Cerebrospinal fluid biomarker candidates associated with human WNV neuroinvasive disease

During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presente

Personalized therapy for mycophenolate:Consensus report by the international association of therapeutic drug monitoring and clinical toxicology

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Study of the protective effect in the offspring of maternal supplementation with docosahexaenoic acid (DHA) during gestation and lactation against metabolic and cognitive alterations induced by high-calorie diet

Résumé : La sous-alimentation ou la suralimentation maternelle sensibilise la progéniture au développement de maladies métaboliques et cognitives. Cependant, une supplémentation en nutriments spécifiques pendant la grossesse peut potentiellement inverser et/ou protéger contre les effets délétères d’une mauvaise alimentation. L’objectif de ce travail de thèse a été de déterminer dans quelle mesure et par quels mécanismes la supplémentation maternelle en acide docosahexaénoïque (DHA) pendant la gestation et la lactation, chez le rat, protège la progéniture contre les désordres cognitifs et métaboliques induits par la dénutrition maternelle ou par une alimentation hypercalorique. Les résultats obtenus montrent que la supplémentation maternelle en DHA prévient le développement, chez la progéniture, de l’intolérance au glucose et la stéatose hépatique associées à l’obésité en inhibant l’expression de gènes qui favorisent la glycolyse, la lipogenèse et la synthèse de triglycérides. En outre, les rats de mères dénutries supplémentées en DHA ont montré de meilleures performances cognitives dans les tests d’anxiété et d’interaction sociale que leurs congénères nés de mères dénutries supplémentées avec du placebo. Nous concluons que la supplémentation maternelle en DHA améliore le développement cognitif de l'enfant et favorise un état métabolique sain en protégeant contre les effets délétères d'un régime obésogène.Maternal under- or over-nutrition sensitizes the offspring to the development of metabolic and cognitive diseases. However, supplementation with specific nutrients during pregnancy can potentially reverse and/or protect against the deleterious effects of unhealthy feeding. The aim of this thesis was to determine to what extent, and by which mechanisms, maternal DHA supplementation during gestation and lactation, in rats, protects the offspring against cognitive and metabolic disorders induced by maternal undernutrition or by a hypercaloric diet. Our results show that maternal DHA supplementation prevents the development, in the offspring, of glucose intolerance and hepatic steatosis associated with obesity by inhibiting the expression of genes that promote glycolysis, lipogenesis, and triglyceride synthesis. In addition, rats from undernourished mothers supplemented with DHA showed better cognitive performance in anxiety and social interaction tests than their counterparts from undernourished mothers supplemented with placebo. These observations allow to conclude that maternal DHA supplementation may not only improve the child's cognitive development, but also promote a healthy metabolic state and exert a protective effect against the deleterious effects of an obesogenic diet

Evolution of the energy service : real necessity or solution for the development and accessibility of electricity in Africa : the case of Djibouti

L’étude présentée dans cette thèse est consacrée à la gestion du service énergétique à Djibouti ainsi qu’à son impact sur l’économie nationale et ceci dans un contexte international marqué par un accroissement des exigences énergétiques, notamment en Afrique subsaharienne. Ainsi, l’étude s’intéresse successivement à l’analyse du réseau de distribution d’électricité à Djibouti ainsi qu’aux différents organismes ayant en charge la gestion de ce service énergétique.L’Etat djiboutien a entrepris une innovation organisationnelle, en mettant en place l’interconnexion afin de diversifier ses sources de production, diminuer sa vulnérabilité et in fine alléger la facture énergétique des consommateurs. C’est pourquoi l’étude s’est intéressée à la question de l’innovation dans le secteur de l’énergie, pour laquelle une enquête quantitative sur le secteur résidentiel de Djibouti a été réalisée et concernant les entreprises, des entretiens semi-directifs ont été menés auprès du secteur hôtelier. Le résultat principal est que l’interconnexion n’a pas eu les effets escomptés, c’est-à-dire baisser la facture énergétique dans le secteur résidentiel et non-résidentiel, mais elle a cependant permis de diminuer les délestages, ce qui a abouti à une légère amélioration de la qualité du service.In a global context marked by a growth of energy demands, particularly in sub-Saharan Africa,this thesis is devoted to the analysis of both the management and impact of energy services in Djibouti. Hence, the study describes the network of electricity distribution in Djibouti and the various organs in charge of this energy service.The government undertook organizational innovation by implementing interconnection with a view of diversifying its production sources, lessening its vulnerability and ultimately reducing people’s energy bill.This is the reason why the study tackles the question of innovation in the energy sector through a quantitative survey on household, with a focus on residential sector in Djibouti. Semi-structured interviews were also conducted the in the hotel sector.Findings show that interconnection proved unfruitful, that is to say that energy bill has not been reduced in both residential and non-residential sector; however, it helped reducing load shedding, which, in turn, resulted in a slight improvement of the quality of the service

Evolution du service énergétique : réelle nécessité ou solution pour le développement et l’accessibilité de l’électricité en Afrique : le cas de Djibouti

In a global context marked by a growth of energy demands, particularly in sub-Saharan Africa,this thesis is devoted to the analysis of both the management and impact of energy services in Djibouti. Hence, the study describes the network of electricity distribution in Djibouti and the various organs in charge of this energy service.The government undertook organizational innovation by implementing interconnection with a view of diversifying its production sources, lessening its vulnerability and ultimately reducing people’s energy bill.This is the reason why the study tackles the question of innovation in the energy sector through a quantitative survey on household, with a focus on residential sector in Djibouti. Semi-structured interviews were also conducted the in the hotel sector.Findings show that interconnection proved unfruitful, that is to say that energy bill has not been reduced in both residential and non-residential sector; however, it helped reducing load shedding, which, in turn, resulted in a slight improvement of the quality of the service.L’étude présentée dans cette thèse est consacrée à la gestion du service énergétique à Djibouti ainsi qu’à son impact sur l’économie nationale et ceci dans un contexte international marqué par un accroissement des exigences énergétiques, notamment en Afrique subsaharienne. Ainsi, l’étude s’intéresse successivement à l’analyse du réseau de distribution d’électricité à Djibouti ainsi qu’aux différents organismes ayant en charge la gestion de ce service énergétique.L’Etat djiboutien a entrepris une innovation organisationnelle, en mettant en place l’interconnexion afin de diversifier ses sources de production, diminuer sa vulnérabilité et in fine alléger la facture énergétique des consommateurs. C’est pourquoi l’étude s’est intéressée à la question de l’innovation dans le secteur de l’énergie, pour laquelle une enquête quantitative sur le secteur résidentiel de Djibouti a été réalisée et concernant les entreprises, des entretiens semi-directifs ont été menés auprès du secteur hôtelier. Le résultat principal est que l’interconnexion n’a pas eu les effets escomptés, c’est-à-dire baisser la facture énergétique dans le secteur résidentiel et non-résidentiel, mais elle a cependant permis de diminuer les délestages, ce qui a abouti à une légère amélioration de la qualité du service

Modélisation pharmacocinétique et pharmacodynamique de population. Analyse des facteurs prédictifs de réponse aux médicaments immunosuppresseurs administrés en transplantation rénale

Thése soutenue à l'UMR-S850 Directeurs : Annick Rousseau, Aurélie Prémau

Pharmacocinétique de population du busulfan intraveineux dans le conditionnement pré-greffe de moelle osseuse chez l'enfant

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation

The premise that lower TAC trough levels are associated with subsequently higher first BPAR risk during the first 12 mo post-transplant was recently questioned. Using our prospectively followed cohort of 528 adult, primary kidney transplant recipients (pooled across four randomized trials) who received reduced TAC dosing plus an IMPDH inhibitor, TAC trough levels measured at seven time points, 7, 14 days, 1, 2, 3, 6 and 9 months post-transplant, were utilized along with Cox's model to determine the multivariable significance of TAC level(t) (a continuous time-dependent covariate equaling the most recently measured TAC level prior to time t) on the hazard rate of developing first BPAR during the first 12 months post-transplant. The percentage developing BPAR during the first 12 months post-transplant was 10.2% (54/528). In univariable analysis, lower TAC level(t) was associated with a significantly higher BPAR rate (P = 0.00006), and its significance was maintained even after controlling for 2 significant baseline predictors (African-American/Hispanic Recipient and Developed DGF) in Cox's model (multivariable P = 0.0003). Use of a cutpoint, TAC level(t) <4.0 vs. ≥4.0 ng/ml, yielded an even greater association with BPAR rate (univariable and multivariable P < 0.000001), with an estimated hazard ratio of 6.33. These results suggest that TAC levels <4.0 ng/ml should be avoided during the first 12 months post-transplant when TAC is used in combination with fixed-dose mycophenolate with or without corticosteroids and induction therapy