Early Initiation of Highly Active Antiretroviral Therapies (HAART) for HIV/aids: The Contribution of a Stochastic Dynamic Model of Choice

Criteria for initiation of highly active antiretroviral treatments (HAART) in HIV-infected patients remain a matter of debate world-wide because short-term benefits have to be balanced with costs of these therapies, and restrictions placed on future treatment options if resistant viral strains develop. In order to take into account irreversibility and inertia effects associated with ex ante choices, we propose a simple stochastic dynamic model of sequential therapeutic choice with intermediary revelation of information, in which the efficiency gains from a new effective Therapy in second period are conditional on the results of the treatment in the previous period. We find that identical patients may be administered different treatments at the optimum; for parameters implying an all or nothing cut decision in period 2, a more forward looking decision rule is required in period 1 because there will be little space for adjustment to its consequences. Another finding is that as soon as risks of resistance due to therapeutic failure of initial treatments are significant, as perhaps in developing countries and in marginalized groups of developed countries, differences in the estimation of this risk should not influence the optimal decision about the size of the HIV-infected population eligible for early antiretroviral Therapy. The decision should then be based on pure efficiency/cost considerations. Le bien-fondé d'administrer précocement des traitements antirétroviraux à haute activité (HAART) aux personnes infectées par le VIH reste l'objet de débats dans le monde car leurs bienfaits à court terme peuvent compromettre les traitements futurs si des souches résistantes du virus se développent. Nous formulons un modèle qui combine irréversibilité et inertie dans un cadre de décision thérapeutique séquentielle. L'information se révèle entre la première et la deuxième période, si bien que la décision thérapeutique de deuxième période est conditionnelle à cette information. Il s'avère que des patients identiques peuvent se voir administrer des traitements différents à l'optimum; de plus, pour des paramètres justifiant des décisions bien tranchées en période 2 (à patients identiques traitement identique), la décision de période 1 est plus complexe car il est alors trop tard pour en renverser les conséquences en période 2. Autre résultat: supposons que le risque de résistance est élevé en cas d'échec thérapeutique du traitement initial (pays en développement; groupes défavorisés); nous montrons alors que les différences dans l'estimation de ce risque n'interviennent pas dans le choix optimal de la taille de la population qui se voit administrer le traitement antirétroviral. L'introduction du traitement relève alors purement de considérations d'efficacité et de coût.therapeutic decisions, uncertainty, information, irreversibility, treatment, learning, errors, décisions thérapeutiques, incertitude,information, irréversibilité, traitement, apprentissage, erreurs

Early Initiation of Highly Active Antiretroviral Therapies for Aids: Dynamic choice with Endogenous and Exogenous Learning

Criteria for initiation of highly active antiretroviral treatments (HAART) in HIV-infected patients remain a matter of debate world-wide because short-term benefits have to be balanced with costs of these therapies, and restrictions placed on future treatment options if resistant viral strains develop. On the other hand, postponing the introduction of HAART may involve a therapeutic opportunity cost if a patient’s health is allowed to deteriorate to such an extent of becoming unable to benefit from new treatments currently under development when they become available. We introduce a two period model where period one treatment adoption is an irreversible act with future, but uncertain, consequences. New information, both endogenous and exogenous, arises over time and shapes the conditions surrounding the second period therapeutic decision. A surprising result is that, under conditions that appear close to those surrounding the HAART debate, the magnitude of the feared resistance effect has no effect on leaves the optimal treatment decision as far as it is high enough. Le bien-fondé d’administrer précocement des traitements antirétroviraux à haute activité (HAART) aux personnes infectées par le VIH reste objet de débats dans le monde, car leurs bienfaits à court terme peuvent compromettre les traitements futurs si se développent des souches résistantes du virus. Par ailleurs retarder le recours aux HAART comporte un coût d’opportunité thérapeutique si la santé du patient se dégrade au point qu’il ne peut plus bénéficier par la suite des traitements encore en cours de développement. Nous formulons un modèle à deux périodes où l’adoption du traitement de première période est irréversible et engage le futur, alors que des informations et connaissances nouvelles, exogènes et endogènes, déterminent les conditions entourant la décision thérapeutique de deuxième période. Paradoxalement, sous des conditions reflétant bien les enjeux du recours aux HAART, il s’avère que l’effet résistance éventuel a d’autant moins de chance d’importer pour la décision optimale, que sa gravité est élevée.therapeutic decisions, uncertainty, information, irreversibility, treatment, endogenous learning, exogenous learning, décisions thérapeutiques, incertitude, information, irréversibilité, traitement, apprentissage endogène, apprentissage exogène

Study of zircaloy-4 cladding air degradation at high temperature

Prix de la Meilleure Communication EuropéenneInternational audienceZircaloy cladding, providing the first containment of UO2 fuel in Pressurised Water Reactors, can be exposed to air during accidental situations. This might occur during reactor operation (in case of a core meltdown accident with subsequent reactor pressure vessel breaching), under shutdown conditions with the upper head of the vessel removed, in spent fuel storage pools after accidental loss of cooling or during degraded transport situations. The fuel assemblies inadequately cooled, heat up and as a result, corrosion of Zircaloy claddings takes place. This paper is devoted to the kinetic analysis of Zy4 corroded at 850°C in 20% oxygen - 80% nitrogen partial pressure atmosphere to support the comprehension of the degradation mechanisms involved during the post-transition stage

Toxin Induction and Protein Extraction from Fusariumspp. Cultures for Proteomic Studies

Fusaria are filamentous fungi able to produce different toxins. Fusarium mycotoxins such as deoxynivalenol, nivalenol, T2, zearelenone, fusaric acid, moniliformin, etc... have adverse effects on both human and animal health and some are considered as pathogenicity factors. Proteomic studies showed to be effective for deciphering toxin production mechanisms (Taylor et al., 2008) as well as for identifying potential pathogenic factors (Paper et al., 2007, Houterman et al., 2007) in Fusaria. It becomes therefore fundamental to establish reliable methods for comparing between proteomic studies in order to rely on true differences found in protein expression among experiments, strains and laboratories. The procedure that will be described should contribute to an increased level of standardization of proteomic procedures by two ways. The filmed protocol is used to increase the level of details that can be described precisely. Moreover, the availability of standardized procedures to process biological replicates should guarantee a higher robustness of data, taking into account also the human factor within the technical reproducibility of the extraction procedure

Periopathogenic bacteria in dental plaque of Congolese patients with periodontitis : a pilot study

Periopathogenic bacteria play an important role in the etiology of periodontal disease. At present, no study screening for periopathogens in the DR Congo was carried out. The aim of this pilot study was to investigate the prevalence of five periopathogens in Congolese patients with periodontitis and to determine the association between these bacteria. Twelve patients (eight women and four men) with a mean age of 45 ± 19 years from those consulted in dental services of two medical centers of Kinshasa from April 2017 to October 2017 were included. Full mouth examination was registered, the probing pocket depth and clinical attachment level were assessed at six sites per tooth. Dental subgingival plaque samples were taken in the deepest pocket per arch in the maxilla and mandible. DNA analysis was performed using DNA-strip technology. The Fisher Exact test and Pearson correlation were used for statistical analysis. Porphyromonas gingivalis and Tannerella forsythia were detected at high level of 92%, Prevotella intermedia at a rate of 75% whereas Treponema denticola was detected in all patients. Aggregatibacter actinomycetemcomitans was not detected. Strong associations were found between three bacteria of the red complex and between T. denticola and P. intermedia (r=1). This first study investigating periopathogens in subgingival plaque of Congolese with periodontitis demonstrated a high prevalence of the red complex (P. gingivalis, T. forsythia and T. denticola). Associations between different bacteria of this complex were strong

Molecular basis of diseases caused by the mtDNA mutation m.8969G>A in the subunit a of ATP synthase

The ATP synthase which provides aerobic eukaryotes with ATP, organizes into a membrane-extrinsic catalytic domain, where ATP is generated, and a membrane-embedded FO domain that shuttles protons across the membrane. We previously identified a mutation in the mitochondrial MT-ATP6 gene (m.8969G>A) in a 14-year-old Chinese female who developed an isolated nephropathy followed by brain and muscle problems. This mutation replaces a highly conserved serine residue into asparagine at amino acid position 148 of the membrane-embedded subunit a of ATP synthase. We showed that an equivalent of this mutation in yeast (aS175N) prevents FO-mediated proton translocation. Herein we identified four first-site intragenic suppressors (aN175D, aN175K, aN175I, and aN175T), which, in light of a recently published atomic structure of yeast FO indicates that the detrimental consequences of the original mutation result from the establishment of hydrogen bonds between aN175 and a nearby glutamate residue (aE172) that was proposed to be critical for the exit of protons from the ATP synthase towards the mitochondrial matrix. Interestingly also, we found that the aS175N mutation can be suppressed by second-site suppressors (aP12S, aI171F, aI171N, aI239F, and aI200M), of which some are very distantly located (by 20-30 Å) from the original mutation. The possibility to compensate through long-range effects the aS175N mutation is an interesting observation that holds promise for the development of therapeutic molecules

Decreasing cytosolic translation is beneficial to yeast and human Tafazzin-deficient cells

Cardiolipin (CL) optimizes diverse mitochondrial processes, including oxidative phosphorylation (OXPHOS). To function properly, CL needs to be unsaturated, which requires the acyltransferase Tafazzin (TAZ). Loss-of-function mutations in the TAZ gene are responsible for the Barth syndrome (BTHS), a rare X-linked cardiomyopathy, presumably because of a diminished OXPHOS capacity. Herein we show that a partial inhibition of cytosolic protein synthesis, either chemically with the use of cycloheximide or by specific genetic mutations, fully restores biogenesis and the activity of the oxidative phosphorylation system in a yeast BTHS model (taz1Δ). Interestingly, the defaults in CL were not suppressed, indicating that they are not primarily responsible for the OXPHOS deficiency in taz1Δ yeast. Low concentrations of cycloheximide in the picomolar range were beneficial to TAZ-deficient HeLa cells, as evidenced by the recovery of a good proliferative capacity. These findings reveal that a diminished capacity of CL remodeling deficient cells to preserve protein homeostasis is likely an important factor contributing to the pathogenesis of BTHS. This in turn, identifies cytosolic translation as a potential therapeutic target for the treatment of this disease

Innovative embedded sensors for power electronic modules: CAPTIF – ANR research project

Innovative embedded sensors for power electronic modules: CAPTIF – ANR research projec

Embedded set of sensors for power electronic modules

This study deals with the challenges for driving Wide Band Gap modules to maturity. In this study, development, integration and signal processing techniques of several types of sensors are studied. Industrial and academic partners, within CAPTIF project, are proposing complementary skills and experiences in the technological and scientific domains: multi-physic sensors, signal processing, integration and reliability for power electronics. Nanoparticle-based strain gauges, temperature sensors and electromagnetic array sensors will be validated and integrated in power an electronic power module. A specific multi-physic model will be developed in order to specify the best location of interest within the power module. These features will result in a better knowledge of real-time current density location, as well as current frequencies. For both sensor types, the data packaging will be challenging spin-offs. Finally, advanced data processing techniques – estimation as well as signal processing – will be adapted to numerous sensor outputs. A clean room process flowchart will be established to guarantee an advanced pre-industrial prototyping

Conception de capteurs intégrés et logiciels pour des modules d'électronique de puissance

Conception de capteurs intégrés et logiciels pour des modules d'électronique de puissanc