Author: "Rishi K. Gupta" - Searchworks@Jio Institute Digital Library Search Results

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1. SARS-CoV-2 human challenge reveals biomarkers that discriminate early and late phases of respiratory viral infections

Author: Joshua Rosenheim, Rishi K. Gupta, Clare Thakker, Tiffeney Mann, Lucy C. K. Bell, Claire M. Broderick, Kieran Madon, Loukas Papargyris, Pete Dayananda, Andrew J. Kwok, James Greenan-Barrett, Helen R. Wagstaffe, Emily Conibear, Joe Fenn, Seran Hakki, Rik G. H. Lindeboom, Lisa M. Dratva, Briac Lemetais, Caroline M. Weight, Cristina Venturini, Myrsini Kaforou, Michael Levin, Mariya Kalinova, Alex J. Mann, Andrew Catchpole, Julian C. Knight, Marko Z. Nikolić, Sarah A. Teichmann, Ben Killingley, Wendy Barclay, Benjamin M. Chain, Ajit Lalvani, Robert S. Heyderman, Christopher Chiu, and Mahdad Noursadeghi
Subjects: Science
Abstract: Abstract Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27, shows a delayed but sustained response restricted to myeloid cells, attributable to gene and cell-specific epigenetic regulation. These findings are reproducible in experimental and naturally acquired infections with influenza, respiratory syncytial virus and rhinovirus. Blood MX1 expression is superior to IFI27 expression for diagnosis of early infection, as a correlate of viral load and for discrimination of virus culture positivity. Therefore, MX1 expression offers potential to stratify patients for antiviral therapy or infection control interventions. Blood IFI27 expression is superior to MX1 expression for diagnostic accuracy across the time course of symptomatic infection and thereby, offers higher diagnostic yield for respiratory virus infections that incur a delay between transmission and testing.
Published: 2024
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2. Clinical utility of WHO-recommended screening tools and development and validation of novel clinical prediction models for pulmonary tuberculosis screening among outpatients living with HIV: an individual participant data meta-analysis

Author: Ashar Dhana, Rishi K. Gupta, Yohhei Hamada, Andre P. Kengne, Andrew D. Kerkhoff, Christina Yoon, Adithya Cattamanchi, Byron W.P. Reeve, Grant Theron, Gcobisa Ndlangalavu, Robin Wood, Paul K. Drain, Claire J. Calderwood, Mahdad Noursadeghi, Tom Boyles, Graeme Meintjes, Gary Maartens, and David A. Barr
Subjects: Diseases of the respiratory system, RC705-779
Abstract: Background: The World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg·L−1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs). Methods: Following a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal–external cross-validation to evaluate performance. Results: We pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg·L−1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91% of tuberculosis cases and require confirmatory testing for 78% of participants. CRP (5 mg·L−1 cut-off), the extended CPM (4.2% threshold) and the CRP-only CPM (3.6% threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36%, respectively. Conclusions: CRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg·L−1 cut-off or in a CPM depends on available resources.
Published: 2023
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3. Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysisResearch in context

Author: Yohhei Hamada, Rishi K. Gupta, Matteo Quartagno, Abbie Izzard, Carlos Acuna-Villaorduna, Neus Altet, Roland Diel, Jose Dominguez, Sian Floyd, Amita Gupta, Helena Huerga, Edward C. Jones-López, Aarti Kinikar, Christoph Lange, Frank van Leth, Qiao Liu, Wei Lu, Peng Lu, Irene Latorre Rueda, Leonardo Martinez, Stanley Kimbung Mbandi, Laura Muñoz, Elisabeth Sánchez Padilla, Mandar Paradkar, Thomas Scriba, Martina Sester, Kwame Shanaube, Surendra K. Sharma, Rosa Sloot, Giovanni Sotgiu, Kannan Thiruvengadam, Richa Vashishtha, Ibrahim Abubakar, and Molebogeng X. Rangaka
Subjects: LTBI, IGRA, Tuberculin skin test, Prophylaxis, Prevention, Medicine (General), R5-920
Abstract: Summary: Background: Evidence on the comparative performance of purified protein derivative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA) for predicting incident active tuberculosis (TB) remains conflicting. We conducted an individual participant data meta-analysis to directly compare the predictive performance for incident TB disease between TST and IGRA to inform policy. Methods: We searched Medline and Embase from 1 January 2002 to 4 September 2020, and studies that were included in previous systematic reviews. We included prospective longitudinal studies in which participants received both TST and IGRA and estimated performance as hazard ratios (HR) for the development of all diagnoses of TB in participants with dichotomised positive test results compared to negative results, using different thresholds of positivity for TST. Secondary analyses included an evaluation of the impact of background TB incidence. We also estimated the sensitivity and specificity for predicting TB. We explored heterogeneity through pre-defined sub-group analyses (e.g. country-level TB incidence). Publication bias was assessed using funnel plots and Egger's test. This review is registered with PROSPERO, CRD42020205667. Findings: We obtained data from 13 studies out of 40 that were considered eligible (N = 32,034 participants: 36% from countries with TB incidence rate ≥100 per 100,000 population). All reported data on TST and QuantiFERON Gold in-Tube (QFT-GIT). The point estimate for the TST was highest with higher cut-offs for positivity and particularly when stratified by bacillus Calmette–Guérin vaccine (BCG) status (15 mm if BCG vaccinated and 5 mm if not [TST5/15 mm]) at 2.88 (95% CI 1.69–4.90). The pooled HR for QFT-GIT was higher than for TST at 4.15 (95% CI 1.97–8.75). The difference was large in countries with TB incidence rate
Published: 2023
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4. Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study

Author: Ewan Carr, Rebecca Bendayan, Daniel Bean, Matt Stammers, Wenjuan Wang, Huayu Zhang, Thomas Searle, Zeljko Kraljevic, Anthony Shek, Hang T. T. Phan, Walter Muruet, Rishi K. Gupta, Anthony J. Shinton, Mike Wyatt, Ting Shi, Xin Zhang, Andrew Pickles, Daniel Stahl, Rosita Zakeri, Mahdad Noursadeghi, Kevin O’Gallagher, Matt Rogers, Amos Folarin, Andreas Karwath, Kristin E. Wickstrøm, Alvaro Köhn-Luque, Luke Slater, Victor Roth Cardoso, Christopher Bourdeaux, Aleksander Rygh Holten, Simon Ball, Chris McWilliams, Lukasz Roguski, Florina Borca, James Batchelor, Erik Koldberg Amundsen, Xiaodong Wu, Georgios V. Gkoutos, Jiaxing Sun, Ashwin Pinto, Bruce Guthrie, Cormac Breen, Abdel Douiri, Honghan Wu, Vasa Curcin, James T. Teo, Ajay M. Shah, and Richard J. B. Dobson
Subjects: NEWS2 score, Blood parameters, COVID-19, Prediction model, Medicine
Abstract: Abstract Background The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. Methods Training cohorts comprised 1276 patients admitted to King’s College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy’s and St Thomas’ Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. Results A baseline model of ‘NEWS2 + age’ had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. Conclusions NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.
Published: 2021
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5. 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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6. Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study

Author: David Price, Mark Roberts, Andrew Walden, Jason Kendall, Clark D Russell, Natalie Pattison, Daniel B Hawcutt, George Koshy, Adam Finn, Ellen G Murphy, Ewen M Harrison, Maria Zambon, Michael Murphy, Tom Solomon, Carrol Gamble, Laura Marsh, Nicholas Barrett, Nigel Chee, Paul Dark, Clive Graham, Andrew Law, Richard J Mellanby, Gail Carson, Jake Dunning, Laura Merson, Ingeborg Welters, Stephen R Knight, Thomas M Drake, Tamas Szakmany, Robert Thompson, Richard Smith, Ian Handel, Kenneth A McLean, Sam Douthwaite, David Baxter, Patrick Lillie, Dougal Atkinson, Chris Dunn, James Moon, Paul Klenerman, Catherine Hartley, Mandeep Phull, Pieter Bothma, Craig Morris, Adam Wolverson, Ana Alegria, Lawrence Wilson, Susan Jain, James Limb, Vanessa Linnett, Chris Dawson, Jason Cupitt, Sam Waddy, Guy Rousseau, Andrew Burtenshaw, Devender Roberts, Samreen Ijaz, Mark Nelson, Anthony Evans, Meera Chand, Wei Shen Lim, Catherine A Shaw, Cameron J Fairfield, Timothy S Walsh, Anil Hormis, Peter W Horby, Marlies Ostermann, Tim Reynolds, Mark Lyttle, Bryan Yates, Chloe Donohue, Anil Sharma, Jenny Child, Elaine Hardy, Julian A Hiscox, Debby Bogaert, Richard Stewart, Martin Williams, Adriano G Rossi, Catherine Cosgrove, David M Griffith, William Greenhalf, Thapas Nagarajan, Saye Khoo, Annemarie B Docherty, Christopher A Green, Hayley E Hardwick, Riinu Pius, Lisa Norman, Louise Sigfrid, Sophie Halpin, Clare Jackson, J Kenneth Baillie, Malcolm G Semple, Manu Shankar-Hari, Carlo Palmieri, Lance Turtle, Stuart Hartshorn, Rishi K Gupta, Tom Fletcher, Michelle Girvan, Peter J M Openshaw, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Graham S Cooke, Alexander J Mentzer, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Vanessa Sancho-Shimizu, Janet T Scott, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, Ryan S Thwaites, Lance C W Turtle, Hayley Hardwick, Wilna Oosthuyzen, Fiona Griffiths, Derek Murphy, Jo Dalton, Egle Saviciute, Stephanie Roberts, Janet Harrison, Marie Connor, Gary Leeming, Ross Hendry, Victoria Shaw, Sarah McDonald, Katie A Ahmed, Jane A Armstrong, Milton Ashworth, Innocent G Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Jordan J Clark, Emily A Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Philip Dyer, Angela Elliott, Lewis W S Fisher, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Rebecca L Jensen, Christopher B Jones, Trevor R Jones, Shadia Khandaker, Katharine King, Robyn T Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S Miah, Joanna Middleton, Joyce Mitchell, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Debby Sales, Victoria E Shaw, Rebecca K Shears, Benjamin Small, Krishanthi S Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jordan Thomas, Erwan Trochu, Eve Wilcock, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Brian Angus, Abdul Ashish, Shahedal Bari, Gavin Barlow, Stella Barnass, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Nicola Best, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Vikki Caruth, David Chadwick, Duncan Chambler, Srikanth Chukkambotla, Tom Clark, Paul Collini, Maria-Teresa Cutino-Moguel, Samir Dervisevic, Phil Donnison, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Duncan Fullerton, Sanjeev Garg, Atul Garg, Jo Godden, Arthur Goldsmith, Daniel Harvey, Peter Havalda, Maria Hobrok, Luke Hodgson, Michael Jacobs, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, Shondipon Laha, Susan Larkin, Tamas Leiner, Jeff Little, 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, Elinoor Moore, Patrick Morgan, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Megan Nagel, Igor Otahal, Mark Pais, Selva Panchatsharam, Hassan Paraiso, Brij Patel, Justin Pepperell, Mark Peters, Stefania Pintus, Jagtur Singh Pooni, Frank Post, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Neil Richardson, Alistair Rose, Brendan Ryan, Taranprit Saluja, Aarti Shah, Prad Shanmuga, Anna Shawcross, Jeremy Sizer, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Pradeep Subudhi, Kate Tatham, Jo Thomas, Chris Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Andrew Ustianowski, Nick Vallotton, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Rachel Wake, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Meme Wijesinghe, Stephen Winchester, Martin Wiselka, Andrew Workman, Peter Young, James Scott-Brown, Will Reynolds, Jolanta Tanianis-Hughes, Chrisopher Fegan, Danai Papakonstantinou, Effrossyni Gkrania-Klotsas, Kerri Devine, Daniel G Wootton, Padmasayee Papineni, Benjamin W A Catterall, Lara Lavelle-Langham, Emily Cass, Alejandra Doce Carracedo, Lisa Flaherty, Nicole Maziere, Hannah Massey, Anthony Holmes, Nicola Carlucci, Matthew K O'Shea, Libby van Tonder, Emma A Hurst, Natalie Z Homer, Scott G Denham, Paul A Holloway, Romit J Samanta, Ana da Silva Filipe, Thushan de Silva, A A Roger Thompson, Ruth Lyons, Murray Wham, Sara Clohisey, Sara McDonald, Seán Keating, Lorna Finch, P Matthew Ridley, J Eunice Zhang, Lee Murphy, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean, Erin L Aldera, Sneha Basude, Steven Laird, and Antonia Ying Wai Ho
Subjects: Medicine
Abstract: Objectives The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors.Design Cross-sectional study.Setting and participants Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009–2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples.Outcome measures Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality.Results Vitamin D insufficiency (total 25(OH)D 25–50 nmol/L) and deficiency (
Published: 2021
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7. The diagnostic performance of novel skin-based in-vivo tests for tuberculosis infection compared with purified protein derivative tuberculin skin tests and blood-based in vitro interferon-γ release assays: a systematic review and meta-analysis

Author: Lena Faust, Molebogeng X Rangaka, Alberto Mateelli, Yohhei Hamada, Daniela Maria Cirillo, Alexei Korobitsyn, Rishi K Gupta, Vladyslav Nikolayevskyy, Claudia M. Denkinger, and Maria Krutikov
Subjects: Purified protein derivative, medicine.medical_specialty, Tuberculosis, Tuberculin Test, business.industry, Tuberculin, HIV Infections, medicine.disease, Sensitivity and Specificity, In vivo tests, QuantiFERON, Infectious Diseases, Latent Tuberculosis, Meta-analysis, Internal medicine, Cohort, BCG Vaccine, Humans, Medicine, Population study, Child, business, Interferon-gamma Release Tests
Abstract: Summary Background Novel skin-based tests for tuberculosis infection might present suitable alternatives to current tests; however, diagnostic performance of new tests compared with the purified protein derivative-tuberculin skin test (TST) or interferon-γ release assays (IGRA) needs systematic assessment. Methods In this systematic review and meta-analysis, we searched English (Medline OVID), Chinese (Chinese Biomedical Literature Database and the China National Knowledge Infrastructure), and Russian (e-library) databases from the inception of each database to May 15, 2019, (with updated search of the Russian and English databases on Oct, 20 2020) using terms “ESAT6” OR “CFP10” AND “skin test” AND “Tuberculosis” OR “C-Tb” OR “Diaskintest”. We included studies reporting on the performance of index tests alone or compared with a comparator. Inclusion criteria varied according to review objectives and performance outcome, but reporting of test cut-offs for positivity applied to study population was required from all studies. We used a hierarchy of reference standards for tuberculosis infection consistent with the 2020 WHO framework to evaluate diagnostic performance. Two authors independently reviewed the titles and abstracts for English and Chinese (LF and MK) and Russian studies (MK and VN). Study quality was assessed with QUADAS-2. Pooled random-effects estimates are presented when appropriate for total agreement proportion, sensitivity in microbiologically confirmed tuberculosis and specificity in cohorts with low risk of tuberculosis infection. This study is registered with PROSPERO, CRD42019135572. Findings We identified 1466 original articles, of which 37 (2·5%) studies, including 10 915 individuals (7111 Diaskintest, 2744 C-Tb, 887 EC, 173 DPPD), were included in the qualitative analysis (29 [78%] studies of Diaskintest, five [15%] studies of C-Tb, two [5%] studies of EC-skintest, and one [3%] study of DPPD). 22 (1·5%) studies including 5810 individuals (3143 Diaskintest, 2129 C-Tb, 538 EC-skintest) were included in the quantitative analysis: 15 (68%) of Diaskintest, five (23%) of C-Tb, and two (9%) of EC-skintest. Tested sub-populations included individuals with HIV, children (0–18 years), and individuals exposed to tuberculosis. Studies were heterogeneous with moderate to high risk of bias. Nine head-to-head studies of index test versus TST and IGRA permitted direct comparisons and pooling. In a mixed cohort of people with and without tuberculosis, Diaskintest pooled agreement with IGRA was 87·16% (95% CI 79·47–92·24) and 55·45% (46·08–64·45) with TST-5 mm cut-off (TST5 mm). Diaskintest sensitivity was 91·18% (95% CI 81·72–95·98) compared with 88·24% (78·20–94·01) for TST5 mm, 89·66 (78·83–95·28) for IGRA QuantiFERON, and 90·91% (79·95–96·16) for TSPOT.TB. C-Tb agreement with IGRA in individuals with active tuberculosis was 79·80% (95% CI 76·10–83·07) compared with 78·92% (74·65–82·63) for TST5 mm/15 mm cut-off (TST5 mm/15 mm). TST5/15mm reflects threshold in cohorts that applied stratified cutoffs: 5 mm for HIV-infected, immunocompromised, or BCG-naive individuals, and 15mm for BCG-vaccinated immunocompetent individuals. C-Tb sensitivity was 74·52% (95% CI 70·39–78·25) compared with a sensitivity of 78·18% (67·75–85·94) for TST5 mm/15 mm, and 71·67% (63·44–78·68) for IGRA. Specificity was 97·85% (95% CI 93·96–99·25) for C-Tb versus 93·31% (90·22–95·48) for TST 15 mm cut-off and 99·15% (79·66–99·97) for IGRA. EC-skintest sensitivity was 86·06% (95% CI 82·39–89·07). Interpretation Novel skin-based tests for tuberculosis infection appear to perform similarly to IGRA or TST; however, study quality varied. Evaluation of test performance, patient-important outcomes, and diagnostic use in current clinical algorithms will inform implementation in key populations. Funding StopTB (New Diagnostics Working Group) and FIND. Translations For the Chinese and Russian translations of the abstract see Supplementary Materials section.
Published: 2022
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8. Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol

Author: Peter Horby, Laura Merson, Gail Carson, Piero Olliaro, Ewen M Harrison, Tom Solomon, Lisa Norman, Jake Dunning, Cathie Sudlow, Kenneth A. McLean, Mark G Pritchard, Antonia Ho, Riinu Pius, Lance Turtle, Olivia Swann, Christopher A Green, Annemarie B Docherty, Carrol Gamble, Malcolm G Semple, J Kenneth Baillie, Stephen R Knight, Iain Buchan, Rishi K Gupta, Cameron J Fairfield, Mahdad Noursadeghi, Peter J. M. Openshaw, Catherine A Shaw, Karl A Holden, Clare Jackson, Sophie Halpin, Aziz Sheikh, Clark D Russell, Hayley E Hardwick, Jonathan S. Nguyen-Van-Tam, Thomas M Drake, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, and UK Research and Innovation
Subjects: Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Adolescent, Coronavirus disease 2019 (COVID-19), Respiratory System, World Health Organization, ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) Investigators, State Medicine, World health, Emerging infections, Humans, Medicine, Hospital Mortality, deterioration, ISARIC4C investigators, Prognostic models, Protocol (science), Science & Technology, SARS-CoV-2, business.industry, Outcome measures, COVID-19, 1103 Clinical Sciences, PERFORMANCE, Prognosis, mortality, prognostic score, Observational Studies as Topic, PREDICTION MODELS, Risk stratification, Emergency medicine, revalidation, business, Life Sciences & Biomedicine, Cohort study
Abstract: Purpose To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19. Methods Prospective observational cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups. Results 76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, –0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions. Conclusion Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making. Trial registration number NCT66726260.
Published: 2021
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9. Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study

Author: Mahdad Noursadeghi, Laura Shallcross, Ivana Pennisi, Ravi Mehta, Graham S Cooke, Dominique Arancon, Jesus Rodriguez-Manzano, Ewurabena Mills, Luca Miglietta, Nelofar Obaray, Myrsini Kaforou, Jethro Herberg, Samuel Channon-Wells, Shiranee Sriskandan, Alexander J. Mentzer, Jessica Lin, H K Li, Ahmad Moniri, Rishi K Gupta, Dominic Habgood-Coote, Michael Levin, Victoria J. Wright, Pantelis Georgiou, and Yueh-Ho Chiu
Subjects: Adult, Microbiology (medical), Medicine (General), medicine.medical_specialty, Adolescent, Communicable Diseases, Microbiology, Cohort Studies, R5-920, Virology, Internal medicine, Pandemic, medicine, Humans, Medical diagnosis, Bacteria, Receiver operating characteristic, SARS-CoV-2, business.industry, COVID-19, Articles, Bacterial Infections, Emergency department, Gene signature, QR1-502, C-Reactive Protein, Infectious Diseases, Virus Diseases, Infectious disease (medical specialty), Case-Control Studies, Cohort, business, Cohort study
Abstract: Summary Background Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to detect viral infections, including COVID-19, among adults with suspected infection who presented to the emergency department. Methods Individuals (aged ≥18 years) presenting with suspected infection to an emergency department at a major teaching hospital in the UK were prospectively recruited as part of the Bioresource in Adult Infectious Diseases (BioAID) discovery cohort. Whole-blood RNA sequencing was done on samples from participants with subsequently confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes that met additional filtering criteria were subjected to feature selection to derive the most parsimonious discriminating signature. We validated the signature via RT-qPCR in a prospective validation cohort of participants who presented to an emergency department with undifferentiated fever, and a second case-control validation cohort of emergency department participants with PCR-positive COVID-19 or bacterial infection. We assessed signature performance by calculating the area under receiver operating characteristic curves (AUROCs), sensitivities, and specificities. Findings A three-gene transcript signature, comprising HERC6, IGF1R, and NAGK, was derived from the discovery cohort of 56 participants with bacterial infections and 27 with viral infections. In the validation cohort of 200 participants, the signature differentiated bacterial from viral infections with an AUROC of 0·976 (95% CI 0·919−1·000), sensitivity of 97·3% (85·8−99·9), and specificity of 100% (63·1−100). The AUROC for C-reactive protein (CRP) was 0·833 (0·694−0·944) and for leukocyte count was 0·938 (0·840−0·986). The signature achieved higher net benefit in decision curve analysis than either CRP or leukocyte count for discriminating viral infections from all other infections. In the second validation analysis, which included SARS-CoV-2-positive participants, the signature discriminated 35 bacterial infections from 34 SARS-CoV-2-positive COVID-19 infections with AUROC of 0·953 (0·893−0·992), sensitivity 88·6%, and specificity of 94·1%. Interpretation This novel three-gene signature discriminates viral infections, including COVID-19, from other emergency infection presentations in adults, outperforming both leukocyte count and CRP, thus potentially providing substantial clinical utility in managing acute presentations with infection. Funding National Institute for Health Research, Medical Research Council, Wellcome Trust, and EU-FP7.
Published: 2021
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10. SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

Author: Felicity Liew, Shubha Talwar, Andy Cross, Brian J. Willett, Sam Scott, Nicola Logan, Matthew K. Siggins, Dawid Swieboda, Jasmin K. Sidhu, Claudia Efstathiou, Shona C. Moore, Chris Davis, Noura Mohamed, Jose Nunag, Clara King, A.A. Roger Thompson, Sarah L. Rowland-Jones, Annemarie B. Docherty, James D. Chalmers, Ling-Pei Ho, Alexander Horsley, Betty Raman, Krisnah Poinasamy, Michael Marks, Onn Min Kon, Luke Howard, Daniel G. Wootton, Susanna Dunachie, Jennifer K. Quint, Rachael A. Evans, Louise V. Wain, Sara Fontanella, Thushan I. de Silva, Antonia Ho, Ewen Harrison, J. Kenneth Baillie, Malcolm G. Semple, Christopher Brightling, Ryan S. Thwaites, Lance Turtle, Peter J.M. Openshaw, 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, Gonçalo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christopher A. Green, William Greenhalf, Julian Griffin, Rishi K. Gupta, Ewen M. Harrison, Antonia Y.W. Ho, Karl Holden, 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, 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, Emma C. Thomson, Lance C.W. Turtle, Maria Zambon, Thomas M. Drake, Cameron J. Fairfield, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Lisa Norman, Riinu Pius, Catherine A. Shaw, Marie Connor, Jo Dalton, Carrol Gamble, Michelle Girvan, Sophie Halpin, Janet Harrison, Clare Jackson, James Lee, Laura Marsh, Daniel Plotkin, Stephanie Roberts, Egle Saviciute, Sara Clohisey, Ross Hendry, Susan Knight, Eva Lahnsteiner, Gary Leeming, Lucy Norris, James Scott-Brown, Sarah Tait, Murray Wham, Richard Clark, Audrey Coutts, Lorna Donelly, Angie Fawkes, Tammy Gilchrist, Katarzyna Hafezi, Louise MacGillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Lee Murphy, Nicola Wrobel, Gail Carson, 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, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, 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, Tassos Grammatikopoulos, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B. Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Joanne Howard, 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, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Thapas Nagarajan, Megan Nagel, Mark Nelson, Lillian Norris, Matthew K. O'Shea, Marlies Ostermann, Igor Otahal, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Padmasayee Papineni, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, 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, Sarah Sarah, Matthias Schmid, Aarti Shah, Manu Shankar-Hari, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jagtur Singh Pooni, Jeremy Sizer, 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, Rachel Vincent, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wootton, Andrew Workman, Bryan Yates, Peter Young, Sarah E. McDonald, Victoria Shaw, Katie A. Ahmed, Jane A. Armstrong, Milton Ashworth, Innocent G. Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Nicola Carlucci, Emily Cass, Benjamin W.A. Catterall, Jordan J. Clark, Emily A. Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Alejandra Doce Carracedo, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis W.S. Fisher, Lisa Flaherty, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Anthony Holmes, 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, Hannah Massey, Nicole Maziere, 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, Seán Keating, Cara Donegan, Rebecca G. Spencer, Chloe Donohue, Fiona Griffiths, Hayley Hardwick, Wilna Oosthuyzen, K. Abel, H. Adamali, D. Adeloye, O. Adeyemi, R. Adrego, L.A. Aguilar Jimenez, S. Ahmad, N. Ahmad Haider, R. Ahmed, N. Ahwireng, M. Ainsworth, B. Al-Sheklly, A. Alamoudi, M. Ali, M. Aljaroof, A.M. All, L. Allan, R.J. Allen, L. Allerton, L. Allsop, P. Almeida, D. Altmann, M. Alvarez Corral, S. Amoils, D. Anderson, C. Antoniades, G. Arbane, A. Arias, C. Armour, L. Armstrong, N. Armstrong, D. Arnold, H. Arnold, A. Ashish, A. Ashworth, M. Ashworth, S. Aslani, H. Assefa-Kebede, C. Atkin, P. Atkin, R. Aul, H. 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Kon, S. Kon, S.S. Kon, S. Koprowska, A. Korszun, I. Koychev, C. Kurasz, P. Kurupati, C. Laing, H. Lamlum, G. Landers, C. Langenberg, D. Lasserson, L. Lavelle-Langham, A. Lawrie, C. Lawson, A. Layton, A. Lea, O.C. Leavy, D. Lee, J-H. Lee, E. Lee, K. Leitch, R. Lenagh, D. Lewis, J. Lewis, K.E. Lewis, V. Lewis, N. Lewis-Burke, X. Li, T. Light, L. Lightstone, W. Lilaonitkul, L. Lim, S. Linford, A. Lingford-Hughes, M. Lipman, K. Liyanage, A. Lloyd, S. Logan, D. Lomas, N.I. Lone, R. Loosley, J.M. Lord, H. Lota, W. Lovegrove, A. Lucey, E. Lukaschuk, A. Lye, C. Lynch, S. MacDonald, G. MacGowan, I. Macharia, J. Mackie, L. Macliver, S. Madathil, G. Madzamba, N. Magee, M.M. Magtoto, N. Mairs, N. Majeed, E. Major, F. Malein, M. Malim, G. Mallison, W.D.-C. Man, S. Mandal, K. Mangion, C. Manisty, R. Manley, K. March, S. Marciniak, P. Marino, M. Mariveles, M. Marks, E. Marouzet, S. Marsh, B. Marshall, M. Marshall, J. Martin, A. Martineau, L.M. Martinez, N. Maskell, D. Matila, W. Matimba-Mupaya, L. Matthews, A. Mbuyisa, S. McAdoo, H. McAllister-Williams, A. McArdle, P. McArdle, D. McAulay, G.P. McCann, H.J.C. drury, J. McCormick, W. McCormick, P. McCourt, L. McGarvey, C. McGee, K. Mcgee, J. McGinness, K. McGlynn, A. McGovern, H. McGuinness, I.B. McInnes, J. McIntosh, E. McIvor, K. McIvor, L. McLeavey, A. McMahon, M.J. McMahon, L. McMorrow, T. Mcnally, M. McNarry, J. McNeill, A. McQueen, H. McShane, C. Mears, C. Megson, S. Megson, P. Mehta, J. Meiring, L. Melling, M. Mencias, D. Menzies, M. Merida Morillas, A. Michael, C. Miller, L. Milligan, C. Mills, N.L. Mills, L. Milner, S. Misra, J. Mitchell, A. Mohamed, N. Mohamed, S. Mohammed, P.L. Molyneaux, W. Monteiro, S. Moriera, A. Morley, L. Morrison, R. Morriss, A. Morrow, A.J. Moss, P. Moss, K. Motohashi, N. Msimanga, E. Mukaetova-Ladinska, U. Munawar, J. Murira, U. Nanda, H. Nassa, M. Nasseri, A. Neal, R. Needham, P. Neill, S. Neubauer, D.E. Newby, H. Newell, T. Newman, A. Newton-Cox, T. Nicholson, D. Nicoll, A. Nikolaidis, C.M. Nolan, M.J. Noonan, C. Norman, P. Novotny, J. Nunag, L. Nwafor, U. Nwanguma, J. Nyaboko, C. O'Brien, K. O'Donnell, D. O'Regan, L. O'Brien, N. Odell, G. Ogg, O. Olaosebikan, C. Oliver, Z. Omar, P.J.M. Openshaw, L. Orriss-Dib, L. Osborne, R. Osbourne, M. Ostermann, C. Overton, J. Owen, J. Oxton, J. Pack, E. Pacpaco, S. Paddick, S. Painter, A. Pakzad, S. Palmer, P. Papineni, K. Paques, K. Paradowski, M. Pareek, D. Parekh, H. Parfrey, C. Pariante, S. Parker, M. Parkes, J. Parmar, S. Patale, B. Patel, M. Patel, S. Patel, D. Pattenadk, M. Pavlides, S. Payne, L. Pearce, J.E. Pearl, D. Peckham, J. Pendlebury, Y. Peng, C. Pennington, I. Peralta, E. Perkins, Z. Peterkin, T. Peto, N. Petousi, J. Petrie, P. Pfeffer, J. Phipps, J. Pimm, K. Piper Hanley, R. Pius, H. Plant, S. Plein, T. Plekhanova, M. Plowright, K. Poinasamy, O. Polgar, L. Poll, J.C. Porter, J. Porter, S. Portukhay, N. Powell, A. Prabhu, J. Pratt, A. Price, C. Price, D. Price, L. Price, A. Prickett, J. Propescu, S. Prosper, S. Pugmire, S. Quaid, J. Quigley, J. Quint, H. Qureshi, I.N. Qureshi, K. Radhakrishnan, N.M. Rahman, M. Ralser, B. Raman, A. Ramos, H. Ramos, J. Rangeley, B. Rangelov, L. Ratcliffe, P. Ravencroft, A. Reddington, R. Reddy, H. Redfearn, D. Redwood, A. Reed, M. Rees, T. Rees, K. Regan, W. Reynolds, C. Ribeiro, A. Richards, E. Richardson, M. Richardson, P. Rivera-Ortega, K. Roberts, E. Robertson, E. Robinson, L. Robinson, L. Roche, C. Roddis, J. Rodger, A. Ross, G. Ross, J. Rossdale, A. Rostron, A. Rowe, A. Rowland, J. Rowland, M.J. Rowland, S.L. Rowland-Jones, K. Roy, M. Roy, I. Rudan, R. Russell, E. Russell, G. Saalmink, R. Sabit, E.K. Sage, T. Samakomva, N. Samani, C. Sampson, K. Samuel, R. Samuel, A. Sanderson, E. Sapey, D. Saralaya, J. Sargant, C. Sarginson, T. Sass, N. Sattar, K. Saunders, R.M. Saunders, P. Saunders, L.C. Saunders, H. Savill, W. Saxon, A. Sayer, J. Schronce, W. Schwaeble, J.T. Scott, K. Scott, N. Selby, M.G. Semple, M. Sereno, T.A. Sewell, A. Shah, K. Shah, P. Shah, M. Shankar-Hari, M. Sharma, C. Sharpe, M. Sharpe, S. Shashaa, A. Shaw, K. Shaw, V. Shaw, A. Sheikh, S. Shelton, L. Shenton, K. Shevket, A. Shikotra, J. Short, S. Siddique, S. Siddiqui, J. Sidebottom, L. Sigfrid, G. Simons, J. Simpson, N. Simpson, A. Singapuri, C. Singh, S. Singh, S.J. Singh, D. Sissons, J. Skeemer, K. Slack, A. Smith, D. Smith, S. Smith, J. Smith, L. Smith, M. Soares, T.S. Solano, R. Solly, A.R. Solstice, T. Soulsby, D. Southern, D. Sowter, M. Spears, L.G. Spencer, F. Speranza, L. Stadon, S. Stanel, N. Steele, M. Steiner, D. Stensel, G. Stephens, L. Stephenson, M. Stern, I. Stewart, R. Stimpson, S. Stockdale, J. Stockley, W. Stoker, R. Stone, W. Storrar, A. Storrie, K. Storton, E. Stringer, S. Strong-Sheldrake, N. Stroud, C. Subbe, C.L. Sudlow, Z. Suleiman, C. Summers, C. Summersgill, D. Sutherland, D.L. Sykes, R. Sykes, N. Talbot, A.L. Tan, L. Tarusan, V. Tavoukjian, A. Taylor, C. Taylor, J. Taylor, A. Te, H. Tedd, C.J. Tee, J. Teixeira, H. Tench, S. Terry, S. Thackray-Nocera, F. Thaivalappil, B. Thamu, D. Thickett, C. Thomas, D.C. Thomas, S. Thomas, A.K. Thomas, T. Thomas-Woods, T. Thompson, A.A.R. Thompson, T. Thornton, M. Thorpe, R.S. Thwaites, J. Tilley, N. Tinker, G.F. Tiongson, M. Tobin, J. Tomlinson, C. Tong, M. Toshner, R. Touyz, K.A. Tripp, E. Tunnicliffe, A. Turnbull, E. Turner, S. Turner, V. Turner, K. Turner, S. Turney, L. Turtle, H. Turton, J. Ugoji, R. Ugwuoke, R. Upthegrove, J. Valabhji, M. Ventura, J. Vere, C. Vickers, B. Vinson, E. Wade, P. Wade, L.V. Wain, T. Wainwright, L.O. Wajero, S. Walder, S. Walker, E. Wall, T. Wallis, S. Walmsley, J.A. Walsh, S. Walsh, L. Warburton, T.J.C. Ward, K. Warwick, H. Wassall, S. Waterson, E. Watson, L. Watson, J. Watson, J. Weir McCall, C. Welch, H. Welch, B. Welsh, S. Wessely, S. West, H. Weston, H. Wheeler, S. White, V. Whitehead, J. Whitney, S. Whittaker, B. Whittam, V. Whitworth, A. Wight, J. Wild, M. Wilkins, D. Wilkinson, B. Williams, N. Williams, J. Williams, S.A. Williams-Howard, M. Willicombe, G. Willis, J. Willoughby, A. Wilson, D. Wilson, I. Wilson, N. Window, M. Witham, R. Wolf-Roberts, C. Wood, F. Woodhead, J. Woods, D.G. Wootton, J. Wormleighton, J. Worsley, D. Wraith, C. Wrey Brown, C. Wright, L. Wright, S. Wright, J. Wyles, I. Wynter, M. Xu, N. Yasmin, S. Yasmin, T. Yates, K.P. Yip, B. Young, S. Young, A. Young, A.J. Yousuf, A. Zawia, L. Zeidan, B. Zhao, B. Zheng, O. Zongo, Investigators, ISARIC4C, group, PHOSP-COVID collaborative, Sigfrid, L, ISARIC4C Investigators, and PHOSP-COVID collaborative group
Subjects: SARS-CoV-2 variants, Mucosal immunity, Nasal antibody, SDG 3 - Good Health and Well-being, Biochemistry, Genetics and Molecular Biology(all), SARS-CoV-2 immunity, Vaccination, COVID-19, General Medicine, Convalescent, General Biochemistry, Genetics and Molecular Biology
Abstract: Data sharing statement This is an Open Access article under the CC BY 4.0 license The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net. ISARIC4C's Independent Data and Material Access Committee welcomes applications for access to data and materials (https://isaric4c.net). The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online: https://phosp.org/resource/. Access to these materials can be granted by contacting phosp@leicester.ac.uk and Phospcontracts@leicester.ac.uk. All data used in this study is available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online: https://phosp.org/resource/. If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement. Supplementary data are available online at https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00584-9/fulltext#supplementaryMaterial . Copyright © 2022 The Author(s). Background: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. Funding: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript. This work is supported by the following grants: The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute for Health and Care Research (grant references: MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). Other grants which have supported this work include: the UK Coronavirus Immunology Consortium [funder reference:1257927], the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit (HPRU) in Respiratory Infections at Imperial College London and NIHR HPRU in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], Health Data Research UK (HDR UK) [grant code: 2021.0155], Medical Research Council [grant code: MC_UU_12014/12], and NIHR Clinical Research Network for providing infrastructure support for this research. FL is supported by an MRC clinical training fellowship [award MR/W000970/1]. LPH is supported by Oxford NIHR Biomedical Research Centre. AART is supported by a BHF Intermediate Clinical Fellowship (FS/18/13/33281). SLRJ receives support from UKRI, GCRF, Rosetrees Trust, BHIVA, EDCTP, Globvac. JDC has grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed. RAE holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). AH is currently supported by UK Research and Innovation. NIHR and NIHR Manchester BRC. BR receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. SJD is funded by an NIHR Global Research Professorship [NIHR300791]. DW is supported by an NIHR Advanced Fellowship. AH has received support from MRC and the Coronavirus Immunology Consortium (MR/V028448/1). LVW has received support from UKRI, GSK/Asthma + Lung UK and NIHR for this study. MGS has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool. JKB is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029). PJMO is supported by a NIHR Senior Investigator Award [award 201385]. LT is supported by the Wellcome Trust [clinical career development fellowship grant number 205228/Z/16/Z], the Centre of Excellence in Infectious Diseases Research (CEIDR) and the Alder Hey Charity.
Published: 2022
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11. Clinical utility of C-reactive protein-based triage for presumptive pulmonary tuberculosis in South African adults

Author: Claire J Calderwood, Byron WP Reeve, Tiffeney Mann, Zaida Palmer, Georgina Nyawo, Hridesh Mishra, Gcobisa Ndlangalavu, Ibrahim Abubakar, Mahdad Noursadeghi, Grant Theron, and Rishi K Gupta
Subjects: Microbiology (medical), Adult, South Africa, Infectious Diseases, C-Reactive Protein, Sputum, Humans, HIV Infections, Mycobacterium tuberculosis, Triage, Tuberculosis, Pulmonary, Sensitivity and Specificity
Abstract: Identification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status.We prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC), and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis and benchmarked against WHO recommendations.Of 932 included individuals, 255 (27%) had culture-confirmed pulmonary TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0·80 (95% confidence interval 0·77-0·83), with sensitivity 93% (89-95%) and specificity 54% (50-58%) using a primary cut-off of ≥10 mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive pulmonary TB case diagnosed (threshold probability 5%). If it is possible to perform more confirmatory tests than this, a 'confirmatory test for all' strategy performed better.CRP achieved the WHO-defined sensitivity, but not specificity, targets for a triage test for pulmonary TB and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status.South African Medical Research Council, EDCTP2, Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, Royal College of Physicians.
Published: 2022

12. New Insights into the Limitations of Host Transcriptional Biomarkers of Tuberculosis

Author: Mahdad Noursadeghi and Rishi K Gupta
Subjects: Pulmonary and Respiratory Medicine, Tuberculosis, Host (biology), business.industry, medicine, Humans, Mycobacterium tuberculosis, Computational biology, Critical Care and Intensive Care Medicine, medicine.disease, business, Biomarkers
Published: 2021
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13. Comparison of midterm results of Platelet Rich Plasma (PRP) versus Steroid for plantar fasciitis: A randomized control trial of 118 patients

Author: Rishi K Gupta, Ankit Khurana, Vaneet Dhankhar, Navneet Goel, and Ashish Goyal
Subjects: 030222 orthopedics, Heel, Visual analogue scale, business.industry, medicine.medical_treatment, Pain relief, Plantar fasciitis, Steroid, law.invention, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Randomized controlled trial, law, Platelet-rich plasma, Anesthesia, medicine, Original Article, Orthopedics and Sports Medicine, 030212 general & internal medicine, medicine.symptom, business, Whole blood
Abstract: Background Plantar fasciitis, which is a common cause of heel pain, often results in significant morbidity. In cases who are not responsive to initial conservative treatment, invasive procedures, often in the form of local infiltration of steroid are required. These procedures are associated with significant complications. Local Platelet Rich Plasma (PRP) infiltration is an emerging addition to these treatments. However, whether it is more effective in reducing pain and improving function than other treatments (such as steroid injections or whole blood) remains controversial. Methods Skeletally mature patients with plantar fasciitis who had failed conservative therapy were randomized using envelope method into 2 groups: PRP and Steroid group. The participants were assessed for pain using Visual Analog Scale on the day of presentation, and then after therapy at 2 weeks, 4 weeks, 3 months, and 6 months. They were additionally assessed on final follow-up using AOFAS hind-foot Score. Results 118 patients were randomized into 2 groups: 58 patients to the PRP group and 60 to the Steroid group. PRP was associated with greater improvement in VAS score and resulted in superior AOFAS score at 6 months as compared to steroid injection. The authors did not find any local or systemic complications in any of the groups. The result and difference were more pronounced as the time from injection increased and maximal benefit was observed at 6 months follow-up. None of the patients needed a repeat injection at 6 months. Conclusion Our study expands on the previous studies to provide a better evidence for superiority of PRP over local injection of steroid in plantar fasciitis, and the authors conclude that PRP provides better pain relief and function as compared to steroid injection. Level of evidence Level 1 Prospective Randomized Control Trial (RCT)
Published: 2021
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14. Prevalence and Clinical Correlates of COVID-19 Outbreak Among Health Care Workers in a Tertiary Level Hospital in Delhi

Author: Ankit Khurana, Kabir Sharma, Rishi K Gupta, G P Kaushal, Vansh Verma, and Manmohan Kohli
Subjects: medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), health care facilities, manpower, and services, media_common.quotation_subject, education, Psychological intervention, Masking (Electronic Health Record), law.invention, Hygiene, law, Health care, Epidemiology, Medicine, Tertiary level, media_common, business.industry, virus diseases, Outbreak, Hydroxychloroquine, Tertiary care hospital, Intensive care unit, Infectious Diseases, Cohort, Emergency medicine, business, medicine.drug
Abstract: COVID-19 has been shown to spread rapidly among Healthcare Workers (HCWs) and there is an urgent need to find and implement various mitigation strategies for these individuals. In this study, we summarize the epidemiological characteristics of the COVID-19 outbreak among HCWs in a tertiary care hospital and compare various parameters and preventive measures taken by infected and uninfected subjects. A retrospective questionnaire and record-based analysis was carried out to evaluate the epidemiological and clinical parameters of the participants. Preventive strategies such as masking, hand hygiene and use of prophylactic agents were compared for infected and uninfected subjects. Appropriate statistical tests were applied wherever required. The average age of participants in the COVID-19 positive group was 35.9 years and 52.1% of the positive HCWs were symptomatic. Three of these subjects needed hospitalization and one required admission to an intensive care unit. The study found a protective role of full course of prophylactic hydroxychloroquine in treated subjects versus untreated controls (p = 0.021) and benefit of N95 masks over others (p
Published: 2021
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15. Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings

Author: Claudia C. Dobler, Laura Muñoz, Joseph Doyle, Berit Lange, Gerrit Woltmann, Takashi Yoshiyama, José Domínguez, Steffen Geis, Christoph Lange, David Roth, Dominik Zenner, Pranabashis Haldar, Neus Altet, James C. Johnston, Anja M. Hauri, Rosa Sloot, Alexei Yavlinsky, Maria Krutikov, Frank van Leth, Marc Lipman, Christine Roder, Ibrahim Abubakar, Molebogeng X Rangaka, Thomas Stig Hermansen, Rishi K Gupta, Martina Sester, Claire J. Calderwood, Robert W Aldridge, Jean-Pierre Zellweger, Roland Diel, Matteo Quartagno, Mahdad Noursadeghi, Maximilian C. Aichelburg, Andrew Copas, Giovanni Sotgiu, Kamila Romanowski, Connie Erkens, APH - Global Health, APH - Methodology, Global Health, AII - Infectious diseases, and Health Sciences
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Risk predictor, Tuberculosis, Adolescent, Tuberculosis/diagnosis, Low transmission, General Biochemistry, Genetics and Molecular Biology, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Tuberculosis diagnosis, Latent Tuberculosis, Risk Factors, Internal medicine, Mycobacterium tuberculosis/pathogenicity, medicine, Humans, Child, biology, business.industry, Tuberculin Test, General Medicine, Random effects model, biology.organism_classification, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Meta-analysis, Female, Latent Tuberculosis/diagnosis, business, Cohort study
Abstract: The risk of tuberculosis (TB) is variable among individuals with latentMycobacterium tuberculosisinfection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide. The risk of developing active tuberculosis (TB) in individuals with latent TB infection is highly variable within and among different risk groups. A personalized risk predictor was developed to better target preventative treatment to individuals at greatest risk, supporting evidence-based clinical decision-making for latent TB.
Published: 2020
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16. Efficacy of Autologous Conditioned Serum (ACS), Platelet-Rich Plasma (PRP), Hyaluronic Acid (HA) and Steroid for Early Osteoarthritis Knee: A Comparative Analysis

Author: Gaurav Akhand, P. Kirubakaran, Navneet Goel, Ashish Goyal, Rishi K Gupta, and Ankit Khurana
Subjects: 030222 orthopedics, medicine.medical_specialty, WOMAC, Visual analogue scale, business.industry, Viscosupplements, Arthritis, 030229 sport sciences, Osteoarthritis, medicine.disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Platelet-rich plasma, Internal medicine, Hyaluronic acid, Orthopedic surgery, medicine, Original Article, Orthopedics and Sports Medicine, business
Abstract: BACKGROUND: Intra-articular injection therapy constituting corticosteroids, viscosupplements and blood-derived products are considered to have a key role in non-operative management of osteoarthritis knee. While corticosteroids and viscosupplements have proven short-term efficacy in early osteoarthritis; orthobiologics are gaining increased attention in osteoarthritis management. The aim of present study was thus to compare two commonly used biologics (platelet-rich plasma/PRP and autologous conditioned serum/ACS) to each other and to established therapies. METHODS: After required institutional clearances, all patients presenting with early primary osteoarthritis knee who had failed initial conservative management and received only unilateral knee injection were included. Patients in the PRP group were compared to the other groups (comprising the HA/hyaluronic acid group, steroid group, and a matched cohort who had been administered ACS for the same indication earlier). Clinical outcome was evaluated using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire and Visual Analogue scale (VAS) pre-injection and at 6 months. RESULTS: ACS and PRP did not have any significant difference in terms of either WOMAC score (p = 0.154) or VAS score at 6 months (p = 0.850). The scores for both these orthobiologics were better than the control groups (HA group and Steroid group). Between the two control groups, HA group had better VAS scores as compared to the Steroid group (p = 0.008). CONCLUSION: The clinical outcomes following intra-articular injection of ACS and PRP are better than controls (HA and steroid), but a difference between the two orthobiologics could not be demonstrated. LEVEL OF EVIDENCE: 3b.
Published: 2020
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17. Rapid synchronous type 1 IFN and virus-specific T cell responses characterize first wave non-severe SARS-CoV-2 infections

Author: Aneesh Chandran, Joshua Rosenheim, Gayathri Nageswaran, Leo Swadling, Gabriele Pollara, Rishi K. Gupta, Alice R. Burton, José Afonso Guerra-Assunção, Annemarie Woolston, Tahel Ronel, Corinna Pade, Joseph M. Gibbons, Blanca Sanz-Magallon Duque De Estrada, Marc Robert de Massy, Matthew Whelan, Amanda Semper, Tim Brooks, Daniel M. Altmann, Rosemary J. Boyton, Áine McKnight, Gabriella Captur, Charlotte Manisty, Thomas Alexander Treibel, James C. Moon, Gillian S. Tomlinson, Mala K. Maini, Benjamin M. Chain, Mahdad Noursadeghi, Medical Research Council (MRC), and National Institute for Health Research
Subjects: SARS-CoV-2, viruses, Interferon Type I, COVID-19, Humans, CD8-Positive T-Lymphocytes, Flow Cytometry, General Biochemistry, Genetics and Molecular Biology
Abstract: Effective control of SARS-CoV-2 infection on primary exposure may reveal correlates of protective immunity to future variants, but we lack insights into immune responses before or at the time virus is first detected. We use blood transcriptomics, multiparameter flow cytometry, and T cell receptor (TCR) sequencing spanning the time of incident non-severe infection in unvaccinated virus-naive individuals to identify rapid type 1 interferon (IFN) responses common to other acute respiratory viruses and cell proliferation responses that discriminate SARS-CoV-2 from other viruses. These peak by the time the virus is first detected and sometimes precede virus detection. Cell proliferation is most evident in CD8 T cells and associated with specific expansion of SARS-CoV-2-reactive TCRs, in contrast to virus-specific antibodies, which lag by 1-2 weeks. Our data support a protective role for early type 1 IFN and CD8 T cell responses, with implications for development of universal T cell vaccines.
Published: 2022

18. SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

Author: Wanwisa Dejnirattisai, Jiandong Huo, Daming Zhou, Jiří Zahradník, Piyada Supasa, Chang Liu, Helen M.E. Duyvesteyn, Helen M. Ginn, Alexander J. Mentzer, Aekkachai Tuekprakhon, Rungtiwa Nutalai, Beibei Wang, Aiste Dijokaite, Suman Khan, Ori Avinoam, Mohammad Bahar, Donal Skelly, Sandra Adele, Sile Ann Johnson, Ali Amini, Thomas G. Ritter, Chris Mason, Christina Dold, Daniel Pan, Sara Assadi, Adam Bellass, Nicola Omo-Dare, David Koeckerling, Amy Flaxman, Daniel Jenkin, Parvinder K. Aley, Merryn Voysey, Sue Ann Costa Clemens, Felipe Gomes Naveca, Valdinete Nascimento, Fernanda Nascimento, Cristiano Fernandes da Costa, Paola Cristina Resende, Alex Pauvolid-Correa, Marilda M. Siqueira, Vicky Baillie, Natali Serafin, Gaurav Kwatra, Kelly Da Silva, Shabir A. Madhi, Marta C. Nunes, Tariq Malik, Peter J.M. Openshaw, J. Kenneth Baillie, Malcolm G. Semple, Alain R. Townsend, Kuan-Ying A. Huang, Tiong Kit Tan, Miles W. Carroll, Paul Klenerman, Eleanor Barnes, Susanna J. Dunachie, Bede Constantinides, Hermione Webster, Derrick Crook, Andrew J. Pollard, Teresa Lambe, Neil G. Paterson, Mark A. Williams, David R. Hall, Elizabeth E. Fry, Juthathip Mongkolsapaya, Jingshan Ren, Gideon Schreiber, David I. Stuart, Gavin R. Screaton, Christopher Conlon, Alexandra S. Deeks, John Frater, Lisa Frending, Siobhan Gardiner, Anni Jämsén, Katie Jeffery, Tom Malone, Eloise Phillips, Lucy Rothwell, Lizzie Stafford, J Kenneth Baillie, 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, Gonçalo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christoper 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, Andrew Law, Matthew R. Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, 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 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, 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 Donnelly, 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 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, Peter Young, National Institute for Health Research, UK Research and Innovation, UKRI MRC COVID-19 Rapid Response Call, University of Oxford, Northwestern Polytechnical University (NPU), Charles University [Prague] (CU), Division of Immunology and Inflammation, Department of Medicine, Imperial College London-Hammersmith Hospital Campus, University of Dayton, Universiteit Gent = Ghent University (UGENT), Computational & Applied Vegetation Ecology (CAVElab), Nanjing University of Science and Technology (NJUST), Weizmann Institute of Science [Rehovot, Israël], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Imperial College London, and Apollo - University of Cambridge Repository
Subjects: variants, receptor interaction, Omicron, SARS-CoV-2, [SDV]Life Sciences [q-bio], OPTIC Consortium, Spike, vaccines, 06 Biological Sciences, Article, General Biochemistry, Genetics and Molecular Biology, RBD, ISARIC4C Consortium, 11 Medical and Health Sciences, immune evasion, Developmental Biology
Abstract: On the 24th November 2021 the sequence of a new SARS CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses., A comprehensive analysis of sera from vaccinees, convalescent patients infected previously by multiple variants and potent monoclonal antibodies from early in the COVID-19 pandemic reveals a substantial overall reduction the ability to neutralize the SARS-CoV-2 Omicron variant, which a third vaccine dose seems to ameliorate. Structural analyses of the Omicron RBD suggest a selective pressure enabling the virus bind ACE2 with increased affinity that is offset by other changes in the receptor binding motif that facilitates immune escape.
Published: 2022
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19. Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study

Author: Fiina Närhi, S Ramani Moonesinghe, Susan D Shenkin, Thomas M Drake, Rachel H Mulholland, Cara Donegan, Jake Dunning, Cameron J Fairfield, Michelle Girvan, Hayley E Hardwick, Antonia Ho, Gary Leeming, Jonathan S Nguyen-Van-Tam, Riinu Pius, Clark D Russell, Catherine A Shaw, Rebecca G Spencer, Lance Turtle, Peter J M Openshaw, J Kenneth Baillie, Ewen M Harrison, Malcolm G Semple, Annemarie B Docherty, 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, Gon¸alo dos Santos Correia, Marc-Emmanuel Dumas, Tom Fletcher, Christopher A Green, William Greenhalf, Julian Griffin, Rishi K Gupta, 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, 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, Lisa Norman, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Jo Dalton, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Daniel Plotkin, James Lee, 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, Peter Young, UK Research and Innovation, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, University of Edinburgh, Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford], Public Health England [London], University of Nottingham, UK (UON), University of Liverpool, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Imperial College London - National Heart and Lung Institute, and Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK
Subjects: Adolescent, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), COVID-19, Health Informatics, World Health Organization, United Kingdom, COVID-19 Drug Treatment, Cohort Studies, Health Information Management, Adrenal Cortex Hormones, Pregnancy, Humans, Decision Sciences (miscellaneous), Female, Prospective Studies, ISARIC4C investigators
Abstract: 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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20. C-reactive protein as a triage tool for adults with presumptive pulmonary tuberculosis in South Africa: a prospective cohort study

Author: Byron Wp Reeve, Grant Theron, Tiffeney Mann, Georgina R Nyawo, Ibrahim Abubakar, Claire J. Calderwood, Mahdad Noursadeghi, Rishi K Gupta, Hridesh Mishra, and Zaida Palmer
Subjects: medicine.medical_specialty, biology, Receiver operating characteristic, business.industry, C-reactive protein, Triage, Confidence interval, Pulmonary tuberculosis, Weight loss, Internal medicine, medicine, biology.protein, Sputum, medicine.symptom, business, Prospective cohort study
Abstract: BackgroundIdentification of an accurate, low-cost triage test for pulmonary TB among people presenting to healthcare facilities is an urgent global research priority. We assessed the diagnostic accuracy and clinical utility of C-reactive protein (CRP) for TB triage among symptomatic adult outpatients, irrespective of HIV status.MethodsWe prospectively enrolled adults reporting at least one (for people with HIV) or two (for people without HIV) symptoms of cough, fever, night sweats, or weight loss at two TB clinics in Cape Town, South Africa. Participants provided sputum for culture and Xpert MTB/RIF Ultra. We evaluated the diagnostic accuracy of CRP (measured using a laboratory-based assay) against a TB-culture reference standard as the area under the receiver operating characteristic curve (AUROC) and sensitivity and specificity at pre-specified thresholds. We assessed clinical utility using decision curve analysis, benchmarked against WHO recommendations.ResultsOf 932 included individuals, 255 (27%) had culture-confirmed TB and 389 (42%) were living with HIV. CRP demonstrated an AUROC of 0.80 (95% confidence interval 0.77–0.83), with sensitivity 93% (89–95%) and specificity 54% (50–58%) using a primary cut-off of ≥10mg/L. Performance was similar among people with HIV to those without. In decision curve analysis, CRP-based triage offered greater clinical utility than confirmatory testing for all up to a number willing to test threshold of 20 confirmatory tests per true positive TB case diagnosed.ConclusionsCRP approached the WHO-defined minimum performance for a TB triage test and showed evidence of clinical utility among symptomatic outpatients, irrespective of HIV status.
Published: 2021
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21. Evaluation of QuantiFERON-TB Gold Plus for Predicting Incident Tuberculosis among Recent Contacts: A Prospective Cohort Study

Author: Ambreen Imran, Jo Southern, Charlotte Jackson, S Lozewicz, Ibrahim Abubakar, Marc Lipman, Rishi K Gupta, Heinke Kunst, and Mahdad Noursadeghi
Subjects: Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Tuberculosis, QUANTIFERON-TB GOLD, business.industry, MEDLINE, Medicine, Letters, Prospective cohort study, business, medicine.disease
Published: 2020

22. Toward a more generalizable blood RNA signature for bacterial and viral infections

Author: Rishi K, Gupta and Mahdad, Noursadeghi
Subjects: Diagnosis, Differential, Virus Diseases, Humans, RNA, Bacterial Infections, General Biochemistry, Genetics and Molecular Biology
Abstract: Host-response profiles can discriminate different infections. A new 8-gene blood RNA signature to discriminate bacterial and viral infections extends our focus hitherto on the case mix from the US and Europe to include that of low- and middle-income countries.
Published: 2022
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23. Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study

Author: Thomas M Drake, Aya M Riad, Cameron J Fairfield, Conor Egan, Stephen R Knight, Riinu Pius, Hayley E Hardwick, Lisa Norman, Catherine A Shaw, Kenneth A McLean, A A Roger Thompson, Antonia Ho, Olivia V Swann, Michael Sullivan, Felipe Soares, Karl A Holden, Laura Merson, Daniel Plotkin, Louise Sigfrid, Thushan I de Silva, Michelle Girvan, Clare Jackson, Clark D Russell, Jake Dunning, Tom Solomon, Gail Carson, Piero Olliaro, Jonathan S Nguyen-Van-Tam, Lance Turtle, Annemarie B Docherty, Peter JM Openshaw, J Kenneth Baillie, Ewen M Harrison, Malcolm G Semple, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Ana da Silva Filipe, Tom Fletcher, Christopher A Green, Julian A Hiscox, Antonia YW Ho, Peter W Horby, Samreen Ijaz, Say Khoo, Paul Klenerman, Andrew Law, Wei Shen Lim, Alexander J Mentzer, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Vanessa Sancho-Shimizu, Janet T Scott, Thushan de Silva, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, AA Roger Thompson, Ryan S Thwaites, Lance CW Turtle, Rishi K Gupta, Carlo Palmieri, Maria Zambon, Marc-Emmanuel Dumas, Julian Griffin, Zoltan Takats, Kanta Chechi, Petros Andrikopoulos, Anthonia Osagie, Michael Olanipekun, Sonia Liggi, Matthew Lewis, Gonçalo dos Santos Correia, Caroline Sands, Panteleimon Takis, Lynn Maslen, Hayley Hardwick, Chloe Donohue, Fiona Griffiths, Wilna Oosthuyzen, Kenneth A Mclean, Derek Murphy, Jo Dalton, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Carrol Gamble, James Lee, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, William Greenhalf, 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, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, 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, 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, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Brendan Ryan, Taranprit Saluja, 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, Peter Young, investigators, ISARIC4C, Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK, Imperial College London - National Heart and Lung Institute, Centre National de la Recherche Scientifique (CNRS), Department of Pathology and Laboratory Medicine, University of California, National Institute for Health Research, and UKRI MRC COVID-19 Rapid Response Call
Subjects: MESH: United Kingdom, Male, Pediatrics, Respiratory Tract Diseases, MESH: Comorbidity, MESH: Hospitalization, Comorbidity, 030204 cardiovascular system & hematology, MESH: World Health Organization, MESH: Clinical Protocols, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: COVID-19, Medicine, Hospital Mortality, Prospective Studies, 030212 general & internal medicine, ISARIC4C investigators, Prospective cohort study, 11 Medical and Health Sciences, MESH: Aged, United Kingdom/epidemiology, Incidence (epidemiology), Clinical Protocols/standards, Age Factors, Articles, General Medicine, MESH: Hospitals, Hospitals, 3. Good health, Hospitalization, Cardiovascular Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cohort, COVID-19/complications, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Cohort study, medicine.medical_specialty, MEDLINE, World Health Organization, MESH: Nervous System Diseases, 03 medical and health sciences, General & Internal Medicine, Humans, MESH: SARS-CoV-2, MESH: Hospital Mortality, Survival analysis, Aged, MESH: Age Factors, MESH: Humans, SARS-CoV-2, business.industry, MESH: Cardiovascular Diseases, COVID-19, medicine.disease, MESH: Male, MESH: Prospective Studies, MESH: Respiratory Tract Diseases, Nervous System Diseases, business, Complication, MESH: Female
Abstract: BackgroundCOVID-19 is a multi-system disease and patients who survive may experience in-hospital complications. These complications are likely to have important short and long-term consequences for patients, healthcare utilisation, healthcare system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and impact of COVID-19 complications, particularly in those who survive using the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK).MethodsA multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 17th January and 4th August 2020. Complications were defined as organ specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. Outcomes included death, critical care use, and ability to self-care at hospital discharge. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.ResultsOf patients admitted to hospital for management of COVID-19, 49.7% (36 367/73 197) experienced at least one complication. The mean age of our cohort was 71.1 years old (SD 18.7), included more males (56.0%, 41 025/73 ) with 81.0% (59 289/73 197) of patients having at least one comorbidity. Males over 60 were most likely to experience a complication (60 y and over, 54.5% [16 579/30 416] in males and 48.2% [11 707/24 288] in females; Under 60 y, 48.8% [5179/10 609] in males, 36.6% [2814/7689] in females). Renal (24.3%, 17 752/73 197), complex respiratory 18.4% (13 486/73 197), and systemic (16.3%, 11 895/73 197) complications were most frequent. Cardiovascular (12.3%, 8973/73 197), neurological (4.3%, 3115/73 197), and gastrointestinal/liver (0.8%, 7901/73 197) complications were also reported. The presence of any complication was associated with significantly worse survival (adjusted HR 1.74, 95% CI 1.64 to 1.84) and increased admission to critical care (adjusted OR 7.25, 95% CI 6.83 to 7.69). Reduced ability to self-care at discharge was significantly greater in patients who experienced a complication (adjusted OR 2.42, 95% CI 2.31 to 2.54) and was greatest in those who experienced neurological complications (adjusted OR 4.39, 95% CI 3.95 to 4.89). ConclusionsComplications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause significant strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.
Published: 2021
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24. Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study

Author: Clark D Russell, Cameron J Fairfield, Thomas M Drake, Lance Turtle, R Andrew Seaton, Dan G Wootton, Louise Sigfrid, Ewen M Harrison, Annemarie B Docherty, Thushan I de Silva, Conor Egan, Riinu Pius, Hayley E Hardwick, Laura Merson, Michelle Girvan, Jake Dunning, Jonathan S Nguyen-Van-Tam, Peter J M Openshaw, J Kenneth Baillie, Malcolm G Semple, Antonia Ho, Peter JM Openshaw, Gail Carson, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Ana da Silva Filipe, Tom Fletcher, Christopher A Green, Julian A Hiscox, Antonia YW Ho, Peter W Horby, Samreen Ijaz, Say Khoo, Paul Klenerman, Andrew Law, Wei Shen Lim, Alexander J Mentzer, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Vanessa Sancho-Shimizu, Janet T Scott, Thushan de Silva, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, AA Roger Thompson, Ryan S Thwaites, Lance CW Turtle, Rishi K Gupta, Carlo Palmieri, Maria Zambon, Hayley Hardwick, Chloe Donohue, Ruth Lyons, Fiona Griffiths, Wilna Oosthuyzen, Lisa Norman, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Catherine A Shaw, Jo Dalton, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, William Greenhalf, 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, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, 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, 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, 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, Matthew K. O'Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Selva Panchatsharam, Danai Papakonstantino, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Brendan Ryan, Taranprit Saluja, 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, Andrew Ustianowski, Nick Vallotton, 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, Peter Young, UK Research and Innovation, and UKRI MRC COVID-19 Rapid Response Call
Subjects: Microbiology (medical), BACTERIAL, medicine.medical_specialty, Secondary infection, Psychological intervention, World Health Organization, medicine.disease_cause, Microbiology, Haemophilus influenzae, Virology, Internal medicine, Pandemic, medicine, Humans, Prospective Studies, ISARIC4C investigators, Prospective cohort study, Pandemics, Case report form, Science & Technology, Coinfection, Diagnostic Tests, Routine, business.industry, STEWARDSHIP, COVID-19, Articles, Bacterial Infections, ADULTS, Antimicrobial, United Kingdom, Anti-Bacterial Agents, Infectious Diseases, Staphylococcus aureus, business, Life Sciences & Biomedicine
Abstract: Background: Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19. Methods: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded. Findings: We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives. Interpretation: In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist. Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.
Published: 2021
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25. Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK

Author: Annemarie B Docherty, Rachel H Mulholland, Nazir I Lone, Christopher P Cheyne, Daniela De Angelis, Karla Diaz-Ordaz, Cara Donegan, Thomas M Drake, Jake Dunning, Sebastian Funk, Marta García-Fiñana, Michelle Girvan, Hayley E Hardwick, Janet Harrison, Antonia Ho, David M Hughes, Ruth H Keogh, Peter D Kirwan, Gary Leeming, Jonathan S Nguyen Van-Tam, Riinu Pius, Clark D Russell, Rebecca G Spencer, Brian DM Tom, Lance Turtle, Peter JM Openshaw, J Kenneth Baillie, Ewen M Harrison, Malcolm G Semple, Gail Carson, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Ana da Silva Filipe, Tom Fletcher, Christopher A Green, Julian A Hiscox, Antonia YW Ho, Peter W Horby, Samreen Ijaz, Say Khoo, Paul Klenerman, Andrew Law, Wei Shen Lim, Alexander J Mentzer, Laura Merson, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Vanessa Sancho-Shimizu, Janet T Scott, Thushan de Silva, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, AA Roger Thompson, Ryan S Thwaites, Lance CW Turtle, Rishi K Gupta, Carlo Palmieri, Maria Zambon, Hayley Hardwick, Chloe Donohue, Ruth Lyons, Fiona Griffiths, Wilna Oosthuyzen, Lisa Norman, Cameron J Fairfield, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Catherine A Shaw, Jo Dalton, Egle Saviciute, Stephanie Roberts, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, William Greenhalf, 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, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L Aldera, Ana Alegria, 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, 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, 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, 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, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Brendan Ryan, Taranprit Saluja, 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, Andrew Ustianowski, Nick Vallotton, 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 Wooton, Andrew Workman, Bryan Yates, Peter Young, Kirwan, Peter D [0000-0001-6904-0500], Apollo - University of Cambridge Repository, Imperial College Healthcare NHS Trust- BRC Funding, GlaxoSmithKline Biologicals, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, and UK Research and Innovation
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, World Health Organization, 1117 Public Health and Health Services, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Clinical Protocols, Internal medicine, Severity of illness, Pandemic, Risk of mortality, medicine, Humans, 030212 general & internal medicine, Hospital Mortality, Prospective Studies, Prospective cohort study, ISARIC4C Investigators, Aged, COVID-19/epidemiology, Aged, 80 and over, business.industry, United Kingdom/epidemiology, Mortality rate, Confounding, COVID-19, 1103 Clinical Sciences, Odds ratio, Articles, Middle Aged, United Kingdom, 030228 respiratory system, Female, business, Cohort study, 1199 Other Medical and Health Sciences
Abstract: Background\ud \ud Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.\ud \ud \ud Methods\ud \ud In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.\ud \ud \ud Findings\ud \ud Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8–32·7) in March 9 to April 26, 2020, to 16·4% (15·0–17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65–0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94–0·95) of the reduction in in-hospital mortality.\ud \ud \ud Interpretation\ud \ud The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.\ud \ud \ud Funding\ud \ud National Institute for Health Research and the Medical Research Council.
Published: 2021
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26. Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study

Author: Rishi K Gupta, Joshua Rosenheim, Lucy C Bell, Aneesh Chandran, Jose A Guerra-Assuncao, Gabriele Pollara, Matthew Whelan, Jessica Artico, George Joy, Hibba Kurdi, Daniel M Altmann, Rosemary J Boyton, Mala K Maini, Aine McKnight, Jonathan Lambourne, Teresa Cutino-Moguel, Charlotte Manisty, Thomas A Treibel, James C Moon, Benjamin M Chain, Mahdad Noursadeghi, Hakam Abbass, Aderonke Abiodun, Mashael Alfarih, Zoe Alldis, Oliver E Amin, Mervyn Andiapen, João B Augusto, Georgiana L Baca, Sasha NL Bailey, Anish N Bhuva, Alex Boulter, Ruth Bowles, Olivia V Bracken, Ben O'Brien, Tim Brooks, Natalie Bullock, David K Butler, Gabriella Captur, Nicola Champion, Carmen Chan, David Collier, Jorge Couto de Sousa, Xose Couto-Parada, Rhodri H Davies, Brooke Douglas, Cecilia Di Genova, Keenan Dieobi-Anene, Mariana O Diniz, Anaya Ellis, Karen Feehan, Malcolm Finlay, Marianna Fontana, Nasim Forooghi, Celia Gaier, Joseph M Gibbons, Derek Gilroy, Matt Hamblin, Gabrielle Harker, Jacqueline Hewson, Lauren M Hickling, Aroon D Hingorani, Lee Howes, Alun Hughes, Gemma Hughes, Rebecca Hughes, Ivie Itua, Victor Jardim, Wing-Yiu Jason Lee, Melaniepetra Jensen, Jessica Jones, Meleri Jones, Vikas Kapil, Kai-Min Lin, Sarah Louth, Vineela Mandadapu, Áine McKnight, Katia Menacho, Celina Mfuko, Oliver Mitchelmore, Christopher Moon, Diana Munoz Sandoval, Sam M Murray, Ashley Otter, Corinna Pade, Susana Palma, Ruth Parker, Kush Patel, Babita Pawarova, Steffen E Petersen, Brian Piniera, Franziska P Pieper, Daniel Pope, Maria Prossora, Lisa Rannigan, Alicja Rapala, Catherine J Reynolds, Amy Richards, Matthew Robathan, Genine Sambile, Nathalie M Schmidt, Amanda Semper, Andreas Seraphim, Mihaela Simion, Angelique Smit, Michelle Sugimoto, Leo Swadling, Stephen Taylor, Nigel Temperton, Stephen Thomas, George D Thornton, Art Tucker, Jessry Veerapen, Mohit Vijayakumar, Sophie Welch, Theresa Wodehouse, Lucinda Wynne, Dan Zahedi, Medical Research Council (MRC), and UKRI
Subjects: Adult, Male, Microbiology (medical), medicine.medical_specialty, Adolescent, Standard score, Sensitivity and Specificity, Corrections, Microbiology, Virology, Internal medicine, Humans, Medicine, Prospective Studies, Prospective cohort study, COVIDsortium Investigators, QR355, Receiver operating characteristic, SARS-CoV-2, business.industry, Risk of infection, COVID-19, Gold standard (test), Articles, Middle Aged, Infectious Diseases, Case-Control Studies, Nested case-control study, Biomarker (medicine), Female, business, Viral load, Biomarkers
Abstract: Summary Background We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing. Methods We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew's Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for "viral infection", "transcriptome", "biomarker", and "blood". We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity. Findings We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27–47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91–0·99), sensitivity 0·84 (0·70–0·93), and specificity 0·95 (0·85–0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91–0·95). Interpretation Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge. Funding Barts Charity, Wellcome Trust, and National Institute of Health Research.
Published: 2021

27. Development and validation of the ISARIC 4C deterioration model for adults hospitalised with COVID-19: a prospective cohort study

Author: Rishi K Gupta, Ewen M Harrison, Antonia Ho, Annemarie B Docherty, Stephen R Knight, Maarten van Smeden, Ibrahim Abubakar, Marc Lipman, Matteo Quartagno, Riinu Pius, Iain Buchan, Gail Carson, Thomas M Drake, Jake Dunning, Cameron J Fairfield, Carrol Gamble, Christopher A Green, Sophie Halpin, Hayley E Hardwick, Karl A Holden, Peter W Horby, Clare Jackson, Kenneth A Mclean, Laura Merson, Jonathan S Nguyen-Van-Tam, Lisa Norman, Piero L Olliaro, Mark G Pritchard, Clark D Russell, James Scott-Brown, Catherine A Shaw, Aziz Sheikh, Tom Solomon, Cathie Sudlow, Olivia V Swann, Lance Turtle, Peter J M Openshaw, J Kenneth Baillie, Malcolm G Semple, Mahdad Noursadeghi, Peter JM Openshaw, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Ana da Silva Filipe, Tom Fletcher, Julian A Hiscox, Antonia Ying Wai Ho, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Wei Shen Lim, Alexander J Mentzer, Alison M Meynert, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Vanessa Sancho-Shimizu, Janet T Scott, Thushan de Silva, Louise Sigfrid, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, AA Roger Thompson, Ryan S Thwaites, Lance CW Turtle, Maria Zambon, Hayley Hardwick, Chloe Donohue, Ruth Lyons, Fiona Griffiths, Wilna Oosthuyzen, Tom M Drake, Stephen Knight, Derek Murphy, Jo Dalton, James Lee, Daniel Plotkin, Michelle Girvan, Scott Mullaney, Claire Petersen, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, William Greenhalf, Victoria Shaw, Sarah 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, Willliam Greenhalf, 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, L Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, 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, Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Ana Alegria, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Nicola Best, Pieter Bothma, David Brealey, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, 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, 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, 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, Igor Otahal, Mark Pais, Selva Panchatsharam, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Brendan Ryan, Taranprit Saluja, 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, Andrew Ustianowski, Nick Vallotton, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Sarah Wilson, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wooton, Andrew Workman, Bryan Yates, Peter Young, National Institute for Health Research, Commission of the European Communities, Medical Research Council (MRC), UKRI MRC COVID-19 Rapid Response Call, UK Research and Innovation, Gupta, Rishi K [0000-0002-6257-1285], Lipman, Marc [0000-0001-7501-4448], Buchan, Iain [0000-0003-3392-1650], and Apollo - University of Cambridge Repository
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Critical Care, Clinical Decision-Making, MEDLINE, Logistic regression, ResearchInstitutes_Networks_Beacons/humanitarian_conflict_response_institute, Severity of Illness Index, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, Patient Admission, Clinical Decision Rules, Severity of illness, Medicine, Humans, 030212 general & internal medicine, Hospital Mortality, Prospective Studies, Prospective cohort study, ISARIC4C Investigators, Aged, Aged, 80 and over, Clinical Deterioration, business.industry, SARS-CoV-2, Reproducibility of Results, COVID-19, 1103 Clinical Sciences, Articles, Middle Aged, Medical research, Prognosis, Respiration, Artificial, United Kingdom, Intensive Care Units, Logistic Models, 030228 respiratory system, Preparedness, Emergency medicine, Cohort, Humanitarian and Conflict Response Institute, Female, business, 1199 Other Medical and Health Sciences
Abstract: Background\ud \ud Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.\ud \ud \ud Methods\ud \ud We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).\ud \ud \ud Findings\ud \ud 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model.\ud \ud \ud Interpretation\ud \ud The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.\ud \ud \ud Funding\ud \ud National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.
Published: 2021
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28. QCOVID in Scotland: time to recalibrate our expectations?

Author: Rishi K Gupta and Maarten van Smeden
Subjects: Pulmonary and Respiratory Medicine, education.field_of_study, Actuarial science, Coronavirus disease 2019 (COVID-19), business.industry, media_common.quotation_subject, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Population, Primary care, Test (assessment), Pandemic, Medicine, Quality (business), education, business, Predictive modelling, media_common
Abstract: The field of prediction modelling has exploded during the COVID-19 pandemic, with countless studies seeking to derive and/or validate models to assist diagnosis of SARS-CoV-2 or to predict clinical outcomes of infection. While the vast majority of reports have been of a poor standard,1 there have been some examples of higher quality work, including the QCOVID prognostic model.2 Whereas most prediction models are intended to predict a single outcome, QCOVID seeks to predict the risk of acquiring and then either dying from or being hospitalised with SARS-CoV-2 in the general population. The model was originally derived using data from 6.1 million people in England during the first pandemic wave (January–April 2020) and showed promising performance in a recent analysis by the Office for National Statistics over a similar time period.3 QCOVID is implemented online,4 although stipulated for research rather than clinical use, and provides distinct probabilities of COVID-19 hospitalisation and COVID-19 mortality. Simpson et al report an external validation of QCOVID using data from Scotland over two periods (1 March 2020 to 30 April 2020 and 1 May 2020 to 30 June 2020), designed to test the performance of the algorithms during time intervals that aligned with the original QCOVID derivation and temporal validation cohorts.5 The authors use a population-based approach, including data from primary care facilities covering an impressive 99% of the Scottish population. The data provided …
Published: 2021
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29. Non-severe SARS-CoV-2 infection is characterised by very early T cell proliferation independent of type 1 interferon responses and distinct from other acute respiratory viruses

Author: Charlotte Manisty, Mahdad Noursadeghi, Amanda Semper, Leo Swadling, Mala K. Maini, Rishi K Gupta, Corrina Pade, Joseph M Gibbons, José Afonso Guerra-Assunção, Matthew Whelan, Gayathrie Nageswaran, Marc Robert de Massy, Tim Brooks, Gabriele Pollara, Tahel Ronel, Joshua Rosenheim, Áine McKnight, Thomas A. Treibel, Aneesh Chandran, Blanca Sanz-Magallon Duque De Estrada, James C. Moon, Rosemary J. Boyton, Annemarie Woolston, Gillian S. Tomlinson, COVIDsortium Investigators, Daniel M. Altmann, and Benjamin M. Chain
Subjects: Cell growth, viruses, T cell, T-cell receptor, Biology, Virus, Transcriptome, medicine.anatomical_structure, Interferon, Immunology, medicine, biology.protein, Cytotoxic T cell, Antibody, medicine.drug
Abstract: The correlates of natural protective immunity to SARS-CoV-2 in the majority who experience asymptomatic infection or non-severe disease are not fully characterised, and remain important as new variants emerge. We addressed this question using blood transcriptomics, multiparameter flow cytometry and T cell receptor (TCR) sequencing spanning the time of incident infection. We identified a type 1 interferon (IFN) response common to other acute respiratory viruses, and a cell proliferation response that discriminated SARS-CoV-2 from other viruses. These responses peaked by the time the virus was first detected, and in some preceded virus detection. Cell proliferation was most evident in CD8 T cells and associated with rapid expansion of SARS-CoV-2 reactive TCRs. We found an equally rapid increase in immunoglobulin transcripts, but circulating virus-specific antibodies lagged by 1-2 weeks. Our data support a protective role for rapid induction of type 1 IFN and CD8 T cell responses to SARS-CoV-2.
Published: 2021
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30. Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection

Author: Hibba Kurdi, Matthew Whelan, Gabriele Pollara, Jonathan Lambourne, James C. Moon, Rosemary J. Boyton, José Afonso Guerra-Assunção, Jessica Artico, Joshua Rosenheim, Daniel M. Altmann, Mahdad Noursadeghi, Teresa Cutino-Moguel, Thomas A. Treibel, Aneesh Chandran, Charlotte Manisty, Mala K. Maini, Lucy C K Bell, George Joy, Rishi K Gupta, Áine McKnight, and Benjamin M. Chain
Subjects: Receiver operating characteristic, business.industry, Transmission (medicine), Convalescence, media_common.quotation_subject, Confidence interval, Virus, Immunology, Biomarker (medicine), Medicine, Prospective cohort study, business, Viral load, media_common
Abstract: We hypothesised that host-response biomarkers of viral infections may contribute to early identification of SARS-CoV-2 infected individuals, critical to breaking chains of transmission. We identified 20 candidate blood transcriptomic signatures of viral infection by systematic review and evaluated their ability to detect SARS-CoV-2 infection, compared to the gold-standard of virus PCR tests, among a prospective cohort of 400 hospital staff subjected to weekly testing when fit to attend work. The transcriptional signatures had limited overlap, but were mostly co-correlated as components of type 1 interferon responses. We reconstructed each signature score in blood RNA sequencing data from 41 individuals over sequential weeks spanning a first positive SARS-CoV-2 PCR, and after 6-month convalescence. A single blood transcript for IFI27 provided the highest accuracy for discriminating individuals at the time of their first positive viral PCR result from uninfected controls, with area under the receiver operating characteristic curve (AUROC) of 0.95 (95% confidence interval 0.91–0.99), sensitivity 0.84 (0.7–0.93) and specificity 0.95 (0.85–0.98) at a predefined test threshold. The test performed equally well in individuals with and without symptoms, correlated with viral load, and identified incident infections one week before the first positive viral PCR with sensitivity 0.4 (0.17–0.69) and specificity 0.95 (0.85–0.98). Our findings strongly support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection, for screening individuals such as contacts of index cases, in order to facilitate early case isolation and early antiviral treatments as they emerge.
Published: 2021
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31. Time series analysis and mechanistic modelling of heterogeneity and sero-reversion in antibody responses to mild SARS‑CoV-2 infection

Author: Teresa Cutino-Moguel, James C. Moon, Ashley Otter, Stephen Taylor, Marianna Fontana, Benjamin M. Chain, Christopher William Moon, Mervyn Andiapen, Jonathan Lambourne, Dylan M. Williams, Daniel M. Altmann, Amanda Semper, Steve Thomas, Melanie Jensen, Mala K. Maini, George Joy, Rishi K Gupta, Mahdad Noursadeghi, Jason J. Lee, Rosemary J. Boyton, Thomas A. Treibel, Meleri Jones, Joseph M Gibbons, Corrina Pade, Joanna Bacon, Jessica Jones, Charlotte Manisty, Áine McKnight, and Medical Research Council (MRC)
Subjects: 0301 basic medicine, Health Personnel, lcsh:Medicine, Antibodies, Viral, Asymptomatic, General Biochemistry, Genetics and Molecular Biology, Serology, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, medicine, Coronavirus Nucleocapsid Proteins, Humans, Prospective cohort study, Neutralizing antibody, lcsh:R5-920, biology, business.industry, SARS-CoV-2, lcsh:R, Viral nucleocapsid, COVID-19, 1103 Clinical Sciences, General Medicine, Phosphoproteins, Antibodies, Neutralizing, Immunoglobulin A, 030104 developmental biology, 030220 oncology & carcinogenesis, SARS-CoV-2, Serology, Mathematical modelling, Sero-reversion, Immunoglobulin G, Humoral immunity, Immunology, Spike Glycoprotein, Coronavirus, biology.protein, Antibody, medicine.symptom, business, lcsh:Medicine (General), Blood sampling, Research Paper
Abstract: BACKGROUND: SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. METHODS: Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. FINDINGS: A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r = 0.57, p
Published: 2020

32. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score

Author: Jonathan S. Nguyen-Van-Tam, Gail Carson, Thomas M Drake, Ewen M Harrison, Aziz Sheikh, Annemarie B Docherty, Tom Solomon, J Kenneth Baillie, Laura Merson, Rishi K Gupta, Antonia Ho, Jake Dunning, Cathie Sudlow, Clark D Russell, Cameron J Fairfield, Peter Horby, Riinu Pius, Malcolm G Semple, Mark G Pritchard, Piero Olliaro, Iain Buchan, Lisa Norman, Sophie Halpin, Stephen R Knight, Clare Jackson, Olivia Swann, Christopher A Green, Catherine A Shaw, Mahdad Noursadeghi, Lance Turtle, Hayley E Hardwick, Karl A Holden, Peter J. M. Openshaw, Carrol Gamble, Kenneth A. McLean, Sigfrid, L, Baillie, JK, Semple, MG, Openshaw, PJM, Carson, G, Alex, B, Bach, B, Barclay, WS, Bogaert, D, Chand, M, Cooke, GS, Docherty, AB, Dunning, J, Da Silva Filipe, A, Fletcher, T, Green, CA, Harrison, EM, Hiscox, JA, Ho, AYW, Horby, PW, Ijaz, S, Khoo, S, Klenerman, P, Law, A, Lim, WS, Mentzer, AJ, Merson, L, Meynert, AM, Noursadeghi, M, Moore, SC, Palmarini, M, Paxton, WA, Pollakis, G, Price, N, Rambaut, A, Robertson, DL, Russell, CD, Sancho-Shimizu, V, Scott, JT, Solomon, T, Sriskandan, S, Stuart, D, Summers, C, Tedder, RS, Thomson, EC, Thwaites, RS, Turtle, LCW, Zambon, M, Hardwick, H, Donohue, C, Ewins, J, Oosthuyzen, W, Griffiths, F, Norman, L, Pius, R, Drake, TM, Fairfield, CJ, Knight, S, Mclean, KA, Murphy, D, Shaw, CA, Dalton, J, Girvan, M, Saviciute, E, Roberts, S, Harrison, J, Marsh, L, Connor, M, Halpin, S, Jackson, C, Gamble, C, Leeming, G, Hendry, R, Scott-Brown, J, Greenhalf, W, Shaw, V, McDonald, S, Ahmed, KA, Armstrong, JA, Ashworth, M, Asiimwe, IG, Bakshi, S, Barlow, SL, Booth, L, Brennan, B, Bullock, K, Catterall, BWA, Clark, JJ, Clarke, EA, Cole, S, Cooper, L, Cox, H, Davis, C, Dincarslan, O, Dunn, C, Dyer, P, Elliott, A, Evans, A, Fisher, LWS, Foster, T, Garcia-Dorival, I, Gunning, P, Hartley, C, Ho, A, Jensen, RL, Jones, CB, Jones, TR, Khandaker, S, King, K, Kiy, RT, Koukorava, C, Lake, A, Lant, S, Latawiec, D, Lavelle-Langham, L, Lefteri, D, Lett, L, Livoti, LA, Mancini, M, McEvoy, L, McLauchlan, J, Metelmann, S, Miah, NS, Middleton, J, Mitchell, J, Murphy, EG, Penrice-Randal, R, Pilgrim, J, Prince, T, Reynolds, W, Ridley, PM, Sales, D, Shaw, VE, Shears, RK, Small, B, Subramaniam, KS, Szemiel, A, Taggart, A, Tanianis-Hughes, J, Thomas, J, Trochu, E, Van Tonder, L, Wilcock, E, Zhang, JE, Adeniji, K, Agranoff, D, Agwuh, K, Ail, D, Alegria, A, Angus, B, Ashish, A, Atkinson, D, Bari, S, Barlow, G, Barnass, S, Barrett, N, Bassford, C, Baxter, D, Beadsworth, M, Bernatoniene, J, Berridge, J, Best, N, Bothma, P, Brealey, D, Brittain-Long, R, Bulteel, N, Burden, T, Burtenshaw, A, Caruth, V, Chadwick, D, Chambler, D, Chee, N, Child, J, Chukkambotla, S, Clark, T, Collini, P, Cosgrove, C, Cupitt, J, Cutino-Moguel, M-T, Dark, P, Dawson, C, Dervisevic, S, Donnison, P, Douthwaite, S, DuRand, I, Dushianthan, A, Dyer, T, Evans, C, Eziefula, C, Fegan, C, Finn, A, Fullerton, D, Garg, S, Garg, A, Godden, J, Goldsmith, A, Graham, C, Hardy, E, Hartshorn, S, Harvey, D, Havalda, P, Hawcutt, DB, Hobrok, M, Hodgson, L, Holme, A, Hormis, A, Jacobs, M, Jain, S, Jennings, P, Kaliappan, A, Kasipandian, V, Kegg, S, Kelsey, M, Kendall, J, Kerrison, C, Kerslake, I, Koch, O, Koduri, G, Koshy, G, Laha, S, Larkin, S, Leiner, T, Lillie, P, Limb, J, Linnett, V, Little, J, MacMahon, M, MacNaughton, E, Mankregod, R, Masson, H, Matovu, E, McCullough, K, McEwen, R, Meda, M, Mills, G, Minton, J, Mirfenderesky, M, Mohandas, K, Mok, Q, Moon, J, Moore, E, Morgan, P, Morris, C, Mortimore, K, Moses, S, Mpenge, M, Mulla, R, Murphy, M, Nagel, M, Nagarajan, T, Nelson, M, Otahal, I, Pais, M, Panchatsharam, S, Paraiso, H, Patel, B, Pepperell, J, Peters, M, Phull, M, Pintus, S, Pooni, JS, Post, F, Price, D, Prout, R, Rae, N, Reschreiter, H, Reynolds, T, Richardson, N, Roberts, M, Roberts, D, Rose, A, Rousseau, G, Ryan, B, Saluja, T, Shah, A, Shanmuga, P, Sharma, A, Shawcross, A, Sizer, J, Smith, R, Snelson, C, Spittle, N, Staines, N, Stambach, T, Stewart, R, Subudhi, P, Szakmany, T, Tatham, K, Thompson, C, Thompson, R, Tridente, A, Tupper-Carey, D, Twagira, M, Ustianowski, A, Vallotton, N, Vincent-Smith, L, Visuvanathan, S, Vuylsteke, A, Waddy, S, Wake, R, Walden, A, Welters, I, Whitehouse, T, Whittaker, P, Whittington, A, Wijesinghe, M, Williams, M, Wilson, L, Wilson, S, Winchester, S, Wiselka, M, Wolverson, A, Wooton, DG, Workman, A, Yates, B, Young, P, National Institute for Health Research, Medical Research Council (MRC), UKRI MRC COVID-19 Rapid Response Call, Semple, Malcolm G [0000-0001-9700-0418], and Apollo - University of Cambridge Repository
Subjects: Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Pneumonia, Viral, Risk Assessment, Corrections, Article, 1117 Public Health and Health Services, Cohort Studies, Betacoronavirus, Level of consciousness, Clinical Protocols, Predictive Value of Tests, Internal medicine, General & Internal Medicine, Medicine, Humans, Derivation, Hospital Mortality, ISARIC4C investigators, Survival rate, Pandemics, Aged, Protocol (science), Aged, 80 and over, Framingham Risk Score, Receiver operating characteristic, business.industry, SARS-CoV-2, Mortality rate, COVID-19, 1103 Clinical Sciences, General Medicine, Middle Aged, Confidence interval, United Kingdom, Hospitalization, Survival Rate, ROC Curve, Predictive value of tests, Cohort, Female, business, Coronavirus Infections, Cohort study
Abstract: ObjectiveTo develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19).DesignProspective observational cohort study.SettingInternational Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium—ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020.ParticipantsAdults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction.Main outcome measureIn-hospital mortality.Results35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73).ConclusionsAn easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations.Study registrationISRCTN66726260
Published: 2020
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33. Characterising heterogeneity and sero-reversion in antibody responses to mild SARS⍰CoV-2 infection: a cohort study using time series analysis and mechanistic modelling

Author: Mervyn Andiapen, Mala K. Maini, Jonathan Lambourne, George Joy, Rishi K Gupta, Amanda Semper, Charlotte Manisty, Stephen Taylor, Mahdad Noursadeghi, Meleri Jones, Timothy Brooks, Marianna Fontana, Jessica Jones, Corinna Pade, Dylan M. Williams, Joseph M Gibbons, Melanie Jensen, Ashley Otter, COVIDsortium Investigators, James C. Moon, Áine McKnight, Wing-Yiu Jason Lee, Rosemary J. Boyton, Thomas A. Treibel, Benny Chain, Daniel M. Altmann, and Maria-Teresa Cutino-Moguel
Subjects: education.field_of_study, biology, business.industry, Population, Viral nucleocapsid, Context (language use), Serology, Immunology, biology.protein, Medicine, Seroconversion, Antibody, business, education, Prospective cohort study, Blood sampling
Abstract: BackgroundSARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity.MethodsHealth-care workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n=12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to previously reported pseudovirus neutralising antibody measurements.FindingsA total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r=0.57, pInterpretationMild SARS-CoV-2 infection is associated with heterogenous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. The application of individual assays for diagnostic and epidemiological serology requires validation in time series analysis.FundingCharitable donations via Barts CharityResearch in contextEvidence before this studyWe searched PubMed, medRxiv, and bioRxiv for [“antibody” OR “serology”] AND [“SARS-CoV-2” OR “COVID-19”]. The available literature highlights widespread use of serology to detect recent SARS-CoV-2 infection in individual patients and in population epidemiological surveys. Antibody to virus spike protein S1 domain is widely reported to correlate with neutralising antibody titres. The existing assays have good sensitivity to detect seroconversion within 14 days of incident infection, but the available longitudinal studies have reported variable rates of decline in antibody levels and reversion to undetectable levels in some people over 3 months. High frequency multi-time point serology data for different antibody targets or assays in longitudinal cohorts from the time of incident infection to greater than 3 months follow up are lacking.Added value of this studyWe combine detailed longitudinal serology using the Euroimmun anti-S1 and Roche anti-nucleocapsid protein (NP) assays in 731 health care workers from the time of the first SARS-CoV-2 epidemic peak in London, UK. In 157 seroconverters (using either assay) we show substantial heterogeneity in semiquantitative antibody measurements over time between individuals and between assays. Mathematical modelling of individual participant antibody production and clearance rates in individuals with at least 8 data points over 21 weeks showed anti-S1 antibodies to have a faster clearance rate, earlier transition from the initial antibody production rate to lower rates, and greater reduction in antibody production rate after this transition, compared to anti-NP antibodies as measured by these assays. As a result, Euroimmun anti-S1 measurements peaked earlier and then reduced more rapidly than Roche anti-NP measurements. In this study, these differences led to 21% anti-S1 sero-reversion, compared to 4% anti-NP sero-reversion over 4-5 months.Implications of all of the available evidenceThe rapid decline in anti-S1 antibodies measured by the Euroimmun assay following infection limits its application for diagnostic and epidemiological screening. If generalisable, these data are consistent with the hypothesis that anti-S1 mediated humoral immunity may not be sustained in some people beyond the initial post-infective period. Further work is required to understand the mechanisms behind the heterogeneity in antibody kinetics between individuals to SARS-CoV-2. Our data point to differential mechanisms regulating humoral immunity against these two viral targets.
Published: 2020
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34. An unfavourable outcome following switching intravenous abatacept and tocilizumab to subcutaneous forms during the COVID-19 pandemic

Author: Michael R. Ehrenstein, Su-Ann Yeoh, Rishi K Gupta, Pauline Buck, and Muhammad Shipa
Subjects: medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Injections, Subcutaneous, MEDLINE, Self Administration, Antibodies, Monoclonal, Humanized, Abatacept, Arthritis, Rheumatoid, chemistry.chemical_compound, Tocilizumab, Rheumatology, Internal medicine, Pandemic, medicine, Humans, Pharmacology (medical), Infusions, Intravenous, AcademicSubjects/MED00360, business.industry, Drug Substitution, SARS-CoV-2, COVID-19, Patient Preference, Treatment Outcome, chemistry, Letter to the Editor (Other), Antirheumatic Agents, Disease Progression, business, Decision Making, Shared, medicine.drug
Published: 2020

35. Development and validation of the 4C Deterioration model for adults hospitalised with COVID-19

Author: Malcolm G Semple, Jake Dunning, Riinu Pius, Clark D Russell, Kenneth A. McLean, Catherine Sudlow, van Smeden M, Gail Carson, Peter J. M. Openshaw, Peter Horby, Iain Buchan, Ewen M Harrison, Ibrahim Abubakar, Lisa Norman, C. Jackson, Aziz Sheikh, Knight, Piero Olliaro, Catherine A Shaw, Matteo Quartagno, Tom Solomon, Olivia Swann, Cameron J Fairfield, Carrol Gamble, Jonathan S. Nguyen-Van-Tam, Mark G Pritchard, Christopher A Green, Laura Merson, Mahdad Noursadeghi, Thomas M Drake, Hayley Hardwick, Marc Lipman, Halpin S, Annemarie B Docherty, James Scott-Brown, Rishi K Gupta, Antonia Ho, Lance Turtle, Karl A Holden, and J K Baillie
Subjects: medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Emergency medicine, medicine, Logistic regression, business, Prognostic models
Abstract: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 are required to inform clinical management decisions. Among 75,016 consecutive adults across England, Scotland and Wales prospectively recruited to the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) study, we developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) using 11 routinely measured variables. We used internal-external cross-validation to show consistent measures of discrimination, calibration and clinical utility across eight geographical regions. We further validated the final model in held-out data from 8,252 individuals in London, with similarly consistent performance (C-statistic 0.77 (95% CI 0.75 to 0.78); calibration-in-the-large 0.01 (−0.04 to 0.06); calibration slope 0.96 (0.90 to 1.02)). Importantly, this model demonstrated higher net benefit than using other candidate scores to inform decision-making. Our 4C Deterioration model thus demonstrates unprecedented clinical utility and generalisability to predict clinical deterioration among adults hospitalised with COVID-19.
Published: 2020
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36. Predictive performance of interferon-γ release assays and tuberculin skin tests

Author: Yohhei Hamada, Ibrahim Abubakar, Alberto Matteelli, Molebogeng X Rangaka, and Rishi K Gupta
Subjects: Infectious Diseases, Interferon γ, business.industry, Latent Tuberculosis, Tuberculin Test, Immunology, Tuberculin, Medicine, Humans, business, Interferon-gamma Release Tests
Published: 2020

37. The relationship between social risk factors and latent tuberculosis infection among individuals residing in England: a cross-sectional study

Author: Rishi K Gupta, Jo Southern, Maria Krutikov, Swaib A. Lule, Ibrahim Abubakar, and Charlotte Jackson
Subjects: medicine.medical_specialty, Tuberculosis, Cross-sectional study, 01 natural sciences, State Medicine, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Risk Factors, Environmental health, Epidemiology, medicine, Humans, lcsh:RC109-216, 030212 general & internal medicine, Prospective Studies, 0101 mathematics, Risk factor, Original Research, lcsh:R5-920, Latent tuberculosis, business.industry, Tuberculin Test, Health Policy, Public health, 010102 general mathematics, public health, Public Health, Environmental and Occupational Health, Odds ratio, medicine.disease, bacterial infections and mycoses, United Kingdom, Social deprivation, Cross-Sectional Studies, England, tuberculosis, epidemiology, lcsh:Medicine (General), business
Abstract: ObjectiveTo investigate the relationship between social risk factors and latent tuberculosis infection (LTBI) among individuals who are eligible for LTBI screening in the United Kingdom (UK).MethodsThis cross-sectional study used data collected in the UK Prognostic Evaluation of Diagnostic Interferon-Gamma Release Assays (IGRAs) Consortium Study which enrolled 9176 recent tuberculosis (TB) contacts and migrants at National Health Service (NHS) facilities and community settings in the UK. The study outcome was LTBI (positive IGRA test (QuantiFERON-TB Gold In-Tube or T-SPOT.TB)). The main exposures were history of smoking, history of substance misuse, homelessness, prison stay and socioeconomic deprivation.Results4914 (56.2%) individuals resided in the most deprived areas and 2536 (27.6%) had LTBI. In the multivariable analysis (adjusting for age, gender, place of birth, ethnicity, HIV status, BCG vaccination and recent TB contact) living in the least deprived areas compared with living in the most deprived areas was associated with reduced odds of LTBI (odds ratio (OR)=0.68, 95% CI: 0.51 to 0.90) while ever been homeless (OR=1.50, 95% CI: 1.02 to 2.21) was associated with increased odds of LTBI. Smoking, homelessness and substance misuse were not associated with LTBI.ConclusionSocial deprivation could be an important risk factor for LTBI, highlighting the social inequality in the burden of TB infection in the UK. Migrants and TB contacts who were socially deprived or homeless were at a significantly higher risk for LTBI, thus tailored intense public health interventions to these groups may help to reduce the risk of future TB disease.Trial registration numberClinicalTrials.gov Registry (NCT01162265).
Published: 2020

38. Systematic evaluation and external validation of 22 prognostic models among hospitalised adults with COVID-19: An observational cohort study

Author: Thomas H. A. Samuels, Wai Keong Wong, Ibrahim Abubakar, Matteo Quartagno, Akish Luintel, Marc Lipman, Rishi K Gupta, Arjun Nair, Maarten van Smeden, Mahdad Noursadeghi, Bryan Williams, Humayra Chowdhury, Michael Marks, and Tommy Rampling
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Receiver operating characteristic, business.industry, MEDLINE, External validation, 030204 cardiovascular system & hematology, Secondary care, 03 medical and health sciences, 0302 clinical medicine, Patient age, Internal medicine, Emergency medicine, Cohort, medicine, Original Article, 030212 general & internal medicine, business, Patient stratification, Prognostic models, Cohort study
Abstract: Background The number of proposed prognostic models for COVID-19 is growing rapidly, but it is unknown whether any are suitable for widespread clinical implementation. Methods We independently externally validated the performance candidate prognostic models, identified through a living systematic review, among consecutive adults admitted to hospital with a final diagnosis of COVID-19. We reconstructed candidate models as per original descriptions and evaluated performance for their original intended outcomes using predictors measured at admission. We assessed discrimination, calibration and net benefit, compared to the default strategies of treating all and no patients, and against the most discriminating predictor in univariable analyses. Results We tested 22 candidate prognostic models among 411 participants with COVID-19, of whom 180 (43.8%) and 115 (28.0%) met the endpoints of clinical deterioration and mortality, respectively. Highest areas under receiver operating characteristic (AUROC) curves were achieved by the NEWS2 score for prediction of deterioration over 24 h (0.78; 95% CI 0.73–0.83), and a novel model for prediction of deterioration, Oxygen saturation on room air and patient age are strong predictors of deterioration and mortality among hospitalised adults with COVID-19, respectively. None of the 22 prognostic models evaluated in this study add incremental value to these univariable predictors.
Published: 2020
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39. Urgent call for greater multilateralism and coordination of covid-19 trials

Author: Marc Lipman, Ibrahim Abubakar, Lucy C K Bell, and Rishi K Gupta
Subjects: medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MEDLINE, General Medicine, 030204 cardiovascular system & hematology, Multilateralism, 03 medical and health sciences, 0302 clinical medicine, medicine, 030212 general & internal medicine, Intensive care medicine, business
Abstract: Glasziou and colleagues discuss the waste in covid-19 research that amplifies pre-existing failures.1 We think the situation goes beyond waste. Delaying publication of trial results after data have been collected and analysed is unethical. It leads to ongoing use of ineffective and potentially toxic compounds, plus avoidable and potentially harmful initiation of new studies using the same compounds. Moreover, the sheer number of small trials runs the risk of falsely finding apparent benefit, which is complicated by the potential misuse …
Published: 2020
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40. Modelling SARS-COV2 Spread in London: Approaches to Lift the Lockdown

Author: Lara Goscé, Paula Spinola, Andrew N. Phillips, Ibrahim Abubakar, and Rishi K Gupta
Subjects: Adult, Microbiology (medical), Adolescent, Coronavirus disease 2019 (COVID-19), Computer science, Pneumonia, Viral, Psychological intervention, Article, Older population, Betacoronavirus, Young Adult, London, Pandemic, Humans, Child, Pandemics, Health policy, Infection Control, Models, Statistical, Actuarial science, SARS-CoV-2, Lift (data mining), Health Policy, Age Factors, Infant, Newborn, other, COVID-19, Infant, Middle Aged, High uptake, Infectious Diseases, Child, Preschool, Coronavirus Infections, Contact tracing
Abstract: Background: The ongoing coronavirus disease 2019 (COVID-19) pandemic is a major global threat. Several mathematical modelling studies have investigated the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), along with the effectiveness of interventions to interrupt transmission nationally in the UK and elsewhere. Methods: We present a mathematical model for the transmission of SARS-CoV2 in London. The model was parametrised using data on notified cases, deaths, contacts, and mobility to analyse the epidemic in the UK capital. We investigated the impact of multiple non pharmaceutical interventions (NPIs) and combinations of these measures on future incidence of COVID-19. Findings: Immediate action at the early stages of an epidemic in the affected districts would have tackled spread. While an extended lockdown is highly effective, other measures such as shielding older populations, universal testing and facemasks can all potentially contribute to a reduction of infections and deaths. However, based on current evidence it seems unlikely they will be as effective as continued lockdown. In order to achieve elimination and lift lockdown within 5 months, the best strategy seems to be a combination of weekly universal testing, contact tracing and use of facemasks, with concurrent lockdown. This approach could potentially reduce deaths by 76% compared with continued lockdown alone. Interpretation: A combination of NPIs such as universal testing, contact tracing and mask use while under lockdown would be associated with least deaths and infections. This approach would require high uptake and sustained local effort but it is potentially feasible as may lead to elimination in a relatively short time scale.
Published: 2020

41. Exploring UK medical school differences: the MedDifs study of selection, teaching, student and F1 perceptions, postgraduate outcomes and fitness to practise

Author: Richard Nzewi, Luke Debenham, Calum MacMillan, Kiran Nadeem, Zoe Carrington, Omar Risk, Rebecca Razey, James Parkin, Sam Myers, Asanish Kalyanasundaram, Mark Awad, Zein Gowie, Julian Purdy, Simon E. V. Phillips, Zoe Wellbelove, Mike Jones, Priscilla Kirkland, Nadine Abbas, Oluseyi Adesalu, Roxanne Tajbakhsh, Oliver Shotton, Adele Heaney, Joseph Brandreth, Benjamin Human, Jamie Mac Donald Burrell, Benjamin Thompson, Wassim Merzougui, Chris Harlow, Matthew South, Angelos Mantelakis, Nora Sangvik Grandal, Samuel C. Barnes, Daniel Sims, Fady Sameh Anis, Hannah Lawrence-Smith, Thomas P. W. Cope, Farris Ziyada, Saad Majeed, Carmel Razzaghi, Jack Eldridge, Rachel Maguire, Amy Harrington, Simon Lubbock, Abdul Muiz Azri Yahaya, Roshan Ullah, Oliver P. Devine, Zoe Cashin, Usman Rasul, Daniel Tadross, Pranoy Sangal, Ngan Hong Ta, Ammar Ahmed, Mehar Chawla, Sarah Freeston, Hugo Layard Horsfall, Sohini Pawar, Eve Lancaster, Harriet Hunter, Richard Clough, Alex Eyre, Sonam Aojula, Prabhjot Singh Malhotra, Elliot Raymond-Taggert, Ciaran Grafton-Clarke, Abdelrahman Said, Katherine Aiken, Ryan Janjuha, Adam Sage, Wing Hang Serene Ho, Shree Vadera, Joyce Omatseye, Aninditya Salma Sopian, Daisy Bassey-Duke, Samuel Penrice, Tom Newman, Sarah Douglas, Helen Gilbert, Jia Jun Ang, Aisha Sooltangos, Leher Gumber, Raisa Ramjan, Nasreen Desai, Shaunak Chatterjee, Oloruntobi Rotimi, Shreya Badhrinarayanan, Chris Clements, Harriet Van Den Tooren, Bronwen Jacob-Ramsdale, Savraj Kalsi, Mrudula Utukuri, Soham Bandyopadhyay, Eleanor Houghton, Meron Esere, Sadhana Kalidindi, Chung Shen Chean, James Coultas, Emma Sanders, Jessica Coulthurst, Ahmed Ashraf, Nick Smith, Whitney General, Katherine Garnett, Emma L Howard, Joanna Rigbye, Rebecca Braine, Saba Houshangi, Christina Hood, Aadam Shah, Praveen Mahendran, Ifrah Hussain, Ben Phillips, Keshni Gudka, Alimatu Sadia Akeredolu, Reza Nasseri, Tobin Joseph, Vinay Mandagere, Charlotte Leeson, Jess Trevett, Anjola Mosuro, Othman Khaled Al-Othman, Thomas Hughes-Gooding, Eimear Reel, Vinnie Christine Daniels, Liora Wittner, Sophie Paddock, Verity Ford, Daniel Smith, Sara Venturini, Rahul Atul Shah, Martha Amy Smith, Matthew Tyler, Charlotte Boreham, Ratan Randhawa, Katie Smart, Richard Thomas Jackson-Taylor, Agnieszka Jakubowska, Andrew Christopher Harborne, Jessica Speller, Sophie Mustoe, Ibrahim Alam, Richard B. Anderson, Mohit Patel, Tess Marshall-Andon, Liam Curry, Elliot John Revell, Sami Hussain, Hassan Baig, Geoffrey Hong Kiat Yong, Emma Aspinall, Robert Spencer, Sajan Khullar, Ryan Samuels, Saleh Jawad, Oliver Jones, Ivan Aganin, Rebecca Davis, Hanelie De Waal, I. C. McManus, Ryan Clark, Adam Moxley, Charlie Caird, Ibrahim T. Fazmin, Natasha Benons, Rosalie Ogborne, Rishi K Gupta, Sahaj Kaur, Melanie Vine, Muzzamil Jelani, James Druce, Julius Elisabeth Richard Lenaerts, Anna Kane, Lucy Holloway, Lady Namera Ejamike, Tom Joseph Syer, Alena Ashby, Sophie McGovern, Simon Davies, Sophia Fitzgerald-Smith, Aradhya Vijayakumar, Stuart Pearce, Kerry Long, Joseph Beecham, Catherine Arthur, Qaisar Khan, Joshua William Kearsley, David Johnston, Ross McAllister, Hannah Douglas, Aamna Ali, McManus, I. C. [0000-0003-3510-4814], Harborne, Andrew Christopher [0000-0003-0937-1492], Horsfall, Hugo Layard [0000-0001-7848-5325], Joseph, Tobin [0000-0002-9283-9895], Smith, Daniel T. [0000-0003-1215-5811], Marshall-Andon, Tess [0000-0001-8909-1639], Samuels, Ryan [0000-0002-0886-7990], Abbas, Nadine [0000-0002-9116-2915], Baig, Hassan [0000-0001-8999-0474], Beecham, Joseph [0000-0002-4390-9164], Benons, Natasha [0000-0002-0750-6560], Caird, Charlie [0000-0001-7553-5585], Clark, Ryan [0000-0002-6143-9098], Cope, Thomas [0000-0003-0247-7411], Coultas, James [0000-0003-3381-8936], Debenham, Luke [0000-0002-3300-7802], Douglas, Sarah [0000-0003-3272-8154], Eldridge, Jack [0000-0001-6792-7714], Hughes-Gooding, Thomas [0000-0001-8483-5686], Jakubowska, Agnieszka [0000-0003-3153-8666], Jones, Oliver [0000-0003-4334-3567], Lancaster, Eve [0000-0001-5703-252X], MacMillan, Calum [0000-0002-8167-0051], McAllister, Ross [0000-0003-1686-1174], Merzougui, Wassim [0000-0001-7398-0095], Phillips, Ben [0000-0002-0489-6700], Risk, Omar [0000-0002-9226-9263], Sage, Adam [0000-0002-7763-404X], Sooltangos, Aisha [0000-0001-5675-1709], Spencer, Robert [0000-0001-9045-6260], Tajbakhsh, Roxanne [0000-0002-3753-6306], Adesalu, Oluseyi [0000-0001-8796-2701], Aganin, Ivan [0000-0002-3711-9430], Aiken, Katherine [0000-0002-3245-7772], Alam, Ibrahim [0000-0003-2853-623X], Ali, Aamna [0000-0003-1255-6113], Anderson, Richard [0000-0003-4734-0208], Anis, Fady Sameh [0000-0002-0950-3777], Arthur, Catherine [0000-0001-9551-6250], Ashraf, Ahmed [0000-0002-3921-8395], Aspinall, Emma [0000-0001-8307-1661], Awad, Mark [0000-0002-6570-010X], Yahaya, Abdul-Muiz Azri [0000-0002-7846-9322], Badhrinarayanan, Shreya [0000-0002-7159-098X], Bandyopadhyay, Soham [0000-0001-6553-3842], Barnes, Sam [0000-0001-6009-406X], Bassey-Duke, Daisy [0000-0002-0408-1042], Boreham, Charlotte [0000-0003-4828-0542], Braine, Rebecca [0000-0003-2751-3378], Brandreth, Joseph [0000-0002-6137-5928], Carrington, Zoe [0000-0002-0006-8334], Chawla, Mehar [0000-0003-0697-815X], Chean, Chung Shen [0000-0002-1625-4078], Clements, Chris [0000-0002-2567-5536], Clough, Richard [0000-0001-6941-7881], Coulthurst, Jessica [0000-0003-0714-9572], Curry, Liam [0000-0002-6906-5502], Daniels, Vinnie Christine [0000-0001-9461-8431], Davies, Simon [0000-0001-5556-7512], Davis, Rebecca [0000-0002-6960-5580], De Waal, Hanelie [0000-0002-9131-9521], Desai, Nasreen [0000-0003-4601-9084], Douglas, Hannah [0000-0001-8113-5465], Druce, James [0000-0001-6849-8560], Ejamike, Lady-Namera [0000-0001-6196-5584], Esere, Meron [0000-0002-1838-0756], Eyre, Alex [0000-0002-0474-5662], Fazmin, Ibrahim Talal [0000-0002-3300-6279], Ford, Verity [0000-0002-1364-8522], Freeston, Sarah [0000-0001-8768-5513], Garnett, Katherine [0000-0003-1135-6478], General, Whitney [0000-0002-9222-4233], Gilbert, Helen [0000-0002-5588-411X], Gowie, Zein [0000-0002-7597-7508], Grafton-Clarke, Ciaran [0000-0002-8537-0806], Gudka, Keshni [0000-0003-0880-6992], Gumber, Leher [0000-0003-0154-1207], Gupta, Rishi [0000-0003-3839-7982], Harlow, Chris [0000-0003-2912-0594], Heaney, Adele [0000-0002-0905-4342], Ho, Wing Hang Serene [0000-0002-2687-3198], Hood, Christina [0000-0001-6821-6324], Howard, Emma [0000-0001-8411-5734], Human, Benjamin [0000-0003-4445-0639], Hunter, Harriet [0000-0002-5204-2371], Hussain, Sami [0000-0002-8654-3617], Jackson-Taylor, Richard Thomas [0000-0002-6949-2977], Jacob-Ramsdale, Bronwen [0000-0001-6215-808X], Jawad, Saleh [0000-0001-8221-9871], Jelani, Muzzamil [0000-0003-3785-415X], Johnston, David [0000-0002-7078-7510], Kalidindi, Sadhana [0000-0002-4274-2913], Kalsi, Savraj [0000-0001-9103-5089], Kalyanasundaram, Asanish [0000-0003-4175-5998], Kane, Anna [0000-0002-6197-2511], Kaur, Sahaj [0000-0002-3446-6082], Al-Othman, Othman Khaled [0000-0001-5930-8593], Khan, Qaisar [0000-0002-5486-4205], Khullar, Sajan [0000-0001-6426-2892], Kirkland, Priscilla [0000-0003-2452-4207], Leeson, Charlotte [0000-0003-4735-2452], Lenaerts, Julius Elisabeth Richard [0000-0002-1626-7792], Long, Kerry [0000-0003-4546-5509], Burrell, Jamie Mac Donald [0000-0002-8175-3973], Maguire, Rachel [0000-0003-4855-5550], Mahendran, Praveen [0000-0002-4084-5222], Majeed, Saad [0000-0003-4289-5597], Malhotra, Prabhjot Singh [0000-0001-7463-3941], Mandagere, Vinay [0000-0002-2969-6457], Mantelakis, Angelos [0000-0001-7109-943X], McGovern, Sophie [0000-0002-6198-7553], Mosuro, Anjola [0000-0002-9013-9289], Moxley, Adam [0000-0001-9794-091X], Mustoe, Sophie [0000-0002-7870-1320], Myers, Sam [0000-0001-6050-4663], Nadeem, Kiran [0000-0001-5988-6780], Newman, Tom [0000-0002-7987-9948], Nzewi, Richard [0000-0002-8159-1302], Ogborne, Rosalie [0000-0003-3327-6030], Omatseye, Joyce [0000-0001-7472-4712], Parkin, James [0000-0002-1861-0822], Patel, Mohit [0000-0003-1168-2759], Pawar, Sohini [0000-0003-0224-5258], Pearce, Stuart [0000-0002-7482-0752], Penrice, Samuel [0000-0002-1142-6686], Ramjan, Raisa [0000-0002-2020-2123], Randhawa, Ratan [0000-0002-4749-4410], Rasul, Usman [0000-0001-5820-1313], Raymond-Taggert, Elliot [0000-0003-1514-6662], Razey, Rebecca [0000-0003-1971-3580], Razzaghi, Carmel [0000-0002-3264-8528], Revell, Elliot John [0000-0001-6025-094X], Rigbye, Joanna [0000-0003-4860-4084], Rotimi, Oloruntobi [0000-0002-1385-1993], Said, Abdelrahman [0000-0002-9801-4202], Sangal, Pranoy [0000-0001-5775-5859], Grandal, Nora Sangvik [0000-0002-2461-7852], Shah, Aadam [0000-0003-1841-5530], Shah, Rahul Atul [0000-0002-6981-7305], Shotton, Oliver [0000-0001-6684-3308], Sims, Daniel [0000-0002-6916-3719], Smith, Martha Amy [0000-0002-4652-3507], Smith, Nick [0000-0003-4478-2772], South, Matthew [0000-0003-2297-1089], Speller, Jessica [0000-0001-5503-4791], Ta, Ngan Hong [0000-0002-8747-5329], Tadross, Daniel [0000-0002-3593-0182], Thompson, Benjamin [0000-0002-2491-5235], Trevett, Jess [0000-0001-5008-1724], Ullah, Roshan [0000-0002-5140-6655], Utukuri, Mrudula [0000-0003-1510-469X], Vadera, Shree [0000-0001-9492-7541], Van Den Tooren, Harriet [0000-0001-9902-7147], Venturini, Sara [0000-0002-9541-0090], Vijayakumar, Aradhya [0000-0002-8702-1087], Vine, Melanie [0000-0002-7978-4375], Wittner, Liora [0000-0003-1271-4839], Yong, Geoffrey Hong Kiat [0000-0003-0103-5793], Ziyada, Farris [0000-0003-2117-7262], Devine, Oliver Patrick [0000-0001-7621-9699], Apollo - University of Cambridge Repository, McManus, IC [0000-0003-3510-4814], and Smith, Daniel T [0000-0003-1215-5811]
Subjects: Male, Students, Medical, 020205 medical informatics, Preparedness, Problem-based learning, media_common.quotation_subject, education, Specialty, lcsh:Medicine, 02 engineering and technology, National Training Study, National Student Survey, 03 medical and health sciences, Patient safety, 0302 clinical medicine, Obstetrics and gynaecology, Perception, 0202 electrical engineering, electronic engineering, information engineering, Medicine, Sanctions, Humans, Quality (business), 030212 general & internal medicine, Fitness to practise, Schools, Medical, GMC sanctions, media_common, Medical education, Postgraduate qualifications, business.industry, lcsh:R, Institutional histories, General Medicine, United Kingdom, Female, Medical school differences, business, Teaching styles, Research Article
Abstract: BackgroundMedical schools differ, particularly in their teaching, but it is unclear whether such differences matter, although influential claims are often made. The Medical School Differences (MedDifs) study brings together a wide range of measures of UK medical schools, including postgraduate performance, fitness to practise issues, specialty choice, preparedness, satisfaction, teaching styles, entry criteria and institutional factors.MethodAggregated data were collected for 50 measures across 29 UK medical schools. Data includeinstitutional history(e.g. rate of production of hospital and GP specialists in the past),curricular influences(e.g. PBL schools, spend per student, staff-student ratio), selection measures(e.g. entry grades),teaching and assessment(e.g. traditional vs PBL, specialty teaching, self-regulated learning), student satisfaction, Foundation selection scores,Foundation satisfaction,postgraduate examination performance andfitness to practise(postgraduate progression, GMC sanctions). Six specialties (General Practice, Psychiatry, Anaesthetics, Obstetrics and Gynaecology, Internal Medicine, Surgery) were examined in more detail.ResultsMedical school differences are stable across time (median alpha = 0.835). The 50 measures were highly correlated, 395 (32.2%) of 1225 correlations being significant withp p Problem-based learning (PBL) schools differ on many measures, including lower performance on postgraduate assessments. While these are in part explained by lower entry grades, a surprising finding is that schools such as PBL schools which reportedgreaterstudent satisfaction with feedback also showedlowerperformance at postgraduate examinations.More medical school teaching of psychiatry, surgery and anaesthetics did not result in more specialist trainees. Schools that taught more general practice did have more graduates entering GP training, but those graduates performed less well in MRCGP examinations, the negative correlation resulting from numbers of GP trainees and exam outcomes being affected both by non-traditional teaching and by greater historical production of GPs.Postgraduate exam outcomes were also higher in schools with more self-regulated learning, but lower in larger medical schools.A path model for 29 measures found a complex causal nexus, most measures causing or being caused by other measures. Postgraduate exam performance was influenced by earlier attainment, at entry to Foundation and entry to medical school (the so-called academic backbone), and by self-regulated learning.Foundation measures of satisfaction, including preparedness, had no subsequent influence on outcomes. Fitness to practise issues were more frequent in schools producing more male graduates and more GPs.ConclusionsMedical schools differ in large numbers of ways that are causally interconnected. Differences between schools in postgraduate examination performance, training problems and GMC sanctions have important implications for the quality of patient care and patient safety.
Published: 2020

42. Evaluation and Improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study

Author: Lukasz Roguski, Matthew Stammers, Andrew Pickles, Matt Rogers, James Batchelor, Honghan Wu, Ewan Carr, Jiaxing Sun, Ashwin Pinto, James T. Teo, Hang T.T. Phan, Vasa Curcin, Ting Shi, Cormac Breen, Daniel Bean, Christopher P Bourdeaux, Thomas Searle, Daniel Stahl, Rosita Zakeri, Anthony J Shinton, Xin Zhang, Abdel Douiri, Anthony Shek, Rishi K Gupta, Kevin O'Gallagher, Chris McWilliams, Zeljko Kraljevic, Huayu Zhang, Xiaodong Wu, Mahdad Noursadeghi, Richard Dobson, Walter Muruet, Bruce Guthrie, Amos Folarin, Ajay M. Shah, Florina Borca, Mike Wyatt, Rebecca Bendayan, and Wenjuan Wang
Subjects: medicine.medical_specialty, business.industry, Renal function, Disease, medicine.disease, Early warning score, Intensive care unit, 3. Good health, law.invention, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, law, Diabetes mellitus, Internal medicine, Cohort, medicine, Clinical endpoint, Absolute neutrophil count, 030212 general & internal medicine, 10. No inequality, business
Abstract: BackgroundThe National Early Warning Score (NEWS2) is currently recommended in the United Kingdom for risk stratification of COVID outcomes, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for severe COVID outcome and identify and validate a set of routinely-collected blood and physiological parameters taken at hospital admission to improve the score.MethodsTraining cohorts comprised 1276 patients admitted to King’s College Hospital NHS Foundation Trust with COVID-19 disease from 1st March to 30th April 2020. External validation cohorts included 5037 patients from four UK NHS Trusts (Guys and St Thomas’ Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID disease (transfer to intensive care unit or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models.ResultsA baseline model of ‘NEWS2 + age’ had poor-to-moderate discrimination for severe COVID infection at 14 days (AUC in training sample = 0.700; 95% CI: 0.680, 0.722; Brier score = 0.192; 95% CI: 0.186, 0.197). A supplemented model adding eight routinely-collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, CRP, estimated GFR, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI: 0.715, 0.757) and these improvements were replicated across five UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites.ConclusionsNEWS2 score had poor-to-moderate discrimination for medium-term COVID outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.Key messagesThe National Early Warning Score (NEWS2), currently recommended for stratification of severe COVID-19 disease in the UK, showed poor-to-moderate discrimination for medium-term outcomes (14-day transfer to ICU or death) among COVID-19 patients.Risk stratification was improved by the addition of routinely-measured blood and physiological parameters routinely at hospital admission (supplemental oxygen, urea, oxygen saturation, CRP, estimated GFR, neutrophil count, neutrophil/lymphocyte ratio) which provided moderate improvements in a risk stratification model for 14-day ICU/death.This improvement over NEWS2 alone was maintained across multiple hospital trusts but the model tended to be miscalibrated with risks of severe outcomes underestimated in most sites.We benefited from existing pipelines for informatics at KCH such as CogStack that allowed rapid extraction and processing of electronic health records. This methodological approach provided rapid insights and allowed us to overcome the complications associated with slow data centralisation approaches.
Published: 2020
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43. Blood transcriptomic biomarkers for tuberculosis screening: time to redefine our target populations?

Author: Rishi K Gupta and Mahdad Noursadeghi
Subjects: Health Services Needs and Demand, business.industry, MEDLINE, General Medicine, Target population, Tuberculosis screening, Computational biology, Transcriptome, Humans, Mass Screening, Tuberculosis, Medicine, Public aspects of medicine, RA1-1270, business, Biomarkers
Published: 2021
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44. Quantitative interferon gamma release assay and tuberculin skin test Results to predict incident tuberculosis: a prospective cohort study

Author: Jennifer Davidson, Charlotte Jackson, Ajit Lalvani, Colin Campbell, Jo Southern, Mahdad Noursadeghi, Marc Lipman, Jonathan J Deeks, Pranab Haldar, Ibrahim Abubakar, Heinke Kunst, Francis Drobniewski, Rishi K Gupta, Alice J Sitch, Oliver Stirrup, Christopher E.M. Griffiths, and CY Tsou
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Tuberculosis, Respiratory System, Tuberculin, Critical Care and Intensive Care Medicine, QuantiFERON, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Epidemiology, latent tuberculosis, Humans, Medicine, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, T-SPOT.TB, 11 Medical and Health Sciences, Skin test results, Latent tuberculosis, Tuberculin Test, business.industry, Incidence, screening, Editorials, Original Articles, Mycobacterium tuberculosis, Middle Aged, medicine.disease, bacterial infections and mycoses, United Kingdom, 030228 respiratory system, quantiferon, Female, epidemiology, business, Biomarkers, Interferon-gamma Release Tests
Abstract: RATIONALE: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. OBJECTIVES: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the tuberculin skin test (TST) might improve prediction of incident TB. METHODS: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by re-linkage to national TB surveillance records (median follow-up 4.7 years). Incidence rates and rate ratios, sensitivities, specificities and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior BCG). MEASUREMENTS AND MAIN RESULTS: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (p
Published: 2019

45. S110 Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and individual participant data meta-analysis

Author: MX Rangaka, Cristina Venturini, Rishi K Gupta, Ibrahim Abubakar, Andrew Copas, Mci Lipman, Hanif Esmail, Carolin T. Turner, and Mahdad Noursadeghi
Subjects: Oncology, medicine.medical_specialty, Tuberculosis, Receiver operating characteristic, business.industry, Individual participant data, Random effects model, medicine.disease, Confidence interval, Meta-analysis, Internal medicine, medicine, Biomarker (medicine), business, Whole blood
Abstract: Background Blood transcriptional signatures may predict risk of tuberculosis (TB). While multiple candidate signatures for active and incipient TB have been identified, it is not known which signature performs best, or whether any meets World Health Organization target product profile (WHO TPP) benchmarks, for incipient TB biomarkers. Methods We performed a systematic review to identify candidate mRNA signatures for incipient TB, along with genome-wide transcriptomic datasets with sampling prior to TB diagnosis. We reconstructed each signature model and directly compared signature performance for diagnosis of incipient TB in the pooled RNAseq dataset, stratified by interval to disease, in a one-stage individual participant data meta-analysis (IPD-MA). Results We tested 17 candidate mRNA signatures in a pooled dataset from four studies conducted in South Africa, Ethiopia, The Gambia and the UK. We included 1,126 samples, with 183 samples from 127 incipient TB cases, Eight signatures (comprising 1–25 transcripts), predominantly reflecting interferon-inducible gene expression, had equivalent diagnostic accuracy for incipient TB over a two-year period with areas under the receiver operating characteristic curves ranging from 0.70 (95% confidence interval 0.64–0.76) to 0.77 (0.71–0.82). The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two standard deviations above the mean of uninfected controls, giving specificities of >90%, the eight signatures achieved sensitivities of 24.7–39.9% over 24 months, rising to 47.1–81.0% over 3 months. Based on pre-test probability of 2%, the eight signatures achieved positive predictive values from 6.8–9.4% over 24 months, rising to 11.1–14.3% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum WHO TPP parameters for incipient TB biomarkers over a two-year period. Sensitivity analyses using two-stage IPD-MA with random effects produced similar AUC, sensitivity and specificity estimates. Conclusions Multiple transcriptional signatures perform with equivalent diagnostic accuracy for incipient TB. These biomarkers reflect short-term risk of TB and only exceed WHO benchmarks if applied to 3–6 month intervals. A screening strategy that incorporates serial testing on a 3–6 monthly basis among carefully selected target groups may be required for optimal implementation of these biomarkers.
Published: 2019
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46. Do higher quantitative interferon gamma release assay or tuberculin skin test results help to predict incident tuberculosis? Data from the UK PREDICT study

Author: Oliver Stirrup, Chris Griffiths, Mahdad Noursadeghi, Colin Campbell, Jo Southern, Jonathan J Deeks, Francis Drobniewski, Heinke Kunst, Ajit Lalvani, CY Tsou, Jennifer Davidson, Marc Lipman, Rishi K Gupta, Alice J Sitch, Charlotte Jackson, Ibrahim Abubakar, and Pranab Haldar
Subjects: Tuberculosis, business.industry, Immunology, medicine, Interferon gamma release assay, Tuberculin, medicine.disease, business, Skin test results
Published: 2019
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47. Blood transcriptional biomarkers for active pulmonary tuberculosis in a high-burden setting: a prospective, observational, diagnostic accuracy study

Author: Jennifer K. Roe, Grant Theron, Carolin T. Turner, Georgina R Nyawo, Robert F. Miller, Rishi K Gupta, Mahdad Noursadeghi, Zaida Palmer, Evdokia Tsaliki, Byron Wp Reeve, and Prasenjit Mondal
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Tuberculosis, Sequencing data, Diagnostic accuracy, Sensitivity and Specificity, 03 medical and health sciences, South Africa, 0302 clinical medicine, Pulmonary tuberculosis, Internal medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Tuberculosis, Pulmonary, Receiver operating characteristic, business.industry, Sequence Analysis, RNA, Sputum, Mycobacterium tuberculosis, Middle Aged, medicine.disease, Triage, 3. Good health, RNA, Bacterial, 030228 respiratory system, ROC Curve, Observational study, Female, medicine.symptom, business, Biomarkers, Transcription Factors
Abstract: Summary Background Blood transcriptional signatures are candidates for non-sputum triage or confirmatory tests of tuberculosis. Prospective head-to-head comparisons of their diagnostic accuracy in real-world settings are necessary to assess their clinical use. We aimed to compare the diagnostic accuracy of candidate transcriptional signatures identified by systematic review, in a setting with a high burden of tuberculosis and HIV. Methods We did a prospective observational study nested within a diagnostic accuracy study of sputum Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Ultra) tests for pulmonary tuberculosis. We recruited consecutive symptomatic adults aged 18 years or older self-presenting to a tuberculosis clinic in Cape Town, South Africa. Participants provided blood for RNA sequencing, and sputum samples for liquid culture and molecular testing using Xpert and Ultra. We assessed the diagnostic accuracy of candidate blood transcriptional signatures for active tuberculosis (including those intended to distinguish active tuberculosis from other diseases) identified by systematic review, compared with culture or Xpert MTB/RIF positivity as the standard reference. In our primary analysis, patients with tuberculosis were defined as those with either a positive liquid culture or Xpert result. Patients with missing blood RNA or sputum results were excluded. Our primary objective was to benchmark the diagnostic accuracy of candidate transcriptional signatures against the WHO target product profile (TPP) for a tuberculosis triage test. Findings Between Feb 12, 2016, and July 18, 2017, we obtained paired sputum and RNA sequencing data from 181 participants, 54 (30%) of whom had confirmed pulmonary tuberculosis. Of 27 eligible signatures identified by systematic review, four achieved the highest diagnostic accuracy with similar area under the receiver operating characteristic curves (Sweeney3: 90·6% [95% CI 85·6–95·6]; Kaforou25: 86·9% [80·9–92·9]; Roe3: 86·9% [80·3–93·5]; and BATF2: 86·8% [80·6–93·1]), independent of age, sex, HIV status, previous tuberculosis, or sputum smear result. At test thresholds that gave 70% specificity (the minimum WHO TPP specificity for a triage test), these four signatures achieved sensitivities between 83·3% (95% CI 71·3–91·0) and 90·7% (80·1–96·0). No signature met the optimum criteria, of 95% sensitivity and 80% specificity proposed by WHO for a triage test, or the minimum criteria (of 65% sensitivity and 98% specificity) for a confirmatory test, but all four correctly identified Ultra-positive, culture-negative patients. Interpretation Selected blood transcriptional signatures met the minimum WHO benchmarks for a tuberculosis triage test but not for a confirmatory test. Further development of the signatures is warranted to investigate their possible effects on clinical and health economic outcomes as part of a triage strategy, or when used as add-on confirmatory test in conjunction with the highly sensitive Ultra test for Mycobacterium tuberculosis DNA. Funding Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, and UK Medical Research Council.
Published: 2019

48. Effectiveness of BCG Vaccination Against Mycobacterium tuberculosis Infection in Adults: A Cross-sectional Analysis of a UK-Based Cohort

Author: Anthea L Katelaris, Punam Mangtani, Marc Lipman, Ajit Lalvani, Rishi K Gupta, Jo Southern, Ibrahim Abubakar, Francis Drobniewski, Charlotte Jackson, Innovate UK, and Imperial College Trust
Subjects: Adult, Male, Tuberculosis, Time Factors, Adolescent, Cross-sectional study, Population, Microbiology, Bacillus Calmette-Guérin vaccine, Young Adult, Latent Tuberculosis, Risk Factors, medicine, Prevalence, Immunology and Allergy, Humans, BCG, Prospective Studies, education, 11 Medical and Health Sciences, education.field_of_study, Latent tuberculosis, vaccine effectiveness, business.industry, Transmission (medicine), Incidence (epidemiology), Vaccination, Age Factors, Infant, Mycobacterium tuberculosis, Middle Aged, 06 Biological Sciences, medicine.disease, bacterial infections and mycoses, United Kingdom, Infectious Diseases, Cross-Sectional Studies, tuberculosis, Relative risk, Child, Preschool, Cohort, BCG Vaccine, Female, business, Interferon-gamma Release Tests, Demography
Abstract: Background The roll-out of anti-retroviral therapy (ART) has changed contexts of human immunodeficiency virus (HIV) risk. Here, we summarise direct estimates of HIV incidence among adolescent girls and young women (AGYW) since ART and before large investments in targeted prevention for AGYW in sub-Saharan Africa. Methods Database searches identified studies reporting HIV incident data from serological samples collected among 15-24 year-old females in 10 countries selected for PEPFAR investment in 2015. Estimates collected between 2005-2015, published or received from authors, were summarised by age and sex, and pooled by region. Findings Fifty-one analyses were identified from nine of the eligible countries (save Lesotho). Directly-observed incidence rates were lowest among AGYW in Kumi, Uganda (0.38%) and highest in KwaZulu-Natal, South Africa (7.8% among 15-19y; 8.6% in 20-24y); fishing communities in Uganda (12.4% and 4.7% among 15-19y and 20-24y females); and among sex workers aged 18-24y in South Africa (13.2%) and Zimbabwe (10.8%). In pooled rates from general population studies, the greatest sex differentials were in the youngest age groups, i.e., 15-19y females compared to males in both Southern African (relative risk=5.94; 95% CI:3.39-10.44) and Eastern African countries (3.22; 95% CI:1.51-6.87), and not significantly different among the oldest (25-29y) in either region. Incidence often peaked earlier (during teenage years) among high-risk compared to general populations. Since 2005, AGYW incidence declined in Rakai (Uganda), Manicaland (Zimbabwe), and among sex workers in Kenya, but not in the highest-risk communities in South Africa. Interpretation Few sources of direct estimates of HIV incidence exist in high-burden countries and trend analyses with age/sex disaggregated data are rare but indicate recent declines among AGYW. In some of the highest-risk settings, however, little evidence exists to suggest ART availability and other efforts slowed transmission by 2016. Despite wide geographic diversity in absolute levels of AGYW incidence, risk relative to males persisted in all settings, with the greatest sex differentials in the youngest age groups. To end new infections among the growing population of adolescents in sub-Saharan Africa, prevention programs must address gender inequalities driving excessive risk among adolescent girls.
Published: 2019

49. Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

Author: Mahdad Noursadeghi, Hanif Esmail, Carolin T. Turner, Marc Lipman, Cristina Venturini, Rishi K Gupta, Andrew Copas, Molebogeng X Rangaka, and Ibrahim Abubakar
Subjects: Adult, Male, Automobile Driving, medicine.medical_specialty, Tuberculosis, Adolescent, Sensitivity and Specificity, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Predictive Value of Tests, Internal medicine, Humans, Medicine, 030212 general & internal medicine, Child, Tuberculosis, Pulmonary, 030304 developmental biology, Whole blood, 0303 health sciences, Receiver operating characteristic, business.industry, Product profile, Mycobacterium tuberculosis, Middle Aged, medicine.disease, Predictive value, Confidence interval, 3. Good health, RNA, Bacterial, ROC Curve, Meta-analysis, Biomarker (medicine), Female, business, Biomarkers, Transcription Factors
Abstract: Summary Background Multiple blood transcriptional signatures have been proposed for identification of active and incipient tuberculosis. We aimed to compare the performance of systematically identified candidate signatures for incipient tuberculosis and to benchmark these against WHO targets. Methods We did a systematic review and individual participant data meta-analysis. We searched Medline and Embase for candidate whole blood mRNA signatures discovered with the primary objective of diagnosis of active or incipient tuberculosis, compared with controls who were healthy or had latent tuberculosis infection. We tested the performance of eligible signatures in whole blood transcriptomic datasets, in which sampling before tuberculosis diagnosis was done and time to disease was available. Culture-confirmed and clinically or radiologically diagnosed pulmonary or extrapulmonary tuberculosis cases were included. Non-progressor (individuals who remained tuberculosis-free during follow-up) samples with less than 6 months of follow-up from the date of sample collection were excluded, as were participants with prevalent tuberculosis and those who received preventive therapy. Scores were calculated for candidate signatures for each participant in the pooled dataset. Receiver operating characteristic curves, sensitivities, and specificities were examined using prespecified intervals to tuberculosis (
Published: 2019
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50. The Analysis of Teaching of Medical Schools (AToMS) survey: an analysis of 47,258 timetabled teaching events in 25 UK medical schools relating to timing, duration, teaching formats, teaching content, and problem-based learning

Author: Anjola Mosuro, Liora Wittner, Reza Nasseri, Zoe Carrington, Emma L Howard, Ifrah Hussain, Ben Phillips, Asanish Kalyanasundaram, Nadine Abbas, Robert Spencer, Keshni Gudka, Zoe Wellbelove, Harriet Hunter, Richard Clough, Alex Eyre, Ahmed Ashraf, Nick Smith, Tobin Joseph, Benjamin Human, Sajan Khullar, Oloruntobi Rotimi, Abdul-Muiz Azri Yahaya, Shreya Badhrinarayanan, Whitney General, Martha Amy Smith, Adele Heaney, Ratan Randhawa, Tom Joseph Syer, Aninditya Salma Sopian, Christina Hood, Katie Smart, Richard Thomas Jackson-Taylor, Jia Jun Ang, Angelos Mantelakis, Shaunak Chatterjee, Bronwen Jacob-Ramsdale, Matthew Tyler, Saba Houshangi, Charlotte Boreham, Wassim Merzougui, Oliver P. Devine, Soham Bandyopadhyay, Tess Marshall-Andon, Liam Curry, Elliot John Revell, Andrew Christopher Harborne, Oliver Shotton, Natasha Benons, Samuel C. Barnes, Sophie McGovern, Daniel Sims, Stuart Pearce, Sami Hussain, Hassan Baig, Catherine Arthur, Tom Newman, Kerry Long, Farris Ziyada, Savraj Kalsi, Agnieszka Jakubowska, Julian Purdy, Rebecca Braine, Julius Elisabeth Richard Lenaerts, Eimear Reel, Joshua William Kearsley, Ross McAllister, Jess Trevett, Jessica Speller, Joseph Beecham, Roshan Ullah, Geoffrey Hong Kiat Yong, Mrudula Utukuri, Sophie Mustoe, Aradhya Vijayakumar, Mohit Patel, Sadhana Kalidindi, Mark Awad, Hugo Layard Horsfall, Ryan Samuels, Eve Lancaster, Carmel Razzaghi, Sonam Aojula, Priscilla Kirkland, Sophie Paddock, Elliot Raymond-Taggert, Omar Risk, Vinay Mandagere, Saleh Jawad, Rebecca Davis, Ngan Hong Ta, Abdelrahman Said, Aadam Shah, Othman Khaled Al-Othman, Usman Rasul, Mehar Chawla, Ryan Janjuha, Wing Hang Serene Ho, I. C. McManus, Sara Venturini, Thomas Hughes-Gooding, Alimatu-Sadia Akeredolu, Verity Ford, Charlie Caird, Aamna Ali, Saad Majeed, Jack Eldridge, Rachel Maguire, Prabhjot Singh Malhotra, Lady-Namera Ejamike, Sarah Freeston, Katherine Aiken, Mike Jones, Oluseyi Adesalu, Shree Vadera, Roxanne Tajbakhsh, Nasreen Desai, Daniel Tadross, Jessica Coulthurst, Vinnie Christine Daniels, Sam Myers, Joseph Brandreth, Chris Clements, Chung Shen Chean, Chris Harlow, Praveen Mahendran, Benjamin Thompson, Adam Moxley, Thomas P. W. Cope, James Druce, Matthew South, Emma Aspinall, Pranoy Sangal, Ammar Ahmed, Ciaran Grafton-Clarke, Daisy Bassey-Duke, Samuel Penrice, Nora Sangvik Grandal, Eleanor Houghton, Amy Harrington, Simon Lubbock, Leher Gumber, Sohini Pawar, Raisa Ramjan, Qaisar Khan, David Johnston, Aisha Sooltangos, Hannah Douglas, Meron Esere, Lucy Holloway, Alena Ashby, Simon Davies, Sophia Fitzgerald-Smith, Hanelie De Waal, Ibrahim T. Fazmin, Rosalie Ogborne, Sahaj Kaur, Melanie Vine, Muzzamil Jelani, Anna Kane, James Coultas, Ibrahim Alam, Jamie Mac Donald Burrell, Hannah Lawrence-Smith, Zoe Cashin, Joyce Omatseye, Sarah Douglas, Helen Gilbert, Harriet Van Den Tooren, Katherine Garnett, Joanna Rigbye, Rebecca Razey, James Parkin, Simon Phillips, Charlotte Leeson, Rahul Atul Shah, Richard Nzewi, Luke Debenham, Zein Gowie, Calum MacMillan, Kiran Nadeem, Fady Sameh Anis, Adam Sage, Emma Sanders, Oliver Jones, Ivan Aganin, Richard B. Anderson, Rishi K Gupta, Ryan Clark, Devine, Oliver Patrick [0000-0001-7621-9699], Harborne, Andrew Christopher [0000-0003-0937-1492], Horsfall, Hugo Layard [0000-0001-7848-5325], Joseph, Tobin [0000-0002-9283-9895], Marshall-Andon, Tess [0000-0001-8909-1639], Samuels, Ryan [0000-0002-0886-7990], Abbas, Nadine [0000-0002-9116-2915], Baig, Hassan [0000-0001-8999-0474], Beecham, Joseph [0000-0002-4390-9164], Benons, Natasha [0000-0002-0750-6560], Caird, Charlie [0000-0001-7553-5585], Clark, Ryan [0000-0002-6143-9098], Cope, Thomas [0000-0003-0247-7411], Coultas, James [0000-0003-3381-8936], Debenham, Luke [0000-0002-3300-7802], Douglas, Sarah [0000-0003-3272-8154], Eldridge, Jack [0000-0001-6792-7714], Hughes-Gooding, Thomas [0000-0001-8483-5686], Jakubowska, Agnieszka [0000-0003-3153-8666], Jones, Oliver [0000-0003-4334-3567], Lancaster, Eve [0000-0001-5703-252X], MacMillan, Calum [0000-0002-8167-0051], McAllister, Ross [0000-0003-1686-1174], Merzougui, Wassim [0000-0001-7398-0095], Phillips, Ben [0000-0002-0489-6700], Risk, Omar [0000-0002-9226-9263], Sage, Adam [0000-0002-7763-404X], Sooltangos, Aisha [0000-0001-5675-1709], Spencer, Robert [0000-0001-9045-6260], Tajbakhsh, Roxanne [0000-0002-3753-6306], Adesalu, Oluseyi [0000-0001-8796-2701], Aganin, Ivan [0000-0002-3711-9430], Aiken, Katherine [0000-0002-3245-7772], Alam, Ibrahim [0000-0003-2853-623X], Ali, Aamna [0000-0003-1255-6113], Anderson, Richard [0000-0003-4734-0208], Anis, Fady Sameh [0000-0002-0950-3777], Arthur, Catherine [0000-0001-9551-6250], Ashraf, Ahmed [0000-0002-3921-8395], Aspinall, Emma [0000-0001-8307-1661], Awad, Mark [0000-0002-6570-010X], Yahaya, Abdul-Muiz Azri [0000-0002-7846-9322], Badhrinarayanan, Shreya [0000-0002-7159-098X], Bandyopadhyay, Soham [0000-0001-6553-3842], Barnes, Sam [0000-0001-6009-406X], Bassey-Duke, Daisy [0000-0002-0408-1042], Boreham, Charlotte [0000-0003-4828-0542], Braine, Rebecca [0000-0003-2751-3378], Brandreth, Joseph [0000-0002-6137-5928], Carrington, Zoe [0000-0002-0006-8334], Chawla, Mehar [0000-0003-0697-815X], Chean, Chung Shen [0000-0002-1625-4078], Clements, Chris [0000-0002-2567-5536], Clough, Richard [0000-0001-6941-7881], Coulthurst, Jessica [0000-0003-0714-9572], Curry, Liam [0000-0002-6906-5502], Daniels, Vinnie Christine [0000-0001-9461-8431], Davies, Simon [0000-0001-5556-7512], Davis, Rebecca [0000-0002-6960-5580], De Waal, Hanelie [0000-0002-9131-9521], Desai, Nasreen [0000-0003-4601-9084], Douglas, Hannah [0000-0001-8113-5465], Druce, James [0000-0001-6849-8560], Ejamike, Lady-Namera [0000-0001-6196-5584], Esere, Meron [0000-0002-1838-0756], Eyre, Alex [0000-0002-0474-5662], Fazmin, Ibrahim Talal [0000-0002-3300-6279], Ford, Verity [0000-0002-1364-8522], Freeston, Sarah [0000-0001-8768-5513], Garnett, Katherine [0000-0003-1135-6478], General, Whitney [0000-0002-9222-4233], Gilbert, Helen [0000-0002-5588-411X], Gowie, Zein [0000-0002-7597-7508], Grafton-Clarke, Ciaran [0000-0002-8537-0806], Gudka, Keshni [0000-0003-0880-6992], Gumber, Leher [0000-0003-0154-1207], Gupta, Rishi [0000-0003-3839-7982], Harlow, Chris [0000-0003-2912-0594], Heaney, Adele [0000-0002-0905-4342], Ho, Wing Hang Serene [0000-0002-2687-3198], Hood, Christina [0000-0001-6821-6324], Howard, Emma [0000-0001-8411-5734], Human, Benjamin [0000-0003-4445-0639], Hunter, Harriet [0000-0002-5204-2371], Hussain, Sami [0000-0002-8654-3617], Jackson-Taylor, Richard Thomas [0000-0002-6949-2977], Jacob-Ramsdale, Bronwen [0000-0001-6215-808X], Jawad, Saleh [0000-0001-8221-9871], Jelani, Muzzamil [0000-0003-3785-415X], Johnston, David [0000-0002-7078-7510], Kalidindi, Sadhana [0000-0002-4274-2913], Kalsi, Savraj [0000-0001-9103-5089], Kalyanasundaram, Asanish [0000-0003-4175-5998], Kane, Anna [0000-0002-6197-2511], Kaur, Sahaj [0000-0002-3446-6082], Al-Othman, Othman Khaled [0000-0001-5930-8593], Khan, Qaisar [0000-0002-5486-4205], Khullar, Sajan [0000-0001-6426-2892], Kirkland, Priscilla [0000-0003-2452-4207], Leeson, Charlotte [0000-0003-4735-2452], Lenaerts, Julius Elisabeth Richard [0000-0002-1626-7792], Long, Kerry [0000-0003-4546-5509], Burrell, Jamie Mac Donald [0000-0002-8175-3973], Maguire, Rachel [0000-0003-4855-5550], Mahendran, Praveen [0000-0002-4084-5222], Majeed, Saad [0000-0003-4289-5597], Malhotra, Prabhjot Singh [0000-0001-7463-3941], Mandagere, Vinay [0000-0002-2969-6457], Mantelakis, Angelos [0000-0001-7109-943X], McGovern, Sophie [0000-0002-6198-7553], Mosuro, Anjola [0000-0002-9013-9289], Moxley, Adam [0000-0001-9794-091X], Mustoe, Sophie [0000-0002-7870-1320], Myers, Sam [0000-0001-6050-4663], Nadeem, Kiran [0000-0001-5988-6780], Newman, Tom [0000-0002-7987-9948], Nzewi, Richard [0000-0002-8159-1302], Ogborne, Rosalie [0000-0003-3327-6030], Omatseye, Joyce [0000-0001-7472-4712], Parkin, James [0000-0002-1861-0822], Patel, Mohit [0000-0003-1168-2759], Pawar, Sohini [0000-0003-0224-5258], Pearce, Stuart [0000-0002-7482-0752], Penrice, Samuel [0000-0002-1142-6686], Ramjan, Raisa [0000-0002-2020-2123], Randhawa, Ratan [0000-0002-4749-4410], Rasul, Usman [0000-0001-5820-1313], Raymond-Taggert, Elliot [0000-0003-1514-6662], Razey, Rebecca [0000-0003-1971-3580], Razzaghi, Carmel [0000-0002-3264-8528], Revell, Elliot John [0000-0001-6025-094X], Rigbye, Joanna [0000-0003-4860-4084], Rotimi, Oloruntobi [0000-0002-1385-1993], Said, Abdelrahman [0000-0002-9801-4202], Sangal, Pranoy [0000-0001-5775-5859], Grandal, Nora Sangvik [0000-0002-2461-7852], Shah, Aadam [0000-0003-1841-5530], Shah, Rahul Atul [0000-0002-6981-7305], Shotton, Oliver [0000-0001-6684-3308], Sims, Daniel [0000-0002-6916-3719], Smith, Martha Amy [0000-0002-4652-3507], Smith, Nick [0000-0003-4478-2772], South, Matthew [0000-0003-2297-1089], Speller, Jessica [0000-0001-5503-4791], Ta, Ngan Hong [0000-0002-8747-5329], Tadross, Daniel [0000-0002-3593-0182], Thompson, Benjamin [0000-0002-2491-5235], Trevett, Jess [0000-0001-5008-1724], Ullah, Roshan [0000-0002-5140-6655], Utukuri, Mrudula [0000-0003-1510-469X], Vadera, Shree [0000-0001-9492-7541], Van Den Tooren, Harriet [0000-0001-9902-7147], Venturini, Sara [0000-0002-9541-0090], Vijayakumar, Aradhya [0000-0002-8702-1087], Vine, Melanie [0000-0002-7978-4375], Wittner, Liora [0000-0003-1271-4839], Yong, Geoffrey Hong Kiat [0000-0003-0103-5793], Ziyada, Farris [0000-0003-2117-7262], McManus, IC [0000-0003-3510-4814], Apollo - University of Cambridge Repository, and McManus, I. C. [0000-0003-3510-4814]
Subjects: Male, 020205 medical informatics, Problem-based learning, lcsh:Medicine, Timetables, Tutorials, 02 engineering and technology, 03 medical and health sciences, Self-regulated learning, 0302 clinical medicine, Clinical teaching, Surveys and Questionnaires, Curriculum mapping, 0202 electrical engineering, electronic engineering, information engineering, Medicine, Humans, 030212 general & internal medicine, Duration (project management), Student perceptions, Medical education, Academic year, business.industry, lcsh:R, General Medicine, United Kingdom, Lectures, Female, Curriculum, Medical school differences, business, Postgraduate training, Teaching styles, Education, Medical, Undergraduate, Research Article
Abstract: Background: \ud What subjects UK medical schools teach, what ways they teach subjects, and how much they teach those subjects is unclear. Whether teaching differences matter is a separate, important question. This study provides a detailed picture of timetabled undergraduate teaching activity at 25 UK medical schools, particularly in relation to problem-based learning (PBL).\ud \ud Method: \ud The Analysis of Teaching of Medical Schools (AToMS) survey used detailed timetables provided by 25 schools with standard 5-year courses. Timetabled teaching events were coded in terms of course year, duration, teaching format, and teaching content. Ten schools used PBL. Teaching times from timetables were validated against two other studies that had assessed GP teaching and lecture, seminar, and tutorial times.\ud \ud Results: \ud A total of 47,258 timetabled teaching events in the academic year 2014/2015 were analysed, including SSCs (student-selected components) and elective studies. A typical UK medical student receives 3960 timetabled hours of teaching during their 5-year course. There was a clear difference between the initial 2 years which mostly contained basic medical science content and the later 3 years which mostly consisted of clinical teaching, although some clinical teaching occurs in the first 2 years. Medical schools differed in duration, format, and content of teaching. Two main factors underlay most of the variation between schools, Traditional vs PBL teaching and Structured vs Unstructured teaching. A curriculum map comparing medical schools was constructed using those factors. PBL schools differed on a number of measures, having more PBL teaching time, fewer lectures, more GP teaching, less surgery, less formal teaching of basic science, and more sessions with unspecified content.\ud \ud Discussion: \ud UK medical schools differ in both format and content of teaching. PBL and non-PBL schools clearly differ, albeit with substantial variation within groups, and overlap in the middle. The important question of whether differences in teaching matter in terms of outcomes is analysed in a companion study (MedDifs) which examines how teaching differences relate to university infrastructure, entry requirements, student perceptions, and outcomes in Foundation Programme and postgraduate training.
Published: 2019

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