Dose escalation of desmoteplase for acute ischemic stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset

<p><b>Background and Purpose:</b> Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke.</p> <p><b>Methods:</b> DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 μg/kg and 125 μg/kg desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined.</p> <p><b>Results:</b> Thirty-seven patients were randomized and received treatment (intent-to-treat; placebo: n=8; 90 μg/kg: n=14; 125 μg/kg: n=15). No symptomatic intracranial hemorrhage occurred. Reperfusion was achieved in 37.5% (95% CI [8.5; 75.5]) of placebo patients, 18.2% (2.3; 51.8) of patients treated with 90 μg/kg desmoteplase, and 53.3% (26.6; 78.7) of patients treated with 125 μg/kg desmoteplase. Good clinical outcome at 90 days occurred in 25.0% (3.2; 65.1) treated with placebo, 28.6% (8.4; 58.1) treated with 90 μg/kg desmoteplase and 60.0% (32.3; 83.7) treated with 125 μg/kg desmoteplase. In the target population (n=25), the difference compared with placebo increased and was statistically significant for good clinical outcome with 125 μg/kg desmoteplase (P=0.022).</p> <p><b>Conclusions:</b> Treatment with IV desmoteplase 3 to 9 hours after ischemic stroke onset appears safe. At a dose of 125 μg/kg desmoteplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria. The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS).</p&gt

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Background So far, more than 170 loci have been associated with circulating lipid levels through genomewide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ~60 000 individuals in the discovery stage and ~90 000 samples in the replication stage. Results Our study resu

Stacking Fault Energy Measurements In Solid Solution Strengthened Ni-cr-fe Alloys Using Synchrotron Radiation

The stacking fault energy (SFE) in a set of experimental Ni-Cr-Fe alloys was determined using line profile analysis on synchrotron X-ray diffraction measurements. The methodology used here is supported by the Warren-Averbach calculations and the relationships among the stacking fault probability (α) and the mean-square microstrain (<ε 2 L>). These parameters were obtained experimentally from cold-worked and annealed specimens extracted from the set of studied Ni-alloys. The obtained results show that the SFE in these alloys is strongly influenced by the kind and quantity of addition elements. Different effects due to the action of carbide-forming elements and the solid solution hardening elements on the SFE are discussed here. The simultaneous addition of Nb, Hf, and, Mo, in the studied Ni-Cr-Fe alloys have generated the stronger decreasing of the SFE. The relationships between SFE and the contributions on electronic structure from each element of additions were established. © 2012 Elsevier B.V.5587075Galen H, F., (2006) JOM, 58 (9), pp. 28-31Bowman, R., (2004) JOM, 56 (9), pp. 7-12Donachie, M., Donachie, S., (2002), p. 439. , Superalloys, A Technical Guide, 2nd edCollins, M.G., Ramirez, A.J., Lippold, J.C., (2004) Weld. J., 83, pp. 39s-49sRamirez, A.J., Lippold, J.C., (2004) Mater. Sci. Eng. A, 380, pp. 259-271Ramirez, A.J., Sowards, J.W., (2006) J. Mater. Process Technol., 179 (20), pp. 212-218Noecker, F.F., Dupont, J.N., (2009) Weld. J., 88 (3), pp. 62s-77sRogers, H.C., (1967) Ductility, p. 55Hull, D., Bacon, D.J., (2001), p. 11. , Introduction to Dislocations, 4th edFrommeyer, G., Brüx, U., Neumann, P., (2003) ISIJ Int., 43 (3), pp. 438-446Grässel, O., (1997) J. de. Phys. IV, 7 (C5), pp. 383-388Ruff, A.W., (1970) Metall. Trans., 1 (9), pp. 2391-2413Reed, R.P., Schramm, R.E., (1974) J. Appl. Phys., 45 (11), pp. 4705-4711Schramm, R.E., Reed, R.P., (1975) Metall. Trans. A, 6, pp. 1345-1351Stokes, A.R., (1948) Proc. Phys. Soc., 61, p. 382Warren, B.E., Warekois, E.P., (1955) Acta metall., 3, pp. 473-479Sambongi, T., (1965) J. Phys. Soc. Jpn., 20 (8), pp. 1370-1374Cheary, R.W., Coelho, A.A., (1996), http://www.ccp14.ac.uk/tutorial/xfit-95/xfit.htmCheary, R.W., Coelho, A., (1992) J. Appl. Crystallogr., 25, pp. 109-121Balzar, D., Ledbetter, H., (1993) J. Appl. Crystallogr., 26, pp. 97-103Balzar, D., (1992) J. Appl. Crystallogr., 25, pp. 559-570Warren, B.E., Averbach, B.L., (1950) J. Appl. Phys., 21, pp. 595-599Schafler, E., (1999) Phys. Status Solidi (a), 175 (2), pp. 501-511Halder, S.K., De, M., Gupta, S.P., (1977) J. Appl. Phys., 48 (8), pp. 3560-3565Chattopadhyay, S.K., Chatterjee, S.K., (1990) J. Mater. Res., 5 (10), pp. 2120-2125Alvin Borges, J.F., Padilha, A.F., Imakuma, K., (1986) Rev. Fis. Apli. Instrum., 1 (4), pp. 1-12Martinez, L.G., Imakuma, K., Padilha, A.F., (1992) Mater. Technol. Steel Res., 63 (5), pp. 221-223Duval, S., Chambreland, S., Caron, P., Blavette, D., (1994) Acta Metall. Mater., 42 (1), pp. 185-194Bower, D.I., Claridge, E., Tsong, I.S.T., (1968) Phys. Status Solidi (b), 29 (2), pp. 617-625Ledbetter, H.M., (1985) J. Appl. Phys., 57 (11), pp. 5069-5070di Masso, L., (1996) J. Phys. IV Suppl. au. J. Phys., 111 (6), pp. 247-250. , C8Glatzel, U., FeUer-Kniepmeier, M., (1991) Scr. Metall. Mater, 25, pp. 1845-1850Symons, D.M., (1997) Metall. Mater. Trans. A, 28 (3), pp. 655-663Siegel, D.J., (2005) Appl. Phys. Lett., 87, p. 121901Tiearney, T.C., Grant, N.J., (1982) Metall. Trans. A, 13, pp. 1827-1836Pettinari, F., (2002) Mat. Sci. Eng. A, 325, pp. 511-519Vanderschaeve, G., Escaig, B., (1978) J. Phys. Lett., 39 (15), pp. 74-77Gallagher, P.C.J., (1970) Met. Trans., 1, pp. 2429-2461Viatte, T., (1996) J. Phys. IV C8 Supp. au. J. Phys., 111 (6), pp. 743-746Zimina, L.N., Burova, N.N., Makushok, O.V., (1986) Met. Sci. Heat Treat., 28 (2), pp. 130-135Kotval, P.S., Venables, J.D., Calder, R.W., (1972) Metall. Trans., 3 (2), pp. 453-458Yukawa, N., (1986) High temperatures alloys for gas turbines and other applications, (PART II), pp. 935-938Tiwari, G.P., Ramanujan, R.V., (2001) J. Mat. Sci., 36, pp. 271-28