies. We recently conceptualized a novel immunotherapeutic approach aiming at redirecting a pre-existing polyclonal antibody response against Epstein-Barr virus (EBV), which chronically infects over 95% of the population, towards defined target cells to mediate their clearance by immune effectors. As a proof-of-concept, we established that this strategy is efficient against cancer cells. We will here generate bi-modular fusion proteins (BMFPs) able to recruit polyclonal endogenous high-affinity antibodies (anti-EBV) towards P. falciparum-infected erythrocytes. BMFPs will be designed based on an EBV antigen coupled to nanobody-derived binding moieties targeting P. falciparum antigens specifically expressed at the surface of cells infected by asexual or sexual parasite forms. Following generation and screening of nanobody libraries specifically targeting parasite-derived proteins, best binders will be fused to the EBV antigen. The efficacy of the resulting BMFP candidates to recruit immune effector mechanisms and mediate infected erythrocytes’ clearance will be evaluated both in vitro and in vivo. The development of BMFP therapeutics, interfering with parasite pathogenicity and/or transmission, could offer new malaria control alternatives and allow a broader therapy access to individuals infected by P. falciparum in sub-Saharan Africa.

Impaired splenic function (hyposplenism) affects more than 0.4% of the French population, half of them splenectomised, portends a serious risk of complications, including severe infections, thromboembolism and leukemia. While many splenectomised patients are fully asplenic, loss of function is partial when the spleen has been damaged by acquired or inherited diseases like sickle cell disease (SCD). In SCD, hyposplenism emerges during infancy but spleen function may persist in adults, and correlate with disease severity. The spleen clears altered red blood cells (RBC) from the circulation. Best markers of hyposplenism thus assess this ability to retain stiff RBC and “pit” those that contain rigid bodies. RBC that have not been pitted in absence of a functional spleen contain nucleic acid-positive bodies (Howell-Jolly bodies, HJB) or empty vacuoles (Pocked RBC). The proportion of these RBC in circulation is highly discriminating. Pocked RBC are 30 times more abundant than HJB and predict hyposplenism with high sensitivity and specificity. Only pocked RBC counts closely correlate with splenic scintigraphy, the reference measure of spleen function. Pocked RBC counts are the most relevant marker of hyposplenism, but current quantification methods are suboptimal. Molecular markers of their vacuoles remain to be identified, and current counting is observer-dependent and slow. Our objective is to improve the relevance and applicability of splenic function markers, as a prerequisite for clinical studies to validate their prognostic & theranostic value. Specific aims are (i) to assess the correlations between residual splenic function and outcome in hyposplenism, and (ii) to establish reliable, observer-independent methods for measuring splenic function by quantifying RBC deformability with new microsphere-based and microfluidic techniques, or set-up counting of Pocked RBC by cytometry or imaging coupled with machine learning. The main barriers to be lifted are the poor adaptation of existing markers of spleen function to the clinical lab workflow, and their elusive validation as predictors of disease severity. The final product is a routine biological test that quantifies splenic function like serum creatinine levels quantify renal function. Important knowledge and medical gaps remain to be filled. Complex physical challenges on RBC as they cross splenic slits are poorly described. The removal of rigid bodies or vacuoles from RBC without cell lysis (the pitting process) is even more complex and can be fully observed experimentally only with highly specific microfluidic devices. On the medical side, there is a pressing need for biomarkers in SCD that accurately inform key treatment decisions, such as the best timing for treatment intensification, before irreversible organ damage occurs. Because the spleen is damaged early in SCD, spleen function markers are potentially informative. Impaired spleen function may altogether reflect past severity and portend a risk of further degradation, because pathogenic subpopulations of RBC are less efficiently cleared from the circulation. In some patients splenectomised for trauma, spleen function reappears due to regrowth of splenic nodules (splenosis). Results from markers will induce a beneficial simplification of follow-up in these patients. Conversely, if hyposplenism is confirmed, patient compliance to vaccination and antibio-prophylaxis will be enhanced with positive impact on prognosis. Our consortium brings together complementary inputs from physicians, physicists, pathophysiologists, and AI specialists. This shapes a cohesive translational task force mastering medical practice and sophisticated in silico and in vitro tools, including the only microfluidic chip with spleen-mimetic slits narrower than 1 micron currently available. We will undertake 6 tasks to find either the first specific markers of pocked RBC or to count them without label. We will also assess their predictive value.

Practice variations in French public psychiatry and associated factors (PRAVA-PSY) Background As in other countries, mental disorders in France represent a significant epidemiologic and economic burden that is expected to increase dramatically. Practice variations across public psychiatric services are a source of inequity and inefficiency and thus challenge the quality of care. While the need for evidence-based policy has been emphasized, research on practice variations in French public psychiatry, which represents two-thirds of mental health care delivered to patients in terms of expenditure, does not exist. Objectives The objectives of our study are threefold: 1/ To produce evidence on practice variations in French adult public psychiatry; 2/ To have a better understanding of the factors associated with mental health care practice variations; a. To identify characteristics of the providers of public psychiatric care that are associated with practice variations b. To identify patient characteristics that are associated with practice variations c. To identify the characteristics of the environments of the providers that are associated with practice variations; 3/ To develop recommendations on how to develop and implement policies to reduce unwarranted practice variations and to direct future research. Methods First, we will use descriptive analysis to describe practice variations and assess their ranges across French adult public psychiatric organizational units (PPOUs) using data from the Summary of medical information for psychiatry (RIM-Psy). A set of variables will be used to describe practice (e.g. average length of stay, annual re-hospitalization rate, etc.). Second, we will investigate factors associated with practice variations for mental disorders by using multivariate modeling. Three steps will be successively undertaken: 1) Hypotheses on predictors of practice variations, including characteristics of providers (PPOUs), their patients and their environments, will be developed to construct an explanatory model for each variable describing practice. 2) Database on predictors will be prepared. 3) Models will be run. Third, on the basis of the results, conclusions will be drawn with experts through a workshop bringing together decision makers, mental health care professionals and patient representatives to issue recommendations to address unwarranted practice variations and thus improve equity and efficiency in the system. Skills in health research services, statistical analysis, workfield psychiatry and health geography are needed for the completion of this project, and a multidisciplinary team has therefore been built. Prospects This project will enable a better understanding of the factors associated with practice variations in French public psychiatric care. These findings will be published in peer-reviewed journals and will have implications for policy-makers as they will provide evidence to improve the organization of public psychiatric care in France. Recommendations will be issued and further work will be developed based on the results of the project.