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1. Feasibility of reporting results of large randomised controlled trials to participants: experience from the Fluoxetine Or Control Under Supervision (FOCUS) trial

Author

Martin Dennis, D Cohen, A Thompson, Graham Ellis, A Khan, L Hunt, X Huang, J Andrews, J Foot, S Wong, A Stevens, D Bailey, S Johnston, R Robinson, A Johnson, S Williams, T Smith, A Ahmed, S Bloom, L Sekaran, D Singh, F Smith, R Greenwood, R Brown, J White, S Arif, S Ross, S Trippier, S Levy, B Patel, M Khan, A Thomas, S Brown, V Jones, D Wood, U Khan, P Nair, A Smith, G Hann, R Williams, M Cooper, S Jackson, M Hassan, P Kumar, A Metcalf, R Patel, A Wright, S Khan, A Bell, M Robinson, K Jones, S Alam, R Shah, J Simpson, K Ali, K Miller, K Kennedy, S Ahmed, L Thomas, M Scott, S Nelson, S Clayton, L Zhang, B Charles, P Lopez, A Fleming, C Lambert, A Shah, J Wong, David Burgess, L Wilson, A Siddiqui, S Kumar, A Hassan, D Cooke, M Williams, P Cooper, S Graham, S Morrison, M Holland, C Green, C Edwards, K Subramanian, K Patel, J Mitchell, J Stewart, S Keenan, C Duggan, S McKenna, M Ward, S Walker, L Wright, M Edwards, N Sattar, J Mcgee, R Butler, M Wilkinson, C Kelly, R Cowan, C Brown, K Moore, L Denny, S Patel, R Rodriguez, J Allen, M Kalita, Gillian Mead, A Bowring, A Edwards, J Scott, J Drew, L Dixon, K Burton, E Brown, E Epstein, R Miller, F Reid, A Jones, P Murphy, A Ali, N Ahmad, S Noor, C Leonard, A Nair, M Naeem, E Douglas, J Thompson, R Evans, C Jenkins, J Wilson, R Anderson, H Wilson, H Stone, J Ward, L Greenhalgh, P Walker, A Hill, K Stagg, S Naqvi, R Scott, M Hughes, P Jones, M Simpson, K Elliott, M Davy, S Young, Karen Innes, Pippa Tyrrell, A David, Steff Lewis, A Bwalya, C Buckley, S Kelly, C Thomas, I Kane, M Hussain, S Shah, J Roberts, D Morales, C McInnes, N Khan, N Weir, L Hill, K Kavanagh, R Clarke, P Thompson, J Price, J Ball, L Benton, E Walton, E Walker, L Burgess, K McCormick, L Wade, C Anderson, S Stevenson, R Blackburn, L Brown, B Clarke, T Khan, S Dhar, L Harrison, S Bell, D Buchanan, A Deary, J Drever, R Fraser, K Innes, C McGill, D Perry, A Barugh, G Blair, Y Chun, E Maschauer, J Forbes, M Hackett, G Hankey, A House, E Lundström, Peter Sandercock, Judith Williamson, Graeme Hankey, Maree Hackett, Veronica Murray, Ray French, David Stott, M MacLeod, F Sullivan, P Langhorne, H Rodgers, N Hunter, R Parakramawansha, A Fazal, P Taylor, W Rutherford, R Buchan, A MacRaild, R Paulton, S Burgess, D McGowan, J Skwarski, F Proudfoot, J Perry, J Bamford, C Bedford, D Waugh, E Veraque, M Kambafwile, L Makawa, P Smalley, M Randall, L Idrovo, T Thirugnana-Chandran, R Vowden, J Jackson, A Bhalla, C Tam, A Rudd, C Gibbs, J Birns, L Lee Carbon, E Cattermole, A Cape, L hurley, K Marks, S Kullane, N Smyth, E Giallombardo, C Eglinton, D Dellafera, P Reidy, M Pitt, L Sykes, A Frith, V Croome, J Duffy, M Hancevic, L Kerwood, C Narh, C Merritt, J Willson, T Jackson, H Bowler, C Kamara, J Howe, K Stocks, G Dunn, K Endean, F Claydon, S Duty, K Harkness, E Richards, M Meegada, A Maatouk, L Barron, K Dakin, R Lindert, A Majid, P Rana, C Brighouse-Johnson, J Greig, M Kyu, S Prasad, B Mclean, I Alam, Z Ahmed, C Roffe, S Brammer, A Barry, C Beardmore, K Finney, P Hollinshead, J Grocott, I Natarajan, J Chembala, R Sanyal, S Lijko, N Abano, A Remegoso, P Ferdinand, S Stevens, C Stephen, P Whitmore, A Butler, C Causley, R Varquez, G Muddegowda, R Carpio, J Hiden, H Denic, J Sword, F Hall, J Cageao, R Curwen, M James, P Mudd, C Roughan, H Kingwell, A Hemsley, C Lohan, S Davenport, T Chapter, M Hough, D Strain, K Gupwell, A Goff, E Cusack, S Todd, R Partridge, G Jennings, K Thorpe, J Stephenson, K Littlewood, M Barber, F Brodie, S Marshall, D Esson, I Coburn, F Ross, V Withers, E Bowie, H Barcroft, L Miller, P Willcoxson, M Keeling, M Donninson, D Daniel, J Coyle, M Elliott, P Wanklyn, J Wightman, E Iveson, A Porteous, N Dyer, M Haritakis, J Bell, C Emms, P Wood, P Cottrell, L Doughty, L Carr, C Anazodo, M O Neill, J Westmoreland, R Mir, C Donne, E Bamford, P Clark Brown, A Stanners, I Ghouri, A Needle, M Eastwood, M Carpenter, P Datta, R Davey, F Razik, G Bateman, J Archer, V Balasubramanian, L Jackson, R Bowers, J Ellam, K Norton, P Guyler, S Tysoe, P Harman, A Kundu, T Dowling, S Chandler, O Omodunbi, T Loganathan, S Kunhunny, D Sinha, M Sheppard, S Kelavkar, K Ng, A Ropun, L Kamuriwo, R Orath Prabakaran, E France, S Rashmi, D Mangion, C Constantin, S Markova, A Hardwick, J Borley, L De Michele Hock, T Lawrence, K Netherton, R Spencer, H Palmer, M Soliman, S Leach, J Sharma, C Taylor, I Wahishi, A Fields, S Butler, J Hindle, E Watson, C Hewitt, C Cullen, D Hamill, Z Mellor, T Fluskey, V Hankin, A Keeling, R Durairaj, J Peters, D Shackcloth, R Tangney, T Hlaing, V Sutton, J Ewing, C Patterson, H Ramadan, R Bellfield, U Hamid, M Hooley, R Ghulam, L Masters, W Gaba, O Quinn, M Tate, N Mohammed, S Sethuraman, L Alwis, K Bharaj, R Pattni, F Justin, M Chauhan, L Eldridge, S Mintias, J Palmones, C Holmes, L Guthrie, N Devitt, J Leonard, M Osborn, L Ball, A Steele, E Dodd, A Holloway, P Baker, I Penwarden, S Caine, S Clarke, L Dow, R Wynn-Williams, J Kennedy, A DeVeciana, P Mathieson, I Reckless, R Teal, G Ford, P Mccann, G Cluckie, G Howell, J Ayer, B Moynihan, R Ghatala, G Cloud, N Al-Samarrai, F Watson, T Adedoyin, N Chopra, L Choy, N Clarke, A Dainty, A Blight, J Selvarajah, W Smith, F Moreton, A Welch, D Kalladka, B Cheripelli, A Lush, S El Tawil, N Day, K Montgomery, H Hamilton, D Ritchie, S Ramachandra, K McLeish, B Badiani, M Abdul-Saheb, A Chamberlain, M Mpelembue, R Bathula, M Lang, J Devine, L Southworth, N Epie, E Owoyele, F Guo, A Oshodi, V Sudkeo, K Thavanesan, D Tiwari, C Ovington, E Rogers, R Bower, B Longland, O David, A Hogan, S Loganathan, C Cox, S Orr, M Keltos, K Rashed, B Williams-Yesson, J Board, S De Bruijn, C Vickers, S Board, J Allison, E Keeling, T Duckett, D Donaldson, C Barron, L Balian, T England, A Hedstrom, E Bedford, M Harper, E Melikyan, W Abbott, M Goldsworthy, M Srinivasan, I Mukherjee, U Ghani, A Yeomans, F Hurford, R Chapman, S Shahzad, N Motherwell, L Tonks, R Young, D Dutta, P Brown, F Davis, J Turfrey, M Obaid, B Cartwright, B Topia, J Spurway, C Hughes, S OConnell, K Collins, R Bakawala, K Chatterjee, T Webster, S Haider, P Rushworth, F Macleod, C Perkins, A Nallasivan, E Burns, S Leason, T Carter, S Seagrave, E Sami, S Parkinson, L Armstrong, S Mawer, G Darnbrook, C Booth, B Hairsine, S Williamson, F Farquhar, B Esisi, T Cassidy, B McClelland, G Mankin, M Bokhari, D Sproates, S Hurdowar, N Sukhdeep, S Razak, N Upton, A Hashmi, K Osman, K Fotherby, A Willberry, D Morgan, G Sahota, K Jennings-Preece, D Butler, K Kauldhar, F Harrington, A Mate, J Skewes, K Adie, K Bond, G Courtauld, C Schofield, L Lucas, A James, S Ellis, B Maund, L Allsop, C Brodie, E Driver, K Harris, M Drake, E Thomas, M Burn, A Hamilton, S Mahalingam, A Benford, D Hilton, A Misra, L Hazell, K Ofori, M Mathew, S Dayal, I Burn, D Bruce, R Burnip, R Hayman, P Earnshaw, P Gamble, S Dima, M Dhakal, G Rogers, L Stephenson, R Nendick, Y Pai, K Nyo, V Cvoro, M Couser, A Tachtatzis, K Ullah, R Cain, N Chapman, S Pound, S McAuley, D Hargroves, B Ransom, K Mears, K Griffiths, L Cowie, T Hammond, T Webb, I Balogun, H Rudenko, A Thomson, D Ceccarelli, A Gillian, E Beranova, A Verrion, N Chattha, N Schumacher, A Bahk, D Sims, R Tongue, M Willmot, C Sutton, E Littleton, J Khaira, S Maiden, J Cunningham, Y Chin, M Bates, K Ahlquist, J Breeds, T Sargent, L Latter, A Pitt Ford, T Levett, N Gainsborough, A Dunne, E Barbon, S Hervey, S Ragab, T Sandell, C Dickson, S Power, J Dube, N Evans, B Wadams, S Elitova, B Aubrey, T Garcia, J Mcilmoyle, C Dickinson, C Jeffs, J Howard, C Armer, J Frudd, A Potter, S Donaldson, D Collas, S Sundayi, L Denham, D Oza, M Bhandari, S Ispoglou, K Sharobeem, A Hayes, J Howard-Brown, S Shanu, S Billingham, G Howard, E Wood, V Pressly, P Crawford, H Burton, A Walters, J Marigold, R Said, C Allen, S Evans, S Egerton, J Hakkak, R Lampard, S Tsang, R Creeden, I Gartrell, F Price, J Pryor, A Hedges, L Moseley, L Mercer, E Warburton, D Handley, S Finlay, N Hannon, A Espanol, H Markus, D Chandrasena, J Sesay, D Hayden, H Hayhoe, J Macdonald, M Bolton, C Farron, E Amis, D Day, A Culbert, L Whitehead, S Crisp, J OConnell, E Osborne, R Beard, P Corrigan, L Mokoena, M Myint, R Krishnamurthy, A Azim, S Whitworth, A Nicolson, M Krasinska-Chavez, J Imam, S Chaplin, J Curtis, L Wood, C McGhee, A Smart, F Donaldson, J Blackburn, C Copeland, P Fitzsimmons, G Fletcher, A Manoj, P Cox, L Trainor, H Allsop, U Sukys, S Valentine, D Jarrett, K Dodsworth, M Wands, C Watkinson, W Golding, J Tandy, K Yip, C James, Y Davies, A Suttling, K Nagaratnam, N Mannava, N Haque, N Shields, K Preston, G Mason, K Short, G Uitenbosch, G Lumsdale, H Emsley, S Sultan, B Walmsley, D Doyle, A McLoughlin, L Hough, B Gregary, S Raj, A Maney, S Blane, G Gamble, A Hague, B Duran, R Whiting, M Harvey, J Homan, L Foote, L Graham, C Lane, L Kemp, J Rowe, H Durman, L Brotherton, N Hunt, A Whitcher, C Pawley, P Sutton, S Mcdonald, D Pak, A Wiltshire, J Balami, C Self, J Jagger, G Healey, M Crofts, A Chakrabarti, C Hmu, J Keshet-Price, G Ravenhill, C Grimmer, T Soe, I Potter, P Tam, M Langley, M Christie, J Irvine, A Joyson, F Annison, D Christie, C Meneses, V Taylor, J Furnace, H Gow, Y Abousleiman, S Goshawk, J Purcell, T Beadling, S Collins, S Sangaralingham, E Munuswamy Vaiyapuri, M Landicho, Y Begum, S Mutton, J Lowe, I Wiggam, S Tauro, S Cuddy, B Wells, A Mohd Nor, N Persad, M Weinling, S Weatherby, D Lashley, A Pace, A Mucha, J Baker, M Marner, J Westcott, N Wilmshurst, D Chadha, M Fairweather, D Walstow, R Fong, M Krishnan, H Thompson Jones, C Lynda, C Clements, T Anjum, S Sharon, D Lynne, S Tucker, D Colwill, E Vasileiadis, A Parry, C Mason, M Holden, K Petrides, T Nishiyama, H Mehta, S Mumani, C Almadenboyle, S Carson, M Stirling, E Tenbruck, D Broughton, A Annamalai, D Tryambake, A Skotnicka, A Sigsworth, S Whitehouse, J Pagan, A Pusalkar, H Beadle, K Chan, P Dangri, A Asokanathan, A Rana, S Gohil, K Crabtree, A Cook, M Massyn, P Aruldoss, S Dabbagh, T Black, R Fennelly, L Nardone, V DiMartino, A Anthony, D Mead, M Tribbeck, B Affley, C Sunderland, E Young, L Goldenberg, P Wilkinson, L Abbott, R Nari, S Lock, A Shakhon, R Pereira, M DSouza, S Dunn, N Cron, A Mckenna, R Sivakumar, S Cook, J Ngeh, R Saksena, J Ketley-O'Donel, R Needle, E Chinery, L Howaniec, C Watchurst, R Erande, M Brezitski, N Passeron, E Elliott, N Oji, D Austin, A Banaras, C Hogan, T Corbett, M Kidd, G Hull, S Punekar, J Nevinson, H Penney, W Wareing, N Hayes, K Bunworth, L Connell, K Mahawish, G Drummond, N Sengupta, M Metiu, C Gonzalez, J Margalef, S Funnell, G Peters, I Chadbourn, H Proeschel, P Ashcroft, S Sharpe, P Cook, D Jenkinson, D Kelly, H Bray, G Gunathilagan, S Tilbey, S Abubakar, A Rajapakse, A Nasar, J Janbieh, L Otter, I Wynter, S Haigh, R Boulton, J Burgoyne, A Boulton, J Vassallo, A Hasan, L Orrell, S Qamar, D Leonard, E Hewitt, M Haque, J Awolesi, E Bradshaw, A Kent, A Hynes, E Nurse, S Raza, U Pallikona, B Edwards, G Morgan, H Tench, R Loosley, K Dennett, T Trugeon-Smith, D Robson, R Rayessa, A Abdul-Hamid, V Lowthorpe, K Mitchelson, E Clarkson, H Rhian, R Kirthivasan, J Topliffe, R Keskeys, F McNeela, E Bohannan, L Cooper, G Zachariah, F Cairns, T James, L Fergey, S Smolen, A Lyle, E Cannon, S Omer, S Mavinamane, S Meenakshisundaram, L Ranga, J Bate, M Hargreaves, S Dealing, S Amlani, G Gulli, M Hawkes-Blackburn, L Francis, S Holland, A Peacocke, J Amero, M Burova, O Speirs, S Brotheridge, S Al Hussayni, H Lyon, C Hare, J Featherstone, M Goorah, J Walford, D Rusk, D Sutton, F Patel, S Duberley, K Hayes, E Ahmed El Nour, S Dyer, E Temlett, J Paterson, S Honour, C Box, R Furness, E Orugun, H Crowther, R Glover, C Brewer, S Thornthwaite, M Sein, K Haque, L Bailey, E Gibson, L Brookes, K Rotchell, K Waltho, C Lindley, P Harlekar, C Culmsee, L Booth, J Ritchie, N Mackenzie, J Barker, M Haley, D Cotterill, L Lane, D Simmons, R Warinton, G Saunders, H Dymond, S Kidd, C Little, Y Neves-Silva, B Nevajda, M Villaruel, U Umasankar, A Man, N Gadi, N Christmas, R Ladner, R Rangasamy, G Butt, W Alvares, M Power, S Hagan, K Dynan, S Crothers, B Wroath, G Douris, D Vahidassr, B Gallen, C McGoldrick, M Bhattad, J Putteril, R Gallifent, E Makanju, M Lepore, C McRedmond, L Arundell, A Goulding, K Kawafi, P Jacob, L Turner, N Saravanan, L Johnson, D Morse, R Namushi, S Humphrey, M Salehin, S Tinsley, T Jones, L Garcia-Alen, L Kalathil, N Gautam, J Horton, J Meir, E Margerum, A Ritchings, K Amor, V Nadarajan, J Laurence, S Fung Lo, S Melander, P Nicholas, E Woodford, G McKenzie, V Le, J Crause, P OMahony, C Orefo, C McDonald, E Osikominu, G Appiatse, A Wardale, M Augustin, R Luder, M Bhargava, G Bhome, V Johnson, D Chesser, H Bridger, E Murali, A Burns, J Graham, M Duffy, E Pitcher, J Gaylard, J Newman, S Punnoose, S Oakley, V Murray, C Bent, R Walker, K Purohit, A Rees, S Besley, O Chohan, L Argandona, L Cuenoud, H Hassan, E Erumere, A OCallaghan, O Redjep, G Auld, P Gompertz, A Song, R Hungwe, H Kabash, T Tarkas, G Livingstone, F Butler, S Bradfield, L Gordon, J Schmit, A Wijewardane, C Medcalf, T Edmunds, R Wills, and C Peixoto

Subjects
Medicine
Abstract

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Published
2020
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2. Immune-mediated facial nerve paralysis in a myeloma patient post B-cell maturation antigen-targeted chimeric antigen receptor T cells

Author

Yamini K. Kathari, Haroon Ahmad, Michael E. Kallen, Rima Koka, Destiny Omili, Thierry Iraguha, Jean Clement, Lily Pham, Mazhar Khalid, Xiaoxuan Fan, Etse Gebru, Patricia Lesho, Esther Park, Nishanthini Dishanthan, Jillian M. Baker, Kenneth A. Dietze, Kim G. Hankey, Ashraf Badros, Jean A. Yared, Saurabh Dahiya, Nancy M. Hardy, Hakan Kocoglu, Tim Luetkens, Aaron P. Rapoport, and Djordje Atanackovic

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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3. Impaired immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CAR T-cell therapy

Author

Saurabh Dahiya, Tim Luetkens, Forat Lutfi, Stephanie Avila, Thierry Iraguha, Philip Margiotta, Kim G. Hankey, Patricia Lesho, Jennie Y. Law, Seung T. Lee, John Baddley, Mehmet Kocoglu, Jean A. Yared, Nancy M. Hardy, Aaron P. Rapoport, and Djordje Atanackovic

Subjects
COVID-19 Vaccines, SARS-CoV-2, Antigens, CD19, Vaccination, Research Letter, Immunity, COVID-19, Humans, Hematology, Neoplasm Recurrence, Local, Immunotherapy, Adoptive
Published
2022

5. Deep dissection of the antiviral immune profile of patients with COVID-19

Author

Djordje Atanackovic, Stephanie V. Avila, Forat Lutfi, Diego de Miguel-Perez, Xiaoxuan Fan, Gabriela Sanchez-Petitto, Erica Vander Mause, Jonathan Siglin, John Baddley, Heather D. Mannuel, Hanan Alkhaldi, Kim G. Hankey, Rena Lapidus, Michael Kleinberg, Joseph Rabin, Carl Shanholtz, Christian Rolfo, Aaron P. Rapoport, Saurabh Dahiya, and Tim Luetkens

Subjects
Adult, Male, COVID-19 Vaccines, QH301-705.5, Medicine (miscellaneous), Adaptive Immunity, Antibodies, Viral, General Biochemistry, Genetics and Molecular Biology, Article, Viral Proteins, Coronavirus Nucleocapsid Proteins, Humans, Biology (General), Aged, SARS-CoV-2, COVID-19, biochemical phenomena, metabolism, and nutrition, Middle Aged, Antibodies, Neutralizing, Immunity, Humoral, Viral infection, Immunoglobulin G, Mutation, Spike Glycoprotein, Coronavirus, Female, General Agricultural and Biological Sciences
Abstract

In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 “South African” variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-β) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines., Atanackovic and coauthors screen COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. They also characterised immune responses in these patients and their findings will help to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response as well as assist the design of immunomonitoring methods for anti-COVID-19 vaccines.

Published
2021

6. The Natural History of Acute Radiation-induced H-ARS and Concomitant Multi-Organ Injury in the Nonhuman Primate: The MCART experience

Author

Catherine Booth, Kim G. Hankey, Thomas J. MacVittie, Greg L. Tudor, Wanchang Cui, George A. Parker, Eric P. Cohen, and Ann M. Farese

Subjects
medicine.medical_specialty, Epidemiology, business.industry, Health, Toxicology and Mutagenesis, Acute kidney injury, Urology, Acute Radiation Syndrome, Context (language use), Dose-Response Relationship, Radiation, Total body irradiation, medicine.disease, Macaca mulatta, Pathophysiology, Article, Haematopoiesis, medicine.anatomical_structure, Bone Marrow, Concomitant, medicine, Animals, Radiology, Nuclear Medicine and imaging, Bone marrow, business, Whole-Body Irradiation
Abstract

The dose response relationship and corresponding values for mid-lethal dose and slope are used to define the dose- and time-dependent parameters of the hematopoietic acute radiation syndrome. The characteristic time course of mortality, morbidity, and secondary endpoints are well defined. The concomitant comorbidities, potential mortality, and other multi-organ injuries that are similarly dose- and time-dependent are less defined. Determination of the natural history or pathophysiology associated with the lethal hematopoietic acute radiation syndrome is a significant gap in knowledge, especially when considered in the context of a nuclear weapon scenario. In this regard, the exposure is likely ill-defined, heterogenous, and nonuniform. These conditions forecast sparing of bone marrow and increased survival from the acute radiation syndrome consequent to threshold doses for the delayed effects of acute radiation exposure due to marrow sparing, medical management, and use of approved medical countermeasures. The intent herein is to provide a composite natural history of the pathophysiology concomitant with the evolution of the potentially lethal hematopoietic acute radiation syndrome derived from studies that focused on total body irradiation and partial body irradiation with bone marrow sparing. The marked differential in estimated LD50/60 from 7.5 Gy to 10.88 Gy for the total body irradiation and partial body irradiation with 5% bone marrow sparing models, respectively, provided a clear distinction between the attendant multiple organ injury and natural history of the two models that included medical management. Total body irradiation was focused on equivalent LD50/60 exposures. The 10 Gy and 11 Gy partial body with 5% bone marrow sparing exposures bracketed the LD50/60 (10.88 Gy). The incidence, progression, and duration of multiple organ injury was described for each exposure protocol within the hematopoietic acute radiation syndrome. The higher threshold doses for the partial body irradiation with bone marrow sparing protocol induced a marked degree of multiple organ injury to include lethal gastrointestinal acute radiation syndrome, prolonged crypt loss and mucosal damage, immune suppression, acute kidney injury, body weight loss, and added clinical comorbidities that defined a complex timeline of organ injury through the acute hematopoietic acute radiation syndrome. The natural history of the acute radiation syndrome presents a 60-d time segment of multi-organ sequelae that is concomitant with the latent period or time to onset of the evolving multi-organ injury of the delayed effects of acute radiation exposure.

Published
2021

7. Therapeutic Response in Patients with Advanced Malignancies Treated with Combined Dendritic Cell–Activated T Cell Based Immunotherapy and Intensity–Modulated Radiotherapy

Author

Kim G. Hankey, Dean L. Mann, Ryuko Watanabe, Yukimasa Aoki, and Kenichiro Hasumi

Subjects
dendritic cells, activated T-cells, combination immunotherapy, intratumoral injection, cancer vaccine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

Published
2011
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8. AEOL 10150 Alleviates Radiation-induced Innate Immune Responses in Non-human Primate Lung Tissue

Author

Wanchang Cui, Kim G. Hankey, Ann M. Farese, Thomas J. MacVittie, Mang Xiao, and Pei Zhang

Subjects
Innate immune system, Lung, medicine.diagnostic_test, Epidemiology, Cell adhesion molecule, Metalloporphyrins, Health, Toxicology and Mutagenesis, Monocyte, medicine.medical_treatment, Biology, Lung injury, Thorax, medicine.disease_cause, Macaca mulatta, Immunity, Innate, Article, medicine.anatomical_structure, Cytokine, Western blot, medicine, Cancer research, Animals, Radiology, Nuclear Medicine and imaging, Oxidative stress
Abstract

PURPOSE: To study the molecular and cellular mechanisms of radiation-induced lung injury (RILI) in a non-human primate model. METHODS AND MATERIALS: Rhesus macaques were irradiated with lethal doses of radiation to the whole thorax. A subset of the irradiated animals was treated with AEOL 10150, a potent catalytic scavenger of reactive oxygen and nitrogen species. Lung tissues were collected at necropsy for molecular and immunohistochemical (IHC) studies. RESULTS: Microarray expression profiling in the irradiated lung tissues identified differentially expressed genes (DEGs) and pathways important in innate immunity. The elevated expression of cytokines (CCL2, CCL11, IL-8), complement factors (CFB, C3), apoptosis-related molecules (p53, PTEN, Bax, p21, MDM2, c-Caspase 3) and adhesion molecules (fibronectin, integrin β6, ICAM-1) were further studied using realtime PCR, Western blot, or IHC. Oxidative stress and pulmonary inflammatory cell infiltration were increased in the irradiated lungs. Treatment with AEOL 10150 significantly decreased oxidative stress and monocyte/macrophage infiltration. CONCLUSIONS: Cytokine/chemokine induced excessive innate immune response after thoracic irradiation plays important roles in RILI. To our knowledge, this is the first study to highlight the role of cytokine/chemokine induced innate immune responses in radiation-induced pulmonary toxicity in a NHP model.

Published
2021

9. Anti-SARS-CoV-2 Immune Responses in Patients Receiving an Allogeneic Stem Cell or Organ Transplant

Author

Nicole M. Glynn, Kim G. Hankey, Erica Vander Mause, Forat Lutfi, Stephanie Avila, Djordje Atanackovic, Hanan Alkhaldi, Saurabh Dahiya, Aaron P. Rapoport, Heather D. Mannuel, Tim Luetkens, Gabriela Sanchez-Petitto, John W Baddley, and Nancy M. Hardy

Subjects
0301 basic medicine, medicine.medical_specialty, Allogeneic transplantation, medicine.medical_treatment, T cells, chemical and pharmacologic phenomena, Case Report, Organ transplantation, immunology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, vaccine, Drug Discovery, Medicine, Pharmacology (medical), antibody responses, Pharmacology, allogeneic stem cell transplant, business.industry, SARS-CoV-2, COVID-19, Immunotherapy, biochemical phenomena, metabolism, and nutrition, Transplantation, Vaccination, 030104 developmental biology, Infectious Diseases, 030220 oncology & carcinogenesis, Humoral immunity, Immunology, bacteria, immunotherapy, business
Abstract

Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.

Published
2021

10. 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

11. Characterizing the Natural History of Acute Radiation Syndrome of the Gastrointestinal Tract: Combining High Mass and Spatial Resolution Using MALDI-FTICR-MSI

Author

Catherine Booth, Jace W. Jones, Kim G. Hankey, Thomas J. MacVittie, Ann M. Farese, Maureen A. Kane, Gregory Tudor, George A. Parker, and Claire L. Carter

Subjects
Male, Pathology, medicine.medical_specialty, Epidemiology, Health, Toxicology and Mutagenesis, Cell, Article, Mass spectrometry imaging, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Radiology, Nuclear Medicine and imaging, Intestinal Mucosa, Receptor, Epithelial cell differentiation, Gastrointestinal tract, Lamina propria, Chemistry, Acute Radiation Syndrome, Lipid Metabolism, Macaca mulatta, Epithelium, Mitochondria, Gastrointestinal Tract, Jejunum, medicine.anatomical_structure, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, 030220 oncology & carcinogenesis, Biomarkers
Abstract

The acute radiation syndrome of the gastrointestinal tract has been histologically characterized, but the molecular and functional mechanisms that lead to these cellular alterations remain enigmatic. Mass spectrometry imaging is the only technique that enables the simultaneous detection and cellular or regional localization of hundreds of biomolecules in a single experiment. This current study utilized matrix-assisted laser desorption/ionization mass spectrometry imaging for the molecular characterization of the first natural history study of gastrointestinal acute radiation syndrome in the nonhuman primate. Jejunum samples were collected at days 4, 8, 11, 15, and 21 following 12-Gy partial-body irradiation with 2.5% bone marrow sparing. Mass spectrometry imaging investigations identified alterations in lipid species that further understanding of the functional alterations that occur over time in the different cellular regions of the jejunum following exposure to high doses of irradiation. Alterations in phosphatidylinositol species informed on dysfunctional epithelial cell differentiation and maturation. Differences in glycosphingolipids of the villi epithelium that would influence the absorptive capacity and functional structure of the brush border membrane were detected. Dichotomous alterations in cardiolipins indicated altered structural and functional integrity of mitochondria. Phosphatidylglycerol species, known regulators of toll-like receptors, were detected and localized to regions in the lamina propria that contained distinct immune cell populations. These results provide molecular insight that can inform on injury mechanism in a nonhuman primate model of the acute radiation syndrome of the gastrointestinal tract. Findings may contribute to the identification of therapeutic targets and the development of new medical countermeasures.

Published
2019

12. The Gastrointestinal Subsyndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose-response Relationship With and Without Medical Management

Author

Ann M. Farese, Catherine Booth, Christopher S Potten, George A. Parker, Thomas J. MacVittie, Kim G. Hankey, Gregory Tudor, and William E. Jackson

Subjects
Gastrointestinal Diseases, Epidemiology, Health, Toxicology and Mutagenesis, Lung injury, Bioinformatics, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Animals, Medicine, Radiology, Nuclear Medicine and imaging, biology, business.industry, Lethal dose, Acute Radiation Syndrome, Dose-Response Relationship, Radiation, biology.organism_classification, Macaca mulatta, Gastrointestinal Tract, Natural history, Dose–response relationship, Rhesus macaque, 030220 oncology & carcinogenesis, Time course, business, Dose rate
Abstract

Well-characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the Food and Drug Administration “animal rule”. Development of a model for the acute GI-ARS requires knowledge of the radiation dose response relationship and time course of mortality and morbidity across the acute and prolonged gastrointestinal radiation syndrome. The nonhuman primate, Rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality relative to the H-, GI-ARS and lung injury. It can be used to assess the natural history of GI damage, concurrent multiple organ injury and aspects of the mechanism of action for acute radiation exposure and treatment. A systematic review of relevant studies that determined the dose response relationship for the gastrointestinal acute and prolonged radiation syndrome in the Rhesus macaque relative to radiation dose, quality, dose rate, exposure uniformity and use of medical management has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present and US HHS REPORT (2002 to present). The following terms were used: Rhesus, total-body irradiation, total-body x-irradiation, TBI, irradiation, gamma radiation, gastrointestinal system, LD50, LD50/60, hematopoietic radiation syndrome, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, gastrointestinal radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,923. Thirty-two (32) studies, utilizing 1,364 total nonhuman primates (NHP), Rhesus Macaca mulatta, were evaluated to provide an informative and consistent review. Ten (10) primary studies provided adequate data to establish dose response relationships (DRR)s for the acute GI-ARS. The DRRs were determined for uniform or non-uniform total-body irradiation (TBI) with 240–250kVp or 2Mev x-radiation, Co-60 gamma radiation, isotope-derived gamma-radiation, reactor- and nuclear weapon-derived mixed gamma:neutron radiation and 6MV LINAC-derived photons delivered at various dose rates from a total-body, bilateral, rotational or unilateral exposure aspect in the absence or presence of medical management. The DRRs established by a probit analysis versus linear dose relationship were characterized by two main parameters or dependent variables, a slope and LD50/15. Respective LD50/15 values for the primary studies without use of medical management that used 250kVp x-radiation (three studies, total n=234), 2Mev x-radiation (n=84) and Co-60 gamma-radiation (n=90) were: 250kVp x-radiation (605rad [572, 636], 581rad [542, 621], and 608rad [369, 871]); Co-60 gamma -radiation (708rad [683, 736]) and 2Mev x-radiation (671rad [632, 715]). The respective slopes were steep and ranged from 0.402 to 1.915 probits per linear dose. The DRR, LD50/15 value and slope were also determined for total-body, non-uniform, unilateral, pulse-rate exposure to reactor-derived mixed gamma:neutron radiation (total n=111). The LD50/15 value was 482rad with a slope of 0.992 [0.142, 1.99]. Two contemporary studies provided DRRs for NHP exposed to TBI or PBI with 5% bone marrow sparing (PBI/BM5) with 6 MV LINAC-derived photons with administration of medical management. The LD50/15 and slopes were: TBI, 11.33 Gy [10.81, 11.75] with a slope of 0.917 [0.701, 1.133]; PBI/BM5, 12.01 Gy [11.71, 12.52] with a slope of 1.001 [0.599, 1.415]. The PBI/BM5 model also provided a modified, longitudinal, image-based histopathology of damage to the small intestine through 180d post exposure relative to normal, un-irradiated age-matched tissue. Secondary studies (12) provided data sets of appropriate limited studies that did not describe a DRR for the GI-ARS but included adequate control data sets or a range of mortality values from high-dose range exposure in the conduct of establishing the DRR for the H-ARS, were used to support the threshold and mid- to high-lethal dose range for the GI-ARS. Tertiary studies (12) provided data sets that supported the incidence, time course, severity, histology, physiology and biomarkers of radiation-induced GI injury in the NHP. The acute GI-ARS and prolonged GI injury were evaluated at threshold doses to include initial concomitant GI injury consequent to TBI at mid- to high-dose lethal H-ARS. The available evidence provided a relatively consistent and reliable data base that characterized the DRR and survival probability over the 15 day time course for the acute GI-ARS in young Rhesus macaques exposed to total-body and partial-body irradiation with several sources of differing radiation quality, dose rate and non-uniform exposure with and without medical management. The GI-ARS occurred with concomitant evolution of the H-ARS. The image-based histopathology provided a clear demonstration of the pronounced radiation-induced damage to the GI system along the longitudinal course from acute to prolonged damage through the 180d study duration. The DRRs for the GI-ARS are characterized by steep slopes and relative LD50/15 values that reflected the biological effect of radiation quality, exposure aspect, dose rate and medical management over a range in time from 1954–2015.

Published
2019

13. MALDI-MSI spatially maps N-glycan alterations to histologically distinct pulmonary pathologies following irradiation

Author

Maureen A. Kane, Thomas J. MacVittie, Claire L. Carter, Kim G. Hankey, George A. Parker, and Ann M. Farese

Subjects
0301 basic medicine, Male, Pathology, medicine.medical_specialty, Glycosylation, Pulmonary Fibrosis, lcsh:Medicine, Inflammation, Lung injury, Article, Imaging, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, Polysaccharides, Edema, Macrophages, Alveolar, medicine, Animals, lcsh:Science, Radiation Injuries, Lung, Pneumonitis, Multidisciplinary, Mass spectrometry, business.industry, Macrophages, lcsh:R, Cancer, Lung Injury, Pneumonia, Hyperplasia, medicine.disease, Macaca mulatta, 030104 developmental biology, Phenotype, chemistry, 030220 oncology & carcinogenesis, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, lcsh:Q, medicine.symptom, business, Mannose
Abstract

Radiation-induced lung injury is a highly complex combination of pathological alterations that develop over time and severity of disease development is dose-dependent. Following exposures to lethal doses of irradiation, morbidity and mortality can occur due to a combination of edema, pneumonitis and fibrosis. Protein glycosylation has essential roles in a plethora of biological and immunological processes. Alterations in glycosylation profiles have been detected in diseases ranging from infection, inflammation and cancer. We utilized mass spectrometry imaging to spatially map N-glycans to distinct pathological alterations during the clinically latent period and at 180 days post-exposure to irradiation. Results identified alterations in a number of high mannose, hybrid and complex N-glycans that were localized to regions of mucus and alveolar-bronchiolar hyperplasia, proliferations of type 2 epithelial cells, accumulations of macrophages, edema and fibrosis. The glycosylation profiles indicate most alterations occur prior to the onset of clinical symptoms as a result of pathological manifestations. Alterations in five N-glycans were identified as a function of time post-exposure. Understanding the functional roles N-glycans play in the development of these pathologies, particularly in the accumulation of macrophages and their phenotype, may lead to new therapeutic avenues for the treatment of radiation-induced lung injury.

Published
2020

14. Successful transfer of anti-SARS-CoV-2 immunity using convalescent plasma in an MM patient with hypogammaglobulinemia and COVID-19

Author

Djordje Atanackovic, Ryan A. Metcalf, Patricia R. Slev, Adam M. Spivak, Robert C. Blaylock, Vicente Planelles, Mohammad M. Sajadi, Yue Zheng, Heather D. Mannuel, Erin T. Larragoite, Mary Steinbach, Aaron P. Rapoport, Tim Luetkens, Emily S Spivak, Thomas B. Martins, Kim G. Hankey, and Stephanie V. Avila

Subjects
viruses, Pneumonia, Viral, 030204 cardiovascular system & hematology, Antibodies, Viral, Immunoglobulin G, Hypogammaglobulinemia, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Immunity, Agammaglobulinemia, medicine, Humans, 030212 general & internal medicine, skin and connective tissue diseases, Pandemics, Multiple myeloma, COVID-19 Serotherapy, Aged, biology, business.industry, SARS-CoV-2, fungi, Immunization, Passive, COVID-19, Hematology, biochemical phenomena, metabolism, and nutrition, medicine.disease, body regions, Pneumonia, Immunoglobulin M, Humoral immunity, Immunology, biology.protein, Female, Exceptional Case Report, Antibody, business, Coronavirus Infections, Multiple Myeloma
Abstract

Key Points A severely immunocompromised patient with MM and COVID19 who received a convalescent plasma product showed SARS-CoV-2 clearance. The convalescent plasma showed humoral immunity against all structural SARS-CoV-2 proteins, which was successfully transferred to the patient.

Published
2020

15. Impaired mRNA Based COVID-19 Vaccine Response in Patients with B-Cell Malignancies after CD19 Directed CAR-T Cell Therapy

Author

Nancy M. Hardy, Kim G. Hankey, Seung Tae Lee, Aaron P. Rapoport, Mehmet Hakan Kocoglu, Nancy Smith, Tim Luetkens, Patricia Lesho, Sherri Bauman, Djordje Atanackovic, Jean A. Yared, Kathleen Ruehle, John W Baddley, Philip Margiotta, Stephanie Avila, Jennie Y. Law, and Saurabh Dahiya

Subjects
704.Cellular Immunotherapies: Clinical, Messenger RNA, Coronavirus disease 2019 (COVID-19), biology, business.industry, Vaccine response, Immunology, Cell Biology, Hematology, Biochemistry, CD19, medicine.anatomical_structure, Cancer research, biology.protein, Medicine, CAR T-cell therapy, In patient, business, B cell
Abstract

Introduction: Patients with hematologic malignancies are at an increased risk of morbidity and mortality from COVID-19 disease (Vijenthira, Blood 2020). This is likely a result of combination of immunodeficiency conferred by the disease and the therapeutics. The immunogenicity of the COVID-19 vaccines in patients with exposure to CD19 directed Chimeric Antigen Receptor (CAR)-T cell therapy is not established. CD19 CAR-T cell therapies cause B-cell aplasia, which in turn can affect humoral immune response against novel antigens. Herein, we present results from our prospectively conducted clinical study to evaluate immune responses against mRNA based COVID-19 vaccines in patients with lymphoma who have received CD19 directed CAR-T cell therapy. Methods: All patients and healthy controls were enrolled in a prospective clinical study evaluating immune responses against commercial COVID-19 RNA vaccines in patients with hematologic malignancies. Plasma samples were generated from heparinized peripheral blood of 4 heathy controls (HCs) receiving the same vaccines and 19 B cell lymphoma patients treated with CD19 CAR- T cells. Samples from ~4 weeks post second dose of the vaccine (d56) were available for 14 CAR-T patients, for 5 CAR-T patients samples were available from ~4 weeks after the first dose (d28). Plasma samples were analyzed in an enzyme-linked immunosorbent assay (ELISA) using different full-length recombinant SARS-CoV-2 proteins and control proteins. Neutralizing activity was measured using the cPass Neutralization Antibody Detection Kit (GenScript Biotech). Results: Results from 4 healthy controls and 19 patients (12 males and 7 females) with lymphoma are reported. Median age for the lymphoma patients is 65 years. Eleven patients had large B cell lymphoma, 5 had follicular lymphoma and 3 had mantle cell lymphoma as primary diagnoses. Seventeen patients had advance stage disease (III/IV stage) and had received a median of 3 prior lines of therapy. All patients received CD19 directed CAR-T cell therapy. Ten patients received Moderna vaccine and 9 received Pfizer vaccine. Median time between CAR-T infusion and first COVID-19 vaccine was 258 days. While the peripheral blood plasma from 3/4 HCs already showed substantial SARS-CoV-2 neutralizing activity at ~4 weeks after the first dose of COVID-19 mRNA vaccine, none of the 5 CD19 CAR-T patients analyzed evidenced any antibody-mediated neutralizing activity in their blood at the same point in time (Figure 1A). Around 4 weeks after receiving the second dose of the vaccine, all 4 HCs tested evidenced complete or almost complete neutralizing activity (Figure 1B). In marked contrast, only 1 out of 14 CAR-T patients analyzed evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity in their blood (Figure 1B). Interestingly, when we asked whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CAR-T patients, we found that that was clearly not the case since anti-Flu, -TT, and -EBV responses were equivalent to the ones observed in HCs (Figure 2A). However, while at ~4 weeks post second dose of the vaccine the HCs showed marked antibody titers against all the viral spike proteins including their "delta" variants (Figure 2B), that was not the case for our CAR-T patients. The vast majority of our CAR-T patients did not evidence IgG antibody responses against any of the SARS-CoV-2 proteins analyzed such as S1, S1 delta, RBD, RBD delta, or S2 (Figure 2B). Conclusion: In this prospectively conducted clinical study, 18 of 19 patients with lymphoma who have received CD19 CAR-T therapy had poor immunogenicity against mRNA based COVID-19 vaccines as measured by neutralization assays and antibody titers. The antibody titers against B.1.617.2 (delta variant, S1 and RBD protein) were also demonstrably poor. The antibody response to common pathogens (flu, EBV, TT) were preserved, suggesting impaired immune response against novel antigens. Long-term follow-up of this study is ongoing. APR and DJ contributed equally Figure 1 Figure 1. Disclosures Dahiya: Kite, a Gilead Company: Consultancy; Atara Biotherapeutics: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Research Funding; Miltenyi Biotech: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees.

Published
2021

16. Eight-Day Point of Care CAR T-Cell Manufacturing on Clinimacs Prodigy from Healthy Donors As a Proof-of-Concept Study

Author

Stephanie Avila, Nancy M. Hardy, Joerg Mittelstaet, Rena G. Lapidus, Saurabh Dahiya, Ron Dudek, Philip Margiotta, Tim Luetkens, John Braxton, Xiaoxuan Fan, Ulrike Abramowski-Mock, John C. McLenithan, Aaron P. Rapoport, Forat Lufti, Djordje Atanackovic, Clarissa Saba, Jean A. Yared, Karen F. Underwood, and Kim G. Hankey

Subjects
Proof of concept, Immunology, Operations management, Cell Biology, Hematology, Car t cells, Psychology, Biochemistry, Point of care
Abstract

Introduction Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy for various forms of cancer, especially hematologic malignancies. However, several factors limit use of CAR T-cells to a wider number of patients. Long manufacturing time (usually 3-4 weeks with standard of care products) poses a big challenge in treating these chemorefractory patients in a timely fashion. Thus, we evaluated the feasibility of a fresh in and fresh out, short, eight-day manufacturing process performed locally to expedite CAR T-cell drug product delivery. Herein we report the results of two experimental runs using this modified short eight-day culture process. Methods We used the CliniMACS Prodigy® closed manufacturing system and modified the 12-day T Cell Transduction (TCT) activity matrix protocol to produce anti-CD19 CAR T-cells in eight days. Normal donor mononuclear cells were collected by leukapheresis and enriched for CD4 and CD8 cells by immunomagnetic bead selection in three stages. Enriched T-cells were activated with MACS GMP T Cell TransACT and cultured at 37°C with 5% CO 2 for 16-24 hours in media supplemented with 12.5mcg/L each of IL-7 and IL-15, and 3% heat-inactivated human AB serum. On day 1 of the process, activated T-cells were transduced with lentiviral vector encoding the anti-CD19 CAR (Lentigen, LTG1563) at a multiplicity of infection (MOI) of 7-10. On day 3, the cells were washed twice and the media volume adjusted to feed the expanding cells. The culture was again fed on day 5 by exchanging half the volume of spent media with fresh supplemented media. Media supplemented with cytokines alone was used for the remaining four washes on day 6, 7 and 8. Transduction efficiency and T-cell subset frequencies were assessed by flow cytometry on the MACSQuant-10 and CAR-T Express Mode package on days 3, 6 and 8. Subsequently, we performed ELISPOT assay for CAR T-cell potency testing and in-vivo efficacy testing in NSG mice bearing Raji B cell lymphoma. Results Refer to Table 1 for details on cell populations of interest for experiment number 1 and 2. The total number of CD3 T-Cells increased from 97% on day 0 to >99.5% on the harvest day (day 8). CD3 T-cells expanded 11.6- and 34.2-fold on day 8 when compared to day 0. Transduction efficiency of ~40% was observed in both experimental runs. Final CD19 CAR T-cells numbers ranged from 9.3-13.3 x 10e8 with viability of CD3+ cells >93% for both the runs. Day 3 of the culture is an important day since a clinical decision to proceed with lymphodepletion must be made to facilitate the fresh in and fresh out approach. Here we observed reliable transduction of T-cells on day 3 with an average efficiency of 15.9%. Day 3 data reliably provided information to proceed with lymphodepletion. A total of 100,000 CD19 CAR T-cells produced in experiment #1 were exposed to beads coated with CD19 protein, BCMA control protein, or T cell-activating beads coated with anti-CD3 and anti-CD28 antibodies in an ELISPOT plate. Spots in figure 1 represents individual CAR T-cells producing IFN-gamma. This novel ELISPOT assay shows high IFN-gamma by CD19 CAR T-cells in response to the target antigen or unspecific stimulation using CD3/CD28 beads. Subsequently, NSG mice received injections of 5x10e5 Raji B cell lymphoma cells stably expressing luciferase into the tail vein. One week later, 4 mice per group received individual i.v. injections of 4x10e6 CD19 CAR T-cells, 0.3x10e6 CD19 CAR T-cells, 4x10e6 mock-transduced CAR T-cells, or media. Survival curves in figure 2 represent survival of the mice after receiving the treatment with best survival seen with 4x10e6 dose. Conclusions In these experimental runs, we were able to generate CD19 CAR+ T-cells in a short eight-day manufacturing process. The final product characteristics (viability, transduction efficiency and doses) were comparable to clinical formulations. Further, point-of-care potency assay suggests high IFN-gamma production and elimination of CD19 tumor in the in vivo murine model. The point-of-care CAR T-cell production allows for shorter vein-to-vein time and offers dramatic reduction in the product cost. Lastly, the novel potency assay via ELISPOT testing allows for rapid and visual functional analysis of the CAR T-cell product. Figure 1 Figure 1. Disclosures Hardy: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Abramowski-Mock: Miltenyi Biotec: Current Employment. Mittelstaet: Miltenyi Biotec: Current Employment. Dudek: Miltenyi Biotec: Current Employment.

Published
2021

17. Acute and Chronic Kidney Injury in a Non-Human Primate Model of Partial-Body Irradiation with Bone Marrow Sparing

Author

Eric P. Cohen, Kim G. Hankey, Alexander Bennett, Ann M. Farese, George A. Parker, and Thomas J. MacVittie

Subjects
Male, Radiation Nephropathy, medicine.medical_specialty, Biophysics, Renal function, Kaplan-Meier Estimate, Kidney, Radiation Dosage, Dexamethasone, Article, Blood Urea Nitrogen, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, Bone Marrow, Animals, Medicine, Radiology, Nuclear Medicine and imaging, Organ Sparing Treatments, Blood urea nitrogen, Radiation, business.industry, Acute kidney injury, Acute Radiation Syndrome, Dose-Response Relationship, Radiation, medicine.disease, Combined Modality Therapy, Macaca mulatta, Anti-Bacterial Agents, Surgery, Radiation Injuries, Experimental, medicine.anatomical_structure, Creatinine, 030220 oncology & carcinogenesis, Anesthesia, Acute Disease, Chronic Disease, Models, Animal, Experimental pathology, Bone marrow, business
Abstract

The development of medical countermeasures against acute and delayed multi-organ injury requires animal models predictive of the human response to radiation and its treatment. Late chronic injury is a well-known feature of radiation nephropathy, but acute kidney injury has not been reported in an appropriate animal model. We have established a single-fraction partial-body irradiation model with minimal marrow sparing in non-human primates. Subject-based medical management was used including parenteral fluids according to prospective morbidity criteria. We show herein that 10 or 11 Gy exposures caused both acute and chronic kidney injury. Acute and chronic kidney injury appear to be dose-independent between 10 and 11 Gy. Acute kidney injury was identified during the first 50 days postirradiation and appeared to resolve before the occurrence of chronic kidney injury, which was progressively more severe up to 180 days postirradiation, which was the end of the study. These findings show that mitigation of the acute radiation syndrome by medical management will unmask delayed late effects that occur months after partial-body irradiation. They further emphasize that both acute and chronic changes in kidney function must be taken into account in the use and timing of mitigators and medical management for acute radiation syndrome and delayed effects of acute radiation exposure (DEARE).

Published
2017

19. Efficacy of Neulasta(®) or Neupogen(®) on H- and GI-ARS mortality and hematopoietic recovery in nonhuman primates after 10 Gy irradiation with 2.5% bone marrow sparing

Author

Thomas J. MacVittie, Karl Prado, Alexander Bennett, William E. Jackson, Allison Gibbs, Kim G. Hankey, and Ann M. Farese

Subjects
Male, medicine.medical_specialty, Filgrastim, Epidemiology, Health, Toxicology and Mutagenesis, Urology, Context (language use), Granulocyte, Neutropenia, Article, 030218 nuclear medicine & medical imaging, Polyethylene Glycols, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, medicine, Animals, Radiology, Nuclear Medicine and imaging, business.industry, Acute Radiation Syndrome, medicine.disease, Macaca mulatta, Hematopoiesis, Gastrointestinal Tract, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Concomitant, Absolute neutrophil count, Hematinics, Bone marrow, business
Abstract

A nonhuman primate model of acute, partial-body, high-dose irradiation with minimal (2.5%) bone marrow sparing was used to assess endogenous gastrointestinal and hematopoietic recovery and the ability of Neulasta (pegylated granulocyte colony-stimulating factor) or Neupogen (granulocyte colony-stimulating factor) to enhance recovery from myelosuppression when administered at an increased interval between exposure and initiation of treatment. A secondary objective was to assess the effect of Neulasta or Neupogen on mortality and morbidity due to the hematopoietic acute radiation syndrome and concomitant gastrointestinal acute radiation syndrome. Nonhuman primates were exposed to 10.0 Gy, 6 MV, linear accelerator-derived photons delivered at 0.80 Gy min. All nonhuman primates received subject-based medical management. Nonhuman primates were dosed daily with control article (5% dextrose in water), initiated on day 1 postexposure; Neulasta (300 μg kg), administered on days 1, 8, and 15 or days 3, 10, and 17 postexposure; or Neupogen (10 μg kg), administered daily postexposure following its initiation on day 1 or day 3 until neutrophil recovery (absolute neutrophil count ≥1,000 cells μL for 3 consecutive days). Mortality in the irradiated cohorts suggested that administration of Neulasta or Neupogen on either schedule did not affect mortality due to gastrointestinal acute radiation syndrome or mitigate mortality due to hematopoietic acute radiation syndrome (plus gastrointestinal damage). Following 10.0 Gy partial-body irradiation with 2.5% bone marrow sparing, the mean duration of neutropenia (absolute neutrophil count

Published
2019

20. Radiation Nephropathy in a Nonhuman Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing-Part 1: Acute and Chronic Kidney Injury and the Influence of Neupogen

Author

Alexander Bennett, Thomas J. MacVittie, Jace W. Jones, Kim G. Hankey, Ann M. Farese, Maureen A. Kane, Eric P. Cohen, and George A. Parker

Subjects
Radiation Nephropathy, Male, medicine.medical_specialty, Filgrastim, Epidemiology, Health, Toxicology and Mutagenesis, Urology, Renal function, Granulocyte, Kidney, 030218 nuclear medicine & medical imaging, Blood cell, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, medicine, Animals, Radiology, Nuclear Medicine and imaging, Renal Insufficiency, Chronic, business.industry, Acute Radiation Syndrome, Acute Kidney Injury, Macaca mulatta, Haematopoiesis, Radiation Injuries, Experimental, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hematinics, Experimental pathology, Bone marrow, business
Abstract

Acute and chronic kidney injury may occur after accidental prompt radiation exposures. We have modeled their occurrence in a nonhuman primate model. Subjects who are exposed to more than 5-Gy prompt irradiation are apt to show blood cell cytopenias and be treated with granulocyte colony-stimulating factors such as Neupogen® or Neulasta® to mitigate the hematologic injury of the acute radiation syndrome. Neupogen or Neulasta are now approved by the US Food and Drug Administration for this indication. This will significantly increase the number of survivors of acute radiation exposures who will be at risk for delayed effects of radiation exposure, which includes acute and chronic kidney injury. The primary objectives of the present two companion manuscripts were to assess natural history of delayed radiation-induced renal injury in a nonhuman primate model of acute, high-dose, partial-body irradiation with 5% bone marrow sparing to include the clinical and histopathological evidence and the effect of Neupogen administration on morbidity and mortality. In this study, 88 nonhuman primates underwent 10- or 11-Gy partial-body irradiation with 5% bone marrow sparing, of which 36 were treated with Neupogen within 1, 3, or 5 d postirradiation. All animals were followed up to 180 d after irradiation. Renal function and histology end points showed early acute and later chronic kidney injury. These end points were not affected by use of Neupogen. We conclude that use of Neupogen to mitigate against the hematopoietic acute radiation syndrome has no impact on acute or chronic kidney injury.

Published
2019

21. Citrulline as a Biomarker in the Non-human Primate Total- and Partial-body Irradiation Models

Author

Catherine Booth, Gregory Tudor, Maureen A. Kane, Alexander Bennett, Ann M. Farese, Kim G. Hankey, Claire L. Carter, Thomas J. MacVittie, and Jace W. Jones

Subjects
Male, medicine.medical_specialty, Pathology, Gastrointestinal Diseases, Epidemiology, Enterocyte, Health, Toxicology and Mutagenesis, Gastrointestinal Injury, Radiation Dosage, Sensitivity and Specificity, Gastroenterology, Article, chemistry.chemical_compound, Internal medicine, medicine, Citrulline, Animals, Radiology, Nuclear Medicine and imaging, Irradiation, Radiation Injuries, Survival rate, business.industry, Reproducibility of Results, Macaca mulatta, Survival Rate, Disease Models, Animal, medicine.anatomical_structure, chemistry, Biomarker (medicine), Histopathology, Bone marrow, business, Biomarkers, Whole-Body Irradiation
Abstract

The use of plasma citrulline as a biomarker for acute and prolonged gastrointestinal injury via exposure to total- and partial-body irradiation (6 MV LINAC-derived photons; 0.80 Gy min−1) in nonhuman primate models was investigated. The irradiation exposure covered gastrointestinal injuries spanning lethal, mid-lethal, and sub-lethal doses. The acute gastrointestinal injury was assessed via measurement of plasma citrulline and small intestinal histopathology over the first 15 days following radiation exposure and included total-body irradiation at 13.0 Gy, 10.5 Gy, and 7.5 Gy and partial-body irradiation at 11.0 Gy with 5% bone marrow sparing. The dosing schemes of 7.5 Gy total-body irradiation and 11.0 Gy partial-body irradiation included time points out to day 60 and day 180, respectively, which allowed for correlation of plasma citrulline to prolonged gastrointestinal injury and survival. Plasma citrulline values were radiation-dependent for all radiation doses under consideration with nadir values ranging from 63–80 % lower than radiation-naïve NHP plasma. The nadir values were observed at day 5 to 7 post irradiation. Longitudinal plasma citrulline profiles demonstrated prolonged gastrointestinal injury resulting from acute high-dose irradiation had long lasting effects on enterocyte function. Moreover, plasma citrulline did not discriminate between total-body or partial-body irradiation over the first 15 days following irradiation and was not predictive of survival based on the radiation models considered herein.

Published
2015

22. Lymphoid and Myeloid Recovery in Rhesus Macaques Following Total Body X-Irradiation

Author

Thomas J. MacVittie, Ann M. Farese, Kim G. Hankey, and Melanie Cohen

Subjects
Male, Myeloid, Epidemiology, Health, Toxicology and Mutagenesis, medicine.medical_treatment, Biology, Radiation Dosage, Article, Immune system, Immune Reconstitution Inflammatory Syndrome, medicine, Animals, Myeloid Cells, Radiology, Nuclear Medicine and imaging, Lymphocytes, Progenitor cell, Leukemia, Radiation-Induced, T-cell receptor excision circles, X-Rays, Lethal dose, Hematopoietic stem cell, Immunosuppression, Recovery of Function, Macaca mulatta, Haematopoiesis, medicine.anatomical_structure, Immunology, Whole-Body Irradiation
Abstract

Recovery from severe immunosuppression requires hematopoietic stem cell reconstitution and effective thymopoiesis to restore a functional immune cell repertoire. Herein, a model of immune cell reconstitution consequent to potentially lethal doses of irradiation is described which may be valuable in evaluating potential medical countermeasures. Male rhesus macaques were total body irradiated by exposure to 6.00 Gy 250 kVp x-radiation (midline tissue dose, 0.13 Gy min-1) resulting in an approximate LD10/60 (n = 5/59). Animals received medical management and hematopoietic and immune cell recovery was assessed (n ≤ 14) through 370 days post exposure. A subset of animals (n ≤ 8) was examined through 700 days. Myeloid recovery was assessed by neutrophil and platelet-related parameters. Lymphoid recovery was assessed by the absolute lymphocyte count and FACS-based phenotyping of B- and T-cell subsets. Recent thymic emigrants were identified by T cell receptor excision circle quantification. Severe neutropenia, lymphopenia and thrombocytopenia resolved within 30 days. Total CD3+ cells μL-1 required 60 days to reach values 60% of normal, followed by subsequent slow recovery to approximately normal by 180 days post irradiation. Recovery of CD3+4+ and CD3+8+ cell memory and naïve subsets were markedly different. Memory populations were ≥ 100% of normal by day 60; whereas, naïve populations were only 57% normal at 180 days and never fully recovered to baseline post irradiation. Total (CD20+) B cells μL-1 were within normal levels by 77 days post exposure. This animal model elucidates the variable T- and B-cell subset recovery kinetics after a potentially lethal dose of total-body irradiation that are dependent on marrow-derived stem and progenitor cell recovery, peripheral homeostatic expansion and thymopoiesis.

Published
2015

23. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation

Author

Thomas J. MacVittie, Kim G. Hankey, Cassandra P. Smith, Allison Gibbs, Pei Zhang, Cheryl Taylor-Howell, Wanchang Cui, and Sean R. Kearney

Subjects
Male, Pathology, medicine.medical_specialty, Epidemiology, Health, Toxicology and Mutagenesis, medicine.medical_treatment, Connective tissue, Spleen, Biology, Article, Lethal Dose 50, Fibrosis, medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, Radiometry, Kidney, Lung, integumentary system, Growth factor, Connective Tissue Growth Factor, Dose-Response Relationship, Radiation, Radiation Exposure, medicine.disease, Macaca mulatta, humanities, Up-Regulation, CTGF, Disease Models, Animal, Viscera, medicine.anatomical_structure, Organ Specificity, Immunohistochemistry
Abstract

Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.

Published
2015

24. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Author

Scott E Kasner, Balakumar Swaminathan, Pablo Lavados, Mukul Sharma, Keith Muir, Roland Veltkamp, Sebastian F Ameriso, Matthias Endres, Helmi Lutsep, Steven R Messé, J David Spence, Krassen Nedeltechev, Kanjana Perera, Gustavo Santo, Veronica Olavarria, Arne Lindgren, Shrikant Bangdiwala, Ashkan Shoamanesh, Scott D Berkowitz, Hardi Mundl, Stuart J Connolly, Robert G Hart, N Abdelhamid, D Abdul Rahman, M Abdul-Saheb, P Abreu, M Abroskina, F Abu Ahmad, S Accassat, M Acciaresi, A Adami, N Ahmad, F Ahmed, M Alberto Hawkes, F Alemseged, A Ali, R Altavilla, L Alwis, P Amarenco, S Amaro, LE Amaya Sanchez, A Amelia Pinto, SF Ameriso, H Amin, T Amino, AK Amjad, E Anagnostou, G Andersen, C Anderson, DC Anderson, M Andrea Falco, F Andres Mackinnon, D Andreu, M Androulakis, M Angel Gamero, G Angel Saredo, R Angeles Diaz, M Angels Font, S Anticoli, A Arauz, AA Arauz Gongora, P Araya, JF Arenillas Lara, S Arias Rivas, M Arnold, S Augustin, W Avelar, E Azevedo, V Babikian, A Bacellar, K Badalyan, HJ Bae, EM Baez Martinez, H Bagelmann, P Bailey, Z Bak, M Baker, A Balazs, D Baldaranov, I Balogun, T Balueva, Z Bankuti, M Bar, A Baranowska, J Bardutzky, S Barker Trejo, J Barlinn, F Baronnet, C Barroso, M Barteys, T Bartolottiova, A Barulin, M Bas, S Bashir, V Basile, R Bathe-Peters, R Bathula, C Batista, H Batur Caglayan, P Baumgartner, R Bazan, O Bazhenova, M Beaudry, J Beer, Y Behnam, C Beilei, A Beinlich, Y Bejot, A Belkin, OR Benavente, A Benjamin, V Berardi, D Bereczki, SD Berkowitz, J Berlingieri, W Berrios, J Berrouschot, M Bhandari, M Bhargavah, H Bicker, T Bicsak, M Bilik, D Bindila, J Birchenall, L Birnbaum, T Black, D Blacker, D Blacquiere, C Blanc-Labarre, C Blank, B Blazejewska-Hyzorek, S Bloch, E Bodiguel, E Bogdanov, L Boos, L Borcsik, N Bornstein, S Bouly, G Braga, I Bragado, MC Bravi, C Brokalaki, W Brola, R Brouns, D Bruce, J Brzoska-Mizgalska, B Buck, M Buksinska-Lisik, J Burke, M Burn, G Bustamante, L Cabrejo, K Cai, S Cajaraville, M Calejo, D Calvet, J Campillo, E Campos Costa, P Camps, H Can Alaydin, E Candeloro, C Canepa, CG Cantu Brito, M Cappellari, C Carcel, P Cardona Portela, F Cardoso, M Carek, M Carletti, J Carlos Portilla, P Caruso, I Casado-Naranjo, P Castellini, D Castro, F Castro Meira, A Cavallini, N Cayuela Caudevilla, S Cenciarelli, C Cereda, P Cerrone, A Chakrabarti, P Chaloulos-Iakovidis, A Chamorro, D Chandrasena, DI Chang, C Che, J Chembala, J Chen, Z Chen, T Chen, H Chen, X Chen, G Chen, L Chen, S Chen, B Cheripelli, M Chin, E Chiquete Anaya, M Chorazy, H Christensen, T Christensen, L Christian, F Chu, CS Chung, W Clark, R Clarke, S Claverie, E Clemente Agostoni, B Clissold, J Coelho, D Cohen, S Colakoglu, D Collas, R Condurso, SJ Connolly, D Consoli, C Constantin, AB Constantino Silva, L Contardo, A Corlobe, M Correia, C Correia, E Cortijo Garcia, B Coull, S Coutts, S Coveney, P Cras, R Crols, S Crozier, A Csanyi, L Csiba, K Csontos, R Csuha, L Cui, L Cunha, S Curtze, M Czerska, A Czlonkowska, M Czurko, M Czuryszkiewicz, M Dagnino, C Dai, A Daineko, G Dalek, D Damgaard, A Danese, K Dani, V Danku, W Dario Toledo, A Dávalos, A De Havenon, J De Keyser, N De Klippel, J De La Torre, A De Pauw, A De Smedt, R De Torres, MM De Vries Basson, J Dearborn, R Deganutto, M Degeorgia, I Deguchi, A Del Giudice, C Delcourt, R Delgado-Mederos, G Della Marca, B Delpont, S Deltour, DL Demets, M Dennis, J Desai, J Devine, I Dhollander, MT Di Mascio, M Diaconu, F Diaz Otero, J Dietzel, E Diez-Tejedor, N Ding, J Ding, M Diomedi, P Dioszeghy, M Distefano, V Domigo, E Dorodnicov, D Dossi, F Doubal, I Druzenko, P Du, J Du, T Duman, Y Duodu, D Dutta, L Dylewicz, J Eckstein, E Ehrensperger, S Ehrlich, G Einer Allende, B Elena Halac, S Elyas, M Endres, JM Engelbrecht, S Engelter, M Epinat, F Eren, M Esbjornsson, B Escribano, I Escudero, B Esisi, B Essa, M Esterbauer, N Evans, D Eveson, S Fabio, L Fang, S Fanta, M Fares, M Fatar, K Faust, A Favate, F Fazekas, M Federica Denaro, A Fedin, P Felipe Amaya, J Feng, K Ferencova, M Fernanda Gilli, MD Fernandez, PN Fernandez Pirrone, J Fernandez Vera, J Ferrari, A Ferreira, G Ferreira Junior, M Fidler, D Field, T Field, C Figueroa, J Fiksa, A Filipov, A Firstenfeld, L Fisch, U Fischer, M Fisselier, U Fiszer, F Fluri, G Fortea, K Fotherby, A Fraczek, E France, G Freitas, S Frey, M Frick, A Friedman, M Friedrich, G Frisullo, W Fryze, B Fuentes Gimeno, H Fujigasaki, K Fukuyama, A Furlan, G Furlanis, J Furnace, M Gabriel, E Gabriel Reich, RJ Gagliardi, F Galati, E Galli Giqueauk, A Gallina, E Gallinella, J Gallo, S Gangadharan, Y Gao, R Garcia Lopez, A Garcia Pastor, SM Garcia Sanchez, M Garnauf, P Garnier, D Gasecki, K Gasic, K Gasiorek, S Gasser, M Gaugg, M Gebreyohanns, K Gebura, J Geng, M Geniz Clavijo, K Georg Haeusler, R Geran, M Geremek, Z Gerocs, D Ghia, D Giannandrea, F Giatsidis, JA Gien Lopez, A Gil Nunez, L Gimenez, E Giralt, A Glabinski, D Gladstone, M Gliem, M Gluszkiewicz, R Goddeau, E Gogoleva, M Gokce, D Goldemund, K Golikov, A Gomes Neto, M Gomez Schneider, M 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Huhtakangas, M Hussain, S Igarashi, AM Iglesias Mohedano, J Ignacio Tembl, M Impellizzeri, Y Inanc, P Ioli, A Irina Aniculaesei, K Ishida, R Itabashi, H Iversen, A Jagolino, K Jakab, S Jander, H Janka, J Jankovych, J Jansen, L Jasek, M Javier Alet, L Javor, X Jin, P Jing, B Joachim, M Joan Macleod, M Johnson, J Jose Martin, C Joyner, K Judit Szabo, A Jun-Oconnell, R Jura, B Kaczorowska, J Kadlcikova, T Kahles, N Kakaletsis, I Kakuk, K Kalinowska, K Kaminska, C Kaneko, I Kanellos, P Kapeller, K Kapica-Topczewska, O Karasz, M Karlinski, JE Karlsson, K Kasa, E Kashaeva, SE Kasner, M Kaste, J Kasza, A Katalin Iljicsov, M Katsurayama, S Kaur, M Kawanishi, S Kaygorodtseva, K Ke, A Kei, J Keilitz, J Kellner, P Kelly, S Kelly, D Kemlink, M Kerekgyarto, I Keskinarkaus, D Khairutdinova, A Khanna, A Khaw, M Kholopov, C Khoumri, S Kirpicheva, H Kirshner, K Kitagawa, S Kittner, R Kivioja, F Klein, D Kleindorfer, T Kleinig, P Klivenyi, S Knecht, Y Kobayashi, A Kobayashi, M Koch, L Koehler, M Koivu, V Kolianov, I Koltsov, T Kondo, I Konkov, S Kopecky, E Korompoki, J Korpela, K Kosarz-Lanczek, A Koutroubi, K Kovacs, T Kovacs, H Kovacs, K Kowalczyk, M Kowalska, D Krajickova, M Kral, C Krarup Hansen, J Kraska, S Krebs, V Krejci, C Kremer, R Kreuzpointer, M Krzyzanowska, D Kucken, A Kulakowska, J Kunzmann, N Kurenkova, A Kuris, I Kurkowska-Jastrzebska, N Kurtenkova, O Kurushina, G Kusnick, M Kustova, T Kuwashiro, J Kwan Cha, A Lago, M Lagutenko, B Lajos, J Lambeck, C Lamy, A Landolfi, S Lanfranconi, W Lang, LB Lara Lezama, B Lara Rodriguez, T Largo, A Lasek-Bal, L Latte, V Lauer, P Lavados, R Le Bouc, R Leal Cantu, H Lechner, K Lecouturier, S Leder, J Lee, BC Lee, A Leger, E Leira, I Leisse, R Leker, G Lembo, L Lenskaya, J Leyden, G Li, M Li, S Li, J Li, G Liamis, H Liang, Z Liang, N Ligot, H Lin, R Lindert, A Lindgren, M Linna, T Litwin, K Liu, X Liu, L Llull, B Lohninger, M Longoni, C Loomis, D Lopes, M Lopez Fernandez, N Lopez Garza, A Lord, S Louw, R Lovasz, T Lowenkopf, Z Lu, SC Lubke-Detring, R Luder, S Lujan, B Luo, L Lupinogina, G Luschin, H Lutsep, A Lvova, J Ly, G.M. Grosse, H Ma, C Ma, M Machado, C Machado, S Macher, J Machetanz, F Macian-Montoro, E Mackey, A Mackey, G Maclean, J Maestre-Moreno, A Magadan, T Magyar, A Mahagney, A Majid, A Majjhoo, K Makaritsis, J Mandzia, M Mangas Guijarro, D Mangion, E Manios, S Mann, L Manning, C Manno, J Manuel Garcia, V Maqueda, M Mar Castellanos, M Mar Freijo, C Marando, S Marcela Lepera, J Marcos Couto, G Maria Bruera, L Maria Greco, A Maria Lorenzo, S Maria Obmann, A Maria Roa, C Marini, I Marinkovic, G Mario Sumay, C Mario Torres, M Marko, S Markova, H Markus, R Marsh, E Marsili, M Marta Esnaola, J Marta Moreno, J Marti-Fabregas, S Martina Angelocola, P Martínez Sánchez, N Martinez-Majander, S Martins, O Marzelik, S Mastrocola, G Matamala, A Matoltsy, B Matosevic, S Matsumoto, A Maud, G Mauri Cabdevila, Z May, Y Mayasi, A Mayr, T Mazzoli, K Mcarthur, L Mccullough, CE Medina Pech, F Medlin, M Mehdiratta, S Mehta, D Mehta, B Mehta, M Melis, E Melnikova, B Mendez, T Mendonca, JJ Mengual Chirifie, N Menon, A Mensch, E Meseguer, S Messe, K Metcalf, N Meyer, F Michas, N Micheletti, R Mikulik, H Milionis, B Miller, T Milling, C Minelli, J Minhas, M Minns, D Mircea, S Mishra, A Mismas, A Mistri, N Mitrovic, H Miyake, B Modrau, A Moey, C Molina, J Molina, A Molis, J Moller, S Molnar, F Moniche, C Monosi, V Monzani, M Moonis, R Morais, L Morales, A Morales, D Morar-Precup, F Moreton, C Moro, E Morozova, M Morton, T Morvan, E Morvan, T Motko, A Mowla, E Mozhejko, G Muddegowda, O Mudhar, T Mueller, C Muhl, KW Muir, H Mundl, S Munoz, C Murphy, S Murphy, A Murtuzova, T Musuka, J Mutzenbach, M Myint, W Mysliwy, M Naccarato, G Naeije, Y Nagakane, I Natarajan, D Navaratnam, A Nave, B Nazliel, K Nedeltchev, J Nel, H Nell, R Nemeth, L Nemeth, O Neto, K Ng, J Ngeh, L Nicolas Chialvo, T Nieminen, M Nikkanen, J Nikl, M Nikoforova, S Nishino, Y Nishiyama, X Njovane, S Nogawa, F Nombela, B Norrving, K Nosek, B Nowak, E Nowakowska-Sledz, G Ntaios, H Numminen, F Nunez, M Obadia, S Oberndorfer, A Obrezan, J 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Prazdnichkova, B Prendl, M Pretorius, P Profice, S Prokopenko, E Pudov, V Pujol Lereis, G Punzo Bravo, F Purroy, J Qiu, X Qu, V Quenardelle, H Quesada Garcia, L Radrizzani, A Radtke, T Raffelsberger, JM Ramirez Moreno, C Ramos-Estebanez, A Rani, P Rapantova, K Rashed, A Rasheed Nihara, J Rasmussen, L Redondo Robles, M Reif, P Reiner, P Rekova, A Renu, M Repetto, P Reyes, S Reyes Morales, JH Rha, J Ribeiro, S Ricci, C Richard, R Rigual, C Rinaldi, C Riveira Rodriguez, B Rizzato, TG Robinson, A Rocco, M Rodrigues, G Rodriguez, A Rodriguez Campello, F Rodriguez Lucci, M Rodriguez Yanez, C Roesler, C Roffe, R Roine, S Roine, A Roldan, F Romana Pezzella, M Romano, JS Roos, C Rosso, C Rostrup Kruuse, Y Roth, R Roukens, L Roveri, D Rozanski, J Rozniecki, C Rozsa, S Rudilosso, G Ruiz Ares, A Ruiz Franco, G Rum, J Ruuskanen, I Rybinnik, K Ryota, J Saarinen, V Saavedra, C Sabben, A Sabet, D Sagris, J Sahlas, N Sakai, P Salamanca, P Salgado, S Salig, T Salletmayr, M Salnikov, O Samoshkina, Y Samson, D Sanak, M Sànchez Cerón, P Santalucia, M Santamaria Cadavid, P Santiago, G Santo, B Sanz Cuesta, J Sargento, A Sarraj, K Sas, A Sas, O Satoshi, S Satsoglou, N Sattar, S Savitz, C Savopoulos, J Saw, M Sawicka, R Sawyer, T Scandura, N Schillinger, J Schindler, F Schlachetzki, I Schneider, R Schuppner, J Schurig, CJ Schwarzbach, M Sebejova, G Seidel, L Sekaran, D Selcuk, J Selvarajah, A Semerano, J Semjen, D Semushina, S Sen, M Seok Park, J Serena, O Serhat Tokgoz, W Serles, F Serrano, M Sevin, L Seynaeve, S Shah, N Shamalov, T Shang, M Sharma, A Sharrief, M Shazam Hussain, I Shchukin, W Shen, E Shepeleva, I Shinsuke, A Shmonin, A Shoamanesh, A Shuaib, A Shulga, G Sibolt, I Sibon, I Sicilia, M Siebert, E Sieczkowska, C Sila, AA Silva, D Silva, P Silva, Y Silva, M Silvestrini, Z Simony, A Simpkins, B Singh, D Sinha, I Sipos, O Skoda, P Skowron, M Skowronska, B Sliwinska, J Slonkova, A Smolkin, A Smyth, P Sobolewski, A Sobota, SI Sohn, M Soldatov, I Solganov, L Soloveva, E Solovyeva, N Sonntag, P Soors, M Sorgun, C Soriano, D Spence, K Spengos, L Sposato, G Staaf, K Stadler, L Stakhovskaya, K Stamatelopoulos, S Steinert, I Stetkarova, M Stiehm, R Stocker, J Stoinski, A Stoll, G Stotts, A Stumpp, P Sucapane, T Suenaga, X Sun, S Sundararajan, J Sung Kim, H Suzuki, N Svaneborg, G Szasz, W Szczuchniak, S Szczyrba, N Szegedi, A Szekely, Z Szewczyk, G Szilagyi, S Szlufik, K Szoboszlai, L Szpisjak, R Sztajzel, L Sztriha, SE Ta Wil, J Taggeselle, K Takamatsu, M Takao, W Taki, S Takizawa, M Talahma, A Tamayo, J Tan, D Tanne, A Tapanainen, T Tapiola, J Tarasiuk, T Tatlisumak, A Tayal, S Tcvetkova, P Teal, J Tejada Garcia, H Tejada Meza, D Tenora, M Terceno, A Terentiou, S Tezcan, D Thaler, A Thomson, E Thouvenot, M Tiainen, I Timberg, S Timsit, A Tinchon, D Tirschwell, C Togay Isikay, K Tokunaga, M Tolino, C Toloza, G Tomelleri, K Tomoyuki, LM Tomppo, Z Tong, L Tong, D Toni, J Torres, C Tossavainen, G Toth, A Tountopoulou, E Touze, M Tovar, K Toyoda, S Trillo, A Trommer, D Tropepi, D Tryambake, H Tu, S Tuetuencue, R Tumova, O Tumpula, G Turc, A Tutaj, J Tynkkynen, S Uchiyama, U Uchwat, L Uhrinyakova, R Ulku Acar, D Uluduz Ugurlu, X Urra, S Urui, M Usero Ruiz, D Vaclavik, K Vahedi, A Valikovics, J Valpas, P Van Acker, W Van Daele, G Vanderschueren, L Vanina Jure, R Varela, Z Varga, J Varvat, N Varvyanskaya, A Vasco Salgado, P Vasko, L Vass, S Vassilopoulou, I Vastagh, P Vazquez, L Vecsei, R Veltkamp, M Venti, M Verdugo, V Verocai, M Veronica Marroquin, C Veronica Simonsini, T Veverka, M Vigl, A Vila, C Vilar, JA Villanueva Osorio, J Virta, E Vitkova, B Voglsperger, J Volna, PA Von Weitzel-Mudersbach, N Vora, I Voznyuk, A Wach-Klink, A Wacongne, D Walters, Y Wang, J Wang, L Wang, X Wang, W Wang, N Wang, D Wang, H Wang, W Warnack, K Wartenberg, R Waters, M Waters, T Webb, J Weber, G Weiss, K Weissenborn, JI Weitz, B Weller, G Wen, G Weng, P Werner, D Werring, P Wester, W Whiteley, R Whiting, T Wijeratne, C Willems, L Wilson, C Wilson, T Winder, J Windt, A Winkler, A Winska-Tereszkiewicz, A Wisniewska, M Wittayer, A Wlodek, A Wojnarowska-Arendt, M Wolf, V Wolff, C Wolter, A Wong, H Wook Nah, H Worthmann, W Wu, S Wu, S Wunderlich, H Wurzinger, DG Wyse, B Xiao, W Xiaopeng, A Ximenez-Carrillo, L Xiong, Y Xiong, W Xiong, Y Xu, J Xu, Z Xu, B Yalo, T Yamada, M Yamasaki, L Yang, Y Yang, X Yang, Q Yang, B Yang, J Yang, I Yasuhiro, M Yee Lam, C Yegappan, S Yip, E Ylikallio, P Ylikotila, A Yongwon Jin, BW Yoon, Y Yoshida, L Yperzeele, H Yuan, H Yuasa, J Zalewska, C Zanferrari, E Zapata, D Zboznovits, I Zelenka, C Zhang, B Zhang, S Zhang, M Zhang, X Zhang, J Zhang, L Zhao, O Zhirnova, L Zhou, J Zielinska-Turek, I Zinchenko, M Ziomek, A Zitzmann, R Zweifler, J Zwiernik, Yperzeele, Laetitia, and NAVIGATE ESUS Investigators

Subjects
Male, International Cooperation, 030204 cardiovascular system & hematology, antiplatelet therapy, law.invention, Neurology (clinical), ischemic stroke, anticoagulation, Cohort Studies, 0302 clinical medicine, Randomized controlled trial, Rivaroxaban, law, Stroke, education.field_of_study, Aspirin, Anticoagulant, Settore BIO/14, Middle Aged, 3. Good health, Treatment Outcome, N/A, Cardiology, Platelet aggregation inhibitor, Settore MED/26 - Neurologia, Female, medicine.drug, medicine.medical_specialty, medicine.drug_class, MEDLINE, Population, Foramen Ovale, Patent, Subgroup analysis, Article, Statistics, Nonparametric, 03 medical and health sciences, Double-Blind Method, Internal medicine, medicine, Humans, education, Aged, business.industry, medicine.disease, Human medicine, business, 030217 neurology & neurosurgery, Platelet Aggregation Inhibitors, Factor Xa Inhibitors
Abstract

Background: \ud Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.\ud \ud Methods: \ud NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.\ud \ud Findings: \ud Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.\ud \ud Interpretation: \ud Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.\ud \ud Funding: \ud Bayer and Janssen.

Published
2018

25. Practice patterns and outcomes after stroke across countries at different economic levels (INTERSTROKE): An international observational study

Author

Peter Langhorne, Martin J O'Donnell, Siu Lim Chin, Hongye Zhang, Denis Xavier, Alvaro Avezum, Nandini Mathur, Melanie Turner, Mary Joan MacLeod, Patricio Lopez-Jaramillo, Albertino Damasceno, Graeme J Hankey, Antonio L Dans, Ahmed Elsayed, Charles Mondo, Mohammad Wasay, Anna Czlonkowska, Christian Weimar, Afzal Hussein Yusufali, Fawaz Al Hussain, Liu Lisheng, Hans-Christoph Diener, Danuta Ryglewicz, Nana Pogosova, Romana Iqbal, Rafael Diaz, Khalid Yusoff, Aytekin Oguz, Xingyu Wang, Ernesto Penaherrera, Fernando Lanas, Okechukwu S Ogah, Adesola Ogunniyi, Helle K Iversen, German Malaga, Zvonko Rumboldt, Daliwonga Magazi, Yongchai Nilanont, Annika Rosengren, Shahram Oveisgharan, Salim Yusuf, M. O'Donnell, S. Yusuf, S. Rangarajan, P. Rao-Melacini, X. Michelle Zhang, S. Islam, C. Kabali, A. Casanova, S.L. Chin, J. DeJesus, M. Dehghan, S. Agapay, M. McQueen, K. Hall, J. Keys, X. Wang, A. Devanath, R. Gupta, D. Prabhakaran, R. Diaz, P. Schygiel, M. Garrote, M.A. Rodriguez, A. Caccavo, R.G. Duran, L. Sposato, J. Molinos, P. Valdez, C.M. Cedrolla, P.G. Nofal, M.F. Huerta, P.M. Desmery, M.C. Zurru, B. Della Vedova, J. Varigos, G. Hankey, T. Kraemer, P. Gates, C. Bladin, G. Herkes, A. Avezum, M.P. Pereira, L. Minuzzo, L. Oliveira, M. Teixeira, H. Reis, A. Carvalho, S. Ouriques Martins, J.J. Carvalho, O. Gebara, C. Minelli, D.C. Oliveira, A.C. Sobral Sousa, A.C. Ferraz de Almeida, M.E. Hernandez, M. Friedrich, D.M. Mota, L.E. Ritt, D. Correa Vila Nova, P. Teal, D. Gladstone, A. Shuaib, F. Silver, D. Dowlatshahi, F. Lanas, D. Carcamo, C. Santibañez, E. Garces, L.S. Liu, H.Y. Zhang, H.P. Fang, M.F. Lian, F. Shen, F.X. Luo, X.X. Wen, Z.Q. Xu, Z.Z. Liu, W. Yan, J.F. Yu, W.K. Wang, L.H. Liu, Y.H. Sun, L.C. Zhou, Z.F. Zhang, J. LV, C.S. Zhang, G. Chen, H.L. Wang, Y. Chen, H. Zheng, J.J. Huang, W.Z. Li, L.J. Wang, J.X. Shi, C.Y. Hu, H.F. Song, R.Y. Ji, D.L. Wang, L.H. Meng, Q.W. Meng, L.J. Duan, H.F. Liu, Y.C. Luo, Q.Y. Zhang, Y.B. Wu, C.R. Wang, J.G. Zhao, S.G. Liu, C.L. Shi, X.Y. Wang, P. Lopez-Jaramillo, A. Martinez, G. Sanchez-Vallejo, D.I. Molina, T. Espinosa, H. Garcia Lozada, D. Gomez-Arbelaez, P.A. Camacho, Z. Rumboldt, I. Lusic, H.K. Iversen, T. Truelsen, C. Back, M.M. Pedersen, E. Peñaherrera, Y.C. Duarte, S. Cevallos, D. Tettamanti, S. Caceres, H.C. Diener, C. Weimar, A. Grau, J. Rother, M. Ritter, T. Back, Y. Winter, P. Pais, D. Xavier, A. Sigamani, N. Mathur, P. Rahul, A. Murali, A.K. Roy, G.R.K. Sarma, T. Matthew, G. Kusumkar, K.A. Salam, U. Karadan, L. Achambat, Y. Singh, J.D. Pandian, R. Verma, V. Atam, A. Agarwal, N. Chidambaram, R. Umarani, S. Ghanta, G.K. Babu, G. Sathyanarayana, G. Sarada, S. Navya Vani, R. Sundararajan, S.S. Sivakumar, R.S. Wadia, S. Bandishti, R.R. Agarwal, I. Mohan, S. Joshi, S. Kulkarni, S. Partha Saradhi, P. Joshi, M. Pandharipande, N. Badnerkar, R. Joshi, S.P. Kalantri, S. Somkumar, S. Chauhan, H. Singh, S. Varma, G.K. Sidhu, R. Singh, K.L. Bansal, A. Bharani, S. Pagare, A. Chouhan, B.N. Mahanta, T.G. Mahanta, G. Rajkonwar, S.K. Diwan, S.N. Mahajan, P. Shaikh, H.R. Devendrappa, B.K. Agrawal, A. Agrawal, D. Khurana, S. Thakur, V. Jain, S. Oveisgharan, A. Bahonar, R. Kelishadi, A. Hossienzadeh, M. Raeisidehkordi, H. Akhavan, T. Walsh, O. Albaker, K. Yusoff, A. Chandramouli, S. Shahadan, Z. Ibrahim, A. Husin, A. Damasceno, V. Lobo, S. Loureiro, V.A. Govo, O.S. Ogah, A. Ogunniyi, R.O. Akinyemi, M.O. Owolabi, M.U. Sani, L.F. Owolabi, R. Iqbal, M. Wasay, A. Raza, G.G. Malaga, M. Lazo-Porras, J.D. Loza-Herrera, A. Acuña-Villaorduña, D. Cardenas-Montero, A. Dans, E. Collantes, D. Morales, A. Roxas, M.V.C. Villarruz-Sulit, A. Czlonkowska, D. Ryglewicz, M. Skowronska, M. Restel, A. Bochynska, K. Chwojnicki, M. Kubach, A. Stowik, M. Wnuk, N. Pogosova, A. Ausheva, A. Karpova, V. Pshenichnikova, A. Vertkin, A. Kursakov, S. Boytsov, F. Al-Hussain, L. DeVilliers, D. Magazi, B. Mayosi, A.S.A. Elsayed, A. Bikhari, Z. Sawaraldahab, H. Hamad, M. ElTaher, A. Abdelhameed, M. Alawad, D. Alkabashi, H. Alsir, A. Rosengren, M. Andreasson, J. Kembro Johansson, B. Cederin, C. Schander, A.C. Elgasen, E. Bertholds, K. Boström Bengtsson, Y. Nilanont, S. Nidhinandana, P. Tatsanavivat, N. Paryoonwiwat, N. Poungvarin, N.C. Suwanwela, S. Tiamkao, R. Tulyapornchote, S. Boonyakarnkul, S. Hanchaiphiboolkul, S. Muengtaweepongsa, K. Watcharasaksilp, P. Sathirapanya, P. Pleumpanupat, A. Oguz, A.A. Akalin, O.T. Caklili, N. Isik, B. Caliskan, B. Sanlisoy, E. Balkuv, H. Tireli, V. Yayla, M. Cabalar, A. Culha, S. Senadim, B. Arpaci, C. Dayan, T. Argun, S. Yilmaz, S. Celiker, A. Kocer, T. Asil, G. Eryigit, C. Mondo, J. Kayima, M. Nakisige, S. Kitoleeko, A.M. Yusufali, B.J. Zuberi, H.Z. Mirza, A.A. Saleh, J.M. BinAdi, F. Hussain, P. Langhorne, K. Muir, M. Walters, C. McAlpine, S. Ghosh, A. Doney, S. Johnston, P. Mudd, T. Black, P. Murphy, D. Jenkinson, D. Kelly, R. Whiting, D. Dutta, L. Shaw, C. Mcfarlane, E. Ronald, and K. McBurnie

Subjects
Male, medicine.medical_specialty, MEDLINE, Medizin, Developing country, 030204 cardiovascular system & hematology, Health Services Accessibility, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, medicine, Humans, Practice Patterns, Physicians', Stroke, Developing Countries, Poverty, Aged, Evidence-Based Medicine, business.industry, Developed Countries, Case-control study, General Medicine, Evidence-based medicine, Middle Aged, medicine.disease, Survival Analysis, purl.org/pe-repo/ocde/ford#3.02.00 [https], Patient Outcome Assessment, Treatment Outcome, Family medicine, Case-Control Studies, Observational study, Female, Interstroke, business, Developed country, 030217 neurology & neurosurgery
Abstract

9 p., Background: Stroke disproportionately affects people in low-income and middle-income countries. Although improvements in stroke care and outcomes have been reported in high-income countries, little is known about practice and outcomes in low and middle-income countries. We aimed to compare patterns of care available and their association with patient outcomes across countries at different economic levels. Methods: We studied the patterns and effect of practice variations (ie, treatments used and access to services) among participants in the INTERSTROKE study, an international observational study that enrolled 13 447 stroke patients from 142 clinical sites in 32 countries between Jan 11, 2007, and Aug 8, 2015. We supplemented patient data with a questionnaire about health-care and stroke service facilities at all participating hospitals. Using univariate and multivariate regression analyses to account for patient casemix and service clustering, we estimated the association between services available, treatments given, and patient outcomes (death or dependency) at 1 month. Findings: We obtained full information for 12 342 (92%) of 13 447 INTERSTROKE patients, from 108 hospitals in 28 countries; 2576 from 38 hospitals in ten high-income countries and 9766 from 70 hospitals in 18 low and middle-income countries. Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p

Published
2018

26. Family-led rehabilitation after stroke in India (ATTEND): a randomised controlled trial

Author

R I Lindley, C S Anderson, L Billot, A Forster, M L Hackett, L A Harvey, S Jan, Q Li, H Liu, P Langhorne, P K Maulik, G V S Murthy, M F Walker, J D Pandian, M Alim, C Felix, A Syrigapu, D K Tugnawat, S J Verma, B R Shamanna, G Hankey, A Thrift, J Bernhardt, M M Mehndiratta, L Jeyaseelan, P Donnelly, D Byrne, S Steley, V Santhosh, S Chilappagari, J Mysore, J Roy, M V Padma, L John, S Aaron, N C Borah, P Vijaya, S Kaul, D Khurana, P N Sylaja, D S Halprashanth, B K Madhusudhan, V Nambiar, S Sureshbabu, M C Khanna, G S Narang, D Chakraborty, S S Chakraborty, B Biswas, S Kaura, H Koundal, P Singh, A Andrias, D S Thambu, I Ramya, J George, A T Prabhakar, P Kirubakaran, P Anbalagan, M Ghose, K Bordoloi, P Gohain, N M Reddy, K V Reddy, T N M Rao, S Alladi, V R R Jalapu, K Manchireddy, A Rajan, S Mehta, C Katoch, B Das, A Jangir, T Kaur, S Sreedharan, S Sivasambath, S Dinesh, B S Shibi, A Thangaraj, A Karunanithi, S M S Sulaiman, K Dehingia, K Das, C Nandini, N J Thomas, T S Dhanya, N Thomas, R Krishna, V Aneesh, S Khullar, S Thouman, and I Sebastian

Subjects
Adult, Male, medicine.medical_specialty, Activities of daily living, Adolescent, medicine.medical_treatment, India, Home Care Services, Hospital-Based, law.invention, 03 medical and health sciences, Disability Evaluation, Young Adult, 0302 clinical medicine, Randomized controlled trial, law, Modified Rankin Scale, Activities of Daily Living, medicine, Humans, Family, Single-Blind Method, 030212 general & internal medicine, Prospective Studies, Stroke, Aged, Aged, 80 and over, Rehabilitation, Intention-to-treat analysis, Family caregivers, business.industry, Stroke Rehabilitation, General Medicine, Middle Aged, medicine.disease, Clinical trial, Caregivers, Socioeconomic Factors, Physical therapy, Quality of Life, Educational Status, Female, business, 030217 neurology & neurosurgery
Abstract

Background: \ud \ud Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care in a low-resource setting.\ud \ud Methods: \ud \ud The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoint done across 14 hospitals in India. Patients aged 18 years or older who had had a stroke within the past month, had residual disability and reasonable expectation of survival, and who had an informal family-nominated caregiver were randomly assigned to intervention or usual care by site coordinators using a secure web-based system with minimisation by site and stroke severity. The family members of participants in the intervention group received additional structured rehabilitation training—including information provision, joint goal setting, carer training, and task-specific training—that was started in hospital and continued at home for up to 2 months. The primary outcome was death or dependency at 6 months, defined by scores 3–6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by masked observers. Analyses were by intention to treat. This trial is registered with Clinical Trials Registry-India (CTRI/2013/04/003557), Australian New Zealand Clinical Trials Registry (ACTRN12613000078752), and Universal Trial Number (U1111-1138-6707).\ud \ud Findings: \ud \ud Between Jan 13, 2014, and Feb 12, 2016, 1250 patients were randomly assigned to intervention (n=623) or control (n=627) groups. 33 patients were lost to follow-up (14 intervention, 19 control) and five patients withdrew (two intervention, three control). At 6 months, 285 (47%) of 607 patients in the intervention group and 287 (47%) of 605 controls were dead or dependent (odds ratio 0·98, 95% CI 0·78–1·23, p=0·87). 72 (12%) patients in the intervention group and 86 (14%) in the control group died (p=0·27), and we observed no difference in rehospitalisation (89 [14%]patients in the intervention group vs 82 [13%] in the control group; p=0·56). We also found no difference in total non-fatal events (112 events in 82 [13%] intervention patients vs 110 events in 79 [13%] control patients; p=0·80).\ud Interpretation: \ud \ud Although task shifting is an attractive solution for health-care sustainability, our results do not support investment in new stroke rehabilitation services that shift tasks to family caregivers, unless new evidence emerges. A future avenue of research should be to investigate the effects of task shifting to health-care assistants or team-based community care.\ud \ud Funding: \ud \ud The National Health and Medical Research Council of Australia.

Published
2017

27. Changes in polysialic acid expression on myeloid cells during differentiation and recruitment to sites of inflammation: Role in phagocytosis

Author

Kim G. Hankey, Alan S. Cross, Anne Jokilammi, Abderrahman El-Maarouf, Lei Zhang, Jukka Finne, Nicholas M. Stamatos, and Wilbur H. Chen

Subjects
Phagocytosis, Inflammation, Biology, ta3111, Biochemistry, Mice, chemistry.chemical_compound, Immune system, Cell Movement, medicine, Animals, Myeloid Cells, RNA, Messenger, chemistry.chemical_classification, Polysialic acid, Original Articles, CD56 Antigen, Hematopoiesis, Neuropilin-2, 3. Good health, Sialic acid, Cell biology, Mice, Inbred C57BL, medicine.anatomical_structure, chemistry, Immunology, Sialic Acids, Neural cell adhesion molecule, Bone marrow, medicine.symptom, Glycoprotein
Abstract

Polysialic acid (polySia) is a unique linear homopolymer of α2,8-linked sialic acid that has been studied extensively as a posttranslational modification of neural cell adhesion molecule in the central nervous system. Only two proteins are known to be polysialylated in cells of the immune system: CD56 on human natural killer cells and murine bone marrow (BM) leukocytes, and neuropilin-2 (NRP-2) on dendritic cells (DCs). We tested the hypothesis that polySia expression is regulated during maturation and migration of leukocytes and plays a role in functional activity. Using wild-type and NCAM(-/-) mice, we show that BM neutrophils express only polysialylated CD56, whereas a subset of BM monocytes expresses polysialylated CD56 and/or another polysialylated protein(s). We demonstrate that polysialylated CD56 expression is progressively down-regulated in wild-type monocytes and monocyte-derived cells during migration from BM through peripheral blood to pulmonary and peritoneal sites of inflammation. Freshly isolated monocyte-derived peritoneal macrophages are devoid of polySia yet re-express polySia on NRP-2 and an additional protein(s) after maintenance in culture. Removal of polySia from these cells enhances phagocytosis of Klebsiella pneumoniae, suggesting that down-regulation of polySia on macrophages facilitates bacterial clearance. Using wild-type and NRP-2(-/-) mice, we demonstrate that NRP-2 and an additional protein(s) are polysialylated by ST8 SiaIV in BM-derived DCs. We conclude that polySia expression in monocyte-derived cells is dynamically regulated by ST8 SiaIV activity and by expression of carrier proteins during recruitment to sites of inflammation and influences cellular interactions with microbes, contributing to innate and adaptive immune responses.

Published
2014

28. A non-human primate model of radiation-induced cachexia

Author

Alexander Bennett, Pei Zhang, Cassandra P. Smith, Sean R. Kearney, Wanchang Cui, Thomas J. MacVittie, Kim G. Hankey, Kory R. Barrow, Allison Gibbs, and Cheryl Taylor-Howell

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Cachexia, Time Factors, medicine.medical_treatment, Activin Receptors, Type II, Inflammation, Myostatin, Article, 03 medical and health sciences, Hemoglobins, 0302 clinical medicine, Weight loss, Internal medicine, Weight Loss, medicine, Animals, Humans, Muscle, Skeletal, Wasting, Serum Albumin, Retrospective Studies, Multidisciplinary, SKP Cullin F-Box Protein Ligases, biology, business.industry, Skeletal muscle, Dose-Response Relationship, Radiation, medicine.disease, Macaca mulatta, humanities, Radiation therapy, Dose–response relationship, Disease Models, Animal, Muscular Atrophy, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, Gamma Rays, 030220 oncology & carcinogenesis, biology.protein, medicine.symptom, business
Abstract

Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20–25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

Published
2016

29. Estimated GFR and the Effect of Intensive Blood Pressure Lowering After Acute Intracerebral Hemorrhage

Author

Danni Zheng, Shoichiro Sato, Hisatomi Arima, Emma Heeley, Candice Delcourt, Yongjun Cao, John Chalmers, Craig S. Anderson, C.S. Anderson, J. Chalmers, H. Arima, S. Davis, E. Heeley, Y. Huang, P. Lavados, B. Neal, M.W. Parsons, R. Lindley, L. Morgenstern, T. Robinson, C. Stapf, C. Tzourio, J.G. Wang, S. Chen, X.Y. Chen, L. Cui, Z. Liu, C. Lu, J. Wang, S. Wu, E. Xu, Q. Yang, C. Zhang, J. Zhang, R. Beer, E. Schmutzhard, P. Redondo, M. Kaste, L. Soinne, T. Tatlisumak, K. Wartenberg, S. Ricci, K. Klijn, E. Azevedo, A. Chamorro, M. Arnold, U. Fischer, S. Kaul, J. Pandian, H. Boyini, S. Singh, A.A. Rabinstein, C. Estol, G. Silva, V.V. Olavarria, T.G. Robinson, R.J. Simes, M.-G. Bousser, G. Hankey, K. Jamrozik, S.C. Johnston, S. Li, K. Bailey, T. Cheung, C. Delcourt, S. Chintapatla, E. Ducasse, T. Erho, J. Hata, B. Holder, E. Knight, M. Leroux, T. Sassé, E. Odgers, R. Walsh, Z. Wolfowicz, G. Chen, S. Fuentes, B. Peng, H.-M. Schneble, M.-X. Wang, L. Billot, S. Heritier, Q. Li, M. Woodward, S. Abimbola, S. Anderson, E. Chan, G. Cheng, P. Chmielnik, S. Leighton, J.-Y. Liu, B. Rasmussen, A. Saxena, S. Tripathy, M. Armenis, M.A. Baig, B. Naidu, G. Starzec, S. Steley, A. Moles, A. Ruiz, M. Zimmermann, J. Marinho, S. Alves, R. Angelim, J. Araujo, L. Kawakami, C. Bustos, F. Gonzalez, P. Munoz Venturelli, X. Chen, R. Jia, N. Li, S. Qu, Y. Shu, A. Song, J. Sun, J. Xiao, Y. Zhao, Q. Huang, E. Vicaut, A. Chamam, M.-C. Viaud, C. Dert, U. Fiedler, V. Jovis, S. Kabla, S. Marchand, A. Pena, V. Rochaud, K. Mallikarjuna, N. Hasan, E. Berge, E.C. Sandset, A.S. Forårsveen, D. Richardson, T. Kumar, S. Lewin, N. Poulter, J. Field, A. Anjum, A. Wilson, H. Perelmuter, A.M. Agarie, A.G. Barboza, L.A. Recchia, I.F. Miranda, S.G. Rauek, R.J. Duplessis, H. Dewey, L. Walker, S. Petrolo, C. Bladin, J. Sturm, D. Crimmins, D. Griffiths, A. Schutz, V. Zenteno, F. Miteff, N. Spratt, E. Kerr, C.R. Levi, T.G. Phan, H. Ma, L. Sanders, C. Moran, K. Wong, S. Read, R. Henderson, A. Wong, R. Hull, G. Skinner, P. Hand, B. Yan, H. Tu, B. Campbell, D.J. Blacker, T. Wijeratne, M. Pathirage, M. Jasinararchchi, Z. Matkovic, S. Celestino, F. Gruber, M.R. Vosko, E. Diabl, S. Rathmaier, B. Pfausler, R. Helbok, F. Fazekas, R. Fischer, B. Poltrum, B. Zechner, U. Trummer, M.P. Rutgers, A. Peeters, A. Dusart, M.-C. Duray, C. Parmentier, S. Ferrao-Santos, R. Brouns, S. De Raedt, A. De Smedt, R.-J. VanHooff, J. De Keyser, S.C.O. Martins, A.G. de Almeida, R. Broudani, N.F. Titton, G.R. de Freitas, F.M. Cardoso, L.M. Giesel, N.A. Lima, A.C. Ferraz de Almeida, R.B. Gomes, T.S. Borges dos Santos, E.M. Veloso Soares, O.L.A. Neto, G.S. Silva, D.L. Gomes, F.A. de Carvalho, M. Miranda, A. Marques, V.F. Zétola, G. de Matia, M.C. Lange, J. Montes, A. Reccius, A. Soto, R. Rivas, C. Klapp, S. Illanes, C. Aguilera, A. Castro, C. Figueroa, J. Benavides, P. Salamanca, M.C. Concha, J. Pajarito, P. Araya, F. Guerra, Y. Li, G. Liu, B. Wang, Y. Chong, M. He, L. Wang, J. Liu, X. Zhang, C. Lai, H. Jiang, S. Cui, Q. Tao, Y. Zhang, S. Yao, M. Xu, H. Xiao, J. Hu, J. Tang, H. Ji, M. Jiang, F. Yu, X. Yang, X. Guo, Y. Wang, L. Wu, Y. Gao, D. Sun, X. Huang, L. Liu, P. Li, Y. Jiang, H. Li, H. Lu, J. Zhou, C. Yuan, X. Qi, F. Qiu, H. Qian, W. Wang, W. Sun, F. Li, R. Liu, Q. Peng, Z. Ren, C. Fan, H. Wang, T. Wang, F. Shi, C. Duan, Z. Chen, X. Tan, Z. Zhao, J. Chen, T. Han, L. Zhang, Q. Hu, Q. Hou, X. Zhao, G. Zeng, L. Ma, F. Wang, L. Zeng, Z. Guo, Y. Fu, Y. Song, L. Tai, X. Liu, X. Su, Y. Yang, R. Dong, Y. Xu, S. Tian, S. Cheng, L. Su, X. Xie, T. Xu, D. Geng, X. Yan, H. Fan, N. Zhao, S. Wang, J. Yang, M. Yan, L. Li, Z. Li, X. Xu, Y. Lian, H. Sun, D. Liu, N. Wang, Q. Tang, Z. Han, L. Feng, Y. Cui, J. Tian, H. Chang, X. Sun, C. Liu, Z. Wen, Q. Lin, L. Sun, B. Hu, M. Zou, Q. Bao, X. Lin, L. Zhao, X. Tian, X. Wang, X. Li, L. Hao, Y. Duan, R. Wang, Z. Wei, S. Ren, H. Ren, Y. Dong, Y. Cheng, W. Liu, J. Han, Z. Zhang, J. Zhu, J. Qian, Y. Sun, K. Liu, F. Long, X. Peng, Q. Zhang, Z. Yuan, C. Wang, M. Huang, P. He, Y. You, J. Xia, L. Zhou, Y. Hou, Y. Qi, L. Mei, R. Lu, L. Ping, S. Zhou, S. Zhang, R. Zou, J. Guo, M. Li, W. Wei, S. Curtze, M. Saarela, D. Strbian, F. Scheperjans, T. De Broucker, C. Henry, R. Cumurciuc, N. Ibos-Augé, A.-C. Zéghoudi, F. Pico, O. Dereeper, M.-C. Simian, C. Boisselier, A. Mahfoud, S. Timsit, F.M. Merrien, B. Guillon, M. Sevin, F. Herisson, C. Magne, A. Ameri, C. Cret, S. Stefanizzi, F. Klapzcynski, C. Denier, M. Sarov-Riviere, P. Reiner, J. Mawet, D. Hervé, F. Buffon, E. Touzé, V. Domigo, C. Lamy, D. Calvet, M. Pasquini, S. Alamowitch, P. Favrole, I.-P. Muresan, S. Crozier, C. Rosso, C. Pires, A. Leger, S. Deltour, C. Cordonnier, H. Henon, C. Rossi, M. Zuber, M. Bruandet, R. Tamazyan, C. Join-Lambert, E. Juettler, T. Krause, S. Maul, M. Endres, G.J. Jungehulsing, M. Hennerici, M. Griebe, T. Sauer, K. Knoll, R. Huber, K. Knauer, C. Knauer, S. Raubold, H. Schneider, H. Hentschel, C. Lautenschläger, E. Schimmel, I. Dzialowski, C. Foerch, M. Lorenz, O. Singer, I.M.R. Meyer dos Santos, A. Hartmann, A. Hamann, A. Schacht, B. Schrader, A. Teíchmann, K.E. Wartenberg, T.J. Mueller, S. Jander, M. Gliem, C. Boettcher, M. Rosenkranz, C. Beck, D. Otto, G. Thomalla, B. Cheng, K.S. Wong, T.W. Leung, Y.O.Y. Soo, S. Prabhakar, S.R. Kesavarapu, P.K. Gajjela, R.R. Chenna, K. Ummer, M. Basheer, A. Andipet, M.K.M. Jagarlapudi, A.U.R. Mohammed, V.G. Pawar, S.S.K. Eranki, Y. Singh, N. Akhtar, N.C. Borah, M. Ghose, N. Choudhury, N.R. Ichaporia, J. Shendge, S. Khese, V. Pamidimukkala, P. Inbamuthaiah, S.R. Nuthakki, N.M.R. Tagallamudi, A.K. Gutti, D. Khurana, P. Kesavarapu, V. Jogi, A. Garg, D. Samanta, G.R.K. Sarma, R. Nadig, T. Mathew, M.A. Anandan, E. Caterbi, A. Zini, M. Cavazzuti, F. Casoni, R. Pentore, F. Falzone, T. Mazzoli, L.M. Greco, C. Menichetti, F. Coppola, S. Cenciarelli, E. Gallinella, A. Mattioni, R. Condurso, I. Sicilia, M. Zampolini, F. Corea, M. Barbi, C. Proietti, D. Toni, A. Pieroni, A. Anzini, A. Falcou, M. Demichele, C.J.M. Klijn, A. Tveiten, E.T. Thortveit, S. Pettersen, N. Holand, B. Hitland, S.H. Johnsen, A. Eltoft, M. Wasay, A. Kamal, A. Iqrar, L. Ali, D. Begum, G. Gama, L. Fonseca, G. Moreira, L.M. Veloso, D. Pinheiro, L. Paredes, C. Rozeira, T. Gregorio, T. Segura Martin, O. Ayo, J. Garcia-Garcia, I. Feria Vilar, I. Gómez Fernández, S. Amaro, X. Urra, V. Obach, A. Cervera, Y. Silva, J. Serena, M. Castellanos, M. Terceno, C. Van Eendenburg, A. Weck, O. Findling, R. Lüdi, E.A. Warburton, D. Day, N. Butler, E. Bumanlag, S. Caine, A. Steele, M. Osborn, E. Dodd, P. Murphy, B. Esisi, E. Brown, R. Hayman, V.K.V. Baliga, M. Minphone, J. Kennedy, I. Reckless, G. Pope, R. Teal, K. Michael, D. Manawadu, L. Kalra, R. Lewis, B. Mistry, E. Cattermole, A. Hassan, L. Mandizvidza, J. Bamford, H. Brooks, C. Bedford, R. Whiting, P. Baines, M. Hussain, M. Harvey, K. Fotherby, S. McBride, P. Bourke, D. Morgan, K. Jennings-Preece, C. Price, S. Huntley, V.E. Riddell, G. Storey, R.L. Lakey, G. Subramanian, D. Jenkinson, J. Kwan, O. David, D. Tiwari, M. James, S. Keenan, H. Eastwood, L. Shaw, P. Kaye, D. Button, B. Madigan, D. Williamson, A. Dixit, J. Davis, M.O. Hossain, G.A. Ford, A. Parry-Jones, V. O'Loughlin, R. Jarapa, Z. Naing, C. Lovelock, J. O'Reilly, U. Khan, A. Bhalla, A. Rudd, J. Birns, D.J. Werring, R. Law, R. Perry, I. Jones, R. Erande, C. Roffe, I. Natarajan, N. Ahmad, K. Finney, J. Lucas, A. Mistri, D. Eveson, R. Marsh, V. Haunton, J.E. Fugate, S.W. Lepore, Neurologian yksikkö, Clinicum, Neurology, Clinical sciences, Neuroprotection & Neuromodulation, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, and Vriendenkring VUB

Subjects
CHRONIC KIDNEY-DISEASE, Male, systolic blood pressure, medicine.medical_treatment, Blood Pressure, 030204 cardiovascular system & hematology, GLOMERULAR-FILTRATION-RATE, 3124 Neurology and psychiatry, RESISTANT HYPERTENSION, 0302 clinical medicine, Modified Rankin Scale, cerebral hemorrhage, cerebrovascular disease, chronic kidney disease (CKD), dialysis, estimated glomerular filtration rate (EGFR), hemodialysis, intensive blood pressure lowering treatment, INTERACT2, intracerebral hemorrhage (ICH), Kidney function, stroke, Stroke, education.field_of_study, OUTCOMES, estimated glomerular filtration rate (eGFR), Antihypertensive Agents/pharmacology, ASSOCIATION, Urology & Nephrology, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, PREVALENCE, Nephrology, Acute Disease, Female, Cerebral Hemorrhage/drug therapy, WHITE-MATTER, Glomerular Filtration Rate, STROKE PATIENTS, medicine.medical_specialty, RENAL-FUNCTION, LONG-TERM, Population, Renal function, Blood Pressure/drug effects, 03 medical and health sciences, Internal medicine, medicine, Humans, education, Dialysis, Antihypertensive Agents, Aged, Cerebral Hemorrhage, Intracerebral hemorrhage, business.industry, 1103 Clinical Sciences, medicine.disease, Surgery, Blood pressure, business, 030217 neurology & neurosurgery, Kidney disease
Abstract

Markku Kaste ja Filip Scheperjans työryhmän jäsenenä. Background: The kidney-brain interaction has been a topic of growing interest. Past studies of the effect of kidney function on intracerebral hemorrhage (ICH) outcomes have yielded inconsistent findings. Although the second, main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) suggests the effectiveness of early intensive blood pressure (BP) lowering in improving functional recovery after ICH, the balance of potential benefits and harms of this treatment in those with decreased kidney function remains uncertain. Study Design: Secondary analysis of INTERACT2, which randomly assigned patients with ICH with elevated systolic BP (SBP) to intensive (target SBP 90, 60-90, and Outcomes: The effect of admission eGFR on the primary outcome of death or major disability at 90 days (defined as modified Rankin Scale scores of 3-6) was analyzed using a multivariable logistic regression model. Potential effect modification of intensive BP lowering treatment by admission eGFR was assessed by interaction terms. Results: Of 2,623 included participants, 912 (35%) and 280 (11%) had mildly and moderately/severely decreased eGFRs, respectively. Patients with moderately/severely decreased eGFRs had the greatest risk for death or major disability at 90 days (adjusted OR, 1.82; 95% CI, 1.28-2.61). Effects of early intensive BP lowering were consistent across different eGFRs (P = 0.5 for homogeneity). Limitations: Generalizability issues arising from a clinical trial population. Conclusions: Decreased eGFR predicts poor outcome in acute ICH. Early intensive BP lowering provides similar treatment effects in patients with ICH with decreased eGFRs. Am J Kidney Dis. 68(1): 94-102. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the CC BY-NC-ND license.

Published
2015

30. National stroke association guidelines for the management of transient ischemic attacks

Author

S. C. Johnston, Louis R. Caplan, Robert G. Hart, Miriam E. Schwarz, Christina E Williams, Kate Fuller, Ralph L. Sacco, A. Algra, G. Hankey, S.A. Josephson, Ronald D. Brown, Peter J. Koudstaal, Steven R. Levine, Mai N. Nguyen-Huynh, Gregory W. Albers, Harold P. Adams, José Biller, Julien Bogousslavsky, J. van Gijn, L.J. Kappelle, Peter M. Rothwell, Neurology, and Cardiology

Subjects
medicine.medical_specialty, Health Planning Guidelines, media_common.quotation_subject, MEDLINE, Internal medicine, medicine, Humans, Quality (business), Transient (computer programming), Association (psychology), Stroke, media_common, business.industry, Conflict of interest, Evidence-based medicine, medicine.disease, United States, Surgery, Ophthalmology, Review Literature as Topic, Systematic review, Neurology, Ischemic Attack, Transient, Cardiology, Neurology (clinical), Medical emergency, business
Abstract

Objective: Transient ischemic attacks are common and important harbingers of subsequent stroke. Management varies widely, and most published guidelines have not been updated in several years. We sought to create comprehensive, unbiased, evidence-based guidelines for the management of patients with transient ischemic attacks. Methods: Fifteen expert panelists were selected based on objective criteria, using publication metrics that predicted nomination by practitioners in the field. Prior published guidelines were identified through systematic review, and recommendations derived from them were rated independently for quality by the experts. Highest quality recommendations were selected and subsequently edited by the panelists using a modified Delphi approach with multiple iterations of questionnaires to reach consensus on new changes. Experts were provided systematic reviews of recent clinical studies and were asked to justify wording changes based on new evidence and to rate the final recommendations based on level of evidence and quality. No expert was allowed to contribute to recommendations on a topic for which there could be any perception of a conflict of interest. Results: Of 257 guidelines documents identified by systematic review, 13 documents containing 137 recommendations met all entry criteria. Six iterations of questionnaires were required to reach consensus on wording of 53 final recommendations. Final recommendations covered initial management, evaluation, medical treatment, surgical treatment, and risk factor management. Interpretation: The final recommendations on the care of patients with transient ischemic attacks emphasize the importance of urgent evaluation and treatment. The novel approach used to develop these guidelines is feasible, allows for rapid updating, and may reduce bias.

Published
2006

31. How Do Stroke Units Improve Patient Outcomes?

Author

Martin Dennis, Heikki Palomäki, Rainer Fogelholm, Juhani Sivenius, T Strand, M Garraway, S WoodDauphinee, D Deleo, M Ilmavirta, Avril Drummond, Charles Warlow, Lalit Kalra, Jim Slattery, H Fraser, B.O. Williams, P. Berman, G. Hankey, Christian Blomstrand, Nadina B. Lincoln, A Svensson, Kjell Asplund, Richard Stevens, Lars Wilhelmsen, Peter Langhorne, Terttu Erilä, Carl Counsell, Elisabeth Hamrin, Bent Indredavik, Markku Kaste, and Helen Rodgers

Subjects
Advanced and Specialized Nursing, medicine.medical_specialty, Rehabilitation, business.industry, medicine.medical_treatment, Stroke units, Stroke unit care, Outcome (game theory), law.invention, Randomized controlled trial, law, Meta-analysis, Physical therapy, Medicine, Neurology (clinical), Cardiology and Cardiovascular Medicine, business
Abstract

Background and Purpose We sought to clarify the way in which organized inpatient (stroke unit) care can produce reductions in case fatality and in the need for institutional care after stroke. Methods We performed a secondary analysis of a collaborative systematic review of all randomized trials that compared organized inpatient (stroke unit) care with contemporary conventional care. Nineteen trials were included, of which 18 (3246 patients) could provide outcome data on death, place of residence, and final functional outcome. Data were less complete (but always available for at least 12 trials; 1611 patients) for subgroup analyses examining timing and cause of death and outcomes in patients with different levels of severity of initial stroke. Results The reduction in case fatality of patients managed in a stroke unit setting developed between 1 and 4 weeks after the index stroke. The reduction in the odds of death was evident across all causes of death and most marked for those deaths considered to be secondary to immobility. However, data were insufficient to permit a firm conclusion. The relative increase in the number of patients discharged home from stroke units as opposed to conventional care was largely attributable to an increase in the number of patients returning home physically independent. Across the range of stroke severity, stroke unit care was associated with nonsignificant increases in the number of patients regaining independence. Conclusions Within the limitations of the available data, we conclude that organized inpatient stroke unit care probably benefits a wide range of stroke patients in a variety of different ways, ie, reducing death from secondary complications of stroke and reducing the need for institutional care through a reduction in disability.

Published
1997

32. Therapeutic Response in Patients with Advanced Malignancies Treated with Combined Dendritic Cell–Activated T Cell Based Immunotherapy and Intensity–Modulated Radiotherapy

Author

Yukimasa Aoki, Kim G. Hankey, Dean L. Mann, Ryuko Watanabe, and Kenichiro Hasumi

Subjects
Cancer Research, Pathology, medicine.medical_specialty, medicine.medical_treatment, T cell, lcsh:RC254-282, Article, Cancer immunotherapy, medicine, dendritic cells, activated T-cells, combination immunotherapy, intratumoral injection, cancer vaccine, business.industry, Cancer, Dendritic cell, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, medicine.anatomical_structure, Oncology, Cancer research, Cancer vaccine, business, Adjuvant, Progressive disease
Abstract

Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

Published
2011
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33. Organised inpatient (stroke unit) care for stroke

Author

L. Kalra, Martin Dennis, N. L. Cabral, B.O. Williams, Lindsay Govan, G. Hankey, Elisabeth Hamrin, M. Britton, Christian Blomstrand, Graeme J. Hankey, Markku Kaste, S. O. Laursen, Bent Indredavik, P. Berman, Kjell Asplund, Christopher J. Weir, Paola Dey, A. Cavallini, and Peter Langhorne

Subjects
Patient Care Team, Medicine General & Introductory Medical Sciences, medicine.medical_specialty, Patient care team, 10 year follow up, business.industry, Stroke units, Rehabilitation unit, Stroke unit care, Prognosis, medicine.disease, law.invention, Stroke, Treatment Outcome, Randomized controlled trial, law, Emergency medicine, Ischemic stroke, medicine, Physical therapy, Humans, business, Hospital Units, Randomized Controlled Trials as Topic
Abstract

BACKGROUND: Organised stroke unit care is provided by multidisciplinary teams that exclusively manage stroke patients in a ward dedicated to stroke patients, with a mobile stroke team or within a generic disability service (mixed rehabilitation ward). OBJECTIVES: To assess the effect of stroke unit care compared with alternative forms of care for people following a stroke. SEARCH METHODS: We searched the trials registers of the Cochrane Stroke Group (January 2013) and the Cochrane Effective Practice and Organisation of Care (EPOC) Group (January 2013), MEDLINE (2008 to September 2012), EMBASE (2008 to September 2012) and CINAHL (1982 to September 2012). In an effort to identify further published, unpublished and ongoing trials, we searched 17 trial registers (January 2013), performed citation tracking of included studies, checked reference lists of relevant articles and contacted trialists. SELECTION CRITERIA: Randomised controlled clinical trials comparing organised inpatient stroke unit care with an alternative service. After formal risk of bias assessment, we have now excluded previously included quasi‐randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors initially assessed eligibility and trial quality. We checked descriptive details and trial data with the co‐ordinators of the original trials. MAIN RESULTS: We included 28 trials, involving 5855 participants, comparing stroke unit care with an alternative service. More‐organised care was consistently associated with improved outcomes. Twenty‐one trials (3994 participants) compared stroke unit care with care provided in general wards. Stroke unit care showed reductions in the odds of death recorded at final (median one year) follow‐up (odds ratio (OR) 0.81, 95% Confidence Interval (CI) 0.69 to 0.94; P = 0.005), the odds of death or institutionalised care (OR 0.78, 95% CI 0.68 to 0.89; P = 0.0003) and the odds of death or dependency (OR 0.79, 95% CI 0.68 to 0.90; P = 0.0007). Sensitivity analyses indicated that the observed benefits remained when the analysis was restricted to securely randomised trials that used unequivocally blinded outcome assessment with a fixed period of follow‐up. Outcomes were independent of patient age, sex, initial stroke severity or stroke type, and appeared to be better in stroke units based in a discrete ward. There was no indication that organised stroke unit care resulted in a longer hospital stay. AUTHORS' CONCLUSIONS: Stroke patients who receive organised inpatient care in a stroke unit are more likely to be alive, independent, and living at home one year after the stroke. The benefits were most apparent in units based in a discrete ward. We observed no systematic increase in the length of inpatient stay.

Published
2007

34. Services for reducing the duration of hospital care for acute stroke patients

Author

G. Hankey and Peter Langhorne

Subjects
Advanced and Specialized Nursing, medicine.medical_specialty, Rehabilitation, business.industry, medicine.medical_treatment, medicine.disease, Hospital care, law.invention, Randomized controlled trial, law, Acute care, Emergency medicine, medicine, Neurology (clinical), Medical emergency, Duration (project management), Cardiology and Cardiovascular Medicine, business, Developed country, Stroke, Acute stroke
Abstract

In most developed countries, stroke patients are admitted to hospital for a period of acute care and rehabilitation. Services have been developed to try and accelerate discharge home and reduce the duration of hospital stay. These have been termed early supported discharge (ESD) services. This review tested whether ESD services could reduce length of stay and improve patient outcome compared with conventional hospital care and discharge arrangements. We searched the Cochrane Specialist Register of Controlled Trials (to August 2004). The contact trialist of all eligible studies was then contacted and asked to provide details of their intervention and control services and to provide individual patient data. We included randomized controlled trials (RCTs) that compared an ESD service with conventional care for hospitalized stroke …

Published
2006

35. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015.

Author

Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, Ahmed M, Aksut B, Alam T, Alam K, Alla F, Alvis-Guzman N, Amrock S, Ansari H, Ärnlöv J, Asayesh H, Atey TM, Avila-Burgos L, Awasthi A, Banerjee A, Barac A, Bärnighausen T, Barregard L, Bedi N, Belay Ketema E, Bennett D, Berhe G, Bhutta Z, Bitew S, Carapetis J, Carrero JJ, Malta DC, Castañeda-Orjuela CA, Castillo-Rivas J, Catalá-López F, Choi JY, Christensen H, Cirillo M, Cooper L Jr, Criqui M, Cundiff D, Damasceno A, Dandona L, Dandona R, Davletov K, Dharmaratne S, Dorairaj P, Dubey M, Ehrenkranz R, El Sayed Zaki M, Faraon EJA, Esteghamati A, Farid T, Farvid M, Feigin V, Ding EL, Fowkes G, Gebrehiwot T, Gillum R, Gold A, Gona P, Gupta R, Habtewold TD, Hafezi-Nejad N, Hailu T, Hailu GB, Hankey G, Hassen HY, Abate KH, Havmoeller R, Hay SI, Horino M, Hotez PJ, Jacobsen K, James S, Javanbakht M, Jeemon P, John D, Jonas J, Kalkonde Y, Karimkhani C, Kasaeian A, Khader Y, Khan A, Khang YH, Khera S, Khoja AT, Khubchandani J, Kim D, Kolte D, Kosen S, Krohn KJ, Kumar GA, Kwan GF, Lal DK, Larsson A, Linn S, Lopez A, Lotufo PA, El Razek HMA, Malekzadeh R, Mazidi M, Meier T, Meles KG, Mensah G, Meretoja A, Mezgebe H, Miller T, Mirrakhimov E, Mohammed S, Moran AE, Musa KI, Narula J, Neal B, Ngalesoni F, Nguyen G, Obermeyer CM, Owolabi M, Patton G, Pedro J, Qato D, Qorbani M, Rahimi K, Rai RK, Rawaf S, Ribeiro A, Safiri S, Salomon JA, Santos I, Santric Milicevic M, Sartorius B, Schutte A, Sepanlou S, Shaikh MA, Shin MJ, Shishehbor M, Shore H, Silva DAS, Sobngwi E, Stranges S, Swaminathan S, Tabarés-Seisdedos R, Tadele Atnafu N, Tesfay F, Thakur JS, Thrift A, Topor-Madry R, Truelsen T, Tyrovolas S, Ukwaja KN, Uthman O, Vasankari T, Vlassov V, Vollset SE, Wakayo T, Watkins D, Weintraub R, Werdecker A, Westerman R, Wiysonge CS, Wolfe C, Workicho A, Xu G, Yano Y, Yip P, Yonemoto N, Younis M, Yu C, Vos T, Naghavi M, and Murray C

Subjects
Adult, Aged, Cause of Death trends, Female, Global Health, Humans, Male, Middle Aged, Morbidity trends, Prevalence, Prospective Studies, Retrospective Studies, Risk Factors, Sex Distribution, Survival Rate trends, Young Adult, Cardiovascular Diseases epidemiology, Life Expectancy trends, Risk Assessment methods
Abstract

Background: The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world., Objectives: The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden., Methods: CVD mortality was estimated from vital registration and verbal autopsy data. CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries. Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights. Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility., Results: In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths). Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0.75., Conclusions: CVDs remain a major cause of health loss for all regions of the world. Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions. Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2017
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36. Social support and subsequent disability: it is not the size of your network that counts.

Author

McLaughlin D, Leung J, Pachana N, Flicker L, Hankey G, and Dobson A

Subjects
Activities of Daily Living, Aged, Aged, 80 and over, Cohort Studies, Female, Geriatric Assessment, Health Surveys, Humans, Male, Prospective Studies, Residence Characteristics, Disability Evaluation, Outcome Assessment, Health Care, Social Support
Abstract

Background: high levels of social support and engagement may help sustain good health and functional ability. However, the definition of social support in previous research has been inconsistent and findings are mixed. The aim of this analysis was to explore the effect of two aspects of social support on subsequent disability in a group of community dwelling older women and men., Methods: data were drawn from two concurrent prospective observational cohort studies of community-based older Australian women (N = 2,013) and men (N = 680). Baseline and follow-up data were drawn from the second (1999) and fifth (2008) surveys of the women and the second (2001) and third (2008) surveys of the men. At baseline, social support was measured by the two subscales (social network and subjective support) of the Duke Social Support Index (DSSI). The outcome measure was Activities of Daily Living (ADLs) and Instrumental Activities of Daily Living (IADLs)., Results: overall, social network size was not associated with subsequent disability in either women or men. After adjusting for health status at baseline, lack of satisfaction with social support was associated with greater difficulties in ADLs and IADLs for both women and men., Conclusions: our results suggest that the provision of social support is insufficient to limit subsequent disability: support provided must be subjectively perceived to be relevant and adequate.

Published
2012
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37. Third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke.

Author

Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S, Venables G, Kobayashi A, Czlonkowska A, Berge E, Slot KB, Murray V, Peeters A, Hankey G, Matz K, Brainin M, Ricci S, Celani MG, Righetti E, Cantisani T, Gubitz G, Phillips S, Arauz A, Prasad K, Correia M, and Lyrer P

Abstract

Background: Intravenous recombinant tissue plasminogen activator (rt-PA) is approved for use in selected patients with ischaemic stroke within 3 hours of symptom onset. IST-3 seeks to determine whether a wider range of patients may benefit., Design: International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rt-PA in acute ischaemic stroke. Suitable patients must be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracerebral haemorrhage. With 1000 patients, the trial can detect a 7% absolute difference in the primary outcome. With 3500 patients, it can detect a 4.0% absolute benefit & with 6000, (mostly treated between 3 & 6 hours), it can detect a 3% benefit. TRIAL PROCEDURES: Patients are entered into the trial by telephoning a fast, secure computerised central randomisation system or via a secure web interface. Repeat brain imaging must be performed at 24-48 hours. The scans are reviewed 'blind' by expert readers. The primary measure of outcome is the proportion of patients alive and independent (Modified Rankin 0-2) at six months (assessed via a postal questionnaire mailed directly to the patient). Secondary outcomes include: events within 7 days (death, recurrent stroke, symptomatic intracranial haemorrhage), outcome at six months (death, functional status, EuroQol)., Trial Registration: ISRCTN25765518.

Published
2008
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39. Active and passive smoking and the risk of subarachnoid hemorrhage: an international population-based case-control study.

Author

Anderson CS, Feigin V, Bennett D, Lin RB, Hankey G, and Jamrozik K

Subjects
Australia epidemiology, Case-Control Studies, Comorbidity, Female, Humans, Incidence, Male, Middle Aged, Multivariate Analysis, New Zealand epidemiology, Odds Ratio, Risk Assessment, Risk Factors, Sex Factors, Smoking Cessation statistics & numerical data, Smoking epidemiology, Subarachnoid Hemorrhage epidemiology, Tobacco Smoke Pollution statistics & numerical data
Abstract

Background and Purpose: This study was undertaken to better clarify the risks associated with cigarette smoking and subarachnoid hemorrhage (SAH)., Methods: The study included 432 incident cases of SAH frequency matched to 473 community SAH-free controls to determine dose-dependent associations of active and passive smoking (at home) and smoking cessation with SAH., Results: Compared with never smokers not exposed to passive smoking, the adjusted odds ratio for SAH among current smokers was 5.0 (95% confidence interval [CI], 3.1 to 8.1); for past smokers, 1.2 (95% CI, 0.8 to 2.0); and for passive smokers, 0.9 (95% CI, 0.6 to 1.5). Current and lifetime exposures showed a clear dose-dependent effect, and risks appeared more prominent in women and for aneurysmal SAH. Approximately 1 in 3 cases of SAH could be attributed to current smoking, but risks decline quickly after smoking cessation, even among heavy smokers., Conclusions: A strong positive association was found between cigarette smoking and SAH, especially for aneurysmal SAH and women, which is virtually eliminated within a few years of smoking cessation. Large opportunities exist for preventing SAH through smoking avoidance and cessation programs.

Published
2004
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40. Triggers of subarachnoid hemorrhage: role of physical exertion, smoking, and alcohol in the Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS).

Author

Anderson C, Ni Mhurchu C, Scott D, Bennett D, Jamrozik K, and Hankey G

Subjects
Adult, Aged, Alcohol Drinking epidemiology, Australia epidemiology, Comorbidity, Cross-Over Studies, Female, Humans, Male, Middle Aged, New Zealand epidemiology, Odds Ratio, Registries statistics & numerical data, Risk Assessment, Smoking epidemiology, Subarachnoid Hemorrhage epidemiology, Urban Population statistics & numerical data, Alcohol Drinking adverse effects, Physical Exertion, Smoking adverse effects, Subarachnoid Hemorrhage etiology
Abstract

Background and Purpose: Unaccustomed strenuous physical exertion can trigger myocardial infarction, but little is known about the mechanisms precipitating subarachnoid hemorrhage (SAH)., Methods: We identified all cases of first-ever SAH among the combined populations (2.8 million) of 4 urban centers in Australia and New Zealand. Information on the type, time, and intensity of exposures in the 26 hours before the onset of SAH was ascertained by structured interviews. We used the case-crossover technique to assess the risk of SAH associated with transient exposures of moderate to extreme physical exertion, heavy cigarette smoking, and binge alcohol consumption., Results: We registered 432 first-ever cases of SAH (62% women; mean age, 56.5 years). A definite time of onset of SAH was established for 393 patients (91%), and information on the levels of physical activity in the preceding 26 hours was obtained in 338 (78%). Of these patients, 19% engaged in moderate to extreme exertion (>or=5 metabolic equivalents) in the 2 hours before SAH, which was associated with a tripling in the risk of SAH (odds ratio [OR], 2.7; 95% CI, 1.6 to 4.6). There was no evidence of any association between heavy cigarette smoking or binge drinking and risk of SAH in the subsequent 2 hours (OR, 1.1; 95% CI, 0.4 to 3.7; and OR, 0.41; 95% CI, - infinity to 5.3). Habitual exercise did not appear to alter the risk of SAH associated with moderate to extreme exertion., Conclusions: Moderate to extreme physical exertion tripled the risk of SAH, but there was no association between transient heavy smoking or binge drinking and risk of SAH. These data suggest that heavy physical activity may trigger SAH.

Published
2003
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41. Platelet glycoprotein Ibalpha Kozak polymorphism is associated with an increased risk of ischemic stroke.

Author

Baker RI, Eikelboom J, Lofthouse E, Staples N, Afshar-Kharghan V, López JA, Shen Y, Berndt MC, and Hankey G

Subjects
Aged, Brain Ischemia epidemiology, Brain Ischemia etiology, Brain Ischemia genetics, Case-Control Studies, Female, Gene Frequency, Genetic Testing, Genotype, Humans, Male, Middle Aged, Protein Subunits, Risk Factors, Stroke epidemiology, Stroke etiology, Tandem Repeat Sequences, Platelet Glycoprotein GPIb-IX Complex genetics, Polymorphism, Genetic, Stroke genetics
Abstract

Platelets are pivotal to the process of arterial thrombosis resulting in ischemic stroke. Occlusive thrombosis is initiated by the interaction of von Willebrand factor (vWf) and platelet glycoprotein (GP) Ibalpha. Three polymorphisms have been described in GP Ibalpha (Kozak T/C polymorphism, variable number of tandem repeats [VNTR], and the human platelet antigen 2a [HPA-2a] [Thr] or HPA-2b [Met] at position 145), each of which may enhance the vWf and GP Ibalpha interaction. This study investigated whether these polymorphisms are candidate genes for first-ever ischemic stroke. A hospital-based case-control study was conducted of 219 cases of first-ever ischemic stroke and 205 community controls randomly selected from the electoral roll and stratified by age, sex, and postal code. The subtypes of stroke were classified, the prevalence of conventional risk factors was recorded, and blood was collected to perform genotyping analysis for Kozak C or T alleles, VNTR, and HPA-2a/b. It was found that the Kozak T/C genotype was over-represented in the stroke group (32.2%) compared with controls (22.8%) (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.03-2.54; P <.03), and the association was still present even after adjusting for conventional risk factors. There was a trend in the increased prevalence of HPA-2a/b in stroke patients (15%) compared with controls (9.9%) (adjusted OR, 1.8; 95% CI, 0.94-3.4; P =.07). No associations were seen with the VNTR polymorphism or with any of the polymorphisms with stroke subtype. It was concluded that the Kozak T/C polymorphism, which is associated with an increase in platelet GP Ibalpha surface expression, is an independent risk factor for first-ever ischemic stroke.

Published
2001
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42. Hormonal factors and risk of aneurysmal subarachnoid hemorrhage: an international population-based, case-control study.

Author

Mhurchu CN, Anderson C, Jamrozik K, Hankey G, and Dunbabin D

Subjects
Age Distribution, Australia epidemiology, Breast Feeding statistics & numerical data, Case-Control Studies, Contraceptives, Oral adverse effects, Demography, Female, Hormone Replacement Therapy adverse effects, Humans, Male, Menstrual Cycle, Middle Aged, New Zealand epidemiology, Odds Ratio, Parity, Prospective Studies, Risk Assessment, Risk Factors, Sex Factors, Hormones adverse effects, Subarachnoid Hemorrhage diagnosis, Subarachnoid Hemorrhage epidemiology
Abstract

Background and Purpose: Subarachnoid hemorrhage (SAH) is more common in women than in men, but the role of hormonal factors in its etiology remains uncertain. The aim of this study was to examine the relationship between hormonal factors and risk of SAH in women., Methods: This was a prospective, multicenter, population-based, case-control study performed in 4 major urban centers in Australia and New Zealand. Two hundred sixty-eight female cases of first-ever aneurysmal SAH occurred during 1995-1998. Controls were 286 frequency-matched women from the general population of each center. Outcome measures included risk of SAH associated with use of oral contraceptive pills (OCPs), hormone replacement therapy (HRT), and various endogenous hormonal factors including menstrual patterns, parity, age at birth of first child, and breast-feeding practices., Results: Cases and controls did not differ with regard to menstrual and reproductive history except in age at birth of first child, where older age was associated with reduced risk of SAH (odds ratio [OR], 0.63; 95% CI, 0.43, 0.91). Relative to never use of HRT, the adjusted OR for ever use of HRT was 0.64 (95% CI, 0.41, 0.98), which did not alter significantly after further adjustment for possible confounding factors. Borderline evidence of an inverse association was detected for past use of HRT (adjusted OR, 0.59; 95% CI, 0.30, 1.13) and current use of HRT (adjusted OR, 0.67; 95% CI, 0.40, 1.13), but there was no evidence of an association for use of OCPs (adjusted OR, 0.97; 95% CI, 0.58, 1.60)., Conclusions: The risks of SAH are lower in women whose first pregnancy is at an older age and women who have ever used HRT but not OCPs. The findings suggest an independent etiologic role for hormonal factors in the pathogenesis of aneurysmal SAH and provide support for a protective role for HRT on risk of SAH in postmenopausal women.

Published
2001
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