Plethysmographic dynamic indices predict fluid responsiveness in septic ventilated patients

Objectives: In septic patients, reliable non-invasive predictors of fluid responsiveness are needed. We hypothesised that the respiratory changes in the amplitude of the plethysmographic pulse wave (ΔPPLET) would allow the prediction of changes in cardiac index following volume administration in mechanically ventilated septic patients. Design: Prospective clinical investigation. Setting: An 11-bed hospital medical intensive care unit. Patients: Twenty-three deeply sedated septic patients mechanically ventilated with tidal volume ≥ 8 ml/kg and equipped with an arterial catheter and apulse oximetry plethysmographic sensor. Interventions: Respiratory changes in pulse pressure (ΔPP), ΔPPLET and cardiac index (transthoracic Doppler echocardiography) were determined before and after volume infusion of colloids (8 ml/kg). Measurements and main results: Twenty-eight volume challenges were performed in 23 patients. Before volume expansion, ΔPP correlated with ΔPPLET (r 2 = 0.71, p < 0.001). Changes in cardiac index after volume expansion significantly (p < 0.001) correlated with baseline ΔPP (r 2 = 0.76) and ΔPPLET (r 2 = 0.50). The patients were defined as responders to fluid challenge when cardiac index increased by at least 15% after the fluid challenge. Such an event occurred 18 times. Before volume challenge, aΔPP value of 12% and aΔPPLET value of 14% allowed discrimination between responders and non-responders with sensitivity of 100% and 94% respectively and specificity of 70% and 80% respectively. Comparison of areas under the receiver operator characteristic curves showed that ΔPP and ΔPPLET predicted similarly fluid responsiveness. Conclusion: The present study found ΔPPLET to be as accurate as ΔPP for predicting fluid responsiveness in mechanically ventilated septic patient

Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients.

International audienceBackground: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p&lt;0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p&lt;0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p&lt;0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity

Plethysmographic dynamic indices predict fluid responsiveness in septic ventilated patients

In septic patients, reliable non-invasive predictors of fluid responsiveness are needed. We hypothesised that the respiratory changes in the amplitude of the plethysmographic pulse wave (DeltaP(PLET)) would allow the prediction of changes in cardiac index following volume administration in mechanically ventilated septic patients

Identifying Patients Harboring Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae on Hospital Admission Is Not That Simple.

International audienc

Impact of a region wide antimicrobial stewardship guideline on urinary tract infection prescription patterns.

International audienceBACKGROUND: Fluoroquinolones are frequently prescribed for non complicated urinary tract infection treatments and have a negative ecological impact. We aimed to substitute them by antibiotics with narrower activity spectrum in order to preserve fluoroquinolone activity in complicated hospital infections. OBJECTIVE: To assess the impact of a multi-modal approach that combines the dispatching of antibiotic prescription guidelines and voluntary attendance at educational sessions on general practitioners' (GP) antibiotic prescription habits. SETTING: This study was led in Franche-Comté, a French eastern region, where GPs were given a guideline recommending a restricted use of fluoroquinolones for urinary tract infections. METHOD: Segmented regression analysis of interrupted time series was used to assess changes in antibiotic prescription. MAIN OUTCOME MEASURE: The antibiotic prescription data of nitrofurantoin, fosfomycin-trometamol and fluoroquinolones for women aged 15-65 years were obtained from the regional agency of health insurance. RESULTS: Twenty months after intervention, the number of nitrofurantoin and fosfomycintrometamol prescriptions increased by 36.8% (95% CI: 30.6-42.2) and 28.5% (95% CI: 22.9-35.4), respectively, while that of norfloxacin decreased by 9.1% (95% CI: -15.3 to -3.5). CONCLUSION: This study suggests that the dispatch of the guideline on urinary tract infection had a moderate impact on antibiotic prescriptions

Clinical outcomes of non–small-cell lung cancer patients with BRAF mutations: results from the French Cooperative Thoracic Intergroup biomarkers France study

International audienceIntroduction - Patients with stage IV non-small-cell lung cancer (NSCLC) and BRAF V600 mutations may benefit from targeted therapies. Chemotherapy outcomes are little known in this population. Methods - The French Cooperative Thoracic Intergroup (IFCT) Biomarkers France study was a national prospective cohort study aiming to describe the molecular characteristics and clinical outcome of all consecutive NSCLC patients (N = 17,664) screened for molecular alterations. We used this data set to set up a case-control analysis. Cases had stage IV BRAF-mutated (BRAF-MT) NSCLC, whereas controls had NSCLC that was wild-type for EGFR, KRAS, HER2, BRAF, PIK3CA and ALK. Each case was matched for sex, age at diagnosis and smoking status to two controls randomly selected. Results - Overall, 83 cases with BRAF mutant disease (66.3% V600E) were matched to 166 controls. Five cases received tyrosine kinase inhibition in the first-line and 16 in the second-line. All others were treated with standard chemotherapy. There was no significant difference in first-line and second-line progression-free survival (PFS) between the groups, as well as in the disease control rate, BRAF mutation was not found to be prognostic of overall survival. We found no significant difference in outcome between the treatment types used in first-line or second-line in patients with BRAF-MT disease compared with controls nor between BRAF V600E or non-V600E compared with controls. Conclusions - BRAF mutation is not a strong prognostic factor in NSCLC. Although taxan-based therapy shows poorest PFS in first-line, no chemotherapy regimen was associated with prognosis