Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

TECHNOLOGY, COOPERATION AND STOCK MARKET VALUE: AN EVENT STUDY OF NEW PARTNERSHIP ANNOUNCEMENTS IN THE BIOTECHNOLOGY AND PHARMACEUTICAL INDUSTRIES

We use the event study methodology to investigate the share price responses to the formation of 281 partnerships in the biotechnology/pharmaceutical industry over the years 1995-2000. The average stock price response is positive, more so than in previous empirical works, which could be interpreted as evidence that interfirm collaboration is particularly valuable in high-technology industries. Research and development (R&D) partnerships also generate higher abnormal returns (relative to production or marketing agreements). On average, smaller firms in the partnership seem to appropriate a very significant share of the cooperative surplus, especially when they receive large technology payments or when the partnership is concluded in the R&D stage. On the other hand, partnership announcements of more profitable firms tend to be associated with higher abnormal returns.Interfirm cooperation, Event study, Pharmaceutical industry,

Thermal-infrared remote sensing of surface water-groundwater exchanges in a restored anastomosing channel (Upper Rhine River, France)

Ecohydrological processes are a key element to consider in functional river restorations. In the framework of a LIFE+ European restoration program, we have investigated the potential for airborne thermal‐infrared remote sensing to map surface water–groundwater exchanges and to identify their driving factors. We focused our attention on anastomosing channels on an artificial island of the Upper Rhine River (Rohrschollen), where a new channel was excavated from the floodplain to reconnect an older channel in its upstream part. These hydraulic engineering works led to an increased inflow from the Rhine Canal. Here, we propose an original data treatment chain to (a) georeference the thermal‐infrared images in geographic information system based on visible images, (b) detect and correct data errors, and (c) identify and locate thermal anomalies attributed to groundwater inputs and hyporheic upwellings. Our results, which have been compared to morpho‐sedimentary data, show that groundwater upwelling in the new channel is controlled by riffle–pool sequences and bars. This channel is characterized by large bedload transport and morphodynamic activity, forming riffles and bars. In the old channel, where riffle–pool sequences no longer exist, due to impacts of engineering works and insufficient morphodynamic effects of the restoration, thermal anomalies appeared to be less pronounced. Groundwater inputs seem to be controlled by former gravel bars outcropping on the banks, as well as by local thinning of the low‐permeability clogging layer on the channel bed

Gender-specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal malignancies: results from a prospective population pharmacokinetic study

This study was initiated to assess the quantitative impact of patient anthropometrics and dihydropyrimidine dehydrogenase (DPYD) mutations on the pharmacokinetics (PK) of 5-fluorouracil (5FU) and to explore limited sampling strategies of 5FU.; We included 32 patients with gastrointestinal malignancies, receiving 46-h continuous-infusional 5FU and performed PK-sampling at baseline, 15, 30, 45 min, 1 and 2 h after the start of infusion and at the end of infusion, for 2 subsequent cycles. Plasma concentrations of 5FU, 5-fluorodihydrouracil (5FUH2), uracil (U) and 5,6-dihydrouracil (UH2) were determined using LC-MS/MS and submitted to population PK analysis using nonlinear mixed-effects modeling. Broad genotyping of DPYD was performed, and the potential impact of the DPYD genotype on the elimination of 5FU was assessed. Limited sampling strategies were evaluated for their accuracy to predict steady-state concentrations of 5FU (CSS(5FU)), using data simulations based on the final PK-model.; The area-under-the concentration-time curve of 5FU (AUC(5FU)) was found to be >20 mg h/L in 33 occasions (58 %), between 20 and 30 mg h/L in 17 occasions (30 %) and  0.001). Limited sampling strategies with time-points >3 h after the start of infusion were not adequate to predict CSS(5FU). Female gender was the only predictor of nausea/emesis in the multivariate model.; Gender-specific elimination of 5FU is supported by the present data and may partly explain the gender-specific association between DPYD risk variants and 5FU-specific toxicity

Measurement of the Mass of the Z-Boson and the Energy Calibration of Lep

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