Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Applications des techniques a membranes aux produits de la vigne. Reflexions sur les perspectives de leur developpement

National audienc

Applications des techniques a membranes aux produits de la vigne. Reflexions sur les perspectives de leur developpement

National audienc

La technologie des membranes

* illus.National audienceLes techniques separatives a membranes connaissent a l'heure actuelle un developpement important. Les traitements par les techniques a membranes intervenant a basse temperature ou sans changement d'etat physique preservent l'integrite des biocomposes; elles doivent donc trouver une place de choix dans les bio-industries. A l'origine d'innovations marquantes en industries laitiere et fromagere, ces technologies, nouvelles pour la filiere vin, peuvent y trouver des applications valorisantes: preparation de mouts destines a la vinification, elaboration de boissons a faible degre d'alcool et de concentres de vins blancs, roses ou rouges, valorisation de sous-produits et derives

Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors

Abstract Background Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors. Methods In this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics. Results Twenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139–427) and 494 (227–761) μg.h/mL at Day 1, and 738 (487–989) and 1071 (678–1464) μg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion. Conclusions The combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination. Trial registration The study was retrospectively registered on ClinicalTrials.gov (number NCT01202032 ) on 2010, Sept 14th

Modelling the association between fibrinogen concentration on admission and mortality in patients with massive transfusion after severe trauma: an analysis of a large regional database

International audienceBackground: The relationship between fibrinogen concentration and traumatic death has been poorly explored after severe trauma. Existing studies analysed this relationship in unselected trauma population, often considering fibrinogen concentration as a categorical variable. The aim of our study was to model the relationship between fibrinogen concentration and in-hospital mortality in severe trauma patients requiring massive transfusion using fibrinogen on admission as a continuous variable.Methods: We designed a retrospective observational study based on prospectively collected data from 2009 to 2015 in seven French level-I trauma centres. All consecutive patients requiring a transfusion of at least 10 packed red blood cells (RBC) within 24 h were included. To assess the relationship between in-hospital death and fibrinogen concentration on admission, we performed generalized linear and additive models with death as a dependent variable. We also assessed the relationship between fibrinogen concentration below 1.5 g.L-1 and potential predictors.Results: Within the study period, 366 patients were included. A non-linear relationship was found between fibrinogen concentration and death. Graphical modelling of this relationship depicted a negative association between fibrinogen levels and death below a fibrinogen concentration of 1.5 g.L-1. Predictors of low fibrinogen concentration (< 1.5 g.L-1) were systolic blood pressure, Glasgow coma scale and haemoglobin concentration on admission.Conclusions: A complex and robust approach for modelling the relationship between fibrinogen and mortality revealed a critical fibrinogen threshold of 1.5 g.L-1 for severe trauma patients requiring massive transfusion. This trigger may guide the administration of procoagulant therapies in this context

AMICal Sat and ATISE: two space missions for auroral monitoring

International audienceA lack of observable quantities renders it generally difficult to confront models of Space Weather with experimental data and drastically reduces the forecast accuracy. This is especially true for the region of Earth’s atmosphere between altitudes of 90 km and 300 km, which is practically inaccessible, except by means of remote sensing techniques. For this reason auroral emissions are an interesting proxy for the physical processes taking place in this region. This paper describes two future space missions, AMICal Sat and ATISE, that will rely on CubeSats to observe the aurora. These satellites will perform measurements of auroral emissions in order to reconstruct the deposition of particle precipitations in auroral regions. ATISE is a 12U CubeSat with a spectrometer and imager payloads. The spectrometer is built using the micro-Spectrometer-On-a-Chip (μSPOC) technology. It will work in the 370–900 nm wavelength range and allow for short exposure times of around 1 s. The spectrometer will have six lines of sight. The joint imager is a miniaturized wide-field imager based on the Teledyne-E2V ONYX detector in combination with a large aperture objective. Observation will be done at the limb and will enable reconstruction of the vertical profile of the auroral emissions. ATISE is planned to be launched in mid 2021. AMICal Sat is a 2U CubeSat that will embed the imager of ATISE and will observe the aurora both in limb and nadir configurations. This imager will enable measuring vertical profiles of the emission when observing in a limb configuration similar to that of ATISE. It will map a large part of the night side auroral oval with a resolution of the order of a few km. Both the spectrometer and imager will be calibrated with a photometric precision better than 10% using the moon as a wide-field, stable and extended source. Ground-based demonstrators of both instruments have been tested in 2017 in Norway and Svalbard. Even though some issues still need to be solved, the first results are very encouraging for the planned future space missions. Data interpretation will be done using the forward Transsolo code, a 1D kinetic code solving the Boltzmann equation along a local vertical and enabling simulation of the thermospheric and ionospheric emissions using precipitation data as input

AMICal Sat and ATISE: two space missions for auroral monitoring

A lack of observable quantities renders it generally difficult to confront models of Space Weather with experimental data and drastically reduces the forecast accuracy. This is especially true for the region of Earth’s atmosphere between altitudes of 90 km and 300 km, which is practically inaccessible, except by means of remote sensing techniques. For this reason auroral emissions are an interesting proxy for the physical processes taking place in this region. This paper describes two future space missions, AMICal Sat and ATISE, that will rely on CubeSats to observe the aurora. These satellites will perform measurements of auroral emissions in order to reconstruct the deposition of particle precipitations in auroral regions. ATISE is a 12U CubeSat with a spectrometer and imager payloads. The spectrometer is built using the micro-Spectrometer-On-a-Chip (μSPOC) technology. It will work in the 370–900 nm wavelength range and allow for short exposure times of around 1 s. The spectrometer will have six lines of sight. The joint imager is a miniaturized wide-field imager based on the Teledyne-E2V ONYX detector in combination with a large aperture objective. Observation will be done at the limb and will enable reconstruction of the vertical profile of the auroral emissions. ATISE is planned to be launched in mid 2021. AMICal Sat is a 2U CubeSat that will embed the imager of ATISE and will observe the aurora both in limb and nadir configurations. This imager will enable measuring vertical profiles of the emission when observing in a limb configuration similar to that of ATISE. It will map a large part of the night side auroral oval with a resolution of the order of a few km. Both the spectrometer and imager will be calibrated with a photometric precision better than 10% using the moon as a wide-field, stable and extended source. Ground-based demonstrators of both instruments have been tested in 2017 in Norway and Svalbard. Even though some issues still need to be solved, the first results are very encouraging for the planned future space missions. Data interpretation will be done using the forward Transsolo code, a 1D kinetic code solving the Boltzmann equation along a local vertical and enabling simulation of the thermospheric and ionospheric emissions using precipitation data as input

Epidural analgesia in critically ill patients with acute pancreatitis: the multicentre randomised controlled EPIPAN study protocol

BACKGROUND: Acute pancreatitis (AP) is associated with high morbidity and mortality in its most severe forms. Most patients with severe AP require intubation and invasive mechanical ventilation, frequently for more than 7 days, which is associated with the worst outcome. Recent increasing evidence from preclinical and clinical studies support the beneficial effects of epidural analgesia (EA) in AP, such as increased gut barrier function and splanchnic, pancreatic and renal perfusion, decreased liver damage and inflammatory response, and reduced mortality. Because recent studies suggest that EA might be a safe procedure in the critically ill, we sought to determine whether EA reduced AP-associated respiratory failure and other major clinical outcomes in patients with AP. METHODS AND ANALYSIS: The Epidural Analgesia for Pancreatitis (EPIPAN) trial is an investigator-initiated, prospective, multicentre, randomised controlled two-arm trial with assessor-blinded outcome assessment. The EPIPAN trial will randomise 148 patients with AP requiring admission to an intensive care unit (ICU) to receive EA (with patient-controlled epidural administration of ropivacaine and sufentanil) combined with standard care based on current recommendations on the treatment of AP (interventional group), or standard care alone (reference group). The primary outcome is the number of ventilator-free days at day 30. Secondary outcomes include main complications of AP (eg, organ failure and mortality, among others), levels of biological markers of systemic inflammation, epithelial lung injury, renal failure, and healthcare-associated costs. ETHICS AND DISSEMINATION: The study was approved by the appropriate ethics committee (CPP Sud-Est VI). Informed consent is required. If the combined application of EA and standard care proves superior to standard care alone in patients with AP in the ICU, the use of EA may become standard practice in experienced centres, thereby decreasing potential complications related to AP and its burden in critically ill patients. The results will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02126332