Cost-Effectiveness Of Treatments For Mild-To-Moderate Obstructive Sleep Apnea In France

International audienceObjectives: Untreated obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with excessive daytime sleepiness, increased risk of cardiovascular (CV) disease, and road traffic accidents (RTAs), which impact survival and health-related quality of life. This study, funded by the French National Authority for Health (HAS), aimed to assess the cost-effectiveness of different treatments (i.e., continuous positive airway pressure [CPAP], dental devices, lifestyle advice, and no treatment) in patients with mild-to-moderate OSAHS in France.Methods: A Markov model was developed to simulate the progression of two cohorts, stratified by CV risk, over a lifetime horizon. Daytime sleepiness and RTAs were taken into account for all patients while CV events were only considered for patients with high CV risk.Results: For patients with low CV risk, incremental cost-effectiveness ratio (ICER) of dental devices versus no treatment varied between 32,976 EUR (moderate OSAHS) and 45,579 EUR (mild OSAHS) per quality-adjusted life-year (QALY), and CPAP versus dental devices, above 256,000 EUR/QALY. For patients with high CV risk, CPAP was associated with a gain of 0.62 QALY compared with no treatment, resulting in an ICER of 10,128 EUR/QALY.Conclusion: The analysis suggests that it is efficient to treat all OSAHS patients with high CV risk with CPAP and that dental devices are more efficient than CPAP for mild-to-moderate OSAHS with low CV risk. However, out-of-pocket costs are currently much higher for dental devices than for CPAP (i.e., 3,326 EUR versus 2,430 EUR) as orthodontic treatment is mainly non-refundable in France

Characterization update of HIV-1 M subtypes diversity and proposal for subtypes A and D sub-subtypes reclassification.

BACKGROUND: The large and constantly evolving HIV-1 pandemic has led to an increasingly complex diversity. Because of some taxonomic difficulties among the most diverse HIV-1 subtypes, and taking advantage of the large amount of sequence data generated in the recent years, we investigated novel lineage patterns among the main HIV-1 subtypes. RESULTS: All HIV full-length genomes available in public databases were analysed (n = 2017). Maximum likelihood phylogenies and pairwise genetic distance were obtained. Clustering patterns and mean distributions of genetic distances were compared within and across the current groups, subtypes and sub-subtypes of HIV-1 to detect and analyse any divergent lineages within previously defined HIV lineages. The level of genetic similarity observed between most HIV clades was deeply consistent with the current classification. However, both subtypes A and D showed evidence of further intra-subtype diversification not fully described by the nomenclature system at the time and could be divided into several distinct sub-subtypes. CONCLUSIONS: With this work, we propose an updated nomenclature of sub-types A and D better reflecting their current genetic diversity and evolutionary patterns. Allowing a more accurate nomenclature and classification system is a necessary step for easier subtyping of HIV strains and a better detection or follow-up of viral epidemiology shifts

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr

New alternative mechanisms of resistance of the human immunodeficiency virus to protease inhibitors resistance : impact of Gag polyprotein mutations and transmembrane envelope glycoprotein (gp41) mutations

En cas d’échec virologique chez des patients recevant un traitement antirétroviral à base d’inhibiteur de protéase (IP), des mutations de résistance dans la protéase sont rarement mises en évidence. En effet, les mécanismes de résistance aux IP apparaissent plus complexes que ce qui a été décrit jusqu’à présent. Récemment, des mécanismes alternatifs de résistance ont été mis en évidence, impliquant la région gag et la région de la glycoprotéine transmembranaire d’enveloppe gp41. Le but de ce travail était d’explorer, à l’aide des technologies de séquençage haut débit, de nouveaux mécanismes alternatifs de résistance aux IP. Dans un premier travail, nous avons montré l’absence d’impact sur la réponse virologique de la présence de variants résistants minoritaires (VRM) aux IP à l’initiation d’un traitement à base d’atazanavir ou de darunavir. Dans une deuxième partie, nous avons mis en évidence, dans la protéase, que 4 mutations (T4A et S37T ; E21D et I72M pour les VIH-1 CRF02_AG) étaient associées à la survenue d’échec virologique à une première ligne de traitement à base d’IP. Des analyses structurales in silico de la protéase ont montré que ces mutations engendraient des déformations au voisinage des résidus mutés, pouvant dans certains cas avoir un impact sur la liaison de l’IP au site actif de la protéase. Dans les régions gag et gp41, respectivement 3 mutations (G62D, N315H et Y441S) et une mutation (I270T) présentes à l’initiation étaient associées à l’échec virologique. L’analyse des séquences à l’échec a identifié l’émergence de mutations dans la protéase (I15V, I64M, K70R, P79A), mais également dans les régions gag (R286K) et gp41 (K106R, E109D, T165S, K172R et V321I). Enfin, nous avons comparé l’utilisation de trois logiciels d’analyse de séquences haut débit (AVA®, SmartGene® et Geneious®) pour la détection et la quantification des VRM du VIH-1. Nos résultats plaident pour un seuil optimal pour la détection et la quantification des VRM à 2%.Virological failure (VF) in patients receiving protease inhibitors (PI)-based regimen is rarely associated with selection of resistance mutations in the protease region. Indeed, mechanisms of resistance of PI are more complex than previously described. Recently, alternative mechanisms showed the impact of mutations in the transmembrane envelope glycoprotein (gp41) or in the Gag polyprotein. The aim of this study is to explore, using ultra-deep sequencing technologies, novel alternative mechanisms for PI resistance. In a first part, we showed that minority resistant variants (MRV) at PI initiation have no impact on virological response to a first-line PI-based regimen containing darunavir or atazanavir. In a second part, we have shown, in the protease region, that 4 mutations (T4A and S37T; E21D and I72M mutations for HIV-1 CRF02_AG) were associated with VF of a first-line PI-based regimen. In silico protease structural analyzes have shown that these mutations generate deformations in the vicinity of the mutated residues, which may in some cases have an impact on the binding of the PI to the protease active site. In the gag region, baseline mutations G62D, N315H, and Y441S were associated with VF. In the gp41 region, baseline I270T mutation was associated with VF. At time of VF, mutations emerged in all 3 regions: I15V, I64M, K70R, P79A in protease, R286K in gag and K106R, E109D, T165S, K172R and V321I. Finally, we compared the use of three software packages for ultra-deep sequencing data analysis (AVA®, SmartGene® and Geneious®) for detection and quantification of HIV-1 MRVs. Our results argue for an optimal threshold for detection and quantification of MRV at 2%

Synthesis of cyano-bridged coordination polymer nanoparticles for medical imaging

Les travaux entrepris au cours de cette thèse ont eu pour objectif d'élaborer de nouvelles nanoparticules magnétiques pour l'imagerie médicale. Ce manuscrit abordera la méthode de synthèse des nanoparticules, leurs caractérisations puis leur évaluation comme agent de contraste pour l'imagerie par résonance magnétique (IRM) et radio-traceur pour la scintigraphie.Dans un premier temps, nous proposerons une méthode de synthèse pour obtenir des nanoparticules magnétiques à base de polymères de coordination cyano-pontés élaborées à partir de précurseurs moléculaires de métaux de transitions et de lanthanides en utilisant des ligands cyanure pontant et stabilisées par des ligands solubles dans l'eau et biocompatibles. Nous présenterons la synthèse, les caractérisations structurales et texturales et les propriétés magnétiques de ces nano-objets de formule générale My[M'(CN)6]z @stabilisant avec M = Fe, Gd, Tb, Y, Ni, Cu ; M' = Fe, Co et stabilisant = PEGNH2, PEG400, Glu-TEG, D-Mannitol, NADG. Nous évaluerons ensuite leur potentielle pour des applications en imagerie médicale. Pour ce faire, nous discuterons de leur capacité à se comporter comme agent de contraste pour l'IRM et comme radio-traceur pour la scintigraphie ou plus précisément la tomographie par émission mono-photonique. Nous développerons une discussion sur les paramètres fondamentaux qui doivent être optimisés afin d'obtenir des nano-objets comme agents de contraste pour l'IRM et dans le but de comprendre le mécanisme de relaxivité de ces nano-objets. Enfin, nous testerons ces agents de contraste et radio-traceurs in vitro et in vivo sur le petit animal. Puis, nous évaluerons la cytotoxicité, la cinétique et les voies d'élimination, la biodistribution, la génotoxicité et la carcinogénèse des nanoparticules utilisées.The goal of the present research is to elaborate new magnetic nanoparticles for medical imaging. This manuscript will describe the nanoparticles' synthesis method, their characterization and their evaluation as contrast agent for magnetic resonance imaging (MRI) and functional probe for scintigraphy.In a first time, we will propose synthesis processes allowing to obtain cyano-bridged coordination polymer based magnetic nanoparticles elaborated from transition metals or lanthanides molecular precursors using cyano-bridged ligands and stabilizing ligands soluble in water and biocompatible. We will introduce the synthesis, structural and textural characterizations and magnetic properties of these nano-objects with general formula My[M'(CN)6]z @stabilizer with M = Fe, Gd, Tb, Y, Ni, Cu ; M' = Fe, Co and stabilizer = PEG NH2, PEG400, Glu-TEG, D-Mannitol, NADG.In a second time, we will evaluate their potential as nanoprobles for application in medical imaging. For that, we will discuss about their capacity to act as a contrast agent for MRI and as a functional probe for scintigraphy or more specifically single photon emission computed tomography (SPECT). We will develop discussion about fundamental parameters which must be optimized to obtain contrast agent nano-objects for MRI and to understand nano-object relaxivity mechanisms. Then, we will test these contrast agents and functional probes in vitro and in vivo on mice. Also, we will evaluate the cytotoxicity, the kinetics and way of elimination, the biodistribution, the genotoxicity and the carcinogenesis of the used nanoparticles

Dégénérescence maculaire liée à l'âge (traitements et conseils du pharmacien d'officine)

LIMOGES-BU Médecine pharmacie (870852108) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

A practical proposal on treatment sequencing of metastatic well-differentiated neuroendocrine tumours

According to the neuroendocrine tumour (NET) characteristics, 3 to 7 different treatment options are available, corresponding to 6 to 5,040 theoretical different sequences. Even though each patient is unique and despite a large heterogeneity in NET characteristics, the present review aims to discuss the main sequences and addresses how one can propose the best sequence to treat metastatic NET (mNET) on a case-by-case basis. Each treatment must be discussed during dedicated multi-disciplinary meetings, and inclusions in clinical trials should be favoured. After a thorough characterization of patients and their mNET, and taking into account the availability of drugs, the first-line treatment should be chosen according to the treatment aim. The latter is determined based on three main topics (efficacy, safety, and patient preferences) that do not necessarily converge and must be defined a priori . At baseline, physicians should design an a priori full therapeutic sequence, which may evolve at each step depending on the response to previous treatment, the occurrence of chronic toxicities, and the patients’ perception of the prior treatment. To improve knowledge in terms of effectiveness and risk of cumulative toxicities regarding the different sequences, real-world data using long follow-up durations are necessary; such issues will not be resolved by randomized clinical trials

HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy dolutegravir + lamivudine in the maintenance DOLULAM pilot study

International audienceBackground: The DOLULAM study assessed the efficacy of dolutegravir + lamivudine dual therapy to maintain virological suppression in heavily treatment-experienced HIV-1-infected adults. No virological failure occurred during the first year of the dual therapy. Objectives: A virological substudy was conducted to assess the prevalence of M184I/V mutations at dual therapy initiation using historical DNA/RNA genotypes and baseline DNA genotype obtained by next-generation sequencing (NGS). Methods: HIV-1 RT sequences were obtained from DNA and/or historical RNA using Sanger technology. HIV-1 DNA RT and integrase NGS was performed using Illumina\textregistered technology. Results: Among the 27 patients enrolled in the DOLULAM study, historical HIV DNA and RNA Sanger sequences were available in 14 and 18 patients, respectively. At the initiation of DOLULAM, DNA NGS genotypes showed that 45% and 21% of the patients harboured minority resistant variants (MRV) in RT and integrase, respectively. Combining all available genotype data, an M184I/V was observed in 17 of 27 (63%) of the patients. Most M184V were detected in historical RNA genotypes (n = 8 of 11), whereas M184I were exclusively detected in DNA genotypes (n = 10, including 7 as MRV). Ten patients displayed defective viral genomes in cellular reservoirs, all including M184I and stop codons. At the time of DOLULAM initiation, M184V was observed in DNA NGS in five patients, including one as MRV. Conclusions: These first NGS data on HIV DNA at initiation of a switch study showed (i) a high proportion of patients harbouring defective viral genomes, whose mutation M184I is a marker, and (ii) a low number of patients in whom M184V remained as a major viral variant in PBMCs

Surgery and Perioperative Management in Small Intestinal Neuroendocrine Tumors

Small-intestinal neuroendocrine tumors (SI-NETs) are the most prevalent small bowel neoplasms with an increasing frequency. In the multimodal management of SI-NETs, surgery plays a key role, either in curative intent, even if R0 resection is feasible in only 20% of patients due to advanced stage at diagnosis, or palliative intent. Surgeons must be informed about the specific surgical management of SI-NETs according to their hormonal secretion, their usual dissemination at the time of diagnosis and the need for bowel-preserving surgery to avoid short bowel syndrome. The aim of this paper is to review the surgical indications and techniques, and perioperative and postoperative management of SI-NETs