Long-term survival of traumatic brain injury and intra-cerebral haemorrhage patients: A multicentric observational cohort.

PURPOSE: Mortality is often assessed during ICU stay and early after, but rarely at later stage. We aimed to compare the long-term mortality between TBI and ICH patients. MATERIALS AND METHODS: From an observational cohort, we studied 580 TBI patients and 435 ICH patients, admitted from January 2013 to February 2021 in 3 ICUs and alive at 7-days post-ICU discharge. We performed a Lasso-penalized Cox survival analysis. RESULTS: We estimated 7-year survival rates at 72.8% (95%CI from 67.3% to 78.7%) for ICH patients and at 84.9% (95%CI from 80.9% to 89.1%) for TBI patients: ICH patients presenting a higher mortality risk than TBI patients. Additionally, we identified variables associated with higher mortality risk (age, ICU length of stay, tracheostomy, low GCS, absence of intracranial pressure monitoring). We also observed anisocoria related with the mortality risk in the early stage after ICU stay. CONCLUSIONS: In this ICU survivor population with a prolonged follow-up, we highlight an acute risk of death after ICU stay, which seems to last longer in ICH patients. Several variables characteristic of disease severity appeared associated with long-term mortality, raising the hypothesis that the most severe patients deserve closer follow-up after ICU stay.

Renal transplantation outcomes in obese patients: a French cohort-based study.

BACKGROUND: Whilst there are a number of publications comparing the relationship between body mass index (BMI) of kidney transplant recipients and graft/patient survival, no study has assessed this for a French patient cohort. METHODS: In this study, cause-specific Cox models were used to study patient and graft survival and several other time-to-event measures. Logistic regressions were performed to study surgical complications at 30 days post-transplantation as well as delayed graft function. RESULTS: Among the 4691 included patients, 747 patients were considered obese with a BMI level greater than 30 kg/m2. We observed a higher mortality for obese recipients (HR = 1.37, p = 0.0086) and higher risks of serious bacterial infections (HR = 1.24, p = 0.0006) and cardiac complications (HR = 1.45, p < 0.0001). We observed a trend towards death censored graft survival (HR = 1.22, p = 0.0666) and no significant increased risk of early surgical complications. CONCLUSIONS: We showed that obesity increased the risk of death and serious bacterial infections and cardiac complications in obese French kidney transplant recipients. Further epidemiologic studies aiming to compare obese recipients versus obese candidates remaining on dialysis are needed to improve the guidelines for obese patient transplant allocation.

SMILE: a predictive model for Scoring the severity of relapses in MultIple scLErosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients. OBJECTIVE: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS. METHODS: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients. RESULTS: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations. CONCLUSION: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

The EKiTE network (epidemiology in kidney transplantation - a European validated database): an initiative epidemiological and translational European collaborative research.

BACKGROUND: Kidney transplantation is considered to be the treatment of choice for people with end-stage renal disease (ESRD). However, due to the shortage of available organs and the increase in the ESRD prevalence in Europe, it is essential to improve transplantation outcomes by studying the related prognostic factors. Today, there is no European registry collecting data to perform such clinical epidemiology studies. MAIN BODY: Entitled EKiTE, for European cohort for Kidney Transplantation Epidemiology, this prospective and multicentric cohort includes patients from Spanish (Barcelona), Belgian (Leuven), Norwegian (Oslo) and French (Paris Necker, Lyon, Nantes, Nancy, Montpellier, Nice and Paris Saint Louis) transplantation centers and currently contains 13,394 adult recipients of kidney (only) transplantation from 2005 and updated annually. A large set of parameters collected from transplantation until graft failure or death with numbers of post-transplantation outcomes. The long-term follow-up and the collected data enable a wide range of possible survival and longitudinal analyses. CONCLUSION: EKiTE is a multicentric cohort aiming to better assess the natural history of the ESRD in European kidney transplant recipients and perform benchmarking of clinical practices. The data are available for clinical epidemiology studies and open for external investigators upon request to the scientific council. Short-term perspectives are to extend EKITE network to other European countries and collect additional parameters in respect of the common thesaurus.

Propensity score-based comparison of the graft failure risk between kidney transplant recipients of standard and expanded criteria donor grafts: Toward increasing the pool of marginal donors.

From a prospective and multicentric French cohort, we proposed an external validation study for the expanded criteria donor (ECD), based on 4833 kidney recipients transplanted for the first time between 2000 and 2014. We estimated the subject-specific effect from a multivariable Cox model. We confirmed a 1.75-fold (95% confidence interval [CI] 1.53-2.00, P < .0001) increase in graft failure risk if a given patient received an ECD graft compared to a graft from a donor with standard criteria (standard criteria donor [SCD]). Complementarily, we estimated the population-average effect using propensity scores. We estimated a 1.34-fold (95% CI 1.09-1.64, P = .0049) increase in graft failure risk among ECD patients receiving an ECD graft compared to receiving a SCD graft. With a 10-year follow-up, it corresponded to a decrease of 8 months of the mean time to graft failure due to ECD transplantation (95% CI 2-14 months). The population-average relative risk due to ECD transplantation and the corresponding absolute effect seem finally not so high. Regarding the increase of quality of life in transplantation, our study constitutes an argument to extend the definition of marginality by considering more grafts at high risk and thereby enlarging the pool of kidney grafts.

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

A literature-based approach to evaluate the predictive capacity of a marker using time-dependent summary receiver operating characteristics.

Meta-analyses are popular tools to summarize the results of publications. Prognostic performances of a marker are usually summarized by meta-analyses of survival curves or hazard ratios. These approaches may detect a difference in survival according to the marker but do not allow evaluation of its prognostic capacity. Time-dependent receiver operating characteristic curves evaluate the ability of a marker to predict time-to-event. In this article, we describe an adaptation of time-dependent summary receiver operating characteristic curves from published survival curves. To achieve this goal, we modeled the marker and the time-to-event distributions using non-linear mixed models. First, we applied this methodology to individual data in kidney transplantation presented as aggregated data, in order to validate the method. Second, we re-analyzed a published meta-analysis, which focused on the capacity of KI-67 to predict the overall survival of patients with breast cancer.

Pretransplant sensitization against angiotensin II type 1 receptor is a risk factor for acute rejection and graft loss.

The angiotensin II type 1 receptor (AT1R) is an emerging target of functional non-HLA antibodies (Ab). We examined the potential of determining the degree of presensitization against AT1R as a risk factor for graft survival and acute rejection (AR). The study included 599 kidney recipients between 1998 and 2007. Serum samples were analyzed in a blinded fashion for anti-AT1R antibodies (AT1R-Abs) using a quantitative solid-phase assay. A threshold of AT1R-Ab levels was statistically determined at 10 U based on the time to graft failure. An extended Cox model determined risk factors for occurrence of graft failure and a first AR episode. AT1R-Abs >10 U were detected in 283 patients (47.2%) before transplantation. Patients who had a level of AT1R-Abs >10 U had a 2.6-fold higher risk of graft failure from 3 years posttransplantation onwards (p = 0.0005) and a 1.9-fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p = 0.0393). Antibody-mediated rejection (AMR) accounted for 1/3 of AR, whereby 71.4% of them were associated with >10 U of pretransplant AT1R-Abs. Pretransplant anti-AT1R-Abs are an independent risk factor for long-term graft loss in association with a higher risk of early AR episodes.

Early steroid withdrawal compared with steroid avoidance correlates with graft failure among kidney transplant recipients with an history of diabetes.

BACKGROUND: Steroid minimization strategies attempt to reduce morbidity in kidney transplantation. Concern still exists regarding long-term outcomes using either steroid withdrawal or steroid avoidance regimens. METHODS: During a 10-year period, 572 primary kidney transplant recipients were treated with basiliximab, calcineurin inhibitors, and mycophenolate mofetil: 417 (72.9%) underwent a steroid-taper regimen over 2-3 months (steroid withdrawal) and 155 (27.1%), complete steroid avoidance (steroid avoidance). RESULTS: Despite no significant difference during the first 3 months (hazard ratio [HR], 1.23; P = .5349), steroid withdrawal recipients showed an increased risk of late acute rejection episodes (HR, 4.06; P = .0585), independent of recipient age >55 years (HR, 1.84; P = .0272). The risk of any adverse event was not different among steroid regimen groups (HR, 0.98; P = .8458), independent of recipient age >55 years (HR, 1.69; P = .0002), delayed graft function (DGF) (HR, 1.54; P = .0001), and positive donor Epstein-Barr virus serology (HR, 0.68; P = .0471). Intention-to-treat analyses revealed a significantly greater risk of graft failure only in diabetic recipients in the steroid withdrawal group (HR, 8.18; P = .0065), independent of confounding risk factors such as recipient age >55 years (HR, 1.99; P = .0244), >4 human leukocyte antigen-A, -B, and -DR incompatibilities (HR, 1.64; P = .0475), and DGF occurrence (HR, 2.63; P < .0001). CONCLUSION: Although both steroid minimization strategies were comparable regarding long-term safety and efficacy, an increased rate of graft failure was observed among diabetics who underwent steroid withdrawal compared with steroid avoidance.

The natural history of clinical operational tolerance after kidney transplantation through twenty-seven cases.

We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3%[p = 0.0455] and 96.7%[p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 ± 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.

BAFF and BAFF-R levels are associated with risk of long-term kidney graft dysfunction and development of donor-specific antibodies.

There are lines of evidence that B cells may play a role in transplantation. B cell activating factor, BAFF, is a homotrimer that has been shown to play a role in B cell survival, maturation and activation. To date, little is known of the role of BAFF and its receptors in transplantation. We analyzed the level of BAFF mRNA and its soluble protein, as well as transcripts coding for its receptors, BAFF-R, TACI and BCMA, in the blood of 143 patients with stable kidney transplant function 5 years or more posttransplantation. Three endpoints were analyzed: the time to renal dysfunction, the time to appearance of anti-HLA antibodies and the time to development of donor-specific antibodies. We established threshold values for BAFF and BAFF-R and showed that (1) stable patients with high BAFF-R levels had a higher risk of developing graft dysfunction, (2) patients with lower levels of BAFF transcripts or a higher level of soluble BAFF had a significantly higher risk of developing donor-specific antibodies. These data suggest that BAFF constitutes a risk factor for renal graft dysfunction and development of donor-specific antibodies. They also suggest that agents targeting BAFF-R interactions may offer new therapeutic opportunities in transplantation.

Time-dependent ROC analysis for a three-class prognostic with application to kidney transplantation.

The medical decision-making community has an extensive literature on the use of receiver operating characteristic (ROC) graphs for diagnostic testing. Heagertybiet al. have recently developed this ROC curve theory within the context of survival data (Biometrics 2000; 56:337-344). The time-dependent ROC method allows evaluating the accuracy of a marker to predict a time-dependent failure, whereas the classic methodology focuses on diagnosis. One limitation to this approach, however, is to analyse a single failure. In many medical situations, a marker can be useful to predict different competitive failures. For example in kidney transplantation, the terminal evolution can be a return to dialysis or the death of the patient. With this application in mind, our paper proposes an extension of the time-dependent ROC method for analysing the accuracy of a marker to predict two competitive events.

A flexible semi-Markov model for interval-censored data and goodness-of-fit testing.

Multi-state approaches are becoming increasingly popular to analyse the complex evolution of patients with chronic diseases. For example, the evolution of kidney transplant recipients can be broken down into several clinical states. With this application in mind, we present a flexible semi-Markov model. The distribution functions are fitted to the durations in states and the relevance of the generalised Weibull distribution is shown. The corresponding likelihood function allows for interval censoring, i.e. the times of transitions and the sequences of states are not available during the elapsed times between two visits. The explanatory variables are introduced through the Markov chain and through the probability density functions of durations. A goodness-of-fit test is also defined to examine the stationarity of the semi-Markov model.

[Local guidelines and quality of antibiotic treatment in urinary tract infections: a clinical audit in two departments of a university hospital]. / Impact de recommandations locales sur la qualité de l'antibiothérapie dans l'infection urinaire. Audit clinique dans 2 services d'un hôpital universitaire.

AIM: To assess the effect of local guidelines implemented at the Nantes University Hospital regarding antibiotic therapy for urinary tract infections. DESIGN: Before/after study of one medical ward and one urologic surgery ward. Quality was measured by two principal criteria: compliance with guidelines and medical justification in the specific clinical situation. Both criteria considered simultaneously the choice of drug, dose and duration of treatment. Deviations from the guidelines were described. RESULTS: 1086 UTI cases were identified over two 12-month periods, before and after the dissemination of guidelines (for prostatitis, pyelonephritis, indwelling catheter-associated UTIs, and other undefined UTIs). The guidelines were applicable in 313 (30%) cases. Overall, after implementation of the guidelines, the percentage of justified prescriptions did not change significantly (41.8% compared with 38.7%, p=0.299), but the percentage of correct (conforming) prescriptions fell (from 30.4% to 15.7%, p=0.0022). The percentages of correct and justified prescriptions differed in the medical (respectively 45.0% and 46.6%,) and surgical units (13.1% and 36.5%). CONCLUSIONS: Issuing guidelines does not necessarily improve the quality of antibiotic therapy for UTIs in hospitals.

[Adequate prescription of antibiotic therapy for urinary tract infections in hospital: identifying and correcting non-observance of guidelines]. / Bonnes pratiques de prescription des antibiotiques pour la prise en charge des infections urinaires en milieu hospitalier: identification des écarts aux recommandations et actions correctrices.

OBJECTIVE: We analyzed the adequacy of antibiotic therapy prescribed for urinary tract infections (UTI): prostatitis, pyelonephritis, indwelling catheter-associated UTIs, or other undefined UTIs. DESIGN: The adequacy of prescriptions to local guidelines was assessed retrospectively in two wards (Internal Medicine and Surgical Urology) of the Nantes University Hospital. The principal criteria involved simultaneously: choice of the molecule, dose, and treatment duration. Non-observances of guidelines were major (non-adequacy of the molecule, prescription of a non-active molecule according to in vitro susceptibility tests, non-appropriate treatment abstention), or minor (non-justified treatment, non-justified bitherapy, no prescription of bitherapy when requested, no treatment adaptation when requested, too short or too long treatment length, dosage mistakes). RESULTS: One thousand eighty-six infections were collected over a 24-month period. The overall rate of adequate prescriptions was 40.1% (46.6% in Internal Medicine and 36.5% in Surgical Urology). In Internal Medicine (226 non observance among 389 prescriptions), the ratio of major non-observance of guidelines was 9.8%. Among them, 44.7% were non-appropriate treatment abstentions. In Surgical Urology (539 non observance out of 695 prescriptions), non-observance related to treatment length were the most frequent. The ratio of major non-observance was 19.9%. Among them, non-adequacy of the molecule reached 60.7%. Non-justified treatment and non-appropriate bitherapies were frequent. CONCLUSIONS: For both units, indwelling catheter-related UTIs and other UTIs accounted for more than 50% of the infections although not detailed in the local guidelines. Identifying and analyzing Non observance may lead to targeted correcting actions to improve prescription quality.