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Background: The role of herpes simplex virus (HSV) reactivation on morbidity/mortality in intensive care unit patients requiring mechanical ventilation remains controversial. Methods: In this multicentre study, non-immunosuppressed adults >18 years old, mechanically ventilated for at least 96 hours and expected to remain on mechanical ventilation for ≥48 hours, with HSV oropharyngeal reactivation, were double-blindly randomized to receive intravenous acyclovir (5 mg/kg tid, for 14 days) or a matching placebo (controls). Randomisation (1:1) was stratified by study site, pre-randomisation mechanical ventilation duration and number of organ failure, and performed using a secure web-based system. The primary endpoint was ventilator-free days from randomisation to day 60. Findings: The 16 participating centres randomised 238 patients: 119 to receive acyclovir and 119 the placebo. On day 60, for acyclovir recipients and controls, respectively, the median (IQR) numbers of ventilator-free days were 35 (0-53) and 36 (0-50) (p=0.17 for between-group comparison); 26 (22%) and 39 (33%) patients had died (risk difference, 0.11, 95% CI, - 0.004 to 0.22, p=0.059). The adverse-event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, p= 0.4), particularly with acute renal failure post-randomisation affecting three acyclovir recipients and two controls. Four patients in the acyclovir group (vs. none in the placebo group) stopped the study drug for treatment-related adverse event. Interpretation: In non-immunosuppressed patients mechanically ventilated for ≥96 hours with HSV reactivation in the throat, intravenous acyclovir use (5 mg/kg tid) did not increase the number of ventilator-free days on day 60, compared to a placebo. Trial Registration: The trial is registered on ClinicalTrials.gov, number NCT02152358. Funding Statement: Direction de la Recherche Clinique et du Developpement and the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2011). Declaration of Interests: No potential conflict of interest relevant to this article was reported. The following conflicts of interest are outside the area of the article. Dr Luyt reports receiving lecture fees from ThermoFischer Brahms, Biomerieux, Merck Sharp & Dohme and Aerogen, and consulting fees from Bayer Healthcare, Carmat and Faron. Dr Jaber reports receiving consulting fees from Drager, Fisher-Paykel, Xenios-Fresenius Medical and Medtronic. Dr Rimmele reports receiving consulting or lecture fees from Fresenius Medical Care, Baxter, Medtronic, Biomerieux, BBraun. Dr Lu reports receiving lectures fees from Aerogen. Dr Combes reports receiving grant support and lectures fees from Maquet and Baxter and consulting fees from Hemovent. Dr Wolff reports receiving consulting fees from Merck Sharp & Dohme, Inotrem, Correvio, Menarini and Pfizer. Dr Chastre reports receiving lecture and consulting fees from Bayer Healthcare, Pfizer, Merck Sharp & Dohme, Aridis, the Medicines Company, Astra Zenecca, Tigenix, Accelerate Diagnotics, Inotrem and Glaxo Smith Kline Ethics Approval Statement: An independent Ethics Committee (Comite de Protection des Personnes Sud Mediterranee 5) approved its protocol.

Importance The role of herpes simplex virus (HSV) reactivation on morbidity and mortality in patients in the intensive care unit requiring mechanical ventilation remains unknown. Objective To determine whether preemptive treatment with intravenous acyclovir reduces the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation. Design, Setting, and Participants A double-blind, placebo-controlled randomized clinical trial was conducted in 16 intensive care units in France. Participants included 239 adults (age, >18 years) who received mechanical ventilation for at least 96 hours and continued to receive mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients were enrolled between February 2, 2014, and February 22, 2018. Interventions Participants were randomized to receive intravenous acyclovir, 5 mg/kg, 3 times daily for 14 days or a matching placebo. Main Outcomes and Measures The primary end point was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included mortality at 60 days. Main analyses were conducted on an intention-to-treat basis. Results Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238 patients, with 119 patients in both the acyclovir and placebo (control) groups (median [IQR] age, 61 [50-70] years; 76 [32%] women) available for primary outcome measurement. On day 60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients and 36 (0-50]) for controls (P = .17 for between-group comparison). Among secondary outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11, 95% CI, –0.004 to 0.22,P = .06). The adverse event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group,P = .40), particularly acute renal failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for treatment-related adverse events. Conclusions and Relevance In patients receiving mechanical ventilation for 96 hours or more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days, did not increase the number of ventilator-free days at day 60, compared with placebo. These findings do not appear to support routine preemptive use of acyclovir in this setting. Trial Registration ClinicalTrials.gov identifier:NCT02152358

Resume L’elargissement des connaissances concernant les mecanismes et les alterations moleculaires conduisant a la cancerogenese a permis l’elaboration de nombreuses therapies ciblees. Plusieurs classes therapeutiques ont ainsi vu le jour et sont actuellement a l’essai. On y trouve notamment des inhibiteurs de dimerisation du recepteur HER-2. Cependant, la plupart de ces therapies ne font preuve que d’une faible activite en monotherapie. Aussi, des essais sont en cours, testant leur efficacite en association avec d’autres molecules de l’arsenal therapeutique disponible en oncologie. Malgre tout, le cancer du sein reste une pathologie souvent mortelle a terme. Dans cette revue, vont etre presentees les etudes les plus prometteuses concernant ces nouvelles therapies ciblees, ainsi que leur association eventuelle a d’autres molecules cytotoxiques.

Since several years, the use of intravenous immunoglobulins (IVIg) has increased. This growth has encouraged some countries to publish guidelines. In parallel, some countries have conducted audits to know how IVIg are used in clinical practice in the light of the available guidelines. The objective of this study was to assess IVIg use in three French university hospitals in 2006. All IVIg administrations were evaluated during 6 months (12 September 2005-12 March 2006) in French university hospitals of Marseille. Different data were recorded for each administration: patient characteristics, indication, formulation and quantity. During the study period, 2802 administrations of IVIg (corresponding to a total quantity of 76 780 g) have been recorded. Four hundred and thirty-five patients received at least one of these administrations. The five most reported indications were multifocal motor neuropathy (11.0% of total quantity), chronic inflammatory demyelinating polyradiculoneuropathy (10.2%), corticoresistant dermatomyositis (10.2%), immune thrombocytopaenia (9.9%) and primary immune deficiency (9.1%). According to available French recommendations, 70% of the IVIg use was for 'acknowledged indications', 9% for 'indications to be assessed' and 18% for 'unwarranted indications'. The

Background In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS. Methods In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO 2 ) to the fraction of inspired oxygen (FiO 2 ) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model. Results The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P = 0.04), after adjustment for both the baseline PaO 2 :FIO 2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P = 0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P = 0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups. Conclusions In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique–Hopitaux de Marseille and the Programme Hospitalier de Recherche Clinique Regional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.)

For several years exotic snakes have been bred in France. In view of the increased risk of envenomation from some of these species, the Poison Centre in Angers has joined forces with several private licensed snake breeders to create an Anti-venom Serum Bank. The main objective of the new organization is to provide an effective means of dealing with bites and subsequent envenomation by exotic snakes by managing a stock of anti-venom serums in a hospital pharmacy, so that cases can be treated as quickly as possible. The hospital pharmacy has the authority to purchase and supply the anti-venom serums. The selection and purchase of the serums is done in conjunction with the French Ministry of Ecology, the French Drug Agency and specialist doctors. At the time of writing, the Antivenom Serum Bank has the capacity to treat about thirty different kinds of envenomation, compared to the 135 exotic venomous snake species officially registered. In the long term the Anti-venom Serum Bank will help eradicate the use of serums from unauthorized sources, evaluate the safety and efficacy of new serums and reduce transport times.

Mathematical models currently used to study the relationship between the prevalence of the resistance to an antibiotic and the amount of drug may not be adequate because they do not integrate temporal and area analyses simultaneously. Furthermore, the forms of such relationship are unknown. We applied the Generalized Additive Model (GAM) to study fluoroquinolone use and the incidence of fluoroquinolone-resistance in Staphylococcus aureus in our institution over a 3-year period. Overall institution and individual hospital unitrestricted analyses were performed. Relative risk (RR) observed for increasing fluoroquinolone use with a 4-month lag from the 25th percentile to the 75th percentile was 1.27 (95% CI: 1.13-1.42). In the surgery units, RR was 1.23 (95% CI: 1.01-1.50) for fluoroquinolone use with a 2-months lag. GAM enabled us to observe for the first time a significant temporal relationship between fluoroquinolone use and the incidence of fluoroquinolone-resistant nosocomial S. aureus isolates.

International audience; Importance: Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality.Objective: To determine whether statin therapy can decrease day-28 mortality in patients with VAP.Design, setting, and participants: Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients.Interventions: Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.Main outcomes and measures: Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14.Results: The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, -3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, -1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score.Conclusions and relevance: In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.Trial registration: clinicaltrials.gov Identifier: NCT01057758.

OBJECTIVES: Thoracic surgery is associated with severe acute postoperative pain, leading to pulmonary complications and hyperalgesiainduced chronic pain. Thoracic patient-controlled epidural analgesia is also considered as the gold-standard postoperative analgesia. As previously described in major digestive surgery, combination with low-dose intravenous (i.v.) ketamine could potentiate epidural analgesia and facilitate pulmonary function recovery following thoracotomy. METHODS: In a randomized, double-blind trial, 60 patients scheduled to undergo thoracotomy were included. All patients received a thoracic epidural catheter placed before surgery, and standardized general anaesthesia. They were allocated to two groups to receive either an i.v. bolus of ketamine at induction, followed by a continuous infusion during surgery and the first 48 h postoperatively, or an i.v. placebo (a saline solution under the same infusion modalities). Cumulative epidural ropivacaine consumption, postoperative pain scores (patient self-rated numeric pain intensity scale), analgesic rescue consumption, residual pain, haemodynamics and respiratory recovery function were recorded from 12 h to 3 months. Data were expressed as mean ± standard deviation or median ± interquartile range (25–75%). The comparisons between ketamine and placebo groups were performed using χ 2 or Fisher’s exact tests for frequencies, and Mann–Whitney tests for quantitative variables. RESULTS: Epidural ropivacaine consumption was similar between groups during the first 48 postoperative hours. Postoperative pain scores and spirometric parameters were not significantly different between groups. But the incidence of postoperative nausea was significantly increased in patients owning to the ketamine group. Finally, the incidence of residual pain was similar between groups at 1 and 3 months following thoracotomy. CONCLUSIONS: Adding i.v. ketamine did not potentiate epidural analgesia neither to reduce acute and chronic postoperative pain nor to improve pulmonary dysfunction following thoracic surgery. Pain scores were low in both groups, mainly because of an optimized analgesia provided by the patient-controlled epidural mode, and might explain this lack of benefit in adding i.v. ketamine.

Research on molecular alteration process mechanisms leading to cancerogenesis permitted the elaboration of many targeted therapies. Some therapeutic classes appeared recently and are currently being tested, including HER-2 dimerization inhibitors. However, most of these therapies are mostly ineffective with monotherapy. Clinical trials are ongoing, testing their efficiency in association with other molecules of the therapeutic arsenal which is available in oncology. Nevertheless, breast cancer remains a pathology life-threatening, most of the time. Within this review will be introduced the most efficient of these targeted therapies, including their eventual association with other cytotoxic molecules.

Since several years, the use of intravenous immunoglobulins (IVIg) has increased. This growth has encouraged some countries to publish guidelines. In parallel, some countries have conducted audits to know how IVIg are used in clinical practice in the light of the available guidelines. The objective of this study was to assess IVIg use in three French university hospitals in 2006. All IVIg administrations were evaluated during 6 months (12 September 2005-12 March 2006) in French university hospitals of Marseille. Different data were recorded for each administration: patient characteristics, indication, formulation and quantity. During the study period, 2802 administrations of IVIg (corresponding to a total quantity of 76 780 g) have been recorded. Four hundred and thirty-five patients received at least one of these administrations. The five most reported indications were multifocal motor neuropathy (11.0% of total quantity), chronic inflammatory demyelinating polyradiculoneuropathy (10.2%), corticoresistant dermatomyositis (10.2%), immune thrombocytopaenia (9.9%) and primary immune deficiency (9.1%). According to available French recommendations, 70% of the IVIg use was for 'acknowledged indications', 9% for 'indications to be assessed' and 18% for 'unwarranted indications'. The 10 most reported indications were 'acknowledged indications' according to available recommendations of the French expert group. Nevertheless, the two most reported indications were not approved by the French Health Products Agency (AFSSAPS) at the time of the study and were approved since.

For several years exotic snakes have been bred in France. In view of the increased risk of envenomation from some of these species, the Poison Centre in Angers has joined forces with several private licensed snake breeders to create an Anti-venom Serum Bank. The main objective of the new organization is to provide an effective means of dealing with bites and subsequent envenomation by exotic snakes by managing a stock of anti-venom serums in a hospital pharmacy, so that cases can be treated as quickly as possible. The hospital pharmacy has the authority to purchase and supply the anti-venom serums. The selection and purchase of the serums is done in conjunction with the French Ministry of Ecology, the French Drug Agency and specialist doctors. At the time of writing, the Antivenom Serum Bank has the capacity to treat about thirty different kinds of envenomation, compared to the 135 exotic venomous snake species officially registered. In the long term the Anti-venom Serum Bank will help eradicate the use of serums from unauthorized sources, evaluate the safety and efficacy of new serums and reduce transport times.