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2. P-242 Oocyte morphology before vitrification is associated with the post-warming survival rate

Author

C.J Li, L.T Hsu, L.H Chen, T.H Chin, S.Y Huang, C.L Chang, H.Y Huang, Y.K Soong, and H.M Wu

Subjects
Reproductive Medicine, Rehabilitation, Obstetrics and Gynecology
Abstract

Study question Although oocyte vitrification is efficient for fertility preservation, the information about damage post-warming is limited. Could the oocyte morphology before vitrification predict the survival rate? Summary answer Precisely measuring the oolemma/whole oocyte surface area ratio may predict the post-warming survival rate before performing oocyte vitrification. What is known already Recent studies suggest that oocyte vitrification has higher post-warming survival and pregnancy rates. However, the oocyte post-warming survival rate depends on the oocyte quality but not maternal age. Furthermore, it has been well received that the cell surface/volume ratio is related to the efficiency of cryoprotective additives permeability. Moreover, the oocyte shows a large perivitelline space (PVS) that is negatively related to clinical outcomes. Nevertheless, no studies precisely defined large PVS by measuring the oolemma/whole oocyte surface area ratio. Therefore, we assessed the correlation between the oolemma/whole oocyte surface area ratio and the post-warming survival rate. Study design, size, duration A retrospective study enrolled 43 IVF cycles undergoing oocyte thawing from 2018 to 2020 at Linkou Chang Gung Memorial Hospital. Participants/materials, setting, methods A total of 161 oocytes were warmed. We excluded the oocyte were shipped to our center, MI stages, and without electric medical images. We retrospectively collected all the electric medical images of warmed oocytes that were measured the surface area of oolemma and whole oocyte using ImageJ. Linear regression and Receiver operating characteristic (ROC) curve analysis were performed for further analysis. Main results and the role of chance Our finding showed that the maternal age (38.1 ± 5.3) at oocyte vitrification was not correlated to survival rate (P = 0.26) and the oolemma/whole oocyte surface area ratio (P = 0.59). However, the ROC curve revealed that the oolemma/whole oocyte surface area ratio could predict the survival rate post-warm (AUC: 0.67, 95%CI: 0.56-0.78). Limitations, reasons for caution Small sample size limited the power of this study, and the higher advanced maternal age group involved in this study may not represent the younger group’s outcomes. Therefore, future studies need to enlarge the sample size to evaluate the prediction efficiency of the oolemma/whole oocyte surface area ratio. Wider implications of the findings Our study demonstrates the possible factor related to oocyte cryo-damage. The lower oolemma/whole oocyte surface area ratio represents the oocyte having a larger PVS that has a higher chance of damage after thawing, which shows that by precisely qualified the size of PVS could evaluate the oocyte quality before vitrification. Trial registration number Not applicable

Published
2022

4. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Author

Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bharath Cheripelli, Tae-Hee Cho, Chi-un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B. Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M. Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K. Mueller, Keith W. Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H. Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H. Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z. Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Keizo Yasui, Toshiro Yonehara, Shinichi Yoshimura, K. Aarnio, F. Alemseged, C. Anderson, T. Ang, M.L. Archer, J. Attia, P. Bailey, A. Balabanski, A. Barber, P.A. Barber, J. Bernhardt, A. Bivard, D. Blacker, C.F. Bladin, A. Brodtmann, D. Cadilhac, B.C.V. Campbell, L. Carey, S. Celestino, L. Chan, W.H. Chang, A. ChangI, C.H. Chen, C.-I. Chen, H.F. Chen, T.C. Chen, W.H. Chen, Y.Y. Chen, C.A. Cheng, E. Cheong, Y.W. Chiou, P.M. Choi, H.J. Chu, C.S. Chuang, T.C. Chung, L. Churilov, B. Clissold, A. Connelly, S. Coote, B. Coulton, E. Cowley, J. Cranefield, S. Curtze, C. D'Este, S.M. Davis, S. Day, P.M. Desmond, H.M. Dewey, C. Ding, G.A. Donnan, R. Drew, S. Eirola, D. Field, T. Frost, C. Garcia-Esperon, K. George, R. Gerraty, R. Grimley, Y.C. Guo, G. Hankey, J. Harvey, S.C. Ho, K. Hogan, D. Howells, P.M. Hsiao, C.H. Hsu, C.T. Hsu, C.-S. Hsu, J.P. Hsu, Y.D. Hsu, Y.T. Hsu, C.J. Hu, C.C. Huang, H.Y. Huang, M.Y. Huang, S.C. Huang, W.S. Huang, D. Jackson, J.S. Jeng, S.K. Jiang, L. Kaauwai, O. Kasari, J. King, T.J. Kleinig, M. Koivu, J. Kolbe, M. Krause, C.W. Kuan, W.L. Kung, C. Kyndt, C.L. Lau, A. Lee, C.Y. Lee, J.T. Lee, Y. Lee, Y.C. Lee, C. Levi, C.R. Levi, L.M. Lien, J.C. Lim, C.C. Lin, C.H. Lin, C.M. Lin, D. Lin, C.H. Liu, J. Liu, Y.C. Lo, P.S. Loh, E. Low, C.H. Lu, C.J. Lu, M.K. Lu, J. Ly, H. Ma, L. Macaulay, R. Macdonnell, E. Mackey, M. Macleod, J. Mahadevan, V. Maxwell, R. McCoy, A. McDonald, S. McModie, A. Meretoja, S. Mishra, P.J. Mitchell, F. Miteff, A. Moore, C. Muller, F. Ng, F.C. Ng, J-L. Ng, W. O'Brian, V. O'Collins, T.J. Oxley, M.W. Parsons, S. Patel, G.S. Peng, L. Pesavento, T. Phan, E. Rodrigues, Z. Ross, A. Sabet, M. Sallaberger, P. Salvaris, D. Shah, G. Sharma, G. Sibolt, M. Simpson, S. Singhal, B. Snow, N. Spratt, R. Stark, J. Sturm, M.C. Sun, Y. Sun, P.S. Sung, Y.F. Sung, M. Suzuki, M. Tan, S.C. Tang, T. Tatlisumak, V. Thijs, M. Tiainen, C.H. Tsai, C.K. Tsai, C.L. Tsai, H.T. Tsai, L.K. Tsai, C.H. Tseng, L.T. Tseng, J. Tsoleridis, H. Tu, H.T-H. Tu, W. Vallat, J. Virta, W.C. Wang, Y.T. Wang, M. Waters, L. Weir, T. Wijeratne, C. Williams, W. Wilson, A.A. Wong, K. Wong, T.Y. Wu, Y.H. Wu, B. Yan, F.C. Yang, Y.W. Yang, N. Yassi, H.L. Yeh, J.H. Yeh, S.J. Yeh, C.H. Yen, D. Young, C.L. Ysai, W.W. Zhang, H. Zhao, L. Zhao, Katharina Althaus-Knaurer, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A. Dixit, Geoffrey Donnan, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R. Lees, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Peter Schellinger, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Rüdiger von Kummer, Joanna Wardlaw, Rebecca A. Betensky, Gregoire Boulouis, Raphael A. Carandang, William A. Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L. Ford, John Hallenbeck, Gordon J. Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Michael H. Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H. Schwamm, Eric Searls, Shlee S. Song, Sidney Starkman, Albert J. Yoo, Ramin Zand, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Monash University [Melbourne], National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Heidelberg, Medical Faculty, Massachusetts General Hospital [Boston], University of Melbourne, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Royal Adelaide Hospital [Adelaide Australia], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Flanders Make [Leuven], Flanders Make, University of Newcastle [Australia] (UoN), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Ruhr-Universität Bochum [Bochum], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Aarhus University Hospital, Cedars-Sinai Medical Center, Florey Institute of Neuroscience and Mental Health [Melbourne, Victoria, Australia], Austin Health, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], China Medical University Hospital [Taichung], Karolinska Institutet [Stockholm], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Texas at Austin [Austin], Collaborators Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators: Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Chi-Un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria Del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Martin Ebinger, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Matthias Endres, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Christian Gerloff, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Robin Lemmens, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-Cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K Mueller, Keith W Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Norbert Nighoghossian, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Peter Ringleb, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Vincent Thijs, Götz Thomalla, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Mayumi Fukuda-Doi, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Manabu Inoue, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Kaori Miwa, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Kazunori Toyoda, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Haruko Yamamoto, Keizo Yasui, Toshiro Yonehara, Sohei Yoshimura, Shinichi Yoshimura, K Aarnio, F Alemseged, C Anderson, T Ang, M L Archer, J Attia, P Bailey, A Balabanski, A Barber, P A Barber, J Bernhardt, A Bivard, D Blacker, C F Bladin, A Brodtmann, D Cadilhac, B C V Campbell, L Carey, S Celestino, L Chan, W H Chang, A ChangI, C H Chen, C-I Chen, H F Chen, T C Chen, W H Chen, Y Y Chen, C A Cheng, E Cheong, Y W Chiou, P M Choi, H J Chu, C S Chuang, T C Chung, L Churilov, B Clissold, A Connelly, S Coote, B Coulton, E Cowley, J Cranefield, S Curtze, C D'Este, S M Davis, S Day, P M Desmond, H M Dewey, C Ding, G A Donnan, R Drew, S Eirola, D Field, T Frost, C Garcia-Esperon, K George, R Gerraty, R Grimley, Y C Guo, G Hankey, J Harvey, S C Ho, K Hogan, D Howells, P M Hsiao, C H Hsu, C T Hsu, C-S Hsu, J P Hsu, Y D Hsu, Y T Hsu, C J Hu, C C Huang, H Y Huang, M Y Huang, S C Huang, W S Huang, D Jackson, J S Jeng, S K Jiang, L Kaauwai, O Kasari, J King, T J Kleinig, M Koivu, J Kolbe, M Krause, C W Kuan, W L Kung, C Kyndt, C L Lau, A Lee, C Y Lee, J T Lee, Y Lee, Y C Lee, C Levi, C R Levi, L M Lien, J C Lim, C C Lin, C H Lin, C M Lin, D Lin, C H Liu, J Liu, Y C Lo, P S Loh, E Low, C H Lu, C J Lu, M K Lu, J Ly, H Ma, L Macaulay, R Macdonnell, E Mackey, M Macleod, J Mahadevan, V Maxwell, R McCoy, A McDonald, S McModie, A Meretoja, S Mishra, P J Mitchell, F Miteff, A Moore, C Muller, F Ng, F C Ng, J-L Ng, W O'Brian, V O'Collins, T J Oxley, M W Parsons, S Patel, G S Peng, L Pesavento, T Phan, E Rodrigues, Z Ross, A Sabet, M Sallaberger, P Salvaris, D Shah, G Sharma, G Sibolt, M Simpson, S Singhal, B Snow, N Spratt, R Stark, J Sturm, M C Sun, Y Sun, P S Sung, Y F Sung, M Suzuki, M Tan, S C Tang, T Tatlisumak, V Thijs, M Tiainen, C H Tsai, C K Tsai, C L Tsai, H T Tsai, L K Tsai, C H Tseng, L T Tseng, J Tsoleridis, H Tu, H T-H Tu, W Vallat, J Virta, W C Wang, Y T Wang, M Waters, L Weir, T Wijeratne, C Williams, W Wilson, A A Wong, K Wong, T Y Wu, Y H Wu, B Yan, F C Yang, Y W Yang, N Yassi, H L Yeh, J H Yeh, S J Yeh, C H Yen, D Young, C L Ysai, W W Zhang, H Zhao, L Zhao, Katharina Althaus-Knaurer, Martin Bendszus, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A Dixit, Geoffrey Donnan, Rainer Dziewas, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Werner Hacke, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R Lees, Didier Leys, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Catherine Oppenheim, Sven Poli, Peter Ringleb, Peter Schellinger, Stefan Schwab, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Danilo Toni, Roland Veltkamp, Rüdiger von Kummer, Nils Wahlgren, Joanna Wardlaw, Rebecca A Betensky, Gregoire Boulouis, Raphael A Carandang, William A Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L Ford, John Hallenbeck, Gordon J Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Arne Lauer, Michael H Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H Schwamm, Eric Searls, Shlee S Song, Sidney Starkman, Steven Warach, Ona Wu, Albert J Yoo, Ramin Zand, University of Newcastle [Callaghan, Australia] (UoN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CarMeN, laboratoire, Yperzeele, Laetitia, Evaluation of Unknown Onset Stroke Thrombolysis trials (EOS) investigators, UCL - SSS/IONS - Institute of NeuroScience, UCL - (MGD) Service de neurologie, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, Clinical sciences, Neuroprotection & Neuromodulation, Radiology and Nuclear Medicine, ANS - Neurovascular Disorders, Neurology, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Center of Experimental and Molecular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ischemic Stroke/*diagnostic imaging/*drug therapy, Tomography, X-Ray Computed/methods, Fibrinolytic Agents/adverse effects/*therapeutic use, 030204 cardiovascular system & hematology, Ischemic Stroke/diagnostic imaging, surgery, 0302 clinical medicine, Modified Rankin Scale, 030212 general & internal medicine, 10. No inequality, Infusions, Intravenous, Stroke, Tomography, Time-to-Treatment, General Medicine, Thrombolysis, X-Ray Computed/methods, Tissue Plasminogen Activator/adverse effects, 3. Good health, [SDV] Life Sciences [q-bio], Diffusion Magnetic Resonance Imaging/methods, Treatment Outcome, Meta-analysis, Tissue Plasminogen Activator, Intravenous, medicine.medical_specialty, Infusions, Intravenous thrombolysis, Neuroimaging, Neuroscience(all), Placebo, Tissue Plasminogen Activator/adverse effects/*therapeutic use, 03 medical and health sciences, Fibrinolytic Agents, Internal medicine, medicine, Humans, ddc:610, Ischemic Stroke, business.industry, neurology, Fibrinolytic Agents/adverse effects, Odds ratio, Recovery of Function, medicine.disease, Clinical research, Diffusion Magnetic Resonance Imaging, Human medicine, business, Tomography, X-Ray Computed, Fibrinolytic agent
Abstract

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Published
2020

5. Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging. a systematic review and meta-analysis of individual patient data

Author

Bruce C V Campbell, Henry Ma, Peter A Ringleb, Mark W Parsons, Leonid Churilov, Martin Bendszus, Christopher R Levi, Chung Hsu, Timothy J Kleinig, Marc Fatar, Didier Leys, Carlos Molina, Tissa Wijeratne, Sami Curtze, Helen M Dewey, P Alan Barber, Kenneth S Butcher, Deidre A De Silva, Christopher F Bladin, Nawaf Yassi, Johannes A R Pfaff, Gagan Sharma, Andrew Bivard, Patricia M Desmond, Stefan Schwab, Peter D Schellinger, Bernard Yan, Peter J Mitchell, Joaquín Serena, Danilo Toni, Vincent Thijs, Werner Hacke, Stephen M Davis, Geoffrey A Donnan, Geoffrey A. Donnan, Stephen M. Davis, Bruce C.V. Campbell, Mark W. Parsons, Peter J. Mitchell, Patricia M. Desmond, Thomas Oxley, Teddy Y. Wu, Darshan Shah, Henry Zhao, Edrich Rodrigues, Patrick Salvaris, Fana Alemseged, Felix Ng, Cameron Williams, Jo-Lyn Ng, Hans T-H. Tu, Amy McDonald, David Jackson, Jessica Tsoleridis, Rachael McCoy, Lauren Pesavento, Louise Weir, Timothy J. Kleinig, S. Patel, J. Harvey, J. Mahadevan, E. Cheong, Anna Balabanski, Michael Waters, Roy Drew, Jennifer Cranefield, Elizabeth Mackey, Sherisse Celestino, Essie Low, Helen M. Dewey, Christopher F. Bladin, Poh Sien Loh, Philip M. Choi, Skye Coote, Tanya Frost, K. Hogan, C. Ding, S. McModie, W.W. Zhang, Christopher Kyndt, A. Moore, Z. Ross, J. Liu, Ferdinand Miteff, Christopher R. Levi, Timothy Ang, Neil Spratt, Carlos Garcia-Esperon, Lara Kaauwai, Thanh G. Phan, John Ly, Shaloo Singhal, Benjamin Clissold, Kitty Wong, Martin Krause, Susan Day, Jonathan Sturm, Bill O'Brian, Rohan Grimley, Marion Simpson, Matthew Lee-Archer, Amy Brodtmann, Bronwyn Coulton, Dennis Young, Andrew A. Wong, Claire Muller, Deborah K. Field, W. Vallat, Vanessa Maxwell, Peter Bailey, Arman Sabet, Sachin Mishra, Meng Tan, K. George, P. Alan Barber, L. Zhao, Atte Meretoja, Turgut Tatlisumak, G. Sibolt, M. Tiainen, M. Koivu, K. Aarnio, J. Virta, O. Kasari, S. Eirola, M.C. Sun, T.C. Chen, C.S. Chuang, Y.Y. Chen, C.M. Lin, S.C. Ho, P.M. Hsiao, C.H. Tsai, W.S. Huang, Y.W. Yang, H.Y. Huang, W.C. Wang, C.H. Liu, M.K. Lu, C.H. Lu, W.L. Kung, S.K. Jiang, Y.H. Wu, S.C. Huang, C.H. Tseng, L.T. Tseng, Y.C. Guo, D. Lin, C.T. Hsu, C.W. Kuan, J.P. Hsu, H.T. Tsai, M. Suzuki, Y. Sun, H.F. Chen, C.J. Lu, C.H. Lin, C.C. Huang, H.J. Chu, C.Y. Lee, W.H. Chang, Y.C. Lo, Y.T. Hsu, C.H. Chen, P.S. Sung, C.L. Ysai, J.S. Jeng, S.C. Tang, L.K. Tsai, S.J. Yeh, Y.C. Lee, Y.T. Wang, T.C. Chung, C.J. Hu, L. Chan, Y.W. Chiou, L.M. Lien, H.L. Yeh, J.H. Yeh, W.H. Chen, C.L. Lau, A. Chang, I.Y. Lee, M.Y. Huang, J.T. Lee, G.S. Peng, J.C. Lim, Y.D. Hsu, C.C. Lin, C.A. Cheng, C.H. Yen, F.C. Yang, C.H. Hsu, Y.F. Sung, C.K. Tsai, C.L. Tsai, A. Lee, Graeme Hankey, David Blacker, Richard Gerraty, C-I. Chen, C-S. Hsu, Elise Cowley, Michele Sallaberger, Barry Snow, John Kolbe, Richard Stark, John King, Richard Macdonnell, John Attia, Catherine D'Este, Julie Bernhardt, Leeanne Carey, Dominique Cadilhac, Craig Anderson, David Howells, A. Barber, Alan Connelly, Malcolm Macleod, Victoria O'Collins, W. Wilson, L. Macaulay, Erich Bluhmki, Christoph Eschenfelder, Peter Ringleb, Peter Schellinger, Nils Wahlgren, Joanna Wardlaw, Catherine Oppenheim, Kennedy R. Lees, Markku Kaste, Rüdiger von Kummer, Gilles Chatellier, Rico Laage, Xavier Nuñez, Christina Ehrenkrona, Ann-Sofie Svenson, Lynda Cove, Kurt Niederkorn, Franz Gruber, Peter Kapeller, Robert Mikulik, Jean-Louis Mas, Jörg Berrouschot, Jan Sobesky, Martin Köhrmann, Thorsten Steiner, Christof Kessler, Rainer Dziewas, Sven Poli, Katharina Althaus-Knaurer, Paolo Bovi, Alain L. Rodriguez, Juan F. Arenillas, Keith Muir, Roland Veltkamp, Anand Dixit, Girish Muddegowda, Lalit Kala, Deidre A. De Silva, Kenneth S. Butcher, G. Byrnes, Andre Peeters, J.B. Chalk, John N. Fink, Thomas E. Kimber, David Schultz, Peter J. Hand, Judith Frayne, Brian M. Tress, John McNeil, R. Burns, C. Johnston, and M. Williams

Subjects
medicine.medical_specialty, acute ischemic stroke, thrombolysis, Perfusion Imaging, medicine.medical_treatment, Perfusion scanning, 030204 cardiovascular system & hematology, Placebo, Brain Ischemia, Time-to-Treatment, 03 medical and health sciences, 0302 clinical medicine, Fibrinolytic Agents, Modified Rankin Scale, Internal medicine, medicine, Humans, Thrombolytic Therapy, rt-pa, 030212 general & internal medicine, Stroke, Cerebral Hemorrhage, business.industry, General Medicine, Odds ratio, Thrombolysis, medicine.disease, 3. Good health, meta-analysis, Diffusion Magnetic Resonance Imaging, Treatment Outcome, Tissue Plasminogen Activator, Meta-analysis, acute stroke therapy, Tomography, X-Ray Computed, business, Fibrinolytic agent
Abstract

Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036.We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66).Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.None.

Published
2019

6. Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

Author

Qin Zheng, Xinzhong Dong, Yixun Geng, Yingying Cheng, Julie H.Y. Huang-Lionnet, Qian Xu, Pang-Yen Tseng, Zhiping Wu, Zhe Li, Junmin Peng, Shuohao Sun, Yiyuan Cui, Yan Wang, Vineeta Tiwari, Bo Xiao, Yun Guan, Vinod Tiwari, Anna L. Blobaum, Shao Qiu He, Srinivasa N. Raja, Corey R. Hopkins, and Liang Han

Subjects
0301 basic medicine, Agonist, Genetically modified mouse, Male, Nociception, Allosteric modulator, medicine.drug_class, Gene Expression, Mice, Transgenic, Pharmacology, Receptors, G-Protein-Coupled, 03 medical and health sciences, Mice, 0302 clinical medicine, Allosteric Regulation, Peripheral Nerve Injuries, medicine, Animals, Humans, Transgenes, Receptor, G protein-coupled receptor, Analgesics, Sulfonamides, Multidisciplinary, business.industry, Chronic pain, medicine.disease, Calcium Channel Blockers, Sciatic Nerve, Peptide Fragments, Disease Models, Animal, 030104 developmental biology, PNAS Plus, Humanized mouse, Benzamides, Cattle, Calcium Channels, Chronic Pain, business, 030217 neurology & neurosurgery
Abstract

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1 This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8-22 (BAM8-22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8-22 to inhibit high-voltage-activated Ca2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8-22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.

Published
2017

7. An integrated process rate analysis of a regional fine particulate matter episode over Yangtze River Delta in 2010

Author

C. Huang, R.S. Yan, H.Y. Huang, L.P. Qiao, G.F. Zhang, David G. Streets, S.R. Lou, Joshua S. Fu, C.H. Chen, Li Li, M. Zhou, S.K. Tao, H.L. Wang, and Yangjun Wang

Subjects
Pollution, Atmospheric Science, Planetary boundary layer, media_common.quotation_subject, Environmental engineering, Humidity, Particulates, Atmospheric sciences, Atmosphere, Environmental science, Surface layer, Scavenging, General Environmental Science, media_common, CMAQ
Abstract

A high PM 2.5 pollution episode was detected in Shanghai in November 2010. The integrated process rate method, an advanced diagnostic tool, was applied to account for the contribution of different atmospheric processes during the high pollution episode in the Yangtze River Delta region (YRD). The PM 2.5 process analysis indicates that the emission of fine particles is the dominant source of high surface PM 2.5 concentrations in the major cities of the YRD like Shanghai, Nanjing, and Hangzhou, following horizontal transportation and aerosols. The PM 2.5 concentration could be reduced due to vertical advection and diffusion from lower levels to the upper air. The aerosols process such as homogeneous nucleation and condensation producing PM 2.5 occurs throughout the PBL layer in urban areas, causing vertical transport from upper levels down to the surface layer. The aerosols process is much more significant in a downwind rural and coastal site like Zhoushan than in the urban areas. The PM 2.5 change initiated by both horizontal transport and vertical transport is much stronger at 40–2000 m height than in the surface layer, while the PM 2.5 change caused by horizontal diffusion is very small. Dry deposition can significantly reduce concentration of the particulates in the surface level of the atmosphere, and wet deposition can remove the particles in the planetary boundary layer (PBL). The cloud processes can either increase PM 2.5 due to the aqueous-phase oxidation of SO 2 and NO 2 or remove PM 2.5 due to cloud scavenging. Solar radiation and humidity are more important to secondary pollution, and they are the significant external factors affecting the chemical reactions among sulfur dioxide, nitrogen oxides, ammonia, volatile compounds and fine particles.

Published
2014

9. Microbial Functional Diversity in Facilities Cultivation Soils of Nitrate Accumulation

Author

N. Wang, Zhou Pei, Qunlu Liu, Feng Haiwei, H.Y. Huang, Shi Weiwei, and Yuee Zhi

Subjects
Microbial diversity, Soil salinity, Soil test, BIOLOG, Microorganism, Soil organic matter, Environmental engineering, chemistry.chemical_element, chemistry.chemical_compound, Bioremediation, Nitrate, chemistry, Environmental chemistry, Soil water, General Earth and Planetary Sciences, Environmental science, Nitrate contaminated soil, Carbon, Secondary salinization, General Environmental Science
Abstract

There are increasing concerns over facilities cultivation soils of nitrate accumulation in China. Nitrate pollution in secondary salinization soil is regarded as having potential effects on soil microbial communities. Our study was conducted to evaluate effects of secondary salinization on soil microbial functional diversity with the BIOLOG method. The results showed that Average well-color development (AWCD) values declined with the rising of nitrate concentrations to some extent. The results also exhibited that the accumulation of nitrate in soil decreased the carbon sources utilization rates and the microbial species diversity indices. It indicated that nitrate has significantly negative effects on the sole-carbon-source metabolic ability of soil microbial communities. The cluster analysis intuitively demonstrated the distance and relationship between each sample: soil samples with high nitrate content were more close to each other, while soil samples with low were more similar in distances. The principal component analysis (PCA) result further validated that nitrate was inversely correlated to microbial carbon sources utilization intensity and microbial diversity. The four carbon substrates, Carbohydrates, Miscellaneous, Amino acids and Polymers, could reflect most of the information about carbon sources utilization. Microorganisms preferred these four carbon substrates were more vulnerable to nitrate. Thus, these four carbon substrates could be one of the prioritized microbe carbon sources in soil bioremediation.

Published
2012

11. Adhesion properties of nitrogen ion implanted ultra-nanocrystalline diamond films on silicon substrate

Author

Wei-Chuan Fang, Huan Niu, H.Y. Huang, N.H. Tai, Umesh Palnitkar, I-Nan Lin, P.T. Joseph, and Hsiu Fung Cheng

Subjects
Materials science, Synthetic diamond, Mechanical Engineering, Analytical chemistry, Diamond, General Chemistry, Chemical vapor deposition, engineering.material, Ion source, Electronic, Optical and Magnetic Materials, law.invention, Secondary ion mass spectrometry, Ion implantation, Chemical engineering, law, Plasma-enhanced chemical vapor deposition, Materials Chemistry, engineering, Electrical and Electronic Engineering, Thin film
Abstract

Ultra-nanocrystalline diamond (UNCD) films prepared by microwave plasma enhanced chemical vapor deposition were implanted using 0.3 MeV nitrogen ions under a dose of 10 13 , 10 14 , and 10 15 ions cm − 2 . While the surface morphology of the UNCD films was not pronounced modified, the crystallinity of the films was changed appreciably due to ion implantation. The scratch test has been used to study the adhesion of the film to the substrate, which illustrated that the critical load, used as a measure of the adhesive strength, is found to increase with ion dose. Secondary ion mass spectroscopy (SIMS) analyses on the interfacial morphology indicated that the main factor in improving the adhesive strength is the modification on interfacial structure through inter-diffusion between film and substrate.

Published
2008

12. Surface integrity of silicon wafers in ultra precision machining

Author

Hong-Tsu Young, H.T. Liao, and H.Y. Huang

Subjects
Engineering drawing, Materials science, business.industry, Mechanical Engineering, Polishing, Industrial and Manufacturing Engineering, Computer Science Applications, Grinding, Machining, Lapping, Control and Systems Engineering, Etching (microfabrication), Surface grinding, Optoelectronics, Wafer, business, Software, Surface integrity
Abstract

Silicon wafers are the most extensively used material for integrated circuit (IC) substrates. Before taking the form of a wafer, a single crystal silicon ingot must go through a series of machining processes, including slicing, lapping, surface grinding, edge profiling, and polishing. A key requirement of the processes is to produce extremely flat surfaces on work pieces up to 350 mm in diameter. A total thickness variation (TTV) of less than 15 μm is strictly demanded by the industry for an 0.18 μm IC process. Furthermore, the surfaces should be smooth (Ra

Published
2006

13. Design Consideration of a High Temperature Superconductor Maglev Vehicle System

Author

Fu Li, Jukun Wang, Xinzhi Wang, Shunliang Wang, Youwen Zeng, Jun Zheng, Honghai Song, Changyan Deng, and H.Y. Huang

Subjects
On board, Superconductivity, Physics, Test line, Acceleration, Maglev, Electrical and Electronic Engineering, Liquid nitrogen, Linear motor, Condensed Matter Physics, Automotive engineering, Magnetic levitation, Electronic, Optical and Magnetic Materials
Abstract

The design consideration of the superhigh speed HTS Maglev vehicle system of 1000 m test line is presented on the basis of the experiment results of HTS Maglev vehicle in the years before last. The gross weight of NdFeB of test line guideway is 6750 kg. The low temperature rectangle-shape liquid nitrogen vessel on board has high mechanical strength at 77 K of the temperature. The vessel has 5 mm of bottom thickness and 12 hours of continuous working time. There are two seats in the HTS Maglev vehicle. The total load of the Maglev vehicle is 500 kg including 150 kg of weight of two passengers in the weight. The vehicle body is the quasiellipsoidal shape, and the outside outline size of the vehicle with shell is about 2.3 m of length 0.95 m of height, and 1.2 m of width. The vehicle is driven by a linear motor which is controlled by a ground controlling system. Drive acceleration is 5 g (about 49 m/s/sup 2/), and the acceleration section length is 300 m. The maximum speed of the vehicle is over 600 km/h when there is no onboard man, and the manned speed is still up to 100 km/h.

Published
2005

14. Method for producing coded micro-carrier and test method by using a novel type biochip

Author

D.Y. Lee, Rong-Nan Huang, H.Y. Huang, J.H. Hsu, W.Y. Chen, P.L. Lin, and R.S. Chang

Subjects
Image fusion, Surface Properties, business.industry, Computer science, Microchemistry, Protein Array Analysis, Process (computing), Bioengineering, Nanotechnology, Image processing, Equipment Design, General Medicine, Test method, Models, Biological, Applied Microbiology and Biotechnology, Identification (information), Digital image processing, Image Processing, Computer-Assisted, Animals, Microelectronics, business, Biochip, Computer hardware, Biotechnology
Abstract

This paper provides a method for producing a novel type coded micro-carrier. A simple and cost effective solution for bio-molecule applications was developed. Application relevant items such as manufacture process, biospecific interaction, and analysis method are discussed. For low cost fabrication, the use of LIGA-like process is suggested. LIGA-like process is used as a dry patterning process in which an intense beam of light from an excimer laser is used to pattern a material directly. This process has found extensive application in the microelectronics industry for patterning of polymer materials. The use of LIGA-like techniques offers two attractive features: first, we can cut the polymer into many tiny micro-carriers with micrometer precision. Second, LIGA-like process allows to encode with high precision spatial information onto the micro-carrier that can be used in the identification of the bio-molecule. This paper gives a description of the basic idea, describes the fabrication of the novel micro-carrier that we called "coded micro-carrier," and of the image processing algorithms used for the analysis of bio-molecules. This study also provides a test method for identifying a bio-molecule, which includes mixing several coded micro-carriers with the hybridized unknown bio-molecules; and identifying the codes on the micro-carrier via image recognition system. The numbers and types of the known micro-carrier can be flexibly adjusted according to the number of tested bio-molecules.

Published
2004

15. Expression of Drosophila neoplastic tumor suppressor genes discslarge, scribble, and lethal giant larvae in the mammalian ovary

Author

Aleksandar Rajkovic, Przemyslaw Szafranski, Scott Goode, JoAnne S. Richards, Julie H.Y Huang, and Scott A. Ochsner

Subjects
Tumor suppressor gene, Ovary, Biology, Oogenesis, law.invention, Mice, law, Genetics, medicine, Animals, Drosophila Proteins, Humans, Molecular Biology, Gene, Ovarian Neoplasms, Tumor Suppressor Proteins, Membrane Proteins, Oocyte, Epithelium, Cell biology, medicine.anatomical_structure, Suppressor, Drosophila, Female, Folliculogenesis, Developmental Biology
Abstract

The similarities and differences in molecular mechanisms regulating invertebrate and mammalian folliculogenesis are starting to be deciphered. In Drosophila, the neoplastic tumor suppressor gene discslarge is crucial for suppressing proliferation and movement of follicle cells relative to the growing oocyte. Lethal giant larvae and scribble play similar roles and have been suggested to collaborate intimately with discslarge. We have identified and determined the expression pattern of murine homologs of these Drosophila genes. In situ data shows that murine discslarge-1, discslarge-3, discslarge-4, lethal giant larvae, and scribble are expressed in both overlapping and distinct patterns in oocytes and granulosa cells in maturing follicles. Disclarge-4 is expressed in the surface epithelium and is lost in mouse carcinogenic surface epithelial cells. All of these genes, as well as discslarge-2 and discslarge-5, are expressed in human ovaries. Our data suggests that as in Drosophila, these tumor suppressors may cooperate during mammalian folliculogenesis, but also have distinct functions.

Published
2003

16. Interacting dimers on the honeycomb lattice: an exact solution of the five-vertex model

Author

F. Y. Wu, H.Y. Huang, Doochul Kim, and H. Kunz

Subjects
Condensed Matter::Quantum Gases, Statistics and Probability, Physics, Specific heat, Dimer, Condensed Matter (cond-mat), FOS: Physical sciences, Condensed Matter, Condensed Matter Physics, 01 natural sciences, Molecular physics, 010305 fluids & plasmas, 3. Good health, Bethe ansatz, chemistry.chemical_compound, Exact solutions in general relativity, chemistry, Lattice (order), 0103 physical sciences, Vertex model, Physics::Atomic and Molecular Clusters, Exponent, Condensed Matter::Strongly Correlated Electrons, 010306 general physics, Phase diagram
Abstract

The problem of close-packed dimers on the honeycomb lattice was solved by Kasteleyn in 1963. Here we extend the solution to include interactions between neighboring dimers in two spatial lattice directions. The solution is obtained by using the method of Bethe ansatz and by converting the dimer problem into a five-vertex problem. The complete phase diagram is obtained and it is found that a new frozen phase, in which the attracting dimers prevail, arises when the interaction is attractive. For repulsive dimer interactions a new first-order line separating two frozen phases occurs. The transitions are continuous and the critical behavior in the disorder regime is found to be the same as in the case of noninteracting dimers characterized by a specific heat exponent $\a=1/2$., Comment: latex, 29 pages + 7 figures

Published
1996

17. Willingness to pay for private primary care services in Hong Kong: are elderly ready to move from the public sector?

Author

Olivia H.Y. Huang, Sian M. Griffiths, Carrie H K Yam, and Su Liu

Subjects
Male, medicine.medical_specialty, Economic growth, Financing, Personal, Choice Behavior, Public-Private Sector Partnerships, Willingness to pay, Surveys and Questionnaires, Health care, medicine, Humans, health care economics and organizations, Aged, Aged, 80 and over, Public Sector, Public economics, Primary Health Care, business.industry, Health Policy, Public health, Public sector, Middle Aged, Private sector, Focus group, Public–private partnership, Hong Kong, Female, Private Sector, Health care reform, business
Abstract

How to provide better primary care and achieve the right level of public-private balance in doing so is at the centre of many healthcare reforms around the world. In a healthcare system like Hong Kong, where inpatient services are largely funded through general taxation and ambulatory services out of pocket, the family doctor model of primary care is underdeveloped. Since 2008, the Government has taken forward various initiatives to promote primary care and encourage more use of private services. However, little is known in Hong Kong or elsewhere about consumers' willingness to pay (WTP) for private services when care is available in the public sector. This study assessed willingness of the Hong Kong elderly to pay for specific primary care and preventive services in the private sector, through a cross-sectional in-person questionnaire survey and focus group discussions among respondents. The survey revealed that the WTP for private services in general was low among the elderly; particularly, reported WTP for chronic conditions and preventive care both fell below the current market prices. Sub-group analysis showed higher WTP among healthier and more affluent elderly. Among other things, concerns over affordability and uncertainty (of price and quality) in the private sector were associated with this low level of WTP. These results suggest that most elderly, who are heavy users of public health services but with limited income, may not use more private services without seeing significant reduction in price. Financial incentives for consumers alone may not be enough to promote primary care or public-private partnership. Public education on the value of prevention and primary care, as well as supply-side interventions should both be considered. Hong Kong's policy-making process of the initiative studied here may also provide lessons for other countries with ongoing healthcare reforms.

Published
2012

18. Can vouchers make a difference to the use of private primary care services by older people? Experience from the healthcare reform programme in Hong Kong

Author

Carrie H K Yam, E K Yeoh, Su Liu, Sian M. Griffiths, and Olivia H.Y. Huang

Subjects
Male, Gerontology, Financing, Government, Health Services for the Aged, Public-Private Sector Partnerships, Risk Assessment, Health administration, Surveys and Questionnaires, Health care, Confidence Intervals, Odds Ratio, Humans, Medicine, Community Health Services, Aged, Aged, 80 and over, Analysis of Variance, Public Sector, Primary Health Care, business.industry, lcsh:Public aspects of medicine, Health Policy, Public sector, lcsh:RA1-1270, Public relations, Private sector, Voucher, Public–private partnership, Cross-Sectional Studies, Logistic Models, Health Care Reform, Hong Kong, Female, Private Sector, Private healthcare, Health care reform, Health Expenditures, business, Research Article, Program Evaluation
Abstract

Background As part of its ongoing healthcare reform, the Hong Kong Government introduced a voucher scheme, intended for encouraging older patients to use primary healthcare services in the private sector, thereby, reducing burden on the overwhelmed public sector. The voucher program is also considered one of the strategies to further develop the public private partnership in healthcare, a policy direction of high political priority as indicated in the Chief Executive Policy Address in 2008-09. This study assessed whether the voucher scheme, as implemented so far, has reached its intended goals, and how it might be further improved in the context of public-private partnership. Methods This was a cross-sectional study using structured questionnaires by face-to-face interviews with older people aged 70 or above in Hong Kong, the target group of the demand-side voucher program. Results 71.2% of 1,026 older people were aware of the new voucher scheme but only 35.0% had ever used it. The majority of the older people used the vouchers for acute curative services in the private sector (82.4%) and spent less on preventive services. Despite the provision of vouchers valued US$30 per year as an incentive to encourage the use of private primary care services, after 12-months of implementation, 66.2% of all respondents agreed with the statement that "the voucher scheme does not change their health seeking behaviours on seeing public or private healthcare professionals". The most common reasons for no change in their behaviours included "I am used to seeing doctors in the public system" and "The amount of the subsidy is too low". Those who usually used a mix of public and private doctors and those with better self-reported health condition compared to last year were more likely to perceive a change in their own health seeking behaviours. Conclusions Our study showed that despite a reasonably high awareness of the voucher scheme, its usage was low. The voucher alone was not enough to realize the government's policy of greater use of the private primary care services. Greater publicity and more variety of media promotion would increase awareness but the effectiveness of vouchers in changing older people's behaviour needs to be revisited. Designating vouchers for use of preventive services with evidence-based practice could be considered. In addition to the demand-side subsidies, improving transparency and comparability of private services against the public sector might be necessary.

Published
2011

19. Unconstrained approach to the extremization of constrained functions

Author

S. Naqvi and H.Y. Huang

Subjects
Combinatorics, Quadratic growth, Rate of convergence, Applied Mathematics, Scalar (mathematics), Applied mathematics, Quadratic function, Performance index, Analysis, Mathematics, Second derivative
Abstract

In this paper, the problem of extremizing a function ƒ(x) subject to the constraint ϑ(x) = 0 is considered. Here, ƒ is a scalar, x an n-vector, and ϑ a q-vector, where 0 ⩽ q < n. This problem is transformed into that of minimizing the unconstrained function R(x, λ), where x and λ are regarded as independent variables. The q-vector λ is the Lagrange multiplier associated with the constraint and the function R(x, λ) is the performance index measuring the cumulative error in the optimum condition and the constraint. The minimum R(x, λ) = 0 of the performance index is sought by applying quadratically convergent algorithms for unconstrained function minimization: the (n + q)-vector y = [x, λ]T is the independent variable associated with the performance index R(y).Since the performance index R(y) involves the first derivatives ƒx and ϑx, the gradient G(y) = Ry(y), which is employed in quadratically convergent algorithms, involves the second derivatives ƒxx and ϑxx. To avoid the explicit use of these second derivatives, a two-point determination of the gradient G(y) is developed: the (n + q)-vector G(y) is computed numerically through only two evaluations of the function R(y).Concerning the one-dimensional determination of the stepsize α, a two-point quasilinearization search is developed. This method requires only two evaluations of the function R(y), but preserves the eventual quadratic convergence of the quasilinearization method. Two terminating conditions are investigated: exact search and one-cycle search.Thus, the method presented here is a first-order method. For the ideal case of a quadratic function subject to a linear constraint, it converges to the solution in n + q iterations, at most. The total computational effort involved is equivalent to, at most, 3(n + q) + 1 evaluations of the function R(y).Three numerical examples are given using both the exact search and the one-cycle search. The results are presented in terms of number of iterations and number of function evaluations for convergence.

Published
1972

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