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Introduction Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF.Methods and analysis HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C–35°C) and normothermia (36.5°C–37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients.Ethics and dissemination The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings.Trial registration number NCT03098706.

Abstract Background There is an increasing interest in beta-blockade as a therapeutic approach to sepsis following consistent experimental findings of attenuation of inflammation and improved survival with beta1 selective antagonist. However, the mechanism of these beneficial effects remains very uncertain. Thus, this study is aimed at investigating the effects of a beta-1 selective blockade on sympathetic/parasympathetic activity in endotoxin-challenged pigs using heart rate variability. The hypothesis is that an adrenergic blockade could promote parasympathetic activity. Indeed, the increase of parasympathetic activity is a mechanism recently described as beneficial in septic states. Methods Fifty-one endotoxin-challenged pigs were studied. After 30 min of endotoxin infusion and 30 min of evolution without intervention, the pigs were randomly assigned the placebo or esmolol treatment and were observed for 200 min. Overall heart rate variability was assessed continuously, in the temporal domain by standard deviation of RR intervals (SDNN, ms),and in the frequency domain by spectral powers of low frequency (LF, ms2 × 103/Hz) and high frequency (HF, ms2 × 103/Hz) bands. Results Variations of power in these frequency bands were interpreted as putative markers of sympathetic (LF) and parasympathetic (HF) activity. In LPS treated animals, Esmolol did not increase SDNN, but instead decreased LF and increased HF power. Conclusion These spectral modifications associated to a beta-blocker treatment after an endotoxemic challenge are interpreted as a significant decrease of sympathetic activity and an indirect increase of vagal autonomic tone.

Following publication of the original article [1], the author reported these required corrections to Fig. 5 and Fig. 6:

When analyzing patient-reported outcome (PRO) data, sources of differential item functioning (DIF) can be multiple and there may be more than one covariate of interest. Hence, it could be of great interest to disentangle their effects. Yet, in the literature on PRO measures, there are many studies where DIF detection is applied separately and independently for each covariate under examination. With such an approach, the covariates under investigation are not introduced together in the analysis, preventing from simultaneously studying their potential DIF effects on the questionnaire items. One issue, among others, is that it may lead to the detection of false-positive effects when covariates are correlated. To overcome this issue, we developed two new algorithms (namely ROSALI-DIF FORWARD and ROSALI-DIF BACKWARD). Our aim was to obtain an iterative item-by-item DIF detection method based on Rasch family models that enable to adjust group comparisons for DIF in presence of two binary covariates. Both algorithms were evaluated through a simulation study under various conditions aiming to be representative of health research contexts. The performance of the algorithms was assessed using: (i) the rates of false and correct detection of DIF, (ii) the DIF size and form recovery, and (iii) the bias in the latent variable level estimation. We compared the performance of the ROSALI-DIF algorithms to the one of another approach based on likelihood penalization. For both algorithms, the rate of false detection of DIF was close to 5%. The DIF size and form influenced the rates of correct detection of DIF. Rates of correct detection was higher with increasing DIF size. Besides, the algorithm fairly identified homogeneous differences in the item threshold parameters, but had more difficulties identifying non-homogeneous differences. Over all, the ROSALI-DIF algorithms performed better than the penalized likelihood approach. Integrating several covariates during the DIF detection process may allow a better assessment and understanding of DIF. This study provides valuable insights regarding the performance of different approaches that could be undertaken to fulfill this aim.

Abstract Background The Posttraumatic growth inventory (PTGI) aims to assess the positive psychological changes that individuals can perceive after a traumatic life event such as a cancer diagnosis. Several French translations of the PTGI have been proposed, but comprehensive data on their psychometric properties are lacking. This study aimed to provide a more complete assessment of the psychometric properties of one of the most used PTGI translations in early-stage breast cancer and melanoma patients. Methods A sample of 379 patients completed the PTGI two years after their cancer diagnosis. A confirmatory analysis was first performed to determine whether the initial five-factor structure of the PTGI was adequate for this French version. As issues were identified in the translation and in the questionnaire structure, we performed an exploratory analysis to determine the most suitable structure for this questionnaire. Validity and reliability of the evidenced structured were then assessed. Results The exploratory analysis evidenced a four-factor structure close to the initial structure: four of the five initial domains were recovered, and items from the unrecovered domain were split into the other domains. This new structure showed good internal consistency and acceptable validity. Conclusions This study highlights that the process of translation and cross-cultural validation of questionnaires is crucial to obtain valid and reliable psychometric instruments. We advise French psycho-oncology researchers and psychotherapists to (i) use the revised translation of Lelorain et al. (2010) proposed in this manuscript and (ii) use the four scores newly evidenced with a grouping of two response categories.

Abstract Background Meaningfully interpreting patient-reported outcomes (PRO) results from randomized clinical trials requires that the PRO scores obtained in the trial have the same meaning across patients and previous applications of the PRO instrument. Calibration of PRO instruments warrants this property. In the Rasch measurement theory (RMT) framework, calibration is performed by fixing the item parameter estimates when measuring the targeted concept for each individual of the trial. The item parameter estimates used for this purpose are typically obtained from a previous “calibration” study. But imposing this constraint on item parameters, instead of freely estimating them directly in the specific sample of the trial, may hamper the ability to detect a treatment effect. The objective of this simulation study was to explore the potential negative impact of calibration of PRO instruments that were developed using RMT on the comparison of results between treatment groups, using different analysis methods. Methods PRO results were simulated following a polytomous Rasch model, for a calibration and a trial sample. Scenarios included varying sample sizes, with instrument of varying number of items and modalities, and varying item parameters distributions. Different treatment effect sizes and distributions of the two patient samples were also explored. Cross-sectional comparison of treatment groups was performed using different methods based on a random effect Rasch model. Calibrated and non-calibrated approaches were compared based on type-I error, power, bias, and variance of the estimates for the difference between groups. Results There was no impact of the calibration approach on type-I error, power, bias, and dispersion of the estimates. Among other findings, mistargeting between the PRO instrument and patients from the trial sample (regarding the level of measured concept) resulted in a lower power and higher position bias than appropriate targeting. Conclusions Calibration does not compromise the ability to accurately assess a treatment effect using a PRO instrument developed within the RMT paradigm in randomized clinical trials. Thus, given its essential role in producing interpretable results, calibration should always be performed when using a PRO instrument developed using RMT as an endpoint in a randomized clinical trial.

Background: Recently intermittent theta burst stimulation (iTBS) proved to be non-inferior to conventional repetitive transcranial magnetic stimulation (10 Hz rTMS) in unipolar depression after failure of one antidepressant trial, but to date no randomized control trial assessed the ability of iTBS to improve depression level and quality of life in more resistant features of depression with a long-term (6 month) follow-up in comparison to 10 Hz rTMS. Objectives/Hypothesis: The aim of our study was to compare the efficacy of 10 Hz rTMS and iTBS in treatment-resistant unipolar depression on response rates (50% decrease of MADRS scores at one month from baseline) and change in quality of life during a 6-month follow-up. In addition, we investigated whether some clinical features at baseline were associated with the response in the different groups. Method: Sixty patients were randomized in a double-blind, controlled study at the University Hospital Center of Nantes, and received 20 sessions of either rTMS or iTBS applied to the left dorsolateral prefrontal cortex targeted by neuronavigation. Statistical analysis used Fischer's exact test and Chi-square test as appropriate, linear mixed model, and logistic regression (occurrence of depressive relapse and factors associated with the therapeutic response). Results: Included patients showed in mean more than 3 antidepressants trials. Response rates were 36.7% and 33.3%, and remission rates were 18.5% and 14.8%, in the iTBS and 10 Hz rTMS groups respectively. Both groups showed a similar significant reduction in depression scores and quality of life improvement at 6 months. We did not find any clinical predictive factor of therapeutic response in this sample. Conclusion: Our study suggests the clinical interest of iTBS stimulation (which is more time saving and cost-effective as conventional rTMS) to provide long-lasting improvement of depression and quality of life in highly resistant unipolar depression.

Abstract Background Patient-Reported Outcomes (PROs) are standardized questionnaires used to measure subjective outcomes such as quality of life in healthcare. They are considered paramount to assess the results of therapeutic interventions. However, because their calibration is relative to internal standards in people’s mind, changes in PRO scores are difficult to interpret. Knowing the smallest value in the score that the patient perceives as change can help. An estimator linking the answers to a Patient Global Rating of Change (PGRC: a question measuring the overall feeling of change) with change in PRO scores is frequently used to obtain this value. In the last 30 years, a plethora of methods have been used to obtain these estimates, but there is no consensus on the appropriate method and no formal definition of this value. Methods We propose a model to explain changes in PRO scores and PGRC answers. Results A PGRC measures a construct called the Perceived Change (PC), whose determinants are elicited. Answering a PGRC requires discretizing a continuous PC into a category using threshold values that are random variables. Therefore, the populational value of the Minimal Perceived Change (MPC) is the location parameter value of the threshold on the PC continuum defining the switch from the absence of change to change. Conclusions We show how this model can help to hypothesize what are the appropriate methods to estimate the MPC and its potential to be a rigorous theoretical basis for future work on the interpretation of change in PRO scores.

ABO blood groups appear to be associated with the risk of SARS-CoV-2 infection, but the underlying mechanisms and their real importance remain unclear. Two hypotheses have been proposed: ABO compatibility-dependence (neutralization by anti-ABO antibodies) and ABO-dependent intrinsic susceptibility (spike protein attachment to histo-blood group glycans). We tested the first hypothesis through an anonymous questionnaire addressed to hospital staff members. We estimated symptomatic secondary attack rates (SAR) for 333 index cases according to spouse ABO blood group compatibility. Incompatibility was associated with a lower SAR (28% vs. 47%; OR 0.43, 95% CI 0.27–0.69), but no ABO dependence was detected in compatible situations. For the second hypothesis, we detected no binding of recombinant SARS-CoV-2 RBD to blood group-containing glycans. Thus, although no intrinsic differences in susceptibility according to ABO blood type were detected, ABO incompatibility strongly decreased the risk of COVID-19 transmission, suggesting that anti-ABO antibodies contribute to virus neutralization.

Objective: The aim of the study was to identify clinical variables associated with changes in specific domains of self-reported depression during treatment by antidepressant and/or repetitive Transcranial Magnetic Stimulation (rTMS) in patients with Major Depressive Disorder (MDD).Methods: Data from a trial involving 170 patients with MDD receiving either venlafaxine, rTMS or both were re-analyzed. Depressive symptoms were assessed each week during the 2 to 6 weeks of treatment with the 13-item Beck Depression Inventory (BDI13). Associations between depression changes on BDI13 domains (Negative Self-Reference, Sad Mood, and Performance Impairment), treatment arm, time, and clinical variables were tested in a mixed linear model.Results: A significant decrease of self-reported depressive symptoms was observed over time. The main characteristics associated with persistent higher depressive symptomatology on Negative Self-Reference domain of the BDI13 were personality disorders (+2.1 points), a past history of suicide attempt(s) (+1.7 points), age under 65 years old (+1.5 points), and female sex (+1.1 points).Conclusions: Early cognitive intervention targeting specifically negative self-referencing process could be considered during pharmacological or rTMS treatment for patients with personality disorders and past history of suicide attempt(s).

In order to investigate patients’ experience of healthcare, repeated assessments of patient-reported outcomes (PRO) are increasingly performed in observational studies and clinical trials. Changes in PRO can however be difficult to interpret in longitudinal settings as patients’ perception of the concept being measured may change over time, leading to response shift (longitudinal measurement non-invariance) and possibly to erroneous interpretation of the observed changes in PRO. Several statistical methods for response shift analysis have been proposed, but they usually assume that response shift occurs in the same way in all individuals within the sample regardless of their characteristics. Many studies aim at comparing the longitudinal change of PRO into two groups of patients (treatment arm, different pathologies, …). The group variable could have an effect on PRO change but also on response shift effect and the perception of the questionnaire at baseline. In this paper, we propose to enhance the ROSALI algorithm based on Rasch Measurement Theory for the analysis of longitudinal PRO data to simultaneously investigate the effects of group on item functioning at the first measurement occasion, on response shift and on changes in PRO over time. ROSALI is subsequently applied to a longitudinal dataset on change in emotional functioning in patients with breast cancer or melanoma during the year following diagnosis. The use of ROSALI provides new insights in the analysis of longitudinal PRO data.

Abstract Background Patients with prostate cancer (PC) may be ready to make trade-offs between their quantity and their quality of life. For instance, elderly patients may prefer the absence of treatment if it is associated with a low-risk of disease progression, compared to treatments aiming at preventing disease progression but with a substantial deterioration of their Health-Related Quality of Life (HRQoL). Therefore, it seems relevant to compare the treatments by considering both survival and HRQoL. In this mini-review, the aim was to question whether the potential trade-offs between survival and HRQoL are considered in high impact factor journals. Methods The study was conducted from the PubMed database for recent papers published between May 01, 2013, and May 01, 2015. We also restricted our search to nine medical journals with 2013 impact factor > 15. Results Among the 30 selected studies, only six collected individual HRQoL as a secondary endpoint by using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. In four studies, the time to HRQoL change was analyzed, but its definitions varied. In two studies, the mean changes in HRQoL between the baseline and the 12- or 16-week follow-up were analyzed. None of the six studies reported in a single endpoint both the quantity and the quality of life. Conclusions Our mini-review, which only focused on recent publications in journals with high-impact, suggests moving PC clinical research towards patient-centered outcomes-based studies. This may help physicians to propose the most appropriate treatment on behalf of patients. We recommend the use of indicators such as Quality-Adjusted Life-Years (QALYs) as principal endpoint in future clinical trials.

Abstract Background Intracranial hypertension (ICH) is a major cause of death after traumatic brain injury (TBI). Continuous hyperosmolar therapy (CHT) has been proposed for the treatment of ICH, but its effectiveness is controversial. We compared the mortality and outcomes in patients with TBI with ICH treated or not with CHT. Methods We included patients with TBI (Glasgow Coma Scale ≤ 12 and trauma-associated lesion on brain computed tomography (CT) scan) from the databases of the prospective multicentre trials Corti-TC, BI-VILI and ATLANREA. CHT consisted of an intravenous infusion of NaCl 20% for 24 hours or more. The primary outcome was the risk of survival at day 90, adjusted for predefined covariates and baseline differences, allowing us to reduce the bias resulting from confounding factors in observational studies. A systematic review was conducted including studies published from 1966 to December 2016. Results Among the 1086 included patients, 545 (51.7%) developed ICH (143 treated and 402 not treated with CHT). In patients with ICH, the relative risk of survival at day 90 with CHT was 1.43 (95% CI, 0.99–2.06, p = 0.05). The adjusted hazard ratio for survival was 1.74 (95% CI, 1.36–2.23, p

ObjectiveThe aims were to review practices concerning Differential Item Functioning (DIF) detection in composite measurement scales, particularly those used in health research, and to provide guidance on how to proceed if statistically significant DIF is detected.MethodsThis work specifically addressed the Rasch model which is the subject of growing interest in the field of health owing to its particularly advantageous properties. There were three steps: 1) Literature review to describe current practices; 2) Simulation study to determine under which conditions encountered in health research studies can erroneous conclusions be drawn from group comparisons when a scale is affected by DIF but which is not considered; 3) Based on steps 1 and 2, formulation of recommendations that were subsequently reviewed by leading internationally recognized experts.ResultsFour key recommendations were formulated to help researchers to determine whether statistically significant DIF is meaningful in practice, according to the kind of DIF (uniform or non-uniform) and the DIF effect size.ConclusionThis work provides the first recommendations on how to deal in practice with the presence of DIF in composite measurement scales used in health research studies.

Patient-reported outcomes (PRO) have gained importance in clinical and epidemiological research and aim at assessing quality of life, anxiety or fatigue for instance. Item Response Theory (IRT) models are increasingly used to validate and analyse PRO. Such models relate observed variables to a latent variable (unobservable variable) which is commonly assumed to be normally distributed. A priori sample size determination is important to obtain adequately powered studies to determine clinically important changes in PRO. In previous developments, the Raschpower method has been proposed for the determination of the power of the test of group effect for the comparison of PRO in cross-sectional studies with an IRT model, the Rasch model. The objective of this work was to evaluate the robustness of this method (which assumes a normal distribution for the latent variable) to violations of distributional assumption. The statistical power of the test of group effect was estimated by the empirical rejection rate in data sets simulated using a non-normally distributed latent variable. It was compared to the power obtained with the Raschpower method. In both cases, the data were analyzed using a latent regression Rasch model including a binary covariate for group effect. For all situations, both methods gave comparable results whatever the deviations from the model assumptions. Given the results, the Raschpower method seems to be robust to the non-normality of the latent trait for determining the power of the test of group effect.

BACKGROUND: Patient-reported outcomes (PRO) that comprise all self-reported measures by the patient are important as endpoint in clinical trials and epidemiological studies. Models from the Item Response Theory (IRT) are increasingly used to analyze these particular outcomes that bring into play a latent variable as these outcomes cannot be directly observed. Preliminary developments have been proposed for sample size and power determination for the comparison of PRO in cross-sectional studies comparing two groups of patients when an IRT model is intended to be used for analysis. The objective of this work was to validate these developments in a large number of situations reflecting real-life studies. METHODOLOGY: The method to determine the power relies on the characteristics of the latent trait and of the questionnaire (distribution of the items), the difference between the latent variable mean in each group and the variance of this difference estimated using Cramer-Rao bound. Different scenarios were considered to evaluate the impact of the characteristics of the questionnaire and of the variance of the latent trait on performances of the Cramer-Rao method. The power obtained using Cramer-Rao method was compared to simulations. PRINCIPAL FINDINGS: Powers achieved with the Cramer-Rao method were close to powers obtained from simulations when the questionnaire was suitable for the studied population. Nevertheless, we have shown an underestimation of power with the Cramer-Rao method when the questionnaire was less suitable for the population. Besides, the Cramer-Rao method stays valid whatever the values of the variance of the latent trait. CONCLUSIONS: The Cramer-Rao method is adequate to determine the power of a test of group effect at design stage for two-group comparison studies including patient-reported outcomes in health sciences. At the design stage, the questionnaire used to measure the intended PRO should be carefully chosen in relation to the studied population.

Subjective health measurements are increasingly used in clinical research, particularly for patient groups comparisons. Two main types of analytical strategies can be used for such data: so-called classical test theory (CTT), relying on observed scores and models coming from Item Response Theory (IRT) relying on a response model relating the items responses to a latent parameter, often called latent trait. Whether IRT or CTT would be the most appropriate method to compare two independent groups of patients on a patient reported outcomes measurement remains unknown and was investigated using simulations. For CTT-based analyses, groups comparison was performed using t-test on the scores. For IRT-based analyses, several methods were compared, according to whether the Rasch model was considered with random effects or with fixed effects, and the group effect was included as a covariate or not. Individual latent traits values were estimated using either a deterministic method or by stochastic approaches. Latent traits were then compared with a t-test. Finally, a two-steps method was performed to compare the latent trait distributions, and a Wald test was performed to test the group effect in the Rasch model including group covariates. The only unbiased IRT-based method was the group covariate Wald's test, performed on the random effects Rasch model. This model displayed the highest observed power, which was similar to the power using the score t-test. These results need to be extended to the case frequently encountered in practice where data are missing and possibly informative.

Infections are the most frequent cause of complications in trauma patients. Post-traumatic immune suppression (IS) exposes patients to pneumonia (PN). The main pathogen involved in PN is Methicillin Susceptible Staphylococcus aureus (MSSA). Dendritic cells () may be centrally involved in the IS. We assessed the consequences of hemorrhage on pneumonia outcomes and investigated its consequences on DCs functions. A murine model of hemorrhagic shock with a subsequent MSSA pneumonia was used. Hemorrhage decreased the survival rate of infected mice, increased systemic dissemination of sepsis and worsened inflammatory lung lesions. The mRNA expression of Tumor Necrosis Factor-alpha (TNF-α), Interferon-beta (IFN-β) and Interleukin (IL)-12p40 were mitigated for hemorrhaged-mice. The effects of hemorrhage on subsequent PN were apparent on the pDCs phenotype (reduced MHC class II, CD80, and CD86 molecule membrane expression). In addition, hemorrhage dramatically decreased CD8(+) cDCs- and CD8(-) cDCs-induced allogeneic T-cell proliferation during PN compared with mice that did not undergo hemorrhage. In conclusion, hemorrhage increased morbidity and mortality associated with PN; induced severe phenotypic disturbances of the pDCs subset and functional alterations of the cDCs subset. After hemorrhage, a preventive treatment with CpG-ODN or Monophosphoryl Lipid A increased transcriptional activity in DCs (TNF-α, IFN-β and IL-12p40) and decreased mortality of post-hemorrhage MSSA pneumonia.