Author: "William Greenhalf" / Topic: medicine.medical_specialty - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"William Greenhalf"' showing total 168 results

Start Over Author "William Greenhalf" Topic medicine.medical_specialty

168 results on '"William Greenhalf"'

1. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study

Author: Kim Mallard, William Greenhalf, Lauren Walker, Susannah Condie, Ellice Marwood, Michael Jacobs, Tom Fletcher, Gareth Griffiths, Geoffrey Saunders, Sean Ewings, Victoria Shaw, Richard Fitzgerald, Kerensa Thorne, Olana Tansley-Hancock, Andrew Owen, Lucy Johnson, Sara Yeats, David G. Lalloo, Wendy Painter, Helen Reynolds, Henry Pertinez, Thomas Jaki, Christie Woods, Keira Fines, Emma Wrixon, Colin Hale, Andrea Corkhill, Katie Bullock, Mike Radford, Emily R. Adams, Nichola Downs, Saye Khoo, Justin Chiong, Wayne Holman, Rebecca Lyon, Pavel Mozgunov, Marcin D Bula, and Jennifer L Gibney
Subjects: Microbiology (medical), Research design, Adult, qv_268.5, medicine.medical_specialty, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Article, law.invention, Randomized controlled trial, Pharmacokinetics, law, Internal medicine, Medicine, Humans, Pharmacology (medical), Symptom onset, Adverse effect, Pharmacology, business.industry, SARS-CoV-2, COVID-19, Bayes Theorem, w_20.5, Infectious Diseases, Clinical research, Treatment Outcome, Research Design, Toxicity, qw_160, business
Abstract: Objectives AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.
Published: 2021

2. Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study

Author: Helen McShane, A Alamoudi, D Parekh, G Burns, R. Gisli Jenkins, Marco Sereno, R Djukanovic, Onn Min Kon, N I Lone, David M. Evans, L Daines, N A Hanley, Z. Omar, William Greenhalf, Nicola Williams, K Storton, Asaf David, T Wallis, E Pacpaco, H McCauley, L. O'Brien, K Hainey, P. Novotny, C Tong, L Ingram, S Gurram, C Avram, C Coleman, Edward T. Bullmore, Richard G. Brown, R Aul, K A Tripp, D. Cristiano, A Michael, Michael C Steiner, Padmasayee Papineni, A Howell, Gail Carson, Peter J. M. Openshaw, Simon Heller, G Madzamba, K Paradowski, S Singh, K Bramham, Teresa Light, David Price, V Shaw, A Yousuf, T Dong, T Hiwot, G Simons, Philip L. Molyneaux, A Ashworth, Ashley C. Brown, N Magee, A L Tan, R A Evans, Mark Toshner, Robert Sykes, W Saxon, S Finney, A Mohamed, P Cairns, Christos P Kotanidis, J D Chalmers, O Adeyemi, L Knibbs, A J Moss, S L Rowland-Jones, O M Kon, L P Ho, A Martineau, B Zhao, M G Crooks, J Meiring, Ewen M Harrison, Louise V. Wain, S Wright, E Robertson, David A. Lomas, H Lamlum, David E. Newby, P Chowdhury, K Mangion, Toby Hillman, E Turner, H McAllister-Williams, S West, J McGinness, B Whittam, T. Gorsuch, K Dempsey, L Mcgarvey, K Poinasamy, K Shevket, Emma Baldry, M Buch, N French, Olivia C. Leavy, Stephen C. J. Parker, H Newell, Louise M. Howard, O. Zongo, P Beirne, C Sharpe, N Mills, C David, M Bayley, Carmine M. Pariante, P Haldar, Z Kausar, A Dipper, I Hall, P McArdle, G Ogg, Rachael A. Evans, A.J. Buttress, M Pareek, Paul E Pfeffer, Denise Anderson, James D. Chalmers, P Kar, Caroline J. Jolley, S Plein, Nigel J. Brunskill, C Oliver, John R. Hurst, Clive Ballard, F Barrett, D Baguley, Nick P. Talbot, N Chaudhuri, A Young, Jonathan P. Busby, H Dobson, K Holmes, Liam G Heaney, Ruth E Barker, Anthony N. Price, David J. Stensel, L Brear, Louise Sigfrid, Marcia Soares, Patrice Carter, J R Hurst, John R. Geddes, Donghyung Lee, L Watson, J M Lord, H Parfrey, N Odell, J Glossop, K. Liyanage, Bryan Williams, S Neubauer, O Elneima, David R Baldwin, G Mallison, C Francis, A Te, D Foote, F Woodhead, A De Soyza, A Atkins, M Stern, A Morley, E Bright, N Basu, Simon E. Brill, D Southern, D Forton, L G Heaney, B Raman, Malcolm G Semple, M Mariveles, Charalambos Antoniades, Nawar Diar Bakerly, Swapna Mandal, Aroon D. Hingorani, E K Sage, Ania Korszun, A Hosseini, Louise Allan, M Toshner, Fergus V. Gleeson, Cherie Armour, J Quigley, S Drain, Thomas Kabir, M Havinden-Williams, Ben G. Marshall, S Patale, C Bourne, L Wright, Rachel L. Batterham, S Jones, S Linford, Salman Siddiqui, C Laing, A Horsley, S Greenwood, A Lingford-Hughes, S. Jose, Stefan Neubauer, S L Dobson, M Rahman, Alex D. McMahon, S Young, A Frankel, Joe Dennis, Claire M. Nolan, J Fuld, J Mayet, Nayia Petousi, Brij Patel, A Fairman, F Speranza, A Bularga, Colin Berry, Charlotte L. Edwardson, A Lloyd, H Jones, N Mairs, H Assefa-Kebede, L Gilmour, D Jones, Siobhan Kelly, I Cruz, Tim Rees, A Haggar, R. Wolf-Roberts, R Flockton, R Dowling, Geraldine Landers, C. Price, P Neill, John B. Cole, A L Key, Elaine Hardy, P Kitterick, Elodie Murali, Carly Welch, P Crisp, Rachel C. Chambers, L Carr, P C Calder, A McQueen, S Defres, A Dewar, F Adeyemi, Avan Aihie Sayer, D W Connell, M Halling-Brown, Neil J. Greening, M Andrews, Linda MacLiver, Kevin A. Davies, E Wade, Elizabeth M. Tunnicliffe, H Jarvis, Kathryn M. Abel, N Hart, A J Yousuf, Nicholas Easom, Alexander Richards, Lee B. Smith, P Dulawan, Janet T Scott, Amisha Singapuri, E Sapey, G Willis, P M George, S Bain, H. Tench, S S Kon, N Window, M J Rowland, A. J. Shah, B Card, A Knighton, P Chowienczyk, Luke Daines, Cathie Sudlow, Joseph Jacob, J Rossdale, S Paddick, Ifan Jones, A Storrie, Sonia Johnson, Huzaifa Adamali, Gail Davies, R G Jenkins, J Murira, Kamlesh Khunti, W Y James, Ajay M. Shah, A B Docherty, Donna J. Menzies, R Morriss, K Piper Hanley, James J Furniss, C Overton, P Mansoori, Phil Harrison, P Greenhaff, A Humphries, H. McGuinness, Gerome Breen, Hayley Hardwick, Davies Adeloye, P Pfeffer, H Lota, Daniel G. Wootton, William Monteiro, A Holbourn, R Hamil, Y Ellis, Traolach S. Brugha, A Alli, D Wraith, Jennifer K Quint, H Atkins, I Peralta, David C. Thomas, A Bolger, J Rodgers, S Portukhay, David Wilson, Michael Sharpe, Steven Kerr, T Plekhanova, J Lewis, S. Quaid, O Olaosebikan, L Lim, K Roy, A Checkley, A Newton Cox, A Dougherty, Bill Deakin, R Pius, A Hoare, N. Dormand, T Craig, Dhruv Parekh, Betty Raman, K E Lewis, Christopher E. Brightling, L G Spencer, Z Suleiman, E R Chilvers, Keith M. Channon, A Saratzis, R Lenagh, N Diar Bakerly, I Macharia, G Kaltsakas, L Morrison, M Ralser, K Fallon, C J Tee, JM Watson, J Nunag, R Gregory, J E Pearl, C Wright, K Regan, D Johnston, P Hogarth, Najib M. Rahman, G P McCann, Julie Evans, N Easom, Joseph Hughes, J Skeemer, H Baxendale, E Hufton, B Elliott, L V Wain, Ardythe L. Morrow, Meenal Patel, S Glover, C Xie, M Harvie, Alan Hughes, David B. Thomas, N Choudhury, Mark J. Tobin, Elizabeta B. Mukaetova-Ladinska, Richard W. Francis, J L Heeney, Shyam Madathil, Ellen Guthrie, S Yasmin, H Turton, M Marks, I Koychev, Melanie J. Davies, John P Greenwood, Daniel Peckham, E Lee, Iain B. McInnes, K Hadley, Charlotte Summers, J Chen, A Prickett, Timothy R Nicholson, K Lewis, A Cross, Jamie Brown, G Ross, H Wheeler, Manu Sharma, Igor Rudan, A Routen, M J Noonan, J Wild, K Jiwa, B. Welsh, Jonathan Pimm, J Kwan, A Lucey, C Favager, K Brindle, Nazir I Lone, Naveed Sattar, C Christie, James E. Mitchell, M Wilkins, C Coupland, T Thornton, Christian P Subbe, Alex Horsley, J Blaikely, G F Toingson, S Walsh, A Lea, Jennifer A. Smith, Margot W. Parkes, M Dixon, Luke Howard, N Majeed, A Hayday, Jack A. Sargeant, Michael Pavlides, K Leitch, J. Pendlebury, Andrew Donaldson, T Peto, Thomas A Jackson, N Rahman, M Gibbons, J Phipps, S Logan, D Wilkinson, J Breeze, D Holgate, R Osbourne, M Hoare, M Malim, Ryan S Thwaites, Stephen R Knight, W Ibrahim, J Rowland, Andrew M. Taylor, B Al-Sheklly, R. Loosley, S Megson, C Summersgill, Z Coburn, R Evans, I Wilson, B Pathmanathan, Jeremy George, A Angyal, S Betts, A Deans, C E Brightling, S Kerr, N Selby, L Price, A Ramos, S N Diwanji, P Kurupati, J S Brown, K Scott, A Sheikh, Krisnah Poinasamy, R Ugwuoke, Teresa Thompson, K Chong-James, Gerry P McCann, John R. Petrie, R Hughes, E. Watson, K McIvor, Trudie Chalder, Melissa Heightman, B Gooptu, H Evans, Thomas Yates, R Ahmed, Nicholas Hart, R Allen, W Schwaeble, J Simpson, Sara Clohisey, Janet M. Lord, R Bell, R Baggott, Clare J Taylor, Keir Lewis, Lynda Connor, F Thaivalappil, Kathryn J Saunders, Lynsey S. Hall, Richard Kevin Stone, Aliki Thomas, L Turtle, H Tedd, L Matthews, J Bambrough, S Stanel, M J McMahon, L Chetham, Enya Daynes, R Hurst, Angela Cook, M Aljaroof, Ling-Pei Ho, Paul Moss, H Arnold, S Fairbairn, Anthony J. Rostron, L Garner, Kyle Harrington, Douglas Grieve, B Connolly, Khalida Ismail, Craig Johnson, E. Russell, T Hussell, S Kon, Claudia Langenberg, E Wall, A Rowland, Miriam Harvey, N Powell, Catherine Pennington, N Armstrong, J C Porter, A Ient, Matthew Hotopf, R Parvin, M Richardson, I Smith, L Lightstone, J. Dasgin, Lynne Armstrong, A Charalambou, J R Geddes, C. Clark, E Gourlay, A Botkai, G Choudhury, J Bonnington, Matthew A. Brown, Paul Dark, S Thackray-Nocera, J Woods, E Stringer, R Free, Aarti Shikotra, J Jacob, P Clift, W Man, Sally J Singh, B King, Nikki Gautam, A Zawia, K McCafferty, L Milligan, S Whittaker, A Elmer, H Chinoy, H Welch, J Haworth, A Shikotra, Matthew J. Rowland, A Singapuri, M McNarry, F. Davies, F Khan, T Mcnally, Alfred A.R. Thompson, A McArdle, V Brown, Helen L. Fisher, M Spears, Peter Jezzard, Morag Henderson, D Thickett, U Munawar, M Broome, Graeme Jones, M. Gummadi, S Marciniak, L Poll, E Calvelo, J Hawkes, D Saralaya, S Walder, Omer Elneima, E M Harrison, C E Bolton, S J Singh, Khalid Shah, S Diver, M Willicombe, M Ainsworth, H Nassa, O C Leavy, D C Thomas, R Upthegrove, C Singh, C Echevarria, Sebastian Edwards, N Lewis-Burke, C Bloomfield, D L Sykes, J Parmar, Sam M. Janes, Simon Wessely, Shaney L Barratt, Judith Clarke, S McAdoo, G MacGowan, Hamish McAuley, L O Wajero, C Dobson, David J. Burn, Daniel Lasserson, Gill Arbane, Matthew Richardson, D McAulay, Rhian M. Touyz, Miles D. Witham, E Major, J Whitney, C J Jolley, Michael Beadsworth, N Goodman, S Walmsley, Daniel F. McAuley, Kath Chapman, Paul Cullinan, Margaret Jones, K P Yip, Nilesh J. Samani, M Bourne, Jeremy S. Brown, A Bloss, Alison M. Lawrie, Timothy Felton, L Bishop, T Sass, Oliver Polgar, M Bakali, N Hawkings, T Chalder, Mujtaba Husain, B Jayaraman, Hannah Bayes, Vicky Kamwa, B Hargadon, Y Peng, C Jolley, D Matila, Clare E. Mackay, J Worsley, R Dharmagunawardena, R Samuel, L Fabbri, R Russell, K Bhui, David W. Clark, S Heller, Anne Dell, J Nyaboko, N Huneke, Michael Marks, L Hesselden, A Greenhalgh, L Broad, M Bakau, Susan P. Walker, Marlies Ostermann, Smitaa Patel, E Fraser, R I Evans, V Whitehead, S Ahmad, C King, B Young, David T Arnold, Paul Klenerman, S Dunn, H McAuley, D Faluyi, B Holroyd-Hind, H Qureshi, E Bradley, Brendan G Cooper, P Shah, L Houchen, Shelley Fletcher, Todd Evans, Andrew Smith, Jill Walsh, Amanda F. Elliott, V Harris, L Holdsworth, A Ford, R Saunders, K Vellore, Jonathan Finch, A McGovern, D Nicoll, A Briggs, J Oxton, G A Davies, Milton Ashworth, T I de Silva, V Lewis, James Stockley, S Byrne, Alison G. Harvey, M Sereno, Marc Lipman, S Terry, A Moss, L. McMorrow, Nick A Maskell, Annemarie B Docherty, R Sabit, J Kenneth Baillie, Jennifer M. Short, Louise Stadon, Aziz Sheikh, S A Williams-Howard, Atul Gupta, D Altmann, J Cavanagh, S Francis, E. Perkins, E McIvor, P Atkin, Julie Williams, D Sutherland, J Rangeley, Derek Bell, J Valabhji, J K Baillie, Isobel D. Stewart, P McCourt, P Rivera-Ortega, N J Greening, Anthony De Soyza, M Dalton, Group, PHOSP-COVID Collaborative, Apollo - University of Cambridge Repository, Baguley, David, National Institute for Health Research, UKRI MRC COVID-19 Rapid Response Call, and UK Research and Innovation
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Health Status, medicine.medical_treatment, MEDLINE, Comorbidity, Disease, Logistic regression, PHOSP-COVID Collaborative Group, 1117 Public Health and Health Services, Cognition, SDG 3 - Good Health and Well-being, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, Mechanical ventilation, United Kingdom/epidemiology, business.industry, COVID-19, 1103 Clinical Sciences, Articles, Middle Aged, Mental health, United Kingdom, Middle age, Hospitalization, Mental Health, Acute Disease, COVID-19/complications, Female, business, 1199 Other Medical and Health Sciences, Follow-Up Studies
Abstract: Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.
Published: 2021

3. hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA

Author: John P. Neoptolemos, Christopher Halloran, Daniel H. Palmer, Ross Carter, Thilo Hackert, Andrew Scarfe, Bengt Glimelius, Richard Charnley, Eithne Costello, Juan W. Valle, Markus M. Lerch, Markus W. Büchler, Niall C. Tebbutt, Richard J. Jackson, Nils O. Elander, Karen Aughton, Julia Mayerle, William Greenhalf, Anthony Evans, David Cunningham, Fiona Campbell, Alan Anthoney, John R. Mackey, Jennifer Shannon, Paula Ghaneh, and David Goldstein
Subjects: Oncology, Cancer Research, medicine.medical_specialty, pyrimidine, medicine.medical_treatment, Equilibrative nucleoside transporter 1, chemotherapy, Article, Internal medicine, Pancreatic cancer, medicine, 5-fluorouracil, RC254-282, Chemotherapy, Cancer och onkologi, Tissue microarray, Predictive marker, biology, business.industry, gemcitabine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cytidine deaminase, medicine.disease, Gemcitabine, Cancer and Oncology, Cancer cell, biology.protein, biomarker, business, predictive marker, prognostic marker, medicine.drug
Abstract: Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine, median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm, 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine, 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.
Published: 2021

4. Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study

Author: Weimin Ye, Víctor Manuel Barberá, PanGenEU Study Investigators, Matthias Löhr, F.X. Real, Josefina Mora, Damian O'Driscoll, Bo Kong, Tatjana Crnogorac-Jurcevic, L. Ilzarbe, Esther Molina-Montes, Enrique Dominguez-Munoz, Jörg Kleeff, Joaquim Balsells, William Greenhalf, Núria Malats, A. Carrato, Aldo Scarpa, José Perea, Manuel Hidalgo, A Farré, Valentina Rosato, Adonina Tardón, Christoph W. Michalski, Michael O'Rorke, Luis Muñoz-Bellvís, C. La Vecchia, Eithne Costello, Xavier Molero, Paulina Gomez-Rubio, Linda Sharp, Mar Iglesias, Mirari Marquez, Thomas M. Gress, and Ignasi Poves
Subjects: Cancer Research, medicine.medical_specialty, Epidemiology, medicine.medical_treatment, case-control study, Gallbladder disease, gallbladder condition, cholecystectomy, Gallbladder Diseases, Gastroenterology, Risk Factors, Internal medicine, Pancreatic cancer, medicine, Humans, Stage (cooking), gallstones, pancreatic cancer risk, Pancreas, business.industry, Gallbladder, Public Health, Environmental and Occupational Health, Case-control study, Gallstones, Odds ratio, medicine.disease, Pancreatic Neoplasms, medicine.anatomical_structure, Logistic Models, Oncology, Case-Control Studies, Cholecystectomy, Gallbladder Neoplasms, business
Abstract: Background and aims: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). Methods: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. Results: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed = 3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed >= 3 years prior PC were close to unity. Conclusion: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.
Published: 2021

5. GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

Author: Mónica P. de Andrés, Richard Jackson, Christian Pilarsky, Anna Melissa Schlitter, Eithne Costello, William Greenhalf, Paula Ghaneh, Thomas Knösel, Daniel Palmer, Petra Rümmele, Wilko Weichert, Markus Büchler, Thilo Hackert, John P. Neoptolemos, Núria Malats, Paola Martinelli, and Francisco X. Real
Subjects: Oncology, endocrine system, medicine.medical_specialty, Tissue microarray, GATA6, business.industry, Proportional hazards model, Transcriptome, Basal (phylogenetics), medicine.anatomical_structure, Internal medicine, medicine, Biomarker (medicine), Prospective cohort study, business, Pancreas
Abstract: ObjectiveGATA6 is a master regulator of pancreatic differentiation and a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression is associated with poor patient outcome.GATA4is the second most expressed GATA factor in the pancreas. The aim was to assess whether, and how, GATA4 contributes to PDAC phenotype and to analyze the association of expression with clinical outcome.DesignWe analyzed PDAC transcriptomic data, stratifying cases according toGATA4andGATA6expression, and identified differentially expressed genes and pathways. A multicenter TMA study to assess GATA4 and GATA6 expression in PDAC samples (n=745) from patients undergoing tumour resection was performed using immunohistochemistry with antibodies of validated specificity. GATA4 and GATA6 levels were dichotomized into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models.ResultsSubtype classification using transcriptomic data revealed thatGATA4mRNA is enriched in classical, compared to basal-like tumours. We classified samples in 4 groups as high/low forGATA4andGATA6. Reduced expression ofGATA4did not have a major transcriptional impact. However, concomitant low expression ofGATA4enhanced the transcriptomic effects ofGATA6low expression. Reduced expression of both proteins in tumours was associated with the worst patient survival.GATA4andGATA6expression significantly decreased in metastases and negatively correlated with basal markers.ConclusionsOur analyses uncover a cooperative interaction betweenGATA4andGATA6to maintain the classical PDAC phenotype and provide compelling clinical rationale for assessing their expression as biomarkers of poor prognosis.SUMMARY BOXWhat is already known about this subject?-Patients with classical-type PDAC have a better outcome-Retrospective analyses suggest that classical-type PDAC is more sensitive to 5-FU-based chemotherapy-GATA6 is a surrogate biomarker of classical tumours and its expression is associated with better survival-GATA4 and GATA6 have overlapping and unique functions during pancreatic and gastrointestinal developmentWhat are the new findings?-Tumours displaying only low GATA4 expression have a transcriptomic profile similar to those with preserved expression of both transcription factors-Combined low expression of GATA4 and GATA6 has the highest transcriptomic impact-In a large multicenter tissue microarray study, patients with tumours showing low expression of both GATA4 and GATA6 have the worst overall survival-Low expression of GATA4 and GATA6 is an independent predictor of survival in patients with resectable PDAC-GATA4 levels are down-regulated in liver metastases and are negatively correlated with basal markers such as KRT5/6, KRT14, and TP63How might it impact on clinical practice in the foreseeable future?-The combined assessment of GATA4 and GATA6 expression may improve prognostic stratification of patients with PDAC-Prospective studies should confirm whether GATA4 and GATA6 expression is also predictive of response to chemotherapy in PDAC patients
Published: 2021

6. 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

7. 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

8. Concordance of human equilibrative nucleoside transporter‐1 expressions between murine ( <scp>10D7G2</scp> ) and rabbit ( <scp>SP120</scp> ) antibodies and association with clinical outcomes of adjuvant chemotherapy for pancreatic cancer: A collaborative study from the <scp>JASPAC</scp> 01 trial

Author: Yasuhiro Shimizu, Hiroto Narimatsu, Akira Fukutomi, Hirochika Toyama, Wataru Takayama, Satoru Yasukawa, Naohiro Sata, Paula Ghaneh, Narikazu Boku, Ryuzo Yamaguchi, Katsuhiko Uesaka, Moriaki Tomikawa, Akio Yanagisawa, Shoji Nakamori, William Greenhalf, Yukiyasu Okamura, Keisuke Yamakita, Soichiro Morinaga, Amane Takahashi, Atsuyuki Maeda, John P. Neoptolemos, and Masaru Konishi
Subjects: Oncology, Cancer Research, medicine.medical_specialty, biology, business.industry, medicine.medical_treatment, Concordance, Hazard ratio, medicine.disease, Equilibrative nucleoside transporter 1, Gemcitabine, Pancreatic cancer, Internal medicine, medicine, biology.protein, Immunohistochemistry, Antibody, business, Adjuvant, medicine.drug
Abstract: BACKGROUND Expression of human equilibrative nucleoside transporter-1 (hENT1) is reported to predict survival of gemcitabine (GEM)-treated patients. However, predictive values of immunohistochemical hENT1 expression may differ according to the antibodies, 10D7G2 and SP120. AIM We aimed to investigate the concordance of immunohistochemical hENT1 expression between the two antibodies and prognosis. METHODS The subjects of this study were totally 332 whose formalin-fixed paraffin-embedded specimens and/or unstained sections were obtained. The individual H-scores and four classifications according to the staining intensity were applied for the evaluation of hENT1 expression by 10D7G2 and SP120, respectively. RESULTS The highest concordance rate (79.8%) was obtained when the cut-off between high and low hENT1 expression using SP120 was set between moderate and strong. There were no correlations of hENT1 mRNA level with H-score (p = .258). Although the hENT1 mRNA level was significantly different among four classifications using SP120 (p = .011), there was no linear relationship among them. Multivariate analyses showed that adjuvant GEM was a significant predictor of the patients with low hENT1 expression using either 10D7G2 (Hazard ratio [HR] 2.39, p = .001) or SP120 (HR 1.84, p
Published: 2021

9. 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

10. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19 a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK

Author: Chloe I Bloom, Thomas M Drake, Annemarie B Docherty, Brian J Lipworth, Sebastian L Johnston, Jonathan S Nguyen-Van-Tam, Gail Carson, Jake Dunning, Ewen M Harrison, J Kenneth Baillie, Malcolm G Semple, Paul Cullinan, Peter J M Openshaw, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Ana da Filipe, Tom Fletcher, Christoper A Green, Julian A Hiscox, Antonia Ying Ho, Peter W Horby, Samreen Ijaz, Saye 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, Clark D Russell, 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, Maria Zambon, Hayley Hardwick, Chloe Donohue, Ruth Lyons, Fiona Griffiths, Wilna Oosthuyzen, Lisa Norman, Riinu Pius, 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, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, William Greenhalf, Victoria Shaw, Sara 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, 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 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, UK Research and Innovation, GlaxoSmithKline Biologicals, UKRI MRC COVID-19 Rapid Response Call, and Medical Research Council (MRC)
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, Adolescent, Pulmonary Disease, Chronic Obstructive/complications, Respiratory System, INHALED CORTICOSTEROIDS, World Health Organization, Risk Assessment, 1117 Public Health and Health Services, Cohort Studies, Pulmonary Disease, Chronic Obstructive, Young Adult, Critical Care Medicine, Clinical Protocols, General & Internal Medicine, Internal medicine, medicine, Humans, Hospital Mortality, Prospective Studies, Young adult, Prospective cohort study, Asthma, Science & Technology, business.industry, Public health, ISARIC investigators, Respiratory disease, Asthma/complications, COVID-19, 1103 Clinical Sciences, Odds ratio, Articles, Middle Aged, medicine.disease, United Kingdom, PREVALENCE, Hospitalization, COVID-19/complications, Female, Risk assessment, business, Life Sciences & Biomedicine, Cohort study, 1199 Other Medical and Health Sciences
Abstract: BACKGROUND: Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use. METHODS: We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age ( FINDINGS: 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16-49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05-1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08-1·27]; p INTERPRETATION: Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease. FUNDING: National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England.
Published: 2021

11. Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study

Author: Thomas M Drake, Cameron J Fairfield, Riinu Pius, Stephen R Knight, Lisa Norman, Michelle Girvan, Hayley E Hardwick, Annemarie B Docherty, Ryan S Thwaites, Peter J M Openshaw, J Kenneth Baillie, Ewen M Harrison, Malcolm G Semple, Peter JM Openshaw, Gail Carson, Beatrice Alex, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Ana da Silva Filipe, Thushan de Silva, Jake Dunning, 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, Shona C Moore, Mahdad Noursadeghi, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D Russell, Vanessa Sancho-Shimizu, Janet T Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, AA Roger Thompson, Emma C Thomson, Lance CW Turtle, Maria Zambon, Chloe Donohue, Fiona Griffiths, Hayley Hardwick, Ruth Lyons, Wilna Oosthuyzen, Kenneth A Mclean, Derek Murphy, Catherine A Shaw, Marie Connor, Jo Dalton, Carrol Gamble, Sophie Halpin, Janet Harrison, Clare Jackson, Laura Marsh, Stephanie Roberts, Egle Saviciute, Sara Clohisey, Ross Hendry, Gary Leeming, James Scott-Brown, Murray Wham, William Greenhalf, Sara McDonald, Victoria Shaw, Seán Keating, 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 WA 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 WS 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, Alan MacLean, Sarah McCafferty, Kirstie Morrice, Lee Murphy, Nicola Wrobel, 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, 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, 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, Thapas Nagarajan, Megan Nagel, Mark Nelson, 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, 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, Sarah Sarah, 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, 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, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wooton, Andrew Workman, Bryan Yates, Peter Young, investigators, ISARIC4C, Horby, PW, UKRI MRC COVID-19 Rapid Response Call, National Institute for Health Research, Medical Research Council (MRC), and UK Research and Innovation
Subjects: medicine.medical_specialty, business.industry, Immunology, Acute kidney injury, Articles, medicine.disease, Logistic regression, Rheumatology, Internal medicine, Cohort, Propensity score matching, Epidemiology, medicine, Immunology and Allergy, Medical prescription, business, Prospective cohort study, ISARIC4C Investigators, Cohort study
Abstract: Background Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease. Methods This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations. Results Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84–1·07; p=0·35), critical care admission (1·01, 0·87–1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80–1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96–1·32; p=0·14), requirement for oxygen (1·00, 0·89–1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92–1·26; p=0·33). Interpretation NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity. Funding National Institute for Health Research and Medical Research Council.
Published: 2021

12. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a phase 1, dose-escalating, randomised controlled study

Author: Kerensa Thorne, Andrew Owen, Justin Chiong, Thomas Jaki, Michael Jacobs, Gareth Griffiths, Sara Yeats, Tom Fletcher, Keira Fines, Susannah Condie, Geoffrey Saunders, Kim Mallard, Colin Hale, Jennifer L Gibney, Mike Radford, Nichola Downs, Olana Tansley-Hancock, Pavel Mozgunov, Marcin D Bula, Andrea Corkhill, Katie Bullock, Wendy Painter, Christie Woods, Victoria Shaw, William Greenhalf, Lauren Walker, David G. Lalloo, Wayne Holman, Richard Fitzgerald, Rebecca Lyon, Lucy Johnson, Henry Pertinez, Ellice Marwood, Sean Ewings, Emma Wrixon, Saye Khoo, Emily R. Adams, and Helen Reynolds
Subjects: medicine.medical_specialty, Clinical research, Pharmacokinetics, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Internal medicine, Toxicity, Medicine, In patient, Adverse effect, business, Excess toxicity
Abstract: BackgroundAGILE is a phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection.MethodsWe undertook a dose-escalating, open-label, randomised-controlled (standard-of-care) Bayesian adaptive phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomised 2:1 in groups of 6 participants to 300mg, 600mg and 800mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was higher than 25%. Secondary outcomes included safety, clinical progression, pharmacokinetics and virologic responses.ResultsOf 103 volunteers screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 400, 600 or 800mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800mg molnupiravir respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800mg was estimated at 0.9%.ConclusionMolnupiravir was safe and well tolerated; a dose of 800mg twice-daily for 5 days was recommended for Phase II evaluation.
Published: 2021

13. 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

14. Standardization of EUS imaging and reporting in high-risk individuals of pancreatic adenocarcinoma: consensus statement of the Pancreatic Cancer Early Detection Consortium

Author: Tamas A. Gonda, James Farrell, Michael Wallace, Lauren Khanna, Eileen Janec, Richard Kwon, Michael Saunders, Uzma D. Siddiqui, Randall Brand, Diane M. Simeone, Laufey Amundadottir, Georg Beyer, Yan Bi, Teresa Brentnall, Darren Carpizo, Alfredo Carrato, Hersh Chandarana, Jennifer Chun, Daniel Chung, Beth Dudley, Julia Earl, Jessica Everett, Melissa Fava, Srinivas Gaddam, Steve Gallinger, Talia Golan, John Graff, William Greenhalf, Aaron Grossberg, Philip Hart, Spring Holter, Chenchan Huang, Gregory Idos, Priyanka Kanth, Fay Kastrinos, Bryson Katona, Vivek Kaul, Kelsey Klute, Sonia Kupfer, Joy Liau, James Lin, James Lindberg, Andrew Lowy, Aimee Lucas, Julia Mayerle, Nipun Merchant, Salvatore Paiella, Jennifer Permuth, Intan Schrader, Rosalie Sears, Jens Siveke, Daniel Sussman, and George Zogopoulos
Subjects: medicine.medical_specialty, Standardization, business.industry, Statement (logic), Clinical study design, Mortality rate, Gastroenterology, MEDLINE, Early detection, Adenocarcinoma, Reference Standards, medicine.disease, digestive system diseases, Endosonography, Pancreatic Neoplasms, Pancreatic cancer, Medicine, Humans, Radiology, Nuclear Medicine and imaging, business, Intensive care medicine, Early Detection of Cancer
Abstract: Background and Aims Pancreatic ductal adenocarcinoma is an aggressive disease most often diagnosed after local progression or metastatic dissemination, precluding resection and resulting in a high mortality rate. For individuals with elevated personal risk of the development of pancreatic cancer, EUS is a frequently used advanced imaging and diagnostic modality. However, there is variability in the expertise and definition of EUS findings among gastroenterologists, as well as lack of standardized reporting of relevant findings at the time of examination. Adoption of standardized EUS reporting, using a universally accepted and agreed upon terminology, is needed. Methods A consensus statement designed to create a standardized reporting template was authored by a multidisciplinary group of experts in pancreatic diseases that includes gastroenterologists, radiologists, surgeons, oncologists, and geneticists. This statement was developed using a modified Delphi process as part of the Pancreatic Cancer Early Detection Consortium (PRECEDE) and >75% agreement was required to reach consensus. Results We identified reporting elements and present standardized reporting templates for EUS indications, procedural data, EUS image capture, and descriptors of findings, tissue sampling, and for postprocedural assessment of adequacy. Conclusions Adoption of this standardized EUS reporting template should improve consistency in clinical decision making for individuals with elevated risk of pancreatic cancer by providing complete and accurate reporting of pancreatic abnormalities. Standardization will also help to facilitate research and clinical trial design by using clearly defined and consistent imaging descriptions, thus allowing for comparison of results across different centers.
Published: 2021

15. Prospective observational study of SARS-CoV-2 infection, transmission and immunity in a cohort of households in Liverpool City Region, UK (COVID-LIV): a study protocol

Author: Daniel Hungerford, Neil French, Carrol Gamble, Laura Marsh, Nigel A Cunliffe, Tracy Moitt, Miren Iturriza-Gómara, Chloe Donohue, William Greenhalf, Lance Turtle, Stephen Aston, Milton Ashworth, Laura Booth, Katie Bullock, Terry Foster, Joanna Middleton, William Reynolds, Victoria E Shaw, Eve Wilcock, Jane Armstrong, Susan Dobson, Ashley P Jones, Wega Setiabudi, Krishanthi Subramaniam, Natasha Marcella Vaselli, Moon Wilton, Gareth Platt, Dean J Naisbitt, Emily R Adams, Lynnette Crossley, Neil Joseph, Lee D Troughton, Samantha Kilada, Katharine Abba, Victoria Simpson, Lynsey Goodwin, Rachael Daws, Shiva S Forootan, Rachel Press, Vida Spaine, Lesley Hands, Kate Bradfield, Carol McNally, Silviya Balabanova, Lynsey Finnetty, Paul J Thomson, Monday Ogese, Kareena Adair, Liam Farrell, Kanoot Jaruthamsophon, Adam Lister, Benjamin W A Catterall, Lara Lavelle-Langham, Emily Cass, Alejandra Doce Carracedo, Lianne Davies, Lisa Flaherty, Melanie Oates, Nicole Maziere, Jennifer Lloyd, Hannah Massey, Anthony Holmes, Nicola Carlucci, Vanessa Brammah, Yasmyn Ramos, Daniel Allen, Debbie Howarth, Jena Lowe, Jayne Jones, Paula Wright, Iain Slack, Simone McLaughlin, Jessica Mason, Thomas Edwards, Claudia McKeown, Elysse Hendrick, Chris Williams, Rachel Byrne, Kate Buist, Gala Garrod, Sophie Owen, and Efstathia Gkioni
Subjects: medicine.medical_specialty, Epidemiology, Population, 030204 cardiovascular system & hematology, State Medicine, wa_110, wa_20_5, immunology, respiratory infections, 03 medical and health sciences, 0302 clinical medicine, Environmental health, medicine, wc_505, Humans, Prospective Studies, 030212 general & internal medicine, education, Prospective cohort study, wa_105, education.field_of_study, Transmission (medicine), business.industry, Incidence (epidemiology), Public health, COVID-19, General Medicine, United Kingdom, virology, 3. Good health, Observational Studies as Topic, Research Design, Cohort, Medicine, Observational study, business
Abstract: IntroductionThe emergence and rapid spread of COVID-19 have caused widespread and catastrophic public health and economic impact, requiring governments to restrict societal activity to reduce the spread of the disease. The role of household transmission in the population spread of SARS-CoV-2, and of host immunity in limiting transmission, is poorly understood. This paper describes a protocol for a prospective observational study of a cohort of households in Liverpool City Region, UK, which addresses the transmission of SARS-CoV-2 between household members and how immunological response to the infection changes over time.Methods and analysisHouseholds in the Liverpool City Region, in which members have not previously tested positive for SARS-CoV-2 with a nucleic acid amplification test, are followed up for an initial period of 12 weeks. Participants are asked to provide weekly self-throat and nasal swabs and record their activity and presence of symptoms. Incidence of infection and household secondary attack rates of COVID-19 are measured. Transmission of SARS-CoV-2 will be investigated against a range of demographic and behavioural variables. Blood and faecal samples are collected at several time points to evaluate immune responses to SARS-CoV-2 infection and prevalence and risk factors for faecal shedding of SARS-CoV-2, respectively.Ethics and disseminationThe study has received approval from the National Health Service Research Ethics Committee; REC Reference: 20/HRA/2297, IRAS Number: 283 464. Results will be disseminated through scientific conferences and peer-reviewed open access publications. A report of the findings will also be shared with participants. The study will quantify the scale and determinants of household transmission of SARS-CoV-2. Additionally, immunological responses before and during the different stages of infection will be analysed, adding to the understanding of the range of immunological response by infection severity.
Published: 2021

16. The holding temperature of blood during a delay to processing can affect serum and plasma protein measurements

Author: Christopher Halloran, Lucy Oldfield, William Greenhalf, Benjamin Small, Milton Ashworth, Eithne Costello, and Anthony Evans
Subjects: Leptin, medicine.medical_specialty, Analyte, medicine.medical_treatment, Science, Article, Internal medicine, medicine, Humans, Insulin, Lead (electronics), Cryopreservation, Multidisciplinary, Chemistry, Blood proteins, Protein Stability, Ice, Healthy subjects, Data interpretation, Endocrinology, Blood Preservation, Medicine, Cytokines, Biomarkers
Abstract: Accurate blood-borne biomarkers are sought for diagnosis, prognosis and treatment stratification. Consistent handling of blood is essential for meaningful data interpretation, however, delays during processing are occasionally unavoidable. We investigated the effects of immediately placing blood samples on ice versus room temperature for 1 h (reference protocol), and holding samples on ice versus room temperature during a 3 h delay to processing. Using Luminex multi-plex assays to assess cytokines (n = 29) and diabetes-associated proteins (n = 15) in healthy subjects, we observed that placing blood samples immediately on ice decreased the serum levels of several cytokines, including PAI-1, MIP1-β, IL-9, RANTES and IL-8. During a delay to processing, some analytes, e.g. leptin and insulin, showed little change in serum or plasma values. However, for approximately half of the analytes studied, a delay, regardless of the holding temperature, altered the measured levels compared to the reference protocol. Effects differed between serum and plasma and for some analytes the direction of change in level varied across individuals. The optimal holding temperature for samples during a delay was analyte-specific. In conclusion, deviations from protocol can lead to significant changes in blood analyte levels. Where possible, protocols for blood handling should be pre-determined in an analyte-specific manner.
Published: 2021

17. Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Author: Tamas A. Gonda, Jessica N. Everett, Michael Wallace, Diane M. Simeone, Laufey Amundadottir, Georg Beyer, Yan Bi, Teresa Brentnall, Darren Carpizo, Alfredo Carrato, Hersh Chandarana, Jennifer Chun, Daniel Chung, Beth Dudley, Julia Earl, Melissa Fava, Srinivas Gaddam, Steve Gallinger, Talia Golan, John Graff, William Greenhalf, Aaron Grossberg, Philip Hart, Spring Holter, Chenchan Huang, Gregory Idos, Priyanka Kanth, Fay Kastrinos, Bryson Katona, Vivek Kaul, Lauren Khanna, Kelsey Klute, Sonia Kupfer, Joy Liau, James Lin, James Lindberg, Andrew Lowy, Aimee Lucas, Julia Mayerle, Nipun Merchant, Salvatore Paiella, Jennifer Permuth, Intan Schrader, Rosalie Sears, Jens Siveke, null Daniel Sussman, and George Zogopoulos
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Heredity, Clinical Decision-Making, Early detection, Endosonography, Predictive Value of Tests, Risk Factors, Pancreatic cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Medical History Taking, Early Detection of Cancer, Aged, Hepatology, business.industry, Incidence, Gastroenterology, Middle Aged, medicine.disease, Prognosis, Pedigree, Pancreatic Neoplasms, Female, business
Published: 2021

18. Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study

Author: Thomas M. Drake, Annemarie B. Docherty, Ewen M. Harrison, Jennifer K. Quint, Huzaifa Adamali, Sarah Agnew, Suresh Babu, Christopher M. Barber, Shaney Barratt, Elisabeth Bendstrup, Stephen Bianchi, Diego Castillo Villegas, Nazia Chaudhuri, Felix Chua, Robina Coker, William Chang, Anjali Crawshaw, Louise E. Crowley, Davinder Dosanjh, Christine A. Fiddler, Ian A. Forrest, Peter M. George, Michael A. Gibbons, Katherine Groom, Sarah Haney, Simon P. Hart, Emily Heiden, Michael Henry, Ling-Pei Ho, Rachel K. Hoyles, John Hutchinson, Killian Hurley, Mark Jones, Steve Jones, Maria Kokosi, Michael Kreuter, Laura S. MacKay, Siva Mahendran, George Margaritopoulos, Maria Molina-Molina, Philip L. Molyneaux, Aiden O’Brien, Katherine O’Reilly, Alice Packham, Helen Parfrey, Venerino Poletti, Joanna C. Porter, Elisabetta Renzoni, Pilar Rivera-Ortega, Anne-Marie Russell, Gauri Saini, Lisa G. Spencer, Giulia M. Stella, Helen Stone, Sharon Sturney, David Thickett, Muhunthan Thillai, Tim Wallis, Katie Ward, Athol U. Wells, Alex West, Melissa Wickremasinghe, Felix Woodhead, Glenn Hearson, Lucy Howard, J. Kenneth Baillie, Peter J. M. Openshaw, Malcolm G. Semple, Iain Stewart, R. Gisli Jenkins, Gail Carson, Beatrice Alex, Benjamin Bach, Wendy S. Barclay, Debby Bogaert, Meera Chand, Graham S. Cooke, Jake Dunning, Ana da Silva Filipe, Tom Fletcher, Christopher A. Green, Julian A. Hiscox, Antonia Ying Wai Ho, Peter W. Horby, Samreen Ijaz, Saye 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, Clark D. Russell, 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, A. A. Roger Thompson, Ryan S. Thwaites, Lance C. W. Turtle, Maria Zambon, Hayley Hardwick, Chloe Donohue, Ruth Lyons, Fiona Griffiths, Wilna Oosthuyzen, Lisa Norman, Riinu Pius, Tom M. Drake, Cameron J. Fairfield, Stephen 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, Gary Leeming, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, 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 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, Willliam Greenhalf, Philip Gunning, Catherine Hartley, Antonia Ho, 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, Shona C. Moore, 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, Anita Holme, 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, 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, Thickett, David [0000-0002-5456-6080], Baillie, J Kenneth [0000-0001-5258-793X], Openshaw, Peter JM [0000-0002-7220-2555], Apollo - University of Cambridge Repository, Action for Pulmonary Fibrosis, National Institute for Health Research, and UK Research and Innovation
Subjects: Male, obesity, Respiratory System, Comorbidity, ResearchInstitutes_Networks_Beacons/humanitarian_conflict_response_institute, Critical Care and Intensive Care Medicine, Idiopathic pulmonary fibrosis, 0302 clinical medicine, 030212 general & internal medicine, Lung, License, 11 Medical and Health Sciences, interstitial lung disease, Aged, 80 and over, Interstitial lung disease, respiratory system, Middle Aged, COVID-19, IPF, ILD, Obesity, Lung Function, hospitalisation, idiopathic pulmonary fibrosis, Europe, Hospitalization, COVID-19/Interstitial Lung Disease, ACUTE EXACERBATION, Humanitarian and Conflict Response Institute, Disease Progression, Female, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), behavioral disciplines and activities, 03 medical and health sciences, Critical Care Medicine, General & Internal Medicine, medicine, Humans, In patient, Obesity, ISARIC4C Investigators, Aged, Retrospective Studies, Science & Technology, business.industry, SARS-CoV-2, COVID-19, Retrospective cohort study, lung function, Original Articles, medicine.disease, Lung function, respiratory tract diseases, Clinical trial, body regions, 030228 respiratory system, Case-Control Studies, Emergency medicine, IDIOPATHIC PULMONARY-FIBROSIS, business, Lung Diseases, Interstitial, Tomography, X-Ray Computed
Abstract: Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non–idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17–2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.
Published: 2020

19. Genetic mechanisms of critical illness in COVID-19

Author: Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D, Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Yang, Wu, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J, Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance, Antonia, Ho, Moore, Shona C, Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, Mcauley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C, Renieri, Johnny, Millar, Alistair, Nichol, Tim, Walsh, Manu, Shankar-Hari, Chris, Ponting, Jen, Meikle, Paul, Finernan, Ellie, Mcmaster, Andy, Law, J Kenneth Baillie, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Nicholas, Parkinson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, J Fernandez Roman, M Lopez Martinez, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, K Baillie, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, J Moreno Cuesta, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Lawton, T, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Laha, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Melling, S, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Padden, G, Egan, J, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, C Castro Delgado, R Pepermans Saluzzio, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Clark, R, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, K Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, Salciute, E, Grauslyte, L, Brealey, D, Raith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, D Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Moore, S, Raynard, D, Fox, H, Riddles, L, King, K, Kimber, S, Hobden, G, Mccarthy, A, Cannons, V, Balagosa, I, Chadbourn, I, Gardner, A, Horner, D, Mclaughlanv, D, Charles, B, Proudfoot, N, Marsden, T, Mcmorrow, L, Blackledge, B, Pendlebury, J, Harvey, A, Apetri, E, Basikolo, C, Catlow, L, Doonan, R, Knowles, K, Lee, S, Lomas, D, Lyons, C, Perez, J, Poulaka, M, Slaughter, M, Slevin, K, Thomas, V, Walker, D, Harris, J, Drummond, A, Tully, R, Dearden, J, Philbin, J, Munt, S, Rishton, C, O'Connor, G, Mulcahy, M, Dobson, E, Cuttler, J, Edward, M, Norris, J, Hanson, K, Poole, A, Rose, A, Sloan, B, Buckley, S, Brooke, H, Smithson, E, Charlesworth, R, Sandhu, R, Thirumaran, M, Wagstaff, V, J Cebrian Suarez, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Solesbury, A, Kittridge, L, Forsey, M, Maloney, G, Cole, J, Davies, R, Hill, H, Thomas, E, Williams, A, Duffin, D, Player, B, Radhakrishnan, J, Gibson, S, Lyle, A, Mcneela, F, Patel, B, Gummadi, M, Sloane, G, Dormand, N, Salmi, S, Farzad, Z, Cristiano, D, Liyanage, K, Thwaites, V, Varghese, M, Meredith, M, Mills, G, Willson, J, Harrington, K, Lenagh, B, Cawthron, K, Masuko, S, Raithatha, A, Bauchmuller, K, Wiles, M, Ahmad, N, Barker, J, Jackson, Y, Kibutu, F, Bird, S, Watson, G, Martin, J, Bevan, E, C Wrey Brown, Trodd, D, English, K, Bell, G, Wilcox, L, Katary, A, Gopal, S, Lake, V, Harris, N, Metherell, S, Radford, E, Moore, F, Bancroft, H, Daglish, J, Sangombe, M, Carmody, M, Rhodes, J, Bellamy, M, Garg, A, Kuravi, A, Virgilio, E, Ranga, P, Butler, J, Botfield, L, Dexter, C, Fletcher, J, Shanmugasundaram, P, Hambrook, G, Burn, I, Manso, K, Thornton, D, Tebbutt, J, Penn, R, Hulme, J, Hussain, S, Maqsood, Z, Joseph, S, Colley, J, Hayes, A, Ahmed, C, Haq, R, Clamp, S, Kumar, R, Purewal, M, Baines, B, Frise, M, Jacques, N, Coles, H, Caterson, J, S Gurung Rai, Brunton, M, Tilney, E, Keating, L, Walden, A, Antcliffe, D, Brett, S, Gordon, A, Templeton, M, Rojo, R, Banach, D, S Sousa Arias, Fernandez, Z, Coghlan, P, Williams, D, Jardine, C, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Garland, Z, Gumbrill, B, Phillips, C, L Ortiz-Ruiz de Gordoa, Peasgood, E, Tridente, A, Shuker, K, Greer, S, Lynch, C, Pothecary, C, Roche, L, Deacon, B, Turner, K, Singh, J, G Sera Howe, Paul, P, Gill, M, Wynter, I, Ratnam, V, Shelton, S, Naisbitt, J, Melville, J, Baruah, R, Morrison, S, Mcgregor, A, Parris, V, Mpelembue, M, Srikaran, S, Dennis, C, Sukha, A, Verlander, M, Holding, K, Riches, K, Downes, C, Swan, C, Rostron, A, Roy, A, Woods, L, Cornell, S, Wakinshaw, F, Creagh-Brown, B, Blackman, H, Salberg, A, Smith, E, Donlon, S, Mtuwa, S, Michalak-Glinska, N, Stone, S, Beazley, C, Pristopan, V, Nikitas, N, Lankester, L, Wells, C, S Raj, A, Fletcher, K, Khade, R, Tsinaslanidis, G, Macmahon, M, Fowler, S, Coventry, T, Stewart, R, Wren, L, Mwaura, E, Mew, L, Scaletta, D, Williams, F, Inweregbu, K, Lancaster, N, Cunningham, M, Daniels, A, Harrison, L, Hope, S, Jones, S, Crew, A, Wray, G, Matthews, J, Crawley, R, Carter, J, Birkinshaw, I, Ingham, J, Scott, Z, Pearson, H, Howard, K, Joy, R, Roche, S, Clark, M, Purvis, S, Morrison, A, Strachan, D, Clements, S, Black, K, Parmar, C, Altabaibeh, A, Simpson, K, Mostoles, L, Gilbert, K, L, Ma, Alvaro, A, Thomas, M, Faulkner, B, Worner, R, Hayes, K, Gendall, E, Blakemore, H, Borislavova, B, Goff, E, Vuylsteke, A, Mwaura, L, Zamikula, J, Garner, L, Mitchell, A, Mepham, S, Cagova, L, Fofano, A, Holcombe, H, Praman, K, Szakmany, T, E Heron, A, Cherian, S, Cutler, S, Roynon-Reed, A, Randell, G, Convery, K, Stammers, K, Fottrell-Gould, D, Hudig, L, Keshet-Price, J, Peters, M, O'Neill, L, Ray, S, Belfield, H, Mchugh, T, Jones, G, Akinkugbe, O, Tomas, A, Abaleke, E, Beech, E, Meghari, H, Yussuf, S, Bamford, A, Hairsine, B, Dooks, E, Farquhar, F, Packham, S, Bates, H, Armstrong, L, Kaye, C, Allan, A, Medhora, J, Liew, J, Botello, A, Anderson, F, Cusack, R, Golding, H, Prager, K, Williams, T, Leggett, S, Golder, K, Male, M, Jones, O, Criste, K, Marani, M, Anumakonda, V, Amin, V, Karthik, K, Kausar, R, Anastasescu, E, Reid, K, Smith, M, Hormis, A, Walker, R, Duncan, T, Uriel, A, Ustianowski, A, T-Michael, H, Bruce, M, Connolly, K, Smith, K, Partridge, R, Griffin, D, Mupudzi, M, Muchenje, N, Martin, D, Filipe, H, Eastgate, C, Jackson, C, Gratrix, A, Foster, L, Martinson, V, Stones, E, Caroline, Abernathy, Parkinson, P, Reed, A, Prendergast, C, Rogers, P, Woodruff, M, Shokkar, R, Kaul, S, Barron, A, Collins, C, Beavis, S, Whileman, A, Dale, K, Hawes, J, Pritchard, K, Gascoyne, R, Stevenson, L, Jha, R, Lim, L, Krishnamurthy, V, Parker, R, Turner-Bone, I, Wilding, L, Reddy, A, Whiteley, S, Wilby, E, Howcroft, C, Aspinwall, A, Charlton, S, Ogg, B, Menzies, D, Pugh, R, Allan, E, Lean, R, Davies, F, Easton, J, Qiu, X, Kumar, S, Darlington, K, Houston, G, O'Brien, P, Geary, T, Allan, J, Meikle, A, Hughes, G, Balasubramaniam, M, Latham, S, Mckenna, E, Flanagan, R, Sathe, S, Davies, E, Chablani, M, Kirkby, A, Netherton, K, Archer, S, Yates, B, Ashbrook-Raby, C, Cole, S, Casey, M, Cabrelli, L, Chapman, S, Hutcheon, A, Whyte, C, Almaden-Boyle, C, Pattison, N, Cruz, C, Vochin, A, Kent, H, Thomas, A, Murdoch, S, David, B, Penacerrada, M, Lubimbi, G, Bastion, V, Wulandari, R, Lorusso, R, Valentine, J, Clarke, D, Serrano-Ruiz, A, Hierons, S, Eckbad, C, Ramos, L, Demetriou, C, Mitchard, S, White, K, White, N, Pitts, S, Branney, D, Frankham, J, Watters, M, Langton, H, Prout, R, Page, V, Varghes, T, Cowton, A, Kay, A, Potts, K, Birt, M, Kent, M, Wilkinson, A, B Jude, E, Turner, V, Savill, H, Mccormick, J, Coulding, M, Siddiqui, S, Mercer, O, Rehman, H, Potla, D, Capps, N, Donaldson, D, Button, H, Martin, T, Hard, K, Agasou, A, Tonks, L, Arden, T, Boyle, P, Carnahan, M, Strickley, J, Adams, C, Childs, D, Rikunenko, R, Leigh, M, Breekes, M, Wilcox, R, Bowes, A, Tiveran, H, Hurford, F, Summers, J, Carter, A, Hussain, Y, Ting, L, Javaid, A, Motherwell, N, Moore, H, Millward, H, Jose, S, Schunki, N, Noakes, A, Clulow, C, Sadera, G, Jacob, R, Jones, C, Blunt, M, Coton, Z, Curgenven, H, S Mohamed Ally, Beaumont, K, Elsaadany, M, Fernandes, K, I Ali Mohamed Ali, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, T Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, A Dela Rosa, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, R, Bi, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, George, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers, V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Brown, A, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Paramsothy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin, K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, M Nauman Akhtar, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Timlick, E, Gorman, C, Otahal, I, Gales, A, Coetzee, S, Sell, C, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, E Treus Gude, Love, N, L van Koutrik, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Tariq, A, Houlden, H, Tucci, A, Hardy, J, Moncur, E, Highgate, J, Cowley, A, Mitra, A, Stead, R, Behan, T, Burnett, C, Newton, M, Heeney, E, Pollard, R, Hatton, J, Patel, A, Kasipandian, V, Allibone, S, M Genetu, R, O'Brien, L, Omar, Z, Perkins, E, Davies, K, Tetla, D, Shelley, B, Irvine, V, Williams, S, Williams, P, Goodsell, J, Tutton, R, Bough, L, Winter-Goodwin, B, Kitson, R, Pinnell, J, Wilson, A, Nortcliffe, T, Wood, T, Home, M, Holdroyd, K, Robinson, M, Shaw, R, Greig, J, Brady, M, Haigh, A, Matupe, L, Usher, M, Mellor, S, Dale, S, Gledhill, L, Shaw, L, Turner, G, Kelly, D, Anwar, B, Riley, H, Sturgeon, H, Ali, A, Thomis, L, Melia, D, Dance, A, Humphreys, S, Frost, I, Gopal, V, Godden, J, Holden, A, Swann, S, Smith, T, Clapham, M, Poultney, U, Harper, R, Rice, P, Reece-Anthony, R, Gurung, B, Moultrie, S, Odam, M, Mayer, A, Bellini, A, Pickard, A, Bryant, J, Roe, N, Sowter, J, Lang, K, Taylor, J, Barry, P, Hobrok, M, Tench, H, Wolf-Roberts, R, Mcguinness, H, Loosley, R, Hawcutt, D, Rad, L, O'Malley, L, Saunderson, P, Seddon, G, Anderson, T, Rogers, N, Ruddy, J, Harkins, M, Beith, C, Mcalpine, A, Ferguson, L, Grant, P, Macfadyen, S, Mclaughlin, M, Baird, T, Rundell, S, Welsh, B, Hamill, R, Fisher, F, Gregory, J, Campbell, A, Smuts, S, Gail, Carson, Beatrice, Alex, Benjamin, Bach, Wendy, S Barclay, Debby, Bogaert, Meera, Chand, Graham, S Cooke, Annemarie, B Docherty, Jake, Dunning, Ana da Silva Filipe, Tom, Fletcher, Christoper, A Green, Ewen, M Harrison, Julian, A Hiscox, Antonia Ying Wai Ho, Peter, W Horby, Samreen, Ijaz, Saye, Khoo, Paul, Klenerman, 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, Richard, S Tedder, Emma, C Thomson, A Roger Thompson, A, Ryan, S Thwaites, Lance C, W Turtle, Maria, Zambon, Hayley, Hardwick, Chloe, Donohue, Ruth, Lyons, Lisa, Norman, Riinu, Pius, Thomas, M Drake, Cameron, J Fairfield, Stephen, R Knight, Kenneth, A Mclean, Derek, Murphy, Catherine, A Shaw, Dalton, Jo, Michelle, Girvan, Egle, Saviciute, Stephanie, Roberts, Janet, Harrison, Laura, Marsh, Marie, Connor, Sophie, Halpin, Clare, Jackson, Carrol, Gamble, Gary, Leeming, Murray, Wham, William, Greenhalf, Victoria, Shaw, Sara, Mcdonald, Seán, Keating, Andrea, Ganna, Patrick, Sulem, David, A van Heel, Mattia, Cordioli, Gardar, Sveinbjornsson, Mari E, K Niemi, Janie, F Shelton, Anjali, J Shastri, Chelsea, Ye, Catherine, H Weldon, Teresa, Filshtein-Sonmez, Daniella, Coker, Antony, Symons, Jorge, Esparza-Gordillo, Stella, Aslibekyan, Adam, Auton, Jose, E Krieger, Emmanuelle, Marques, Cinthia, E Jannes, Mari, Francesca, Daga, Sergio, Baldassarri, Margherita, Benetti, Elisa, Simone, Furini, Fallerini, Chiara, Fava, Francesca, Floriana, Valentino, Gabriella, Doddato, Annarita, Giliberti, Tita, Rossella, Amitrano, Sara, Bruttini, Mirella, Croci, Susanna, Meloni, Ilaria, Pinto, ANNA MARIA, Frullanti, Elisa, Mencarelli, MARIA ANTONIETTA, LO RIZZO, Caterina, Montagnani, Francesca, DI SARNO, Laura, Tommasi, Andrea, Palmieri, Maria, Emiliozzi, Arianna, Fabbiani, Massimiliano, Rossetti, Barbara, Zanelli, Giacomo, Bargagli, Elena, Bergantini, Laura, D'Alessandro, Miriana, Cameli, Paolo, David, Bennet, Anedda, Federico, Marcantonio, Simona, Scolletta, Sabino, Franchi, Federico, Mazzei, MARIA ANTONIETTA, Guerrini, Susanna, Conticini, Edoardo, Cantarini, Luca, Frediani, Bruno, Danilo, Tacconi, SPERTILLI RAFFAELLI, Chiara, Marco, Feri, Alice, Donati, Scala, Raffaele, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Croci, Leonardo, Gian Piero Caldarelli, Maurizio, Spagnesi, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Cappelli, Silvia, Anna, Canaccini, Verzuri, Agnese, Valentina, Anemoli, Agostino, Ognibene, Massimo, Vaghi, Antonella D'Arminio Monforte, Esther, Merlini, Mario, U Mondelli, Stefania, Mantovani, Serena, Ludovisi, Massimo, Girardis, Sophie, Venturelli, Marco, Sita, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Maria Eugenia Quiros-Roldan, Paola, Magro, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Giuseppe, Merla, Filippo, Aucella, Pamela, Raggi, Carmen, Marciano, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Valente, Serafina, Marco, Mandalà, Giorli, Alessia, Salerni, Lorenzo, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Stefano, Baratti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Domenico, A Coviello, Cristina, Mussini, Giancarlo, Bosio, Enrico, Martinelli, Sandro, Mancarella, Luisa, Tavecchia, Lia, Crotti, Nicola, Picchiotti, Marco, Gori, Chiara, Gabbi, Maurizio, Sanarico, Stefano, Ceri, Pietro, Pinoli, Francesco, Raimondi, Filippo, Biscarini, Alessandra, Stella, Alessandra, Shen, Xia, Ponting, Chris P, Fawkes, Angie, Tenesa, Albert, Caulfield, Mark, Scott, Richard, Rowan, Kathy, Murphy, Lee, Openshaw, Peter J M, Semple, Malcolm G, Law, Andrew, Vitart, Veronique, Wilson, James F, Baillie, J Kenneth, Pairo-Castineira, E, Clohisey, S, Klaric, L, Bretherick, A, Rawlik, K, Pasko, D, Walker, S, Parkinson, N, Fourman, M, Russell, C, Furniss, J, Richmond, A, Gountouna, E, Wrobel, N, Harrison, D, Wang, B, Wu, Y, Meynert, A, Griffiths, F, Oosthuyzen, W, Kousathanas, A, Moutsianas, L, Yang, Z, Zhai, R, Zheng, C, Grimes, G, Beale, R, Millar, J, Shih, B, Keating, S, Zechner, M, Haley, C, Porteous, D, Hayward, C, Yang, J, Knight, J, Summers, C, Shankar-Hari, M, Klenerman, P, Turtle, L, Ho, A, Moore, S, Hinds, C, Horby, P, Nichol, A, Maslove, D, Ling, L, Mcauley, D, Montgomery, H, Walsh, T, Pereira, A, Renieri, A, Ponting, C, Meikle, J, Finernan, P, Mcmaster, E, Law, A, Baillie, J, Paterson, T, Wackett, T, Armstrong, R, Clark, R, Coutts, A, Donnelly, L, Gilchrist, T, Hafezi, K, Macgillivray, L, Maclean, A, Mccafferty, S, Morrice, K, Weaver, J, Boz, C, Golightly, A, Ward, M, Mal, H, Szoor-McElhinney, H, Brown, A, Hendry, R, Stenhouse, A, Cullum, L, Law, D, Law, S, Law, R, Swets, M, Day, N, Taneski, F, Duncan, E, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, Roman, J, Martinez, M, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, Moreno Cuesta, J, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Lawton, T, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Laha, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Melling, S, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Padden, G, Egan, J, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, Delgado, C, Saluzzio, R, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, Salciute, E, Grauslyte, L, Brealey, D, Raith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Raynard, D, Fox, H, Riddles, L, King, K, Kimber, S, Hobden, G, Mccarthy, A, Cannons, V, Balagosa, I, Chadbourn, I, Gardner, A, Horner, D, Mclaughlanv, D, Charles, B, Proudfoot, N, Marsden, T, Mcmorrow, L, Blackledge, B, Pendlebury, J, Harvey, A, Apetri, E, Basikolo, C, Catlow, L, Doonan, R, Knowles, K, Lee, S, Lomas, D, Lyons, C, Perez, J, Poulaka, M, Slaughter, M, Slevin, K, Thomas, V, Walker, D, Harris, J, Drummond, A, Tully, R, Dearden, J, Philbin, J, Munt, S, Rishton, C, O'Connor, G, Mulcahy, M, Dobson, E, Cuttler, J, Edward, M, Norris, J, Hanson, K, Poole, A, Rose, A, Sloan, B, Buckley, S, Brooke, H, Smithson, E, Charlesworth, R, Sandhu, R, Thirumaran, M, Wagstaff, V, Suarez, J, Kaliappan, A, Vertue, M, Nicholson, A, Riches, J, Solesbury, A, Kittridge, L, Forsey, M, Maloney, G, Cole, J, Davies, R, Hill, H, Thomas, E, Williams, A, Duffin, D, Player, B, Radhakrishnan, J, Gibson, S, Lyle, A, Mcneela, F, Patel, B, Gummadi, M, Sloane, G, Dormand, N, Salmi, S, Farzad, Z, Cristiano, D, Liyanage, K, Thwaites, V, Varghese, M, Meredith, M, Mills, G, Willson, J, Harrington, K, Lenagh, B, Cawthron, K, Masuko, S, Raithatha, A, Bauchmuller, K, Wiles, M, Ahmad, N, Barker, J, Jackson, Y, Kibutu, F, Bird, S, Watson, G, Martin, J, Bevan, E, Brown, C, Trodd, D, English, K, Bell, G, Wilcox, L, Katary, A, Gopal, S, Lake, V, Harris, N, Metherell, S, Radford, E, Moore, F, Bancroft, H, Daglish, J, Sangombe, M, Carmody, M, Rhodes, J, Bellamy, M, Garg, A, Kuravi, A, Virgilio, E, Ranga, P, Butler, J, Botfield, L, Dexter, C, Fletcher, J, Shanmugasundaram, P, Hambrook, G, Burn, I, Manso, K, Thornton, D, Tebbutt, J, Penn, R, Hulme, J, Hussain, S, Maqsood, Z, Joseph, S, Colley, J, Hayes, A, Ahmed, C, Haq, R, Clamp, S, Kumar, R, Purewal, M, Baines, B, Frise, M, Jacques, N, Coles, H, Caterson, J, Rai, S, Brunton, M, Tilney, E, Keating, L, Walden, A, Antcliffe, D, Brett, S, Gordon, A, Templeton, M, Rojo, R, Banach, D, Arias, S, Fernandez, Z, Coghlan, P, Williams, D, Jardine, C, Bewley, J, Sweet, K, Grimmer, L, Johnson, R, Garland, Z, Gumbrill, B, Phillips, C, Ortiz-Ruiz de Gordoa, L, Peasgood, E, Tridente, A, Shuker, K, Greer, S, Lynch, C, Pothecary, C, Roche, L, Deacon, B, Turner, K, Singh, J, Howe, G, Paul, P, Gill, M, Wynter, I, Ratnam, V, Shelton, S, Naisbitt, J, Melville, J, Baruah, R, Morrison, S, Mcgregor, A, Parris, V, Mpelembue, M, Srikaran, S, Dennis, C, Sukha, A, Verlander, M, Holding, K, Riches, K, Downes, C, Swan, C, Rostron, A, Roy, A, Woods, L, Cornell, S, Wakinshaw, F, Creagh-Brown, B, Blackman, H, Salberg, A, Smith, E, Donlon, S, Mtuwa, S, Michalak-Glinska, N, Stone, S, Beazley, C, Pristopan, V, Nikitas, N, Lankester, L, Wells, C, Raj, A, Fletcher, K, Khade, R, Tsinaslanidis, G, Macmahon, M, Fowler, S, Coventry, T, Stewart, R, Wren, L, Mwaura, E, Mew, L, Scaletta, D, Williams, F, Inweregbu, K, Lancaster, N, Cunningham, M, Daniels, A, Harrison, L, Hope, S, Jones, S, Crew, A, Wray, G, Matthews, J, Crawley, R, Carter, J, Birkinshaw, I, Ingham, J, Scott, Z, Pearson, H, Howard, K, Joy, R, Roche, S, Clark, M, Purvis, S, Morrison, A, Strachan, D, Clements, S, Black, K, Parmar, C, Altabaibeh, A, Simpson, K, Mostoles, L, Gilbert, K, Ma, L, Alvaro, A, Thomas, M, Faulkner, B, Worner, R, Hayes, K, Gendall, E, Blakemore, H, Borislavova, B, Goff, E, Vuylsteke, A, Mwaura, L, Zamikula, J, Garner, L, Mitchell, A, Mepham, S, Cagova, L, Fofano, A, Holcombe, H, Praman, K, Szakmany, T, Heron, A, Cherian, S, Cutler, S, Roynon-Reed, A, Randell, G, Convery, K, Stammers, K, Fottrell-Gould, D, Hudig, L, Keshet-Price, J, Peters, M, O'Neill, L, Ray, S, Belfield, H, Mchugh, T, Jones, G, Akinkugbe, O, Tomas, A, Abaleke, E, Beech, E, Meghari, H, Yussuf, S, Bamford, A, Hairsine, B, Dooks, E, Farquhar, F, Packham, S, Bates, H, Armstrong, L, Kaye, C, Allan, A, Medhora, J, Liew, J, Botello, A, Anderson, F, Cusack, R, Golding, H, Prager, K, Williams, T, Leggett, S, Golder, K, Male, M, Jones, O, Criste, K, Marani, M, Anumakonda, V, Amin, V, Karthik, K, Kausar, R, Anastasescu, E, Reid, K, Smith, M, Hormis, A, Walker, R, Duncan, T, Uriel, A, Ustianowski, A, T-Michael, H, Bruce, M, Connolly, K, Smith, K, Partridge, R, Griffin, D, Mupudzi, M, Muchenje, N, Martin, D, Filipe, H, Eastgate, C, Jackson, C, Gratrix, A, Foster, L, Martinson, V, Stones, E, Abernathy, C, Parkinson, P, Reed, A, Prendergast, C, Rogers, P, Woodruff, M, Shokkar, R, Kaul, S, Barron, A, Collins, C, Beavis, S, Whileman, A, Dale, K, Hawes, J, Pritchard, K, Gascoyne, R, Stevenson, L, Jha, R, Lim, L, Krishnamurthy, V, Parker, R, Turner-Bone, I, Wilding, L, Reddy, A, Whiteley, S, Wilby, E, Howcroft, C, Aspinwall, A, Charlton, S, Ogg, B, Menzies, D, Pugh, R, Allan, E, Lean, R, Davies, F, Easton, J, Qiu, X, Kumar, S, Darlington, K, Houston, G, O'Brien, P, Geary, T, Allan, J, Meikle, A, Hughes, G, Balasubramaniam, M, Latham, S, Mckenna, E, Flanagan, R, Sathe, S, Davies, E, Chablani, M, Kirkby, A, Netherton, K, Archer, S, Yates, B, Ashbrook-Raby, C, Cole, S, Casey, M, Cabrelli, L, Chapman, S, Hutcheon, A, Whyte, C, Almaden-Boyle, C, Pattison, N, Cruz, C, Vochin, A, Kent, H, Thomas, A, Murdoch, S, David, B, Penacerrada, M, Lubimbi, G, Bastion, V, Wulandari, R, Lorusso, R, Valentine, J, Clarke, D, Serrano-Ruiz, A, Hierons, S, Eckbad, C, Ramos, L, Demetriou, C, Mitchard, S, White, K, White, N, Pitts, S, Branney, D, Frankham, J, Watters, M, Langton, H, Prout, R, Page, V, Varghes, T, Cowton, A, Kay, A, Potts, K, Birt, M, Kent, M, Wilkinson, A, Jude, E, Turner, V, Savill, H, Mccormick, J, Coulding, M, Siddiqui, S, Mercer, O, Rehman, H, Potla, D, Capps, N, Donaldson, D, Button, H, Martin, T, Hard, K, Agasou, A, Tonks, L, Arden, T, Boyle, P, Carnahan, M, Strickley, J, Adams, C, Childs, D, Rikunenko, R, Leigh, M, Breekes, M, Wilcox, R, Bowes, A, Tiveran, H, Hurford, F, Summers, J, Carter, A, Hussain, Y, Ting, L, Javaid, A, Motherwell, N, Moore, H, Millward, H, Jose, S, Schunki, N, Noakes, A, Clulow, C, Sadera, G, Jacob, R, Jones, C, Blunt, M, Coton, Z, Curgenven, H, Ally, S, Beaumont, K, Elsaadany, M, Fernandes, K, Ali Mohamed Ali, I, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, Dela Rosa, A, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, Bi, R, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, George, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers, V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Paramsothy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin, K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, Nauman Akhtar, M, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Timlick, E, Gorman, C, Otahal, I, Gales, A, Coetzee, S, Sell, C, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, Gude, E, Love, N, van Koutrik, L, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Tariq, A, Houlden, H, Tucci, A, Hardy, J, Moncur, E, Highgate, J, Cowley, A, Mitra, A, Stead, R, Behan, T, Burnett, C, Newton, M, Heeney, E, Pollard, R, Hatton, J, Patel, A, Kasipandian, V, Allibone, S, Genetu, R, O'Brien, L, Omar, Z, Perkins, E, Davies, K, Tetla, D, Shelley, B, Irvine, V, Williams, S, Williams, P, Goodsell, J, Tutton, R, Bough, L, Winter-Goodwin, B, Kitson, R, Pinnell, J, Wilson, A, Nortcliffe, T, Wood, T, Home, M, Holdroyd, K, Robinson, M, Shaw, R, Greig, J, Brady, M, Haigh, A, Matupe, L, Usher, M, Mellor, S, Dale, S, Gledhill, L, Shaw, L, Turner, G, Kelly, D, Anwar, B, Riley, H, Sturgeon, H, Ali, A, Thomis, L, Melia, D, Dance, A, Humphreys, S, Frost, I, Gopal, V, Godden, J, Holden, A, Swann, S, Smith, T, Clapham, M, Poultney, U, Harper, R, Rice, P, Reece-Anthony, R, Gurung, B, Moultrie, S, Odam, M, Mayer, A, Bellini, A, Pickard, A, Bryant, J, Roe, N, Sowter, J, Lang, K, Taylor, J, Barry, P, Hobrok, M, Tench, H, Wolf-Roberts, R, Mcguinness, H, Loosley, R, Hawcutt, D, Rad, L, O'Malley, L, Saunderson, P, Seddon, G, Anderson, T, Rogers, N, Ruddy, J, Harkins, M, Beith, C, Mcalpine, A, Ferguson, L, Grant, P, Macfadyen, S, Mclaughlin, M, Baird, T, Rundell, S, Welsh, B, Hamill, R, Fisher, F, Gregory, J, Campbell, A, Smuts, S, Kenneth Baillie, J, Carson, G, Alex, B, Bach, B, Barclay, W, Bogaert, D, Chand, M, Cooke, G, Docherty, A, Dunning, J, da Silva Filipe, A, Fletcher, T, Green, C, Harrison, E, Hiscox, J, Ijaz, S, Khoo, S, Lim, W, Mentzer, A, Merson, L, Noursadeghi, M, Palmarini, M, Paxton, W, Pollakis, G, Price, N, Rambaut, A, Robertson, D, Sancho-Shimizu, V, Scott, J, de Silva, T, Sigfrid, L, Solomon, T, Sriskandan, S, Stuart, D, Tedder, R, Thomson, E, Thompson, A, Thwaites, R, Zambon, M, Hardwick, H, Donohue, C, Lyons, R, Norman, L, Pius, R, Drake, T, Fairfield, C, Knight, S, Mclean, K, Murphy, D, Shaw, C, Dalton, J, Girvan, M, Saviciute, E, Roberts, S, Harrison, J, Marsh, L, Connor, M, Halpin, S, Gamble, C, Leeming, G, Wham, M, Greenhalf, W, Shaw, V, Mcdonald, S, Ganna, A, Sulem, P, van Heel, D, Cordioli, M, Sveinbjornsson, G, Niemi, M, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Krieger, J, Marques, E, Jannes, C, Mari, F, Daga, S, Baldassarri, M, Benetti, E, Furini, S, Fallerini, C, Fava, F, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Pinto, A, Frullanti, E, Mencarelli, M, Rizzo, C, Montagnani, F, Di Sarno, L, Tommasi, A, Palmieri, M, Emiliozzi, A, Fabbiani, M, Rossetti, B, Zanelli, G, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennet, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Vaghi, M, D'Arminio Monforte, A, Merlini, E, Mondelli, M, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Sita, M, Cossarizza, A, Antinori, A, Vergori, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Castelli, F, Quiros-Roldan, M, Magro, P, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Baratti, S, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Picchiotti, N, Gori, M, Gabbi, C, Sanarico, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Shen, X, Fawkes, A, Tenesa, A, Caulfield, M, Scott, R, Rowan, K, Murphy, L, Openshaw, P, Semple, M, Vitart, V, Wilson, J, Pairo-Castineira, Erola [0000-0002-2423-3090], Klaric, Lucija [0000-0003-3105-8929], Bretherick, Andrew D [0000-0001-9258-3140], Rawlik, Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Fourman, Max Head [0000-0001-7381-2278], Russell, Clark D [0000-0002-9873-8243], Gountouna, Elvina [0000-0001-7870-2780], Wang, Bo [0000-0002-1580-797X], Wu, Yang [0000-0002-0128-7280], Kousathanas, Athanasios [0000-0001-6265-6521], Moutsianas, Loukas [0000-0001-5453-345X], Zhai, Ranran [0000-0002-5834-9120], Beale, Rupert [0000-0002-6705-8560], Keating, Sean [0000-0001-8552-5604], Haley, Chris [0000-0002-9811-0210], Porteous, David J [0000-0003-1249-6106], Hayward, Caroline [0000-0002-9405-9550], Yang, Jian [0000-0003-2001-2474], Knight, Julian [0000-0002-0377-5536], Summers, Charlotte [0000-0002-7269-2873], Shankar-Hari, Manu [0000-0002-5338-2538], Turtle, Lance [0000-0002-0778-1693], Moore, Shona C [0000-0001-8610-2806], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Renieri, Alessandra [0000-0002-0846-9220], Shen, Xia [0000-0003-4390-1979], Ponting, Chris P [0000-0003-0202-7816], Tenesa, Albert [0000-0003-4884-4475], Caulfield, Mark [0000-0001-9295-3594], Rowan, Kathy [0000-0001-8217-5602], Murphy, Lee [0000-0001-6467-7449], Openshaw, Peter JM [0000-0002-7220-2555], Semple, Malcolm G [0000-0001-9700-0418], Law, Andrew [0000-0003-1868-2364], Vitart, Veronique [0000-0002-4991-3797], Wilson, James F [0000-0001-5751-9178], Baillie, J Kenneth [0000-0001-5258-793X], Apollo - University of Cambridge Repository, Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Fourman, M. H., Russell, C. D., Furniss, J., Richmond, A., Gountouna, E., Wrobel, N., Harrison, D., Wang, B., Wu, Y., Meynert, A., Griffiths, F., Oosthuyzen, W., Kousathanas, A., Moutsianas, L., Yang, Z., Zhai, R., Zheng, C., Grimes, G., Beale, R., Millar, J., Shih, B., Keating, S., Zechner, M., Haley, C., Porteous, D. J., Hayward, C., Yang, J., Knight, J., Summers, C., Shankar-Hari, M., Klenerman, P., Turtle, L., Ho, A., Moore, S. C., Hinds, C., Horby, P., Nichol, A., Maslove, D., Ling, L., Mcauley, D., Montgomery, H., Walsh, T., Pereira, A. C., Renieri, A., Ponting, C., Meikle, J., Finernan, P., Mcmaster, E., Law, A., Baillie, J. K., Paterson, T., Wackett, T., Armstrong, R., Clark, R., Coutts, A., Donnelly, L., Gilchrist, T., Hafezi, K., Macgillivray, L., Maclean, A., Mccafferty, S., Morrice, K., Weaver, J., Boz, C., Golightly, A., Ward, M., Mal, H., Szoor-McElhinney, H., Brown, A., Hendry, R., Stenhouse, A., Cullum, L., Law, D., Law, S., Law, R., Swets, M., Day, N., Taneski, F., Duncan, E., Collier, D., Wood, S., Zak, A., Borra, C., Matharu, M., May, P., Alldis, Z., Mitchelmore, O., Bowles, R., Easthope, A., Bibi, F., Lancoma-Malcolm, I., Gurasashvili, J., Pheby, J., Shiel, J., Bolton, M., Patel, M., Taylor, M., Zongo, O., Ebano, P., Harding, P., Astin-Chamberlain, R., Choudhury, Y., Cox, A., Kallon, D., Burton, M., Hall, R., Blowes, S., Prime, Z., Biddle, J., Prysyazhna, O., Newman, T., Tierney, C., Kassam, J., Ostermann, M., Campos, S., Bociek, A., Lim, R., Grau, N., Jones, T. O., Whitton, C., Marotti, M., Arbane, G., Bonner, S., Hugill, K., Reid, J., Welters, I., Waugh, V., Williams, K., Shaw, D., Roman, J. F., Martinez, M. L., Johnson, E., Waite, A., Johnston, B., Hamilton, D., Mulla, S., Mcphail, M., Smith, J., Barclay, L., Hope, D., Mcculloch, C., Mcquillan, L., Clark, S., Singleton, J., Priestley, K., Rea, N., Callaghan, M., Campbell, R., Andrew, G., Marshall, L., Mckechnie, S., Hutton, P., Bashyal, A., Davidson, N., Polgarova, P., Stroud, K., Pathan, N., Elston, K., Agrawal, S., Battle, C., Newey, L., Rees, T., Harford, R., Brinkworth, E., Williams, M., Murphy, C., White, I., Croft, M., Bandla, N., Gellamucho, M., Tomlinson, J., Turner, H., Davies, M., Quinn, A., Hussain, I., Thompson, C., Parker, H., Bradley, R., Griffiths, R., Scriven, J., Nilsson, A., Bates, M., Dasgin, J., Gill, J., Puxty, A., Cathcart, S., Salutous, D., Turner, L., Duffy, K., Puxty, K., Joseph, A., Herdman-Grant, R., Simms, R., Swain, A., Naranjo, A., Crowe, R., Sollesta, K., Loveridge, A., Baptista, D., Morino, E., Davey, M., Golden, D., Jones, J., Moreno Cuesta, J., Haldeos, A., Bakthavatsalam, D., Vincent, R., Elhassan, M., Xavier, K., Ganesan, A., Purohit, D., Abdelrazik, M., Morgan, J., Akeroyd, L., Bano, S., Lawton, T., Warren, D., Bromley, M., Sellick, K., Gurr, L., Wilkinson, B., Nagarajan, V., Szedlak, P., Cupitt, J., Stoddard, E., Benham, L., Preston, S., Laha, S., Slawson, N., Bradshaw, Z., Brown, J., Caswell, M., Melling, S., Bamford, P., Faulkner, M., Cawley, K., Jeffrey, H., London, E., Sainsbury, H., Nagra, I., Nasir, F., Dunmore, C., Jones, R., Abraheem, A., Al-Moasseb, M., Girach, R., Padden, G., Egan, J., Brantwood, C., Alexander, P., Bradley-Potts, J., Allen, S., Felton, T., Manna, S., Farnell-Ward, S., Leaver, S., Queiroz, J., Maccacari, E., Dawson, D., Delgado, C. C., Saluzzio, R. P., Ezeobu, O., Ding, L., Sicat, C., Kanu, R., Durrant, G., Texeira, J., Harrison, A., Samakomva, T., Willis, H., Hopkins, B., Thrasyvoulou, L., Jackson, M., Zaki, A., Tibke, C., Bennett, S., Woodyatt, W., Kent, A., Goodwin, E., Brandwood, C., Smith, L., Rooney, K., Thomson, N., Rodden, N., Hughes, E., Mcglynn, D., Clark, C., Clark, P., Abel, L., Sundaram, R., Gemmell, L., Brett, M., Hornsby, J., Macgoey, P., Price, R., Digby, B., O'Neil, P., Mcconnell, P., Henderson, P., Henderson, S., Sim, M., Kennedy-Hay, S., Mcparland, C., Rooney, L., Baxter, N., Pogson, D., Rose, S., Daly, Z., Brimfield, L., Phull, M. K., Hussain, M., Pogreban, T., Rosaroso, L., Salciute, E., Grauslyte, L., Brealey, D., Raith, E., Maccallum, N., Bercades, G., Hass, I., Smyth, D., Reyes, A., Martir, G., Clement, I. D., Webster, K., Hays, C., Gulati, A., Hodgson, L., Margarson, M., Gomez, R., Baird, Y., Thirlwall, Y., Folkes, L., Butler, A., Meadows, E., Moore, S., Raynard, D., Fox, H., Riddles, L., King, K., Kimber, S., Hobden, G., Mccarthy, A., Cannons, V., Balagosa, I., Chadbourn, I., Gardner, A., Horner, D., Mclaughlanv, D., Charles, B., Proudfoot, N., Marsden, T., Mcmorrow, L., Blackledge, B., Pendlebury, J., Harvey, A., Apetri, E., Basikolo, C., Catlow, L., Doonan, R., Knowles, K., Lee, S., Lomas, D., Lyons, C., Perez, J., Poulaka, M., Slaughter, M., Slevin, K., Thomas, V., Walker, D., Harris, J., Drummond, A., Tully, R., Dearden, J., Philbin, J., Munt, S., Rishton, C., O'Connor, G., Mulcahy, M., Dobson, E., Cuttler, J., Edward, M., Norris, J., Hanson, K., Poole, A., Rose, A., Sloan, B., Buckley, S., Brooke, H., Smithson, E., Charlesworth, R., Sandhu, R., Thirumaran, M., Wagstaff, V., Suarez, J. C., Kaliappan, A., Vertue, M., Nicholson, A., Riches, J., Solesbury, A., Kittridge, L., Forsey, M., Maloney, G., Cole, J., Davies, R., Hill, H., Thomas, E., Williams, A., Duffin, D., Player, B., Radhakrishnan, J., Gibson, S., Lyle, A., Mcneela, F., Patel, B., Gummadi, M., Sloane, G., Dormand, N., Salmi, S., Farzad, Z., Cristiano, D., Liyanage, K., Thwaites, V., Varghese, M., Meredith, M., Mills, G., Willson, J., Harrington, K., Lenagh, B., Cawthron, K., Masuko, S., Raithatha, A., Bauchmuller, K., Wiles, M., Ahmad, N., Barker, J., Jackson, Y., Kibutu, F., Bird, S., Watson, G., Martin, J., Bevan, E., Brown, C. W., Trodd, D., English, K., Bell, G., Wilcox, L., Katary, A., Gopal, S., Lake, V., Harris, N., Metherell, S., Radford, E., Moore, F., Bancroft, H., Daglish, J., Sangombe, M., Carmody, M., Rhodes, J., Bellamy, M., Garg, A., Kuravi, A., Virgilio, E., Ranga, P., Butler, J., Botfield, L., Dexter, C., Fletcher, J., Shanmugasundaram, P., Hambrook, G., Burn, I., Manso, K., Thornton, D., Tebbutt, J., Penn, R., Hulme, J., Hussain, S., Maqsood, Z., Joseph, S., Colley, J., Hayes, A., Ahmed, C., Haq, R., Clamp, S., Kumar, R., Purewal, M., Baines, B., Frise, M., Jacques, N., Coles, H., Caterson, J., Rai, S. G., Brunton, M., Tilney, E., Keating, L., Walden, A., Antcliffe, D., Brett, S., Gordon, A., Templeton, M., Rojo, R., Banach, D., Arias, S. S., Fernandez, Z., Coghlan, P., Williams, D., Jardine, C., Bewley, J., Sweet, K., Grimmer, L., Johnson, R., Garland, Z., Gumbrill, B., Phillips, C., Ortiz-Ruiz de Gordoa, L., Peasgood, E., Tridente, A., Shuker, K., Greer, S., Lynch, C., Pothecary, C., Roche, L., Deacon, B., Turner, K., Singh, J., Howe, G. S., Paul, P., Gill, M., Wynter, I., Ratnam, V., Shelton, S., Naisbitt, J., Melville, J., Baruah, R., Morrison, S., Mcgregor, A., Parris, V., Mpelembue, M., Srikaran, S., Dennis, C., Sukha, A., Verlander, M., Holding, K., Riches, K., Downes, C., Swan, C., Rostron, A., Roy, A., Woods, L., Cornell, S., Wakinshaw, F., Creagh-Brown, B., Blackman, H., Salberg, A., Smith, E., Donlon, S., Mtuwa, S., Michalak-Glinska, N., Stone, S., Beazley, C., Pristopan, V., Nikitas, N., Lankester, L., Wells, C., Raj, A. S., Fletcher, K., Khade, R., Tsinaslanidis, G., Macmahon, M., Fowler, S., Coventry, T., Stewart, R., Wren, L., Mwaura, E., Mew, L., Scaletta, D., Williams, F., Inweregbu, K., Lancaster, N., Cunningham, M., Daniels, A., Harrison, L., Hope, S., Jones, S., Crew, A., Wray, G., Matthews, J., Crawley, R., Carter, J., Birkinshaw, I., Ingham, J., Scott, Z., Pearson, H., Howard, K., Joy, R., Roche, S., Clark, M., Purvis, S., Morrison, A., Strachan, D., Clements, S., Black, K., Parmar, C., Altabaibeh, A., Simpson, K., Mostoles, L., Gilbert, K., Ma, L., Alvaro, A., Thomas, M., Faulkner, B., Worner, R., Hayes, K., Gendall, E., Blakemore, H., Borislavova, B., Goff, E., Vuylsteke, A., Mwaura, L., Zamikula, J., Garner, L., Mitchell, A., Mepham, S., Cagova, L., Fofano, A., Holcombe, H., Praman, K., Szakmany, T., Heron, A. E., Cherian, S., Cutler, S., Roynon-Reed, A., Randell, G., Convery, K., Stammers, K., Fottrell-Gould, D., Hudig, L., Keshet-Price, J., Peters, M., O'Neill, L., Ray, S., Belfield, H., Mchugh, T., Jones, G., Akinkugbe, O., Tomas, A., Abaleke, E., Beech, E., Meghari, H., Yussuf, S., Bamford, A., Hairsine, B., Dooks, E., Farquhar, F., Packham, S., Bates, H., Armstrong, L., Kaye, C., Allan, A., Medhora, J., Liew, J., Botello, A., Anderson, F., Cusack, R., Golding, H., Prager, K., Williams, T., Leggett, S., Golder, K., Male, M., Jones, O., Criste, K., Marani, M., Anumakonda, V., Amin, V., Karthik, K., Kausar, R., Anastasescu, E., Reid, K., Smith, M., Hormis, A., Walker, R., Duncan, T., Uriel, A., Ustianowski, A., T-Michael, H., Bruce, M., Connolly, K., Smith, K., Partridge, R., Griffin, D., Mupudzi, M., Muchenje, N., Martin, D., Filipe, H., Eastgate, C., Jackson, C., Gratrix, A., Foster, L., Martinson, V., Stones, E., Abernathy, C., Parkinson, P., Reed, A., Prendergast, C., Rogers, P., Woodruff, M., Shokkar, R., Kaul, S., Barron, A., Collins, C., Beavis, S., Whileman, A., Dale, K., Hawes, J., Pritchard, K., Gascoyne, R., Stevenson, L., Jha, R., Lim, L., Krishnamurthy, V., Parker, R., Turner-Bone, I., Wilding, L., Reddy, A., Whiteley, S., Wilby, E., Howcroft, C., Aspinwall, A., Charlton, S., Ogg, B., Menzies, D., Pugh, R., Allan, E., Lean, R., Davies, F., Easton, J., Qiu, X., Kumar, S., Darlington, K., Houston, G., O'Brien, P., Geary, T., Allan, J., Meikle, A., Hughes, G., Balasubramaniam, M., Latham, S., Mckenna, E., Flanagan, R., Sathe, S., Davies, E., Chablani, M., Kirkby, A., Netherton, K., Archer, S., Yates, B., Ashbrook-Raby, C., Cole, S., Casey, M., Cabrelli, L., Chapman, S., Hutcheon, A., Whyte, C., Almaden-Boyle, C., Pattison, N., Cruz, C., Vochin, A., Kent, H., Thomas, A., Murdoch, S., David, B., Penacerrada, M., Lubimbi, G., Bastion, V., Wulandari, R., Lorusso, R., Valentine, J., Clarke, D., Serrano-Ruiz, A., Hierons, S., Eckbad, C., Ramos, L., Demetriou, C., Mitchard, S., White, K., White, N., Pitts, S., Branney, D., Frankham, J., Watters, M., Langton, H., Prout, R., Page, V., Varghes, T., Cowton, A., Kay, A., Potts, K., Birt, M., Kent, M., Wilkinson, A., Jude, E. B., Turner, V., Savill, H., Mccormick, J., Coulding, M., Siddiqui, S., Mercer, O., Rehman, H., Potla, D., Capps, N., Donaldson, D., Button, H., Martin, T., Hard, K., Agasou, A., Tonks, L., Arden, T., Boyle, P., Carnahan, M., Strickley, J., Adams, C., Childs, D., Rikunenko, R., Leigh, M., Breekes, M., Wilcox, R., Bowes, A., Tiveran, H., Hurford, F., Summers, J., Carter, A., Hussain, Y., Ting, L., Javaid, A., Motherwell, N., Moore, H., Millward, H., Jose, S., Schunki, N., Noakes, A., Clulow, C., Sadera, G., Jacob, R., Jones, C., Blunt, M., Coton, Z., Curgenven, H., Ally, S. M., Beaumont, K., Elsaadany, M., Fernandes, K., Ali Mohamed Ali, I., Rangarajan, H., Sarathy, V., Selvanayagam, S., Vedage, D., White, M., Truman, N., Chukkambotla, S., Keith, S., Cockerill-Taylor, J., Ryan-Smith, J., Bolton, R., Springle, P., Dykes, J., Thomas, J., Khan, M., Hijazi, M. T., Massey, E., Croston, G., Reschreiter, H., Camsooksai, J., Patch, S., Jenkins, S., Humphrey, C., Wadams, B., Msiska, M., Adanini, O., Attwood, B., Parsons, P., Tatham, K., Jhanji, S., Black, E., Dela Rosa, A., Howle, R., Thomas, B., Bemand, T., Raobaikady, R., Saha, R., Staines, N., Daniel, A., Finn, J., Hutter, J., Doble, P., Shovelton, C., Pawley, C., Kannan, T., Hill, M., Combes, E., Monnery, S., Joefield, T., Popescu, M., Thankachen, M., Oblak, M., Little, J., Mcivor, S., Brady, A., Whittle, H., Prady, H., Chan, R., Ahmed, A., Morris, A., Gibson, C., Gordon, E., Keenan, S., Quinn, H., Benyon, S., Marriott, S., Zitter, L., Park, L., Baines, K., Lyons, M., Holland, M., Keenan, N., Young, M., Garrioch, S., Dawson, J., Tolson, M., Scholefield, B., Bi, R., Richardson, N., Schumacher, N., Cosier, T., Millen, G., Higham, A., Turki, S., Allen, L., Crisp, N., Hazleton, T., Knight, A., Deery, J., Price, C., Turney, S., Tilbey, S., Beranova, E., Wright, D., George, L., Twiss, S., Wadd, S., Postlethwaite, K., Gondo, P., Masunda, B., Kayani, A., Hadebe, B., Whiteside, J., Clarke, N., Donnison, P., Trim, F., Leadbitter, I., Butcher, D., O'Sullivan, S., Purewal, B., Bell, S., Rivers, V., O'Leary, R., Birch, J., Collins, E., Anderson, S., Hammerton, K., Andrews, E., Burns, K., Edmond, I., Todd, A., Donnachie, J., Turner, P., Prentice, L., Symon, L., Runciman, N., Auld, F., Halkes, M., Mercer, P., Thornton, L., Debreceni, G., Wilkins, J., Crickmore, V., Subramanian, G., Marshall, R., Jennings, C., Latif, M., Bunni, L., Spivey, M., Bean, S., Burt, K., Linnett, V., Ritzema, J., Sanderson, A., Mccormick, W., Bokhari, M., Kapoor, R., Loader, D., Ayers, A., Harrison, W., North, J., Belagodu, Z., Paramsothy, R., Olufuwa, O., Gherman, A., Fuller, B., Stuart, C., Kelsall, O., Davis, C., Wild, L., Wood, H., Thrush, J., Durie, A., Austin, K., Archer, K., Anderson, P., Vigurs, C., Thorpe, C., Knights, E., Boyle, N., Price, A., Kubisz-Pudelko, A., Wood, D., Lewis, A., Board, S., Pippard, L., Perry, J., Beesley, K., Rattray, A., Lee, E., Lennon, L., Douglas, K., Bell, D., Boyle, R., Glass, L., Nauman Akhtar, M., Dent, K., Potoczna, D., Pearson, S., Horsley, E., Spencer, S., Mullan, D., Skinner, D., Gaylard, J., Barber, R., Hewitt, C., Hilldrith, A., Shepardson, S., Wills, M., Jackson-Lawrence, K., Gupta, A., Timlick, E., Gorman, C., Otahal, I., Gales, A., Coetzee, S., Sell, C., Raj, M., Peiu, M., Quaid, S., Watson, E., Elliott, K., Mallinson, J., Chandler, B., Turnbull, A., Finch, C., Holl, C., Cooper, J., Evans, A., Khaliq, W., Collins, A., Gude, E. T., Love, N., van Koutrik, L., Hunt, J., Kaye, D., Fisher, E., Brayne, A., Tuckey, V., Jackson, P., Parkin, J., Tariq, A., Houlden, H., Tucci, A., Hardy, J., Moncur, E., Highgate, J., Cowley, A., Mitra, A., Stead, R., Behan, T., Burnett, C., Newton, M., Heeney, E., Pollard, R., Hatton, J., Patel, A., Kasipandian, V., Allibone, S., Genetu, R. M., O'Brien, L., Omar, Z., Perkins, E., Davies, K., Tetla, D., Shelley, B., Irvine, V., Williams, S., Williams, P., Goodsell, J., Tutton, R., Bough, L., Winter-Goodwin, B., Kitson, R., Pinnell, J., Wilson, A., Nortcliffe, T., Wood, T., Home, M., Holdroyd, K., Robinson, M., Shaw, R., Greig, J., Brady, M., Haigh, A., Matupe, L., Usher, M., Mellor, S., Dale, S., Gledhill, L., Shaw, L., Turner, G., Kelly, D., Anwar, B., Riley, H., Sturgeon, H., Ali, A., Thomis, L., Melia, D., Dance, A., Humphreys, S., Frost, I., Gopal, V., Godden, J., Holden, A., Swann, S., Smith, T., Clapham, M., Poultney, U., Harper, R., Rice, P., Reece-Anthony, R., Gurung, B., Moultrie, S., Odam, M., Mayer, A., Bellini, A., Pickard, A., Bryant, J., Roe, N., Sowter, J., Lang, K., Taylor, J., Barry, P., Hobrok, M., Tench, H., Wolf-Roberts, R., Mcguinness, H., Loosley, R., Hawcutt, D., Rad, L., O'Malley, L., Saunderson, P., Seddon, G., Anderson, T., Rogers, N., Ruddy, J., Harkins, M., Beith, C., Mcalpine, A., Ferguson, L., Grant, P., Macfadyen, S., Mclaughlin, M., Baird, T., Rundell, S., Welsh, B., Hamill, R., Fisher, F., Gregory, J., Campbell, A., Smuts, S., Kenneth Baillie, J., Carson, G., Alex, B., Bach, B., Barclay, W. S., Bogaert, D., Chand, M., Cooke, G. S., Docherty, A. B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C. A., Harrison, E. M., Hiscox, J. A., Ho, A. Y. W., Horby, P. W., Ijaz, S., Khoo, S., Lim, W. S., Mentzer, A. J., Merson, L., Meynert, A. M., Noursadeghi, M., Palmarini, M., Paxton, W. A., Pollakis, G., Price, N., Rambaut, A., Robertson, D. L., Sancho-Shimizu, V., Scott, J. T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R. S., Thomson, E. C., Thompson, A. A. R., Thwaites, R. S., Turtle, L. C. W., Zambon, M., Hardwick, H., Donohue, C., Lyons, R., Norman, L., Pius, R., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Murphy, D., Shaw, C. A., Dalton, J., Girvan, M., Saviciute, E., Roberts, S., Harrison, J., Marsh, L., Connor, M., Halpin, S., Gamble, C., Leeming, G., Wham, M., Greenhalf, W., Shaw, V., Mcdonald, S., Ganna, A., Sulem, P., van Heel, D. A., Cordioli, M., Sveinbjornsson, G., Niemi, M. E. K., Shelton, J. F., Shastri, A. J., Ye, C., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Esparza-Gordillo, J., Aslibekyan, S., Auton, A., Krieger, J. E., Marques, E., Jannes, C. E., Mari, F., Daga, S., Baldassarri, M., Benetti, E., Furini, S., Fallerini, C., Fava, F., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Frullanti, E., Mencarelli, M. A., Rizzo, C. L., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D'Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Picchiotti, N., Gori, M., Gabbi, C., Sanarico, M., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Murphy, L., Openshaw, P. J. M., Semple, M. G., Vitart, V., and Wilson, J. F.
Subjects: 0301 basic medicine, Male, CCR2, Chromosomes, Human, Pair 21, Genome-wide association study, Receptor, Interferon alpha-beta, Disease, Bioinformatics, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, 0302 clinical medicine, Receptors, 2',5'-Oligoadenylate Synthetase, Pair 12, genetics, Lung, BRACOVID Investigators, Multidisciplinary, GenOMICC Investigators, Tyrosine kinase 2, 030220 oncology & carcinogenesis, Multigene Family, Medical genetics, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, medicine.medical_specialty, Critical Care, Receptors, CCR2, General Science & Technology, Critical Illness, Chromosomes, 03 medical and health sciences, Intensive care, Mendelian randomization, Immunogenetics, medicine, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12, Pair 19, SARS-CoV-2, business.industry, Drug Repositioning, COVID-19, United Kingdom, COVID-19 Human Genetics Initiative, 030104 developmental biology, Viral infection, Chromosomes, Human, Pair 19, Genome-Wide Association Study, Pharmacogenomics, ISARICC Investigators, Pair 21, 2', business
Abstract: Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079,P=1.65×10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1,OAS2andOAS3); on chromosome 19p13.2 (rs74956615,P=2.3×10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069,P=3.98× 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757,P=4.99×10−8) in the interferon receptor geneIFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression ofIFNAR2, or high expression ofTYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptorCCR2is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.
Published: 2020
Full Text: View/download PDF

20. International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club

Author: Carlos Fernandez-del Castillo, Julia Mayerle, William Greenhalf, Markus M. Lerch, Andrea Sheel, Philippe Lévy, Patrick Maisonneuve, Chris E. Forsmark, Maiken Thyregod Jørgensen, Vinciane Rebours, Jörg Kleeff, John P. Neoptolemos, Shuiji Isaji, Kyoichi Takaori, Christopher Halloran, Steve Pandol, Dhiraj Yadav, Pramod Kumar Garg, Thomas M. Gress, Péter Hegyi, Randall E. Brand, Suresh T. Chari, Marc G. Besselink, David C. Whitcomb, C. Mel Wilcox, Tooru Shimosegawa, Surgery, CCA - Cancer Treatment and Quality of Life, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, Endocrinology, Diabetes and Metabolism, 0302 clinical medicine, Japan, Trypsin, EUS, Aged, 80 and over, Hereditary pancreatitis, Evidence-Based Medicine, Age Factors, Gastroenterology, Middle Aged, medicine.anatomical_structure, Trypsin Inhibitor, Kazal Pancreatic, Population Surveillance, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Club, Pancreas, Adult, CT scan, medicine.medical_specialty, Consensus, Guidelines as Topic, 03 medical and health sciences, Pancreatitis, Chronic, Pancreatic cancer, Internal medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, In patient, Life Style, Aged, Markers, Hepatology, business.industry, Evidence-based medicine, medicine.disease, United States, Pancreatic Neoplasms, Treatment, Increased risk, Risk factors, Pancreatitis, Surgery, business
Abstract: Background Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP. Methods The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach’s alpha reliability coefficient. Results In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP. Conclusions Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation.
Published: 2020

21. Author Correction: A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis

Author: Stephen J McWilliam, Alan R. Smyth, William Greenhalf, Victoria Shaw, Ashley P Jones, Anna Rosala-Hallas, Thomas Jaki, Rosalind L Smyth, and Munir Pirmohamed
Subjects: medicine.medical_specialty, Multidisciplinary, Kidney Toxicity, business.industry, lcsh:R, Aminoglycoside, lcsh:Medicine, medicine.disease, Cystic fibrosis, law.invention, Randomized controlled trial, law, Internal medicine, medicine, lcsh:Q, Rosuvastatin, lcsh:Science, business, medicine.drug
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020

22. Early detection of pancreatic cancer

Author: Christopher V. Almario, Anne Marie Lennon, Lucy Oldfield, Christie Y. Jeon, Christopher Halloran, Debiao Li, Stephen P. Pereira, Margaret G. Keane, Alexander Ney, Eugene J. Koay, Stephen J. Pandol, Eithne Costello, William Greenhalf, and Phil A. Hart
Subjects: Oncology, Adult, Diagnostic Imaging, Male, medicine.medical_specialty, MEDLINE, Asymptomatic, Article, 03 medical and health sciences, 0302 clinical medicine, Deep Learning, Artificial Intelligence, Risk Factors, Diabetes mellitus, Pancreatic cancer, Internal medicine, medicine, Carcinoma, Biomarkers, Tumor, Electronic Health Records, Humans, Mass Screening, Genetic Predisposition to Disease, Survival rate, Early Detection of Cancer, Aged, Aged, 80 and over, Hepatology, business.industry, Gastroenterology, Cancer, Middle Aged, medicine.disease, Pancreatic Neoplasms, Diabetes Mellitus, Type 2, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, CA19-9, Female, medicine.symptom, Pancreatic Cyst, business, Social Media, Carcinoma, Pancreatic Ductal
Abstract: Pancreatic ductal adenocarcinoma is most frequently detected at an advanced stage. Such late detection restricts treatment options and contributes to a dismal 5-year survival rate of 3-15%. Pancreatic ductal adenocarcinoma is relatively uncommon and screening of the asymptomatic adult population is not feasible or recommended with current modalities. However, screening of individuals in high-risk groups is recommended. Here, we review groups at high risk for pancreatic ductal adenocarcinoma, including individuals with inherited predisposition and patients with pancreatic cystic lesions. We discuss studies aimed at finding ways of identifying pancreatic ductal adenocarcinoma in high-risk groups, such as among individuals with new-onset diabetes mellitus and people attending primary and secondary care practices with symptoms that suggest this cancer. We review early detection biomarkers, explore the potential of using social media for detection, appraise prediction models developed using electronic health records and research data, and examine the application of artificial intelligence to medical imaging for the purposes of early detection.
Published: 2020

23. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Author: John P. Neoptolemos, Markus W. Büchler, Jakob R. Izbicki, Ben Schöttker, Cosmeri Rizzato, Cornelia Schroeder, Salvatore Paiella, Hanneke W. M. van Laarhoven, William Greenhalf, Simona Bursi, Renata Talar-Wojnarowska, Christos Dervenis, Ludmila Vodickova, Francesca Tavano, Giulia Martina Cavestro, Thilo Hackert, Claudio Pasquali, Ewa Małecka-Panas, Gabriele Capurso, Andrea Mambrini, Daniele Campa, Andrea Padoan, Ioannis S. Papanikolaou, Raffaele Pezzilli, Péter Hegyi, Beatrice Mohelnikova-Duchonova, Federica Gemignani, Michael F. Nentwich, Pavel Vodicka, Stefano Landi, Richárd Szmola, Anna Caterina Milanetto, Eithne Costello, Rudolf Kaaks, Laura Ginocchi, Bernd Holleczek, Erika Darvasi, Verena Katzke, Evaristo Maiello, Manuel Gentiluomo, Ondrej Strouhal, Orazio Palmieri, Juozas Kupcinskas, Alice Alessandra Galeotti, Viktor Hlavac, George Theodoropoulos, Audrius Ivanauskas, Maria Gazouli, Ferenc Izbéki, Federico Canzian, Oliver Strobel, Ofure Obazee, Martin Lovecek, Timothy J. Key, Domenica Gioffreda, Pavel Soucek, Ugo Boggi, Krzysztof Jamroziak, Cosimo Sperti, Maarten F. Bijlsma, Yogesh K. Vashist, Andrea Szentesi, Hermann Brenner, Livia Archibugi, Giuseppe Vanella, Daniela Basso, Radiotherapy, Center of Experimental and Molecular Medicine, CCA - Cancer Treatment and Quality of Life, Oncology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Galeotti, A. A., Gentiluomo, M., Rizzato, C., Obazee, O., Neoptolemos, J. P., Pasquali, C., Nentwich, M., Cavestro, G. M., Pezzilli, R., Greenhalf, W., Holleczek, B., Schroeder, C., Schottker, B., Ivanauskas, A., Ginocchi, L., Key, T. J., Hegyi, P., Archibugi, L., Darvasi, E., Basso, D., Sperti, C., Bijlsma, M. F., Palmieri, O., Hlavac, V., Talar-Wojnarowska, R., Mohelnikova-Duchonova, B., Hackert, T., Vashist, Y., Strouhal, O., Van Laarhoven, H., Tavano, F., Lovecek, M., Dervenis, C., Izbeki, F., Padoan, A., Malecka-Panas, E., Maiello, E., Vanella, G., Capurso, G., Izbicki, J. R., Theodoropoulos, G. E., Jamroziak, K., Katzke, V., Kaaks, R., Mambrini, A., Papanikolaou, I. S., Szmola, R., Szentesi, A., Kupcinskas, J., Bursi, S., Costello, E., Boggi, U., Milanetto, A. C., Landi, S., Gazouli, M., Vodickova, L., Soucek, P., Gioffreda, D., Gemignani, F., Brenner, H., Strobel, O., Buchler, M., Vodicka, P., Paiella, S., Canzian, F., and Campa, D.
Subjects: 0301 basic medicine, Oncology, Male, medicine.medical_specialty, Multifactorial Inheritance, Pancreatic disease, genetic epidemiology, Population, Single-nucleotide polymorphism, Disease, pancreas and biliary tract, Polymorphism, Single Nucleotide, Risk Assessment, ABO Blood-Group System, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Pancreatic cancer, Internal medicine, Genetics, medicine, oncology, Humans, education, Genetics (clinical), Alleles, Early Detection of Cancer, Genetic association, education.field_of_study, business.industry, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Genetic epidemiology, 030220 oncology & carcinogenesis, Cohort, Female, business, Carcinoma, Pancreatic Ductal
Abstract: BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.ObjectiveWe generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.MethodsWe tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.ResultsThe scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).ConclusionWe found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
Published: 2020

24. Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

Author: Rudolf Kaaks, Thilo Hackert, Federico Canzian, Livia Archibugi, H. Bas Bueno-de-Mesquita, Angelo Andriulli, Juozas Kupcinskas, Kai Uwe Saum, Yogesh K. Vashist, Andrea Mambrini, Kay-Tee Khaw, Andrea Szentesi, Rita T. Lawlor, Laimas Virginijus Jonaitis, Domenica Gioffreda, Raffaele Pezzilli, Katarina Cuk, Daniela Basso, Ludmila Vodickova, Claudio Pasquali, Pavel Vodicka, Oliver Strobel, Martin Lovecek, Péter Hegyi, Chiara Valsuani, Krzysztof Jamroziak, Gabriele Capurso, Renata Talar-Wojnarowska, Martina Matarazzi, Jakob R. Izbicki, Niccola Funel, Hanneke W. M. van Laarhoven, Pavel Soucek, Daniele Campa, Beatrice Mohelnikova-Duchonova, Francesca Federici, Hermann Brenner, Franco Bambi, Anna Katharina König, Carlo Federico Zambon, Verena Katzke, Maarten F. Bijlsma, William Greenhalf, Francesca Tavano, Felice Pirozzi, Gianfranco Delle Fave, Ofure Obazee, Cosimo Sperti, Jörg Kaiser, Giulia Martina Cavestro, Timothy J. Key, and Stefano Landi
Subjects: Genetics, Oncology, Cancer Research, medicine.medical_specialty, Pancreatic disease, Cancer, Single-nucleotide polymorphism, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Genetic marker, 030220 oncology & carcinogenesis, Pancreatic cancer, Internal medicine, Mendelian randomization, medicine, SNP, Risk assessment
Abstract: Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.
Published: 2018

25. Increased plasma levels of galectin-1 in pancreatic cancer: potential use as biomarker

Author: John P. Neoptolemos, Luis Barranco, Neus Martínez-Bosch, Julie Earl, Carlos A. Orozco, Alfredo Carrato, Laura Visa, Pilar Navarro, Lucy Oldfield, William Greenhalf, Mireia Moreno, Mar Iglesias, Eithne Costello, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Generalitat de Catalunya, Asociación Española de Pancreatología, Asociación Cáncer de Páncreas (España), Asociación Española Contra el Cáncer, Xarxa de Bancs de Tumors de Catalunya, and Colciencias (Colombia)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, pancreatic cancer, education, chronic pancreatitis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Pancreatic cancer, Galectin-1, medicine, galectin-1, Blood test, In patient, medicine.diagnostic_test, business.industry, Cancer, Biomarker, Plasma levels, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, biomarker, Biomarker (medicine), Pancreatitis, business, Chronic pancreatitis, Biomarkers
Abstract: Pancreatic ductal adenocarcinoma (PDA) is the most frequent type of pancreatic cancer and one of the deadliest diseases overall. New biomarkers are urgently needed to allow early diagnosis, one of the only factors that currently improves prognosis. Here we analyzed whether the detection of circulating galectin-1 (Gal-1), a soluble carbohydrate-binding protein overexpressed in PDA tissue samples, can be used as a biomarker for PDA. Gal-1 levels were determined by ELISA in plasma from healthy controls and patients diagnosed with PDA, using three independent cohorts. Patients with chronic pancreatitis (CP) were also included in the study to analyze the potential of Gal-1 to discriminate between cancer and inflammatory process. Plasma Gal-1 levels were significantly increased in patients with PDA as compared to controls in all three cohorts. Gal-1 sensitivity and specificity values were similar to that of the CA19-9 biomarker (the only FDA-approved blood test biomarker for PDA), and the combination of Gal-1 and CA19-9 significantly improved their individual discriminatory powers. Moreover, high levels of Gal-1 were associated with lower survival in patients with non-resected tumors. Collectively, our data indicate a strong potential of using circulating Gal-1 levels as a biomarker for detection and prognostics of patients with PDA., This work was supported by grants from the Spanish Ministerio de Economía y Competitividad/ ISCIII-FEDER (PI14/00125; PI17/00199), the Carmen Delgado/ Miguel Pérez-Mateo AESPANC-ACANPAN 2016 grant and the “Generalitat de Catalunya” (2014/SGR/143 and 2017/ SGR/255) to P.N., ISCIII PI15/02101, EU TRANSCAN AC14/00033 and AECC grants to A.C., and grants from Instituto de Salud Carlos III/FEDER (PT17/0015/0011) and the “Xarxa de Bancs de tumors” sponsored by Pla Director d’Oncologia de Catalunya (XBTC). CAO received funding from the International PhD studies Fellowship “Créditos Beca Francisco José de Caldas” n° 529-2011 Colciencias, Colombia.
Published: 2018

26. Therapeutic developments in pancreatic cancer: current and future perspectives

Author: Jörg Kleeff, Daniel H. Palmer, Patrick Michl, Eithne Costello, William Greenhalf, and John P. Neoptolemos
Subjects: 0301 basic medicine, medicine.medical_specialty, Biomedical Research, Palliative care, medicine.medical_treatment, Antineoplastic Agents, 03 medical and health sciences, 0302 clinical medicine, Cancer immunotherapy, Borderline resectable, Pancreatic cancer, medicine, Humans, Combined Modality Therapy, Precision Medicine, Intensive care medicine, Hepatology, business.industry, Palliative Care, Gastroenterology, Immunotherapy, Precision medicine, medicine.disease, Pancreatic Neoplasms, Radiation therapy, 030104 developmental biology, 030220 oncology & carcinogenesis, business, Forecasting
Abstract: The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.
Published: 2018

27. Detecting pancreatic cancer in individuals with new-onset diabetes mellitus: why and how?

Author: Rohith Rao, Lucy Oldfield, Christopher Halloran, Tejpal Purewal, William Greenhalf, and Eithne Costello
Subjects: Oncology, medicine.medical_specialty, Hepatology, New onset diabetes, business.industry, Endocrinology, Diabetes and Metabolism, Internal medicine, Pancreatic cancer, Gastroenterology, medicine, medicine.disease, business
Published: 2020

28. Abstract 1193: Digital quantification of GATA6 expression from immunohistochemistry is associated with overall survival after surgery for pancreatic cancer in the ESPAC trials

Author: Steven Gallinger, Shawn Hutchison, John P. Neoptolemos, Christopher Halloran, Jennifer J. Knox, Kai Duan, Richard J. Jackson, Paula Ghaneh, Julie M. Wilson, Markus W. Büchler, Stephanie Ramotar, Faiyaz Notta, Thilo Hackert, Grainne M. O'Kane, William Greenhalf, Robert C. Grant, Anna Dodd, Daniel H. Palmer, Eithne Costello-Goldring, and Sandra Fischer
Subjects: Cancer Research, medicine.medical_specialty, Tissue microarray, business.industry, Concordance, Hazard ratio, Cancer, Digital pathology, medicine.disease, Surgery, medicine.anatomical_structure, Oncology, Pancreatic cancer, medicine, Adenocarcinoma, business, Lymph node
Abstract: Introduction: GATA6, a transcription factor involved in pancreaticogenesis, correlates with major transcriptomic subtypes of pancreatic cancer, and early evidence suggests a potential role as a prognostic biomarker. In this study, we tested whether semi-automated digital quantification of GATA6 immunohistochemistry (IHC) was associated with overall survival (OS) after surgical resection of pancreatic cancer in randomized trials of adjuvant chemotherapy. Materials and Methods: Tissue microarrays of pancreatic adenocarcinoma specimens were stained for GATA6 expression using IHC. Specimens came from patients in the ESPAC-3 and ESPAC-4 randomized phase III trials comparing adjuvant chemotherapy regimens. Two pathologists blinded to clinical data independently assessed GATA6 protein expression in cores using a customized computer algorithm from the open-source digital pathology software QuPath. Briefly, the digital assistant provided GATA6 IHC semiquantitative scores (0-4) for individual cells, which were made available to the pathologist for review. This semi-automated digital quantification of GATA6 expression was compared to manual quantification as previously reported (Grant et al., AACR Pancreatic Cancer, 2020). Concordance between pathologists across tissue cores was calculated using a weighted kappa statistic for scores 0 through 4, and an unweighted kappa statistic for high (3-4) and low (0-2) expression levels. Discrepancies were resolved through consensus. Median OS was estimated in GATA6 high and low subgroups using Kaplan-Meier curves. OS was compared using Cox proportional hazard regressions adjusting for adjuvant chemotherapy treatment, lymph node status, and post-operative CA-19-9. Results: GATA6 expression was quantified in 230 patients using the semi-automated digital and manual approaches. Inter-observer concordance markedly improved with digital assistance compared to the manual approach (weighted kappa statistic across all scores 0.69 versus 0.41, unweighted kappa statistic comparing high and low expression 0.71 versus 0.25). GATA6 expression measured using the semi-automated digital approach was significantly associated with OS: median OS was 25.7 months in GATA6 low cancers versus 42.4 months in GATA6 high cancers, with an adjusted hazard ratio of 1.58 (95% confidence interval 1.10-2.28, P=0.014). Conclusion: GATA6 IHC is a prognostic biomarker for pancreatic cancers treated with surgical resection and adjuvant chemotherapy that can be consistently and reliably quantified using digital assistance. Citation Format: Robert C. Grant, Kai Duan, Richard Jackson, William Greenhalf, Eithne Costello-Goldring, Paula Ghaneh, Christopher Halloran, Daniel Palmer, Thilo Hackert, Markus Buchler, Shawn Hutchison, Stephanie Ramotar, Anna Dodd, Julie Wilson, Faiyaz Notta, Grainne O'Kane, Jennifer Knox, John Neoptolemos, Steven Gallinger, Sandra Fischer. Digital quantification of GATA6 expression from immunohistochemistry is associated with overall survival after surgery for pancreatic cancer in the ESPAC trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1193.
Published: 2021

29. How the COVID-19 pandemic has impacted participation of a pancreatic cancer screening programme

Author: William Greenhalf, P. Hopley, O. Edgington, Ioannis Sarantitis, Christopher Halloran, and A. Boughey
Subjects: medicine.medical_specialty, 2019-20 coronavirus outbreak, Hepatology, Coronavirus disease 2019 (COVID-19), business.industry, Endocrinology, Diabetes and Metabolism, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Gastroenterology, medicine.disease, Screening programme, Pancreatic cancer, Pandemic, medicine, Intensive care medicine, business
Published: 2021

30. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

Author: Domenica Gioffreda, Yasuhiro Shimizu, Serena Stigliano, Hidemi Ito, Kay-Tee Khaw, Carlo Lombardo, Martin Oliverius, Ioannis Papaconstantinou, Irena Valantiene, Pavel Soucek, Claudio Pasquali, Kazuo Hara, Verena Katzke, Federico Canzian, Hendrik Strothmann, Andrea Mambrini, Paola Fogar, Gabriele Capurso, Raffaele Pezzilli, Katarina Cuk, Anna Latiano, Olivier R. Busch, Chiara Valsuani, Katja Butterbach, Oliver Strobel, Jakob R. Izbicki, Pavel Vodicka, Thilo Hackert, William Greenhalf, Cosimo Sperti, Anna Katharina König, Angelo Andriulli, Francesca Tavano, Petra H.M. Peeters, Renata Talar-Wojnarowska, Willem Niesen, Giulia Martina Cavestro, Keitaro Matsuo, Beatrice Mohelnikova-Duchonova, Frederike Dijk, Yogesh K. Vashist, Stefano Landi, Maurizio Cantore, Hermann Brenner, Roberto Valente, Daniele Campa, Manuela Pastore, H. Bas Bueno-de-Mesquita, Carlo Federico Zambon, Roberto Salvia, Milena Di Leo, Maria Gazouli, Theron Johnson, Ewa Małecka-Panas, Timothy J. Key, Peter Macinga, Rudolf Kaaks, and Juozas Kupcinskas
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Pancreatic disease, endocrine system diseases, business.industry, Case-control study, Context (language use), medicine.disease, Bioinformatics, digestive system diseases, Minor allele frequency, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Pancreatic cancer, Internal medicine, medicine, Genetic predisposition, Pancreatitis, chronic, Risk factor, business
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.
Published: 2017

31. Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy

Author: William Greenhalf, Paula Ghaneh, Robert Jones, Daniel H. Palmer, James Dodd, N. Bird, Mohamed Elmasry, John P. Neoptolemos, Neil R. Kitteringham, Eftychia E. Psarelli, and Hassan Malik
Subjects: 0301 basic medicine, Oncology, Antimetabolites, Antineoplastic, medicine.medical_specialty, medicine.medical_treatment, Deoxycytidine, Disease-Free Survival, Equilibrative Nucleoside Transporter 1, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Biomarkers, Tumor, medicine, Adjuvant therapy, Carcinoma, Humans, Chemotherapy, Predictive marker, business.industry, Prognosis, medicine.disease, Gemcitabine, Chemotherapy regimen, Pancreatic Neoplasms, 030104 developmental biology, chemistry, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Surgery, business, Adjuvant, Carcinoma, Pancreatic Ductal, medicine.drug
Abstract: Background Human equilibrative nucleoside transporters (hENTs) are transmembranous proteins that facilitate the uptake of nucleosides and nucleoside analogues, such as gemcitabine, into the cell. The abundance of hENT1 transporters in resected pancreatic ductal adenocarcinoma (PDAC) might make hENT1 a potential biomarker of response to adjuvant chemotherapy. The aim of this study was to see whether hENT1 expression, as determined by immunohistochemistry, was a suitable predictive marker for subsequent treatment with gemcitabine-based adjuvant chemotherapy. Methods A systematic review was performed, searching databases from January 1997 to January 2016. Articles pertaining to hENT1 immunohistochemical analysis in resected PDAC specimens from patients who subsequently underwent adjuvant gemcitabine-based chemotherapy were identified. Eligible studies were required to contain survival data, reporting specifically overall survival (OS) and disease-free survival (DFS) with associated hazard ratios (HRs) stratified by hENT1 status. Results Of 42 articles reviewed, eight were suitable for review, with seven selected for quantitative meta-analysis. The total number of patients included in the meta-analysis was 770 (405 hENT1-negative, 365 hENT1-positive). Immunohistochemically detected hENT1 expression was significantly associated with both prolonged DFS (HR 0·58, 95 per cent c.i. 0·42 to 0·79) and OS (HR 0·52, 0·38 to 0·72) in patients receiving adjuvant gemcitabine but not those having fluoropyrimidine-based adjuvant therapy. Conclusion Expression of hENT1 is a suitable prognostic biomarker in patients undergoing adjuvant gemcitabine-based chemotherapy.
Published: 2017

32. UK Early Detection Initiative (UK-EDI) for Pancreatic Cancer

Author: P. Dan, Eftychia-Eirini Psarelli, Christopher Halloran, Tejpal Purewal, R. Hanson, Eithne Costello, L. Alison, Paula Ghaneh, P. Christiansen, Lucy Oldfield, William Greenhalf, and R Van Der Meer
Subjects: Oncology, medicine.medical_specialty, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Internal medicine, Pancreatic cancer, Gastroenterology, medicine, Early detection, medicine.disease, business
Published: 2020

33. Natural history of SPINK1 germline mutation related-pancreatitis

Author: William Greenhalf, Louis de Mestier, Marie Rouanet, Louis Buscail, Vinciane Rebours, John P. Neoptolemos, Christopher Halloran, Claude Férec, Emmanuelle Masson, Nelly Muller, Philippe Ruszniewski, Philippe Lévy, Ioannis Sarantitis, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), University of Liverpool, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Universität Heidelberg [Heidelberg], CCSD, Accord Elsevier, ECLA, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, Research paper, PDAC, pancreatic ductal adenocarcinoma, [SDV]Life Sciences [q-bio], lcsh:Medicine, Gastroenterology, 0302 clinical medicine, SPINK1, DM, diabetes mellitus, lcsh:R5-920, PRSS1, serine protease 1, Incidence, Diabetes, General Medicine, EPI, exocrine pancreatic insufficiency, Middle Aged, 3. Good health, Natural history, [SDV] Life Sciences [q-bio], Trypsin Inhibitor, Kazal Pancreatic, 030220 oncology & carcinogenesis, Cohort, Female, lcsh:Medicine (General), EUS, endoscopic ultrasound, Adult, medicine.medical_specialty, SPINK1, serine protease inhibitor kazal type 1, Adolescent, Genotype, Abbreviation list: CFTR, cystic fibrosis transmembrane conductance regulator gene, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Young Adult, Germline mutation, SRP, SPINK1-related pancreatitis, CTRC, chymotrypsin C, Genetic, Internal medicine, Diabetes mellitus, Pancreatic cancer, medicine, Humans, Pancreatic exocrine insufficiency, Genetic Predisposition to Disease, CP, chronic pancreatitis, Exocrine pancreatic insufficiency, Germ-Line Mutation, business.industry, lcsh:R, Cancer, medicine.disease, IP, idiopathic pancreatitis, Pancreatic Neoplasms, 030104 developmental biology, Pancreatitis, Mutation, CAPS, international cancer of the pancreas screening, business, Follow-Up Studies
Abstract: Background: The aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP). Methods: All SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected. Findings: 209 and 302 patients were included in the SPINK1 and control groups (median follow-up: 8.3 years (3.7–17.4) vs 5.3 (2.5–8.8)).The median age at onset of symptoms was 20.1 years (17.5–22.8) in the SPINK1 group versus 41.2 (35.2–45.2). The age of exocrine pancreatic insufficiency (EPI) onset in the SPINK1 group was 49.5 (44.5–54.6) years vs. 65.2 (62.1–68.3), p
Published: 2019

34. A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis

Author: Thomas Jaki, Alan R. Smyth, Anna Rosala-Hallas, Victoria Shaw, William Greenhalf, Munir Pirmohamed, Stephen J McWilliam, Ashley P Jones, and Rosalind L Smyth
Subjects: Male, medicine.medical_specialty, Adolescent, Cystic Fibrosis, Urinary system, 030232 urology & nephrology, lcsh:Medicine, 030204 cardiovascular system & hematology, Predictive markers, Paediatric research, Cystic fibrosis, Article, law.invention, Nephrotoxicity, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Tobramycin, Humans, Rosuvastatin, Hepatitis A Virus Cellular Receptor 1, Rosuvastatin Calcium, lcsh:Science, Adverse effect, Child, Author Correction, Multidisciplinary, business.industry, lcsh:R, nutritional and metabolic diseases, medicine.disease, Acute kidney injury, Anti-Bacterial Agents, Toxin-induced nephropathy, Cohort, lcsh:Q, Female, Kidney Diseases, business, medicine.drug
Abstract: The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n = 23, control n = 27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n = 20, control n = 24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87–1.35, p = 0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.
Published: 2019

35. Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer

Author: Enno Langhoff, Markus W. Büchler, Georg Beyer, Matthias Sendler, Elisabetta Goni, John P. Neoptolemos, Christopher Halloran, Stephan Kruger, Christiane Bruns, Ujjwal M. Mahajan, Jens Werner, Claus Belka, Julia Mayerle, William Greenhalf, Thomas Kirchner, Steffen Ormanns, Stefan Boeck, Markus M. Lerch, Thomas Kohlmann, Yue Zhao, Felix Lämmerhirt, Eithne Costello, Jan G. D’Haese, Michael von Bergwelt-Baildon, Volker Heinemann, Qi Li, Manuela Marron, Frank-Ulrich Weiss, and Paula Ganeh
Subjects: Oncology, 0303 health sciences, Cancer Research, medicine.medical_specialty, Predictive marker, business.industry, Hazard ratio, Neoplasms, Immunohistochemistry, Pharmaceutical adjuvants, Cell lines, Gemcitabine, Pancreatic ductal adenocarcinoma, Cathepsin d, Fluorouracil, Immunologic adjuvants, Biological markers, Espac trial, Pancreatic cancer, Proteolytic enzymes, Cancer, medicine.disease, Article, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, 030304 developmental biology, medicine.drug
Abstract: Background Cathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown. Methods CatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n = 69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided. Results Median overall survival was 23.75 months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20 (95% CI = 23.75 to 31.90) months for low CatD expression (χ2LR, 1DF = 4.00; P = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; P = .02) but not in 5-fluorouracil-treated (z stat = 0.21; P = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ2LR, 1DF = 6.80; P = .009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, P = .008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance. Conclusions Adjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy.
Published: 2019

36. Familial pancreatic adenocarcinoma: A retrospective analysis of germline genetic testing in a French multicentre cohort

Author: Marie Muller, Pascal Hammel, Florence Coulet, William Greenhalf, Angelique Riffault, Sandra Granier, Chrystelle Colas, Olivier Ingster, Meriem Benfoda, Philippe Jonveaux, Melissa Parrin, Vinciane Rebours, Philippe Lévy, Mathias Schwartz, Mickael Mary, Louis de Mestier, Clément Korenbaum, Jérôme Cros, and Nadem Soufir
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, endocrine system diseases, 030105 genetics & heredity, medicine.disease_cause, Germline, Cohort Studies, 03 medical and health sciences, Young Adult, CDKN2A, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Testing, Genetics (clinical), Genetic testing, Aged, BAP1, medicine.diagnostic_test, business.industry, Carcinoma, Middle Aged, medicine.disease, digestive system diseases, FANCA, Neoplasm Proteins, Pancreatic Neoplasms, 030104 developmental biology, Germ Cells, Adenocarcinoma, Female, Carcinogenesis, business
Abstract: The rate of genetic diagnosis of French patients with familial pancreatic ductal adenocarcinoma (PDAC) is not known. We report germline genetic testing data from 133 index cases meeting criteria for familial pancreatic cancer (FPC) as well as 87 'FPC-like' index cases who did not fulfilled strict FPC definition but were evocative for a PDAC predisposition. The overall rate of genetic diagnosis (in BRCA1, BRCA2, CDKN2A, and ATM genes) was 8.3% in FPC patients and 4.6% in FPC-like patients, consistent with the literature in other populations. Genetic variants were also identified in FANCA and BAP1 genes, as well as in the CDKN2A p12 transcript. This pancreas-specific transcript is a known key player in driving pancreatic oncogenesis. This might be the first described case of a PDAC genetic predisposition due to a variant in this specific transcript.
Published: 2019

37. Lack of Association for Reported Endocrine Pancreatic Cancer Risk Loci in the PANDoRA Consortium

Author: Rudolf Kaaks, Stefano Landi, Felice Pirozzi, Luca Landoni, Ofure Obazee, William Greenhalf, Daniela Basso, Eithne Costello, Gabriele Capurso, Oliver Strobel, Francesca Tavano, Timothy J. Key, Federico Canzian, Claudio Pasquali, Rita T. Lawlor, Domenica Gioffreda, Franco Bambi, John P. Neoptolemos, Kay-Tee Khaw, Renata Talar-Wojnarowska, Daniele Campa, Vincenzo Corbo, Carlo Federico Zambon, Verena Katzke, Francesco Panzuto, Valbona Liço, Manuela Pastore, Krzysztof Jamroziak, Thilo Hackert, Carlo Lombardo, Giulia Zerboni, and Anna Caterina Milanetto
Subjects: 0301 basic medicine, medicine.medical_specialty, Pancreatic disease, Single-nucleotide polymorphism, Context (language use), Neuroendocrine tumors, Biology, Bioinformatics, polymorphism, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Epidemiology, neuroendocrine tumors, epidemiology, medicine, Humans, Genetic Predisposition to Disease, pancreatic endocrine tumors, Genetic association, Aged, Cancer, Middle Aged, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Etiology, epidemiology, neuroendocrine tumors
Abstract: Background: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms for which very little is known about either environmental or genetic risk factors. Only a handful of association studies have been performed so far, suggesting a small number of risk loci. Methods: To replicate the best findings, we have selected 16 SNPs suggested in previous studies to be relevant in PNET etiogenesis. We genotyped the selected SNPs (rs16944, rs1052536, rs1059293, rs1136410, rs1143634, rs2069762, rs2236302, rs2387632, rs3212961, rs3734299, rs3803258, rs4962081, rs7234941, rs7243091, rs12957119, and rs1800629) in 344 PNET sporadic cases and 2,721 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium. Results: After correction for multiple testing, we did not observe any statistically significant association between the SNPs and PNET risk. We also used three online bioinformatic tools (HaploReg, RegulomeDB, and GTEx) to predict a possible functional role of the SNPs, but we did not observe any clear indication. Conclusions: None of the selected SNPs were convincingly associated with PNET risk in the PANDoRA consortium. Impact: We can exclude a major role of the selected polymorphisms in PNET etiology, and this highlights the need for replication of epidemiologic findings in independent populations, especially in rare diseases such as PNETs. Cancer Epidemiol Biomarkers Prev; 26(8); 1349–51. ©2017 AACR.
Published: 2019

38. Pancreas-specific plasma amylase for assessment and diagnosis of chronic pancreatitis: New insights on an old topic

Author: Robert Sutton, Christopher Halloran, Henrik Krarup, Jeppe Hagstrup Christensen, William Greenhalf, Jakob Lykke Poulsen, Andrea Sheel, Asbjørn Mohr Drewes, and Søren Schou Olesen
Subjects: Male, medicine.medical_specialty, Pancreatic alpha-Amylases, Gastroenterology, chronic pancreatitis, Diabetes Complications, clinical stage, Predictive Value of Tests, Diabetes mellitus, Internal medicine, Pancreatitis, Chronic, medicine, Humans, Amylase, Prospective Studies, Exocrine pancreatic insufficiency, Aged, diabetes, biology, business.industry, Diagnostic test, Original Articles, Middle Aged, medicine.disease, exocrine pancreatic insufficiency, Pancreatic Function Tests, medicine.anatomical_structure, Cross-Sectional Studies, Oncology, diagnostic test, biology.protein, Pancreatitis, Exocrine Pancreatic Insufficiency, Female, Pancreas, business
Abstract: © Author(s) 2019. Background: Pancreatic function testing and imaging are used to inform the diagnosis of chronic pancreatitis, but most of these methods are time- and cost-consuming or lack diagnostic accuracy. Objective: We investigated the utility of pancreas-specific plasma amylase for assessment and diagnosis of chronic pancreatitis. Design: This was a prospective study of 121 consecutive patients with chronic pancreatitis and a reference population of 94 healthy controls. Pancreas-specific plasma amylase level was determined and analysed for its association with exocrine pancreatic insufficiency, diabetes and other clinical variables. Receiver operating characteristic curve analyses were performed to determine the diagnostic utility of plasma amylase for diagnosing chronic pancreatitis and to study associations with disease severity. The findings were validated in a further cohort of 57 patients with chronic pancreatitis. Results: Significant and independent associations between plasma amylase level and duration of chronic pancreatitis as well as the presence of exocrine pancreatic insufficiency and diabetes were observed (all p < 0.001). An amylase level below 17.3 U/l had a high specificity (94%) and moderate sensitivity (59%) for the diagnosis of chronic pancreatitis. Diagnostic performance was influenced by disease stage with the best performance observed for advanced disease. The findings were replicated in the validation cohort. Conclusion: Pancreas-specific plasma amylase may provide a clinically useful mean for assessment and diagnosis of chronic pancreatitis.
Published: 2019

39. UK–EDI: Detecting Pancreatic Cancer with DM

Author: Eftychia E. Psarelli, Stephen P. Pereira, Anthony Evans, Claire Jenkinson, Eithne Costello, William Greenhalf, Lucy Oldfield, Paula Ghaneh, Usha Menon, Christopher Halloran, John F. Timms, Rohith Rao, and Tejpal Purewal
Subjects: Oncology, medicine.medical_specialty, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Internal medicine, Pancreatic cancer, Gastroenterology, medicine, medicine.disease, business
Published: 2020

40. EARLY DETECTION OF PANCREATIC ADENOCARCINOMA IN ‘AT-RISK’ POPULATIONS USING A BIOMARKER PANEL IN URINE (UROPANC)

Author: Oleg Blyuss, Stephen P. Pereira, Daria Jach, Silvana Debernardi, Patrick Wilson, Tatjana Crnogorac-Jurcevic, Melody Ni, Alexander Ney, William Greenhalf, Greta Brezgyte, and Stephen W. Duffy
Subjects: Oncology, medicine.medical_specialty, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Gastroenterology, Early detection, Urine, Biomarker panel, medicine.disease, Internal medicine, medicine, Adenocarcinoma, business
Published: 2020

41. Abstract PO-005: GATA6 expression is prognostic after surgical resection of pancreatic cancer: results from the ESPAC trials

Author: Paula Ghaneh, Julie M. Wilson, Eithne Costello-Goldring, Daniel H. Palmer, Faiyaz Notta, Shawn Hutchison, Steven Gallinger, Markus W. Büchler, Thilo Hackert, Stephanie Ramotar, Sandra Fischer, Richard J. Jackson, John P. Neoptolemos, Christopher Halloran, Robert C. Grant, Anna Dodd, Jennifer J. Knox, Kai Duan, William Greenhalf, and Grainne M. O'Kane
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Hazard ratio, Cancer, medicine.disease, Gemcitabine, Capecitabine, Folinic acid, Fluorouracil, Internal medicine, Pancreatic cancer, medicine, business, medicine.drug, Tumor marker
Abstract: Introduction No biomarker is clinically available to predict prognosis after surgical resection of pancreatic cancer beyond CA-19-9, a classical tumor marker. GATA6 is a transcription factor necessary for pancreaticogenesis that associates with the major transcriptomic subtypes of pancreatic cancer. In this study, we evaluated the prognostic utility of GATA6 expression in randomised adjuvant chemotherapy trials. Materials and Methods We retrospectively analyzed resection specimens in tissue microarrays from patients who participated in two international randomized phase III trials of adjuvant chemotherapy after resection of pancreatic ductal adenocarcinoma: ESPAC-3, which compared fluorouracil plus folinic acid with gemcitabine; and ESPAC-4, which compared gemcitabine plus capecitabine with gemcitabine alone. GATA6 expression was measured using immunohistochemistry. Expression levels from 0 to 4 were scored through consensus between two pathologists who were blinded to clinical characteristics and outcome. Concordance on each tissue core was assessed using a weighted kappa score. Overall survival (OS) was assessed using Kaplan-Meier curves and compared between GATA6 expression levels using univariate Cox proportional hazard regression models and multivariate models that adjusted for lymph node status, post-operative CA-19-9, and treatment arms. After an initial analysis of all five levels, expression levels were regrouped into low (0-2) and high (3-4). Our primary objective was to assess for a prognostic association between GATA6 and OS. Secondary analyses considered predictive associations with the addition of capecitabine to gemcitabine using an interaction term, and associations with baseline characteristics using Wilcoxon and Fisher-exact tests. Results: 26 patients from ESPAC-3 and 205 patients from ESPAC-4 were included. 7, 18, 130, 74, and 2 patients had GATA6 expression levels of 0, 1, 2, 3, and 4, respectively. Concordance between pathologists was moderate (weighted kappa 0.41). GATA6 expression was significantly associated with overall survival when regrouped into low (0–2, N=155) and high (3–4, N=76) expression. Low GATA6 expression was associated with shorter OS (median OS 26.1 months, 95% confidence interval (CI) 22.9–30.4 versus 42.4 months, 95% CI 30.2–56.5, univariate hazard ratio (HR) 1.70, 95% CI 1.31–2.41, P=0.002), which persisted after adjustment for potential confounders (multivariate HR 1.57, 95% CI 1.09–2.62, P=0.016). GATA6 expression was not significantly associated with baseline characteristics or predictive of differential benefit from the addition of capecitabine to gemcitabine. Conclusion: Low GATA6 expression is significantly associated with inferior OS after surgical resection of pancreatic cancer. Future research will automate the measurement of GATA6 expression using image analyses. Citation Format: Robert C. Grant, Kai Duan, Richard Jackson, William Greenhalf, Eithne Costello-Goldring, Paula Ghaneh, Christopher Halloran, Daniel Palmer, Thilo Hackert, Markus Buchler, Shawn Hutchison, Stephanie Ramotar, Anna Dodd, Julie Wilson, Faiyaz Notta, Grainne O'Kane, Jennifer Knox, John Neoptolemos, Steven Gallinger, Sandra Fischer. GATA6 expression is prognostic after surgical resection of pancreatic cancer: results from the ESPAC trials [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-005.
Published: 2020

42. Prevalence of diabetes mellitus among individuals undergoing pancreatic surgery

Author: Christopher Halloran, J. Hale, L. Taylor, Paula Ghaneh, B. Crosby, Eithne Costello, William Greenhalf, Rohith Rao, Lucy Oldfield, and Anthony Evans
Subjects: medicine.medical_specialty, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Internal medicine, Diabetes mellitus, Gastroenterology, medicine, business, medicine.disease, Pancreatic surgery
Published: 2020

43. The holding temperature of blood during a delay to processing can affect serum and plasma protein concentrations

Author: Christopher Halloran, B. Small, Eithne Costello-Goldring, Lucy Oldfield, William Greenhalf, and M. Ashworth
Subjects: medicine.medical_specialty, Endocrinology, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Internal medicine, Gastroenterology, Medicine, business, Affect (psychology), Blood proteins
Published: 2020

44. Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer

Author: Guruprasad P. Aithal, Michael H. Chapman, Andrea Sheel, Markus M. Lerch, William Greenhalf, Z. Hamady, Stephen P. Pereira, Michael Raraty, Pascal Hammel, Roger Carter, J.A. Nicholson, Richard J. Jackson, Tom Hanna, Colin J. McKay, Roger Mountford, Christopher Halloran, C. Grocock, Ioannis Sarantitis, Sara Harrison, Ammad Farooq, Eithne Costello, Jayapal Ramesh, Andrew Smith, and Paula Ghaneh
Subjects: Oncology, Endoscopic ultrasound, Adult, Male, medicine.medical_specialty, endocrine system diseases, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Interquartile range, Risk Factors, Internal medicine, Pancreatic cancer, medicine, Genetic predisposition, Humans, Family, Genetic Predisposition to Disease, Registries, Early Detection of Cancer, Aged, Aged, 80 and over, Hereditary pancreatitis, Hepatology, medicine.diagnostic_test, business.industry, Carcinoma, Gastroenterology, Cancer, Middle Aged, medicine.disease, Pedigree, Europe, Pancreatic Neoplasms, medicine.anatomical_structure, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, business, Pancreas, Cohort study
Abstract: Objectives: Intraductal Papillary Mucinous Neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified Familial Pancreatic Cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC.Methods: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred.Results: There was a median (interquartile range, IQR) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct, BD). The PDAC case occurred in the top 10% of risk, the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P=0.63).Conclusions: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN
Published: 2018

45. Genetic determinants of telomere length and risk of pancreatic cancer: a PANDoRA study

Author: Claudio Pasquali, Raffaele Pezzilli, Katarina Cuk, Krzysztof Jamroziak, Gabriele Capurso, Pavel Vodicka, Timothy J. Key, Giulia Martina Cavestro, Kai Uwe Saum, Yogesh K. Vashist, Oliver Strobel, Martin Lovecek, H. Bas Bueno-de-Mesquita, Andrea Szentesi, Ofure Obazee, Angelo Andriulli, Andrea Mambrini, Cosimo Sperti, Kay-Tee Khaw, Rita T. Lawlor, Jörg Kaiser, Federico Canzian, Hanneke W. M. van Laarhoven, Livia Archibugi, Renata Talar-Wojnarowska, Martina Matarazzi, Jakob R. Izbicki, Gianfranco Delle Fave, Daniele Campa, Felice Pirozzi, Francesca Federici, Carlo Federico Zambon, Anna Katharina König, Thilo Hackert, Péter Hegyi, Chiara Valsuani, Stefano Landi, Hermann Brenner, Laimas Virginijus Jonaitis, Beatrice Mohelnikova-Duchonova, Franco Bambi, Domenica Gioffreda, Rudolf Kaaks, Niccola Funel, Pavel Soucek, Juozas Kupcinskas, Ludmila Vodickova, Daniela Basso, Maarten F. Bijlsma, William Greenhalf, Francesca Tavano, and Verena Katzke
Subjects: Oncology, medicine.medical_specialty, Pancreatic disease, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, Gastroenterology, Cancer, Single-nucleotide polymorphism, medicine.disease, Telomere, Continuous variable, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Pancreatic cancer, Mendelian randomization, medicine, SNP, 030211 gastroenterology & hepatology, business
Abstract: Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54x10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87x10-6 , ptrend = 3.27x10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98x10-9 for highest vs. lowest quintile; p = 1.82x10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer. This article is protected by copyright. All rights reserved.
Published: 2018

46. Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms

Author: Renata Talar-Wojnarowska, Claudio Pasquali, Daniele Campa, Maria Rinzivillo, Valbona Liço, Cinzia Cantù, Federico Canzian, Rita T. Lawlor, Thilo Hackert, Gabriele Capurso, Oliver Strobel, Maria Gazouli, Krzysztof Jamroziak, Antonio De Bonis, Ewa Małecka-Panas, Angelo Andriulli, Livia Archibugi, Paola Fogar, Niccola Funel, Anna Caterina Milanetto, Christos Dervenis, William Greenhalf, Francesca Tavano, Stefano Landi, John P. Neoptolemos, Daniela Basso, Ofure Obazee, Luca Landoni, Carlo Federico Zambon, and Timothy J. Key
Subjects: Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, age of onset genes genetic predisposition to disease pancreatic diseases pancreatic neoplasm single nucleotide polymorphism research whites genetics neoplasms islet cell tumor pancreatic adenocarcinoma stratification pancreatic ductal adenocarcinoma false-positive results genome-wide association study causality neoplasm grading, Pancreatic disease, Genotype, PANDoRA consortium, PDAC, genetic susceptibility, pNEN, Single-nucleotide polymorphism, Genome-wide association study, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Pancreatic cancer, Biomarkers, Tumor, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Aged, business.industry, Genetic variants, Case-control study, General Medicine, Middle Aged, medicine.disease, Carcinoma, Neuroendocrine, Pancreatic Neoplasms, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Adenocarcinoma, Female, Carcinogenesis, Pancreas, business, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study
Abstract: Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n = 23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants-rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50-year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some single nucleotide polymorphisms to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes.
Published: 2018

47. Cytoplasmic HuR Status Predicts Disease-free Survival in Resected Pancreatic Cancer: A Post-hoc Analysis From the International Phase III ESPAC-3 Clinical Trial

Author: Talar Tatarian, Jordan M. Winter, Paula Ghaneh, Wei Jiang, Charles J. Yeo, Amanda Grigoli, Nooreen Dabbish, Benjamin E. Leiby, Eithne Costello, Daniel H. Palmer, Masaya Jimbo, Jonathan R. Brody, William Greenhalf, John P. Neoptolemos, Christopher Halloran, and Markus W. Büchler
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Pathology, Cytoplasm, health care facilities, manpower, and services, medicine.medical_treatment, education, Antineoplastic Agents, Deoxycytidine, Article, Disease-Free Survival, ELAV-Like Protein 1, 03 medical and health sciences, 0302 clinical medicine, Pancreatectomy, Internal medicine, Pancreatic cancer, medicine, Adjuvant therapy, Carcinoma, Biomarkers, Tumor, Humans, Aged, Predictive marker, business.industry, Cancer, Middle Aged, medicine.disease, Immunohistochemistry, Gemcitabine, Clinical trial, Pancreatic Neoplasms, 030104 developmental biology, Treatment Outcome, Chemotherapy, Adjuvant, Tissue Array Analysis, 030220 oncology & carcinogenesis, Surgery, Female, Fluorouracil, business, medicine.drug, Carcinoma, Pancreatic Ductal
Abstract: OBJECTIVES: We tested cytoplasmic HuR (cHuR) as a predictive marker for response to chemotherapy by examining tumor samples from the international European Study Group of Pancreatic Cancer-3 trial, in which patients with resected pancreatic ductal adenocarcinoma (PDA) received either gemcitabine (GEM) or 5-fluorouracil (5-FU) adjuvant monotherapy. BACKGROUND: Previous studies have implicated the mRNA-binding protein, HuR (ELAVL1), as a predictive marker for PDA treatment response in the adjuvant setting. These studies were, however, based on small cohorts of patients outside of a clinical trial, or a clinical trial in which patients received multimodality therapy with concomitant radiation. METHODS: Tissue samples from 379 patients with PDA enrolled in the European Study Group of Pancreatic Cancer-3 trial were immunolabeled with an anti-HuR antibody and scored for cHuR expression. Patients were dichotomized into groups of high versus low cHuR expression. RESULTS: There was no association between cHuR expression and prognosis in the overall cohort [disease-free survival (DFS), P = 0.44; overall survival, P = 0.41). Median DFS for patients with high cHuR was significantly greater for patients treated with 5-FU compared to GEM [20.1 months, confidence interval (CI): 8.3–36.4 vs 10.9 months, CI: 7.5–14.2; P = 0.04]. Median DFS was similar between the treatment arms in patients with low cHuR (5-FU, 12.8 months, CI: 10.6–14.6 vs GEM, 12.9 months, CI: 11.2–15.4). CONCLUSIONS: Patients with high cHuR-expressing tumors may benefit from 5-FU-based adjuvant therapy as compared to GEM, whereas those patients with low cHuR appear to have no survival advantage with GEM compared with 5-FU. Further studies are needed to validate HuR as a biomarker in both future monotherapy and multiagent regimens.
Published: 2018

48. Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer

Author: John P. Neoptolemos, Christopher Halloran, Eithne Costello, Roger Carter, Fiona Campbell, David Goldstein, Daniel H. Palmer, Niall C. Tebbutt, Nils O. Elander, Karen Aughton, Paula Ghaneh, Alan Anthoney, Bengt Glimelius, Mark Deakin, Juan W. Valle, Alec McDonald, Markus M. Lerch, Trevor Cox, Julia Mayerle, Christos Dervenis, William Greenhalf, Andrew Scarfe, Richard Charnley, Jenny Shannon, Attila Oláh, M.W. Büchler, and John R. Mackey
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_treatment, pancreatic cancer, Leucovorin, Dihydropyrimidine dehydrogenase (DPD), Deoxycytidine, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, randomized trial, Medicine, 5-fluorouracil, Randomized Controlled Trials as Topic, Aged, 80 and over, Manchester Cancer Research Centre, Hazard ratio, gemcitabine, Middle Aged, Prognosis, Immunohistochemistry, human equilibrative nucleoside transporter 1 (hENT1), 030220 oncology & carcinogenesis, Female, Fluorouracil, Adjuvant, Carcinoma, Pancreatic Ductal, medicine.drug, Adult, medicine.medical_specialty, Article, Equilibrative Nucleoside Transporter 1, 03 medical and health sciences, Folinic acid, adjuvant, Internal medicine, Pancreatic cancer, Biomarkers, Tumor, Dihydropyrimidine dehydrogenase, Humans, predictive, Dihydrouracil Dehydrogenase (NADP), Aged, Cancer och onkologi, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, medicine.disease, Survival Analysis, Gemcitabine, Confidence interval, Pancreatic Neoplasms, 030104 developmental biology, Tissue Array Analysis, Cancer and Oncology, business, prognostic
Abstract: Background: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. Methods: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). Results: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). Conclusion: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.
Published: 2018

49. Incidence of Post-ERCP Pancreatitis From Direct Pancreatic Juice Collection in Hereditary Pancreatitis and Familial Pancreatic Cancer Before and After the Introduction of Prophylactic Pancreatic Stents and Rectal Diclofenac

Author: J. Butler, James Nicholson, Guruprasad P. Aithal, Marianne Johnstone, Michael Raraty, Robert Sutton, Howard Smart, William Greenhalf, Richard J. Jackson, Jonathan Evans, Sara Harrison, Trevor Cox, Martin Lombard, Nathan Howes, John P. Neoptolemos, Christopher Halloran, Sanchoy Sarkar, Thomas Hanna, C. Grocock, and Paula Ghaneh
Subjects: Adult, Male, medicine.medical_specialty, Diclofenac, Endocrinology, Diabetes and Metabolism, Risk Assessment, Gastroenterology, Endocrinology, Pancreatic Juice, Administration, Rectal, Predictive Value of Tests, Risk Factors, Pancreatitis, Chronic, Internal medicine, Pancreatic cancer, Biomarkers, Tumor, Odds Ratio, Internal Medicine, medicine, Humans, Genetic Testing, Prospective Studies, Registries, Prospective cohort study, Cholangiopancreatography, Endoscopic Retrograde, Hereditary pancreatitis, Endoscopic retrograde cholangiopancreatography, Hepatology, medicine.diagnostic_test, business.industry, Incidence, Incidence (epidemiology), Anti-Inflammatory Agents, Non-Steroidal, Odds ratio, Middle Aged, medicine.disease, United Kingdom, Pancreatic Neoplasms, Logistic Models, Treatment Outcome, Pancreatitis, Multivariate Analysis, Pancreatic juice, Female, Stents, business
Abstract: Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP).A prospective study (1999-2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008.There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06-0.84) in favor of prophylaxis (0.035).Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening.
Published: 2015

50. A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk

Author: Marta Rava, Linda Sharp, William Greenhalf, Rita T. Lawlor, Víctor Manuel Barberá, Matthias Löhr, Cristina Bosetti, Thomas M. Gress, Michael O'Rorke, Adonina Tardón, Christoph W. Michalski, Bo Kong, Enrique Dominguez-Munoz, L. Ilzarbe, Ignasi Poves, José Perea, Jörg Kleeff, Jiaqi Huang, Joaquim Balsells, Eithne Costello, Núria Malats, Damian O'Driscoll, Mar Iglesias, Valentina Rosato, Janet Piñero, Alba Gutiérrez-Sacristán, Carmen Guillén-Ponce, Paulina Gomez-Rubio, Francisco X. Real, Josefina Mora, Xavier Molero, Tatjana Crnogorac-Jurcevic, Mirari Marquez, Liam J. Murray, P. Pelaez, Aldo Scarpa, Manuel Hidalgo, Alfredo Carrato, Luis Muñoz-Bellvís, C. La Vecchia, Laura I. Furlong, Esther Molina-Montes, Antoni Farré, Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, and Transducción de Señales en Bacterias
Subjects: 0301 basic medicine, Oncology, Pathology, Systems Analysis, Time Factors, endocrine system diseases, Comorbidity, 0302 clinical medicine, Risk Factors, Databases, Genetic, Odds Ratio, Cluster Analysis, education.field_of_study, Principal Component Analysis, multimorbidity, pancreatic cancer, risk, Systems Biology, Hematology, 3. Good health, Europe, 030220 oncology & carcinogenesis, medicine.symptom, Carcinoma, Pancreatic Ductal, Risk, medicine.medical_specialty, Population, Risk Assessment, 03 medical and health sciences, Pancreatic cancer, Internal medicine, Diabetes mellitus, medicine, Biomarkers, Tumor, Humans, education, Multimorbidity, Asthma, Pàncrees -- Càncer, business.industry, Heartburn, Cancer, Computational Biology, Odds ratio, medicine.disease, Genética, digestive system diseases, Pancreatic Neoplasms, 030104 developmental biology, Logistic Models, Case-Control Studies, Multivariate Analysis, Metabolic syndrome, business, Factor Analysis, Statistical
Abstract: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (
Published: 2017

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

168 results on '"William Greenhalf"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources