Training of Instrumentalists and Development of New Technologies on SOFIA

This white paper is submitted to the Astronomy and Astrophysics 2010 Decadal Survey (Astro2010)1 Committee on the State of the Profession to emphasize the potential of the Stratospheric Observatory for Infrared Astronomy (SOFIA) to contribute to the training of instrumentalists and observers, and to related technology developments. This potential goes beyond the primary mission of SOFIA, which is to carry out unique, high priority astronomical research. SOFIA is a Boeing 747SP aircraft with a 2.5 meter telescope. It will enable astronomical observations anywhere, any time, and at most wavelengths between 0.3 microns and 1.6 mm not accessible from ground-based observatories. These attributes, accruing from the mobility and flight altitude of SOFIA, guarantee a wealth of scientific return. Its instrument teams (nine in the first generation) and guest investigators will do suborbital astronomy in a shirt-sleeve environment. The project will invest $10M per year in science instrument development over a lifetime of 20 years. This, frequent flight opportunities, and operation that enables rapid changes of science instruments and hands-on in-flight access to the instruments, assure a unique and extensive potential - both for training young instrumentalists and for encouraging and deploying nascent technologies. Novel instruments covering optical, infrared, and submillimeter bands can be developed for and tested on SOFIA by their developers (including apprentices) for their own observations and for those of guest observers, to validate technologies and maximize observational effectiveness.Comment: 10 pages, no figures, White Paper for Astro 2010 Survey Committee on State of the Professio

Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model

<div><p>Introduction</p><p>Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors.</p><p>Objective</p><p>To evaluate the ability of andexanet to reverse anticoagulation <i>in vitro</i> and reduce bleeding in rabbits administered edoxaban.</p><p>Materials and methods</p><p><i>In vitro</i> studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury.</p><p>Results</p><p>Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters <i>in vitro</i>. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; <i>P</i><0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; <i>P</i><0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; <i>P</i> = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, <i>P</i><0.0001) and unbound edoxaban (r = 0.5951, <i>P</i> = 0.0035).</p><p>Conclusion</p><p>These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.</p></div

<i>In vitro</i> reversal of edoxaban-induced inhibition of thrombin generation in human plasma.

<p>Plasma samples contained edoxaban at 0 (◇), 250 (△), 500 (□), and 1000 (○) ng/mL (0, 0.46, 0.91, 1.82 μM) and increasing concentrations of andexanet (0, 0.05, 0.1, 0.5, 1.0, 2.0, 2.5, 3.0 μM). Data (ETP) were plotted as mean ± standard deviation from two separate experiments. Additional thrombin generation parameters are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195122#pone.0195122.s003" target="_blank">S2 Fig</a>.</p

Change in pharmacokinetic parameters following administration of andexanet in edoxaban-anticoagulated rabbits.

<p>(A) Total edoxaban plasma concentration. (B) Unbound edoxaban plasma concentration. Total and unbound (pharmacologically active) edoxaban plasma levels were determined by LC/MS/MS with a turbo-ion spray source using an internal standard (edoxaban-D6) as described in Materials and Methods. Pharmacologically active unbound edoxaban was separated using an HTD96b apparatus at 37°C for approximately 4 hours with gentle vortexing. (C) Andexanet plasma concentration was determined by ELISA with paired antibodies recognizing human FX/FXa. Andexanet standard was freshly prepared in blocking buffer with the same lot material used in this study for 8-point curve (0–200 ng/mL). Data are plotted as mean ± standard deviation.</p