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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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3. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author

S. Abiru, John F. Dillon, Yasuhiro Miyake, Piero Portincasa, Giancarlo Spinzi, R. Harvey, T. Ngatchu, Agostino Colli, M. Taniai, K. Flahive, Masanori Abe, B. Hoeroldt, S. Holder, Howard Curtis, María Isabel Colombo, C. MacNicol, Gang Xie, Andrew Chilton, H. Hussaini, Cristina Rigamonti, M. Kato, Shintaro Yagi, G. Abouda, D. Tyrer, Chris D. Evans, Christopher I. Amos, K. Koss, Kazuaki Chayama, P. Premchand, K. Migita, Simon Panter, Marco Marzioni, Silvia Colombo, Konstantinos N. Lazaridis, M. Yagura, Ashley Brown, D. Gocher, Domenico Alvaro, K. Murata, Mark Wright, Piero Luigi Almasio, C. Healey, A. Ciaccio, N. Wheatley, Vincenzo Cardinale, T. Delahooke, Chiara Milani, T. Shewan, W. Stableforth, S. Levi, Mark L. Green, James V. Jones, Y. Baird, Aftab Ala, Burroughs Ak, D. Williams, K. Ario, P. Sanghi, Hemant Gupta, P. Southern, L. Farrington, M. Hamilton, Andrew D. Higham, I. Yabuuchi, H. Yatsuhashi, Lorenzo Morini, T. Yamamoto, Douglas Thorburn, M. Carnahan, N. Nishida, Susan Slininger, M. Koga, K. Honda, Annarosa Floreani, Andrew Douglass, K. Netherton, M. Yasunami, Hirohito Tsubouchi, F. Donato, K. Walker, U. Shmueli, Paolo Muratori, Ray Mathew, J. Maiden, E. Dungca, Subramaniam Ramakrishnan, S. Vyas, Helen Sweeting, Subrata Saha, T. Komeda, T. Komatsu, H. J. Lee, Maria Consiglia Bragazzi, T. Komura, C. Thomas, C. Shallcross, C. Duggan, J. Kordula, F. Muscariu, Lourdes Cumlat, Imran Patanwala, Giulia Cardamone, L. Morgan, J. Brighton, Masao Honda, H. Nakamura, David Jones, Raj Srirajaskanthan, M. E. Gershwin, T. Muro, L. Stafford, N. Fukushima, Graham P. Butcher, Andrea Crosignani, George Lipscomb, K. Hirata, Y. Nagaoki, S. Mann, Paul G. Richardson, David A Elphick, M. Mupudzi, Y. Ohara, E. Grieve, Gayle Clifford, Claudio Tiribelli, M. Quinn, G. Van Duyvenvoorde, E. Archer, Tatsuki Ichikawa, J. Maltby, T. Arinaga-Hino, Simon Williams, A. King, Yasuni Nakanuma, H. Doyle, A. Brind, Nora Cazzagon, H. Ota, Daphne D’Amato, K. Hogben, H. Wooldridge, J. Wilkins, Shuichi Kaneko, L. Hankey, Gordon Wood, Andrew Fraser, K. Martin, A. Naqvi, M. Ninkovic, M. Patel, Yoshihiko Maehara, Kapil Kapur, I. Amey, Vincenza Calvaruso, Kenichi Harada, T. Yamashita, James Neuberger, N. Taylor, T. Lee, J. Featherstone, C. Lawlor, K. Seward, Satoshi Yamagiwa, Andrea Galli, L. Tan, Kentaro Kikuchi, K. Furuta, Mark A. Ainsworth, Hiromasa Ohira, Esther Unitt, Yosuke Kawai, N. Lancaster, D. Simpson, R. Shidrawi, I. Salam, A.J. Bell, Pietro Andreone, J. Ishida, Voi Shim Wong, N Fisher, Andrew C. Douds, R. Penn, Matthew Foxton, A. Watson, Andrew Mason, S. Walsh, Hiromi Ishibashi, Daniel M. Forton, Giovanni Casella, H. Takaki, K. Yamauchi, Pietro Lampertico, Osamu Yokosuka, M. Koda, M. Davies, H. Mitchison, P. Gyawali, G. Bird, M. Hughes, L. Jones, C. Hamilton, A. Hynes, R. Galaska, Fabio Marra, Debasish Das, C. Cowley, A. Fouracres, Yasuhiko Sugawara, E. Mita, T. Saoshiro, Akinobu Taketomi, Robert P. Myers, R. Przemioslo, F. Wright, L. Hobson, L. Currie, J. Allison, J. Hails, Noriyo Yamashiki, Massimo Zuin, C. Grimley, Alessio Gerussi, S. Besley, Stefano Duga, A. Piotrowicz, H. Kouno, L. Dali-kemmery, H. Sakai, M. Mizokami, Stefano Fagiuoli, Amy Davis, Pier Maria Battezzati, Masao Nagasaki, Luigi Muratori, A. Mori, S. Desmennu, S. Jones, R. Abrahams, Keith George, F. Makita, J. Brown, D. Gorard, Satoru Joshita, M. Mills, Pierluigi Toniutto, S. Campbell, J. Butterworth, S. Dyer, Filomena Morisco, Norihiro Kokudo, T. Yapp, C. Shorrock, Floriano Rosina, E. Walker, Shinji Uemoto, H. Takahashi, Simon M. Rushbrook, K. Amor, E. Marshall, J. Browning, S. Batham, Luca Fabris, Paul R. Banim, Meenakshi Narain, M. Harada, Dermot Gleeson, N. Hirashima, M. Kikuchi, T. Nikami, Gideon M. Hirschfield, Carlo Ferrari, G. Prasad, O. Chirag, Katsushi Tokunaga, M. Nasseri, Rosanna Asselta, Y. Lu, Ken Shirabe, D. Sirdefield, George F. Mells, K. Sugi, R. Ayres, G. Whatley, A. Singhal, M. Leoni, N. Sivaramakrishnan, T. Harding, Rupert Ransford, Anton V J Gunasekera, C. Mulvaney-Jones, D. Ramanaden, M. Mendall, Muhammad F. Dawwas, Dave Jones, Luca Valenti, Earl J. Williams, Markus Gess, Peter Bramley, A. McNair, E. Hashimoto, P. Townshend, C. Ford, Mario Strazzabosco, Luca Miele, Matthew J Brookes, J. Colley, Mark Wilkinson, H. Dewhurst, Charles Millson, E. Shpuza, Shinji Shimoda, T. Himoto, P. Kitchen, M. Nakamuta, Hiroaki Nishimura, Martin Lombard, Kevork M. Peltekian, M. Pitcher, G. Lim, L. Graves, C. Palmer, S. Lord, S. Katsushima, S. Tripoli, Andrew Austin, N. White, B. Grover, S. Congreave, M. Prince, Rebecca Jones, K. Hirano, A. Shepherd, Y. Mano, Michael A. Heneghan, Richard Sandford, L. O'Donohoe, Marco Carbone, S. A. Rolls, Patrick Goggin, M. L. Cowan, M. Crossey, A. Loftus, K. Young, Mesbah Rahman, Cameron N. Ghent, E. Nambela, M. Xiong, L. Grellier, Sunil Dolwani, Antonio Picciotto, Gill Watts, Alberto Mattalia, Elvezia Maria Paraboschi, J. Orpe, Takeji Umemura, Yuki Hitomi, Fiona H. Gordon, Shotaro Sakisaka, A. Dias, Chin Lye Ch'ng, M. Carter, A. Mandal, Yufang Shi, Takafumi Ichida, N. Masaki, M. Oblak, S. Nagaoka, Kevin Yoong, O. Gervais, Minoru Nakamura, Kazuhiko Nakao, S. Taylor-Robinson, L. Kent, Sushma Saksena, A. Affronti, K. Boulton, R. Ede, H. Pateman, K. Yoshizawa, G. Bray, H. Ebinuma, Yeng Ang, Akio Ido, John Ramage, Richard Sturgess, C. Gray, E. Durant, M. Hayes, A. Saeed, J. Keggans, J. Gitahi, T. Valliani, Edoardo G. Giannini, C. Foale, A. Palegwala, Lory Saveria Crocè, K. Matsushita, S. Shaukat, J. Mclindon, S. Pearson, A. Barnardo, A. Wright, Mirko Tarocchi, R Marley, M. Kent, C. Dickson, A. Gibbins, J. Whiteman, S. Singhal, Richard Aspinall, M. Ito, Laura Cristoferi, Maurizia Rossana Brunetto, J. Booth, A. Bathgate, Morikazu Onji, A. Grant, A. Paton, Y. Aiba, P. Chan, J. Sayer, S. Whalley, T. Mathialahan, J. Gotto, T. Kanda, B. Williams, K. Elliott, P. Raymode, Akinobu Takaki, V. Silvestre, I. Gee, C. Hovell, Graham R. Foster, D. Cotterill, G. 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Battezzati P.M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L.S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C.L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali F., Rees I., Salam I., Narain M., Brown A., Taylor-Robinson S., Williams S., Grellier L., Banim P., Das D., Chilton A., Heneghan M., Curtis H., Gess M., Drake I., Aldersley M., Davies M., Jones R., McNair A., Srirajaskanthan R., Pitcher M., Sen S., Bird G., Barnardo A., Kitchen P., Yoong K., Chirag O., Sivaramakrishnan N., MacFaul G., Jones D., Shah A., Evans C., Saha S., Pollock K., Bramley P., Mukhopadhya A., Fraser A., Mills P., Shallcross C., Campbell S., Bathgate A., Shepherd A., Dillon J., Rushbrook S., Przemioslo R., Macdonald C., Metcalf J., Shmueli U., Davis A., Naqvi A., Lee T., Ryder S.D., Collier J., Klass H., Ninkovic M., Cramp M., Sharer N., Aspinall R., Goggin P., Ghosh D., Douds A., Hoeroldt B., Booth J., Williams E., Hussaini H., Stableforth W., Ayres R., Thorburn D., Marshall E., Burroughs A., Mann S., Lombard M., Richardson P., Patanwala I., Maltby J., Brookes M., Mathew R., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Panter S., Shearman J., Bray G., Butcher G., Forton D., Mclindon J., Cowan M., Whatley G., Mandal A., Gupta H., Sanghi P., Jain S., Pereira S., Prasad G., Watts G., Wright M., Neuberger J., Gordon F., Unitt E., Grant A., Delahooke T., Higham A., Brind A., Cox M., Ramakrishnan S., King A., Collins C., Whalley S., Li A., Fraser J., Bell A., Wong V.S., Singhal A., Gee I., Ang Y., Ransford R., Gotto J., Millson C., Bowles J., Thomas C., Harrison M., Galaska R., Kendall J., Whiteman J., Lawlor C., Gray C., Elliott K., Mulvaney-Jones C., Hobson L., Van Duyvenvoorde G., Loftus A., Seward K., Penn R., Maiden J., Damant R., Hails J., Cloudsdale R., Silvestre V., Glenn S., Dungca E., Wheatley N., Doyle H., Kent M., Hamilton C., Braim D., Wooldridge H., Abrahams R., Paton A., Lancaster N., Gibbins A., Hogben K., Desousa P., Muscariu F., Musselwhite J., McKay A., Tan L., Foale C., Brighton J., Flahive K., Nambela E., Townshend P., Ford C., Holder S., Palmer C., Featherstone J., Nasseri M., 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G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S.-S., Gervais O., Migita K., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Higuchi N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Takikawa H., Ohira H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M.E., Seldin M.F., Invernizzi P., Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor-Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Ninkovic, M, Cramp, M, Sharer, N, Aspinall, R, Goggin, P, Ghosh, D, Douds, A, Hoeroldt, B, Booth, J, Williams, E, Hussaini, H, Stableforth, W, Ayres, R, Thorburn, D, Marshall, E, Burroughs, A, Mann, S, Lombard, M, Richardson, P, Patanwala, I, Maltby, J, Brookes, M, Mathew, R, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Panter, S, Shearman, J, Bray, G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Higuchi, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Takikawa, H, Ohira, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P, and LiveR North

Subjects
Canadian-US PBC Consortium, 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Disease, PBC, Settore MED/03 - GENETICA MEDICA, Linkage Disequilibrium, 0302 clinical medicine, UK-PBC Consortium, Genotype, Mitochondrial Precursor Protein Import Complex Proteins, Italian PBC Genetics Study Group, Odds Ratio, X-Wide Association Study, Japan PBC-GWAS Consortium, X chromosome, Genetics, Liver Cirrhosis, Biliary, Gastroenterology, Forkhead Transcription Factors, DNA-Binding Proteins, Shal Potassium Channels, 030211 gastroenterology & hepatology, Female, Adult, Monosaccharide Transport Proteins, Superenhancer, Locus (genetics), Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Proto-Oncogene Proteins, Endopeptidases, Humans, Cell Lineage, Genetic Predisposition to Disease, Meta-analysi, Genetic association, Chromosomes, Human, X, Gastroenterology & Hepatology, Hepatology, 1103 Clinical Sciences, Meta-analysis, 030104 developmental biology, Genetic Loci, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Carrier Proteins, Genome-Wide Association Study
Abstract

Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Published
2021

4. INHIBITION AND THE STIMULUS CONTROL OF OPERANT BEHAVIOR1

Author

G. William Farthing, Eliot Hearst, and Serena S. Besley

Subjects
Behavioral Neuroscience, Inhibitory control, Experimental and Cognitive Psychology, Neutral stimulus, Operant conditioning, Articles, Fear conditioning, Stimulus (physiology), Stimulus control, Psychology, Neuroscience
Abstract

A variety of methods, definitions, and theoretical notions that have been used in the study of inhibitory stimulus control were reviewed and evaluated. Preliminary data from several new operant methods were also described. It was proposed that future workers distinguish clearly between two forms of inhibitory control: (a) the learned power of a specific stimulus to reduce behavior, and (b) a dimensional effect, in which responding increases as values progressively more distant from the value of that specific stimulus along some dimension are presented (generalization gradient). Conclusions from several important recent studies were shown to be strongly dependent on the individual experimenter's criterion for deciding when a stimulus is inhibitory. The concept of inhibition seems a very valuable one for the field of operant behavior, and it deserves more attention than it has received in the past.

Published
1970

5. Sensitive method for the detection of experimental brain lesions

Author

Charles L. Sheridan and Serena S. Besley

Subjects
Cerebral Cortex, Male, Pathology, medicine.medical_specialty, business.industry, 05 social sciences, Experimental and Cognitive Psychology, Reversal Learning, 030229 sport sciences, 050105 experimental psychology, Sensory Systems, Rats, Discrimination Learning, Form Perception, 03 medical and health sciences, 0302 clinical medicine, Methods, Brain lesions, Medicine, Animals, 0501 psychology and cognitive sciences, business, Dominance, Cerebral, Ocular Physiological Phenomena
Abstract

Small anterior lesions were placed unilaterally in 7 albino rats whose opposite hemispheres had previously been trained in diametrically opposed pattern-discrimination habits. Performances mediated by the lesioned hemisphere were significantly impaired, implicating extrastriate anterior cortex in the mediation of pattern discrimination. Traditional methods entailing the use of far more massive anterior lesions have failed to detect similar effects.

Published
1973

6. Maintaining a High-Quality Screening Collection: The GSK Experience.

Author

Gomez-Sanchez R, Besley S, Quayle J, Green J, Warren-Godkin N, Areri I, and Zeliku Z

Subjects
Chromatography, Liquid, Dimethyl Sulfoxide, Humans, Mass Spectrometry, Quality Control, Solvents, Drug Industry methods, Drug Stability, Drug Storage methods, High-Throughput Screening Assays methods
Abstract

The storage of screening collections in DMSO is commonplace in the pharmaceutical industry. To ensure a high-quality screening collection, and hence effective and efficient high-throughput screening, all compounds entering the GlaxoSmithKline (GSK) screening collection undergo a liquid chromatography-mass spectrometry (LC-MS) quality control (QC). It is generally accepted that even under optimal conditions, a small percentage of these compounds are unstable after prolonged storage in DMSO. This article presents how these QC data can be mined using a data-driven clustering algorithm to identify chemical substructures likely to cause degradation in DMSO. This knowledge provides new structural filters for use in excluding compounds with these undesirable substructures from the collection. This information also suggests an efficient, targeted approach to compound collection clean-up initiatives. Stability studies are also designed to maintain a high-quality screening collection. To define the best practice for the storage and handling of solution samples, GSK has undertaken stability experiments for two decades, initially to support the implementation of new automated liquid stores and, subsequently, to enhance storage and use of compounds in solution through an understanding of compound degradation under storage and assay conditions.

Published
2021
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7. A direct-to-biology high-throughput chemistry approach to reactive fragment screening.

Author

Thomas RP, Heap RE, Zappacosta F, Grant EK, Pogány P, Besley S, Fallon DJ, Hann MM, House D, Tomkinson NCO, and Bush JT

Abstract

Methods for rapid identification of chemical tools are essential for the validation of emerging targets and to provide medicinal chemistry starting points for the development of new medicines. Here, we report a screening platform that combines 'direct-to-biology' high-throughput chemistry (D2B-HTC) with photoreactive fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates in 24 h and their subsequent screening as crude reaction products with a protein target without purification. Screening the HTC-PhABit library with carbonic anhydrase I (CAI) afforded 7 hits (0.7% hit rate), which were found to covalently crosslink in the Zn 2+ binding pocket. A powerful advantage of the D2B-HTC screening platform is the ability to rapidly perform iterative design-make-test cycles, accelerating the development and optimisation of chemical tools and medicinal chemistry starting points with little investment of resource., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Published
2021
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8. A Phenotypic Approach for the Identification of New Molecules for Targeted Protein Degradation Applications.

Author

Stacey P, Lithgow H, Lewell X, Konopacka A, Besley S, Green G, Whatling R, Law R, Röth S, Sapkota GP, Smith IED, Burley GA, Harling J, Benowitz AB, Queisser MA, and Muelbaier M

Subjects
Humans, Protein Binding, Small Molecule Libraries, Ubiquitin-Protein Ligases metabolism, Ubiquitination, Drug Discovery methods, Drug Evaluation, Preclinical methods, Proteolysis drug effects
Abstract

Targeted protein degradation is an emerging new strategy for the modulation of intracellular protein levels with applications in chemical biology and drug discovery. One approach to enable this strategy is to redirect the ubiquitin-proteasome system to mark and degrade target proteins of interest (POIs) through the use of proteolysis targeting chimeras (PROTACs). Although great progress has been made in enabling PROTACs as a platform, there are still a limited number of E3 ligases that have been employed for PROTAC design. Herein we report a novel phenotypic screening approach for the identification of E3 ligase binders. The key concept underlying this approach is the high-throughput modification of screening compounds with a chloroalkane moiety to generate HaloPROTACs in situ, which were then evaluated for their ability to degrade a GFP-HaloTag fusion protein in a cellular context. As proof of concept, we demonstrated that we could generate and detect functional HaloPROTACs in situ, using a validated Von Hippel-Lindau (VHL) binder that successfully degraded the GFP-HaloTag fusion protein in living cells. We then used this method to prepare and screen a library of approximately 2000 prospective E3 ligase-recruiting molecules.

Published
2021
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9. Method Development and Application of an Accelerated Solution Stability Screen for Drug Discovery.

Author

Gomez-Sanchez R, Besley S, Zeliku Z, and Young RJ

Subjects
Chromatography, Liquid, Drug Development standards, Drug Discovery standards, Drug Evaluation, Preclinical standards, Drug Stability, High-Throughput Screening Assays, Humans, Hydrogen-Ion Concentration, Mass Spectrometry, Oxidation-Reduction, Solubility, Solvents, Drug Development methods, Drug Discovery methods, Drug Evaluation, Preclinical methods
Abstract

An important aspect to understand about an experimental molecule in drug discovery is its stability in solution. A compound that degrades might be eliciting its apparent effect via a degradation product, so it is important to understand the solution stability profile of a compound early on in the drug discovery process. Improvements and application of a streamlined, higher-throughput method for testing solution stability to support drug discovery are described. Mass spectrometry detection has been incorporated into the screen to allow for the identification of degradation products. The amount of compound needed for the assay has been significantly reduced using 10 mM DMSO solutions instead of solid material. The buffers used in the screen provide the stability-pH profile of compounds with additional variations to assess liabilities under oxidizing and reducing conditions. In this article, we discuss the method development, screen validation, guidelines for result interpretation, and results for a set of marketed drugs to illustrate the application of the screen.

Published
2020
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10. Inhibition and the stimulus control of operant behavior.

Author

Hearst E, Besley S, and Farthing GW

Abstract

A variety of methods, definitions, and theoretical notions that have been used in the study of inhibitory stimulus control were reviewed and evaluated. Preliminary data from several new operant methods were also described. It was proposed that future workers distinguish clearly between two forms of inhibitory control: (a) the learned power of a specific stimulus to reduce behavior, and (b) a dimensional effect, in which responding increases as values progressively more distant from the value of that specific stimulus along some dimension are presented (generalization gradient). Conclusions from several important recent studies were shown to be strongly dependent on the individual experimenter's criterion for deciding when a stimulus is inhibitory. The concept of inhibition seems a very valuable one for the field of operant behavior, and it deserves more attention than it has received in the past.

Published
1970
Full Text
View/download PDF

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