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391 results on '"Singhal, B."'

101. FrontMatter.

Author

Singhal, B. B. S. and Gupta, R. P.

Published
2010

106. Epilepsy in the Tropics: II. Clinical Presentations, Pathophysiology, Immunologic Diagnosis, Economics, and Therapy

Author

Bittencourt, P. R. M., primary, Adamolekum, B., additional, Bharucha, N., additional, Carpio, A., additional, Cossio, O. H., additional, Danesi, M. A., additional, Dumas, M., additional, Fernandes, J. G., additional, Genton, P., additional, Manreza, M. L., additional, Meinardi, H., additional, Ordinario, A., additional, Senanayake, N., additional, Shakir, R., additional, Singhal, B. S., additional, and Sotelo, J., additional

Published
1996
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109. LEAF SURFACE SCANNING ELECTRON MICROSCOPY OF 16 MU LBERY GENOTYPES (Morus SPP.) WITH RESPECT TO THEIR FEEDING VALUE IN SILKWORM (Bombyx MORI L.) REARING.

Author

Singhal, B. K., Baqual, M. F., Khan, M. A., Bindroo, B. B., and Dhar, A.

Subjects
*MULBERRY, *SERICULTURE, *INSECT food, *FOLIAR diagnosis, *SCANNING electron microscopy, *STOMATA, *TRICHOMES
Abstract

Mulberry (Morus spp.) is the only silkworm (Bombyx mori L.) food plant. In Indian sub tropics, S-146 is the only popular and ruling mulberry genotype for silkworm rearing. As a result, mulberry leaf availability is always the limiting factor, and therefore, sub tropics are contributing less than 1% of the country's total silk production compared with more than 60% under tropical conditions. Besides climatic conditions, this is due to a very limited number of mulberry genotypes available in this region for silkworm rearing. However, in the mean time, 15 mulberry genotypes viz. 'Tr-10', 'Chinese White', 'K-2', 'Sujanpur Local', 'BC2-59', 'S-1635', 'C-1730', 'Mandalaya', 'S-30' (Vishala), 'RFS-175', 'Anantha', 'C-2016', 'C-2017', 'S-41' and 'V-1' were also introduced in the sub tropics, but remained unexplored. In sericulture, leaf surface is also an important parameter for, both, the silkworm's acceptability of not having any feeding impediment and the mulberry improvement programs. The objective of this study was to explore the possibilities of using these 16 mulberry genotypes for their leaf surface characteristics by scanning electron microscopy and using them for sericulture. Based on leaf yield, stomatal size, stomatal number per unit of area and trichomes and idioblasts length, these genotypes were grouped into different categories. The mulberry genotype 'Mandalaya', in addition to the ruling genotype 'S-146' excelled because of their higher leaf yield and desired leaf surface characteristics. Furthermore, the genotypes 'K-2', 'S-41' and 'Sujanpur Local' are also suggested to develop high yield mulberry genotypes in the Indian sub tropics. [ABSTRACT FROM AUTHOR]

Published
2010
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112. CNS involvement in malignant atrophic papulosis (Kohlmeier-Degos disease): vasculopathy and coagulopathy.

Author

Dastur, D K, Singhal, B S, and Shroff, H J

Abstract

The clinical features in a 42 year old man with malignant atrophic papulosis with CNS involvement are described. They included mental dysfunction, paraesthesiae, weakness of left limbs, with pyramidal tract signs, bilateral ptosis, progressing to total ophthalmoplegia and obtundation. There were two crops of characteristic papular lesions on trunk and limbs, with terminal evidence of a coagulopathy and bruises, resulting in death in six months. Papular biopsy revealed multiple microinfarcts in the dermal collagen. The brain showed multiple small haemorrhagic infarcts of both hemispheres, the lower mid-brain, pons and a cerebellar peduncle. Microscopy showed fibrin exudation in the leptomeninges, various stages of thrombosis of small arteries without inflammatory reaction, and corresponding acute and subacute microinfarcts. The pathogenetic basis of the disease appeared to be a combined vasculopathy and coagulopathy. [ABSTRACT FROM AUTHOR]

Published
1981

118. Tasar silkworm seed sector: Status and future approaches.

Author

Mishra, R. K., Rao, P. R. T., Nandi, S., Singhal, B. K., and Kalla, P. K.

Subjects
SEED industry, SEED quality, OAK tasar silkworm, SERICULTURE, SILKWORM diseases, PREVENTION
Abstract

The concept of development and adoption of private seed rearers/graineurs promoted by BTSSO to ensure multiplication of basic seed to commercial seed by the state agencies and its reach to the tasar farmers, indeed proved effective. Technical guidance for quality seed production with emphasis on disease monitoring and implementation of appropriate practices also came handy. However, the incremental demand for tasar seed makes it imperative for a coordinated effort by the Central Silk Board and the Department of Sericulture besides encouraging participation of NGOs and the private agencies to cater to the demand. [ABSTRACT FROM AUTHOR]

Published
2015

120. Long-term disability trajectories in primary progressivs MS patients - a latent class growth analysis

Author

Signori, A., Izquierdo, G., Lugaresi, A., Hupperts, R., Grand Maison, F., Sola, P., Horakova, D., Havrdova, E., Prat, A., Girard, M., Duquette, P., Boz, C., Gramond, P., Terzi, M., Singhal, B., Alroughani, R., Petersen, T., Ramo, C., Oreia-Guevara, C., Spitaleri, D., Shaygannejad, V., Butzkueven, H., Kalincik, T., Jokubaitis, V., Mark Slee, Bolanos, R. F., Sanchez-Menoyo, J. L., Pucci, E., Granella, F., Lechner-Scott, J., Iuliano, G., Hughes, S., Bergamaschi, R., Taylor, B., Verheul, F., Rio, M. E., Amato, M. P., Sajedi, S. A., Majdinasab, N., Pesch, V., Sormani, M. P., Trojano, M., and Sbase Study Grp, M.

121. Effect of relapse phenotype on the accumulation of disability in relapsing-remitting multiple sclerosis

Author

Stewart, T., Jokubaitis, V., Spelman, T., Havrdova, E., Horakova, D., Trojano, M., Izquierdo, G., Girard, M., Duquette, P., Prat, A., Lugaresi, A., Grammond, P., Grand Maison, F., Sola, P., Hupperts, R., Petersen, T., Pucci, E., Bergamaschi, R., Boz, C., Eva Kubala Havrdova, Lechner-Scott, J., Alroughani, R., Ramo, C., Pesch, V., Fernandez-Bolanos, R., Iuliano, G., Rio, M. E., Granella, F., Slee, M., Verheul, F., Spitaleri, D. L. A., Amato, M. P., Hodgkinson, S., Mccombe, P., Cabrera-Gomez, J. A., Barnett, M., Flechter, S., Olascoaga, J., Vucic, S., Sanchez-Menoyo, J. L., Cristiano, E., Saladino, M. L., Moore, F., Gray, O., Shuey, N., Rozsa, C., Singhal, B., Shaw, C., Butzkueven, H., Kalincik, T., and Sbase Study Grp, M.

122. ALICE Electromagnetic Calorimeter Technical Design Report

Author

Cormier, T., Cortese, P., Dellacasa, G., Gemme, R., Sitta, L., Ramello, M., Ahmad, A., Ahmad, N., M. Danish, A., Irfan, M., Khan, A., Kamal, M., Bilandzic, A., Botje, M., Kraus, I., Krzewicki, M., Kuijer, P., Kolk R. Van, Der, Snellings, N., Belogianni, A., Christakoglou, P., Fragkiadakis, M., Ganoti, P., Potirakis, S., Spyropoulou-Stassinaki, M., Tagridis, C., Vassiliou, E., Tsilis, M., E. Bruno, G., D'Erasmo, G., D. Di, Bari, C. Di, Giglio, M. Fiore, E., Ghidini, B., Mastroserio, A., Minafra, F., Navach, F., Perrino, D., Posa, F., Romita, R., Sgura, R., Santoro, I., Elia, D., Fini, R., Lenti, V., Manzari, V., Nappi, E., Nicassio, M., Volpe, V., Paticchio, G., Hu, S., Li, X., Lu, S., Zhou, Q., Wen, S., Alme, J., Bablock, S., Kanaki, K., Klovning, A., T. Larsen, D., Nystrand, J., Ovrebekk, G., Pommeresch, B., Richter, M., Röhrich, D., Ullaland, K., Yang, B., Wagner, H., H. Helstrup, H., Hetland, K., Helstrup, B., Kileng, K., Red, B., Blyth, S., Gray, H., Horner, M., Jacobs, P., Janina Odyniec, Grazyna, Ploskon, M., J. Van, Leeuwen, Symons, M., Dash, A., Dash, S., Jena, C., Mahapatra, D., Viyogi, S., Rath, Y., Bhasin, A., Bombara, M., Evans, D., T. Jones, G., Jones, P., Jovanovic, P., Jusko, A., Krivda, M., Lazzeroni, C., Lietava, R., Platt, R., Snow, H., D. Villalobos, Baillie, O. Tapia, Takaki, Alici, A., Antinori, S., Arcelli, S., Basile, M., Cifarelli-Strolin, L., Falchieri, D., Masetti, M., Preghenella, R., Scioli, G., Zichichi, A., Silenzi, A., Antonioli, P., G. Cara, Romeo, Cindolo, F., Costa, F., Hatzifotiadou, D., Laurenti, G., Luvisetto, M., Margotti, A., Nania, R., Noferini, F., Pesci, A., Scapparone, E., Zampolli, C., Williams, C., Cerny, V., Fekete, V., Janik, R., Pikna, M., Siska, M., Sitár, B., Szarka, P., Strmen, I., C. Rei, C., Berceanu, I., Catanescu, V., Herghelegiu, A., Petris, M., Petrovici, M., Pop C. Rei, A., Schiaua, A., Pop, C., Felea, D., Gheata, A., Haiduc, M., Hasegan, D., Mitu, C., Sevcenco, A., Zgura, I., Stan, I., Barnafoldi, G., Boldizsar, L., Dénes, E., Hamar, G., Lévai, Peter, Tolyhy, L., Molnar, T., A. De, Falco, Floris, M., Puddu, G., Usai, S., L. Serci, G., Becker, B., Cicalò, C., Masoni, A., Woehri, E., Siddi, H., Cleymans, J., D. De, Vaux, Fearick, R., Vilakazi, A., Szostak, Z., Barbera, R., Blanco, F., Giudice, N., P. La, Rocca, Noto, F., Petta, C., Riggi, A., Pulvirenti, F., Badalà, A., Fichera, F., Grimaldi, A., Librizzi, F., Palmeri, A., S. Pappalardo, G., Vernet, S., Urso, R., Aglieri-Rinella, G., Anelli, G., Antinori, F., Augustinus, A., Bächler, J., Belikov, J., Betev, L., Boccioli, M., Bruckner, G., Brun, R., Buncic, P., Cali, I., Campagnolo, R., Campbell, M., Carena, F., Carena, W., Carminati, F., Chapeland, S., Cheshkov, C., V. Chibante, Barroso, (cern) Chochula, P., (cern) Colla, A., De Cataldo, G., De Groot, J., Di Mauro, A., Divi, R., W. Fabjan, C., Formenti, F., Fuchs, U., Gheata, M., F. Grosse-Oetringhaus, J., Grosso, R., Z. Khristov, P., Jirdén, L., Kapusta, S., Klein-Bösing, C., Kluge, A., Lackner, F., Leistam, L., Lippmann, C., Makhlyueva, I., Martinengo, P., Meoni, M., Morsch, A., Müller, H., Musa, L., Oldenburg, M., Osmic, F., Perini, D., J. Peters, A., Rademakers, A., P. Revol, J., Riedler, P., Riegler, W., Rosinsky, P., Rossegger, S., Roukoutakis, F., Safarík, K., Salgueira Dominquesda Silva, R., Schossmaier, K., Schükraft, J., Shahoyan, R., Soos, C., Stefanini, G., Swoboda, D., Tadel, M., Taureg, H., Tavlet, M., Torcatode-Matos, C., Tydesjo, H., Wallet, P., Vande Vyvre, L., Agarwal, M., Bhati, A., Kumar, L., Kumar, N., Baldit, A., Barret, V., Bastid, N., Blanchard, G., Castor, J., Crochet, P., Devaux, A., Dupieux, P., Force, P., Guernane, R., Lecoq, J., López, X., Manceau, L., Manso, F., Saturnini, P., Rosnet, P., Humanic, T., Kisiel, A., Lisa, M., Truesdale, B., Nilsen, D., G. Bearden, I., Bggild, H., Christensen, C., J. Gaardhje, J., Nielsen, K., S. Gulbrandsen, B., Bartke, J., Kornas, E., Kowalski, M., Rybicki, A., Matyja, A., I. Leon, Monzon, Doenigus, B., Foka, P., Frankenfeld, U., Garabatos, J., Gutbrod, H., Ivanov, M., Malzacher, P., Marin, A., Masciocchi, S., Miskowiec, D., Schmidt, C., Schmidt, H., Schwarz, K., Soyk, D., Wiechula, D., Vranic, J., Oeschler, H., Bellwied, R., Li, Q., Mlynarz, J., Pavlinov, A., Petrov, V., Pompei, F., A. Pruneau, C., Voloshin, A., Rumbers, S., Antipin, K., Antonczyk, D., Appelshäuser, H., Blume, C., Büsching, H., Hartig, M., Kliemant, M., Kniege, S., Kramer, F., Sommer, R., Renfordt, W., Bianchi, N., P. Capitani, G., A. Casanova, Diaz, Conesa-Balbastre, G., Cunqueiro, L., M. Del, Franco, P. Di, Nezza, Fantoni, A., Hasch, D., Muccifora, V., R. Reolon, A., Orlandi, F., Ronchetti, A., Pesci, W., Viticchie, R., Vieira, A., Berdnikov, Y., Ivanov, V., Khanzadeev, A., Kryshen, E., Nikulin, V., Polyakov, V., Samsonov, V., Zhalov, A., Zalite, M., Bourrion, O., Furget, C., Gadrat, S., Kox, S., Real, J.S., Muraz, J., A. Abrahantes, Quintana, K. Lopez, Torres, Shtejer, E., Alt, T., Angelov, V., Bottger, S., J. De, Cuveland, Gorbunov, S., Kalcher, S., Kebschull, U., Kisel, I., Lara, C., Lindenstruth, V., Panse, R., Reichling, C., Rettig, F., Schneider, R., Steinbeck, T., Troger, J., Thader, G., Busch, O., M. De, Gaspari, Emschermann, D., Glässel, P., Herrmann, N., Kweon, M., J. Mercado, Perez, Oyama, K., Radomski, S., Rusanov, I., Schicker, R., Schweda, K., Soltveit, H., Soualah, R., Stachel, J., Tsiledakis, G., Windelband, Y., Wang, B., Äystö, J., Bondila, M., R. Diaz, Valdes, Kim, D., Malkiewicz, T., Oinonen, M., Trzaska, J., Rak, W., Horaguchi, T., Shigaki, K., Torii, T., Sugitate, H., M. M. Don, D., Pinsky, B., Mayes, L., Raniwala, R., Raniwala, S., Bala, R., Sen-Gupta, A., Mahajan, A., Potukuchi, B., Sharma, S., Sambyal, S., Batyunya, B., Jancurova, L., Kutovsky, M., Nomokonov, P., Pocheptsov, T., Shabratova, G., Vala, M., S. Vodopyanov, A., Zinchenko, Y., Zanevskiy, A., Baek, Y., Jung, H., Jung, W., Kang, E., S. Kim, D., W. Kim, D., N. Kim, H., S. Kim, J., Kim, M., S. Lee, K., C. Lee, S., Borshchov, V., Zinovjev, B., Grynyov, G., Garishvili, I., Hamblen, J., Hornback, D., Martashvili, I., F. Sorensen, K., P. Read, S., S. Bose, S., Chattopadhyay, S., Das, I., Pal, S., Bose, P., Roy, T., Sinha, P., Ahammed, Z., M. Dutta, Majumdar, Ganti, M., Mohanty, B., Mondal, M., Nayak, T., Prasad, S., Saini, J., Singaraju, R., Sinha, V., Singhal, B., Krawutschke, T., Bán, J., Králik, I., Kravcakova, A., Pastircák, B., Sándor, L., Urbán, J., Vrláková, J., Dainese, A., A. Vannucci, R., Ricci, L., Soltz, A., Glenn, R., Christiansen, P., Dobrin, A., Gros, P., Åke Gustafsson, Hans, Oskarsson, A., Österman, L., Stenlund, I., Otterlund, E., Cheynis, B., Ducroux, L., Y. Grossiord, J., Nendaz, F., Cheynis, R., Tieulent, Y., Zoccarato, B., Zoccarato, R., Acero, A., Cardenas-Montes, M., Gonzales-Zamora, P., Guevara P. Ladrón, De, Montes, E., Rubio, J., A. Perez, Griffo, Serradilla, M., Rubio, E., Camacho, E., Contreras, J., Gago, A., Herrera-Corral, G., L. Montano, Zetina, Zepeda, C., Pérez, A., Alfaro, R., Anzo, A., Belmont-Moreno, E., H. Gonzales-Trueba, L., Grabskii, V., Leon, H., Sandoval, A., Menchaca-Rocha, A., Cuautle, E., Diaz, L., Domnguez, I., I. Maldonado, Cervantes, A. Ortiz, Velazquez, Paic, G., D. Perez, Astudillo, Podesta, P., Sokolov, L., Serkin, O., Feshchenko, V., Gorlychev, V., Guber, F., Karavicheva, T., Karpechev, E., Kurepin, A., N. Kurepin, A., Maevskaya, A., Feshchenko, I., Pshenichnov, A., Reshetin, V., Reshetin, I., Akindinov, A., Grishuk, Y., Kiselev, S., Mal'Kevich, D., Polozov, P., Sharkov, E., Vetlitskiy, I., Zagreev, K., Voloshin, B., Aleksandrov, D., Blau, D., Dobretsov, V., Fokin, S., Ippolitov, M., Kazantsev, A., Kozlov, K., Kucheriaev, Y., Man'Ko, V., Moukhanova, T., Nyanin, A., Nikolaev, S., Nikulin, S., Peresunko, D., Ryabinkin, E., Sibiryak, Yu, Vasilev, A., Yushmanov, A., Vinogradov, I., Bogdanov, A., Grigoriev, V., Kaplin, V., Loginov, N., Kondratieva, V., Nandi, B., Varma, P., Pujahari, R., Bathen, B., Baumann, C., Dietel, T., Glasow, R., Gottschlag, H., Rammler, M., Reygers, K., Santo, R., Wilk, J., Wessels, A., Aphecetche, L., Batigne, G., Benhabib, L., Bourdaud, G., Bouvier, S., Cussonneau, J., Delagrange, H., Dialinas, M., Estienne, M., Finck, C., Germain, M., Ichou, R., Le Bris, N., Lefèvre, F., Luquin, L., Garcia Martinez, G., Pillot, P., Roy, C., Tournaire, Y., Schutz, A., Aronsson, T., Baumgart, S., Bruna, E., Caines, H., W. Harris, J., Heinz, M., Knospe, A., Nattrass, C., Smirnov, J., Putschke, N., Pestov, A., Frolov, Y., C. Awes, T., Enokizono, A., W. Stankus, P., Young, D., R. Silvermyr, G., Gorbunov, M., Cherney, Y., Bimbot, L., Chambert, V., Charpy, A., Espagnon, B., Hrivnacova, I., Lafage, V., Y. Le, Bornec, Malek, M., Peyre, J., Pouthas, J., Rousseau, S., C. Willis, L., Suire, N., Aamodt, K., Arsene, I., Bravina, L., Hille, P., Kvaerno, H., Lvhiden, G., Milosevic, J., Nyiri, A., Skaali, B., Tveter, T., Wikne, K., Tywoniuk, J., Lunardon, M., Morando, M., Moretto, S., Scarlassara, F., Viesti, G., F. Segato, G., Bombonati, C., Fabris, D., Faivre, J., Turrisi, A., Pepato, R., Bielcik, J., Pachr, M., Petracek, V., Pospisil, V., Wagner, V., Mares, J., Polák, K., Závada, P., Bogolyubsky, M., Kharlov, Y., Onuchin, V., Polichtchouk, B., Sadovsky, S., Stolpovsky, A., Soloviev, P., A. Fernandez, Tellez, Lopez-Ramirez, R., I. Martínez, M., Muñoz, J., S. Tejeda, Munoz, G. Roman, Lopez, Adamov, D., Bielckova, J., Kapitan, J., Kushpil, S., Sumbera, V., Kushpil, M., Meddi, F., S. Di, Liberto, A. Urciuoli, M., M. Mazzoni, G., Baldisseri, A., Borel, H., J. Castillo, Castellanos, L. Charvet, J., Orsini, F., Staley, H., Pereira, F., A. De, Caro, D. De, Gruttola, S. De, Pasquale, Fusco-Girard, M., Guarnaccia, C., Pagano, P., Virgili, G., Russo, T., Boswell, B., R. Brown, C., Donoghue, A., L. Klay, J., Ward, S., M. Lewis, R., Armesto, N., Gonzales-Ferreiro, E., Pajares, C., Basmanov, V., Budnikov, D., Demanov, V., Filchagin, S., Ilkaev, R., Kuryakin, A., Mamonov, A., Nazarenko, S., Nazarov, G., Punin, A., Punin, V., Vinogradov, O., Vikhlyantsev, Y., Hwang, S., Gotovac, S., Vickovic, E., Mudnic, L., Asryan, A., Braun, M., Derkach, D., Feililov, G., Ivanov, A., Kolevatov, R., Kolojvari, A., Kondratiev, V., Vechernin, V., Zarochentsev, L., Vinogradov, A., Bonnet, D., P. Coffin, J., Hyppolite, B., Kuhn, C., R. Lutz, J., Ricaud, H., Michalon, A., Hamagaki, H., Beolè, S., Chiavassa, E., Cobanoglu, O., Ferretti, A., Gagliardi, M., Gallio, M., Marzari-Chiesa, A., Masera, M., Poggio, F., Senyukov, S., Vercellin, D., Stocco, E., Alessandro, B., Arnaldi, R., Cerello, P., Crescio, E., N. De, Marco, Giubellino, P., Monteno, M., Musso, A., Oppedisano, C., Piccotti, A., Prino, F., Riccati, L., Tosello, E., Scomparin, F., Bregant, M., Camerini, P., Cattaruzza, E., Contin, G., V. Margagliotti, G., Rossi, A., Venaruzzo, R., Rui, M., Fragiacomo, E., Grion, N., Vacchi, A., Rachevski, A., Miake, Y., A. De, Haas, Ivan, C., Kamermans, R., Mischke, A., Nooren, G., Oskamp, C., Peitzmann, T., Brink E. Van, Den, Simili, A., Deloff, A., Dobrowolski, T., Ilkiv, I., Kurashvili, P., Redlich, K., Siemiarczuk, T., Wilk, G., Stefanek, G., Kikola, D., Pawlak, T., Peryt, W., Pluta, J., Traczyk, M., Szuba, T., Srivastava, R., Scharenberg, B., Schockert, R., Keidel, B., Cai, X., Ding, H., Mao, Y., Wan, R., Wang, Y., Xu, C., Yang, C., Zhou, Z., Yin, D., Cao, X., Liu G. Su, Y., A. Grigorian, A., R. Gulkanian, H., Harutyunyan, A., Hayrapetyan, A., Poghosyan, M., Poghosyan, T., Anticic, T., Susa, T., Nikolic, V., Cormier, T., Cortese, P., Dellacasa, G., Gemme, R., Sitta, L., Ramello, M., Ahmad, A., Ahmad, N., M. Danish, A., Irfan, M., Khan, A., Kamal, M., Bilandzic, A., Botje, M., Kraus, I., Krzewicki, M., Kuijer, P., Kolk R. Van, Der, Snellings, N., Belogianni, A., Christakoglou, P., Fragkiadakis, M., Ganoti, P., Potirakis, S., Spyropoulou-Stassinaki, M., Tagridis, C., Vassiliou, E., Tsilis, M., E. Bruno, G., D'Erasmo, G., D. Di, Bari, C. Di, Giglio, M. Fiore, E., Ghidini, B., Mastroserio, A., Minafra, F., Navach, F., Perrino, D., Posa, F., Romita, R., Sgura, R., Santoro, I., Elia, D., Fini, R., Lenti, V., Manzari, V., Nappi, E., Nicassio, M., Volpe, V., Paticchio, G., Hu, S., Li, X., Lu, S., Zhou, Q., Wen, S., Alme, J., Bablock, S., Kanaki, K., Klovning, A., T. Larsen, D., Nystrand, J., Ovrebekk, G., Pommeresch, B., Richter, M., Röhrich, D., Ullaland, K., Yang, B., Wagner, H., H. Helstrup, H., Hetland, K., Helstrup, B., Kileng, K., Red, B., Blyth, S., Gray, H., Horner, M., Jacobs, P., Janina Odyniec, Grazyna, Ploskon, M., J. Van, Leeuwen, Symons, M., Dash, A., Dash, S., Jena, C., Mahapatra, D., Viyogi, S., Rath, Y., Bhasin, A., Bombara, M., Evans, D., T. Jones, G., Jones, P., Jovanovic, P., Jusko, A., Krivda, M., Lazzeroni, C., Lietava, R., Platt, R., Snow, H., D. Villalobos, Baillie, O. Tapia, Takaki, Alici, A., Antinori, S., Arcelli, S., Basile, M., Cifarelli-Strolin, L., Falchieri, D., Masetti, M., Preghenella, R., Scioli, G., Zichichi, A., Silenzi, A., Antonioli, P., G. Cara, Romeo, Cindolo, F., Costa, F., Hatzifotiadou, D., Laurenti, G., Luvisetto, M., Margotti, A., Nania, R., Noferini, F., Pesci, A., Scapparone, E., Zampolli, C., Williams, C., Cerny, V., Fekete, V., Janik, R., Pikna, M., Siska, M., Sitár, B., Szarka, P., Strmen, I., C. Rei, C., Berceanu, I., Catanescu, V., Herghelegiu, A., Petris, M., Petrovici, M., Pop C. Rei, A., Schiaua, A., Pop, C., Felea, D., Gheata, A., Haiduc, M., Hasegan, D., Mitu, C., Sevcenco, A., Zgura, I., Stan, I., Barnafoldi, G., Boldizsar, L., Dénes, E., Hamar, G., Lévai, Peter, Tolyhy, L., Molnar, T., A. De, Falco, Floris, M., Puddu, G., Usai, S., L. Serci, G., Becker, B., Cicalò, C., Masoni, A., Woehri, E., Siddi, H., Cleymans, J., D. De, Vaux, Fearick, R., Vilakazi, A., Szostak, Z., Barbera, R., Blanco, F., Giudice, N., P. 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126. Multiple sclerosis in Asia

Author

KUROIWA, Y., primary, HUNG, T.-P., additional, LANDSBOROUGH, D., additional, PARK, C. S., additional, SINGHAL, B. S., additional, SOEMARGO, S., additional, VEJJAJIVA, A., additional, and SHIBASAKI, H., additional

Published
1977
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129. Spontaneous Intracranial Hypotension- two cases including one treated with Epidural blood patch.

Author

Rajan, Shah, Pankaj, Agarwal, Suresh, Menon, and S., Singhal B.

Subjects
ORTHOSTATIC hypotension, HEADACHE, CEREBROSPINAL fluid, HEAD injuries, LUMBAR puncture, BRAIN imaging, DEMENTIA
Abstract

Spontaneous intracranial hypotension (SIH) is characterized by orthostatic headache (OH), low CSF pressure and DPME (diffuse pachymeningeal gadolinium enhancement) in the absence of head trauma or lumbar puncture. Two patients are described. Subtle marfanoid features such as tall stature and long slender fingers were noted in one patient with a history of shoulder dislocation. MRI spine revealed a CSF leak in the mid-thoracic region. Headache recovered completely with conservative treatment and brain imaging findings had resolved on one year follow up. The other patient in whom CSF leak could not be demonstrated, developed dementia, rapidly worsening encephalopathy and became comatose, necessitating urgent epidural blood patch (EBP) with 25 cc of autologous blood, after which immediate and complete symptomatic relief was obtained. A second EBP was required a few days later and also provided complete and sustained clinical benefit, without subsequent recurrence. Both patients had OH and showed bilateral subdural fluid collections, DPME and "sagging" of brain on MRI. A high index of suspicion, recognizing the orthostatic nature of headache, and typical findings on contrast enhanced MRI should point to the diagnosis of SIH. Reversible dementia, encephalopathy and coma may rarely be encountered in SIH. EBP can be very effective treatment in patients unresponsive to conservative measures. [ABSTRACT FROM AUTHOR]

Published
2008

130. Primary CNS Lymphoma in the Immunocompetent: A study of 24 cases.

Author

Agarwal, Pankaj, R., Rithesh, Singhal, B. S., and Smruti, B. K.

Subjects
CENTRAL nervous system tumors, LYMPHOMAS, INTRACRANIAL tumors, TUMOR markers
Abstract

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkins lymphoma, constituting around 1 % of all intracranial tumors. In the last few decades, the incidence of PCNSL has increased several-fold. 24 immunocompetent patients with PCNSL admitted in our institution over three years were studied with respect to clinical, radiological and pathological characteristics, treatment protocol, response, post-treatment cognitive decline and five prognostic variables as per the International Extranodal Lymphoma Study group (IELSG). Most patients presented in the sixth decade with focal neurologic deficits (79%), behavioral changes or cognitive decline (58%). Lesions were primarily parenchymal (100%), commonly multiple (75%), and often affected deep periventricular structures (58%). Almost all lesions showed typical dense homogenous enhancement (95.8%), however absence of contrast enhancement was encountered in one patient (4.1%). Average time from symptom onset to diagnosis was about 3 months. Common differential diagnoses were glioma, metastases, tuberculoma and demyelinating lesions. Empirical corticosteroid administration delayed or confounded the diagnosis in at least two patients. High grade diffuse large B cell Lymphoma was the most common histopathological subtype (100%). Most patients (72.7%) responded well to high dose methotrexate-based chemotherapy with or without radiation, with an overall median survival of 12.3 months, although later relapse occurred in few patients (6.2%), requiring further treatment. Treatment- related cognitive decline occurred in 25% of survivors at a mean follow up duration of 14.5 months. As seen with previous studies, advanced age at presentation (>60 years), poor performance status, deep brain involvement, elevated CSF protein and elevated serum LDH were all poor prognostic markers, and high IELSG scores correlated with worse prognosis (100%). [ABSTRACT FROM AUTHOR]

Published
2008

132. MISCELLANY.

Author

Singhal, B. K.

Subjects
SILK industry, SERICULTURE, RESEARCH & development, CONFERENCES & conventions
Published
2018

133. Mulberry to Control Human Diabetes.

Author

Singhal, B. K., Khan, M. A., and Bindroo, B. B.

Subjects
MULBERRY, DIABETES, BLOOD cholesterol, BLOOD sugar, WEIGHT loss, ALTERNATIVE medicine
Abstract

The article discusses the use of the mulberry plant to control diabetes. Researchers note that chemical compounds found in the mulberry leaf such as nitrogen containing sugars can help restrict the entry of monosaccharides in the circulatory system and decrease levels of total cholesterol in the body. In relation to this, the presence of antioxidants, isoquercitrin and astragalin in mulberry leaf extract can contribute to weight loss by suppressing the intestinal action of alpha-glucosidase.

Published
2011

134. Female gynandromorphy - a rare biological event in DABA bi-voltine Antheraea mylitta D. ecorace.

Author

Rathore, M. S., Chandrashekhariah, M., Singhal, B. K., and Sahay, A.

Subjects
*ANTHERAEA, *GYNANDROMORPHISM, *INSECT embryology, *INSECT sex differences, *INSECT embryos
Abstract

The article reports on the female gynandromorphy characteristic exhibited in the DABA bi-voltine race of Antheraea mylitta. Topics include the embryonic development in this insect, factors that affect the embryogenesis including temperature, viral infections, and hybrid cross, and the male and female characters exhibited by them.

Published
2018

135. 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
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136. Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder

Author

Guillermo Izquierdo, Ayse Altintas, Tomas Kalincik, Petra Nytrova, Charles B Malpas, Roberto Bergamaschi, Ilya Kister, Diana Ferraro, Aysun Soysal, Helmut Butzkueven, Sara Eichau, Francois Grand'Maison, Guy Laureys, Jeannette Lechner-Scott, Jyh Yung Hor, Pamela A. McCombe, Yara Dadalti Fragoso, Steve Vucic, Rana Karabudak, Raed Alroughani, Cavit Boz, Celia Oreja-Guevara, Eugenio Pucci, Tünde Csépány, Patrizia Sola, Serkan Ozakbas, Bhim Singhal, Francesco Patti, Maria Trojano, Franco Granella, Marco Onofrj, Alessandra Lugaresi, Recai Turkoglu, Mark Marriott, Murat Terzi, Amy Kunchok, Talal Al-Harbi, Magdolna Simó, Javier Olascoaga, Eva Havrdova, Bassem Yamout, Kunchok A., Malpas C., Nytrova P., Havrdova E.K., Alroughani R., Terzi M., Yamout B., Hor J.Y., Karabudak R., Boz C., Ozakbas S., Olascoaga J., Simo M., Granella F., Patti F., McCombe P., Csepany T., Singhal B., Bergamaschi R., Fragoso Y., Al-Harbi T., Turkoglu R., Lechner-Scott J., Laureys G., Oreja-Guevara C., Pucci E., Sola P., Ferraro D., Altintas A., Soysal A., Vucic S., Grand'Maison F., Izquierdo G., Eichau S., Lugaresi A., Onofrj M., Trojano M., Marriott M., Butzkueven H., Kister I., Kalincik T., and Ondokuz Mayıs Üniversitesi

Subjects
Male, Time Factors, Azathioprine, Severity of Illness Index, 0302 clinical medicine, Natalizumab, Recurrence, Outcome Assessment, Health Care, Disability, Immunosuppression, Neuromyelitis optica spectrum disorder, Predictors, Relapses, Therapy, 030212 general & internal medicine, Registries, Relapse, Hazard ratio, Neuromyelitis Optica, Age Factors, General Medicine, Middle Aged, Neurology, Cohort, Disease Progression, Female, Rituximab, medicine.drug, Cohort study, Adult, medicine.medical_specialty, 03 medical and health sciences, Internal medicine, medicine, Humans, Immunologic Factors, Aquaporin 4, Neuromyelitis optica, Expanded Disability Status Scale, Proportional hazards model, business.industry, Mycophenolic Acid, medicine.disease, Immunoglobulin G, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies, Predictor
Abstract

Altintas, Ayse/0000-0002-8524-5087; Laureys, Guy/0000-0002-1708-4373; Vucic, Steve/0000-0002-8323-873X; patti, francesco/0000-0002-6923-0846; Kister, Ilya/0000-0003-3549-949X; Lugaresi, Alessandra/0000-0003-2902-5589 WOS: 000521648000049 PubMed: 31877445 Background: Aquaporin-4-IgG positive (AQP4-IgG(+)) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG + NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG + NMOSD. Method: This MSBase cohort study of AQP4-IgG + NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model. Results: 206 AQP4-IgG + patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p < 0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (beta = 0.45 (per decade), p < 0.001) and disease duration (beta = 0.07 per year, p < 0.001). A slower increase in EDSS was associated with azathioprine (beta = -0.48, p < 0.001), mycophenolate mofetil (beta = -0.69, p = 0.04) and rituximab (beta = -0.35, p = 0.024). Interpretation: This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766, 1080518]; MerckMerck & Company; BiogenBiogen; NovartisNovartis; Bayer-ScheringBayer AG; Sanofi-Genzyme; Teva This study was financially supported by National Health and Medical Research Council of Australia [project grants 1083539 and 1129189, and fellowships 1140766 and 1080518]. The MSBase Foundation is a not-for-profit organization that receives support from Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

Published
2020

137. Risk of secondary progressive multiple sclerosis: A longitudinal study

Author

Michael Barnett, Bhim Singhal, Maria Trojano, Franco Granella, Neil Shuey, Guillermo Izquierdo, Dana Horakova, Helmut Butzkueven, Talal Al-Harbi, Maria Laura Saladino, Cameron Shaw, Adam Fambiatos, Bart Van Wijmeersch, Serkan Ozakbas, Tünde Csépány, Freek Verheul, Cavit Boz, Tim Spelman, Pierre Duquette, Jeannette Lechner-Scott, Bassem Yamout, Roberto Bergamaschi, Vincent Van Pesch, Claudio Solaro, Edgardo Cristiano, Patrizia Sola, Vilija Jokubaitis, Jae Kwan Jun, Alessandra Lugaresi, Javier Olascoaga, Aysun Soysal, Thor Petersen, Mark Slee, Raed Alroughani, Francois Grand'Maison, Orla Gray, Tomas Kalincik, Marc Girard, Gerardo Iuliano, Anneke van der Walt, Eva Havrdova, Jose Luis Sanchez-Menoyo, Radek Ampapa, Julie Prevost, Steve Vucic, Pamela A. McCombe, Recai Turkoglu, Yara Dadalti Fragoso, Jordana Hughes, Olga Skibina, Murat Terzi, Eugenio Pucci, Diana Ferraro, Pierre Grammond, Fraser Moore, Ayse Altintas, Suzanne Hodgkinson, Youssef Sidhom, Norma Deri, Alexandre Prat, Raymond Hupperts, Daniele Spitaleri, Bruce V. Taylor, Fambiatos A., Jokubaitis V., Horakova D., Kubala Havrdova E., Trojano M., Prat A., Girard M., Duquette P., Lugaresi A., Izquierdo G., Grand'Maison F., Grammond P., Sola P., Ferraro D., Alroughani R., Terzi M., Hupperts R., Boz C., Lechner-Scott J., Pucci E., Bergamaschi R., Van Pesch V., Ozakbas S., Granella F., Turkoglu R., Iuliano G., Spitaleri D., McCombe P., Solaro C., Slee M., Ampapa R., Soysal A., Petersen T., Sanchez-Menoyo J.L., Verheul F., Prevost J., Sidhom Y., Van Wijmeersch B., Vucic S., Cristiano E., Saladino M.L., Deri N., Barnett M., Olascoaga J., Moore F., Skibina O., Gray O., Fragoso Y., Yamout B., Shaw C., Singhal B., Shuey N., Hodgkinson S., Altintas A., Al-Harbi T., Csepany T., Taylor B., Hughes J., Jun J.-K., van der Walt A., Spelman T., Butzkueven H., Kalincik T., Ondokuz Mayıs Üniversitesi, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, Risk, medicine.medical_specialty, Longitudinal study, Immunologic Factors, multiple sclerosis, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, disease modifying therapies, prognostics, Internal medicine, Severity of illness, Medicine, Humans, Longitudinal Studies, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Disease progression, prediction, Multiple Sclerosis, Chronic Progressive, medicine.disease, SPMS, Clinical neurology, Natural history, Neurology, multiple sclerosi, disease modifying therapie, Disease Progression, Secondary progressive multiple sclerosis, Female, Neurology (clinical), business, prognostic, 030217 neurology & neurosurgery
Abstract

Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; McCombe, Pamela/0000-0003-2704-8517; Altintas, Ayse/0000-0002-8524-5087; Jokubaitis, Vilija G./0000-0002-3942-4340; Slee, Mark/0000-0003-4323-2453; Lugaresi, Alessandra/0000-0003-2902-5589; van Pesch, Vincent/0000-0003-2885-9004; Vucic, Steve/0000-0002-8323-873X WOS: 000481049900001 PubMed: 31397221 Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766]; BiogenBiogen; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva; MerckMerck & Company; NovartisNovartis The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1083539 and 1129189 and fellowship 1140766). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Roche, Novartis, Bayer Schering, Sanofi Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

Published
2020
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140. Risk of relapse phenotype recurrence in multiple sclerosis

Author

Daniele Spitaleri, Joseph Herbert, Jeannette Lechner-Scott, Bhim Singhal, Tomas Kalincik, Carmen Adella Sirbu, Maria Edite Rio, Marc Girard, Celia Oreja-Guevara, Norbert Vella, Pierre Duquette, Raymond Hupperts, Francois Grand'Maison, Vincent Van Pesch, Alessandra Lugaresi, Maria Pia Amato, Raed Alroughani, Thor Petersen, Marcela Fiol, Gerardo Iuliano, Steve Vucic, Giorgio Giuliani, Ricardo Fernandez-Bolanos, Guillermo Izquierdo, Tatjana Petkovska-Boskova, Freek Verheul, Michael Barnett, Helmut Butzkueven, Mark Paine, Maria Laura Saladino, Jose Antonio Cabrera-Gomez, Erik van Munster, Maria Trojano, Roberto Bergamaschi, S. Flechter, Danny Liew, Orla Gray, Katherine Buzzard, Edgardo Cristiano, Cavit Boz, Mark Slee, Cameron Shaw, Aldo Savino, Vilija Jokubaitis, Csilla Rozsa, Fraser Moore, Pierre Grammond, John Parratt, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Kalincik T, Buzzard K, Jokubaitis V, Trojano M, Duquette P, Guillermo I, Girard M, Lugaresi A, Grammond P, Grand'maison F, Oreja-Guevara C, Boz C, Hupperts R, Petersen T, Giuliani G, Iuliano G, Lechner-Scott J, Barnett M, Bergamaschi R, Van Pesch V, Amato MP, van Munster E, Fernandez-Bolanos R, Verheul F, Fiol M, Cristiano E, Slee M, Rio ME, Spitaleri D, Alroughani R, Gray O, Saladino ML, Flechter S, Herbert J, Cabrera-Gomez JA, Vella N, Paine M, Shaw C, Moore F, Vucic S, Savino A, Singhal B, Petkovska-Boskova T, Parratt J, Sirbu CA, Rozsa C, Liew D, Butzkueven H, and on behalf of the MSBase Study Group

Subjects
Adult, Male, Risk, medicine.medical_specialty, phenotype, Disease, Logistic regression, MSBase, Multiple sclerosis, Disability Evaluation, Multiple Sclerosis, Relapsing-Remitting, Recurrence, Internal medicine, medicine, Humans, multiple sclerosis, relapse, symptom, prognosis, Aged, business.industry, Age Factors, presentation of neurological diseases, Middle Aged, medicine.disease, Phenotype, Natural history, Institutional repository, Neurology, Immunology, Disease Progression, Female, Observational study, prognosis, Neurology (clinical), business, Progressive disease
Abstract

Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.

Published
2014
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141. Foreword

Author

Bangha, I and Singhal, B

Published
2016

142. The Functional Connectome Mediating Circadian Synchrony in the Suprachiasmatic Nucleus.

Author

Nikhil KL, Singhal B, Granados-Fuentes D, Li JS, Kiss IZ, and Herzog ED

Abstract

Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the Suprachiasmatic Nucleus (SCN). While anatomical, molecular, and genetic approaches have revealed diverse cell types and signaling mechanisms, the network wiring that enables SCN cells to communicate and synchronize remains unclear. To overcome the challenges of revealing functional connectivity from fixed tissue, we developed MITE (Mutual Information & Transfer Entropy), an information theory approach that infers directed cell-cell connections with high fidelity. By analyzing 3447 hours of continuously recorded clock gene expression from 9011 cells in 17 mice, we found that the functional connectome of SCN was highly conserved bilaterally and across mice, sparse, and organized into a dorsomedial and a ventrolateral module. While most connections were local, we discovered long-range connections from ventral cells to cells in both the ventral and dorsal SCN. Based on their functional connectivity, SCN cells can be characterized as circadian signal generators, broadcasters, sinks, or bridges. For example, a subset of VIP neurons acts as hubs that generate circadian signals critical to synchronize daily rhythms across the SCN neural network. Simulations of the experimentally inferred SCN networks recapitulated the stereotypical dorsal-to-ventral wave of daily PER2 expression and ability to spontaneously synchronize, revealing that SCN emergent dynamics are sculpted by cell-cell connectivity. We conclude that MITE provides a powerful method to infer functional connectomes, and that the conserved architecture of cell-cell connections mediates circadian synchrony across space and time in the mammalian SCN., Competing Interests: Competing interests The authors declare no competing interests.

Published
2024
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143. Phylum-level studies of bacterial cutinases for unravelling enzymatic specificity toward PET degradation: an in silico approach.

Author

Kumar S, Chaudhary B, and Singhal B

Subjects
Substrate Specificity, Polyethylene Terephthalates metabolism, Polyethylene Terephthalates chemistry, Biodegradation, Environmental, Computer Simulation, Phylogeny, Carboxylic Ester Hydrolases metabolism, Carboxylic Ester Hydrolases genetics, Carboxylic Ester Hydrolases chemistry, Bacteria enzymology, Bacteria genetics, Bacteria classification, Bacteria metabolism, Bacterial Proteins genetics, Bacterial Proteins metabolism, Bacterial Proteins chemistry, Molecular Docking Simulation
Abstract

The overwhelming use of PET plastic in various day-to-day activities led to the voluminous increase in PET waste and growing environmental hazards. A plethora of methods have been used that are associated with secondary pollutants. Therefore, microbial degradation of PET provides a sustainable approach due to its versatile metabolic diversity and capacity. The present work highlights the cutinase enzyme's role in PET degradation. This study focuses on the bacterial cutinases homologs screened from 43 reported phylum of bacteria. The reported bacterial cutinases for plastic degradation have been chosen as reference sequences, and 917 sequences have shown homology across the bacterial phyla. The dienelactone hydrolase (DLH) domain was identified for attaining specificity towards PET binding in 196 of 917 sequences. Various computational tools have been used for the physicochemical characterization of 196 sequences. The analysis revealed that most selected sequences are hydrophilic, extracellular, and thermally stable. Based on this analysis, 17 sequences have been further pursued for three-dimensional structure prediction and validation. The molecular docking studies of 17 selected sequences revealed efficient PET binding with the three sequences derived from the phylum Bacteroidota, the lowest binding energy of -5.9 kcal/mol, Armatimonadota, and Nitrososphaerota with -5.8 kcal/mol. The two enzyme sequences retrieved from the phylum Bacteroidota and Armatimonadota are metagenomically derived. Therefore, the present studies concluded that there is a high probability of finding cutinase homologs in various environmental resources that can be further explored for PET degradation., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Published
2024
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144. Optimal phase-selective entrainment of electrochemical oscillators with different phase response curves.

Author

Luis Ocampo-Espindola J, Singhal B, Li JS, and Kiss IZ

Abstract

We investigate the entrainment of electrochemical oscillators with different phase response curves (PRCs) using a global signal: the goal is to achieve the desired phase configuration using a minimum-power waveform. Establishing the desired phase relationships in a highly nonlinear networked system exhibiting significant heterogeneities, such as different conditions or parameters for the oscillators, presents a considerable challenge because different units respond differently to the common global entraining signal. In this work, we apply an optimal phase-selective entrainment technique in both a kinetic model and experiments involving electrochemical oscillators in achieving phase synchronized states. We estimate the PRCs of the oscillators at different circuit potentials and external resistance, and entrain pairs and small sets of four oscillators in various phase configurations. We show that for small PRC variations, phase assignment can be achieved using an averaged PRC in the control design. However, when the PRCs are sufficiently different, individual PRCs are needed to entrain the system with the expected phase relationships. The results show that oscillator assemblies with heterogeneous PRCs can be effectively entrained to desired phase configurations in practical settings. These findings open new avenues to applications in biological and engineered oscillator systems where synchronization patterns are essential for system performance., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Published
2024
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145. Identification of network interactions from time series data: An iterative approach.

Author

Singhal B, Li S, and Li JS

Abstract

The first step toward advancing our understanding of complex networks involves determining their connectivity structures from the time series data. These networks are often high-dimensional, and in practice, only a limited amount of data can be collected. In this work, we formulate the network inference task as a bilinear optimization problem and propose an iterative algorithm with sequential initialization to solve this bilinear program. We demonstrate the scalability of our approach to network size and its robustness against measurement noise, hyper-parameter variation, and deviations from the network model. Results across experimental and simulated datasets, comprising oscillatory, non-oscillatory, and chaotic dynamics, showcase the superior inference accuracy of our technique compared to existing methods., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Published
2024
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146. Modulatory Effects of Vitamin D: A Possible Approach to Mitigate Air Pollution Related Pregnancy Complications.

Author

Singhal B, Chauhan S, Soni N, Gurjar V, Joshi V, Kaur P, Ratre P, Kumari R, and Mishra PK

Abstract

Approximately 99% of people on the planet breathe air that exceeds the World Health Organization's permitted threshold for pollution. South Asia is home to the world's most polluted cities. Population-based studies have suggested that women's reproductive health outcomes are worsening due to air pollution. Preeclampsia, miscarriage, gestational diabetes, high blood pressure, and unfavorable birth outcomes, including preterm birth, low birth weight, or even stillbirth are all linked to exposure to air pollution during pregnancy. It is estimated that 0.61 million deaths in India alone were related to indoor air pollution. Females frequently cook in the household using solid fuel as a primary combustion source. Women in the regions with the highest population density are disproportionately affected by high levels of poor-quality indoor air. Recently, it has been proposed that air pollution has a distinct role in the onset of vitamin D deficiency. Numerous studies have explored associations between low vitamin D level and various female reproductive health conditions since the discovery of the vitamin D receptor. It is worthy to note that some of these reproductive health conditions positively correlate with the severity of air pollution. In this study, the evidence has been synthesized on vitamin D's protective properties and dietary and pharmaceutical interventions have been discussed to show their beneficial effects in decreasing the long-term negative impacts of air pollution on women's health., Competing Interests: Conflicts of Interest The authors have no relevant financial or non-financial interest to disclose., (Copyright© 2024, Journal of Reproduction & Infertility.)

Published
2024
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147. Data-driven control of oscillator networks with population-level measurement.

Author

Vu M, Singhal B, Zeng S, and Li JS

Abstract

Controlling complex networks of nonlinear limit-cycle oscillators is an important problem pertinent to various applications in engineering and natural sciences. While in recent years the control of oscillator populations with comprehensive biophysical models or simplified models, e.g., phase models, has seen notable advances, learning appropriate controls directly from data without prior model assumptions or pre-existing data remains a challenging and less developed area of research. In this paper, we address this problem by leveraging the network's current dynamics to iteratively learn an appropriate control online without constructing a global model of the system. We illustrate through a range of numerical simulations that the proposed technique can effectively regulate synchrony in various oscillator networks after a small number of trials using only one input and one noisy population-level output measurement. We provide a theoretical analysis of our approach, illustrate its robustness to system variations, and compare its performance with existing model-based and data-driven approaches., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Published
2024
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148. Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

Author

Li Y, Saul A, Taylor B, Ponsonby AL, Simpson-Yap S, Blizzard L, Broadley S, Lechner-Scott J, Karabudak R, Patti F, Eichau S, Onofrj M, Ozakbas S, Horakova D, Kubala Havrdova E, Grand'Maison F, Alroughani R, Gerlach O, Amato MP, Altintas A, Girard M, Duquette P, Blanco Y, Ramo-Tello C, Laureys G, Kalincik T, Khoury SJ, Shaygannejad V, Etemadifar M, Singhal B, Mrabet S, Foschi M, Habek M, John N, Hughes S, McCombe P, Ampapa R, van der Walt A, Butzkueven H, de Gans K, McGuigan C, Oreja-Guevara C, Sa MJ, Petersen T, Al-Harbi T, Sempere AP, Van Wijmeersch B, Grigoriadis N, Prevost J, Gray O, Castillo-Triviño T, Macdonell R, Lugaresi A, Sajedi SA, and van der Mei I

Subjects
Adult, Female, Humans, Male, Middle Aged, Age of Onset, Australia epidemiology, Case-Control Studies, Recurrence, Risk Factors, Multicenter Studies as Topic, Multiple Sclerosis epidemiology, Multiple Sclerosis etiology, Multiple Sclerosis, Chronic Progressive epidemiology, Multiple Sclerosis, Chronic Progressive etiology
Abstract

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications., (© 2023. The Author(s).)

Published
2024
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149. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Author

Sharmin S, Roos I, Simpson-Yap S, Malpas C, Sánchez MM, Ozakbas S, Horakova D, Havrdova EK, Patti F, Alroughani R, Izquierdo G, Eichau S, Boz C, Zakaria M, Onofrj M, Lugaresi A, Weinstock-Guttman B, Prat A, Girard M, Duquette P, Terzi M, Amato MP, Karabudak R, Grand'Maison F, Khoury SJ, Grammond P, Lechner-Scott J, Buzzard K, Skibina O, van der Walt A, Butzkueven H, Turkoglu R, Altintas A, Maimone D, Kermode A, Shalaby N, Pesch VV, Butler E, Sidhom Y, Gouider R, Mrabet S, Gerlach O, Soysal A, Barnett M, Kuhle J, Hughes S, Sa MJ, Hodgkinson S, Oreja-Guevara C, Ampapa R, Petersen T, Ramo-Tello C, Spitaleri D, McCombe P, Taylor B, Prevost J, Foschi M, Slee M, McGuigan C, Laureys G, Hijfte LV, de Gans K, Solaro C, Oh J, Macdonell R, Aguera-Morales E, Singhal B, Gray O, Garber J, Wijmeersch BV, Simu M, Castillo-Triviño T, Sanchez-Menoyo JL, Khurana D, Al-Asmi A, Al-Harbi T, Deri N, Fragoso Y, Lalive PH, Sinnige LGF, Shaw C, Shuey N, Csepany T, Sempere AP, Moore F, Decoo D, Willekens B, Gobbi C, Massey J, Hardy T, Parratt J, and Kalincik T

Subjects
Humans, Ultraviolet Rays, Disease Progression, Neoplasm Recurrence, Local, Multiple Sclerosis, Chronic Progressive epidemiology, Multiple Sclerosis epidemiology, Multiple Sclerosis diagnosis, Multiple Sclerosis, Relapsing-Remitting epidemiology
Abstract

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2023
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150. Finding influential nodes in networks using pinning control: Centrality measures confirmed with electrochemical oscillators.

Author

Bomela W, Sebek M, Nagao R, Singhal B, Kiss IZ, and Li JS

Abstract

The spatiotemporal organization of networks of dynamical units can break down resulting in diseases (e.g., in the brain) or large-scale malfunctions (e.g., power grid blackouts). Re-establishment of function then requires identification of the optimal intervention site from which the network behavior is most efficiently re-stabilized. Here, we consider one such scenario with a network of units with oscillatory dynamics, which can be suppressed by sufficiently strong coupling and stabilizing a single unit, i.e., pinning control. We analyze the stability of the network with hyperbolas in the control gain vs coupling strength state space and identify the most influential node (MIN) as the node that requires the weakest coupling to stabilize the network in the limit of very strong control gain. A computationally efficient method, based on the Moore-Penrose pseudoinverse of the network Laplacian matrix, was found to be efficient in identifying the MIN. In addition, we have found that in some networks, the MIN relocates when the control gain is changed, and thus, different nodes are the most influential ones for weakly and strongly coupled networks. A control theoretic measure is proposed to identify networks with unique or relocating MINs. We have identified real-world networks with relocating MINs, such as social and power grid networks. The results were confirmed in experiments with networks of chemical reactions, where oscillations in the networks were effectively suppressed through the pinning of a single reaction site determined by the computational method., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Published
2023
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