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Breast cancer (BC) is the leading cause of cancer and cancer mortality among women worldwide. Surgery is the primary therapeutic strategy of BC in most of the cases. Efficient carcinologic and aesthetic resection requires breast surgeons to accurately understand medical images. Virtual reality (VR) is a promising avenue to improve surgical diagnosis and planning by producing high-precision images. Hereafter we report three cases of patients for which using AVATAR medical device for 3D visualization with VR would have helped to decide surgical strategy and adapt surgical procedure. The three cases are real-life examples of using the VR-AVATAR medical device for breast cancer surgery treatment: evaluation of the tumor response to neoadjuvant chemotherapy, decision for breast conservative or radical treatment, decision for loco-regional treatment in metastatic setting. Through these three real-life cases, we describe the potential impact of VR-AVATAR medical device use in clinical daily practice in breast cancer surgery. It seems like a useful tool, easy to use, providing high-quality images, helping with surgery planning and decisions.

Background Therapeutic failure is a frequent issue in the management of post-operative peritonitis. Objectives A post hoc analysis of the prospective, multicentre DURAPOP trial analysed the risk factors for failures in post-operative peritonitis following adequate source control and empirical antibiotic therapy in critically ill patients. Patients and methods Overall failures assessed post-operatively between Day 8 and Day 45 were defined as a composite of death and/or surgical and/or microbiological failures. Risk factors for failures were assessed using logistic regression analyses. Results Among the 236 analysed patients, overall failures were reported in 141 (59.7%) patients, including 30 (12.7%) deaths, 81 (34.3%) surgical and 95 (40.2%) microbiological failures. In the multivariate analysis, the risk factors associated with overall failures were documented piperacillin/tazobactam therapy [adjusted OR (aOR) 2.10; 95% CI 1.17–3.75] and renal replacement therapy on the day of reoperation (aOR 2.96; 95% CI 1.05–8.34). The risk factors for death were age (aOR 1.08 per year; 95% CI 1.03–1.12), renal replacement therapy on reoperation (aOR 3.95; 95% CI 1.36–11.49) and diabetes (OR 6.95; 95% CI 1.34–36.03). The risk factors associated with surgical failure were documented piperacillin/tazobactam therapy (aOR 1.99; 95% CI 1.13–3.51), peritoneal cultures containing Klebsiella spp. (aOR 2.45; 95% CI 1.02–5.88) and pancreatic source of infection (aOR 2.91; 95% CI 1.21–7.01). No specific risk factors were identified for microbiological failure. Conclusions Our data suggest a predominant role of comorbidities, the severity of post-operative peritonitis and possibly of documented piperacillin/tazobactam treatment on the occurrence of therapeutic failures, regardless of their type.

The efficiency of a Rotating Detonation Combustor (RDC) strongly depends on the transitory injection process of fresh reactants in the combustion chamber: poor propellant mixing induces losses of combustion efficiency and consequently low detonation speed and unstable detonation propagation. Moreover, dilution of fresh reactants with burnt gases during injection increases the deflagration losses and decreases the pressure gain provided by the detonation. Numerical simulation can help design an efficient injector to reduce these losses. In this study, the modeling strategy previously proposed by ONERA to simulate the transitory injection process is applied to two existing experimental RDC (from Nagoya University and TU Berlin) and one in-development RDC from ONERA. The computational domain represents only one injection element, convenient for a parametric study at low computational cost. A custom initial condition is used to model the expansion process of burnt gases past a detonation wave. The initial condition parameters are discussed and a method is proposed to correctly set them. The TU Berlin RDC is studied in more detail: mixing efficiency up to 70% is obtained, and 5% of deflagration losses are estimated according to the assumptions of the simulation. Based on the numerical results, detonation speed was evaluated at various distances from the injection plane taking into account the heterogeneities of the fresh mixture. The measured speed lies within the predicted range.

International audience; Aim: To compare methods of quantifying serum hepcidin (based on MS and ELISA) and their ability to diagnose true iron deficiency anemia in critically ill patients. Materials & methods: Serum hepcidin was measured in 119 critically ill patients included in the HEPCIDANE clinical trial, using either an ultra-sensitive ELISA kit (from DRG) or two different MS methods. Results: The results show a good correlation between the different methods studied. The Bland–Altman analysis and the Kappa test for clinical groups show a good or very good agreement between the different tests. Conclusion: ELISA or MS show a satisfactory commutability to quantify serum hepcidin. This is of great importance for the determination of therapeutic strategies in iron deficiency.

International audience; Background: Ventilator-associated pneumonia (VAP) is the most frequent health care-associated infection in severely ill patients, and aspiration of contaminated oropharyngeal content around the cuff of the tracheal tube is the main route of contamination.Research question: Is continuous regulation of tracheal cuff pressure using a pneumatic device superior to manual assessment three times daily using a portable manometer (routine care) in preventing VAP in patients with severe trauma?Study design and methods: In this open-label, randomized controlled superiority trial conducted in 13 French ICUs, adults (age ≥ 18 years) with severe trauma (Injury Severity Score > 15) and requiring invasive mechanical ventilation for ≥ 48 h were enrolled. Patients were randomly assigned (1:1) via a secure Web-based random number generator in permuted blocks of variable sizes to one of two groups according to the method of tracheal cuff pressure control. The primary outcome was the proportion of patients developing VAP within 28 days following the tracheal intubation, as determined by two assessors masked to group assignment, in the modified intention-to-treat population. This study is closed to new participants.Results: A total of 434 patients were recruited between July 31, 2015, and February 15, 2018, of whom 216 were assigned to the intervention group and 218 to the control group. Seventy-three patients (33.8%) developed at least one episode of VAP within 28 days following the tracheal intubation in the intervention group compared with 64 patients (29.4%) in the control group (adjusted subdistribution hazard ratio, 0.96; 95% CI, 0.76-1.20; P = .71). No serious adverse events related to the use of the pneumatic device were noted.Interpretation: Continuous regulation of cuff pressure of the tracheal tube using a pneumatic device was not superior to routine care in preventing VAP in patients with severe trauma.Clinical trial registration: ClinicalTrials.gov; No.: NCT02534974; URL: www.clinicaltrials.gov.

BACKGROUND: Although no survival benefit has been demonstrated by treating early breast cancer (BC) with neoadjuvant chemotherapy (NAC), it is now widely accepted as first intention strategy in triple negative and HER2-positive BC. However, the benefit of the neoadjuvant strategy is controversial in luminal tumours. The latter are considered as poor responder to chemotherapy and it remains unknown if delaying time to surgery by providing NAC as first treatment might be deleterious. The aim of this study was to compare the prognosis of patients with Luminal B BC treated with either NAC, either adjuvant chemotherapy. MATERIALS AND METHODS: We retrospectively identified in our institutional database 188 patients with grade 3 luminal B BC treated with NAC and 1203 patients treated with the same adjuvant chemotherapy (AC). To deal with the selection bias, the contribution of each subject was weighted by a propensity score (PS): 1/PS for patient with the NAC strategy and 1/(1-PS) for patients with the AC strategy. This enables to generate a pseudo-population with a balanced covariates combination between groups. We evaluated the disease free survival (DFS), the distant metastasis free survival (DMFS) and the overall survival (OS) using a weighted Cox model. To analyse the effect of NAC in high-risk subgroups, we introduced in the model interaction effects with the initial tumour size and the initial clinical nodal status. RESULTS: By construction, patients, tumor characteristics and trastuzumab use were similar between the population treated with NAC and the population treated with adjuvant CT. After PS weighting and adjustment on confounding factors, DFS (HR = 2.56, 95%IC [1.73 - 3.78]; p< 0.001), DMFS (HR = 1.28, 95%IC [1 - 1.63]; p < 0.001) and OS were lower in the NAC group (HR = 1.51, 95%IC [1.10-2.09]]; p = 0.01) when compared with the group of patients treated with adjuvant chemotherapy.The interaction test between the initial clinical nodal status, initial clinical tumour size and survival endpoints was significant, highlighting a different prognostic effect of NAC versus AC in nodes-positive than in node-negative patients, and a different prognostic effect of NAC versus AC in small than in large tumours. No significant DFS nor OS difference was found in node-negative patients. In node-positive patients with tumour larger than 20mm, the risk of death was nearly doubled when comparing NAC strategy to AC strategy (HR=2.30, 95%CI [1.34-3.4]), while the highest deleterious impact on OS of the NAC strategy against the AC strategy was observed in node-positive patients with a tumour size smaller than ≤20mm (HR=3.52, 95%CI [1.59-7.8]). CONCLUSION: In node-positive, grade 3, luminal B tumours, receiving NAC seems associated with an impaired survival when compared with receiving the same treatment in the adjuvant setting. Our results suggest that surgery as first treatment could be the preferred option, even if breast-conserving surgery cannot be obtained. In tumors smaller than 20mm, NAC strategy should be avoided irrespective of the nodal status. Citation Format: Enora Laas, Thomas Gaillard, Jean Guillaume Feron, Jean-Yves Pierga, Florence Coussy, Beatriz Grandal, Audrey Bellesoeur, Eléonore De Guillebon, Sonia Rozette, Clemence Evrevin, Lucie Laot, Marick Lae, Anne Sophie Hamy, Fabien Reyal. Impact of neoadjuvant chemotherapy on survival in luminal B tumours: A propensity score weighted analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-35.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is increasingly being used for locally advanced breast cancers (BCs) or aggressive BC tumors. However, no survival benefit of the neoadjuvant approach over receiving chemotherapy in the adjuvant setting has been proven so far in HER2-positive early breast cancer (BC) patients. The objective of this study was to compare the prognosis of patients with an HER2-positive BC treated with NAC to patients treated with adjuvant chemotherapy (AC). MATERIALS AND METHODS: We retrospectively identified in our institutional database 203 patients with HER2-positive BCs treated with NAC plus trastuzumab and 701 patients treated with adjuvant chemotherapy. As the treatment was not randomly allocated, we used a propensity score with an Inverse probability of received treatment weighting (IPTW) to generate a pseudo-population in which each covariate combination was balanced between treatment groups. The disease free (DFS), distant metastasis free (DMFS) and overall survival (OS) were evaluated using a weighted Cox model. The interactions with poor prognosis factors (initial tumour size, tumour grade, hormone receptor status and initial clinical nodal status) were tested to evaluate the effect of the NAC in high-risk tumours. RESULTS: By construction, patients, tumor characteristics and trastuzumab use were similar between the population treated with NAC and the population treated with adjuvant CT. No difference was found regarding DFS (p=0.3) neither DMFS (p=0.4) in the global population. However, there was a significant interaction effect between the strategy and the initial clinical nodal status, with a DFS benefit of NAC over AC in the node-positive group (HR 0.53 CI95% [0.31- 0.89]), as well as for DMFS (HR 0.39 95%CI [0.20-0.77]). We found a significant benefit in OS with the neoadjuvant strategy when compared with the adjuvant strategy (HR = 0.12 95%CI [0.03-0.47], p=0.002) and this difference was significant irrespective of tumour size, initial clinical nodal status and hormone receptor status. CONCLUSION: In patients with HER2-positive BCs, receiving NAC is associated with an improved OS when compared with chemotherapy received in the adjuvant setting. Our results support the fact that NAC should become a standard of care in HER2-positive tumours. Citation Format: Enora Laas, Arnaud Bresset, Jean Guillaume Feron, Jean-Yves Pierga, Florence Coussy, Audrey Bellesoeur, Beatriz Grandal, Eléonore De Guillebon, Sonia Rozette, Clemence Evrevin, Thomas Gaillard, Marick Lae, Anne Sophie Hamy, Fabien Reyal. Survival benefit of neoadjuvant chemotherapy versus adjuvant chemotherapy in HER2-positive early breast cancer: A propensity score-weighted analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-36.

Since the validation of the sentinel node technique (SLN) for vulvar cancer 20 years ago, this technique has been introduced in the management of operable cervical cancer and endometrial cancer. For cervical cancer a “one fits all” attitude has mainly been presented. However, this approach, consisting of a frozen section during the operation, can be discussed in some stages. We present and discuss the main option for each stage, as well as some secondary possibilities. For endometrial cancer, SLN is now the technique of choice for the nodal staging of low- and intermediate-risk groups. Some discussion exists for the high-risk group. We also discuss the impacts of using preoperatively the molecular classification of endometrial cancer. Patients with POLE or TP53 mutations could have different nodal staging. The story of SLN in uterine cancers is not finished. We propose a comprehensive algorithm of SLN in early cervical and endometrial cancers. However, several ongoing trials will give us important data in the coming years. They could substantially change these propositions.

Survival disparities persist in ovarian cancer and may be linked to the environments in which patients live. The main objective of this study was to analyze the global impact of the area of residence of ovarian cancer patients on overall survival. The data were obtained from the Surveillance, Epidemiology and End Results (SEER) database. We included all the patients with epithelial ovarian cancers diagnosed between 2010 and 2016. The areas of residence were analyzed by the hierarchical clustering of the principal components to group similar counties. A multivariable Cox proportional hazards model was then fitted to evaluate the independent effect of each predictor on overall survival. We included a total of 16,806 patients. The clustering algorithm assigned the 607 counties to four clusters, with cluster 1 being the most disadvantaged and cluster 4 having the highest socioeconomic status and best access to care. The area of residence cluster remained a statistically significant independent predictor of overall survival in the multivariable analysis. The patients living in cluster 1 had a risk of death more than 25% higher than that of the patients living in cluster 4. This study highlights the importance of considering the sociodemographic factors within the patient’s area of residence when developing a care plan and follow-up.

Introduction Whereas spontaneous onset of labor and vaginal delivery for breech presentation is considered to be a safe and effective option in selected cases, the safety of induction of labor is not established yet. The objectives of this study were to describe the outcomes of pregnancy in women induced with a fetus in breech presentation and compare the outcomes with those undergoing planned cesarean delivery. Material and methods We performed a secondary analysis of the observational prospective multicenter PREMODA study, including all singleton breech deliveries after 37 weeks in 174 centers in France and Belgium. We excluded women with spontaneous onset of labor, scarred uterus or intrauterine fetal death. Our study population consisted of women with either induction of labor or planned cesarean delivery. The primary outcome was the composite criteria of neonatal mortality and serious morbidity used in the Term Breech Trial and in the PREMODA prospective cohort. Results Our study population consisted of 4138 women, 218 with induction of labor and 3920 with planned cesarean. Two-thirds (67.4%) of the women in the induction of labor group delivered vaginally. There was no significant difference between the groups for the primary outcome (48 [1.2%] in the planned cesarean group vs 3 [1.4%] in the induction of labor group, P = 0.75). Moreover, none of the criteria of the composite primary outcome was significantly more frequent in the induction of labor group. Conclusions Induction of labor for breech presentation does not seem to increase neonatal mortality or severe neonatal morbidity compared with planned cesarean delivery.

To determine if the time-to-chemotherapy (TTC) after primary macroscopic complete cytoreductive surgery (CRS) influences recurrence-free survival (RFS) and overall survival (OS) in patients with epithelial ovarian cancer (EOC). We conducted an observational multicenter retrospective cohort analysis of women with EOC treated from September 2006 to November 2016 in nine institutions in France (FRANCOGYN research group) with maintained EOC databases. We included women with EOC (all FIGO stages) who underwent primary complete macroscopic CRS prior to platinum-based adjuvant chemotherapy. Two hundred thirty-three patients were included: 73 (31.3%) in the early-stage group (ESG) (FIGO I-II), and 160 (68.7%) in the advanced-stage group (ASG) (FIGO III-IV). Median TTC was 43 days (36–56). The median OS was 77.2 months (65.9–106.6). OS was lower in the ASG when TTC exceeded 8 weeks (70.5 vs. 59.3 months, p = 0.04). No impact on OS was found when TTC was below or above 6 weeks (78.5 and 66.8 months, respectively, p = 0.25). In the whole population, TTC had no impact on RFS or OS. None of the factors studied were associated with an increase in TTC. Chemotherapy should be initiated as soon as possible after CRS. A TTC greater than 8 weeks is associated with poorer OS in patients with advanced stage EOC.

International audience; Barbiturates are proposed as a second/third line treatment for intracranial hypertension in traumatic brain injury (TBI) patients, but the literature remains uncertain regarding their benefit/risk balance. We aimed to evaluate the impact of barbiturates therapy in TBI patients with early intracranial hypertension on the intensive care unit (ICU) survival, the occurrence of ventilator-associated pneumonia (VAP), and the patient’s functional status at three months. We used the French AtlanREA prospective cohort of trauma patients. Using a propensity score-based methodology (inverse probability of treatment weighting), we compared patients having received barbiturates within the first 24 hours of admission (barbiturates group) and those who did not (control group). We used cause-specific Cox models for ICU survival and risk of VAP, and logistic regression for the 3-month Glasgow Outcome Scale (GOS) evaluation. Among the 1396 patients with severe trauma, 383 had intracranial hypertension on admission and were analyzed. Among them, 96 (25.1%) received barbiturates. The early use of barbiturates was significantly associated with increased ICU mortality (HR = 1.85, 95%CI 1.03–3.33). However, barbiturates treatment was not significantly associated with VAP (HR = 1.02, 95%CI 0.75–1.41) or 3-month GOS (OR = 1.67, 95%CI 0.84–3.33). Regarding the absence of relevant clinical trials, our results suggest that each early prescription of barbiturates requires a careful assessment of the benefit/risk ratio.

We describe methods for physics-based protein design and some recent applications from our work. We present the physical interpretation of a MC simulation in sequence space and show that sequences and conformations form a well-defined statistical ensemble, explored with Monte Carlo and Boltzmann sampling. The folded state energy combines molecular mechanics for solutes with continuum electrostatics for solvent. We usually assume one or a few fixed protein backbone structures and discrete side chain rotamers. Methods based on molecular dynamics, which introduce additional backbone and side chain flexibility, are under development. The redesign of a PDZ domain and an aminoacyl-tRNA synthetase enzyme were successful. We describe a versatile, adaptive, Wang-Landau MC method that can be used to design for substrate affinity, catalytic rate, catalytic efficiency, or the specificity of these properties. The methods are transferable to all biomolecules, can be systematically improved, and give physical insights.

International audience; Therapeutic strategies for epithelial ovarian cancers are evolving with the advent of immunotherapy, such as PD-L1 inhibitors, with encouraging results. However, little data are available on PDL-1 expression in ovarian cancers. Thus, we set out to determine the PD-L1 expression according to histological subtype. We evaluated the expression of two PD-L1 clones-QR1 and E1L3N-with two scores, one based on the percentage of labeled tumor cells (tumor proportion score, TPS) and the other on labeled immune cells (combined proportion score, CPS) in a consecutive retrospective series of 232 ovarian cancers. PD-L1 expression was more frequent in high grade serous carcinoma (27.5% with E1L3N clone and 41.5% with QR1 clone), grade 3 endometrioid carcinoma (25% with E1L3N clone and 50% with QR1 clone), and clear-cell carcinomas (27.3% with E1L3N clone and 29.6% with QR1 clone) than other histological subtypes with CPS score. Using the CPS score, 17% of cases were labeled with E1L3N vs 28% with QR1. Using the TPS score, 14% of cases were positive to E1L3N vs 17% for QR1. For TPS and CPS, respectively, 77% and 78% of the QR1 cases were concordant with E1L3N for the thresholds of 1%. Overall and progression-free survival between PD-L1 positive and PD-L1 negative patients were not different across all histological types, and each subtype in particular for serous carcinomas expressing PD-L1. Expression of PD-L1 is relatively uncommon in epithelium ovarian tumors. When positive, usually

We describe methods and software for physics-based protein design. The folded state energy combines molecular mechanics with Generalized Born solvent. Sequence and conformation space are sampled with Replica Exchange Monte Carlo, assuming one or a few fixed protein backbone structures and discrete side chain rotamers. Whole protein design and enzyme design are presented as illustrations. Full redesign of three PDZ domains was done using a simple, empirical, unfolded state model. Designed sequences were very similar to natural ones. Enzyme redesign exploited a powerful, adaptive, importance sampling approach that allows the design to directly target substrate binding, reaction rate, catalytic efficiency, or the specificity of these properties. Redesign of tyrosyl-tRNA synthetase stereospecificity is reported as an example.

Designed enzymes are of fundamental and technological interest. Experimental directed evolution still has significant limitations, and computational approaches are a complementary route. A designed enzyme should satisfy multiple criteria: stability, substrate binding, transition state binding. Such multi-objective design is computationally challenging. Two recent studies used adaptive importance sampling Monte Carlo to redesign proteins for ligand binding. By first flattening the energy landscape of the apo protein, they obtained positive design for the bound state and negative design for the unbound. We have now extended the method to design an enzyme for specific transition state binding, i.e., for its catalytic power. We considered methionyl-tRNA synthetase (MetRS), which attaches methionine (Met) to its cognate tRNA, establishing codon identity. Previously, MetRS and other synthetases have been redesigned by experimental directed evolution to accept noncanonical amino acids as substrates, leading to genetic code expansion. Here, we have redesigned MetRS computationally to bind several ligands: the Met analog azidonorleucine, methionyl-adenylate (MetAMP), and the activated ligands that form the transition state for MetAMP production. Enzyme mutants known to have azidonorleucine activity were recovered by the design calculations, and 17 mutants predicted to bind MetAMP were characterized experimentally and all found to be active. Mutants predicted to have low activation free energies for MetAMP production were found to be active and the predicted reaction rates agreed well with the experimental values. We suggest the present method should become the paradigm for computational enzyme design., Author summary Designed enzymes are of major interest. Experimental directed evolution still has significant limitations, and computational approaches are another route. Enzymes must be stable, bind substrates, and be powerful catalysts. It is challenging to design for all these properties. A method to design substrate binding was proposed recently. It used an adaptive Monte Carlo method to explore mutations of a few amino acids near the substrate. A bias energy was gradually “learned” such that, in the absence of the ligand, the simulation visited most of the possible protein mutations with comparable probabilities. Remarkably, a simulation of the protein:ligand complex, including the bias, will then preferentially sample tight-binding sequences. We generalized the method to design binding specificity. We tested it for the methionyl-tRNA synthetase enzyme, which has been engineered in order to expand the genetic code. We redesigned the enzyme to obtain variants with low activation free energies for the catalytic step. The variants proposed by the simulations were shown experimentally to be active, and the predicted activation free energies were in reasonable agreement with the experimental values. We expect the new method will become the paradigm for computational enzyme design.

Objective The aim of this study was to develop a new diagnostic tool to predict lymph node metastasis (LNM) in patients with advanced epithelial ovarian cancer undergoing primary cytoreductive surgery. Materials and method The FRANCOGYN group’s multicenter retrospective ovarian cancer cohort furnished the patient population on which we developed a logistic regression model. The prediction model equation enabled us to create LNM risk groups with simple lymphadenectomy decision rules associated with a user-friendly free interactive web application called shinyLNM. Results 277 patients from the FRANCOGYN cohort were included; 115 with no LNM and 162 with LNM. Three variables were independently and significantly (p Conclusion This new tool may prove useful for improving surgical planning and provide useful information for patients.

International audience

International audience; Detonation applied to propulsion could result in a promising increase of the thermodynamic efficiency of the engine cycle. Numerical simulations of the detonation propagating in the Continuous Detonation Wave Rocket Engine (CDWRE) are currently performed but still do not account for realistic injection process. The assumption of an ideal injected premix is generally chosen for convenience to obtain theoretical results. Comparison of the numerical results with experiments is difficult because of the clear difference of the injection configurations. Some physical aspects of the separate injection of the components used in experiments are not clearly assessed. This study is included in a wider numerical project aimed at designing and optimizing a realistic CDWRE. The optimization process is presently focused on the injector. One element of the injection hole pattern is considered assuming that this element is periodically repeated over the injector head. The aim of the work presented here is to model and analyze the refill process of the components in the combustion chamber behind the rotating detonation. The simulation starts just after the passage of the detonation over the considered injection element. This simulation gives information on the way the injected propellants recreate the reactive mixture for the next detonation. In the first step, two-dimensional (2D) computations helped us to set up the methodology and to study the dynamic response of the fresh components injected. A comparison between 2D homogeneous and separate injections is provided. In the second step, three-dimensional (3D) computations have been performed with a separate injection suitable for the CDWRE operation. Some performance parameters are evaluated such as mixing efficiency or filling of the domain.; La détonation appliquée à la propulsion pourrait conduire à une augmentation prometteuse du rendement thermodynamique du cycle moteur. Les simulations numériques actuelles de la propagation d'une détonation dans un moteur fusée à détonation rotative (CDWRE) ne tiennent pas compte d'une injection réaliste en majorité. On adopte généralement l'hypothèse simplificatrice de l'injection d'un prémélange pour obtenir des résultats théoriques. La comparaison entre les résultats numériques et expérimentaux est difficile par la nette différence entre les configurations d'injection utilisée. Quelques aspects physiques de l'injection séparée des ergols utilisée dans les expériences ne sont pas encore bien connus. Cette étude est incluse dans un projet numérique plus large destiné à concevoir et optimiser un CDWRE réaliste. La procédure d'optimisation est ici centrée sur l'injecteur. Un élément du motif d'injection constitué de trous est considéré en supposant que cet élément est périodiquement répété sur le plan d'injection. Le but de ce travail est de modéliser et d'analyser le processus de réinjection des ergols dans la chambre de combustion derrière la détonation rotative. La simulation commence juste après le passage de la détonation au-dessus de l'élément d'injection considéré. Cette simulation donne des informations sur la façon dont l'injection des ergols permet de recréer la couche de mélange réactive pour la prochaine détonation. Premièrement, des simulations 2D ont permis de mettre en place la méthodologie et d'étudier la réponse dynamique du mélange frais injecté. Une comparaison entre les résultats 2D d'injections homogène et séparée est montrée. Ensuite, des simulations 3D ont été réalisées avec une injection séparée adaptée au fonctionnement du CDWRE. Quelques indices de performance sont évalués comme l'efficacité de mélange et le remplissage du domaine.

Importance Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear. Objective To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury. Design, Setting, and Participants Multicenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020. Interventions Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension. Main Outcomes and Measures The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality. Results Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47;P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, −2.6% [95% CI, −12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, −4.9% [95% CI, −12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]). Conclusions and Relevance Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference. Trial Registration ClinicalTrials.gov Identifier:NCT03143751

The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed.Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC40 or80) or toxicity (Cmin24.3 mg/L) targets.Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin.Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

International audience; With the increasing number of protein structures available, there is a need for tools capable of automating the comparison of ensembles of structures, a common requirement in structural biology and bioinformatics. PSSweb is a web server for protein structural statistics. It takes as input an ensemble of PDB files of protein structures, performs a multiple sequence alignment and computes structural statistics for each position of the alignment. Different optional functionalities are proposed: structure superposition, Cartesian coordinate statistics, dihedral angle calculation and statistics, and a cluster analysis based on dihedral angles. An interactive report is generated, containing a summary of the results, tables, figures and 3D visualization of superposed structures. The server is available at http://pssweb.org.

interaction correlated with a positive change in their impact factor from their first adoption of Twitter to date. Recognizing that correlation does not imply causation, we examined this perceived relationship. Seven of 25 (28%) indexed anaesthesia journals have a Twitter account. We correlated Twitter presence, user/content interaction and validated metrics of social-media influence (Klout and BirdSong scores) with the journal’s current impact factor. We also looked at the change in impact factor since Twitter adoption by each journal and the number of article citations (Fig. 1). Comparison was made with the change in impact factor of anaesthesia journals without Twitter accounts over the same period. An active Twitter account with a high Klout score directlycorrelated with higher journal impact factor (P=0.034) and with a greater number of article citations (P=0.016) than journals not embracing social media. A highly-performing Twitter account was also associated with an increase in impact factor in the period after Twitter adoption (P=0.01), while journals without a social media presence, on average, saw a net stasis or decline in their impact factor. Twitter offers a unique platform for fast dissemination and discussion of the latest publications in anaesthesia. With smartphones and tablet devices allowing constant access to social media, anaesthetists communicate via social media to discuss journal publications and respond to journal editors. To encourage further adoption by our academic journals, we share our observations of a positive correlation between journal editorial interaction on Twitter and a subsequent increase in journal impact factor. Journals which did not actively embrace Twitter as a 21st-century Letter to (and from) the Editor saw a net stasis or even decline in impact factor.

Introduction The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infections and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury. Methods Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the seven-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated. Results The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P

Redonner confiance et fierté aux citoyens envers notre système démocratique et notre vie politique passe par l’instauration d’une certaine instabilité, reposant sur la représentativité et la responsabilité. La représentativité entraîne une augmentation du nombre des votants et une refonte du système de scrutin. La responsabilité doit s’effectuer à tous les niveaux de la société : les citoyens, les élus certes, mais également les sondages et les médias. Toutes ces mesures visent à redonner le pouvoir au peuple, le principe même de la démocratie. To restore citizens’ confidence and pride in our democratic system and political life, we must achieve a certain instability based on representati­veness and responsibility. A truly representative democratic system leads to an increase in the number of voters, in addition to transforming the ballot process. Responsibility must be shared not only by citizens and their elected representatives, but also by pollsters and the media. The goal is to restore power to the people, in compliance with the core principle of democracy.

International audience; DNA structural deformations and dynamics are crucial to its interactions in the cell. Theoretical simulations are essential tools to explore the structure, dynamics, and thermodynamics of biomolecules in a systematic way. Molecular mechanics force fields for DNA have benefited from constant improvements during the last decades. Several studies have evaluated and compared available force fields when the solvent is modeled by explicit molecules. On the other hand, few systematic studies have assessed the quality of duplex DNA models when implicit solvation is employed. The interest of an implicit modeling of the solvent consists in the important gain in the simulation performance and conformational sampling speed. In this study, respective influences of the force field and the implicit solvation model choice on DNA simulation quality are evaluated. To this end, extensive implicit solvent duplex DNA simulations are performed, attempting to reach both conformational and sequence diversity convergence. Structural parameters are extracted from simulations and statistically compared to available experimental and explicit solvation simulation data. Our results quantitatively expose the respective strengths and weaknesses of the different DNA force fields and implicit solvation models studied. This work can lead to the suggestion of improvements to current DNA theoretical models.

International audience; Far infrared spectra of zwitterionic, cationic, and anionic forms of aliphatic amino acids in solid state have been studied experimentally. Measurements were done on glycine, L-alanine, L-valine, L-leucine, and L-isoleucine powder samples and film samples obtained from dried solutions prepared at pH ranging from 1 to 13. Solid state density functional theory calculations were also performed, and detailed potential energy distributions were obtained from normal mode results. A good correspondence between experimental and simulated spectra was achieved and this allowed us to propose an almost complete band assignment for the far infrared spectra of zwitterionic forms. In the 700-50 cm(-1) range, three regions were identified, each corresponding to a characteristic set of normal modes. A first region between 700 and 450 cm(-1) mainly contained the carboxylate bending, rocking, and wagging modes as well as the ammonium torsional mode. The 450-250 cm(-1) region was representative of backbone and sidechain skeletal bending modes. At last, the low wavenumber zone, below 250 cm(-1), was characteristic of carboxylate and skeletal torsional modes and of lattice modes. Assignments are also proposed for glycine cationic and anionic forms, but could not be obtained for all aliphatic amino acids due to the lack of structural data. This work is intended to provide fundamental information for the understanding of peptides vibrational properties.

Iron deficiency (ID) is very frequent in cardiac patients and has been associated with altered cardiac function. The correction of ID in patients with heart failure improves clinical symptoms, in patients with or without anemia [1, 2]. Alteration of mitochondrial metabolism due to ID may be responsible for these observations.

Background: Anemia is a significant problem in patients on ICU. Its commonest cause, iron deficiency (ID), is difficult to diagnosed in the context of inflammation. Hepcidin is a new marker of ID. We aimed to assess whether hepcidin levels would accurately guide treatment of ID in critically ill anemic patients after a prolonged ICU stay and affect the post-ICU outcomes. Methods: In a controlled, single-blinded, multicenter study, anemic (WHO definition) critically ill patients with an ICU stay ≥5 days were randomized when discharge was expected to either intervention by hepcidin treatment protocol or control. In the intervention arm patients were treated with intravenous iron (1g of ferric carboxymaltose) when hepcidin was Results: Of 405 randomized patients, 399 were analyzed (201 in intervention and 198 in control arm). 220(55%) had ID at discharge (i.e. an hepcidin vs 33(11;90) days for intervention and control respectively, median difference -1(-3;1) days, p=0.78). D90 mortality was significantly lower in the intervention arm (16(8%) vs 33(16.6%) deaths, absolute risk difference -8.7 (-15.1 to -2.3)%, p=0.008). Conclusion: Treatment of ID diagnosed according to hepcidin levels did not reduce the post-ICU LOS, but may reduce the long-term mortality in critically ill patients about to be discharged after a prolonged stay. Trial Registration: www.clinicaltrial.gov NCT02276690 (October 28, 2014; Retrospectively registered)