Gestion des soins non programmés en médecine générale dans le secteur du Sud Gironde.

INTRODUCTION: Unscheduled care (UC) is a current issue, particularly in the context of COVID-19 outbreak. UC is at the center of health policies, mainly in terms of the negative impact they have on hospital emergency services. This occurs in a context of imbalance between increasing health needs and changing healthcare offer. AIM: The aim of this study was to describe the organization of general practitioners in UC management in South-West France. METHOD: Our research was based on the combination of a cross-sectional descriptive study by self-questionnaire, and a collection of qualitative data via semi-structured interviews. RESULTS: 79% of practitioners delegated their hotline to a "medical secretary"; 67% had a specific organization to manage UC, especially by means of dedicated slots; 88% proposed a structured management of UC. The secretary appeared to be a necessary link for managing UC requests, mainly through the role of sorting, regulating and scheduling UC appointments. Group work was highlighted as a means to distribute the response to UC requests more fairly, to carry out unscheduled home visits and to prevent healthcare refusal. Nevertheless, this group management seemed difficult to implement outside of medical centers, especially at the level of health territory. CONCLUSION: the majority of GPs had implemented structured and shared management of UC, but they needed help and support to organize themselves across a territory, for example within the framework of "territorial health professional communities".

Development and pilot testing of a tool to assess evidence-based practice skills among French general practitioners.

BACKGROUND: There is currently an absence of valid and relevant instruments to evaluate how Evidence-based Practice (EBP) training improves, beyond knowledge, physicians' skills. Our aim was to develop and test a tool to assess physicians' EBP skills. METHODS: The tool we developed includes four parts to assess the necessary skills for applying EBP steps: clinical question formulation; literature search; critical appraisal of literature; synthesis and decision making. We evaluated content and face validity, then tested applicability of the tool and whether external observers could reliably use it to assess acquired skills. We estimated Kappa coefficients to measure concordance between raters. RESULTS: Twelve general practice (GP) residents and eleven GP teachers from the University of Bordeaux, France, were asked to: formulate four clinical questions (diagnostic, prognosis, treatment, and aetiology) from a proposed clinical vignette, find articles or guidelines to answer four relevant provided questions, analyse an original article answering one of these questions, synthesize knowledge from provided synopses, and decide about the four clinical questions. Concordance between two external raters was excellent for their assessment of participants' appraisal of the significance of article results (K = 0.83), and good for assessment of the formulation of a diagnostic question (K = 0.76), PubMed/Medline (K = 0.71) or guideline (K = 0.67) search, and of appraisal of methodological validity of articles (K = 0.68). CONCLUSIONS: Our tool allows an in-depth analysis of EBP skills, thus could supplement existing instruments focused on knowledge or specific EBP step. The actual usefulness of such tools to improve care and population health remains to be evaluated.

Private or salaried practice: how do young general practitioners make their career choice? A qualitative study.

BACKGROUND: Young French postgraduates in general practice increasingly prefer salaried practice to private practice in spite of the financial incentives offered by the French government or local communities to encourage the latter. This study aimed to explore the determinants of choice between private or salaried practice among young general practitioners. METHODS: A qualitative study was conducted in the South West of France. Semi-structured interviews of young general practitioners were audio-recorded until data saturation. Recordings were transcribed and then analyzed according to Grounded Theory by three researchers working independently. RESULTS: Sixteen general practitioners participated in this study. For salaried and private doctors, the main factors governing their choice were occupational factors: working conditions, need of varied scope of practice, quality of the doctor-patient relationship or career flexibility. Other factors such as postgraduate training, having worked as a locum or self-interest were also determining. Young general practitioners all expected a work-life balance. The fee-for-service scheme or home visits may have discouraged young general practitioners from choosing private practice. CONCLUSIONS: National health policies should increase the attractiveness of ambulatory general practice by promoting the diversification of modes of remuneration and encouraging the organization of group exercises in multidisciplinary medical homes and community health centers.

HIV-1-associated PKA acts as a cofactor for genome reverse transcription.

BACKGROUND: Host cell proteins, including cellular kinases, are embarked into intact HIV-1 particles. We have previously shown that the Cα catalytic subunit of cAMP-dependent protein kinase is packaged within HIV-1 virions as an enzymatically active form able to phosphorylate a synthetic substrate in vitro (Cartier et al. J. Biol. Chem. 278:35211 (2003)). The present study was conceived to investigate the contribution of HIV-1-associated PKA to the retroviral life cycle. RESULTS: NL4.3 viruses were produced from cells cultured in the presence of PKA inhibitors H89 (H89-NL4.3) or Myr-PKI (PKI-NL4.3) and analyzed for viral replication. Despite being mature and normally assembled, and containing expected levels of genomic RNA and RT enzymatic activity, such viruses showed poor infectivity. Indeed, infection generated reduced amounts of strong-strop minus strand DNA, while incoming RNA levels in target cells were unaffected. Decreased cDNA synthesis was also evidenced in intact H89-NL4.3 and PKI-NL4.3 cell free particles using endogenous reverse transcription (ERT) experiments. Moreover, similar defects were reproduced when wild type NL4.3 particles preincubated with PKA inhibitors were subjected to ERT reactions. CONCLUSIONS: Altogether, our results indicate that HIV-1-associated PKA is required for early reverse transcription of the retroviral genome both in cell free intact viruses and in target cells. Accordingly, virus-associated PKA behaves as a cofactor of an intraviral process required for optimal reverse transcription and for early post-entry events.

Polarized expression of the membrane ASP protein derived from HIV-1 antisense transcription in T cells.

BACKGROUND: Retroviral gene expression generally depends on a full-length transcript that initiates in the 5' LTR, which is either left unspliced or alternatively spliced. We and others have demonstrated the existence of antisense transcription initiating in the 3' LTR in human lymphotropic retroviruses, including HTLV-1, HTLV-2, and HIV-1. Such transcripts have been postulated to encode antisense proteins important for the establishment of viral infections. The antisense strand of the HIV-1 proviral DNA contains an ORF termed asp, coding for a highly hydrophobic protein. However, although anti-ASP antibodies have been described to be present in HIV-1-infected patients, its in vivo expression requires further support. The objective of this present study was to clearly demonstrate that ASP is effectively expressed in infected T cells and to provide a better characterization of its subcellular localization. RESULTS: We first investigated the subcellular localization of ASP by transfecting Jurkat T cells with vectors expressing ASP tagged with the Flag epitope to its N-terminus. Using immunofluorescence microscopy, we found that ASP localized to the plasma membrane in transfected Jurkat T cells, but with different staining patterns. In addition to an entire distribution to the plasma membrane, ASP showed an asymmetric localization and could also be detected in membrane connections between two cells. We then infected Jurkat T cells with NL4.3 virus coding for ASP tagged with the Flag epitope at its C-terminal end. By this approach, we were capable of showing that ASP is effectively expressed from the HIV-1 3' LTR in infected T cells, with an asymmetric localization of the viral protein at the plasma membrane. CONCLUSION: These results demonstrate for the first time that ASP can be detected when expressed from full-length HIV-1 proviral DNA and that its localization is consistent with Jurkat T cells overexpressing ASP.

Chikungunya triggers an autophagic process which promotes viral replication.

BACKGROUND: Chikungunya Virus (ChikV) surprised by a massive re-emerging outbreak in Indian Ocean in 2006, reaching Europe in 2007 and exhibited exceptional severe physiopathology in infants and elderly patients. In this context, it is important to analyze the innate immune host responses triggered against ChikV. Autophagy has been shown to be an important component of the innate immune response and is involved in host defense elimination of different pathogens. However, the autophagic process was recently observed to be hijacked by virus for their own replication. Here we provide the first evidence that hallmarks of autophagy are specifically found in HEK.293 infected cells and are involved in ChikV replication. METHODS: To test the capacity of ChikV to mobilize the autophagic machinery, we performed fluorescence microscopy experiments on HEK.GFP.LC3 stable cells, and followed the LC3 distribution during the time course of ChikV infection. To confirm this, we performed electron microscopy on HEK.293 infected cells. To test the effect of ChikV-induced-autophagy on viral replication, we blocked the autophagic process, either by pharmacological (3-MA) or genetic inhibition (siRNA against the transcript of Beclin 1, an autophagic protein), and analyzed the percentage of infected cells and the viral RNA load released in the supernatant. Moreover, the effect of induction of autophagy by Rapamycin on viral replication was tested. RESULTS: The increasing number of GFP-LC3 positive cells with a punctate staining together with the enhanced number of GFP-LC3 dots per cell showed that ChikV triggered an autophagic process in HEK.293 infected cells. Those results were confirmed by electron microscopy analysis since numerous membrane-bound vacuoles characteristic of autophagosomes were observed in infected cells. Moreover, we found that inhibition of autophagy, either by biochemical reagent and RNA interference, dramatically decreases ChikV replication. CONCLUSIONS: Taken together, our results suggest that autophagy may play a promoting role in ChikV replication. Investigating in details the relationship between autophagy and viral replication will greatly improve our knowledge of the pathogenesis of ChikV and provide insight for the design of candidate antiviral therapeutics.

Electrostatic repulsion between HIV-1 capsid proteins modulates hexamer plasticity and in vitro assembly.

Capsid protein (CA) is the major component of the human immunodeficiency virus type 1 (HIV-1) core. Three major phosphorylation sites have been identified at positions S(109), S(149) and S(178) in the amino-acid sequence of CA. Here, we investigated the possible consequences of phosphorylation at these sites on the CA hexamer organization and plasticity using in silico approaches. The biological relevance of molecular modeling was then evaluated by analyzing the in vitro assembly properties of bacterially expressed CA bearing S(109)D, S(149)D, or S(178)D substitutions that mimic constitutive phosphorylation at these sites. We found that a constitutive negative charge at position 109 or 149 impaired the capacity of mature CA to assemble in vitro. In vivo, HIV-1 mutants bearing the corresponding mutation showed dramatic alterations of core morphology. At the level of CA hexamer, S(149) phosphorylation generates inter-monomer repulsions, while phosphorylation at position 109 resulted in cleavage of important bonds required for preserving the stability of the edifice. Addition of a negative charge at position 178 allowed efficient assembly of CA into core-like structures in vitro and in vivo and significantly increased CA hexamer stability when modeled in silico. All mutant viruses studied lacked infectivity since they were unable to produce proviral DNA. Altogether our data indicate that negative charges, that mimic phosphorylation, modulate assembling capacity of CA and affect structural properties of CA hexamers and of HIV-1 cores. In the context of the assembled core, phosphorylation at these sites may be considered as an event interfering with core organization and HIV-1 replicative cycle.

Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4.

HIV-1 envelope glycoproteins (Env), expressed at the cell surface, induce apoptosis of uninfected CD4+ T cells, contributing to the development of AIDS. Here we demonstrate that, independently of HIV replication, transfected or HIV-infected cells that express Env induced autophagy and accumulation of Beclin 1 in uninfected CD4+ T lymphocytes via CXCR4. The same phenomena occurred in a T cell line and in transfected HEK.293 cells that expressed both wild-type CXCR4 and a truncated form of CD4 that is unable to bind the lymphocyte-specific protein kinase Lck. Env-mediated autophagy is required to trigger CD4+ T cell apoptosis since blockade of autophagy at different steps, by either drugs (3-methyladenine and bafilomycin A1) or siRNAs specific for Beclin 1/Atg6 and Atg7 genes, totally inhibited the apoptotic process. Furthermore, CD4+ T cells still underwent Env-mediated cell death with autophagic features when apoptosis was inhibited. These results suggest that HIV-infected cells can induce autophagy in bystander CD4+ T lymphocytes through contact of Env with CXCR4, leading to apoptotic cell death, a mechanism most likely contributing to immunodeficiency.

The development of self-efficacy beliefs during general practice vocational training: an exploratory study.

INTRODUCTION: Retention of general practitioners (GPs) is crucial to ensure appropriate primary care. However, some recently qualified GPs feel unprepared for practice, which may lead them to leave the profession or restrict their scope of practice. The development of self-efficacy beliefs during vocational training may be an important factor in this phenomenon. METHODS: Five focus groups with a total of 28 GP trainees and recent graduates were conducted in Belgium and France. Initial analysis using the immersion-crystallisation method was followed by analysis using Bandura's self-efficacy framework. RESULTS: Participants described beginning their training with low self-efficacy beliefs. Most participants described how they overcame stressful situations. Some, however, seemed to be developing avoidance strategies. Successfully resolving patient problems, sharing experiences with peers and receiving positive feedback from supervisors, colleagues and patients were conducive to the development of positive self-efficacy beliefs. DISCUSSION: Although low self-efficacy beliefs are natural at the beginning of training, participants seemed to develop in two ways, either overcoming their fears or avoiding them. Identifying the pattern of trainees' responses to allow tailoring of interventions should be investigated by those who run training programs. Interventions could include reassurance, peer interaction and an appropriate degree of autonomy.

What does it mean to be a family physician?: Exploratory study with family medicine residents from 3 countries.

OBJECTIVE: To explore the conceptions that family medicine residents from 3 countries have of the roles and responsibilities of family physicians in order to gain a better understanding of challenges that might transcend the specific contexts of different health care systems. DESIGN: Qualitative study using focus groups. SETTING: Resident training programs in France, Belgium, and Canada. PARTICIPANTS: A total of 57 residents in the last year of training. METHOD: Ten focus groups were conducted in 3 countries: 2 in France, 3 in Belgium, and 5 in Canada. All focus groups were held in different cities, with residents registered in different universities in France and Canada and with residents from the same university in Belgium. The study was informed by Abbott's conceptual framework on the system of professions. Each 90-minute focus group was moderated by the same researchers. The transcripts were analyzed according to the immersion-crystallization method. MAIN FINDINGS: Respondents shared common conceptions of the family physician's role: continuity of care and patient advocacy were seen as the foundations of the discipline. Respondents also shared a sense of discomfort about how accessible they were expected to be for patients and about the scope of family practice. They saw family medicine as flexible and reported that they strove for balance between their professional and personal life goals. All respondents strongly believed that their profession was undervalued by the medical schools where they trained. CONCLUSION: This exploratory study suggests that there are more similarities than differences in the understanding that future family physicians from different countries have of their discipline and of their careers. We observed a tension between a desire to develop a "new general practice" and the more traditional vision of the discipline. The culture in academic settings appears to contribute to the persistent low appeal of being a primary care physician.

Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation.

Maturation of human immunodeficiency virus type 1 (HIV-1) particles is a key step for viral infectivity. This process can be blocked using maturation inhibitors (MIs) that affect the cleavage of the capsid-spacer peptide 1 (CA-SP1) junction. Here, we investigated the mechanisms underlying the activity of EP-39, a bevirimat (BVM) derivative with better hydrosolubility. To this aim, we selected in vitro EP-39- and BVM-resistant mutants. We found that EP-39-resistant viruses have four mutations within the CA domain (CA-A194T, CA-T200N, CA-V230I, and CA-V230A) and one in the first residue of SP1 (SP1-A1V). We also identified six mutations that confer BVM resistance (CA-A194T, CA-L231F, CA-L231M, SP1-A1V, SP1-S5N and SP1-V7A). To characterize the EP-39 and BVM-resistant mutants, we studied EP-39 effects on mutant virus replication and performed a biochemical analysis with both MIs. We observed common and distinct characteristics, suggesting that, although EP-39 and BVM share the same chemical skeleton, they could interact in a different way with the Gag polyprotein precursor (Pr55Gag). Using an in silico approach, we observed that EP-39 and BVM present different predicted positions on the hexameric crystal structure of the CACTD-SP1 Gag fragment. To clearly understand the relationship between assembly and maturation, we investigated the impact of all identified mutations on virus assembly by expressing Pr55Gag mutants. Finally, using NMR, we have shown that the interaction of EP-39 with a peptide carrying the SP1-A1V mutation (CA-SP1(A1V)-NC) is almost suppressed in comparison with the wild type peptide. These results suggest that EP-39 and BVM could interact differently with the Pr55Gag lattice and that the mutation of the first SP1 residue induces a loss of interaction between Pr55Gag and EP-39.

VSV-G pseudotyping rescues HIV-1 CA mutations that impair core assembly or stability.

BACKGROUND: The machinery of early HIV-1 replication still remains to be elucidated. Recently the viral core was reported to persist in the infected cell cytoplasm as an assembled particle, giving rise to the reverse transcription complex responsible for the synthesis of proviral DNA and its transport to the nucleus. Numerous studies have demonstrated that reverse transcription of the HIV-1 genome into proviral DNA is tightly dependent upon proper assembly of the capsid (CA) protein into mature cores that display appropriate stability. The functional impact of structural properties of the core in early replicative steps has yet to be determined. RESULTS: Here, we show that infectivity of HIV-1 mutants bearing S149A and S178A mutations in CA can be efficiently restored when pseudotyped with vesicular stomatitis virus envelope glycoprotein, that addresses the mutant cores through the endocytic pathway rather than by fusion at the plasma membrane. The mechanisms by which these mutations disrupt virus infectivity were investigated. S149A and S178A mutants were unable to complete reverse transcription and/or produce 2-LTR DNA. Morphological analysis of viral particles and in vitro uncoating assays of isolated cores demonstrated that infectivity defects resulted from disruption of the viral core assembly and stability for S149A and S178A mutants, respectively. Consistent with these results, both mutants failed to saturate TRIM-antiviral restriction activity. CONCLUSION: Defects generated at the level of core assembly and stability by S149A and S178A mutations are sensitive to the way of delivery of viral nucleoprotein complexes into the target cell. Addressing CA mutants through the endocytic pathway may compensate for defects generated at the reverse transcription/nuclear import level subsequent to impairment of core assembly or stability.

The inhibition of assembly of HIV-1 virus-like particles by 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB) is counteracted by Vif and requires its Zinc-binding domain.

BACKGROUND: DSB, the 3-O-(3',3'dimethylsuccinyl) derivative of betulinic acid, blocks the last step of protease-mediated processing of HIV-1 Gag precursor (Pr55Gag), which leads to immature, noninfectious virions. When administered to Pr55Gag-expressing insect cells (Sf9), DSB inhibits the assembly and budding of membrane-enveloped virus-like particles (VLP). In order to explore the possibility that viral factors could modulate the susceptibility to DSB of the VLP assembly process, several viral proteins were coexpressed individually with Pr55Gag in DSB-treated cells, and VLP yields assayed in the extracellular medium. RESULTS: Wild-type Vif (Vifwt) restored the VLP production in DSB-treated cells to levels observed in control, untreated cells. DSB-counteracting effect was also observed with Vif mutants defective in encapsidation into VLP, suggesting that packaging and anti-DSB effect were separate functions in Vif. The anti-DSB effect was abolished for VifC133S and VifS116V, two mutants which lacked the zinc binding domain (ZBD) formed by the four H(108)C(114)C(133)H(139) coordinates with a Zn atom. Electron microscopic analysis of cells coexpressing Pr55Gag and Vifwt showed that a large proportion of VLP budded into cytoplasmic vesicles and were released from Sf9 cells by exocytosis. However, in the presence of mutant VifC133S or VifS116V, most of the VLP assembled and budded at the plasma membrane, as in control cells expressing Pr55Gag alone. CONCLUSION: The function of HIV-1 Vif protein which negated the DSB inhibition of VLP assembly was independent of its packaging capability, but depended on the integrity of ZBD. In the presence of Vifwt, but not with ZBD mutants VifC133S and VifS116V, VLP were redirected to a vesicular compartment and egressed via the exocytic pathway.

Intracellular assembly and budding of the Murine Leukemia Virus in infected cells.

BACKGROUND: Murine Leukemia Virus (MLV) assembly has been long thought to occur exclusively at the plasma membrane. Current models of retroviral particle assembly describe the recruitment of the host vacuolar protein sorting machinery to the cell surface to induce the budding of new particles. Previous fluorescence microscopy study reported the vesicular traffic of the MLV components (Gag, Env and RNA). Here, electron microscopy (EM) associated with immunolabeling approaches were used to go deeply into the assembly of the "prototypic" MLV in chronically infected NIH3T3 cells. RESULTS: Beside the virus budding events seen at the cell surface of infected cells, we observed that intracellular budding events could also occur inside the intracellular vacuoles in which many VLPs accumulated. EM in situ hybridization and immunolabeling analyses confirmed that these latter were MLV particles. Similar intracellular particles were detected in cells expressing MLV Gag alone. Compartments containing the MLV particles were identified as late endosomes using Lamp1 endosomal/lysosomal marker and BSA-gold pulse-chase experiments. In addition, infectious activity was detected in lysates of infected cells. CONCLUSION: Altogether, our results showed that assembly of MLV could occur in part in intracellular compartments of infected murine cells and participate in the production of infectious viruses. These observations suggested that MLV budding could present similarities with the particular intracellular budding of HIV in infected macrophages.

Assessing chronic pain in general practice: are guidelines relevant? A cluster randomized controlled trial.

OBJECTIVES: To evaluate the impact of using pain assessment scales on the management of musculoskeletal chronic pain. METHODS: Cluster-randomized controlled multicentre trial in French general practice settings. Practices were randomized by region before patient recruitment. The inclusion concerned patients suffering from musculoskeletal chronic pain. General practitioners assigned to the scale group used two validated assessment instruments; those assigned to the control group cared for their patients according to their usual practice. The primary end-point was the level of relief obtained and the secondary changes in prescription of painkilling modalities. RESULTS: A total of 155 general practitioners included 772 successive patients suffering from musculoskeletal chronic pain. The control group reported a mean level of relief of 50.7% compared with one of 41.1% in the scale group (p<0.0001). In the intervention group, physicians decreased significantly their prescription of level two painkillers. CONCLUSIONS: In general practice, the use of pain assessment scales is not associated with greater pain relief. The lesser level of pain relief obtained in the scale group does provide evidence that using pain assessment scales does not enhance the relief of chronic pain in patients in primary care. Guidelines which recommend the systematic use of scales for the assessment and monitoring of chronic pain are not tailored to either the context or the patients encountered in the primary care setting.

Factors and motivations associated with use of e-cigarette among primary care patients in a prospective cohort study: e-TAC study protocol.

INTRODUCTION: While the relationship between electronic cigarette use and smoking has often been studied, the association between electronic cigarette use and socioeconomic factors has received less attention. This is a study protocol aiming to describe the relationship between the consumption of psychoactive products (in particular: smoking) or some socioeconomic factors and the evolution of the use of electronic cigarette in primary healthcare over 1 year. METHODS AND ANALYSIS: Electronic cigarette, Tobacco, Alcohol and Cannabis (e-TAC) is a prospective multisite cohort study, including 473 patients at baseline and carrying out in general practices in the Aquitaine area (France). The volunteer patients participated in the study regardless of their initial reason for consultation. They filled out a self-administered questionnaire at baseline and will also do so after 12 months by phone, email or letter. The study will focus on the factors that explain the experimentation with or the current use of the electronic cigarette, as well as factors associated with their evolutions over time using multivariate logistic regression modelling or Cox regression modelling. ETHICS AND DISSEMINATION: This study received ethical approval from the University of Bordeaux Committee for the protection of persons. It was also approved by the National Commission for Data Processing and Freedoms. Findings will be submitted for publication in peer-reviewed journals and we will disseminate them by presentations at national or international conferences. TRIAL REGISTRATION NUMBER: RCB: 2015-A00778-41; Pre-results.

[Benefits and risks for primary prevention with statins in the elderly]. / Bénéfices et risques des statines en prévention primaire chez la personne âgée.

CONTEXT: Statins in primary prevention before 75 years old reduce cardiovascular events from 20 to 30% and mortality from 10% with acceptable side effects. We investigated whether these results persisted for patients aged 75 and older taking statin. METHOD: Methodic review of large randomized clinical trials and meta-analyzes that included patients 75 years and older treated with statins in primary prevention. RESULTS: Since the 1990s, a score of randomized controlled trials studying statins versus placebo in primary prevention were published and studied in meta-analyses. Exclusion criteria, including persons older than 70 years, are often restrictive. The impact on all-cause mortality in the four main studies and meta-analyses in over 75 years has not been demonstrated. On the other hand, a recent meta-analyses of observational studies including subjects between 70 and 89 years treated with statins found that low total cholesterol was associated with a moderate decrease in cardiovascular mortality, with no decrease in all-cause mortality. Moreover, in a common context of comorbidities in this age group, statins may be responsible for many adverse effects, drug interactions and impaired quality of life. CONCLUSION: Given the lack of formal evidence of effectiveness in terms of all-cause mortality and a high level of adverse effects, the benefit/risk of primary prevention with statins is not established in the elderly. The economic weight of statin prescriptions and their possible impact on quality of life justify an economic analysis of discontinuing statin therapy for people 75 years and older.

[Clinical features, care pathways and behaviors of patients with high level of cardiovascular risk: transversal study in south-west region of France]. / Profil clinique, parcours de soins et comportements des patients à haut risque cardiovasculaire : étude transversale en Aquitaine.

INTRODUCTION: To screen and to follow-up the patients with high cardiovascular risk in general practice may amplify the decrease of the cardiovascular morbi-mortality observed since a few years. The objective of this study is to identify the patients with high cardiovascular risk and to describe the management of these patients by general practitioners in Aquitaine. METHODS: Transversal study of a sample of patients from 18 to 70 years old with high cardiovascular risk (combining at least 3 factors), included by voluntary general practitioners (GP). RESULTS: Forty-seven GP included 102 patients, presenting on average 3.7 risk factors among which 2.6 modifiable. The target values were reached for 59 % of patients with high blood pressure, 56 % of patients with diabetes and 53 % of patients with high cholesterol level. The analysis of care pathways identified the cardiologist as the privileged interlocutor. The doctors thought that seven patients out of 10 could change their risk behaviors. For the patients, the scale of declared importance to change was 6.6 on 10 for tobacco, 6.0 for food habits and 6.2 for physical activity. The confidence in their capacity to change was 3.8 on 10 for the tobacco, 5.2 for the food habits and 4.7 for the physical activity. DISCUSSION: Although doctors' sample is not representative, these results give an original overview of the management of patients with high cardiovascular risk and their care pathways. Medical treatments were globally in accordance with guidelines. The difficulty to change risk behaviors illustrates the necessity of patient therapeutic education.

Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site.

Bevirimat (2), the first-in-class HIV-1 maturation inhibitor, shows a low efficacy due essentially to the natural polymorphism of its target, the CA-SP1 junction. Moreover, its low hydrosolubility makes it difficult to study its interaction with the CA-SP1 junction. We have synthesized new derivatives of bevirimat by adding different hydrophilic substituents at the C-28 position to improve their hydrosolubility and perform the structural study of a complex by NMR. Synthesis of the new derivatives, the effect of substituents at the C-28 position and their hydrosolubility are discussed. The ability of these molecules to inhibit viral infection and their cytotoxicity is assessed. Compared to the well-known bevirimat (2), one of our compounds (16) shows a higher hydrosolubility associated with a 2.5 fold increase in activity, a higher selectivity index and a better antiviral profile. Moreover, for the first time a direct interaction between a derivative of bevirimat (16) and the domain CA-SP1-NC is shown by NMR. Information from this study should allow us to decipher the mechanism by which bevirimat inhibits HIV-1 maturation and how the natural polymorphism of the spacer peptide SP1 triggers resistance to inhibitors.