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1. COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls.

Author

Kowdley, Kris V, Hirschfield, Gideon M, Coombs, Charles, Malecha, Elizabeth S, Bessonova, Leona, Li, Jing, Rathnayaka, Nuvan, Mells, George, Jones, David E, Trivedi, Palak J, Hansen, Bettina E, Smith, Rachel, Wason, James, Hiu, Shaun, Kareithi, Dorcas N, Mason, Andrew L, Bowlus, Christopher L, Muller, Kate, Carbone, Marco, Berenguer, Marina, Milkiewicz, Piotr, Adekunle, Femi, and Villamil, Alejandra

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Chronic Liver Disease and Cirrhosis, Clinical Research, Rare Diseases, Digestive Diseases, Women's Health, Liver Disease, 6.1 Pharmaceuticals, Oral and gastrointestinal, Gastroenterology & Hepatology, Clinical sciences
Abstract

ObjectivesObeticholic acid (OCA) treatment for primary biliary cholangitis (PBC) was conditionally approved in the phase 3 POISE trial. The COBALT confirmatory trial assessed whether clinical outcomes in PBC patients improve with OCA therapy.MethodsPatients randomized to OCA (5-10 mg) were compared with placebo (randomized controlled trial [RCT]) or external control (EC). The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥15, uncontrolled ascites, or hospitalization for hepatic decompensation. A prespecified propensity score-weighted EC group was derived from a US healthcare claims database.ResultsIn the RCT, the primary endpoint occurred in 28.6% of OCA (n=168) and 28.9% of placebo patients (n=166; intent-to-treat [ITT] analysis hazard ratio [HR]=1.01, 95% CI=0.68-1.51), but functional unblinding and crossover to commercial therapy occurred, especially in the placebo arm. Correcting for these using inverse probability of censoring weighting (IPCW) and as-treated analyses shifted the HR to favor OCA. In the EC (n=1051), the weighted primary endpoint occurred in 10.1% of OCA and 21.5% of non-OCA patients (HR=0.39; 95% CI=0.22-0.69; P=0.001). No new safety signals were identified in the RCT.ConclusionsFunctional unblinding and treatment crossover, particularly in the placebo arm, confounded the ITT estimate of outcomes associated with OCA in the RCT. Comparison with the real-world EC showed that OCA treatment significantly reduced the risk of negative clinical outcomes. These analyses demonstrate the value of EC data in confirmatory trials and suggest that treatment with OCA improves clinical outcomes in patients with PBC.

Published
2024

2. Latent class mixed modelling for phenotypic stratification of primary biliary cholangitis patients on first line treatment

Author

Mulcahy, Victoria, Rouanet, Anais, Gerussi, Alessio, Duckworth, Adam, Flack, Steve, Carbone, Marco, Tom, Brian, and Mells, George

Subjects
Statistics - Applications, 92C60
Abstract

In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid (the UDCA response) accurately predicts long-term outcome. In this study we sought to use liver biochemistry, and in particular alkaline phosphatase (ALP), as a surrogate marker of disease activity, for phenotypic stratification in PBC using a computational modelling approach. Our aim here was to identify distinct disease subgroups of patients with distinct disease trajectories. Methods: We used longitudinal ALP results from 1,601 PBC patients on first line treatment with UDCA, and applied latent class mixed modelling (LCMM), to identify distinct phenotypic subgroups, each with distinct disease trajectories, and risks of end stage liver disease (ESLD). Results: We identified four well discriminated phenotypic subgroups within our PBC cohort, each with distinct disease trajectories., Comment: 17 pages, 5 figures, 10 tables

Published
2022

3. Critical shortfalls in the management of PBC: Results of a UK-wide, population-based evaluation of care delivery

Author

Abbas, Nadir, Smith, Rachel, Flack, Steven, Bains, Vikram, Aspinall, Richard J., Jones, Rebecca L., Burke, Laura, Thorburn, Douglas, Heneghan, Michael, Yeoman, Andrew, Leithead, Joanna, Braniff, Conor, Robertson, Andrew, Mitchell, Chris, Thain, Collette, Mitchell-Thain, Robert, Jones, David, Trivedi, Palak J., Mells, George F., and Alrubaiy, Laith

Published
2024
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4. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Author

Brevini, Teresa, Maes, Mailis, Webb, Gwilym J., John, Binu V., Fuchs, Claudia D., Buescher, Gustav, Wang, Lu, Griffiths, Chelsea, Brown, Marnie L., Scott, III, William E., Pereyra-Gerber, Pehuén, Gelson, William T. H., Brown, Stephanie, Dillon, Scott, Muraro, Daniele, Sharp, Jo, Neary, Megan, Box, Helen, Tatham, Lee, Stewart, James, Curley, Paul, Pertinez, Henry, Forrest, Sally, Mlcochova, Petra, Varankar, Sagar S., Darvish-Damavandi, Mahnaz, Mulcahy, Victoria L., Kuc, Rhoda E., Williams, Thomas L., Heslop, James A., Rossetti, Davide, Tysoe, Olivia C., Galanakis, Vasileios, Vila-Gonzalez, Marta, Crozier, Thomas W. M., Bargehr, Johannes, Sinha, Sanjay, Upponi, Sara S., Fear, Corrina, Swift, Lisa, Saeb-Parsy, Kourosh, Davies, Susan E., Wester, Axel, Hagström, Hannes, Melum, Espen, Clements, Darran, Humphreys, Peter, Herriott, Jo, Kijak, Edyta, Cox, Helen, Bramwell, Chloe, Valentijn, Anthony, Illingworth, Christopher J. R., Dahman, Bassam, Bastaich, Dustin R., Ferreira, Raphaella D., Marjot, Thomas, Barnes, Eleanor, Moon, Andrew M., Barritt, IV, Alfred S., Gupta, Ravindra K., Baker, Stephen, Davenport, Anthony P., Corbett, Gareth, Gorgoulis, Vassilis G., Buczacki, Simon J. A., Lee, Joo-Hyeon, Matheson, Nicholas J., Trauner, Michael, Fisher, Andrew J., Gibbs, Paul, Butler, Andrew J., Watson, Christopher J. E., Mells, George F., Dougan, Gordon, Owen, Andrew, Lohse, Ansgar W., Vallier, Ludovic, and Sampaziotis, Fotios

Published
2023
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5. UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis

Author

Abbas, Nadir, Culver, Emma L., Thorburn, Douglas, Halliday, Neil, Crothers, Hannah, Dyson, Jessica K., Phaw, April, Aspinall, Richard, Khakoo, Salim I., Kallis, Yiannis, Smith, Belinda, Patanwala, Imran, McCune, Anne, Chimakurthi, Chenchu R., Hegade, Vinod, Orrell, Michael, Jones, Rebecca, Mells, George, Thain, Colette, Thain, Robert-Mitchell, Jones, David, Hirschfield, Gideon, and Trivedi, Palak J.

Published
2023
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7. Anti–Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct–Ligated Mice

Author

Gee, Lucy M.V., Barron-Millar, Ben, Leslie, Jack, Richardson, Claire, Zaki, Marco Y.W., Luli, Saimir, Burgoyne, Rachel A., Cameron, Rainie I.T., Smith, Graham R., Brain, John G., Innes, Barbara, Jopson, Laura, Dyson, Jessica K., McKay, Katherine R.C., Pechlivanis, Alexandros, Holmes, Elaine, Berlinguer-Palmini, Rolando, Victorelli, Stella, Mells, George F., Sandford, Richard N., Palmer, Jeremy, Kirby, John A., Kiourtis, Christos, Mokochinski, Joao, Hall, Zoe, Bird, Thomas G., Borthwick, Lee A., Morris, Christopher M., Hanson, Peter S., Jurk, Diana, Stoll, Elizabeth A., LeBeau, Fiona E.N., Jones, David E.J., and Oakley, Fiona

Published
2023
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8. THU-125 Key questions that patients with primary biliary cholangitis should ask their physician -Delphi method-

Author

Werner, Ellen, primary, van Hooff, Maria C., additional, Abbas, Nadir, additional, Gerussi, Alessio, additional, Willemse, José A., additional, Mitchell-Thain, Robert, additional, Leburgue, Angela, additional, Hirschfield, Gideon M., additional, Corpechot, Christophe, additional, Schramm, Christoph, additional, Levy, Cynthia, additional, Nevens, Frederik, additional, Verbeek, Jef, additional, Mason, Andrew L., additional, Dalekos, George, additional, Cazzagon, Nora, additional, Mells, George F., additional, Kowdley, Kris V., additional, Carbone, Marco, additional, Jones, David E., additional, Hansen, Bettina E., additional, Trivedi, Palak J., additional, and van der Meer, Adriaan J., additional

Published
2024
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9. THU-101 Non-invasive tests for ruling out high-risk esophageal varices in patients with primary biliary cholangitis based on the cholestasis degree

Author

Calvaruso, Vincenza, primary, Celsa, Ciro, additional, Cristoferi, Laura, additional, Scaravaglio, Miki, additional, Nofit, Eugenia, additional, Smith, Rachel, additional, Kaur, Senamjit, additional, Di Maria, Gabriele, additional, Capodicasa, Luigi, additional, Cadamuro, Luca, additional, Gerussi, Alessio, additional, Malinverno, Federica, additional, Lampertico, Pietro, additional, Cazzagon, Nora, additional, Marzioni, Marco, additional, Vespasiani-Gentilucci, Umberto, additional, Colapietro, Francesca, additional, Andreone, Pietro, additional, Lleo, Ana, additional, Rigamonti, Cristina, additional, Viganò, Mauro, additional, Giannini, Edoardo, additional, Russello, Maurizio, additional, Vanni, Ester, additional, Cerini, Federica, additional, Orlandini, Alessandra, additional, Brunetto, Maurizia, additional, Niro, Grazia Anna, additional, Vettori, Giovanni, additional, Castellaneta, Antonino, additional, Cardinale, Vincenzo, additional, Alvaro, Domenico, additional, Mega, Andrea, additional, Palitti, Valeria Pace, additional, Bellanti, Francesco, additional, Marco, Vito Di, additional, Mells, George, additional, Culver, Emma, additional, Invernizzi, Pietro, additional, Camma, Calogero, additional, and Carbone, Marco, additional

Published
2024
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10. Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Author

Jones, David EJ, primary, Beuers, Ulrich, additional, Bonder, Alan, additional, Carbone, Marco, additional, Culver, Emma, additional, Dyson, Jessica, additional, Gish, Robert G, additional, Hansen, Bettina E, additional, Hirschfield, Gideon, additional, Jones, Rebecca, additional, Kowdley, Kris, additional, Kremer, Andreas E., additional, Lindor, Keith, additional, Mayo, Marlyn, additional, Mells, George, additional, Neuberger, James, additional, Prince, Martin, additional, Swain, Mark, additional, Tanaka, Atsushi, additional, Thorburn, Douglas, additional, Trauner, Michael, additional, Trivedi, Palak, additional, Weltman, Martin, additional, Yeoman, Andrew, additional, and Levy, Cynthia, additional

Published
2024
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12. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Author

Ji, Sun-Gou, Juran, Brian D, Mucha, Sören, Folseraas, Trine, Jostins, Luke, Melum, Espen, Kumasaka, Natsuhiko, Atkinson, Elizabeth J, Schlicht, Erik M, Liu, Jimmy Z, Shah, Tejas, Gutierrez-Achury, Javier, Boberg, Kirsten M, Bergquist, Annika, Vermeire, Severine, Eksteen, Bertus, Durie, Peter R, Farkkila, Martti, Müller, Tobias, Schramm, Christoph, Sterneck, Martina, Weismüller, Tobias J, Gotthardt, Daniel N, Ellinghaus, David, Braun, Felix, Teufel, Andreas, Laudes, Mattias, Lieb, Wolfgang, Jacobs, Gunnar, Beuers, Ulrich, Weersma, Rinse K, Wijmenga, Cisca, Marschall, Hanns-Ulrich, Milkiewicz, Piotr, Pares, Albert, Kontula, Kimmo, Chazouillères, Olivier, Invernizzi, Pietro, Goode, Elizabeth, Spiess, Kelly, Moore, Carmel, Sambrook, Jennifer, Ouwehand, Willem H, Roberts, David J, Danesh, John, Floreani, Annarosa, Gulamhusein, Aliya F, Eaton, John E, Schreiber, Stefan, Coltescu, Catalina, Bowlus, Christopher L, Luketic, Velimir A, Odin, Joseph A, Chopra, Kapil B, Kowdley, Kris V, Chalasani, Naga, Manns, Michael P, Srivastava, Brijesh, Mells, George, Sandford, Richard N, Alexander, Graeme, Gaffney, Daniel J, Chapman, Roger W, Hirschfield, Gideon M, de Andrade, Mariza, Rushbrook, Simon M, Franke, Andre, Karlsen, Tom H, Lazaridis, Konstantinos N, and Anderson, Carl A

Subjects
Human Genome, Digestive Diseases, Autoimmune Disease, Digestive Diseases - (Gallbladder), Genetics, Rare Diseases, Inflammatory Bowel Disease, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Adaptor Proteins, Signal Transducing, Alleles, Cholangitis, Sclerosing, Colitis, Ulcerative, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, RNA, Messenger, Risk Factors, UK-PSC Consortium, International IBD Genetics Consortium, International PSC Study Group, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.

Published
2017

14. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Author

Thomas, Caradog, Rahman, Meshbah, Yapp, Tom, Lye Ch'ng, Chin, Harrison, Melanie, Sturgess, Richard, Galaska, Roman, Healey, Chris, Whiteman, Jessica, Czaijkowski, Marek, Gray, Catherine, Gunasekera, Anton, Gyawli, Pranab, Premchand, Purushothaman, Mann, Steven, Elliott, Keith, Kapur, Kapil, Watson, Alan, Foster, Graham, Trembling, Paul, Subhani, Javaid, Harvey, Rory, McCorry, Roger, Adgey, Carolyn, Hobson, Lucie, Mulvaney-Jones, Caroline, Evans, Richard, Mathialahan, Thiriloganathan, Ramanaden, David, Gasem, Jaber, Van Duyvenvoorde, Greta, Shorrock, Christopher, Seward, Katie, Southern, Paul, Tibble, Jeremy, Penn, Ruth, Gorard, David, Maiden, Jane, Damant, Rose, Palegwala, Altaf, Jones, Susan, Alexander, Graeme, Mells, George, Sandford, Richard, Dolwani, Sunil, Prince, Martin, Silvestre, Valeria, Foxton, Matthew, Dungca, Eleanor, Mitchison, Harriet, Wheatley, Natalie, Gooding, Ian, Doyle, Helen, Karmo, Mazn, Kent, Melanie, Saksena, Sushma, Braim, Delyth, Patel, Minesh, Lord, Susan, Ede, Roland, Paton, Alison, Austin, Andrew, Lancaster, Nicola, Sayer, Joanna, Gibbins, Andrew, Hogben, Karen, Hovell, Chris, Fisher, Neil, Carter, Martyn, Koss, Konrad, Musselwhite, Janine, Muscariu, Florin, Piotreowicz, Andrzej, McKay, Alexandra, Grimley, Charles, Neal, David, Ting Tan, Lai, Lim, Guan, Brighton, Jacqueline, Foale, Carole, Ala, Aftab, Saeed, Athar, Flahive, Kerry, Wood, Gordon, Townshend, Paula, Ford, Chris, Brown, Jonathan, Kordula, Jean, Bowles, Jane, Wilkinson, Mark, Palmer, Caroline, Ramage, John, Gordon, Harriet, Featherstone, James, Ridpath, Jo, Ngatchu, Theodore, Levi, Sass, Shaukat, Syed, Sadeghian, Joy, Shidrawi, Ray, Williams, Bronwen, Abouda, George, Jones, Sarah, Duggan, Claire, Hynes, Abigail, Narain, Mark, Rees, Ian, Salam, Imroz, Crossey, Mary, Taylor-Robinson, Simon, Brown, Ashley, MacNicol, Carolyn, Williams, Simon, Wilhelmsen, Elva, Banim, Paul, Raymode, Parizade, Chilton, Andrew, Das, Debasish, Lee, Hye-Jeong, Curtis, Howard, Heneghan, Michael, Gess, Markus, Durant, Emma, Drake, IM, Bishop, Rebecca, Davies, Mervyn, Jones, Rebecca, Aldersley, Mark, Ncube, Noma, McNair, Alistair, Srirajaskanthan, Raj, Sen, Sambit, Casey, Rebecca, Bird, George, Mendall, Mike, Cowley, Caroline, Barnardo, Adrian, Kitchen, Paul, Yoong, Kevin, Amore, Kelly, Sirdefield, Dawn, Orpe, Jacky, Mathew, Ray, MacFaul, George, Wrigth, Aruna, Shah, Amir, Evans, Chris, Keggans, Janie, Bird, Bridget, Baxter, Gwen, Saha, Subrata, Pollock, Katharine, Hughes, Maggie, Bramley, Peter, Grieve, Emma, Young, Karin, Fraser, Andrew, Mukhopadhya, Ashis, Ocker, Kate, Mills, Peter, Hines, Francis, Shallcross, Chris, Wilkins, Joy, Grellier, Leonie, Campbell, Stewart, Martin, Kirsty, Bathgate, Andrew, Innes, Caron, Shepherd, Alan, Rushbrook, Simon, Valliani, Talal, Przemioslo, Robert, Fairlamb, Helen, Macdonald, Chris, Eastick, Anne, Metcalf, Jane, Tanqueray, Elizabeth, Shmueli, Udi, Holbrook, Becky, Davis, Andrew, Browning, Julie, Naqvi, Asifabbas, Walker, Kirsten, Lee, Tom, Verheyden, Juliette, Slininger, Susan, Ryder, Stephen D, Chapman, Roger, Collier, Jane, O'Donnell, Denise, Stafford, Lizzie, Williamson, Kate, Kent, Linda, Klass, Howard, Ninkovic, Mary, March, Linda, Cramp, Matthew, Simpson, Diane, Dickson, Christine, Sharer, Nicholas, Hayes, Maria, Goggin, Patrick, Quinne, Mary, Pearson, Sallyanne, Hoeroldt, Barbara, Jones, Linda, Wright, Alice, Booth, Jonathan, Loftus, Alison, Lipscomb, George, Dewhurst, Hannah, Gunter, Emma, Williams, Earl, Fouracres, Anna, Farrington, Liz, Graves, Lyn, Hussaini, Hyder, Stableforth, Bill, Marriott, Suzie, Ayres, Reuben, Leoni, Marina, Burroughs, Andrew, Marshall, Eileen, Thorburn, Douglas, Tyrer, David, Martin, Kate, Lombard, Martin, Patanwala, Imran, Dali-Kemmery, Lola, Lambourne, Victoria, Maltby, Julia, Vyas, Samir, Colley, Julie, Shinder, Bal, Singhal, Saket, Jones, Jayne, Mills, Marisa, Gleeson, Dermot, Carnahan, Mandy, Butterworth, Jeff, Boulton, Kerenza, Taylor, Natalie, George, Keith, Harding, Tim, Tregonning, Julie, Douglass, Andrew, Brown, Carly, Clifford, Gayle, Panter, Simon, Gocher, Denise, Shearman, Jeremy, Bray, Gary, Hamilton, Maria, Butcher, Graham, Forton, Daniel, Mclindon, John, Curtis, Janette, Das, Debashis, Shewan, Tracey, Cowan, Matthew, Whatley, Gregory, Nasseri, Mariam, Grover, Bob, Sivaramakrishnan, Nurani, Ducker, Samantha, Houghton, Kathryn, Jones, David, Griffiths, Laura, Tripoli, Sherill, Pitcher, Maxton, Shpuza, Ervin, White, Nikki, Ghosh, Deb, Douds, Andrew, Green, Marie, Brookes, Matthew, Cumlat, Lourdes, Wong, Voi Shim, Warner, Karen, Netherton, Kimberley, Mandal, Adtya, Jain, Snjiv, Gupta, Hemant, Sanghi, Pradeep, Pereira, Steve, Neuberger, James, Gunson, Bridget, Hirschfield, Gideon, Lim, Reina Teegan, Gallagher, Susan, Clement, Darren, Brind, Alison, Watts, Gill, Mupudzi, Mcdonald, Wright, Mark, Gitahi, Jane, Gordon, Fiona, Gocher, Denis, Unitt, Esther, Pateman, Hilary, Batham, Sally, Delahooke, Toby, Grant, Allister, Conder, Jill, Higham, Andrew, Cox, Mark, O'Donohoe, Lynn, Currie, Lynn, King, Alistair, Oblak, Metod, Collins, Carole, Whalley, Simon, Quinn, Marie, Baird, Yolanda, Amey, Isobel, Fraser, Jocelyn, Li, Andy, Cotterill, Donna, Bell, Andrew, Singhal, Amit, Gee, Ian, Greer, Sandra, Ang, Yeng, Ransford, Rupert, Allison, Joanna, Gotto, James, Dyer, Simon, Sweeting, Helen, Millson, Charles, Invernizzi, Pietro, Carbone, Marco, Cristoferi, Laura, Bonato, Giulia, Malinverno, Federica, Bernuzzi, Francesca, Alvaro, Domenico, Labbadia, Giancarlo, Bragazzi, Maria Consiglia, Andreone, Pietro, Muratori, Luigi, Azzaroli, Francesco, Floreani, Annarosa, Galli, Andrea, Tarocchi, Mirko, Giannini, Edoardo, Miele, Luca, Gasbarrini, Antonio, Grieco, Antonio, Marrone, Giuseppe, Donato, Maria Francesca, Valenti, Luca, Marra, Fabio, Marzioni, Marco, Maroni, Luca, Rigamonti, Cristina, Zuin, Massimo, Battezzati, Pier Maria, Picciotto, Antonino, Nardi, Alessandra, Flack, Steve, Carpino, Guido, Varvaropoulou, Nikoletta, Gavrila, Caius, Spicer, Ann, Badrock, Jonathan, Cardinale, Vincenzo, Ainsworth, Holly F, Heneghan, Michael A, Neuberger, James M, Donato, Maria F, Kirby, John, Mitchell-Thain, Robert, Sampaziotis, Fotios, Gaudio, Eugenio, Ronca, Vincenzo, Gerussi, Alessio, Stocken, Deborah D, Cordell, Heather J, Hirschfield, Gideon M, Alexander, Graeme J, Sandford, Richard N, Jones, David E, and Mells, George F

Published
2018
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16. Critical shortfalls in the management of PBC: results of a UK-wide, population-based evaluation of care delivery

Author

Abbas, Nadir, primary, Smith, Rachel, additional, Flack, Steven, additional, Bains, Vikram, additional, Aspinall, Richard J., additional, Jones, Rebecca L., additional, Burke, Laura, additional, Thorburn, Douglas, additional, Heneghan, Michael, additional, Yeoman, Andrew, additional, Leithead, Joanna, additional, Braniff, Conor, additional, Robertson, Andrew, additional, Mitchell, Chris, additional, Thain, Collette, additional, Mitchell-Thain, Robert, additional, Jones, David, additional, Trivedi, Palak J., additional, Mells, George F., additional, Alrubaiy, Laith, additional, Jones, Rebecca, additional, Mells, George, additional, Trivedi, Palak, additional, Flack, Steve, additional, Abbas, Nadir, additional, Abdelsalam, Basma Ahmed, additional, Abdul, Samad, additional, Abduljabbar, Duaa, additional, Abusrewil, Anwar, additional, Adams, Lauren, additional, Adam, Mohamed, additional, Ahmed, Salman, additional, Ali, Jawad, additional, Aldridge, Robin, additional, Al Imran, Tanzil, additional, Alleyne, Lance, additional, Al-Shakhshir, Sarah, additional, Al-Talib, Ismaeel, additional, Amin, Muhammad Nauman, additional, Anand, Tanmay, additional, Arms-Williams, Bradley, additional, Ashraf, Fahad, additional, Ashraf, Muteeb, additional, Aslam, Usama, additional, Asmat, Huma, additional, Aung, Zaw Myo, additional, Au-Yeung, Desson, additional, Aydogan, Rosewan, additional, Babar, Nauman, additional, Baig, Faisal, additional, Bamidele, Opeyemi, additional, Banerjee, Arindam, additional, Baqai, M Fahd, additional, Barakat, Ezzeldin, additional, Barcan, Alina, additional, Bennett, Kris, additional, Bhandal, Mandeep Kaur, additional, Bhushan, Azad, additional, Bonello, Karl, additional, Bordom, Daniel, additional, Bower, Joshua, additional, Bray, Gary, additional, Brennan, Paul, additional, Brown, Rebecca, additional, Brunchi, Andrei, additional, Burns, Karen, additional, Campbell, Iona, additional, Campbell, Roisin, additional, Caracostea, Andra, additional, Carbonell, M., additional, Cargill, Zillah, additional, Cathcart, Jennifer, additional, Chahal, Manpreet, additional, Chakrabarty, Gayatri, additional, Cheung, Michelle, additional, Chikhlia, Anmol, additional, Choon, Xin Yi, additional, Chung, Yooyun, additional, Clancy, Jennifer, additional, Coleman, Emma, additional, Cooper, Christopher, additional, Cox, Zoe, additional, Coyle, Jo, additional, Crocombe, Dominic, additional, Crombie, Joanna, additional, Cumlat, Lourdes, additional, Davies, Courtney, additional, Dearden, Janet, additional, Delaney, Mollie, additional, Dickson, Bruce, additional, Dolman, Grace, additional, Donnelly, Hannah, additional, Dunn, Rebecca, additional, Eales, Louise, additional, Easaw, Jonathan, additional, El Gindy, Mostafa, additional, Ellwood, Kathy, additional, Elsaie, Maged, additional, El-Sayed, Ahmed, additional, Evans, Louise, additional, Farrow, Samantha, additional, Fellows, Helen, additional, Foxton, Matthew, additional, George, Keith, additional, Gerges, Andrew, additional, Giles, Ben, additional, Gomez, David, additional, Goodman, Stephanie, additional, Gopaul, Akshaye, additional, Gormley, Sarah, additional, Gouda, Mahmoud, additional, Gupta-Kaistha, Aarav, additional, Guthrie, Sarah, additional, Hackett, Richard, additional, Hadjinicolaou, Andreas, additional, Halliday, Neil, additional, Hamzah, Basem, additional, Haq, Bisam-ul, additional, Hassall, James, additional, Herman, Omar, additional, Hewitt, Mathew, additional, Hicks, Amy, additional, Hill, Lorraine, additional, Hlaing, Htar Htar, additional, Howard, Anna, additional, Hsu, Catherine, additional, Iqbal, Muhammad Javaid, additional, Isibor, Jumi, additional, Ismail, Asem, additional, Jamal, Jamal W., additional, James, Joel, additional, Javid, Pernia, additional, Javed, Nasir, additional, Jeyanesan, Dhaarica, additional, Jones, Rhiannon, additional, Jopson, Laura, additional, Aleem, M. Junaid, additional, Kallis, Yiannis, additional, Kanwar, Sophia, additional, Karim, Syed, additional, Kelly, Christopher, additional, Khalid, Muhammad Usman, additional, Khan, Asif, additional, Khani, Aria, additional, Kim, Yun, additional, King, Jade, additional, Kirby, Meera, additional, Koo, Sara, additional, Kovammal, Shemin, additional, Kronsten, Victoria, additional, Lagundoye, Ayo, additional, Lam, Jonathan, additional, Lam, Wai Liam, additional, Layard, Brooke, additional, Liaros, Angela, additional, Linn, Thinzar, additional, Lofthouse, Megan, additional, Lynch, Ruairi, additional, Madayala, Mohan, additional, Mahalingam, Aarani, additional, Mahgoub, Moawad, additional, Manan, Abdul, additional, Martin, Vanessa, additional, Masterman, Ben, additional, Matthews, Charmaine, additional, Martini, Iana, additional, Maxan, Maria-Emanuela, additional, McCallion, Nicola, additional, McCormack, Matthew, additional, McDermott, Sarah, additional, McDowell, Hannah, additional, McHugh, Kate, additional, Michail, Stephanie, additional, Mistry, Neil, additional, Mohandas, Dhanoop, additional, Mole, Sean, additional, Moore-Gillon, Claudia, additional, Morgan, James, additional, Morris, Sean, additional, Murray, Jennifer, additional, Murthy, Sruthi, additional, Nasiri, Ruhullah, additional, Nasim, Muhammad Ahsan, additional, Nathwani, Rooshi, additional, Nicholson, Edward, additional, Nigam, Gaurav, additional, Nomani, Murtaza, additional, Nixon, Kirsty, additional, Ogle, Laura, additional, Okeke, Olaku, additional, Olabintan, Olaolu, additional, Ming San, Elaine Ong, additional, Orpen-Palmer, Josh, additional, Orrell, Michael, additional, Osuoha, Glenda, additional, Owen, Christina, additional, Pandya, Aashish, additional, Papamargaritis, Ioannis, additional, Parker, Maurizio, additional, Perera, Suvey, additional, Perry, Alex, additional, Perry, Robert, additional, Peters, Rory, additional, Phaw, Naw April, additional, Phillips, Abimbola, additional, Phoolchund, Anju, additional, Pillay, Lushen, additional, Platten, Emily, additional, Pohl, Keith, additional, Possamai, Lucia, additional, Praman, Krithivasan, additional, Prasad, Yash, additional, Punton, Andrew, additional, Rahimi, Abdul Hameed, additional, Ramful, Satyasheel, additional, Ratcliff, Naomi, additional, Rehman, Zaira, additional, Riggott, Christy, additional, Robinson, Emma, additional, Rushbrook, Simon, additional, Salih, Nafisa, additional, Samuel, David, additional, Saunsbury, Emma, additional, Scott, Jenny, additional, Shah, Jayshri, additional, Shearer, Jessica, additional, Sheth, Abhishek, additional, Sidhu, Harsimranjit, additional, Silcock, Abigail, additional, Sinclair, Sophie, additional, Singh, Prabhsimran, additional, Sinha, Rohit, additional, Smith, Belinda, additional, Sood, R., additional, Spyridou, Chrysoula, additional, Steen, Jennifer, additional, Stephen, Kate, additional, Stevenson, Jason, additional, Sumanariu, Elena, additional, Summers, Nikki, additional, Sweeney, Liz, additional, Tan, Huey, additional, Taylor, Olivia, additional, Tham, Jennifer, additional, Thatcher, Amy, additional, Jones, Helen Thompson, additional, Tufail, Qamar, additional, Udayachandran, Varun, additional, Vakeeswarasarma, Vithushan, additional, Parambil, Jessiya Veliyankodan, additional, Vithayathil, Mathew, additional, Volcek, Edvard, additional, Vyas, Anand, additional, Waddell, Katy, additional, Webb, Gwilym, additional, Westlake, Emily, additional, Wetten, Aaron, additional, White, Helen, additional, Willsmore, James, additional, Wooding, Jenna, additional, Wye, John, additional, Yeoh, Irvin, additional, Zahedi, Faisal, additional, Zaman, Shakir, additional, Zotescu, Andreea, additional, and Zulfikar, Seema, additional

Published
2023
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17. Ursodeoxycholic acid and severe COVID-19 outcomes in people with liver disease: a cohort study using the OpenSAFELY platform

Author

Costello, Ruth E, primary, Waller, Karen MJ, additional, Smith, Rachel, additional, Mells, George F, additional, Wong, Angel YS, additional, Schultze, Anna, additional, Mahalingasivam, Viyaasan, additional, Herrett, Emily, additional, Zheng, Bang, additional, Lin, Liang-Yu, additional, Mehrkar, Amir, additional, Bacon, Sebastian CJ, additional, Goldacre, Ben, additional, Tomlinson, Laurie A, additional, Tazare, John, additional, and Rentsch, Christopher T., additional

Published
2023
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21. P32 Statistical colocalization identifies twenty-four novel risk loci associated with disease risk of primary biliary cholangitis

Author

Mulcahy, Victoria, primary, Cordell, Heather, additional, Juran, Brian, additional, Atkinson, Elizabeth, additional, Carbone, Marco, additional, Asselta, Rosanna, additional, Andrade, Mariza de, additional, Jones, David, additional, Sandford, Richard, additional, Lazaridis, Konstantinos, additional, Amos, Chris, additional, Hirschfield, Gideon, additional, Seldin, Michael, additional, Invernizzi, Pietro, additional, Siminovitch, Katherine, additional, Wallace, Chris, additional, and Mells, George, additional

Published
2023
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23. Identification of potential targets amenable to novel therapeutics to treat symptoms in primary biliary cholangitis

Author

Wetten, Aaron, primary, Barron-Millar, Ben, additional, Ogle, Laura, additional, Mells, George, additional, Flack, Steven, additional, Hegade, Vinod, additional, Sandford, Richard, additional, Kirby, John, additional, Palmer, Jeremy, additional, Brotherston, Sophie, additional, Jopson, Laura, additional, Brain, John, additional, Smith, Graham, additional, Rushton, Steve, additional, Jones, Rebecca L., additional, Rushbrook, Simon, additional, Thorburn, Douglas, additional, Ryder, Stephen, additional, Hirschfield, Gideon, additional, Jones, David, additional, and Dyson, Jessica, additional

Published
2023
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24. Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis

Author

Martinez-Gili, Laura, primary, Pechlivanis, Alexandros, additional, McDonald, Julie A.K., additional, Begum, Sofina, additional, Badrock, Jonathan, additional, Dyson, Jessica K., additional, Jones, Rebecca, additional, Hirschfield, Gideon, additional, Ryder, Stephen D., additional, Sandford, Richard, additional, Rushbrook, Simon, additional, Thorburn, Douglas, additional, Taylor-Robinson, Simon D., additional, Crossey, Mary M.E., additional, Marchesi, Julian R., additional, Mells, George, additional, Holmes, Elaine, additional, and Jones, David, additional

Published
2023
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25. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study

Author

Jones, David, Boudes, Pol F, Swain, Mark G, Bowlus, Christopher L, Galambos, Michael R, Bacon, Bruce R, Doerffel, Yvonne, Gitlin, Norman, Gordon, Stuart C, Odin, Joseph A, Sheridan, David, Wörns, Markus-Alexander, Clark, Virginia, Corless, Linsey, Hartmann, Heinz, Jonas, Mark E, Kremer, Andreas E, Mells, George F, Buggisch, Peter, Freilich, Bradley L, Levy, Cynthia, Vierling, John M, Bernstein, David E, Hartleb, Marek, Janczewska, Ewa, Rochling, Fedja, Shah, Hemant, Shiffman, Mitchell L, Smith, John H, Choi, Yun-Jung, Steinberg, Alexandra, Varga, Monika, Chera, Harinder, Martin, Robert, McWherter, Charles A, and Hirschfield, Gideon M

Published
2017
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27. Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

Author

Mulcahy, Victoria, Liaskou, Evaggelia, Martin, Jose-Ezequiel, Kotagiri, Prasanti, Badrock, Jonathan, Jones, Rebecca L, Rushbrook, Simon M, Ryder, Stephen D, Thorburn, Douglas, Taylor-Robinson, Simon D, Clark, Graeme, Cordell, Heather J, Sandford, Richard N, Jones, David E, Hirschfield, Gideon M, Mells, George F, Mulcahy, Victoria [0000-0001-7091-4789], Liaskou, Evaggelia [0000-0002-9820-4698], Martin, Jose-Ezequiel [0000-0002-0051-8868], Kotagiri, Prasanti [0000-0002-9806-4349], Ryder, Stephen D [0000-0001-9649-4444], Thorburn, Douglas [0000-0002-5610-5448], Taylor-Robinson, Simon D [0000-0002-8811-1834], Clark, Graeme [0000-0002-5543-2789], Cordell, Heather J [0000-0002-1879-5572], Jones, David E [0000-0002-0083-5564], Hirschfield, Gideon M [0000-0002-6736-2255], Mells, George F [0000-0002-7962-5286], and Apollo - University of Cambridge Repository

Subjects
2 Aetiology, Hepatology, Liver Cirrhosis, Biliary, Inflammatory and immune system, Human Genome, Ursodeoxycholic Acid, Immunity, Clinical Research, FOS: Biological sciences, Genetics, Leukocytes, Mononuclear, 2.1 Biological and endogenous factors, Humans, Digestive Diseases, Transcriptome, Biotechnology
Abstract

BACKGROUND AIMS: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. METHODS: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. RESULTS: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q

Published
2022

28. Corrigendum to: “An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs” [J Hepatol 75 (2021) 572-581]

Author

Cordell, Heather J., primary, Fryett, James J., additional, Ueno, Kazuko, additional, Darlay, Rebecca, additional, Aiba, Yoshihiro, additional, Hitomi, Yuki, additional, Kawashima, Minae, additional, Nishida, Nao, additional, Khor, Seik-Soon, additional, Gervais, Olivier, additional, Kawai, Yosuke, additional, Nagasaki, Masao, additional, Tokunaga, Katsushi, additional, Tang, Ruqi, additional, Shi, Yongyong, additional, Li, Zhiqiang, additional, Juran, Brian D., additional, Atkinson, Elizabeth J., additional, Gerussi, Alessio, additional, Carbone, Marco, additional, Asselta, Rosanna, additional, Cheung, Angela, additional, de Andrade, Mariza, additional, Baras, Aris, additional, Horowitz, Julie, additional, Ferreira, Manuel A.R., additional, Sun, Dylan, additional, Jones, David E., additional, Flack, Steven, additional, Spicer, Ann, additional, Mulcahy, Victoria L., additional, Byan, Jinyoung, additional, Han, Younghun, additional, Sandford, Richard N., additional, Lazaridis, Konstantinos N., additional, Amos, Christopher I., additional, Hirschfield, Gideon M., additional, Seldin, Michael F., additional, Invernizzi, Pietro, additional, Siminovitch, Katherine A., additional, Ma, Xiong, additional, Nakamura, Minoru, additional, and Mells, George F., additional

Published
2023
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29. Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

Author

Mulcahy, Victoria, primary, Liaskou, Evaggelia, additional, Martin, Jose-Ezequiel, additional, Kotagiri, Prasanti, additional, Badrock, Jonathan, additional, Jones, Rebecca L., additional, Rushbrook, Simon M, additional, Ryder, Stephen D., additional, Thorburn, Douglas, additional, Taylor-Robinson, Simon D., additional, Clark, Graeme, additional, Cordell, Heather J., additional, Sandford, Richard N., additional, Jones, David E., additional, Hirschfield, Gideon M., additional, and Mells, George F., additional

Published
2023
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32. Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

Author

Wetten, Aaron, primary, Ogle, Laura, additional, Mells, George, additional, Hegade, Vinod S., additional, Jopson, Laura, additional, Corrigan, Margaret, additional, Palmer, Jeremy, additional, Johansson, Maja, additional, Bäckström, Torbjörn, additional, Doverskog, Magnus, additional, Jones, David E. J., additional, and Dyson, Jessica K., additional

Published
2022
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33. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls

Author

Murillo Perez, C. Fiorella, primary, Fisher, Holly, additional, Hiu, Shaun, additional, Kareithi, Dorcas, additional, Adekunle, Femi, additional, Mayne, Tracy, additional, Malecha, Elizabeth, additional, Ness, Erik, additional, van der Meer, Adriaan J., additional, Lammers, Willem J., additional, Trivedi, Palak J., additional, Battezzati, Pier Maria, additional, Nevens, Frederik, additional, Kowdley, Kris V., additional, Bruns, Tony, additional, Cazzagon, Nora, additional, Floreani, Annarosa, additional, Mason, Andrew L., additional, Parés, Albert, additional, Londoño, Maria-Carlota, additional, Invernizzi, Pietro, additional, Carbone, Marco, additional, Lleo, Ana, additional, Mayo, Marlyn J., additional, Dalekos, George N., additional, Gatselis, Nikolaos K., additional, Thorburn, Douglas, additional, Verhelst, Xavier, additional, Gulamhusein, Aliya, additional, Janssen, Harry L.A., additional, Smith, Rachel, additional, Flack, Steve, additional, Mulcahy, Victoria, additional, Trauner, Michael, additional, Bowlus, Christopher L., additional, Lindor, Keith D., additional, Corpechot, Christophe, additional, Jones, David, additional, Mells, George, additional, Hirschfield, Gideon M., additional, Wason, James, additional, Hansen, Bettina E., additional, Sturgess, Richard, additional, Healey, Christopher, additional, Gunasekera, Anton, additional, Kallis, Yiannis, additional, Wright, Gavin, additional, Mathialahan, Thiriloganathan, additional, Evans, Richard, additional, Gasem, Jaber, additional, Ramanaden, David, additional, Ward, Emma, additional, Bhalme, Mahesh, additional, Southern, Paul, additional, Maggs, James, additional, Yousif, Mohamed, additional, Srivastava, Brijesh, additional, Foxton, Matthew, additional, Collins, Carole, additional, Prasad, Yash, additional, Porras-Perez, Francisco, additional, Yapp, Tom, additional, Patel, Minesh, additional, Ede, Roland, additional, Carte, Martyn, additional, Koss, Konrad, additional, Sattianayagam, Prayman, additional, Grimley, Charles, additional, Tidbury, Jude, additional, Mansour, Dina, additional, Beckley, Matilda, additional, Hollywood, Coral, additional, Ramag, John, additional, Gordon, Harriet, additional, Ridpath, Joanne, additional, Grover, Bob, additional, Abouda, George, additional, Rees, Ian, additional, Narain, Mark, additional, Salam, Imroz, additional, Banim, Paul, additional, Das, Debasish, additional, Matthews, Helen, additional, Mohammed, Faiyaz, additional, Jones, Rebecca, additional, Sen, Sambit, additional, Bird, George, additional, Prince, Martin, additional, Prasad, Geeta, additional, Kitchen, Paul, additional, Hutchinson, John, additional, Gupta, Prakash, additional, Shah, Amir, additional, Saha, Subrata, additional, Pollock, Katharine, additional, Barclay, Stephen, additional, McDonald, Natasha, additional, Rushbrook, Simon, additional, Przemioslo, Robert, additional, Millar, Andrew, additional, Mitchell, Steven, additional, Davis, Andrew, additional, Naqvi, Asifabbas, additional, Lee, Tom, additional, Ryder, Stephen, additional, Collier, Jane, additional, Cramp, Matthew, additional, Aspinal, Richard, additional, Booth, Jonathan, additional, Williams, Earl, additional, Hussaini, Hyder, additional, Christie, John, additional, Chaudhry, Tehreem, additional, Mann, Stephen, additional, Ala, Aftab, additional, Maltby, Julia, additional, Corbett, Chris, additional, Singhal, Saket, additional, Hoeroldt, Barbara, additional, Butterworth, Jeff, additional, Douglas, Andrew, additional, Sinha, Rohit, additional, Panter, Simon, additional, Shearman, Jeremy, additional, Bray, Gary, additional, Roberts, Michael, additional, Forton, Daniel, additional, Taylor, Nicola, additional, Jafar, Wisam, additional, Cowan, Matthew, additional, Ch'ng, Chin Lye, additional, Rahman, Mesbah, additional, Wesley, Emma, additional, Jain, Sanjiv, additional, Mandal, Aditya, additional, Wright, Mark, additional, Trivedi, Palak, additional, Gordon, Fiona, additional, Unitt, Esther, additional, Austin, Andrew, additional, Palegwala, Altaf, additional, Vemala, Vishwaraj, additional, Higham, Andrew, additional, Fraser, Jocelyn, additional, Li, Andy, additional, Ramakrishnan, Subramaniam, additional, King, Alistair, additional, Whalley, Simon, additional, Gee, Ian, additional, Keld, Richard, additional, Fellows, Helen, additional, Gotto, James, additional, and Millson, Charles, additional

Published
2022
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34. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Author

Brevini, Teresa, Maes, Mailis, Webb, Gwilym J, John, Binu V, Fuchs, Claudia D, Buescher, Gustav, Wang, Lu, Griffiths, Chelsea, Brown, Marnie L, Scott, William E, Pereyra-Gerber, Pehuén, Gelson, William TH, Brown, Stephanie, Dillon, Scott, Muraro, Daniele, Sharp, Jo, Neary, Megan, Box, Helen, Tatham, Lee, Stewart, James, Curley, Paul, Pertinez, Henry, Forrest, Sally, Mlcochova, Petra, Varankar, Sagar S, Darvish-Damavandi, Mahnaz, Mulcahy, Victoria L, Kuc, Rhoda E, Williams, Thomas L, Heslop, James A, Rossetti, Davide, Tysoe, Olivia C, Galanakis, Vasileios, Vila-Gonzalez, Marta, Crozier, Thomas WM, Bargehr, Johannes, Sinha, Sanjay, Upponi, Sara S, Fear, Corrina, Swift, Lisa, Saeb-Parsy, Kourosh, Davies, Susan E, Wester, Axel, Hagström, Hannes, Melum, Espen, Clements, Darran, Humphreys, Peter, Herriott, Jo, Kijak, Edyta, Cox, Helen, Bramwell, Chloe, Valentijn, Anthony, Illingworth, Christopher, UK-PBC Consortium, Dahman, Bassam, Bastaich, Dustin R, Ferreira, Raphaella D, Marjot, Thomas, Barnes, Eleanor, Moon, Andrew M, Barritt, Alfred S, Gupta, Ravindra K, Baker, Stephen, Davenport, Anthony P, Corbett, Gareth, Gorgoulis, Vassilis G, Buczacki, Simon JA, Lee, Joo-Hyeon, Matheson, Nicholas J, Trauner, Michael, Fisher, Andrew J, Gibbs, Paul, Butler, Andrew J, Watson, Christopher JE, Mells, George F, Dougan, Gordon, Owen, Andrew, Lohse, Ansgar W, Vallier, Ludovic, Sampaziotis, Fotios, Brevini, Teresa [0000-0002-3581-5379], Maes, Mailis [0000-0002-0266-6557], Wang, Lu [0000-0002-4418-8602], Brown, Marnie L [0000-0001-6463-0288], Scott, William E [0000-0003-1515-0514], Sharp, Jo [0000-0001-8482-5736], Neary, Megan [0000-0002-4960-2139], Tatham, Lee [0000-0001-9448-8876], Stewart, James [0000-0002-8928-2037], Darvish-Damavandi, Mahnaz [0000-0003-0226-2621], Williams, Thomas L [0000-0002-1051-0595], Crozier, Thomas WM [0000-0003-0951-4588], Bargehr, Johannes [0000-0002-9304-3573], Sinha, Sanjay [0000-0001-5900-1209], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Wester, Axel [0000-0003-3634-6591], Melum, Espen [0000-0001-6903-6878], Bramwell, Chloe [0000-0001-8274-457X], Barnes, Eleanor [0000-0002-0860-0831], Moon, Andrew M [0000-0001-7163-2062], Gupta, Ravindra K [0000-0001-9751-1808], Baker, Stephen [0000-0003-1308-5755], Davenport, Anthony P [0000-0002-2096-3117], Gorgoulis, Vassilis G [0000-0001-9001-4112], Buczacki, Simon JA [0000-0002-2975-416X], Lee, Joo-Hyeon [0000-0002-7364-6422], Matheson, Nicholas J [0000-0002-3318-1851], Trauner, Michael [0000-0002-1275-6425], Fisher, Andrew J [0000-0003-4822-7223], Watson, Christopher JE [0000-0002-0590-4901], Owen, Andrew [0000-0002-9819-7651], Vallier, Ludovic [0000-0002-3848-2602], Sampaziotis, Fotios [0000-0003-0812-7586], and Apollo - University of Cambridge Repository

Subjects
Transcription, Genetic, SARS-CoV-2, Ursodeoxycholic Acid, COVID-19, Reproducibility of Results, COVID-19 Drug Treatment, Liver Transplantation, Organoids, Mice, Nasal Mucosa, Liver, Cricetinae, UK-PBC Consortium, Animals, Humans, Receptors, Virus, Angiotensin-Converting Enzyme 2, Registries, Lung, Retrospective Studies
Abstract

Acknowledgements: We thank the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) for supporting the COVID-Hep and SECURE-Liver registries; S. Marciniak and P. J. Lehner for comments and feedback on the manuscript; I. Goodfellow for providing the viral isolate; M. Wills and S. Clare for all their work ensuring a safe CL-3 working environment; C. Cormie for general lab support; the NIHR Cambridge BRC Cell Phenotyping Hub for their help with flow cytometry and processing of samples; the building staff of the Jeffrey Cheah Biomedical Centre for maintaining the institute open and safe during the period of lockdown; K. Füssel for coordinating the volunteer study and sample collection at the University Medical Centre Hamburg-Eppendorf; J. Hails, K.-I. Nikitopoulou and A. Ford for collecting blood samples; M. Colzani for advising on flow cytometry; A. Wiblin for advising on antibodies; and the Cambridge Biorepository for Translational Medicine for the provision of human tissue used in the study. T.B. was supported by an EASL Juan Rodès PhD fellowship. F.S. was supported by a UKRI Future Leaders fellowship, the Evelyn trust, an NIHR Clinical Lectureship, the Academy of Medical Sciences Starter Grant for Clinical Lecturers, the Addenbrooke’s Charitable Trust and the Rosetrees Trust. In addition, the F.S. laboratory is supported by the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre and the core support grant from the Wellcome Trust and Medical Research Council (MRC) of the Wellcome–Medical Research Council Cambridge Stem Cell Institute. The L.V. laboratory is funded by the ERC advanced grant New-Chol, the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre and the core support grant from the Wellcome Trust and MRC of the Wellcome–Medical Research Council Cambridge Stem Cell Institute. M.M., S.F. and G.D. are funded by the NIHR Cambridge Biomedical Research Centre and NIHR AMR Research Capital Funding Scheme (NIHR200640). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. V.L.M. was funded by an MRC Clinical Research Training Fellowship. G.F.M. was funded by a post-doctoral fellowship from the National Institute for Health Research (NIHR) Rare Diseases–Translational Research Collaboration (RD-TRC) and by an MRC Clinical Academic Research Partnership (CARP) award. The UK-PBC Nested Cohort study was funded by an MRC Stratified Medicine award (MR/L001489/1). C.J.R.I. was supported by the Medical Research Council (MC_UU_12014). T.M. is funded by a Wellcome Trust Clinical Research Training Fellowship (102176/B/13/Z). The A.P.D. laboratory was supported by BHF TG/18/4/33770, Wellcome Trust 203814/Z/16/A and Addenbrooke’s Charitable Trust. The COVID-Hep.net registry was supported by the European Association for the Study of the Liver (EASL) and the SECURE-Liver registry was supported by the American Association for the Study of Liver Disease (AASLD). The lung perfusion experiment was supported by the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Organ Donation and Transplantation at Newcastle University and the University of Cambridge in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the author(s) and not necessarily those of the NIHR, the Department of Health and Social Care or NHSBT. G.B. is funded by the European Reference Network for Hepatological Diseases (ERN RARE LIVER). A.O. acknowledges funding for preclinical research on treatment and prevention of COVID-19 from Unitaid (2020-38-LONGEVITY), the Engineering and Physical Sciences Research Council (EPSRC; EP/R024804/1), the Wellcome Trust (222489/Z/21/Z) and UK Research and Innovation (UKRI; BB/W010801/1). N.J.M. acknowledges funding from the MRC (CSF ref. MR/P008801/1 to N.J.M.), NHSBT (grant ref. WPA15-02 to N.J.M.) and Addenbrooke’s Charitable Trust (grant ref. to 900239 N.J.M.). This research was funded in whole, or in part, by the Wellcome Trust (203151/Z/16/Z, 203151/A/16/Z) and the UKRI Medical Research Council (MC_PC_17230). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission., Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

Published
2022

35. O07 Results of the first national audit of PBC management reveal significant variation in care delivery across the UK

Author

Smith, Rachel, primary, Abbas, Nadir, additional, Flack, Steve, additional, Yeoman, Andrew, additional, Thorburn, Douglas, additional, Aspinall, Richard, additional, Jones, Rebecca, additional, Leithead, Joanna, additional, Braniff, Conor, additional, Heneghan, Michael, additional, Thain, Collette, additional, Mitchell, Chris, additional, Mitchell-Thain, Robert, additional, Jones, David, additional, Trivedi, Palak, additional, Mells, George, additional, and Al-Rubaiy, Laith, additional

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2022
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36. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

Author

Cordell, Heather J., primary, Fryett, James J., additional, Ueno, Kazuko, additional, Darlay, Rebecca, additional, Aiba, Yoshihiro, additional, Hitomi, Yuki, additional, Kawashima, Minae, additional, Nishida, Nao, additional, Khor, Seik-Soon, additional, Gervais, Olivier, additional, Kawai, Yosuke, additional, Nagasaki, Masao, additional, Tokunaga, Katsushi, additional, Tang, Ruqi, additional, Shi, Yongyong, additional, Li, Zhiqiang, additional, Juran, Brian D., additional, Atkinson, Elizabeth J., additional, Gerussi, Alessio, additional, Carbone, Marco, additional, Asselta, Rosanna, additional, Cheung, Angela, additional, de Andrade, Mariza, additional, Baras, Aris, additional, Horowitz, Julie, additional, Ferreira, Manuel A.R., additional, Sun, Dylan, additional, Jones, David E., additional, Flack, Steven, additional, Spicer, Ann, additional, Mulcahy, Victoria L., additional, Byun, Jinyoung, additional, Han, Younghun, additional, Sandford, Richard N., additional, Lazaridis, Konstantinos N., additional, Amos, Christopher I., additional, Hirschfield, Gideon M., additional, Seldin, Michael F., additional, Invernizzi, Pietro, additional, Siminovitch, Katherine A., additional, Ma, Xiong, additional, Nakamura, Minoru, additional, Mells, George F., additional, Mason, Andrew, additional, Vincent, Catherine, additional, Xie, Gang, additional, Zhang, Jinyi, additional, Affronti, Andrea, additional, Almasio, Piero L., additional, Alvaro, Domenico, additional, Andreone, Pietro, additional, Andriulli, Angelo, additional, Azzaroli, Francesco, additional, Battezzati, Pier Maria, additional, Benedetti, Antonio, additional, Bragazzi, MariaConsiglia, additional, Brunetto, Maurizia, additional, Bruno, Savino, additional, Calvaruso, Vincenza, additional, Cardinale, Vincenzo, additional, Casella, Giovanni, additional, Cazzagon, Nora, additional, Ciaccio, Antonio, additional, Coco, Barbara, additional, Colli, Agostino, additional, Colloredo, Guido, additional, Colombo, Massimo, additional, Colombo, Silvia, additional, Cristoferi, Laura, additional, Cursaro, Carmela, additional, Crocè, Lory Saveria, additional, Crosignani, Andrea, additional, D’Amato, Daphne, additional, Donato, Francesca, additional, Elia, Gianfranco, additional, Fabris, Luca, additional, Fagiuoli, Stefano, additional, Ferrari, Carlo, additional, Floreani, Annarosa, additional, Galli, Andrea, additional, Giannini, Edoardo, additional, Grattagliano, Ignazio, additional, Lampertico, Pietro, additional, Lleo, Ana, additional, Malinverno, Federica, additional, Mancuso, Clara, additional, Marra, Fabio, additional, Marzioni, Marco, additional, Massironi, Sara, additional, Mattalia, Alberto, additional, Miele, Luca, additional, Milani, Chiara, additional, Morini, Lorenzo, additional, Morisco, Filomena, additional, Muratori, Luigi, additional, Muratori, Paolo, additional, Niro, Grazia A., additional, O’Donnell, Sarah, additional, Picciotto, Antonio, additional, Portincasa, Piero, additional, Rigamonti, Cristina, additional, Ronca, Vincenzo, additional, Rosina, Floriano, additional, Spinzi, Giancarlo, additional, Strazzabosco, Mario, additional, Tarocchi, Mirko, additional, Tiribelli, Claudio, additional, Toniutto, Pierluigi, additional, Valenti, Luca, additional, Vinci, Maria, additional, Zuin, Massimo, additional, Nakamura, Hitomi, additional, Abiru, Seigo, additional, Nagaoka, Shinya, additional, Komori, Atsumasa, additional, Yatsuhashi, Hiroshi, additional, Ishibashi, Hiromi, additional, Ito, Masahiro, additional, Migita, Kiyoshi, additional, Ohira, Hiromasa, additional, Katsushima, Shinji, additional, Naganuma, Atsushi, additional, Sugi, Kazuhiro, additional, Komatsu, Tatsuji, additional, Mannami, Tomohiko, additional, Matsushita, Kouki, additional, Yoshizawa, Kaname, additional, Makita, Fujio, additional, Nikami, Toshiki, additional, Nishimura, Hideo, additional, Kouno, Hiroshi, additional, Kouno, Hirotaka, additional, Ota, Hajime, additional, Komura, Takuya, additional, Nakamura, Yoko, additional, Shimada, Masaaki, additional, Hirashima, Noboru, additional, Komeda, Toshiki, additional, Ario, Keisuke, additional, Nakamuta, Makoto, additional, Yamashita, Tsutomu, additional, Furuta, Kiyoshi, additional, Kikuchi, Masahiro, additional, Naeshiro, Noriaki, additional, Takahashi, Hironao, additional, Mano, Yutaka, additional, Tsunematsu, Seiji, additional, Yabuuchi, Iwao, additional, Shimada, Yusuke, additional, Yamauchi, Kazuhiko, additional, Sugimoto, Rie, additional, Sakai, Hironori, additional, Mita, Eiji, additional, Koda, Masaharu, additional, Tsuruta, Satoru, additional, Kamitsukasa, Hiroshi, additional, Sato, Takeaki, additional, Masaki, Naohiko, additional, Kobata, Tatsuro, additional, Fukushima, Nobuyoshi, additional, Ohara, Yukio, additional, Muro, Toyokichi, additional, Takesaki, Eiichi, additional, Takaki, Hitoshi, additional, Yamamoto, Tetsuo, additional, Kato, Michio, additional, Nagaoki, Yuko, additional, Hayashi, Shigeki, additional, Ishida, Jinya, additional, Watanabe, Yukio, additional, Kobayashi, Masakazu, additional, Koga, Michiaki, additional, Saoshiro, Takeo, additional, Yagura, Michiyasu, additional, Hirata, Keisuke, additional, Tanaka, Atsushu, additional, Takikawa, Hajime, additional, Zeniya, Mikio, additional, Abe, Masanori, additional, Onji, Morikazu, additional, Kaneko, Shuichi, additional, Honda, Masao, additional, Arai, Kuniaki, additional, Arinaga-Hino, Teruko, additional, Hashimoto, Etsuko, additional, Taniai, Makiko, additional, Umemura, Takeji, additional, Joshita, Satoru, additional, Nakao, Kazuhiko, additional, Ichikawa, Tatsuki, additional, Shibata, Hidetaka, additional, Yamagiwa, Satoshi, additional, Seike, Masataka, additional, Honda, Koichi, additional, Sakisaka, Shotaro, additional, Takeyama, Yasuaki, additional, Harada, Masaru, additional, Senju, Michio, additional, Yokosuka, Osamu, additional, Kanda, Tatsuo, additional, Ueno, Yoshiyuki, additional, Kikuchi, Kentaro, additional, Ebinuma, Hirotoshi, additional, Himoto, Takashi, additional, Yasunami, Michio, additional, Murata, Kazumoto, additional, Mizokami, Masashi, additional, Kawata, Kazuhito, additional, Shimoda, Shinji, additional, Miyake, Yasuhiro, additional, Takaki, Akinobu, additional, Yamamoto, Kazuhide, additional, Hirano, Katsuji, additional, Ichida, Takafumi, additional, Ido, Akio, additional, Tsubouchi, Hirohito, additional, Chayama, Kazuaki, additional, Harada, Kenichi, additional, Nakanuma, Yasuni, additional, Maehara, Yoshihiko, additional, Taketomi, Akinobu, additional, Shirabe, Ken, additional, Soejima, Yuji, additional, Mori, Akira, additional, Yagi, Shintaro, additional, Uemoto, Shinji, additional, H, Egawa, additional, Tanaka, Tomohiro, additional, Yamashiki, Noriyo, additional, Tamura, Sumito, additional, Sugawara, Yasuhiro, additional, Kokudo, Norihiro, additional, Chalasani, Naga, additional, Luketic, Vel, additional, Odin, Joseph, additional, Chopra, Kapil, additional, Abecasis, Goncalo, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Economides, Aris, additional, Lotta, Luca A., additional, Overton, John D., additional, Reid, Jeffrey G., additional, Shuldiner, Alan, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Schleicher, Thomas D., additional, Padilla, Maria Sotiropoulos, additional, Toledo, Karina, additional, Widom, Louis, additional, Wolf, Sarah E., additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Ulloa, Ricardo H., additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Barnard, Leland, additional, Blumenfeld, Andrew, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Maxwell, Evan K., additional, Salerno, William, additional, Staples, Jeffrey C., additional, Jones, Marcus B., additional, Mitnaul, Lyndon J., additional, Sturgess, Richard, additional, Healey, Christopher, additional, Yeoman, Andrew, additional, Gunasekera, Anton VJ., additional, Kooner, Paul, additional, Kapur, Kapil, additional, Sathyanarayana, V., additional, Kallis, Yiannis, additional, Subhani, Javaid, additional, Harvey, Rory, additional, McCorry, Roger, additional, Rooney, Paul, additional, Ramanaden, David, additional, Evans, Richard, additional, Mathialahan, Thiriloganathan, additional, Gasem, Jaber, additional, Shorrock, Christopher, additional, Bhalme, Mahesh, additional, Southern, Paul, additional, Tibble, Jeremy A., additional, Gorard, David A., additional, Jones, Susan, additional, Mells, George, additional, Mulcahy, Victoria, additional, Srivastava, Brijesh, additional, Foxton, Matthew R., additional, Collins, Carole E., additional, Elphick, David, additional, Karmo, Mazn, additional, Porras-Perez, Francisco, additional, Mendall, Michael, additional, Yapp, Tom, additional, Patel, Minesh, additional, Ede, Roland, additional, Sayer, Joanne, additional, Jupp, James, additional, Fisher, Neil, additional, Carter, Martyn J., additional, Koss, Konrad, additional, Shah, Jayshri, additional, Piotrowicz, Andrzej, additional, Scott, Glyn, additional, Grimley, Charles, additional, Gooding, Ian R., additional, Williams, Simon, additional, Tidbury, Judith, additional, Lim, Guan, additional, Cheent, Kuldeep, additional, Levi, Sass, additional, Mansour, Dina, additional, Beckley, Matilda, additional, Hollywood, Coral, additional, Wong, Terry, additional, Marley, Richard, additional, Ramage, John, additional, Gordon, Harriet M., additional, Ridpath, Jo, additional, Ngatchu, Theodore, additional, Bob Grover, Vijay Paul, additional, Shidrawi, Ray G., additional, Abouda, George, additional, Corless, L., additional, Narain, Mark, additional, Rees, Ian, additional, Brown, Ashley, additional, Taylor-Robinson, Simon, additional, Wilkins, Joy, additional, Grellier, Leonie, additional, Banim, Paul, additional, Das, Debasish, additional, Heneghan, Michael A., additional, Curtis, Howard, additional, Matthews, Helen C., additional, Mohammed, Faiyaz, additional, Aldersley, Mark, additional, Srirajaskanthan, Raj, additional, Walker, Giles, additional, McNair, Alistair, additional, Sharif, Amar, additional, Sen, Sambit, additional, Bird, George, additional, Prince, Martin I., additional, Prasad, Geeta, additional, Kitchen, Paul, additional, Barnardo, Adrian, additional, Oza, Chirag, additional, Sivaramakrishnan, Nurani N., additional, Gupta, Prakash, additional, Shah, Amir, additional, Evans, Chris DJ., additional, Saha, Subrata, additional, Pollock, Katharine, additional, Bramley, Peter, additional, Mukhopadhya, Ashis, additional, Barclay, Stephen T., additional, McDonald, Natasha, additional, Bathgate, Andrew J., additional, Palmer, Kelvin, additional, Dillon, John F., additional, Rushbrook, Simon M., additional, Przemioslo, Robert, additional, McDonald, Chris, additional, Millar, Andrew, additional, Tai, Cheh, additional, Mitchell, Stephen, additional, Metcalf, Jane, additional, Shaukat, Syed, additional, Ninkovic, Mary, additional, Shmueli, Udi, additional, Davis, Andrew, additional, Naqvi, Asifabbas, additional, Lee, Tom JW., additional, Ryder, Stephen, additional, Collier, Jane, additional, Klass, Howard, additional, Cramp, Matthew E., additional, Sharer, Nichols, additional, Aspinall, Richard, additional, Ghosh, Deb, additional, Douds, Andrew C., additional, Booth, Jonathan, additional, Williams, Earl, additional, Hussaini, Hyder, additional, Christie, John, additional, Mann, Steven, additional, Thorburn, Douglas, additional, Marshall, Aileen, additional, Patanwala, Imran, additional, Ala, Aftab, additional, Maltby, Julia, additional, Matthew, Ray, additional, Corbett, Chris, additional, Vyas, Sam, additional, Singhal, Saket, additional, Gleeson, Dermot, additional, Misra, Sharat, additional, Butterworth, Jeff, additional, George, Keith, additional, Harding, Tim, additional, Douglass, Andrew, additional, Mitchison, Harriet, additional, Panter, Simon, additional, Shearman, Jeremy, additional, Bray, Gary, additional, Roberts, Michael, additional, Butcher, Graham, additional, Forton, Daniel, additional, Mahmood, Zahid, additional, Cowan, Matthew, additional, Das, Debashis, additional, Ch'ng, Chin Lye, additional, Rahman, Mesbah, additional, Whatley, Gregory C.A., additional, Wesley, Emma, additional, Mandal, Aditya, additional, Jain, Sanjiv, additional, Pereira, Stephen P., additional, Wright, Mark, additional, Trivedi, Palak, additional, Gordon, Fiona H., additional, Unitt, Esther, additional, Palejwala, Altaf, additional, Austin, Andrew, additional, Vemala, Vishwaraj, additional, Grant, Allister, additional, Higham, Andrew D., additional, Brind, Alison, additional, Mathew, Ray, additional, Cox, Mark, additional, Ramakrishnan, Subramaniam, additional, King, Alistair, additional, Whalley, Simon, additional, Fraser, Jocelyn, additional, Thomson, S.J., additional, Bell, Andrew, additional, Wong, Voi Shim, additional, Kia, Richard, additional, Gee, Ian, additional, Keld, Richard, additional, Ransford, Rupert, additional, Gotto, James, additional, and Millson, Charles, additional

Published
2021
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37. Critical shortfalls in the management of PBC: results of the first nationwide, population-based study of care delivery across the U.K.

Author

Abbas, Nadir, primary, Smith, Rachel, additional, Flack, Steve, additional, Aspinall, Richard, additional, Jones, Rebecca L., additional, Leithead, Joanna, additional, Thorburn, Douglas, additional, Braniff, Conor, additional, Heneghan, Michael, additional, Yeoman, Andrew, additional, Thain, Collette, additional, Mitchell, Chris, additional, Mitchell-Thain, Robert, additional, Jones, David, additional, Trivedi, Palak, additional, Mells, George, additional, and Al-Rubaiy, Laith, additional

Published
2022
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38. UK-PBC National Audit: a collaborative success in identifying critical shortfalls

Author

Burke, Laura, primary, Flack, Steven, additional, Jones, Rebecca L, additional, Aspinall, Richard J, additional, Heneghan, Michael A, additional, Thorburn, Doug, additional, Jones, David EJ, additional, Braniff, Conor, additional, Thain, Collette, additional, Yeoman, Andrew, additional, Leithead, Joanna A, additional, Trivedi, Palak, additional, Mells, George, additional, and Alrubaiy, Laith, additional

Published
2022
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39. The National Audit of Primary Biliary Cholangitis (PBC) in the United Kingdom: Defining the Audit Dataset and Data Collection System

Author

Burke, Laura, primary, Flack, Steve, additional, Jones, Rebecca, additional, Aspinall, Richard J, additional, Thorburn, Douglas, additional, Jones, David E, additional, Braniff, Conor, additional, Thain, Collette, additional, Yeoman, Andrew, additional, Leithead, Joanna A, additional, Trivedi, Palak J, additional, Mells, George, additional, and Alrubaiy, Laith, additional

Published
2022
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40. The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study

Author

Jones, David E.J., primary, Wetten, Aaron, additional, Barron-Millar, Ben, additional, Ogle, Laura, additional, Mells, George, additional, Flack, Steven, additional, Sandford, Richard, additional, Kirby, John, additional, Palmer, Jeremy, additional, Brotherston, Sophie, additional, Jopson, Laura, additional, Brain, John, additional, Smith, Graham R., additional, Rushton, Steve, additional, Jones, Rebecca, additional, Rushbrook, Simon, additional, Thorburn, Douglas, additional, Ryder, Stephen D., additional, Hirschfield, Gideon, additional, and Dyson, Jessica K., additional

Published
2022
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42. Su1357: PATIENTS WITH PRIMARY BILIARY CHOLANGITIS TREATED WITH LONG-TERM OBETICHOLIC ACID IN A TRIAL-SETTING DEMONSTRATE BETTER EVENT-FREE SURVIVAL OUTCOMES THAN EXTERNAL CONTROLS FROM THE GLOBAL PBC AND UK-PBC STUDY GROUPS

Author

Perez, C. Fiorella Murillo, primary, Kowdley, Kris V., additional, Fisher, Holly, additional, Hiu, Shaun, additional, Adekunle, Femi, additional, Mayne, Tracy, additional, Malecha, Elizabeth Smoot, additional, Ness, Erik, additional, Meer, Adriaan J. van der, additional, Lammers, Willem J., additional, Trivedi, Palak, additional, Battezzati, Pier Maria, additional, Nevens, Frederik, additional, Bruns, Tony, additional, Cazzagon, Nora, additional, Floreani, Annarosa, additional, Mason, Andrew L., additional, Ponsioen, Cyriel Y., additional, Parés, Albert, additional, Londoño, Maria, additional, Invernizzi, Pietro, additional, Carbone, Marco, additional, Lleo, Ana, additional, Mayo, Marlyn J., additional, Dalekos, George N., additional, Gatselis, Nikolaos, additional, Thorburn, Douglas, additional, Verhelst, Xavier, additional, Gulamhusein, Aliya, additional, Janssen, Harry L., additional, Lindor, Keith D., additional, Corpechot, Christophe, additional, Jones, Dave E., additional, Mells, George, additional, Hirschfield, Gideon, additional, Wason, James, additional, and Hansen, Bettina E., additional

Published
2022
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44. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Cordell, Heather J., primary, Fryett, James J., additional, Ueno, Kazuko, additional, Darlay, Rebecca, additional, Aiba, Yoshihiro, additional, Hitomi, Yuki, additional, Kawashima, Minae, additional, Nishida, Nao, additional, Khor, Seik-Soon, additional, Gervais, Olivier, additional, Kawai, Yosuke, additional, Nagasaki, Masao, additional, Tokunaga, Katsushi, additional, Tang, Ruqi, additional, Shi, Yongyong, additional, Li, Zhiqiang, additional, Juran, Brian D., additional, Atkinson, Elizabeth J., additional, Gerussi, Alessio, additional, Carbone, Marco, additional, Asselta, Rosanna, additional, Cheung, Angela, additional, de Andrade, Mariza, additional, Baras, Aris, additional, Horowitz, Julie, additional, Ferreira, Manuel A.R., additional, Sun, Dylan, additional, Jones, David E., additional, Flack, Steven, additional, Spicer, Ann, additional, Mulcahy, Victoria L., additional, Byan, Jinyoung, additional, Han, Younghun, additional, Sandford, Richard N., additional, Lazaridis, Konstantinos N., additional, Amos, Christopher I., additional, Hirschfield, Gideon M., additional, Seldin, Michael F., additional, Invernizzi, Pietro, additional, Siminovitch, Katherine A., additional, Ma, Xiong, additional, Nakamura, Minoru, additional, Mells, George F., additional, Mason, Andrew, additional, Vincent, Catherine, additional, Xie, Gang, additional, Zhang, Jinyi, additional, Affronti, Andrea, additional, Almasio, Piero L., additional, Alvaro, Domenico, additional, Andreone, Pietro, additional, Andriulli, Angelo, additional, Azzaroli, Francesco, additional, Battezzati, Pier Maria, additional, Benedetti, Antonio, additional, Bragazzi, MariaConsiglia, additional, Brunetto, Maurizia, additional, Bruno, Savino, additional, Calvaruso, Vincenza, additional, Cardinale, Vincenzo, additional, Casella, Giovanni, additional, Cazzagon, Nora, additional, Ciaccio, Antonio, additional, Coco, Barbara, additional, Colli, Agostino, additional, Colloredo, Guido, additional, Colombo, Massimo, additional, Colombo, Silvia, additional, Cristoferi, Laura, additional, Cursaro, Carmela, additional, Crocè, Lory Saveria, additional, Crosignani, Andrea, additional, D’Amato, Daphne, additional, Donato, Francesca, additional, Elia, Gianfranco, additional, Fabris, Luca, additional, Fagiuoli, Stefano, additional, Ferrari, Carlo, additional, Floreani, Annarosa, additional, Galli, Andrea, additional, Giannini, Edoardo, additional, Grattagliano, Ignazio, additional, Lampertico, Pietro, additional, Lleo, Ana, additional, Malinverno, Federica, additional, Mancuso, Clara, additional, Marra, Fabio, additional, Marzioni, Marco, additional, Massironi, Sara, additional, Mattalia, Alberto, additional, Miele, Luca, additional, Milani, Chiara, additional, Morini, Lorenzo, additional, Morisco, Filomena, additional, Muratori, Luigi, additional, Muratori, Paolo, additional, Niro, Grazia A., additional, O’Donnell, Sarah, additional, Picciotto, Antonio, additional, Portincasa, Piero, additional, Rigamonti, Cristina, additional, Ronca, Vincenzo, additional, Rosina, Floriano, additional, Spinzi, Giancarlo, additional, Strazzabosco, Mario, additional, Tarocchi, Mirko, additional, Tiribelli, Claudio, additional, Toniutto, Pierluigi, additional, Valenti, Luca, additional, Vinci, Maria, additional, Zuin, Massimo, additional, Nakamura, Hitomi, additional, Abiru, Seigo, additional, Nagaoka, Shinya, additional, Komori, Atsumasa, additional, Yatsuhashi, Hiroshi, additional, Ishibashi, Hiromi, additional, Ito, Masahiro, additional, Migita, Kiyoshi, additional, Ohira, Hiromasa, additional, Katsushima, Shinji, additional, Naganuma, Atsushi, additional, Sugi, Kazuhiro, additional, Komatsu, Tatsuji, additional, Mannami, Tomohiko, additional, Matsushita, Kouki, additional, Yoshizawa, Kaname, additional, Makita, Fujio, additional, Nikami, Toshiki, additional, Nishimura, Hideo, additional, Kouno, Hiroshi, additional, Kouno, Hirotaka, additional, Ota, Hajime, additional, Komura, Takuya, additional, Nakamura, Yoko, additional, Shimada, Masaaki, additional, Hirashima, Noboru, additional, Komeda, Toshiki, additional, Ario, Keisuke, additional, Nakamuta, Makoto, additional, Yamashita, Tsutomu, additional, Furuta, Kiyoshi, additional, Kikuchi, Masahiro, additional, Naeshiro, Noriaki, additional, Takahashi, Hironao, additional, Mano, Yutaka, additional, Tsunematsu, Seiji, additional, Yabuuchi, Iwao, additional, Shimada, Yusuke, additional, Yamauchi, Kazuhiko, additional, Sugimoto, Rie, additional, Sakai, Hironori, additional, Mita, Eiji, additional, Koda, Masaharu, additional, Tsuruta, Satoru, additional, Kamitsukasa, Hiroshi, additional, Sato, Takeaki, additional, Masaki, Naohiko, additional, Kobata, Tatsuro, additional, Fukushima, Nobuyoshi, additional, Ohara, Yukio, additional, Muro, Toyokichi, additional, Takesaki, Eiichi, additional, Takaki, Hitoshi, additional, Yamamoto, Tetsuo, additional, Kato, Michio, additional, Nagaoki, Yuko, additional, Hayashi, Shigeki, additional, Ishida, Jinya, additional, Watanabe, Yukio, additional, Kobayashi, Masakazu, additional, Koga, Michiaki, additional, Saoshiro, Takeo, additional, Yagura, Michiyasu, additional, Hirata, Keisuke, additional, Tanaka, Atsushu, additional, Takikawa, Hajime, additional, Zeniya, Mikio, additional, Abe, Masanori, additional, Onji, Morikazu, additional, Kaneko, Shuichi, additional, Honda, Masao, additional, Arai, Kuniaki, additional, Arinaga-Hino, Teruko, additional, Hashimoto, Etsuko, additional, Taniai, Makiko, additional, Umemura, Takeji, additional, Joshita, Satoru, additional, Nakao, Kazuhiko, additional, Ichikawa, Tatsuki, additional, Shibata, Hidetaka, additional, Yamagiwa, Satoshi, additional, Seike, Masataka, additional, Honda, Koichi, additional, Sakisaka, Shotaro, additional, Takeyama, Yasuaki, additional, Harada, Masaru, additional, Senju, Michio, additional, Yokosuka, Osamu, additional, Kanda, Tatsuo, additional, Ueno, Yoshiyuki, additional, Kikuchi, Kentaro, additional, Ebinuma, Hirotoshi, additional, Himoto, Takashi, additional, Yasunami, Michio, additional, Murata, Kazumoto, additional, Mizokami, Masashi, additional, Kawata, Kazuhito, additional, Shimoda, Shinji, additional, Miyake, Yasuhiro, additional, Takaki, Akinobu, additional, Yamamoto, Kazuhide, additional, Hirano, Katsuji, additional, Ichida, Takafumi, additional, Ido, Akio, additional, Tsubouchi, Hirohito, additional, Chayama, Kazuaki, additional, Harada, Kenichi, additional, Nakanuma, Yasuni, additional, Maehara, Yoshihiko, additional, Taketomi, Akinobu, additional, Shirabe, Ken, additional, Soejima, Yuji, additional, Mori, Akira, additional, Yagi, Shintaro, additional, Uemoto, Shinji, additional, H, Egawa, additional, Tanaka, Tomohiro, additional, Yamashiki, Noriyo, additional, Tamura, Sumito, additional, Sugawara, Yasuhiro, additional, Kokudo, Norihiro, additional, Chalasani, Naga, additional, Luketic, Vel, additional, Odin, Joseph, additional, Chopra, Kapil, additional, Abecasis, Goncalo, additional, Cantor, Michael, additional, Coppola, Giovanni, additional, Economides, Aris, additional, Lotta, Luca A., additional, Overton, John D., additional, Reid, Jeffrey G., additional, Shuldiner, Alan, additional, Beechert, Christina, additional, Forsythe, Caitlin, additional, Fuller, Erin D., additional, Gu, Zhenhua, additional, Lattari, Michael, additional, Lopez, Alexander, additional, Schleicher, Thomas D., additional, Padilla, Maria Sotiropoulos, additional, Toledo, Karina, additional, Widom, Louis, additional, Wolf, Sarah E., additional, Pradhan, Manasi, additional, Manoochehri, Kia, additional, Ulloa, Ricardo H., additional, Bai, Xiaodong, additional, Balasubramanian, Suganthi, additional, Barnard, Leland, additional, Blumenfeld, Andrew, additional, Eom, Gisu, additional, Habegger, Lukas, additional, Hawes, Alicia, additional, Khalid, Shareef, additional, Maxwell, Evan K., additional, Salerno, William, additional, Staples, Jeffrey C., additional, Jones, Marcus B., additional, Mitnaul, Lyndon J., additional, Sturgess, Richard, additional, Healey, Christopher, additional, Yeoman, Andrew, additional, Gunasekera, Anton VJ., additional, Kooner, Paul, additional, Kapur, Kapil, additional, Sathyanarayana, V., additional, Kallis, Yiannis, additional, Subhani, Javaid, additional, Harvey, Rory, additional, McCorry, Roger, additional, Rooney, Paul, additional, Ramanaden, David, additional, Evans, Richard, additional, Mathialahan, Thiriloganathan, additional, Gasem, Jaber, additional, Shorrock, Christopher, additional, Bhalme, Mahesh, additional, Southern, Paul, additional, Tibble, Jeremy A., additional, Gorard, David A., additional, Jones, Susan, additional, Mells, George, additional, Mulcahy, Victoria, additional, Srivastava, Brijesh, additional, Foxton, Matthew R., additional, Collins, Carole E., additional, Elphick, David, additional, Karmo, Mazn, additional, Porras-Perez, Francisco, additional, Mendall, Michael, additional, Yapp, Tom, additional, Patel, Minesh, additional, Ede, Roland, additional, Sayer, Joanne, additional, Jupp, James, additional, Fisher, Neil, additional, Carter, Martyn J., additional, Koss, Konrad, additional, Shah, Jayshri, additional, Piotrowicz, Andrzej, additional, Scott, Glyn, additional, Grimley, Charles, additional, Gooding, Ian R., additional, Williams, Simon, additional, Tidbury, Judith, additional, Lim, Guan, additional, Cheent, Kuldeep, additional, Levi, Sass, additional, Mansour, Dina, additional, Beckley, Matilda, additional, Hollywood, Coral, additional, Wong, Terry, additional, Marley, Richard, additional, Ramage, John, additional, Gordon, Harriet M., additional, Ridpath, Jo, additional, Ngatchu, Theodore, additional, Bob Grover, Vijay Paul, additional, Shidrawi, Ray G., additional, Abouda, George, additional, Corless, L., additional, Narain, Mark, additional, Rees, Ian, additional, Brown, Ashley, additional, Taylor-Robinson, Simon, additional, Wilkins, Joy, additional, Grellier, Leonie, additional, Banim, Paul, additional, Das, Debasish, additional, Heneghan, Michael A., additional, Curtis, Howard, additional, Matthews, Helen C., additional, Mohammed, Faiyaz, additional, Aldersley, Mark, additional, Srirajaskanthan, Raj, additional, Walker, Giles, additional, McNair, Alistair, additional, Sharif, Amar, additional, Sen, Sambit, additional, Bird, George, additional, Prince, Martin I., additional, Prasad, Geeta, additional, Kitchen, Paul, additional, Barnardo, Adrian, additional, Oza, Chirag, additional, Sivaramakrishnan, Nurani N., additional, Gupta, Prakash, additional, Shah, Amir, additional, Evans, Chris DJ., additional, Saha, Subrata, additional, Pollock, Katharine, additional, Bramley, Peter, additional, Mukhopadhya, Ashis, additional, Barclay, Stephen T., additional, McDonald, Natasha, additional, Bathgate, Andrew J., additional, Palmer, Kelvin, additional, Dillon, John F., additional, Rushbrook, Simon M., additional, Przemioslo, Robert, additional, McDonald, Chris, additional, Millar, Andrew, additional, Tai, Cheh, additional, Mitchell, Stephen, additional, Metcalf, Jane, additional, Shaukat, Syed, additional, Ninkovic, Mary, additional, Shmueli, Udi, additional, Davis, Andrew, additional, Naqvi, Asifabbas, additional, Lee, Tom JW., additional, Ryder, Stephen, additional, Collier, Jane, additional, Klass, Howard, additional, Cramp, Matthew E., additional, Sharer, Nichols, additional, Aspinall, Richard, additional, Ghosh, Deb, additional, Douds, Andrew C., additional, Booth, Jonathan, additional, Williams, Earl, additional, Hussaini, Hyder, additional, Christie, John, additional, Mann, Steven, additional, Thorburn, Douglas, additional, Marshall, Aileen, additional, Patanwala, Imran, additional, Ala, Aftab, additional, Maltby, Julia, additional, Matthew, Ray, additional, Corbett, Chris, additional, Vyas, Sam, additional, Singhal, Saket, additional, Gleeson, Dermot, additional, Misra, Sharat, additional, Butterworth, Jeff, additional, George, Keith, additional, Harding, Tim, additional, Douglass, Andrew, additional, Mitchison, Harriet, additional, Panter, Simon, additional, Shearman, Jeremy, additional, Bray, Gary, additional, Roberts, Michael, additional, Butcher, Graham, additional, Forton, Daniel, additional, Mahmood, Zahid, additional, Cowan, Matthew, additional, Das, Debashis, additional, Ch’ng, Chin Lye, additional, Rahman, Mesbah, additional, Whatley, Gregory C.A., additional, Wesley, Emma, additional, Mandal, Aditya, additional, Jain, Sanjiv, additional, Pereira, Stephen P., additional, Wright, Mark, additional, Trivedi, Palak, additional, Gordon, Fiona H., additional, Unitt, Esther, additional, Palejwala, Altaf, additional, Austin, Andrew, additional, Vemala, Vishwaraj, additional, Grant, Allister, additional, Higham, Andrew D., additional, Brind, Alison, additional, Mathew, Ray, additional, Cox, Mark, additional, Ramakrishnan, Subramaniam, additional, King, Alistair, additional, Whalley, Simon, additional, Fraser, Jocelyn, additional, Thomson, S.J., additional, Bell, Andrew, additional, Wong, Voi Shim, additional, Kia, Richard, additional, Gee, Ian, additional, Keld, Richard, additional, Ransford, Rupert, additional, Gotto, James, additional, and Millson, Charles, additional

Published
2021
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45. Neurosteroid activation of gaba-a receptors : a potential treatment target for symptoms in primary biliary cholangitis?

Author

Wetten, Aaron, Ogle, Laura, Mells, George, Hegade, Vinod S., Jopson, Laura, Corrigan, Margaret, Palmer, Jeremy, Johansson, Maja, Bäckström, Torbjörn, Doverskog, Magnus, Jones, David E. J., Dyson, Jessica K., Wetten, Aaron, Ogle, Laura, Mells, George, Hegade, Vinod S., Jopson, Laura, Corrigan, Margaret, Palmer, Jeremy, Johansson, Maja, Bäckström, Torbjörn, Doverskog, Magnus, Jones, David E. J., and Dyson, Jessica K.

Abstract

Background and Aims: A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients. Method: Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms. Results: There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients (r (120) = -0.53, p < 0.001) but not healthy controls (r (39) = -0.21, p = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition (u = 1034, p = 0.02), emotional (u = 1374, p = 0.004), and itch (u = 795, p = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u = 423 p = 0.001). Conclusion: Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.

Published
2022
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46. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls

Author

Murillo Perez, C. Fiorella, Fisher, Holly, Hiu, Shaun, Kareithi, Dorcas, Adekunle, Femi, Mayne, Tracy, Malecha, Elizabeth, Ness, Erik, van der Meer, Adriaan J., Lammers, Willem J., Trivedi, Palak J., Battezzati, Pier Maria, Nevens, Frederik, Kowdley, Kris V., Bruns, Tony, Cazzagon, Nora, Floreani, Annarosa, Mason, Andrew L., Parés, Albert, Londoño, Maria Carlota, Invernizzi, Pietro, Carbone, Marco, Lleo, Ana, Mayo, Marlyn J., Dalekos, George N., Gatselis, Nikolaos K., Thorburn, Douglas, Verhelst, Xavier, Gulamhusein, Aliya, Janssen, Harry L.A., Smith, Rachel, Flack, Steve, Mulcahy, Victoria, Trauner, Michael, Bowlus, Christopher L., Lindor, Keith D., Corpechot, Christophe, Jones, David, Mells, George, Hirschfield, Gideon M., Wason, James, Hansen, Bettina E., Murillo Perez, C. Fiorella, Fisher, Holly, Hiu, Shaun, Kareithi, Dorcas, Adekunle, Femi, Mayne, Tracy, Malecha, Elizabeth, Ness, Erik, van der Meer, Adriaan J., Lammers, Willem J., Trivedi, Palak J., Battezzati, Pier Maria, Nevens, Frederik, Kowdley, Kris V., Bruns, Tony, Cazzagon, Nora, Floreani, Annarosa, Mason, Andrew L., Parés, Albert, Londoño, Maria Carlota, Invernizzi, Pietro, Carbone, Marco, Lleo, Ana, Mayo, Marlyn J., Dalekos, George N., Gatselis, Nikolaos K., Thorburn, Douglas, Verhelst, Xavier, Gulamhusein, Aliya, Janssen, Harry L.A., Smith, Rachel, Flack, Steve, Mulcahy, Victoria, Trauner, Michael, Bowlus, Christopher L., Lindor, Keith D., Corpechot, Christophe, Jones, David, Mells, George, Hirschfield, Gideon M., Wason, James, and Hansen, Bettina E.

Abstract

Background & Aims: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA–treated external controls. Methods: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. Results: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10–0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12–0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03–1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09–1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21–0.85) including hepatic decompensation. Conclusions: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.

Published
2022

47. The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis

Author

Barron-Millar, Ben, Ogle, Laura, Mells, George, Flack, Steven, Badrock, Jonathan, Sandford, Richard, Kirby, John, Palmer, Jeremy, Jopson, Laura, Brain, John, Smith, Graham R, Rushton, Steve, Hegade, Vinod S, Jones, Rebecca, Rushbrook, Simon, Thorburn, Douglas, Ryder, Steve, Hirschfield, Gideon, UK-PBC Research Consortium, Dyson, Jessica K, Jones, David EJ, Sandford, Richard [0000-0002-7437-0560], and Apollo - University of Cambridge Repository

Subjects
Male, Proteome, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, Epithelial Cells, Middle Aged, Case-Control Studies, Humans, Female, Treatment Failure, Chemokines, Biliary Tract, Biomarkers, Aged
Abstract

Funder: UK‐PBC MRC Stratified Medicine, Funder: Pfizer; Id: http://dx.doi.org/10.13039/100004319, BACKGROUND AND AIMS: Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in nonresponders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment. APPROACH AND RESULTS: Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA-treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C-X-C motif chemokine ligand 11 and C-C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83-0.91). CONCLUSIONS: UDCA under-response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies.

Published
2021

48. rs9459874 and rs1012656 in CCR6/FGFR1OP confer susceptibility to primary biliary cholangitis

Author

Hitomi, Yuki, primary, Aiba, Yoshihiro, additional, Ueno, Kazuko, additional, Nishida, Nao, additional, Kawai, Yosuke, additional, Kawashima, Minae, additional, Yasunami, Michio, additional, Gervais, Olivier, additional, Ito, Masahiro, additional, Cordell, Heather J., additional, Mells, George F., additional, Nagasaki, Masao, additional, Tokunaga, Katsushi, additional, Tsuiji, Makoto, additional, and Nakamura, Minoru, additional

Published
2022
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49. OWE-6 Multicentre evaluation of second line therapies in primary biliary cholangitis: UK experience

Author

Abbas, Nadir, primary, Culver, Emma, additional, Thorburn, Douglas, additional, Halliday, Neil, additional, Crothers, Hannah, additional, Dyson, Jessica K, additional, Phaw, April, additional, Aspinall, Richard, additional, Khakoo, Salim I, additional, Kallis, Yiannis, additional, Smith, Belinda, additional, Patanwala, Imran, additional, Mccune, Anne, additional, Hegade, Vinod, additional, Chimakurthi, Chenchu R, additional, Jones, Rebecca, additional, Orrell, Michael, additional, Mells, George, additional, Jones, David, additional, Hirschfield, Gideon, additional, and Trivedi, Palak J, additional

Published
2021
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50. The UK-PBC Risk Scores: Derivation and Validation of a Scoring System for Long-Term Prediction of End-Stage Liver Disease in Primary Biliary Cholangitis

Author

Carbone, Marco, Sharp, Stephen J., Flack, Steve, Paximadas, Dimitrios, Spiess, Kelly, Adgey, Carolyn, Griffiths, Laura, Lim, Reyna, Trembling, Paul, Williamson, Kate, Wareham, Nick J., Aldersley, Mark, Bathgate, Andrew, Burroughs, Andrew K., Heneghan, Michael A., Neuberger, James M., Thorburn, Douglas, Hirschfield, Gideon M., Cordell, Heather J., Alexander, Graeme J., Jones, David E.J., Sandford, Richard N., and Mells, George F.

Published
2016
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