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Monkeypox: a review of epidemiological modelling studies and how modelling has led to mechanistic insight
- Marina Banuet-Martinez, Yang Yang, Behnaz Jafari, Avneet Kaur, Zahid A. Butt, Helen H. Chen, Svetlana Yanushkevich, Iain R. Moyles, Jane M. Heffernan, Chapin S. Korosec
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- Journal:
- Epidemiology & Infection / Volume 151 / 2023
- Published online by Cambridge University Press:
- 23 May 2023, e121
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Human monkeypox (mpox) virus is a viral zoonosis that belongs to the Orthopoxvirus genus of the Poxviridae family, which presents with similar symptoms as those seen in human smallpox patients. Mpox is an increasing concern globally, with over 80,000 cases in non-endemic countries as of December 2022. In this review, we provide a brief history and ecology of mpox, its basic virology, and the key differences in mpox viral fitness traits before and after 2022. We summarize and critique current knowledge from epidemiological mathematical models, within-host models, and between-host transmission models using the One Health approach, where we distinguish between models that focus on immunity from vaccination, geography, climatic variables, as well as animal models. We report various epidemiological parameters, such as the reproduction number, R0, in a condensed format to facilitate comparison between studies. We focus on how mathematical modelling studies have led to novel mechanistic insight into mpox transmission and pathogenesis. As mpox is predicted to lead to further infection peaks in many historically non-endemic countries, mathematical modelling studies of mpox can provide rapid actionable insights into viral dynamics to guide public health measures and mitigation strategies.
Evidence of on-going transmission of Shiga toxin-producing Escherichia coli O157:H7 following a foodborne outbreak
- Saira Butt, Alison Smith-Palmer, Allan Shand, Eisin McDonald, Lesley Allison, Jane Maund, Anand Fernandes, Bhavita Vishram, David R. Greig, Claire Jenkins, Richard Elson
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- Journal:
- Epidemiology & Infection / Volume 149 / 2021
- Published online by Cambridge University Press:
- 07 June 2021, e147
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In August 2019, public health surveillance systems in Scotland and England identified seven, geographically dispersed cases infected with the same strain (defined as isolates that fell within the same five single nucleotide polymorphism single linage cluster) of Shiga toxin-producing Escherichia coli O157:H7. Epidemiological analysis of enhanced surveillance questionnaire data identified handling raw beef and shopping from the same national retailer (retailer A) as the common exposure. Concurrently, a microbiological survey of minced beef at retail identified the same strain in a sample of minced beef sold by retailer A, providing microbiological evidence of the link. Between September and November 2019, a further four primary and two secondary cases infected with the same strain were identified; two cases developed haemolytic uraemic syndrome. None of the four primary cases reported consumption of beef from retailer A and the transmission route of these subsequent cases was not identified, although all four primary cases visited the same petting farm. Generally, outbreaks of STEC O157:H7 in the UK appear to be distinct, short-lived events; however, on-going transmission linked to contaminated food, animals or environmental exposures and person-to-person contact do occur. Although outbreaks of STEC caused by contaminated fresh produce are increasingly common, undercooked meat products remain a risk of infection.
Impact of a brief worry-based cognitive therapy group in psychosis: a study of feasibility and acceptability
- Helen Courtney, Lucy White, Thomas Richardson, Ben Dasyam, Jo Tedbury, Jane Butt
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- Journal:
- The Cognitive Behaviour Therapist / Volume 12 / 2019
- Published online by Cambridge University Press:
- 29 April 2019, e29
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Previous research suggests that CBT focusing on worry in those with persecutory delusions reduces paranoia, severity of delusions and associated distress. This preliminary case series aimed to see whether it is feasible and acceptable to deliver worry-focused CBT in a group setting to those with psychosis. A secondary aim was to examine possible clinical changes. Two groups totalling 11 participants were run for seven sessions using the Worry Intervention Trial manual. Qualitative and quantitative data about the experience of being in the group was also collected via questionnaires, as was data on number of sessions attended. Measures were delivered pre- and post-group and at 3-month follow-up. These included a worry scale, a measure of delusional belief and associated distress and quality of life measures. Of the 11 participants who started the group, nine completed the group. Qualitative and quantitative feedback indicated that most of the participants found it acceptable and helpful, and that discussing these issues in a group setting was not only tolerable but often beneficial. Reliable Change Index indicated that 6/7 of the group members showed reliable reductions in their levels of worry post-group and 5/7 at follow-up. There were positive changes on other measures, which appeared to be more pronounced at follow-up. Delivering a worry intervention in a group format appears to be acceptable and feasible. Further research with a larger sample and control group is indicated to test the clinical effectiveness of this intervention.
Key learning aims(1) To understand the role of worry in psychosis.
(2) To learn about the possible feasibility of working on worry in a group setting.
(3) To be aware of potential clinical changes from the group.
(4) To consider acceptability for participants of working on worries in a group setting.
Habitual dietary fibre intake influences gut microbiota response to an inulin-type fructan prebiotic: a randomised, double-blind, placebo-controlled, cross-over, human intervention study
- Genelle Healey, Rinki Murphy, Christine Butts, Louise Brough, Kevin Whelan, Jane Coad
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- Journal:
- British Journal of Nutrition / Volume 119 / Issue 2 / 28 January 2018
- Published online by Cambridge University Press:
- 08 January 2018, pp. 176-189
- Print publication:
- 28 January 2018
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Dysbiotic gut microbiota have been implicated in human disease. Diet-based therapeutic strategies have been used to manipulate the gut microbiota towards a more favourable profile. However, it has been demonstrated that large inter-individual variability exists in gut microbiota response to a dietary intervention. The primary objective of this study was to investigate whether habitually low dietary fibre (LDF) v. high dietary fibre (HDF) intakes influence gut microbiota response to an inulin-type fructan prebiotic. In this randomised, double-blind, placebo-controlled, cross-over study, thirty-four healthy participants were classified as LDF or HDF consumers. Gut microbiota composition (16S rRNA bacterial gene sequencing) and SCFA concentrations were assessed following 3 weeks of daily prebiotic supplementation (Orafti® Synergy 1; 16 g/d) or placebo (Glucidex® 29 Premium; 16 g/d), as well as after 3 weeks of the alternative intervention, following a 3-week washout period. In the LDF group, the prebiotic intervention led to an increase in Bifidobacterium (P=0·001). In the HDF group, the prebiotic intervention led to an increase in Bifidobacterium (P<0·001) and Faecalibacterium (P=0·010) and decreases in Coprococcus (P=0·010), Dorea (P=0·043) and Ruminococcus (Lachnospiraceae family) (P=0·032). This study demonstrates that those with HDF intakes have a greater gut microbiota response and are therefore more likely to benefit from an inulin-type fructan prebiotic than those with LDF intakes. Future studies aiming to modulate the gut microbiota and improve host health, using an inulin-type fructan prebiotic, should take habitual dietary fibre intake into account.
Contributors
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- By Mitchell Aboulafia, Frederick Adams, Marilyn McCord Adams, Robert M. Adams, Laird Addis, James W. Allard, David Allison, William P. Alston, Karl Ameriks, C. Anthony Anderson, David Leech Anderson, Lanier Anderson, Roger Ariew, David Armstrong, Denis G. Arnold, E. J. Ashworth, Margaret Atherton, Robin Attfield, Bruce Aune, Edward Wilson Averill, Jody Azzouni, Kent Bach, Andrew Bailey, Lynne Rudder Baker, Thomas R. Baldwin, Jon Barwise, George Bealer, William Bechtel, Lawrence C. Becker, Mark A. Bedau, Ernst Behler, José A. Benardete, Ermanno Bencivenga, Jan Berg, Michael Bergmann, Robert L. Bernasconi, Sven Bernecker, Bernard Berofsky, Rod Bertolet, Charles J. Beyer, Christian Beyer, Joseph Bien, Joseph Bien, Peg Birmingham, Ivan Boh, James Bohman, Daniel Bonevac, Laurence BonJour, William J. Bouwsma, Raymond D. Bradley, Myles Brand, Richard B. Brandt, Michael E. Bratman, Stephen E. Braude, Daniel Breazeale, Angela Breitenbach, Jason Bridges, David O. Brink, Gordon G. Brittan, Justin Broackes, Dan W. Brock, Aaron Bronfman, Jeffrey E. Brower, Bartosz Brozek, Anthony Brueckner, Jeffrey Bub, Lara Buchak, Otavio Bueno, Ann E. Bumpus, Robert W. Burch, John Burgess, Arthur W. Burks, Panayot Butchvarov, Robert E. Butts, Marina Bykova, Patrick Byrne, David Carr, Noël Carroll, Edward S. Casey, Victor Caston, Victor Caston, Albert Casullo, Robert L. Causey, Alan K. L. Chan, Ruth Chang, Deen K. Chatterjee, Andrew Chignell, Roderick M. Chisholm, Kelly J. Clark, E. J. Coffman, Robin Collins, Brian P. Copenhaver, John Corcoran, John Cottingham, Roger Crisp, Frederick J. Crosson, Antonio S. Cua, Phillip D. Cummins, Martin Curd, Adam Cureton, Andrew Cutrofello, Stephen Darwall, Paul Sheldon Davies, Wayne A. Davis, Timothy Joseph Day, Claudio de Almeida, Mario De Caro, Mario De Caro, John Deigh, C. F. Delaney, Daniel C. Dennett, Michael R. DePaul, Michael Detlefsen, Daniel Trent Devereux, Philip E. Devine, John M. Dillon, Martin C. Dillon, Robert DiSalle, Mary Domski, Alan Donagan, Paul Draper, Fred Dretske, Mircea Dumitru, Wilhelm Dupré, Gerald Dworkin, John Earman, Ellery Eells, Catherine Z. Elgin, Berent Enç, Ronald P. Endicott, Edward Erwin, John Etchemendy, C. Stephen Evans, Susan L. Feagin, Solomon Feferman, Richard Feldman, Arthur Fine, Maurice A. Finocchiaro, William FitzPatrick, Richard E. Flathman, Gvozden Flego, Richard Foley, Graeme Forbes, Rainer Forst, Malcolm R. Forster, Daniel Fouke, Patrick Francken, Samuel Freeman, Elizabeth Fricker, Miranda Fricker, Michael Friedman, Michael Fuerstein, Richard A. Fumerton, Alan Gabbey, Pieranna Garavaso, Daniel Garber, Jorge L. A. Garcia, Robert K. Garcia, Don Garrett, Philip Gasper, Gerald Gaus, Berys Gaut, Bernard Gert, Roger F. Gibson, Cody Gilmore, Carl Ginet, Alan H. Goldman, Alvin I. Goldman, Alfonso Gömez-Lobo, Lenn E. Goodman, Robert M. Gordon, Stefan Gosepath, Jorge J. E. Gracia, Daniel W. Graham, George A. Graham, Peter J. Graham, Richard E. Grandy, I. Grattan-Guinness, John Greco, Philip T. Grier, Nicholas Griffin, Nicholas Griffin, David A. Griffiths, Paul J. Griffiths, Stephen R. Grimm, Charles L. Griswold, Charles B. Guignon, Pete A. Y. Gunter, Dimitri Gutas, Gary Gutting, Paul Guyer, Kwame Gyekye, Oscar A. Haac, Raul Hakli, Raul Hakli, Michael Hallett, Edward C. Halper, Jean Hampton, R. James Hankinson, K. R. Hanley, Russell Hardin, Robert M. Harnish, William Harper, David Harrah, Kevin Hart, Ali Hasan, William Hasker, John Haugeland, Roger Hausheer, William Heald, Peter Heath, Richard Heck, John F. Heil, Vincent F. Hendricks, Stephen Hetherington, Francis Heylighen, Kathleen Marie Higgins, Risto Hilpinen, Harold T. Hodes, Joshua Hoffman, Alan Holland, Robert L. Holmes, Richard Holton, Brad W. Hooker, Terence E. Horgan, Tamara Horowitz, Paul Horwich, Vittorio Hösle, Paul Hoβfeld, Daniel Howard-Snyder, Frances Howard-Snyder, Anne Hudson, Deal W. Hudson, Carl A. Huffman, David L. Hull, Patricia Huntington, Thomas Hurka, Paul Hurley, Rosalind Hursthouse, Guillermo Hurtado, Ronald E. Hustwit, Sarah Hutton, Jonathan Jenkins Ichikawa, Harry A. Ide, David Ingram, Philip J. Ivanhoe, Alfred L. Ivry, Frank Jackson, Dale Jacquette, Joseph Jedwab, Richard Jeffrey, David Alan Johnson, Edward Johnson, Mark D. Jordan, Richard Joyce, Hwa Yol Jung, Robert Hillary Kane, Tomis Kapitan, Jacquelyn Ann K. Kegley, James A. Keller, Ralph Kennedy, Sergei Khoruzhii, Jaegwon Kim, Yersu Kim, Nathan L. King, Patricia Kitcher, Peter D. Klein, E. D. Klemke, Virginia Klenk, George L. Kline, Christian Klotz, Simo Knuuttila, Joseph J. Kockelmans, Konstantin Kolenda, Sebastian Tomasz Kołodziejczyk, Isaac Kramnick, Richard Kraut, Fred Kroon, Manfred Kuehn, Steven T. Kuhn, Henry E. Kyburg, John Lachs, Jennifer Lackey, Stephen E. Lahey, Andrea Lavazza, Thomas H. Leahey, Joo Heung Lee, Keith Lehrer, Dorothy Leland, Noah M. Lemos, Ernest LePore, Sarah-Jane Leslie, Isaac Levi, Andrew Levine, Alan E. Lewis, Daniel E. Little, Shu-hsien Liu, Shu-hsien Liu, Alan K. L. Chan, Brian Loar, Lawrence B. Lombard, John Longeway, Dominic McIver Lopes, Michael J. Loux, E. J. Lowe, Steven Luper, Eugene C. Luschei, William G. Lycan, David Lyons, David Macarthur, Danielle Macbeth, Scott MacDonald, Jacob L. Mackey, Louis H. Mackey, Penelope Mackie, Edward H. Madden, Penelope Maddy, G. B. Madison, Bernd Magnus, Pekka Mäkelä, Rudolf A. Makkreel, David Manley, William E. Mann (W.E.M.), Vladimir Marchenkov, Peter Markie, Jean-Pierre Marquis, Ausonio Marras, Mike W. Martin, A. P. Martinich, William L. McBride, David McCabe, Storrs McCall, Hugh J. McCann, Robert N. McCauley, John J. McDermott, Sarah McGrath, Ralph McInerny, Daniel J. McKaughan, Thomas McKay, Michael McKinsey, Brian P. McLaughlin, Ernan McMullin, Anthonie Meijers, Jack W. Meiland, William Jason Melanson, Alfred R. Mele, Joseph R. Mendola, Christopher Menzel, Michael J. Meyer, Christian B. Miller, David W. Miller, Peter Millican, Robert N. Minor, Phillip Mitsis, James A. Montmarquet, Michael S. Moore, Tim Moore, Benjamin Morison, Donald R. Morrison, Stephen J. Morse, Paul K. Moser, Alexander P. D. Mourelatos, Ian Mueller, James Bernard Murphy, Mark C. Murphy, Steven Nadler, Jan Narveson, Alan Nelson, Jerome Neu, Samuel Newlands, Kai Nielsen, Ilkka Niiniluoto, Carlos G. Noreña, Calvin G. Normore, David Fate Norton, Nikolaj Nottelmann, Donald Nute, David S. Oderberg, Steve Odin, Michael O’Rourke, Willard G. Oxtoby, Heinz Paetzold, George S. Pappas, Anthony J. Parel, Lydia Patton, R. P. Peerenboom, Francis Jeffry Pelletier, Adriaan T. Peperzak, Derk Pereboom, Jaroslav Peregrin, Glen Pettigrove, Philip Pettit, Edmund L. Pincoffs, Andrew Pinsent, Robert B. Pippin, Alvin Plantinga, Louis P. Pojman, Richard H. Popkin, John F. Post, Carl J. Posy, William J. Prior, Richard Purtill, Michael Quante, Philip L. Quinn, Philip L. Quinn, Elizabeth S. Radcliffe, Diana Raffman, Gerard Raulet, Stephen L. Read, Andrews Reath, Andrew Reisner, Nicholas Rescher, Henry S. Richardson, Robert C. Richardson, Thomas Ricketts, Wayne D. Riggs, Mark Roberts, Robert C. Roberts, Luke Robinson, Alexander Rosenberg, Gary Rosenkranz, Bernice Glatzer Rosenthal, Adina L. Roskies, William L. Rowe, T. M. Rudavsky, Michael Ruse, Bruce Russell, Lilly-Marlene Russow, Dan Ryder, R. M. Sainsbury, Joseph Salerno, Nathan Salmon, Wesley C. Salmon, Constantine Sandis, David H. Sanford, Marco Santambrogio, David Sapire, Ruth A. Saunders, Geoffrey Sayre-McCord, Charles Sayward, James P. Scanlan, Richard Schacht, Tamar Schapiro, Frederick F. Schmitt, Jerome B. Schneewind, Calvin O. Schrag, Alan D. Schrift, George F. Schumm, Jean-Loup Seban, David N. Sedley, Kenneth Seeskin, Krister Segerberg, Charlene Haddock Seigfried, Dennis M. Senchuk, James F. Sennett, William Lad Sessions, Stewart Shapiro, Tommie Shelby, Donald W. Sherburne, Christopher Shields, Roger A. Shiner, Sydney Shoemaker, Robert K. Shope, Kwong-loi Shun, Wilfried Sieg, A. John Simmons, Robert L. Simon, Marcus G. Singer, Georgette Sinkler, Walter Sinnott-Armstrong, Matti T. Sintonen, Lawrence Sklar, Brian Skyrms, Robert C. Sleigh, Michael Anthony Slote, Hans Sluga, Barry Smith, Michael Smith, Robin Smith, Robert Sokolowski, Robert C. Solomon, Marta Soniewicka, Philip Soper, Ernest Sosa, Nicholas Southwood, Paul Vincent Spade, T. L. S. Sprigge, Eric O. Springsted, George J. Stack, Rebecca Stangl, Jason Stanley, Florian Steinberger, Sören Stenlund, Christopher Stephens, James P. Sterba, Josef Stern, Matthias Steup, M. A. Stewart, Leopold Stubenberg, Edith Dudley Sulla, Frederick Suppe, Jere Paul Surber, David George Sussman, Sigrún Svavarsdóttir, Zeno G. Swijtink, Richard Swinburne, Charles C. Taliaferro, Robert B. Talisse, John Tasioulas, Paul Teller, Larry S. Temkin, Mark Textor, H. S. Thayer, Peter Thielke, Alan Thomas, Amie L. Thomasson, Katherine Thomson-Jones, Joshua C. Thurow, Vzalerie Tiberius, Terrence N. Tice, Paul Tidman, Mark C. Timmons, William Tolhurst, James E. Tomberlin, Rosemarie Tong, Lawrence Torcello, Kelly Trogdon, J. D. Trout, Robert E. Tully, Raimo Tuomela, John Turri, Martin M. Tweedale, Thomas Uebel, Jennifer Uleman, James Van Cleve, Harry van der Linden, Peter van Inwagen, Bryan W. Van Norden, René van Woudenberg, Donald Phillip Verene, Samantha Vice, Thomas Vinci, Donald Wayne Viney, Barbara Von Eckardt, Peter B. M. Vranas, Steven J. Wagner, William J. Wainwright, Paul E. Walker, Robert E. Wall, Craig Walton, Douglas Walton, Eric Watkins, Richard A. Watson, Michael V. Wedin, Rudolph H. Weingartner, Paul Weirich, Paul J. Weithman, Carl Wellman, Howard Wettstein, Samuel C. Wheeler, Stephen A. White, Jennifer Whiting, Edward R. Wierenga, Michael Williams, Fred Wilson, W. Kent Wilson, Kenneth P. Winkler, John F. Wippel, Jan Woleński, Allan B. Wolter, Nicholas P. Wolterstorff, Rega Wood, W. Jay Wood, Paul Woodruff, Alison Wylie, Gideon Yaffe, Takashi Yagisawa, Yutaka Yamamoto, Keith E. Yandell, Xiaomei Yang, Dean Zimmerman, Günter Zoller, Catherine Zuckert, Michael Zuckert, Jack A. Zupko (J.A.Z.)
- Edited by Robert Audi, University of Notre Dame, Indiana
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- Book:
- The Cambridge Dictionary of Philosophy
- Published online:
- 05 August 2015
- Print publication:
- 27 April 2015, pp ix-xxx
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- By Elissa Asp, Carl Bache, Tom Bartlett, Margaret Berry, Wendy L. Bowcher, David G. Butt, Víctor M. Castel, Robin P. Fawcett, Lise Fontaine, Maria Freddi, José María Gil, M.A.K. Halliday, Ruqaiya Hasan, Jane H. Johnson, Astika Kappagoda, Sydney Lamb, Ana Elina Martínez-Insua, Donna R. Miller, Alison Moore, Michael O’Donnell, Pedro Henrique Lima Praxedes Filho, Elke Teich, Geoff Thompson, Kathryn Tuckwell, Claire Urbach
- Edited by Lise Fontaine, Cardiff University, Tom Bartlett, Cardiff University, Gerard O'Grady, Cardiff University
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- Book:
- Systemic Functional Linguistics
- Published online:
- 18 December 2013
- Print publication:
- 19 December 2013, pp xvii-xviii
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Respiratory syncytial virus prophylaxis in children with cardiac disease: a retrospective single-centre study
- Michelle Butt, Amanda Symington, Marianne Janes, Susan Steele, LouAnn Elliott, Catherine Chant-Gambacort, Tapas Mondal, Bosco Paes
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- Journal:
- Cardiology in the Young / Volume 24 / Issue 2 / April 2014
- Published online by Cambridge University Press:
- 29 April 2013, pp. 337-343
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Objectives
To examine the characteristics of congenital heart disease patients hospitalised with respiratory syncytial virus infection after prophylaxis and determine the associated comorbidities and the incidence of breakthrough respiratory syncytial virus infections.
Study designThis is a retrospective, single-centre study that was conducted over a period of 7 years. Respiratory syncytial virus infection was identified by classification codes and confirmed by virological tests. Data on baseline demographics, cardiac anomalies, other underlying disease, criteria for hospitalisation, type of respiratory illness and management, complications, and palivizumab prophylaxis were analysed by standard descriptive methods and comparative statistics.
ResultsA total of 30 patients were enrolled. The majority were ≤2 years (n = 24). The mean admission age was 15.1 months (standard deviation = 18.3). In all, 90% were acyanotic, 40% had haemodynamically significant disease, and 60% had ≥1 underlying medical illness. Patients were admitted with: respiratory distress (86.7%), hypoxaemia (66.7%), fever (60%), inability to maintain oral intake (36.7%), and apnoea (16.7%). More than 50% required mechanical ventilation and intensive care with a median stay of 11 days (range: 1–43); the length of hospital stay for all children was 10 days (range: 1–65). Complications included: concurrent bacterial sepsis (20%), electrolyte abnormalities (16.7%), and worsening pulmonary hypertension (13.3%). Of 10 infants ≤2 years with haemodynamically significant heart disease, four had received prophylaxis. There was one death, which was attributed to respiratory syncytial virus infection.
ConclusionsOverall, 185 infants ≤2 years with haemodynamically significant cardiac disease received prophylaxis. In all, six qualifying infants missed immunisation and were hospitalised. Breakthrough respiratory syncytial virus infections occurred in 2.2%, demonstrating good efficacy of palivizumab in this population compared with the original, multi-centre, randomised trial.
Contributors
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- By Pina Amin, Sir Sabaratnam Arulkumaran, Sarah L. Bell, M. J. Blott, Hajeera Butt, Edwin Chandraharan, Joanna Crofts, Mark Denbow, Mandish K. Dhanjal, Stergios K. Doumouchtsis, Timothy J. Draycott, Rohan D'Souza, David Fraser, Guy Jackson, Nina Johns, Tracey Johnston, Justin C. Konje, Audrey Long, Louay S. Louis, Paul A. Mannix, Mahishee Mehta, Nutan Mishra, Sambit Mukhopadhyay, Deirdre J. Murphy, Vivek Nama, Osric Navti, Catherine Nelson-Piercy, Jane E. Norman, Geraldine O'Sullivan, Sara Paterson-Brown, Leonie Penna, Neelam Potdar, Helen Scholefield, Jason Scott, Dimitrios M. Siassakos, Gordon C. S. Smith, Lisa Story, Bryony Strachan, Devi Subramanian, Abdul H. Sultan, Ranee Thakar, Austin Ugwumadu, Rajesh Varma, James J. Walker, Steve Walkinshaw, Richard Warren, Melissa Whitten, Melissa K. Whitworth, Julian Woolfson, Steve Yentis
- Edited by Richard Warren, Sabaratnam Arulkumaran
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- Book:
- Best Practice in Labour and Delivery
- Published online:
- 15 March 2010
- Print publication:
- 17 September 2009, pp vii-x
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