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1. Discriminatory changes in circulating metabolites as a predictor of hepatocellular cancer in patients with MAFLD

Author

Haonan Lu, Jacob George, Mohammed Eslam, Augusto Villanueva, Luigi Bolondi, Helen L. Reeves, Misti McCain, Edward Chambers, Caroline Ward, Dewi Sartika, Caroline Sands, Lynn Maslen, Matthew R. Lewis, Ramya Ramaswami, and Rohini Sharma

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Objectives:The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterised by perturbations in lipid handling, inflammation and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC. Design:We assessed the profile of 273 lipid and small molecule metabolites by ultra‐performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-MS) in serum from patients with MAFLD (n=113) and MAFLD-associated HCC (n = 144) from six different centres. Regression models were used to identify a predictive model of HCC using minimal circulating features. Results:Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, successfully predicted the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789), which was enhanced with the addition of cirrhosis to the model (AUC 0.855). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p

Published
2022
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2. Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study

Author

Fiina Närhi, BMedSci, S Ramani Moonesinghe, ProfMD[Res], Susan D Shenkin, PhD, Thomas M Drake, MBChB, Rachel H Mulholland, MSci, Cara Donegan, BSc, Jake Dunning, PhD, Cameron J Fairfield, MBChB, Michelle Girvan, BSc, Hayley E Hardwick, Antonia Ho, PhD, Gary Leeming, BA, Jonathan S Nguyen-Van-Tam, ProfPhD, Riinu Pius, PhD, Clark D Russell, MBChB, Catherine A Shaw, PhD, Rebecca G Spencer, LLM, Lance Turtle, PhD, Peter J M Openshaw, ProfPhD, J Kenneth Baillie, ProfPhD, Ewen M Harrison, ProfPhD, Malcolm G Semple, ProfPhD, Annemarie B Docherty, PhD, J Kenneth Baillie, Malcolm G Semple, Peter JM Openshaw, Gail Carson, Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Kanta Chechi, Graham S Cooke, Ana da Silva Filipe, Thushan de Silva, Annemarie B Docherty, Gon¸alo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christopher A Green, William Greenhalf, Julian Griffin, Rishi K Gupta, Ewen M Harrison, Julian A Hiscox, Antonia YW Ho, Peter W Horby, Samreen Ijaz, Say Khoo, Paul Klenerman, Andrew Law, Matthew Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Alexander J Mentzer, Laura Merson, Alison M Meynert, Shona C Moore, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D Russell, Vanessa Sancho-Shimizu, Caroline Sands, Janet T Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Olivia V Swann, Zoltan Takats, Panteleimon Takis, Richard S Tedder, AA Roger Thompson, Emma C Thomson, Ryan S Thwaites, Lance CW Turtle, Maria Zambon, Hayley Hardwick, Chloe Donohue, Fiona Griffiths, Wilna Oosthuyzen, Cara Donegan, Rebecca G Spencer, Lisa Norman, Riinu Pius, Thomas M Drake, Cameron J Fairfield, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Catherine A Shaw, Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Daniel Plotkin, James Lee, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, Victoria Shaw, Sarah E McDonald, Seán Keating, Katie A. Ahmed, Jane A Armstrong, Milton Ashworth, Innocent G Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin WA Catterall, Jordan J Clark, Emily A Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis WS Fisher, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Rebecca L Jensen, Christopher B Jones, Trevor R Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S Miah, Joanna Middleton, Joyce Mitchell, Ellen G Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P. Matthew Ridley, Debby Sales, Victoria E Shaw, Rebecca K Shears, Benjamin Small, Krishanthi S Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. Eunice Zhang, Lisa Flaherty, Nicole Maziere, Emily Cass, Alejandra Doce Carracedo, Nicola Carlucci, Anthony Holmes, Hannah Massey, Lee Murphy, Sarah McCafferty, Richard Clark, Angie Fawkes, Kirstie Morrice, Alan Maclean, Nicola Wrobel, Lorna Donelly, Audrey Coutts, Katarzyna Hafezi, Louise MacGillivray, Tammy Gilchrist, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Sam Allen, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Colin Berry, Nicola Best, Pieter Bothma, David Chadwick, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Andrew Drummond, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Clive Graham, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Mariyam Mirfenderesky, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Lillian Norris, Matthew K. O'Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Tim Planche, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Bobby Ruge, Brendan Ryan, Taranprit Saluja, Matthias Schmid, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Manu Shankar-Hari, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Nick Vallotton, Rama Vancheeswaran, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Padmasayee Papineni, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Sarah Sarah, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wootton, Andrew Workman, Bryan Yates, and Peter Young

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Summary: Background: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. Methods: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. Findings: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. Interpretation: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. Funding: UK National Institute for Health Research and UK Medical Research Council.

Published
2022
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3. The impact of viral mutations on recognition by SARS-CoV-2 specific T cells

Author

Thushan I. de Silva, Guihai Liu, Benjamin B. Lindsey, Danning Dong, Shona C. Moore, Nienyun Sharon Hsu, Dhruv Shah, Dannielle Wellington, Alexander J. Mentzer, Adrienn Angyal, Rebecca Brown, Matthew D. Parker, Zixi Ying, Xuan Yao, Lance Turtle, Susanna Dunachie, Mala K. Maini, Graham Ogg, Julian C. Knight, Yanchun Peng, Sarah L. Rowland-Jones, Tao Dong, David M. Aanensen, Khalil Abudahab, Helen Adams, Alexander Adams, Safiah Afifi, Dinesh Aggarwal, Shazaad S.Y. Ahmad, Louise Aigrain, Adela Alcolea-Medina, Nabil-Fareed Alikhan, Elias Allara, Roberto Amato, Tara Annett, Stephen Aplin, Cristina V. Ariani, Hibo Asad, Amy Ash, Paula Ashfield, Fiona Ashford, Laura Atkinson, Stephen W. Attwood, Cressida Auckland, Alp Aydin, David J. Baker, Paul Baker, Carlos E. Balcazar, Jonathan Ball, Jeffrey C. Barrett, Magdalena Barrow, Edward Barton, Matthew Bashton, Andrew R. Bassett, Rahul Batra, Chris Baxter, Nadua Bayzid, Charlotte Beaver, Angela H. Beckett, Shaun M. Beckwith, Luke Bedford, Robert Beer, Andrew Beggs, Katherine L. Bellis, Louise Berry, Beatrice Bertolusso, Angus Best, Emma Betteridge, David Bibby, Kelly Bicknell, Debbie Binns, Alec Birchley, Paul W. Bird, Chloe Bishop, Rachel Blacow, Victoria Blakey, Beth Blane, Frances Bolt, James Bonfield, Stephen Bonner, David Bonsall, Tim Boswell, Andrew Bosworth, Yann Bourgeois, Olivia Boyd, Declan T. Bradley, Cassie Breen, Catherine Bresner, Judith Breuer, Stephen Bridgett, Iraad F. Bronner, Ellena Brooks, Alice Broos, Julianne R. Brown, Giselda Bucca, Sarah L. Buchan, David Buck, Matthew Bull, Phillipa J. Burns, Shirelle Burton-Fanning, Timothy Byaruhanga, Matthew Byott, Sharon Campbell, Alessandro M. Carabelli, James S. Cargill, Matthew Carlile, Silvia F. Carvalho, Anna Casey, Anibolina Castigador, Jana Catalan, Vicki Chalker, Nicola J. Chaloner, Meera Chand, Joseph G. Chappell, Themoula Charalampous, Wendy Chatterton, Yasmin Chaudhry, Carol M. Churcher, Gemma Clark, Phillip Clarke, Benjamin J. Cogger, Kevin Cole, Jennifer Collins, Rachel Colquhoun, Thomas R. Connor, Kate F. Cook, Jason Coombes, Sally Corden, Claire Cormie, Nicholas Cortes, Marius Cotic, Seb Cotton, Simon Cottrell, Lindsay Coupland, MacGregor Cox, Alison Cox, Noel Craine, Liam Crawford, Aidan Cross, Matthew R. Crown, Dorian Crudgington, Nicola Cumley, Tanya Curran, Martin D. Curran, Ana da Silva Filipe, Gavin Dabrera, Alistair C. Darby, Rose K. Davidson, Alisha Davies, Robert M. Davies, Thomas Davis, Daniela de Angelis, Elen De Lacy, Leonardo de Oliveira Martins, Johnny Debebe, Rebecca Denton-Smith, Samir Dervisevic, Rebecca Dewar, Jayasree Dey, Joana Dias, Donald Dobie, Matthew J. Dorman, Fatima Downing, Megan Driscoll, Louis du Plessis, Nichola Duckworth, Jillian Durham, Kirstine Eastick, Lisa J. Easton, Richard Eccles, Jonathan Edgeworth, Sue Edwards, Kate El Bouzidi, Sahar Eldirdiri, Nicholas Ellaby, Scott Elliott, Gary Eltringham, Leah Ensell, Michelle J. Erkiert, Marina Escalera Zamudio, Sarah Essex, Johnathan M. Evans, Cariad Evans, William Everson, Derek J. Fairley, Karlie Fallon, Arezou Fanaie, Ben W. Farr, Christopher Fearn, Theresa Feltwell, Lynne Ferguson, Laia Fina, Flavia Flaviani, Vicki M. Fleming, Sally Forrest, Ebenezer Foster-Nyarko, Benjamin H. Foulkes, Luke Foulser, Mireille Fragakis, Dan Frampton, Sarah Francois, Christophe Fraser, Timothy M. Freeman, Helen Fryer, Marc Fuchs, William Fuller, Kavitha Gajee, Katerina Galai, Abbie Gallagher, Eileen Gallagher, Michael D. Gallagher, Marta Gallis, Amy Gaskin, Bree Gatica-Wilcox, Lily Geidelberg, Matthew Gemmell, Iliana Georgana, Ryan P. George, Laura Gifford, Lauren Gilbert, Sophia T. Girgis, Sharon Glaysher, Emily J. Goldstein, Tanya Golubchik, Andrea N. Gomes, Sónia Gonçalves, Ian G. Goodfellow, Scott Goodwin, Salman Goudarzi, Marina Gourtovaia, Clive Graham, Lee Graham, Paul R. Grant, Luke R. Green, Angie Green, Jane Greenaway, Richard Gregory, Martyn Guest, Rory N. Gunson, Ravi K. Gupta, Bernardo Gutierrez, Sam T. Haldenby, William L. Hamilton, Samantha E. Hansford, Tanzina Haque, Kathryn A. Harris, Ian Harrison, Ewan M. Harrison, Jennifer Hart, John A. Hartley, William T. Harvey, Matthew Harvey, Mohammed O. Hassan-Ibrahim, Judith Heaney, Thomas Helmer, John H. Henderson, Andrew R. Hesketh, Jessica Hey, David Heyburn, Ellen E. Higginson, Verity Hill, Jack D. Hill, Rachel A. Hilson, Ember Hilvers, Matthew T.G. Holden, Amy Hollis, Christopher W. Holmes, Nadine Holmes, Alison H. Holmes, Richard Hopes, Hailey R. Hornsby, Myra Hosmillo, Catherine Houlihan, Hannah C. Howson-Wells, Jonathan Hubb, Hannah Huckson, Warwick Hughes, Joseph Hughes, Margaret Hughes, Stephanie Hutchings, Giles Idle, Chris J. Illingworth, Robert Impey, Dianne Irish-Tavares, Miren Iturriza-Gomara, Rhys Izuagbe, Chris Jackson, Ben Jackson, Leigh M. Jackson, Kathryn A. Jackson, David K. Jackson, Aminu S. Jahun, Victoria James, Keith James, Christopher Jeanes, Aaron R. Jeffries, Sarah Jeremiah, Andrew Jermy, Michaela John, Rob Johnson, Kate Johnson, Ian Johnston, Owen Jones, Sophie Jones, Hannah Jones, Christopher R. Jones, Neil Jones, Amelia Joseph, Sarah Judges, Gemma L. Kay, Sally Kay, Jon-Paul Keatley, Alexander J. Keeley, Anita Kenyon, Leanne M. Kermack, Manjinder Khakh, Stephen P. Kidd, Maimuna Kimuli, Stuart Kirk, Christine Kitchen, Katie Kitchman, Bridget A. Knight, Cherian Koshy, Moritz U.G. Kraemer, Sara Kumziene-Summerhayes, Dominic Kwiatkowski, Angie Lackenby, Kenneth G. Laing, Temi Lampejo, Cordelia F. Langford, Deborah Lavin, Andrew I. Lawton, Jack Lee, David Lee, Stefanie V. Lensing, Steven Leonard, Lisa J. Levett, Thanh Le-Viet, Jonathan Lewis, Kevin Lewis, Jennifier Liddle, Steven Liggett, Patrick J. Lillie, Michelle M. Lister, Rich Livett, Stephanie Lo, Nicholas J. Loman, Matthew W. Loose, Stavroula F. Louka, Katie F. Loveson, Sarah Lowdon, Hannah Lowe, Helen L. Lowe, Anita O. Lucaci, Catherine Ludden, Jessica Lynch, Ronan A. Lyons, Katrina Lythgoe, Nicholas W. Machin, George MacIntyre-Cockett, Andrew Mack, Ben Macklin, Alasdair Maclean, Emily Macnaughton, Pinglawathee Madona, Mailis Maes, Laurentiu Maftei, Adhyana I.K. Mahanama, Tabitha W. Mahungu, Daniel Mair, Joshua Maksimovic, Cassandra S. Malone, Daniel Maloney, Nikos Manesis, Robin Manley, Anna Mantzouratou, Angela Marchbank, Arun Mariappan, Inigo Martincorena, Rocio T. Martinez Nunez, Alison E. Mather, Patrick Maxwell, Megan Mayhew, Tamyo Mbisa, Clare M. McCann, Shane A. McCarthy, Kathryn McCluggage, Patrick C. McClure, J.T. McCrone, Martin P. McHugh, James P. McKenna, Caoimhe McKerr, Georgina M. McManus, Claire L. McMurray, Claire McMurray, Alan McNally, Lizzie Meadows, Nathan Medd, Oliver Megram, Mirko Menegazzo, Ian Merrick, Stephen L. Michell, Michelle L. Michelsen, Mariyam Mirfenderesky, Jeremy Mirza, Julia Miskelly, Emma Moles-Garcia, Robin J. Moll, Zoltan Molnar, Irene M. Monahan, Matteo Mondani, Siddharth Mookerjee, Christopher Moore, Jonathan Moore, Nathan Moore, Catherine Moore, Helen Morcrette, Sian Morgan, Mari Morgan, Matilde Mori, Arthur Morriss, Samuel Moses, Craig Mower, Peter Muir, Afrida Mukaddas, Florence Munemo, Robert Munn, Abigail Murray, Leanne J. Murray, Darren R. Murray, Manasa Mutingwende, Richard Myers, Eleni Nastouli, Gaia Nebbia, Andrew Nelson, Charlotte Nelson, Sam Nicholls, Jenna Nichols, Roberto Nicodemi, Kyriaki Nomikou, Justin O’Grady, Sarah O'Brien, Mina Odedra, Natasha Ohemeng-Kumi, Karen Oliver, Richard J. Orton, Husam Osman, xeine O'Toole, Nicole Pacchiarini, Debra Padgett, Andrew J. Page, Emily J. Park, Naomi R. Park, Surendra Parmar, David G. Partridge, David Pascall, Amita Patel, Bindi Patel, Steve Paterson, Brendan A.I. Payne, Sharon J. Peacock, Clare Pearson, Emanuela Pelosi, Benita Percival, Jon Perkins, Malorie Perry, Malte L. Pinckert, Steven Platt, Olga Podplomyk, Manoj Pohare, Marcus Pond, Cassie F. Pope, Radoslaw Poplawski, Jessica Powell, Jennifer Poyner, Liam Prestwood, Anna Price, James R. Price, Jacqui A. Prieto, David T. Pritchard, Sophie J. Prosolek, Georgia Pugh, Monika Pusok, Oliver G. Pybus, Hannah M. Pymont, Michael A. Quail, Joshua Quick, Clara Radulescu, Jayna Raghwani, Manon Ragonnet-Cronin, Lucille Rainbow, Diana Rajan, Shavanthi Rajatileka, Newara A. Ramadan, Andrew Rambaut, John Ramble, Paul A. Randell, Paul Randell, Liz Ratcliffe, Veena Raviprakash, Mohammad Raza, Nicholas M. Redshaw, Sara Rey, Nicola Reynolds, Alex Richter, David L. Robertson, Esther Robinson, Samuel C. Robson, Fiona Rogan, Stefan Rooke, Will Rowe, Sunando Roy, Steven Rudder, Chris Ruis, Steven Rushton, Felicity Ryan, Kordo Saeed, Buddhini Samaraweera, Christine M. Sambles, Roy Sanderson, Theo Sanderson, Fei Sang, Thea Sass, Emily Scher, Garren Scott, Carol Scott, Jasveen Sehmi, Sharif Shaaban, Divya Shah, Jessica Shaw, Ekaterina Shelest, James G. Shepherd, Liz A. Sheridan, Nicola Sheriff, Lesley Shirley, John Sillitoe, Siona Silviera, David A. Simpson, Aditi Singh, Dawn Singleton, Timofey Skvortsov, Tim J. Sloan, Graciela Sluga, Ken Smith, Kim S. Smith, Perminder Smith, Darren L. Smith, Louise Smith, Colin P. Smith, Nikki Smith, Katherine L. Smollett, Luke B. Snell, Thomas Somassa, Joel Southgate, Karla Spellman, Michael H. Spencer Chapman, Lewis G. Spurgin, Moira J. Spyer, Rachael Stanley, William Stanley, Thomas D. Stanton, Igor Starinskij, Joanne Stockton, Susanne Stonehouse, Nathaniel Storey, David J. Studholme, Malur Sudhanva, Emma Swindells, Yusri Taha, Ngee Keong Tan, Julian W. Tang, Miao Tang, Ben E.W. Taylor, Joshua F. Taylor, Sarah Taylor, Ben Temperton, Kate E. Templeton, Claire Thomas, Laura Thomson, Emma C. Thomson, Alicia Thornton, Scott A.J. Thurston, John A. Todd, Rachael Tomb, Lily Tong, Gerry Tonkin-Hill, M. Estee Torok, Jaime M. Tovar-Corona, Amy Trebes, Alexander J. Trotter, Ioulia Tsatsani, Robyn Turnbull, Katherine A. Twohig, Helen Umpleby, Anthony P. Underwood, Edith E. Vamos, Tetyana I. Vasylyeva, Sreenu Vattipally, Gabrielle Vernet, Barry B. Vipond, Erik M. Volz, Sarah Walsh, Dennis Wang, Ben Warne, Joanna Warwick-Dugdale, Elizabeth Wastnedge, Joanne Watkins, Louisa K. Watson, Sheila Waugh, Hermione J. Webster, Danni Weldon, Elaine Westwick, Thomas Whalley, Helen Wheeler, Mark Whitehead, Max Whiteley, Andrew Whitwham, Claudia Wierzbicki, Nicholas J. Willford, Lesley-Anne Williams, Rebecca Williams, Cheryl Williams, Chris Williams, Charlotte A. Williams, Rachel J. Williams, Thomas Williams, Catryn Williams, Kathleen A. Williamson, Eleri Wilson-Davies, Eric Witele, Karen T. Withell, Adam A. Witney, Paige Wolverson, Nick Wong, Trudy Workman, Victoria Wright, Derek W. Wright, Tim Wyatt, Sarah Wyllie, Li Xu-McCrae, Mehmet Yavus, Geraldine Yaze, Corin A. Yeats, Gonzalo Yebra, Wen C. Yew, Gregory R. Young, Jamie Young, Alex E. Zarebski, Peijun Zhang, J. Kenneth Baillie, Malcolm G. Semple, Peter J.M. Openshaw, Gail Carson, Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, Wendy S. Barclay, Debby Bogaert, Kanta Chechi, Graham S. Cooke, Annemarie B. Docherty, Gonçalo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christopher A. Green, William Greenhalf, Julian L. Griffin, Rishi K. Gupta, Ewen M. Harrison, Julian A. Hiscox, Antonia Ying Wai Ho, Peter W. Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Matthew R. Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Laura Merson, Alison M. Meynert, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A. Paxton, Georgios Pollakis, Nicholas Price, Clark D. Russell, Vanessa Sancho-Shimizu, Caroline J. Sands, Janet T. Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Olivia V. Swann, Zoltan Takats, Panteleimon Takis, Richard S. Tedder, A.A. Roger Thompson, Ryan S. Thwaites, Maria Zambon, Hayley Hardwick, Chloe Donohue, Fiona Griffiths, Wilna Oosthuyzen, Cara Donegan, Rebecca G. Spencer, Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Daniel Plotkin, James Lee, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, Victoria Shaw, Sarah E. McDonald, Seán Keating, Katie A. Ahmed, Jane A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L. Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin W.A. Catterall, Jordan J. Clark, Emily A. Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis W.S. Fisher, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Rebecca L. Jensen, Christopher B. Jones, Trevor R. Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A. Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S. Miah, Joanna Middleton, Joyce Mitchell, Ellen G. Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P. Matthew Ridley, Debby Sales, Victoria E. Shaw, Rebecca K. Shears, Benjamin Small, Krishanthi S. Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. Eunice Zhang, Lisa Flaherty, Nicole Maziere, Emily Cass, Alejandra Doce Carracedo, Nicola Carlucci, Anthony Holmes, Hannah Massey, Lee Murphy, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Sam Allen, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Colin Berry, Nicola Best, Pieter Bothma, David Chadwick, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Phil Donnison, Sam Douthwaite, Andrew Drummond, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B. Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Lillian Norris, Matthew K. O'Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Tim Planche, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Bobby Ruge, Brendan Ryan, Taranprit Saluja, Matthias L. Schmid, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Manu Shankar-Hari, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Nick Vallotton, Rama Vancheeswaran, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Padmasayee Papineni, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G. Wootton, Andrew Workman, Bryan Yates, and Peter Young

Subjects
Phylogenetics, Molecular biology, Immunology, Immune response, Virology, Science
Abstract

Summary: We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

Published
2021
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