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Etat de la question Les progres en transplantation hepatique et les changements epidemiologiques recents ont conduit a une augmentation du nombre de receveurs âges de plus de 65 ans, et ce malgre un contexte de penurie d’organes. Nous avons etudie l’impact de l’âge avance des receveurs sur la mortalite a cinq et dix ans d’une transplantation hepatique. Materiel et methodes Les patients majeurs transplantes pour la premiere fois entre 2007 et 2017, enregistres dans la base nationale de l’Agence de la biomedecine francaise etaient inclus. Des modeles flexibles de survie observee et de survie nette ont ete utilises pour tenir compte des effets dependants du temps et/ou non log-lineaires et de la mortalite attendue pour chaque patient compte tenu de son sexe et de son âge. Resultats Au total, 7610 patients ont ete inclus (âge moyen a la greffe de 55 ans [± 10,5]). Plus les receveurs etaient âges, meilleure etait leur fonction hepatique. Les analyses de survie observee comme de survie nette ont montre une association significative entre l’augmentation de l’âge du receveur et le risque de deces. Cependant si cet effet pejoratif etait majeur dans la premiere annee suivant la greffe, il diminuait progressivement au cours du suivi. Une difference absolue de 8 % (50 % versus 42 %) de survie nette persiste malgre tout a 10 ans entre des receveurs de 28 et 71 ans. Conclusion Malgre une selection des candidats âges, l’âge a la greffe etait associe a une augmentation du risque de deces, particulierement marquee dans la premiere annee suivant la transplantation. Cet effet diminuait ensuite mais restait present a cinq et dix ans de la greffe, y compris apres prise en compte de la mortalite attendue par âge et par sexe dans la population francaise.

Introduction The dose-response relationship is considered as one of the major criteria when the causality of a relationship between an exposure and an outcome is discussed. This criterion is mainly studied in observational studies but may be also of interest in Randomized Controlled Trial (RCT), particularly if the administered dose of treatment varies over time and between patients. Maintenance trials with a long follow-up meet these characteristics. We reanalyzed a maintenance trial in digestive oncology (PRODIGE 9 trial) in order to explore the dose-response relationship between the maintenance treatment and overall survival (OS). Methods The PRODIGE 9 study was a maintenance trial assessing the benefit of maintaining bevacizumab during chemotherapy-free intervals (CFI) in patients with a stage IV colon cancer. We defined five time-updated maintenance exposures: cumulative exposure (CE); relative exposure (RE) either expressed as a continuous (patient's CE divided by the standard deviation of the distribution of CE in the population at risk) or as a categorical variable (‘with quantiles of the distribution of the CE as cut-offs); and two variables that took into account delay since the administration thus allowing a decrease exposure over time: time-updated theoretical blood concentration (TBC) and weighted cumulative exposure (WCE). We defined these exposures using either bevacizumab received during the entire follow-up (total dose) or only during CFI, resulting in ten different exposures. These variables were then included in independent Cox models with an origin fixed at the beginning of the maintenance treatment, and with overall survival (OS) as the outcome. All models were adjusted on the group of randomization (group) and compared using the Akaike Information Criterium (AIC). Results Of the initial 494 patients included in the RCT, 382 were alive and had not experienced progression at the beginning of the maintenance treatment and were thus included in the present study. All exposure variables (CE, RE, TBC and WCE) improved the quality of the model that include only the group of randomization. The best AIC was obtained when adjusting on TBC and WCE. RE led to a moderate improvement of the goodness of fit and CE only led to a small improvement. WCE was associated with a strong protective effect during the first twenty days after administration, and after 200 days. For continuous and categorical RE the highest risk was observed for medium RE, in comparison with low and high REs which were associated with a lower risk. We did not observe major differences between models using the total dose of bevacizumab and those using only the dose received during CFI. Excluding the group of randomization also did not change the estimated effects. Discussion Of the many significant results observed in this reanalysis, only the effect of RE can be considered as a possible evidence of a protective effect of the treatment on overall survival. Indeed, even if TBC and WCE led to the best goodness of fit, their definition can induce immortal time bias and can lead them to act as a mediator variable. The protective effect of low RE is difficult to explain but might be related to an early immortal-time period. Adjustment on the treatment group did not modify the dose-effect relationship. Further analysis should rely on more complex models like structural equation models to disentangle the real impact of the administered dose of bevacizumab on outcomes.

Background In sub-Saharan Africa, problems of access to relevant and high-quality facility-based statistics hinder the assessment of safe motherhood programs. The objective of this study was to assess the quality of data collected in referral hospitals in Mali and Senegal after the routine information system (RIS) was strengthened. Methods This was a multicenter observational study conducted during the pre-intervention period of a randomized controlled trial (trial QUARITE). The RIS was strengthened based on technical, organizational and behavioral factors. We included all women who gave birth in the 46 referral hospitals from October 1, 2007 to October 30, 2008. The completeness, completion and accuracy rates were monitored every 3 months in each hospital. The cost of investment needed to strengthen the existing RIS was also determined. Results The mean completeness rate ranged from 94 to 97% depending on the study period. The completion and accuracy rates increased during the study period from 72% and 79% to 87% and 93%, respectively (significant differences). The average investment per hospital was less than 1% of state subsidies for public hospitals. Conclusion Strengthening the existing information system has set up an economically and technologically appropriate system for monitoring maternal and perinatal health in Senegal and Mali. We encourage policy makers and researchers from countries with limited resources to invest in RIS to improve and monitor the performance of health systems.

Introduction Les etudes pronostiques estiment souvent des courbes de survie qui decrivent comment la probabilite d’un evenement d’interet change avec la duree de suivi, pour des patients avec differents vecteurs de covariables. Cependant, la validite de ces estimations, et des predictions de risque qui en resultent, depend en grande partie de la precision de l’estimation des effets des covariables evaluees. Pour eviter les hypotheses de risques proportionnels et de linearite conventionnelles, des extensions flexibles du modele de Cox a risques proportionnels incorporent des effets non lineaires (NL) et/ou des effets dependants du temps (TD). Cependant, leur impact sur l’estimation des courbes de survie n’est pas clair. Methodes Nous proposons un modele multivarie flexible pour estimer des courbes de survie individuelles, conditionnelles aux effets NL et/ou TD des covariables. Les fonctions TD et NL ainsi que le logarithme de la fonction de risque de base sont representes par des fonctions splines. Nous validons par simulations nos estimations des courbes de survie et les comparons avec les estimations conventionnelles, basees sur le modele de Cox a risques proportionnels combine avec l’estimateur de Breslow. Nous appliquons alors notre methode pour reevaluer les effets de plusieurs facteurs pronostiques sur la mortalite apres un choc septique. La cohorte etudiee inclus tous les adultes avec un diagnostic de choc septique, admis dans 14 unites de soins intensifs dans 10 hopitaux du Nord-Est de la France, entre octobre 2009 et septembre 2011. L’instant initial est defini comme l’initiation de vasopresseurs en reponse au choc septique et l’evenement d’interet est le deces (toute cause confondue) dans les trois premiers mois suivant le choc septique. Les patients toujours vivants trois mois apres le choc septique ont ete censures a trois mois. La duree de suivie mediane est de 63,5 jours et on observe 433 deces parmi les 858 patients ayant des donnees completes. Resultats Les simulations demontrent que la prise en compte des effets TD et NL peut grandement ameliorer les resultats des etudes pronostiques et que nos estimations flexibles des courbes de survie etaient non biaisees et avaient des erreurs quadratiques moyennes beaucoup plus faibles que les estimations conventionnelles. Dans les analyses appliquees a la mortalite apres un choc septique, notre modele a tres significativement ameliore la deviance (LRT = 84,8, df = 20, p Conclusion La prise en compte des effets non lineaires et/ou dependants du temps des facteurs pronostiques peut considerablement ameliorer la precision des etudes pronostiques.

In sub-Saharan Africa, problems of access to relevant and high-quality facility-based statistics hinder the assessment of safe motherhood programs. The objective of this study was to assess the quality of data collected in referral hospitals in Mali and Senegal after the routine information system (RIS) was strengthened.This was a multicenter observational study conducted during the pre-intervention period of a randomized controlled trial (trial QUARITE). The RIS was strengthened based on technical, organizational and behavioral factors. We included all women who gave birth in the 46 referral hospitals from October 1, 2007 to October 30, 2008. The completeness, completion and accuracy rates were monitored every 3 months in each hospital. The cost of investment needed to strengthen the existing RIS was also determined.The mean completeness rate ranged from 94 to 97% depending on the study period. The completion and accuracy rates increased during the study period from 72% and 79% to 87% and 93%, respectively (significant differences). The average investment per hospital was less than 1% of state subsidies for public hospitals.Strengthening the existing information system has set up an economically and technologically appropriate system for monitoring maternal and perinatal health in Senegal and Mali. We encourage policy makers and researchers from countries with limited resources to invest in RIS to improve and monitor the performance of health systems.