Supporting innovation in health care: A short experience in a dedicated unit of the French Ministry of Public Health.

INTRODUCTION: The Delegation for Innovation in Health Care (DIES) was created by the Ministry of Solidarity and Health to centralize and support innovative health care projects. Following its dissolution, only two and a half years after its creation, the members of this delegation aimed to present the projects, which were submitted and treated by the DIES. METHODS: All potential project leaders were free to explain the objectives of their project to our team. These projects were then classified according to their objective, their type, the medical specialty concerned, the target population and their purpose. The DIES graded the degree of innovation, advised on the need for complementary scientific evaluation and oriented the personnel in charge towards fitting financing structures. RESULTS: Between April 2016 and December 2018, the DIES received 269 potential project leaders, almost exclusively from the national territory of France, focused on diversified medical specialties with a slight predilection for chronic diseases and disabilities. The projects were often at an economically tenuous stage of development. Less than 5% of the projects concerned drug therapy. More than a third involved medical devices, including "surgical" projects (predominately orthopedics), disability compensation methodology, vascular problems and bandages. E-health, the organization of care, and a "non-classifiable" category that included wellness projects each represented 20% of the projects. Almost 80% of these projects had some electronically (e-) based mechanism. Only 15% of all projects had the ambition to meet an unmet or poorly covered need. Only about a third of the project leaders presented a clinical or medico-economic evaluation with sufficiently rigorous methodology to assess the achievement of their objectives. CONCLUSION: Innovative health projects are dominated by the search for improvement in the organization of the health care system and the care pathway with e-connected applications. Evaluation of the vast majority of these projects is very difficult and this situation reinforces the idea that these requests should be centralized to improve support for promoters of innovation.

Age-dependent effects of Armc5 haploinsufficiency on adrenocortical function.

Inactivating mutations in the Armadillo repeat-containing 5 (ARMC5) gene have recently been discovered in primary macronodular adrenal hyperplasia (PMAH), a cause of Cushing syndrome. Biallelic ARMC5 inactivation in PMAH suggested that ARMC5 may have tumor suppressor functions in the adrenal cortex. We generated and characterized a new mouse model of Armc5 deficiency. Almost all Armc5 knockout mice died during early embryonic development, around 6.5 and 8.5 days. Knockout embryos did not undergo gastrulation, as demonstrated by the absence of mesoderm development at E7.5. Armc5 heterozygote mice (Armc5+/-) developed normally but at the age of 1 year, their corticosterone levels decreased; this was associated with a decrease of protein kinase A (PKA) catalytic subunit α (Cα) expression both at the RNA and protein levels that were also seen in human patients with PMAH and ARMC5 defects. However, this was transient, as corticosterone levels normalized later, followed by the development of hypercorticosteronemia in one-third of the mice at 18 months of age, which was associated with increases in PKA and Cα expression. Adrenocortical tissue analysis from Armc5+/- mice at 18 months showed an abnormal activation of the Wnt/ß-catenin signaling pathway in a subset of zona fasciculata cells. These data confirm that Armc5 plays an important role in early mouse embryonic development. Our new mouse line can be used to study tissue-specific effects of Armc5. Finally, Armc5 haploinsufficiency leads to Cushing syndrome in mice, but only later in life, and this involves PKA, its catalytic subunit Cα, and the Wnt/ß-catenin pathway.

From ß-catenin to ARM-repeat proteins in adrenocortical disorders.

Armadillo-containing proteins (ACPs) are a large family of evolutionary conserved proteins, characterized by the tandem repeat copy of a 42 amino acids motif, which forms a 3 dimensional protein-protein interaction domain. This permits ACPs to interact with plenty of partners and consequently, most of these proteins have several independent cellular roles. Perhaps the most well-known protein of this family is ß-catenin, which is crucial in the regulation of development and adult tissue homeostasis through its 2 independent functions, acting in cellular adhesion in addition to being a transcriptional co-activator. APCs have important functions in many tissues, but here we summarize the adrenocortical role of 2 well-described ACPs, ß-catenin (CTNNB1), Adenomatous Polyposis Coli (APC), and discuss the possible role in the adrenal cortex of the most recently discovered, Armadillo-repeat containing 5 (ARMC5).