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Abstract Background The benefits of comprehensive geriatric assessment (CGA) are well established for hospital care but less so for primary care. Our primary objective was to assess the effect of two multifaceted interventions based on a CGA adapted for primary care on a composite criterion combining all-cause mortality, emergency department visits, unplanned hospital admissions, and institutionalisation. Methods This open-label, pragmatic, three-arm, cluster-randomised controlled trial involved 39 general practices in France. It included 634 patients aged 70 years or over with chronic health conditions and/or an unplanned hospital admission in the past 3 months, between 05/2016 and 08/2018. Interventions were in arm 1: a systematic nurse-led CGA; arm 2: a GP-led CGA, at the GP’s discretion; arm 3: standard care. The primary composite endpoint was assessed at 12 months. The secondary endpoints included: components of the composite endpoint, health-related quality of life (Duke Health Profile), functional status (Katz Activities of Daily Living Index) and medications (number) at 12 months. Pairwise comparisons between the experimental groups and the control were tested. The main analysis was performed on the intention-to-treat (ITT) population, after imputing missing information and adjusting for baseline imbalances by mixed effects regressions. Results For the primary composite outcome, no statistically significant difference was found between arm 1 and the control (adjusted odds ratio [aOR] = 0.81 [95%CI 0.54–1.21], P = 0.31), whereas arm 2 and the control differed significantly (aOR = 0.60 [0.39–0.93], P = 0.022). A statistically lower risk of unplanned hospital admission in arm 2 vs control (aOR = 0.57 [0.36–0.92], P = 0.020)) was observed, while no statistically significant differences were found for the other components and between arm 1 and the control. None of the other secondary endpoints differed between arms. Conclusions Our study led in community-dwelling older patients with chronic conditions found no significant effect of a CGA adapted for primary care on mortality, functional independence and quality of life, but suggests that a GP-led CGA may reduce the risk of unplanned hospital admission. Our study demonstrates the feasibility of incorporating CGA into clinical practice and highlights its potential benefits when applied on a case-by-case basis, guided by the GPs who develop the resulting PCP. Trial registration NCT02664454.

Abstract Background To describe French general practioners’ (GPs) adaptation strategies to ensure follow-up care of nursing home patients during the first wave of COVID-19 (May 2020) and to identify factors associated with each strategy. Methods A national cross-sectional study was conducted with online questionnaires in May 2020 among GPs practicing in France (metropolitan and overseas) and usually providing nursing home visits before pandemic. The outcome was defined as the GPs’ adaptation strategies for managing nursing home patients and was categorized into four groups: Maintenance of Nursing Home Visits NHV (reference), Stopping NHV, Numeric adaptation (teleconsultations only), Mixed adaptation (NHV and teleconsultations). The probability of adaptation strategies was analyzed by multilevel logistic models in which the GPs represented level 1 and the counties level 2. We applied three random-intercept multilevel logistic models with the county of GP’s practice as random effect. Results This analysis included 2,146 responses by GPs coming from 98 French counties. Overall, 40.4% of GPs maintained NHV, while other strategies were: Stopping visits (24.1%), Numeric adaptation (15.4%), Mixed adaptation (20.1%). Several individual (age, training GP, perceived status of being at high risk of severe COVID, compliance with temporary delegation of the patient’s management) and territorial factors (excess mortality rate due to COVID-19, GPs’ density, proportion of over-75s, presence of reinforcement measures for nursing home patients) were identified as associated with each strategy. Conclusions This study highlights a rapid adaptation of general practice to keep supporting nursing home patients. Heterogeneity of adaptation strategies could reflect both the lack of national guidelines and the heterogeneity among GPs’ usual practices. Policymakers should take actions at a territorial level (subnational) to strengthen support to nursing home patients considering adaptations to the local context of the pandemic outbreak and perspective of local actors.

El trabajo se realizó en el marco del diplomado Gestión integral de cooperativas agropecuarias sobre bases de intercooperación, con el objetivo de promover el empoderamiento de la mujer rural en iniciativas económicas en intercooperación entre cooperativas agropecuarias. Entre los principales métodos de investigación aplicados estuvieron el documental, la entrevista abierta y grupal. Se obtuvo información que permitió identificar las fortalezas y debilidades del empoderamiento de las mujeres en las iniciativas económicas. Se realizó la triangulación los resultados luego de la aplicación de los métodos y se logró determinar la problemática antes planteada. Sobre la base de los problemas críticos identificados, se elaboró el plan de acción que fue evaluado por criterio de los usuarios a través de la adecuación del marco lógico. Se obtuvo como resultado que el 95% de los participantes emitió una valoración de satisfacción individual favorable y el Índice de Satisfacción Grupal (ISG) se logra movilizar a las mujeres y cooperativistas a las acciones del plan para su capacitación. Además, se hacen explícitos los impactos esperados en el contexto estudiado y algunos de los resultados preliminares alcanzados.

Abstract Background Blood transcriptomic analysis is widely used to provide a detailed picture of a physiological state with potential outcomes for applications in diagnostics and monitoring of the immune response to vaccines. However, multi-species transcriptomic analysis is still a challenge from a technological point of view and a standardized workflow is urgently needed to allow interspecies comparisons. Results Here, we propose a single and complete total RNA-Seq workflow to generate reliable transcriptomic data from blood samples from humans and from animals typically used in preclinical models. Blood samples from a maximum of six individuals and four different species (rabbit, non-human primate, mouse and human) were extracted and sequenced in triplicates. The workflow was evaluated using different wet-lab and dry-lab criteria, including RNA quality and quantity, the library molarity, the number of raw sequencing reads, the Phred-score quality, the GC content, the performance of ribosomal-RNA and globin depletion, the presence of residual DNA, the strandness, the percentage of coding genes, the number of genes expressed, and the presence of saturation plateau in rarefaction curves. We identified key criteria and their associated thresholds to be achieved for validating the transcriptomic workflow. In this study, we also generated an automated analysis of the transcriptomic data that streamlines the validation of the dataset generated. Conclusions Our study has developed an end-to-end workflow that should improve the standardization and the inter-species comparison in blood transcriptomics studies. In the context of vaccines and drug development, RNA sequencing data from preclinical models can be directly compared with clinical data and used to identify potential biomarkers of value to monitor safety and efficacy.

Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2-/- animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2-/- TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2-/- TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2-/- TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects.

Objectives: Visual aids (VAs) seem effective to improve doctor-patient communication. The objective was to describe how VAs are used in consultation and what French general practitioners (GPs) expect of them. Methods: Cross-sectional study using a self-administered questionnaire among French GPs in 2019. Descriptive and multinominal logistic regression analyses were performed. Results: Of the 376 respondents, 70% used VAs at least weekly and 34% daily; 94% considered VAs useful/very useful; 77% felt they did not use VAs enough. Sketches were the most used VAs and considered the most useful. Younger age was significantly associated with a higher rate of use of simple digital images. VAs were mainly used to describe anatomy and facilitate patient comprehension. Main reasons for not using VAs more often were time spent searching, lack of habit and poor quality of available VAs. Many GPs requested a database of good quality VAs. Conclusions: GPs use VAs regularly in consultations but would like to use them more often. Informing GPs of the usefulness of VAs, training them to draw adapted sketches and creating a good quality databank are some possible strategies to increase the use of VAs. Innovation: This study described in detail the use of VAs as tool for doctor-patient communication.

BACKGROUND Slow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODS The Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTS Thirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3–4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSION Sirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATION ClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDING The Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant “ReVAMP” (LFCR grant 21CVD03), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.

Abstract Context There is an uneven distribution of general practitioners (GPs) across territories of developed countries leading to inequalities in access to health care. Countries are implementing incentive or coercive policies depending on the characteristics of their health system. Several studies suggest that the location of practical training may influence the location of GPs’ practices. The objective of this study is to investigate the existence of a relationship between training supervision and evolution of the density of GPs in French municipalities between 2018 and 2021. Methods The evolution of the density of GPs in almost all French municipalities between 2018 and 2021 was followed up. A bivariate statistical analysis was carried out to look for a relationship between the evolution of the density of GPs and the number of training supervisors. Other bivariate analyses were carried out with other factors likely to influence the density of GPs, such as the existence of financial aid in the territory or the age of GPs. A multivariate analysis with all the significant variables in bivariate analysis was then carried out using the stepwise descending method. Results A total of 34 990 (99.9%) French municipalities were included in the follow-up. Among these, 9427 (26.9%) had a GP and 3866 (11%) had a GP involved in the training supervision. The density of GPs in French cities decreased on average by 2.17% between 2018 and 2021. Territories without training supervisors decreased by 4.63% while those with at least one increased by 1.36% (p

Some coastal structures must be redesigned in the future due to rising sea levels caused by climate change. The design of structures subjected to the actions of waves requires an accurate estimate of the long return period of such parameters as wave height, wave period, storm surge and more specifically their joint exceedance probabilities. The simplified Defra method that is currently used in particular for European coastal structures makes it possible to directly connect the joint exceedance probabilities to the product of the univariate probabilities by means of a single factor. These schematic correlations do not, however, represent all the complexity of the reality because of the use of this single factor. That may lead to damaging errors in coastal structure design. The aim of this paper is therefore to remedy the lack of robustness of these current approaches. To this end, we use copula theory with a copula function that aggregates joint distribution functions to their univariate margins. We select a bivariate copula that is adapted to our application by the likelihood method. In order to integrate extreme events, we also resort to the notion of tail dependence. The optimal copula parameter is estimated through the analysis of the tail dependence coefficient, the likelihood method and the mean error. The most robust copulas for our practical case with applications in Saint-Malo and Le Havre (in northern France) are the Clayton copula and the survival Gumbel copula. The originality of this paper is the creation of a new and robust trivariate copula with an analysis of the sensitivity to the method of construction and to the choice of the copula. Firstly, we select the best fitting of the bivariate copula with its parameter for the two most correlated univariate margins. Secondly, we build a trivariate function. For this purpose, we aggregate the bivariate function with the remaining univariate margin with its parameter. We show that this trivariate function satisfies the mathematical properties of the copula. We finally represent joint trivariate exceedance probabilities for a return period of 10, 100 and 1000 years. We finally conclude that the choice of the bivariate copula is more important for the accuracy of the trivariate copula than its own construction.

Abstract Background Early‐onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low‐density lipoprotein receptor‐related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility. Method and Results We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1‐L4 BMD Z‐score −2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single‐variant LRP5 carriers, double‐variant carriers had a significantly lower BMD Z‐score (−4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait. Conclusion Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two‐variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next‐generation sequence analyses of bone fragility.

Normal aging is associated with vasopressin neuron adaptation, but little is known about its effects on the release of apelin, an aquaretic peptide colocalized with vasopressin. We found that plasma vasopressin concentrations were higher and plasma apelin concentrations lower in aged rats than in younger adults. The response of AVP/apelin neurons to osmotic challenge was impaired in aged rats. The overactivity of vasopressin neurons was sustained partly by the increased expression of Transient receptor potential vanilloid2 (Trpv2), because central Trpv blocker injection reversed the age-induced increase in plasma vasopressin concentration without modifying plasma apelin concentration. The morphofunctional plasticity of the supraoptic nucleus neuron-astrocyte network normally observed during chronic dehydration in adults appeared to be impaired in aged rats as well. IL-6 overproduction by astrocytes and low-grade microglial neuroinflammation may contribute to the modification of neuronal functioning during aging. Indeed, central treatment with antibodies against IL-6 decreased plasma vasopressin levels and increased plasma apelin concentration toward the values observed in younger adults. Conversely, minocycline treatment (inhibiting microglial metabolism) did not affect plasma vasopressin concentration, but increased plasma apelin concentration toward control values for younger adults. This study is the first to demonstrate dual vasopressin/apelin adaptation mediated by inflammatory molecules and neuronal Trpv2, during aging.

Subchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism.OA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by real-time quantitative PCR. The role of osteoprotegerin (OPG) in the bone-cartilage crosstalk was tested using an OPG neutralizing antibody.Bone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p

We have developed a model for designing antimalarial drugs based on interference with an essential metabolism developed by Plasmodium during its intraerythrocytic cycle, phospholipid (PL) metabolism. The most promising drug interference is choline transporter blockage, which provides Plasmodium with a supply of precursor for synthesis of phosphatidylcholine (PC), the major PL of infected erythrocytes. Choline entry is a limiting step in this metabolic pathway and occurs by a facilitated-diffusion system involving an asymmetric carrier operating according to a cyclic model. Choline transport in the erythrocytes is not sodium dependent nor stereospecific as demonstrated using stereoisomers of alpha and beta methylcholine. These last two characteristics along with distinct effects of nitrogen substitution on transport rate demonstrate that choline transport in the infected erythrocyte possesses characteristics quite distinct from that of the nervous system. This indicates a possible discrimination between the antimalarial activity (inhibition of choline transport in the infected erythrocyte) and a possible toxic effect through inhibition of choline entry in synaptosomes. Apart from the de novo pathway of choline, PC can be synthesized by N-methylation from phosphatidylethanolamine (PE). There is a de novo pathway for PE biosynthesis from ethanolamine in infected cells but phosphatidylserine (PS) decarboxylation also occurs. In addition, PE can be directly and abundantly synthesized from serine decarboxylation into ethanolamine, a pathway which is absent from the host. The variety of the pathways that exist for the biosynthesis of one given PL led us to investigate whether an equilibrium can occur between all PL metabolic pathways. Indeed, if alternative (compensative) pathway(s) can operate after blockage of the de novo PC biosynthesis pathway this would indicate a potential mechanism for resistance acquisition. Up until now, there is no evidence of such a compensative process occurring in Plasmodium-infected erythrocytes under physiological conditions. Besides, the discovery of a highly parasite-specific pathway (serine decarboxylation and the presence of PS synthase) constitutes a very attractive and promising target, which could be attacked if resistances are built up against choline analogs. Indeed, potential inhibitions of the serine decarboxylase pathway could be very useful in acting instead of, or in surgery with, choline analogs.