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1. Outcomes of heliox use in children with respiratory compromise: A 10‐year single institution experience

Author

Ashley Young, Eli Stein, Matthew Rowland, Taher Valika, Saied Ghadersohi, and Inbal Hazkani

Subjects
definitive airway surgery, heliox, helium, respiratory compromise, stridor, upper airway obstruction, Otorhinolaryngology, RF1-547, Surgery, RD1-811
Abstract

Abstract Objective Heliox, a mixture of helium and oxygen, has been shown to improve laminar airflow and decrease airway resistance in children. This study aims to describe the outcomes of heliox use in children with respiratory compromise and to identify variables associated with a need for airway surgical intervention. Methods A retrospective cohort study of patients who received heliox between 2012 and 2022 at a tertiary care children's hospital. Results A hundred and thirty‐eight heliox treatments were recorded in 119 children. Twelve patients were excluded. Most (n = 100, 84%) patients had significant comorbidities. On average, patients spent a cumulative mean of 94 ± 187 h on heliox therapy per hospital admission. Patients with croup or asthma without known airway pathology presented at an older age than patients with other indications for heliox therapy (4.0 ± 4.7 vs. 2.2 ± 3.6 years, p = 0.04) and were significantly less likely to have background diseases (n = 14, 52% vs. n = 74, 93%, p

Published
2024
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2. Monitoring Saltmarsh Restoration in the Upper Bay of Fundy Using Multi-Temporal Sentinel-2 Imagery and Random Forests Classifier

Author

Swarna M. Naojee, Armand LaRocque, Brigitte Leblon, Gregory S. Norris, Myriam A. Barbeau, and Matthew Rowland

Subjects
saltmarsh vegetation recovery, remote sensing, Sentinel-2, supervised image classification, random forests, Science
Abstract

Saltmarshes provide important ecosystem services, including coastline protection, but face decline due to human activities and climate change. There are increasing efforts to conserve and restore saltmarshes worldwide. Our study evaluated the effectiveness of Sentinel-2 satellite imagery to monitor landcover changes using a saltmarsh restoration project undergoing its 9th to 12th year of recovery in the megatidal Bay of Fundy in Maritime Canada. Specifically, in 2019–2022, five satellite images per growing season were acquired. Random Forests classification for 13 landcover classes (ranging from bare mud to various plant communities) achieved a high overall classification accuracy, peaking at 96.43% in 2021. Field validation points confirmed this, with high validation accuracies reaching 93.02%. The classification results successfully distinguished ecologically significant classes, such as Spartina alterniflora–S. patens mix. Our results reveal the appearance of high marsh species in restoration sites and elevational-based zonation patterns, indicating progression. They demonstrate the potential of Sentinel-2 imagery for monitoring saltmarsh restoration projects in north temperate latitudes, aiding management efforts.

Published
2024
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3. Editorial: Outcomes in subarachnoid hemorrhage

Author

Sarah E. Nelson, Isabel Fragata, Matthew Rowland, and Airton Leonardo de Oliveira Manoel

Subjects
subarachnoid hemorrhage, outcomes, research, prognostication, biomarker, Neurology. Diseases of the nervous system, RC346-429
Published
2023
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4. Musculoskeletal health state and physical function of intensive care unit survivors: protocol for a UK multicentre prospective cohort study (the MSK-ICU study)

Author

Mark A Williams, Owen Gustafson, Michael Schlüssel, Helen Dawes, Matthew Rowland, and Elizabeth King

Subjects
Medicine
Abstract

Introduction Survivors of critical illness frequently experience long-term physical impairment, decreased health-related quality of life and low rates of return to employment. There has been limited investigation of the underlying problems affecting physical function post-intensive care unit (ICU) admission. Musculoskeletal (MSK) conditions may be complex in presentation, with ICU survivors potentially at greater risk of their development due to the rapid muscle mass loss seen in ICU. The MSK health state of ICU survivors and its impact on physical function remain largely unknown. The aim of the MSK-ICU study is to determine and characterise the MSK health state of ICU survivors 6 months following admission to ICU, in order to inform development of targeted rehabilitation interventions.Methods and analysis The MSK-ICU study is a multicentre prospective longitudinal cohort study, evaluating the MSK health state of ICU survivors 6 months after admission to ICU. The study consists of a primary study and two substudies. The primary study will be a telephone follow-up of adults admitted to ICU for more than 48 hours, collecting data on MSK health state, quality of life, employment, anxiety and depression and symptoms of post-traumatic stress disorder. The planned sample size is 334 participants. Multivariable regression will be used to identify prognostic factors for a worse MSK health state, as measured by the MSK-Health Questionnaire. In substudy 1, participants who self-report any MSK problem will undergo a detailed, in-person MSK physical assessment of pain, peripheral joint range of movement and strength. In substudy 2, participants reporting a severe MSK problem will undergo a detailed physical assessment of mobility, function and muscle architecture.Ethics and dissemination Ethical approval has been obtained through the North of Scotland Research Ethics Committee 2 (21/NS/0143). We aim to disseminate the findings through international conferences, international peer-reviewed journals and social media.Trial registration number ISRCTN24998809.

Published
2023
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5. CATALYST trial protocol: a multicentre, open-label, phase II, multiarm trial for an early and accelerated evaluation of the potential treatments for COVID-19 in hospitalised adults

Author

Dhruv Parekh, Simon Gates, Julian Bion, Tonny Veenith, Matthew Rowland, Tony Whitehouse, Anna Rowe, Pamela Kearns, Benjamin A. Fisher, Daniel Slade, Rowena Sharpe, David R. Thickett, James Scriven, Sarah J. Bowden, Joshua S. Savage, and Duncan Richards

Subjects
Medicine
Abstract

Introduction Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs.Methods and analysis The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment.Ethics and dissemination The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.Trial registration numbers EudraCT2020-001684-89, ISRCTN40580903.

Published
2021
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6. Adapting the UK Biobank Brain Imaging Protocol and Analysis Pipeline for the C-MORE Multi-Organ Study of COVID-19 Survivors

Author

Ludovica Griffanti, Betty Raman, Fidel Alfaro-Almagro, Nicola Filippini, Mark Philip Cassar, Fintan Sheerin, Thomas W. Okell, Flora A. Kennedy McConnell, Michael A. Chappell, Chaoyue Wang, Christoph Arthofer, Frederik J. Lange, Jesper Andersson, Clare E. Mackay, Elizabeth M. Tunnicliffe, Matthew Rowland, Stefan Neubauer, Karla L. Miller, Peter Jezzard, and Stephen M. Smith

Subjects
UK Biobank (UKB), brain magnetic resonance imaging (MRI), COVID-19, SARS-CoV-2, multi-organ MRI, Neurology. Diseases of the nervous system, RC346-429
Abstract

SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the possible effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study. The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 min. The automated imaging pipeline derives 1,575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, IDPs related to atrophy, small vessel disease and olfactory bulbs were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed some group differences between recovered COVID-19 patients and controls, across severity groups, but not across anosmia groups. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in other large-scale studies. The protocol, pipeline code and data are openly available and will further contribute to the understanding of the medium to long-term effects of COVID-19.

Published
2021
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7. Protocol for a prospective, controlled, cross-sectional, diagnostic accuracy study to evaluate the specificity and sensitivity of ambulatory monitoring systems in the prompt detection of hypoxia and during movement

Author

Sarah Vollam, Owen Gustafson, Jody Ede, Peter J Watkinson, Akshay Shah, Matthew Rowland, Lionel Tarassenko, Cristian Roman, Philippa Piper, Louise Young, Mauro Santos, Marco A F Pimentel, and Mirae Harford

Subjects
Medicine
Abstract

Introduction Automated continuous ambulatory monitoring may provide an alternative to intermittent manual vital signs monitoring. This has the potential to improve frequency of measurements, timely escalation of care and patient safety. However, a major barrier to the implementation of these wearable devices in the ward environment is their uncertain reliability, efficiency and data fidelity. The purpose of this study is to test performance of selected devices in a simulated clinical setting including during movement and low levels of peripheral oxygen saturation.Methods and analysis This is a single centre, prospective, controlled, cross-sectional, diagnostic accuracy study to determine the specificity and sensitivity of currently available ambulatory vital signs monitoring equipment in the detection of hypoxia and the effect of movement on data acquisition. We will recruit up to 45 healthy volunteers who will attend a single study visit; starting with a movement phase and followed by the hypoxia exposure phase where we will gradually decrease saturation levels down to 80%. We will simultaneously test one chest patch, one wrist worn only and three wrist worn with finger probe devices against ‘clinical standard ‘and ‘gold standard’ references. We will measure peripheral oxygen saturations, pulse rate, heart rate and respiratory rate continuously and arterial blood gases intermittently throughout the study.Ethics and dissemination This study has received ethical approval by the East of Scotland Research Ethics Service REC 2 (19/ES/0008). The results will be broadly distributed through conference presentations and peer-reviewed publications.Trial registration number ISRCTN61535692 registered on 10/06/2019.

Published
2020
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8. Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: a study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study)

Author

Dhruv Parekh, David Thickett, Gemma Slinn, Peter Brocklehurst, Danny Mcauley, Maria Wittmann, Teresa Melody, Jaimin Patel, Gavin Perkins, Markus Kredel, Peter Kranke, Christian Stoppe, Lars Hummitzsch, Norbert Weiler, Karin Amrein, Sabine Westphal, Jean-Charles Preiser, Andrea Berghold, Regina Riedl, Philipp Eller, Peter Schellongowski, Patrick Meybohm, Corinna Marschalek, Rene Schmutz, Martin Clodi, Michael Resl, Mario Krasser, Matthias Michlmayr, Johann Reisinger, Alexandra Schiller, Nicolas Dominik Verheyen, Dirk von Lewinski, Marlene Sandra Deininger, Andreas Muench, Holger Simonis, Paul Zajic, Ines Lindenau, Alexander Holl, Alexander Pichler, Tadeja Urbanic Purkart, Katharina Ritsch, Simon Schmidt, Romuald Bellmann, Anna Brandtner, Adelheid Ditlbacher, Julia Hasslacher, Michael Joannidis, Andreas Peer, Klemens Zotter, Christoph Martin Biedermann, Andreas Valentin, Franz Wimmer, Susanne Demschar, Markus Koestenberger, Rudolf Likar, Stefan Neuwersch, Michael Pogatschnigg, Brigitte Trummer, Martin Duenser, Jens Meier, Johann Kainz, Romana Sommer, Otmar Schindler, Alexander Lehr, Guenter Mesaric, Yasmin Tinawi, Norbert Watzinger, Randolf Hammerl, Peter Krippl, Stefan Langner, Martin Lux, Matthias Unteregger, Gerwig Fruehauf, Barbara Gruber, Bertram Harzl, Viktor Wutzl, Juergen Berghofer, Nadine Fuch, Gilbert Hainzl, Isolde Pessentheiner, Michael Zink, Petra Hoernler, Ernst Trampitsch, Jakob Muehlbacher, Philipp Riss, Roman Ullrich, Martin Bernardi, Michael Hiesmayr, Katharina Kovac, Cecilia Veraar, Bernhard Zapletal, Elisabeth Lobmeyr, Esther Tiller, Georg Hinterholzer, Daniel Mydza, Sabine Schmaldienst, Maxime van Cutsem, Marianne Blockmans, Alain D’hondt, Vincent Fraipont, Sophie Jacquet, Caroline Abbenhuijs, Katarina Helenarova, Romain Courcelle, Dominique Durand, Amedee Ego, Amina Khaldi, Itesa Nancy Matumikina, Kai Zacharowski, Simone Lindau, Philipp Helmer, Gunnar Elke, Guenther Zick, Tobias Becher, Dirk Schaedler, Matthias Kott, Barbara Vogt, Ingmar Lautenschlaeger, Georg Fuernau, Christian Putensen, Stefan Ehrentraut, Barbara Kapfer, Thomas Felbinger, Ines Kaufmann, Bjoern Andrew Rempiss, Claudia Spiess, Stefan Schaller, Tobias Schlesinger, Magdalena Sitter, Jan Stumpner, Nico Schlegel, Christoph Schimmer, Ekkehard Kunze, Thomas Kerz, Dominik Wesp, Axel Neule, Florian Ringel, Mario Maggiorini, Stephan Jakob, Joerg Schefold, Rebekah Wale, Marlies Ostermann, Matthew Morgan, Mervyn Singer, and Matthew Rowland

Subjects
Medicine
Abstract

Introduction Observational studies have demonstrated an association between vitamin D deficiency and increased risk of morbidity and mortality in critically ill patients. Cohort studies and pilot trials have suggested promising beneficial effects of vitamin D replacement in the critical ill, at least in patients with severe vitamin D deficiency. As vitamin D is a simple, low-cost and safe intervention, it has potential to improve survival in critically ill patients.Methods and analysis In this randomised, placebo-controlled, double-blind, multicentre, international trial, 2400 adult patients with severe vitamin D deficiency (25-hydroxyvitamin D≤12 ng/mL) will be randomised in a 1:1 ratio by www.randomizer.at to receive a loading dose of 540 000 IU cholecalciferol within 72 hours after intensive care unit (ICU) admission, followed by 4000 IU daily for 90 days or placebo. Hypercalcaemia may occur as a side effect, but is monitored by regular checks of the calcium level. The primary outcome is all-cause mortality at 28 days after randomisation. Secondary outcomes are: ICU, hospital, 90-day and 1-year mortality; hospital and ICU length of stay, change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment (SOFA) score, number of organ failures; hospital and ICU readmission until day 90; discharge destination, self-reported infections requiring antibiotics until day 90 and health-related quality of life. Recruitment status is ongoing.Ethics and dissemination National ethical approval was obtained by the Ethics Committee of the University of Graz for Austria, Erasme University Brussels (Belgium) and University Hospital Frankfurt (Germany), and will further be gained according to individual national processes. On completion, results will be published in a peer-reviewed scientific journal. The study findings will be presented at national and international meetings with abstracts online.Trial registration NCT03188796, EudraCT-No: 2016-002460-13.

Published
2019
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10. Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19

Author

Christos P Kotanidis, Cheng Xie, Donna Alexander, Jonathan C L Rodrigues, Katie Burnham, Alexander Mentzer, Daniel O’Connor, Julian Knight, Muhammad Siddique, Helen Lockstone, Sheena Thomas, Rafail Kotronias, Evangelos K Oikonomou, Ileana Badi, Maria Lyasheva, Cheerag Shirodaria, Sheila F Lumley, Bede Constantinides, Nicholas Sanderson, Gillian Rodger, Kevin K Chau, Archie Lodge, Maria Tsakok, Fergus Gleeson, David Adlam, Praveen Rao, Das Indrajeet, Aparna Deshpande, Amrita Bajaj, Benjamin J Hudson, Vivek Srivastava, Shakil Farid, George Krasopoulos, Rana Sayeed, Ling-Pei Ho, Stefan Neubauer, David E Newby, Keith M Channon, John Deanfield, Charalambos Antoniades, David J Ahern, Zhichao Ai, Mark Ainsworth, Chris Allan, Alice Allcock, Brian Angus, M Azim Ansari, Carolina Arancibia-Cárcamo, Dominik Aschenbrenner, Moustafa Attar, J Kenneth Baillie, Eleanor Barnes, Rachael Bashford-Rogers, Archana Bashyal, Sally Beer, Georgina Berridge, Amy Beveridge, Sagida Bibi, Tihana Bicanic, Luke Blackwell, Paul Bowness, Andrew Brent, Andrew Brown, John Broxholme, David Buck, Helen Byrne, Susana Camara, Ivan Candido Ferreira, Philip Charles, Wentao Chen, Yi-Ling Chen, Amanda Chong, Elizabeth Clutterbuck, Mark Coles, Christopher Conlon, Richard Cornall, Adam Cribbs, Fabiola Curion, Emma Davenport, Neil Davidson, Simon Davis, Calliope Dendrou, Julie Dequaire, Lea Dib, James Docker, Christina Dold, Tao Dong, Damien Downes, Hal Drakesmith, Susanna Dunachie, David Duncan, Chris Eijsbouts, Robert Esnouf, Alexis Espinosa, Rachel Etherington, Benjamin Fairfax, Rory Fairhead, Hai Fang, Shayan Fassih, Sally Felle, Maria Fernandez Mendoza, Ricardo Ferreira, Roman Fischer, Thomas Foord, Aden Forrow, John Frater, Anastasia Fries, Veronica Gallardo Sanchez, Lucy Garner, Clementine Geeves, Dominique Georgiou, Leila Godfrey, Tanya Golubchik, Maria Gomez Vazquez, Angie Green, Hong Harper, Heather Harrington, Raphael Heilig, Svenja Hester, Jennifer Hill, Charles Hinds, Clare Hird, Renee Hoekzema, Benjamin Hollis, Jim Hughes, Paula Hutton, Matthew Jackson-Wood, Ashwin Jainarayanan, Anna James-Bott, Kathrin Jansen, Katie Jeffery, Elizabeth Jones, Luke Jostins, Georgina Kerr, David Kim, Paul Klenerman, Vinod Kumar, Piyush Kumar Sharma, Prathiba Kurupati, Andrew Kwok, Angela Lee, Aline Linder, Teresa Lockett, Lorne Lonie, Maria Lopopolo, Martyna Lukoseviciute, Jian Luo, Spyridoula Marinou, Brian Marsden, Jose Martinez, Philippa Matthews, Michalina Mazurczyk, Simon McGowan, Stuart McKechnie, Adam Mead, Yuxin Mi, Claudia Monaco, Ruddy Montadon, Giorgio Napolitani, Isar Nassiri, Alex Novak, Darragh O'Brien, Daniel O'Connor, Denise O'Donnell, Graham Ogg, Lauren Overend, Inhye Park, Ian Pavord, Yanchun Peng, Frank Penkava, Mariana Pereira Pinho, Elena Perez, Andrew Pollard, Fiona Powrie, Bethan Psaila, T Phuong Quan, Emmanouela Repapi, Santiago Revale, Laura Silva-Reyes, Jean-Baptiste Richard, Charlotte Rich-Griffin, Thomas Ritter, Christine Rollier, Matthew Rowland, Fabian Ruehle, Mariolina Salio, Stephen Nicholas Sansom, Raphael Sanches Peres, Alberto Santos Delgado, Tatjana Sauka-Spengler, Ron Schwessinger, Giuseppe Scozzafava, Gavin Screaton, Anna Seigal, Malcolm Semple, Martin Sergeant, Christina Simoglou Karali, David Sims, Donal Skelly, Hubert Slawinski, Alberto Sobrinodiaz, Nikolaos Sousos, Lizzie Stafford, Lisa Stockdale, Marie Strickland, Otto Sumray, Bo Sun, Chelsea Taylor, Stephen Taylor, Adan Taylor, Supat Thongjuea, Hannah Thraves, John Todd, Adriana Tomic, Orion Tong, Amy Trebes, Dominik Trzupek, Felicia Anna Tucci, Lance Turtle, Irina Udalova, Holm Uhlig, Erinke van Grinsven, Iolanda Vendrell, Marije Verheul, Alexandru Voda, Guanlin Wang, Lihui Wang, Dapeng Wang, Peter Watkinson, Robert Watson, Michael Weinberger, Justin Whalley, Lorna Witty, Katherine Wray, Luzheng Xue, Hing Yuen Yeung, Zixi Yin, Rebecca Young, Jonathan Youngs, Ping Zhang, Yasemin-Xiomara Zurke, Adrian Banning, Alexios Antonopoulos, Andrew Kelion, Attila Kardos, Benjamin Hudson, Bon-Kwon Koo, Christos Kotanidis, Ciara Mahon, Colin Berry, David Newby, Derek Connolly, Diane Scaletta, Ed Nicol, Elisa McAlindon, Evangelos Oikonomou, Francesca Pugliese, Gianluca Pontone, Giulia Benedetti, Guo-Wei He, Henry West, Hidekazu Kondo, Imre Benedek, Intrajeet Das, John Graby, John Greenwood, Jonathan Rodrigues, Junbo Ge, Keith Channon, Larissa Fabritz, Li-Juan Fan, Lucy Kingham, Marco Guglielmo, Matthias Schmitt, Meinrad Beer, Michelle Anderson, Milind Desai, Mohamed Marwan, Naohiko Takahashi, Nehal Mehta, Neng Dai, Nicholas Screaton, Nikant Sabharwal, Pál Maurovich-Horvat, Rajesh Kharbanda, Rebecca Preston, Richard Wood, Ron Blankstein, Ronak Rajani, Saeed Mirsadraee, Shahzad Munir, Steffen Klömpken, Steffen Petersen, Stephan Achenbach, Susan Anthony, Sze Mak, Tarun Mittal, Theodora Benedek, Vinoda Sharma, and Wen-Hua Lin

Subjects
Inflammation, SARS-CoV-2, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Angiography, Medicine (miscellaneous), COVID-19, Health Informatics, State Medicine, Health Information Management, Artificial Intelligence, Cytokines, Humans, Decision Sciences (miscellaneous), Prospective Studies, Tomography, X-Ray Computed
Abstract

Contains fulltext : 286832.pdf (Publisher’s version ) (Open Access) BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [

Published
2022

11. Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19

Author

Linzy Houchen-Wolloff, Krisnah Poinasamy, Kate Holmes, Maryrose Tarpey, Claire Hastie, Kelly Raihani, Natalie Rogers, Nikki Smith, Dawn Adams, Paul Burgess, Jean Clark, Clare Cranage, Mahadev Desai, Nicola Geary, Rhyan Gill, Jitendra Mangwani, Lily Staunton, Colin Berry, Charlotte E Bolton, Trudie Chalder, James Chalmers, Anthony De Soyza, Omer Elneima, John Geddes, Simon Heller, Ling-Pei Ho, Joseph Jacob, Hamish McAuley, Aarti Parmar, Jennifer K Quint, Betty Raman, Matthew Rowland, Amisha Singapuri, Sally J Singh, David Thomas, Mark R Toshner, Louise V Wain, Alex Robert Horsley, Michael Marks, Christopher E Brightling, Rachael A Evans, Bolton, Charlotte E [0000-0002-9578-2249], Elneima, Omer [0000-0003-2480-8840], Quint, Jennifer K [0000-0003-0149-4869], Toshner, Mark R [0000-0002-3969-6143], Horsley, Alex Robert [0000-0003-1828-0058], Brightling, Christopher E [0000-0002-5803-5121], Evans, Rachael A [0000-0002-1667-868X], and Apollo - University of Cambridge Repository

Subjects
Adult, Pulmonary and Respiratory Medicine, Post-Acute COVID-19 Syndrome, Caregivers, Health Priorities, Disease Progression, COVID-19, Humans, Research Personnel
Abstract

Given the large numbers of people infected and high rates of ongoing morbidity, research is clearly required to address the needs of adult survivors of COVID-19 living with ongoing symptoms (long COVID). To help direct resource and research efforts, we completed a research prioritisation process incorporating views from adults with ongoing symptoms of COVID-19, carers, clinicians and clinical researchers. The final top 10 research questions were agreed at an independently mediated workshop and included: identifying underlying mechanisms of long COVID, establishing diagnostic tools, understanding trajectory of recovery and evaluating the role of interventions both during the acute and persistent phases of the illness.

Published
2022

12. Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial

Author

Benjamin A Fisher, Tonny Veenith, Daniel Slade, Charlotte Gaskell, Matthew Rowland, Tony Whitehouse, James Scriven, Dhruv Parekh, Madhu S Balasubramaniam, Graham Cooke, Nick Morley, Zoe Gabriel, Matthew P Wise, Joanna Porter, Helen McShane, Ling-Pei Ho, Philip N Newsome, Anna Rowe, Rowena Sharpe, David R Thickett, Julian Bion, Simon Gates, Duncan Richards, Pamela Kearns, Bryan Williams, Rebecca Turner, Vincenzo Libri, Francis Mussai, Gary Middleton, Sarah Bowden, Mansoor Bangash, Fang Gao-Smith, Jaimin Patel, Elizabeth Sapey, Mark Thomas, Mark Coles, Peter Watkinson, Naj Rahman, Brian Angus, Alexander J. Mentzer, Alex Novak, Marc Feldman, Alex Richter, Sian Faustini, Camilla Bathurst, Joseph Van de Wiel, Susie Mee, Karen James, Bushra Rahman, Karen Turner, Adam Hill, Anthony Gordon, Christina Yap, Michael Matthay, Danny McAuley, Andrew Hall, Paul Dark, Andrew McMichael, Investigators, CATALYST, National Institute for Health Research, UK Research and Innovation, and NIHR

Subjects
PNEUMONIA, Pulmonary and Respiratory Medicine, Adolescent, BLOCKADE, Respiratory System, Antibodies, Monoclonal, Humanized, COVID-19/drug therapy, 1117 Public Health and Health Services, Critical Care Medicine, General & Internal Medicine, Humans, TUMOR-NECROSIS-FACTOR, Science & Technology, SARS-CoV-2, COVID-19, CATALYST investigators, 1103 Clinical Sciences, Bayes Theorem, Standard of Care, Articles, COLONY-STIMULATING FACTOR, Infliximab, COVID-19 Drug Treatment, Infliximab/therapeutic use, Treatment Outcome, Life Sciences & Biomedicine, 1199 Other Medical and Health Sciences
Abstract

Background: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. Methods: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. Findings: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment–time interactions were –0·09 (95% CI –0·19 to 0·00) for namilumab and 0·06 (–0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. Interpretation: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation—as measured by CRP concentration—in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19.

Published
2022
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13. Musculoskeletal health state and physical function of intensive care unit survivors: protocol for a UK multicentre prospective cohort study (the MSK-ICU study)

Author

Owen Gustafson, Elizabeth King, Michael Schlussel, Matthew Rowland, Helen Dawes, and Mark A Williams

Subjects
General Medicine
Abstract

IntroductionSurvivors of critical illness frequently experience long-term physical impairment, decreased health-related quality of life and low rates of return to employment. There has been limited investigation of the underlying problems affecting physical function post-intensive care unit (ICU) admission. Musculoskeletal (MSK) conditions may be complex in presentation, with ICU survivors potentially at greater risk of their development due to the rapid muscle mass loss seen in ICU. The MSK health state of ICU survivors and its impact on physical function remain largely unknown. The aim of the MSK-ICU study is to determine and characterise the MSK health state of ICU survivors 6 months following admission to ICU, in order to inform development of targeted rehabilitation interventions.Methods and analysisThe MSK-ICU study is a multicentre prospective longitudinal cohort study, evaluating the MSK health state of ICU survivors 6 months after admission to ICU. The study consists of a primary study and two substudies. The primary study will be a telephone follow-up of adults admitted to ICU for more than 48 hours, collecting data on MSK health state, quality of life, employment, anxiety and depression and symptoms of post-traumatic stress disorder. The planned sample size is 334 participants. Multivariable regression will be used to identify prognostic factors for a worse MSK health state, as measured by the MSK-Health Questionnaire. In substudy 1, participants who self-report any MSK problem will undergo a detailed, in-person MSK physical assessment of pain, peripheral joint range of movement and strength. In substudy 2, participants reporting a severe MSK problem will undergo a detailed physical assessment of mobility, function and muscle architecture.Ethics and disseminationEthical approval has been obtained through the North of Scotland Research Ethics Committee 2 (21/NS/0143). We aim to disseminate the findings through international conferences, international peer-reviewed journals and social media.Trial registration numberISRCTN24998809.

Published
2023
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16. EP.TH.164Staging CXR preoperatively in invasive breast cancer, is it time it should be abandoned? A single-centre cohort review of its utility

Author

Matthew Rowland and Claire Fung

Subjects
Single centre, medicine.medical_specialty, Breast cancer, business.industry, General surgery, Cohort, medicine, Surgery, medicine.disease, business
Abstract

Aim The use of preoperative chest x-rays (pCXR) for staging in invasive breast cancer has uncertain benefit. This review aimed to ascertain its utility in this cohort in a single centre. Methods Retrospective cohort review of consecutive patients with invasive breast cancer planned for surgery for 2018 was carried out. An 18-month follow-up allowed the identification of any subsequent lung pathology that may have potentially been seen on pCXR. Patients who had staging CT instead were excluded. Formal reports of pCXR and any subsequent imaging were reviewed. Results 244 patients with invasive breast cancer that was planned for surgery for 2018 were identified, 214 of whom had pCXR. 194 had no abnormalities reported. 16 had lung pathology; eight were indeterminate and were advised to have follow-up imaging. Of the six who had follow-up CTs, three had lung nodules; they were all subsequently discharged from follow-up as they were determined as benign. At 18 months, nine patients had new thoracic pathology: two had metastatic lung disease; six had lung nodules requiring follow-up. All nine patients’ pCXRs were reported as normal. Conclusions pCXR for invasive breast cancer has limited, if any, utility; it does not identify any management-altering pathology. Those that developed malignancy were not predicted by pCXR, but identified by post-operative symptoms, or on staging CT directed by post-operative nodal status. pCXR in this cohort, in the absence of respiratory symptoms, should therefore be discontinued. This would reduce cost, radiation exposure, hospital footfall, radiology reporting time, and likely improve patient satisfaction.

Published
2021
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17. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

Author

David J. Ahern, Zhichao Ai, Mark Ainsworth, Chris Allan, Alice Allcock, Brian Angus, M. Azim Ansari, Carolina V. Arancibia-Cárcamo, Dominik Aschenbrenner, Moustafa Attar, J. Kenneth Baillie, Eleanor Barnes, Rachael Bashford-Rogers, Archana Bashyal, Sally Beer, Georgina Berridge, Amy Beveridge, Sagida Bibi, Tihana Bicanic, Luke Blackwell, Paul Bowness, Andrew Brent, Andrew Brown, John Broxholme, David Buck, Katie L. Burnham, Helen Byrne, Susana Camara, Ivan Candido Ferreira, Philip Charles, Wentao Chen, Yi-Ling Chen, Amanda Chong, Elizabeth A. Clutterbuck, Mark Coles, Christopher P. Conlon, Richard Cornall, Adam P. Cribbs, Fabiola Curion, Emma E. Davenport, Neil Davidson, Simon Davis, Calliope A. Dendrou, Julie Dequaire, Lea Dib, James Docker, Christina Dold, Tao Dong, Damien Downes, Hal Drakesmith, Susanna J. Dunachie, David A. Duncan, Chris Eijsbouts, Robert Esnouf, Alexis Espinosa, Rachel Etherington, Benjamin Fairfax, Rory Fairhead, Hai Fang, Shayan Fassih, Sally Felle, Maria Fernandez Mendoza, Ricardo Ferreira, Roman Fischer, Thomas Foord, Aden Forrow, John Frater, Anastasia Fries, Veronica Gallardo Sanchez, Lucy C. Garner, Clementine Geeves, Dominique Georgiou, Leila Godfrey, Tanya Golubchik, Maria Gomez Vazquez, Angie Green, Hong Harper, Heather A. Harrington, Raphael Heilig, Svenja Hester, Jennifer Hill, Charles Hinds, Clare Hird, Ling-Pei Ho, Renee Hoekzema, Benjamin Hollis, Jim Hughes, Paula Hutton, Matthew A. Jackson-Wood, Ashwin Jainarayanan, Anna James-Bott, Kathrin Jansen, Katie Jeffery, Elizabeth Jones, Luke Jostins, Georgina Kerr, David Kim, Paul Klenerman, Julian C. Knight, Vinod Kumar, Piyush Kumar Sharma, Prathiba Kurupati, Andrew Kwok, Angela Lee, Aline Linder, Teresa Lockett, Lorne Lonie, Maria Lopopolo, Martyna Lukoseviciute, Jian Luo, Spyridoula Marinou, Brian Marsden, Jose Martinez, Philippa C. Matthews, Michalina Mazurczyk, Simon McGowan, Stuart McKechnie, Adam Mead, Alexander J. Mentzer, Yuxin Mi, Claudia Monaco, Ruddy Montadon, Giorgio Napolitani, Isar Nassiri, Alex Novak, Darragh P. O'Brien, Daniel O'Connor, Denise O'Donnell, Graham Ogg, Lauren Overend, Inhye Park, Ian Pavord, Yanchun Peng, Frank Penkava, Mariana Pereira Pinho, Elena Perez, Andrew J. Pollard, Fiona Powrie, Bethan Psaila, T. Phuong Quan, Emmanouela Repapi, Santiago Revale, Laura Silva-Reyes, Jean-Baptiste Richard, Charlotte Rich-Griffin, Thomas Ritter, Christine S. Rollier, Matthew Rowland, Fabian Ruehle, Mariolina Salio, Stephen Nicholas Sansom, Raphael Sanches Peres, Alberto Santos Delgado, Tatjana Sauka-Spengler, Ron Schwessinger, Giuseppe Scozzafava, Gavin Screaton, Anna Seigal, Malcolm G. Semple, Martin Sergeant, Christina Simoglou Karali, David Sims, Donal Skelly, Hubert Slawinski, Alberto Sobrinodiaz, Nikolaos Sousos, Lizzie Stafford, Lisa Stockdale, Marie Strickland, Otto Sumray, Bo Sun, Chelsea Taylor, Stephen Taylor, Adan Taylor, Supat Thongjuea, Hannah Thraves, John A. Todd, Adriana Tomic, Orion Tong, Amy Trebes, Dominik Trzupek, Felicia Anna Tucci, Lance Turtle, Irina Udalova, Holm Uhlig, Erinke van Grinsven, Iolanda Vendrell, Marije Verheul, Alexandru Voda, Guanlin Wang, Lihui Wang, Dapeng Wang, Peter Watkinson, Robert Watson, Michael Weinberger, Justin Whalley, Lorna Witty, Katherine Wray, Luzheng Xue, Hing Yuen Yeung, Zixi Yin, Rebecca K. Young, Jonathan Youngs, Ping Zhang, Yasemin-Xiomara Zurke, Cribbs, AP, and Consortium, COvid-19 Multi-omics Blood ATlas (COMBAT)

Subjects
Resource, Adult, Male, Myeloid, Proteome, coronavirus, Cell Cycle Proteins, Disease, Severity of Illness Index, General Biochemistry, Genetics and Molecular Biology, Monocytes, Sepsis, Machine Learning, Mitogen-Activated Protein Kinase 14, transcriptomics, Immune system, proteomics, blood, Influenza, Human, medicine, Humans, Lymphocytes, Progenitor cell, Principal Component Analysis, epigenetics, business.industry, SARS-CoV-2, Clinical study design, Acute-phase protein, COVID-19, personalized medicine, Blood Proteins, multi-omics, Middle Aged, medicine.disease, Coronavirus, Transcription Factor AP-1, medicine.anatomical_structure, Drug development, Immunology, Female, immune, business, Biomarkers
Abstract

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design and personalized medicine approaches for COVID-19., Graphical Abstract, A multi-omic analysis of patient blood samples reveals both similarities and specific features of COVID-19 when compared with samples obtained from sepsis or influenza patients which could yield better targetted therapies for severe COVID-19.

Published
2021
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20. Gynaecomastia: when and why to refer to specialist care

Author

Hannah L Bromley, Ashu Gandhi, Matthew Rowland, Nigel Lord, Rajiv V. Dave, and Paul Wright

Subjects
Male, Pediatrics, medicine.medical_specialty, Referral, media_common.quotation_subject, Physical examination, Asymptomatic, Clinical Practice, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, 030212 general & internal medicine, Pathological, media_common, medicine.diagnostic_test, business.industry, 030503 health policy & services, Testosterone (patch), body regions, Etiology, Gynecomastia, Age of onset, medicine.symptom, Worry, 0305 other medical science, Family Practice, business
Abstract

Gynaecomastia is the commonest male breast complaint. Most cases are benign but the condition may signify a serious underlying illness. The challenge in primary care is to identify which patients with gynaecomastia are at greatest risk of pathological aetiology, so that they may be offered prompt specialty-appropriate referral and treatment. This article offers guidance on the assessment and management of patients with gynaecomastia, including when and why to refer to secondary care. Gynaecomastia refers to the enlargement of male glandular breast tissue. The condition develops because of an imbalance in the male oestrogen:testosterone ratio from a relative oestrogen excess or testosterone deficiency. Pseudo-gynaecomastia is caused by an excess of adipose tissue and does not warrant investigation or treatment. Gynaecomastia is frequently observed in general practice. Prevalence is between 35%–65% in males aged 50–69 years in the UK.1 Patients typically describe a soft swelling in one or usually both breasts. Tenderness, social embarrassment, or worry about cancer are typical reasons for presentation to primary care. Other men are asymptomatic and gynaecomastia may be noted incidentally on physical examination of the chest. Physiological gynaecomastia is common in newborns, adolescence, and senility. Most do not require investigation or referral. Neonatal gynaecomastia arises from the placental transfer of oestrogen. Over half of all adolescent boys will experience transient gynaecomastia during puberty due to a lag in testosterone secretion, with median age of onset at 14 years.2 Physiological gynaecomastia is common among males aged >50 years as testosterone levels fall with increasing age. Adult gynaecomastia is most commonly idiopathic (Figure 1). Male …

Published
2021

29. How does the multidisciplinary team use systemic neo-adjuvant chemotherapy & does it facilitate breast conserving surgery in a symptomatic practice?

Author

Maria Bramley, Matthew Rowland, Grit Dabritz, and Christine McKenna

Subjects
medicine.medical_specialty, Oncology, business.industry, medicine.medical_treatment, General surgery, Breast-conserving surgery, Medicine, Surgery, General Medicine, business, Multidisciplinary team, Neo adjuvant chemotherapy
Published
2017
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31. How to cement a diversity policy

Author

Matthew Rowland

Subjects
Value (ethics), Talent development, Organizational Behavior and Human Resource Management, ComputingMilieux_THECOMPUTINGPROFESSION, business.industry, Talent management, Key (cryptography), Business, Marketing, Employee development, Nature versus nurture, Diversity (business), Career development
Abstract

Purpose – Highlights the importance of talent development in organizations, focusing on the strategies designed by Mindleaders ThirdForce in accordance with the most recent Bersin trends and Chartered Institute of Personnel and Development research.Design/methodology/approach – Examines the reasoning behind implementing talent‐development strategies, questions that have to be answered and steps that have to be taken to ensure correct measures are put in place.Findings – Argues that talent‐development strategies can help companies to nurture in‐house talent and presents findings to support the view that this approach is likely to provide a long‐term competitive edge.Practical implications – Advances the view that organizations that implement talent‐development strategies are better placed to succeed and meet challenges brought about by the economic downturn.Social implications – Argues that talent management becomes more, not less, important in an economic downturn.Originality/value – Highlights the benefi...

Published
2011
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35. Graphical Interpretation of Exergy

Author

Daisie D. Boettner, Jonathan Bodenhamer, Matthew Rowland, James E. Bluman, and A. O¨zer Arnas

Subjects
Exergy, Engineering, Work (thermodynamics), business.industry, Control theory, Closed system, Heat pump and refrigeration cycle, Exergy efficiency, Process (computing), Refrigeration, State (functional analysis), business
Abstract

Exergy is a system thermodynamic property defined only with respect to the system’s surroundings. For a specified system state, exergy is the maximum potential useful work available from the system as it achieves equilibrium with the surroundings. For students exergy can be a very abstract concept. This paper presents a graphical means to clarify the concept of exergy for a closed system, demonstrating exergy at any state i corresponds to the sum of the net work of a power cycle that incorporates a process from system state i to the dead state and the net work of a refrigeration/heat pump cycle required to move the system from the dead state to state i.

Published
2011
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36. Closing the homework feedback loop, an alternative approach to homework grading

Author

Eric M. Mockensturm, Matthew Rowland, and James E. Bluman

Subjects
Computer science, media_common.quotation_subject, Physics education, Pedagogy, ComputingMilieux_COMPUTERSANDEDUCATION, Mathematics education, Feedback loop, Student learning, Discretion, Grading (education), media_common
Abstract

This paper studies an alternative grading method for homework assignments designed to increase student learning and motivation. The method emphasizes correct completion of student work, even if multiple turn-ins are required. After submitting homework, the instructor checks the accuracy of the work. Incorrect work is returned to the students the morning after its initial due date. Students are then given a day or two to correct their work and re-submit. This cycle is repeated as many times as necessary at the teacher's discretion. Grades are based on the number of iterations required for the work to be correct. Results from the study show that while student learning was not measurably affected, student motivation to perform well on the homework assignments increased. This rise in motivation may be dependent on the context within which the method is employed — it seems to work better for higher level technical electives than for larger common courses.

Published
2010
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37. Measurement of complement activation via plasma soluble C5b-9 comparison with terminal complement complex staining in a series of kidney biopsies

Author

Carolyn Wijaya, Christine Burns, Sharron Hall, Melissa Farmer, Denise Jones, Matthew Rowlandson, Peter Choi, Mark Formby, and Theo de Malmanche

Subjects
Dermatology, RL1-803, Diseases of the circulatory (Cardiovascular) system, RC666-701, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Introduction: With the emergence of therapeutic complement inhibitors, there is a need to identify patients with complement-driven inflammation. C5b-9 is the terminal product of the three complement pathways, and therefore a marker of total complement activation. We present a pilot study which aims to assess whether plasma soluble C5b-9 (sC5b-9) correlates with terminal complement complex (TCC) staining in kidney tissue. The secondary aim was to assess the utility of plasma sC5b-9 as part of routine work up in kidney patients undergoing kidney biopsy. Methods: 37 patients undergoing kidney biopsy had plasma sC5b-9 and TCC staining on kidney tissue performed. Additional blood markers including creatinine, haemoglobin, CRP, Factor H, Factor I and midkine levels were also taken. These parameters were correlated with the histological diagnoses. Patients were divided into a diseased group (n=31), and a control group (n=6) consisting of transplanted kidneys with minor or no changes. Of the biopsies in the control group, 50% were performed as per protocol, and the other 50% were performed due to clinical need. Results: There was no correlation found between plasma sC5b-9 and TCC kidney staining. Elevated sC5b-9 levels were found in a heterogeneous group of patients, but were associated with higher CRP and lower haemoglobin levels. Overall, there was more TCC kidney staining in the diseased group compared with the control group, and a trend was observed of diabetic, primary membranous nephropathy and amyloidosis patients having more intense glomerular and peritubular/interstitial staining. Discussion/Conclusion: Plasma sC5b-9 as a marker of total complement activation does not correlate with TCC kidney staining. This discordance suggests that plasma sC5b-9 and TCC staining are distinct markers of disease. TCC staining reflects chronicity and tissue deposition of complement over time. Conversely, plasma sC5b-9 concentrations change rapidly and reflect systemic complement activation. Complement activation was present in a heterogeneous group of kidney disease, indicating the underlying role of complement in many disorders.

Published
2023
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39. Metoclopramide disposition in normal and uremic humans

Author

Wright, Matthew Rowland

Abstract

Metoclopramide (MCP) is a potent antinauseant/ antiemetic and gastrointestinal motility modifier. MCP finds clinical use in a wide variety of situations and is administered on both an acute and chronic basis. This thesis examines the pharmacokinetics of MCP in both normal, healthy volunteers and in uremic subjects on a maintenance hemodialysis program. Specifically, in the normal, healthy volunteers, the dose-linearity, and absolute and relative bioavailabilities are examined. In the uremics, the effects of chronic renal failure on MCP kinetics, the removal of MCP by hemodialysis, and the effects of hemodialysis on MCP kinetics are examined. Based on early reports, the pharmacokinetics of MCP were claimed to be dose-dependent and the absolute bioavailability extremely variable. However, many of these early studies suffered from methodological problems which limit the credibility of their findings. Based on a four-way crossover study involving six normal, healthy volunteers we find, in contrast to previous results, that the kinetics of MCP are linear over the dose range of 5 -20 mg, the absolute bioavailability is 76 ± 38 %, and the relative bioavailability of a solution dosage form vs the tablet dosage form is approximately 1. Although renal clearance accounts for only about 20 % of the total body clearance of MCP in normals, uremia has been shown to substantially alter MCP kinetics in both rat and man. There appears to be at least a two-fold decrease in total body clearance with an attendent, proportional increase in elimination half-life and insignificant change in volume of distribution. Hemodialysis is relatively ineffective in clearing MCP from the body and this inefficiency is probably related to the relatively large volume of distribution of MCP. Hemodialysis also has no effects on the apparent kinetic parameters following its termination. In addition, results from a single patient who received a kidney transplant show that the renewed renal function is accompanied by an apparent reversion of all kinetic parameters to within normal limits within 15 days of transplantation.

Published
1987
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40. DEVELOPMENT OF INSTRUMENTATION AND CONTROL SYSTEMS FOR AN INTEGRAL LARGE SCALE PRESSURIZED WATER REACTOR

Author

Lish, Matthew Rowland Morrow

Subjects
Integral reactors, dynamic modeling, monitoring and diagnostics, Controls and Control Theory, Nuclear Engineering, Systems Engineering
Abstract

Small and large scale integral light water reactors are being developed to supply electrical power and to meet the needs of process heat, primarily for water desalination. This dissertation research focuses on the instrumentation and control of a large integral inherently safe light water reactor (designated as I2S-LWR) which is being designed as part of a grant by the U.S. Department of Energy Integrated Research Project (IRP). This 969 MWe integral pressurized water reactor (PWR) incorporates as many passive safety features as possible while maintaining competitive costs with current light water reactors. In support of this work, the University of Tennessee has been engaged in research to solve the instrumentation and control challenges posed by such a reactor design. This dissertation is a contribution to this effort. The objectives of this dissertation are to establish the feasibility and conceptual development of instrumentation strategies and control approaches for the I2S-LWR, with consideration to the state of the art of the field. The objectives of this work are accomplished by the completion of the following tasks: Assessment of instrumentation needs and technology gaps associated with the instrumentation of the I2S-LWR for process monitoring and control purposes. Development of dynamic models of a large integral PWR core, micro-channel heat exchangers (MCHX) that are contained within the reactor pressure vessel, and steam flashing drums located external to the containment building. Development and demonstration of control strategies for reactor power regulation, steam flashing drum pressure regulation, and flashing drum water level regulation for steady state and load-following conditions. Simulation, detection, and diagnosis of process anomalies in the I2S-LWR model. This dissertation is innovative and significant in that it reports the first instrumentation and control study of nuclear steam supply by integral pressurized water reactor coupled to an isenthalpic expansion vessel for steam generation. Further, this dissertation addresses the instrumentation and control challenges associated with integral reactors, as well as improvements to inherent safety possible in the instrumentation and control design of integral reactors. The results of analysis and simulation demonstrate the successful development of dynamic modeling, control strategies, and instrumentation for a large integral PWR.

Published
2016

41. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19

Author

Angus, Derek, Derde, Lennie, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen, de Jong, Menno, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Higgins, Alisa, Horvat, Christopher, Hullegie, Sebastiaan, Kruger, Peter, Lamontagne, Francois, Lawler, Patrick, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, Mcauley, Daniel, Mcglothin, Anna, Mcguinness, Shay, Mcverry, Bryan, Montgomery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Rowan, Kathryn, Sanil, Ashish, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Turner, Anne, van de Veerdonk, Frank, Venkatesh, Balasubramanian, Zarychanski, Ryan, Berry, Scott, Lewis, Roger, Mcarthur, Colin, Webb, Steven, Gordon, Anthony, NIHR, Hôpital Raymond Poincaré [AP-HP], Writing Committee for the REMAP-CAP Investigators, Farah Al-Beidh, Derek Angus, Djillali Annane, Yaseen Arabi, Wilma van Bentum-Puijk, Scott Berry, Abigail Beane, Zahra Bhimani, Marc Bonten, Charlotte Bradbury, Frank Brunkhorst, Meredith Buxton, Allen Cheng, Menno De Jong, Lennie Derde, Lise Estcourt, Herman Goossens, Anthony Gordon, Cameron Green, Rashan Haniffa, Francois Lamontagne, Patrick Lawler, Edward Litton, John Marshall, Colin McArthur, Daniel McAuley, Shay McGuinness, Bryan McVerry, Stephanie Montgomery, Paul Mouncey, Srinivas Murthy, Alistair Nichol, Rachael Parke, Kathryn Rowan, Christopher Seymour, Anne Turner, Frank van de Veerdonk, Steve Webb, Ryan Zarychanski, Lewis Campbell, Andrew Forbes, David Gattas, Stephane Heritier, Lisa Higgins, Peter Kruger, Sandra Peake, Jeffrey Presneill, Ian Seppelt, Tony Trapani, Paul Young, Sean Bagshaw, Nick Daneman, Niall Ferguson, Cheryl Misak, Marlene Santos, Sebastiaan Hullegie, Mathias Pletz, Gernot Rohde, Kathy Rowan, Brian Alexander, Kim Basile, Timothy Girard, Christopher Horvat, David Huang, Kelsey Linstrum, Jennifer Vates, Richard Beasley, Robert Fowler, Steve McGloughlin, Susan Morpeth, David Paterson, Bala Venkatesh, Tim Uyeki, Kenneth Baillie, Eamon Duffy, Rob Fowler, Thomas Hills, Katrina Orr, Asad Patanwala, Steve Tong, Mihai Netea, Shilesh Bihari, Marc Carrier, Dean Fergusson, Ewan Goligher, Ghady Haidar, Beverley Hunt, Anand Kumar, Mike Laffan, Patrick Lawless, Sylvain Lother, Peter McCallum, Saskia Middeldopr, Zoe McQuilten, Matthew Neal, John Pasi, Roger Schutgens, Simon Stanworth, Alexis Turgeon, Alexandra Weissman, Neill Adhikari, Matthew Anstey, Emily Brant, Angelique de Man, Francois Lamonagne, Marie-Helene Masse, Andrew Udy, Donald Arnold, Phillipe Begin, Richard Charlewood, Michael Chasse, Mark Coyne, Jamie Cooper, James Daly, Iain Gosbell, Heli Harvala-Simmonds, Tom Hills, Sheila MacLennan, David Menon, John McDyer, Nicole Pridee, David Roberts, Manu Shankar-Hari, Helen Thomas, Alan Tinmouth, Darrell Triulzi, Tim Walsh, Erica Wood, Carolyn Calfee, Cecilia O’Kane, Murali Shyamsundar, Pratik Sinha, Taylor Thompson, Ian Young, Shailesh Bihari, Carol Hodgson, John Laffey, Danny McAuley, Neil Orford, Ary Neto, Michelle Detry, Mark Fitzgerald, Roger Lewis, Anna McGlothlin, Ashish Sanil, Christina Saunders, Lindsay Berry, Elizabeth Lorenzi, Eliza Miller, Vanessa Singh, Claire Zammit, Wilma van Bentum Puijk, Wietske Bouwman, Yara Mangindaan, Lorraine Parker, Svenja Peters, Ilse Rietveld, Kik Raymakers, Radhika Ganpat, Nicole Brillinger, Rene Markgraf, Kate Ainscough, Kathy Brickell, Aisha Anjum, Janis-Best Lane, Alvin Richards-Belle, Michelle Saull, Daisy Wiley, Julian Bion, Jason Connor, Simon Gates, Victoria Manax, Tom van der Poll, John Reynolds, Marloes van Beurden, Evelien Effelaar, Joost Schotsman, Craig Boyd, Cain Harland, Audrey Shearer, Jess Wren, Giles Clermont, William Garrard, Kyle Kalchthaler, Andrew King, Daniel Ricketts, Salim Malakoutis, Oscar Marroquin, Edvin Music, Kevin Quinn, Heidi Cate, Karen Pearson, Joanne Collins, Jane Hanson, Penny Williams, Shane Jackson, Adeeba Asghar, Sarah Dyas, Mihaela Sutu, Sheenagh Murphy, Dawn Williamson, Nhlanhla Mguni, Alison Potter, David Porter, Jayne Goodwin, Clare Rook, Susie Harrison, Hannah Williams, Hilary Campbell, Kaatje Lomme, James Williamson, Jonathan Sheffield, Willian van’t Hoff, Phobe McCracken, Meredith Young, Jasmin Board, Emma Mart, Cameron Knott, Julie Smith, Catherine Boschert, Julia Affleck, Mahesh Ramanan, Ramsy D’Souza, Kelsey Pateman, Arif Shakih, Winston Cheung, Mark Kol, Helen Wong, Asim Shah, Atul Wagh, Joanne Simpson, Graeme Duke, Peter Chan, Brittney Cartner, Stephanie Hunter, Russell Laver, Tapaswi Shrestha, Adrian Regli, Annamaria Pellicano, James McCullough, Mandy Tallott, Nikhil Kumar, Rakshit Panwar, Gail Brinkerhoff, Cassandra Koppen, Federica Cazzola, Matthew Brain, Sarah Mineall, Roy Fischer, Vishwanath Biradar, Natalie Soar, Hayden White, Kristen Estensen, Lynette Morrison, Joanne Smith, Melanie Cooper, Monash Health, Yahya Shehabi, Wisam Al-Bassam, Amanda Hulley, Christina Whitehead, Julie Lowrey, Rebecca Gresha, James Walsham, Jason Meyer, Meg Harward, Ellen Venz, Patricia Williams, Catherine Kurenda, Kirsy Smith, Margaret Smith, Rebecca Garcia, Deborah Barge, Deborah Byrne, Kathleen Byrne, Alana Driscoll, Louise Fortune, Pierre Janin, Elizabeth Yarad, Naomi Hammond, Frances Bass, Angela Ashelford, Sharon Waterson, Steve Wedd, Robert McNamara, Heidi Buhr, Jennifer Coles, Sacha Schweikert, Bradley Wibrow, Rashmi Rauniyar, Erina Myers, Ed Fysh, Ashlish Dawda, Bhaumik Mevavala, Ed Litton, Janet Ferrier, Priya Nair, Hergen Buscher, Claire Reynolds, John Santamaria, Leanne Barbazza, Jennifer Homes, Roger Smith, Lauren Murray, Jane Brailsford, Loretta Forbes, Teena Maguire, Vasanth Mariappa, Judith Smith, Scott Simpson, Matthew Maiden, Allsion Bone, Michelle Horton, Tania Salerno, Martin Sterba, Wenli Geng, Pieter Depuydt, Jan De Waele, Liesbet De Bus, Jan Fierens, Stephanie Bracke, Brenda Reeve, William Dechert, Michaël Chassé, François Martin Carrier, Dounia Boumahni, Fatna Benettaib, Ali Ghamraoui, David Bellemare, Ève Cloutier, Charles Francoeur, François Lamontagne, Frédérick D’Aragon, Elaine Carbonneau, Julie Leblond, Gloria Vazquez-Grande, Nicole Marten, Maggie Wilson, Martin Albert, Karim Serri, Alexandros Cavayas, Mathilde Duplaix, Virginie Williams, Bram Rochwerg, Tim Karachi, Simon Oczkowski, John Centofanti, Tina Millen, Erick Duan, Jennifer Tsang, Lisa Patterson, Shane English, Irene Watpool, Rebecca Porteous, Sydney Miezitis, Lauralyn McIntyre, Laurent Brochard, Karen Burns, Gyan Sandhu, Imrana Khalid, Alexandra Binnie, Elizabeth Powell, Alexandra McMillan, Tracy Luk, Noah Aref, Zdravko Andric, Sabina Cviljevic, Renata Đimoti, Marija Zapalac, Gordan Mirković, Bruno Baršić, Marko Kutleša, Viktor Kotarski, Ana Vujaklija Brajković, Jakša Babel, Helena Sever, Lidija Dragija, Ira Kušan, Suvi Vaara, Leena Pettilä, Jonna Heinonen, Anne Kuitunen, Sari Karlsson, Annukka Vahtera, Heikki Kiiski, Sanna Ristimäki, Amine Azaiz, Cyril Charron, Mathieu Godement, Guillaume Geri, Antoine Vieillard-Baron, Franck Pourcine, Mehran Monchi, David Luis, Romain Mercier, Anne Sagnier, Nathalie Verrier, Cecile Caplin, Shidasp Siami, Christelle Aparicio, Sarah Vautier, Asma Jeblaoui, Muriel Fartoukh, Laura Courtin, Vincent Labbe, Cécile Leparco, Grégoire Muller, Mai-Anh Nay, Toufik Kamel, Dalila Benzekri, Sophie Jacquier, Emmanuelle Mercier, Delphine Chartier, Charlotte Salmon, PierreFrançois Dequin, Francis Schneider, Guillaume Morel, Sylvie L’Hotellier, Julio Badie, Fernando Daniel Berdaguer, Sylvain Malfroy, Chaouki Mezher, Charlotte Bourgoin, Bruno Megarbane, Sebastian Voicu, Nicolas Deye, Isabelle Malissin, Laetitia Sutterlin, Christophe Guitton, Cédric Darreau, Mickaël Landais, Nicolas Chudeau, Alain Robert, Pierre Moine, Nicholas Heming, Virginie Maxime, Isabelle Bossard, Tiphaine Barbarin 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Ferguson, Katharine Sellers, Joanne Bradley-Potts, David Yates, Isobel Birkinshaw, Kay Kell, Nicola Marshall, Lisa Carr-Knott, Charlotte Summers, and Mégarbane, Bruno

Subjects
[SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, General Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Writing Committee for the REMAP-CAP Investigators, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, General & Internal Medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 11 Medical and Health Sciences
Abstract

Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Published
2020
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