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453 results on '"Christopher Holmes"'

1. Identification and validation of a machine learning model of complete response to radiation in rectal cancer reveals immune infiltrate and TGFβ as key predictorsResearch in context

Author

Enric Domingo, Sanjay Rathee, Andrew Blake, Leslie Samuel, Graeme Murray, David Sebag-Montefiore, Simon Gollins, Nicholas West, Rubina Begum, Susan Richman, Phil Quirke, Keara Redmond, Aikaterini Chatzipli, Alessandro Barberis, Sylvana Hassanieh, Umair Mahmood, Michael Youdell, Ultan McDermott, Viktor Koelzer, Simon Leedham, Ian Tomlinson, Philip Dunne, Francesca M. Buffa, Timothy S. Maughan, Francesca Buffa, Geoffrey Higgins, Christopher Holmes, Timothy Maughan, Gillies McKenna, James Robineau, Philip Quirke, Matthew Seymour, Richard Kennedy, Mark Lawler, Manuel Salto-Tellez, Peter Campbell, Claire Hardy, Simon Bach, Andrew Beggs, Jean-Baptiste Cazier, Gary Middleton, Dion Morton, Celina Whalley, Louise Brown, Richard Kaplan, Richard Wilson, Richard Adams, Richard Sullivan, Paul Harkin, Steven Walker, Jim Hill, Chieh-Hsi Wu, and Dennis Horgan

Subjects
Rectal neoplasms, Radiotherapy, Precision medicine, Prediction, TGFβ, Immune response, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: It is uncertain which biological features underpin the response of rectal cancer (RC) to radiotherapy. No biomarker is currently in clinical use to select patients for treatment modifications. Methods: We identified two cohorts of patients (total N = 249) with RC treated with neoadjuvant radiotherapy (45Gy/25) plus fluoropyrimidine. This discovery set included 57 cases with pathological complete response (pCR) to chemoradiotherapy (23%). Pre-treatment cancer biopsies were assessed using transcriptome-wide mRNA expression and targeted DNA sequencing for copy number and driver mutations. Biological candidate and machine learning (ML) approaches were used to identify predictors of pCR to radiotherapy independent of tumour stage. Findings were assessed in 107 cases from an independent validation set (GSE87211). Findings: Three gene expression sets showed significant independent associations with pCR: Fibroblast-TGFβ Response Signature (F-TBRS) with radioresistance; and cytotoxic lymphocyte (CL) expression signature and consensus molecular subtype CMS1 with radiosensitivity. These associations were replicated in the validation cohort. In parallel, a gradient boosting machine model comprising the expression of 33 genes generated in the discovery cohort showed high performance in GSE87211 with 90% sensitivity, 86% specificity. Biological and ML signatures indicated similar mechanisms underlying radiation response, and showed better AUC and p-values than published transcriptomic signatures of radiation response in RC. Interpretation: RCs responding completely to chemoradiotherapy (CRT) have biological characteristics of immune response and absence of immune inhibitory TGFβ signalling. These tumours may be identified with a potential biomarker based on a 33 gene expression signature. This could help select patients likely to respond to treatment with a primary radiotherapy approach as for anal cancer. Conversely, those with predicted radioresistance may be candidates for clinical trials evaluating addition of immune-oncology agents and stromal TGFβ signalling inhibition. Funding: The Stratification in Colorectal Cancer Consortium (S:CORT) was funded by the Medical Research Council and Cancer Research UK (MR/M016587/1).

Published
2024
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2. Flexible Photonic Sensors: Investigation of an Approach Based on Ratiometric Power in Few-Mode Waveguides for Bending Measurement

Author

Andrea Annunziato, Mike Godfrey, Francesco Anelli, Janice Dulieu-Barton, Christopher Holmes, and Francesco Prudenzano

Subjects
Coupled mode theory, flexible photonics, bending, optical fiber sensor, Bragg grating, Electrical engineering. Electronics. Nuclear engineering, TK1-9971
Abstract

A novel approach to monitor the degree of bending via flexible photonics devices, using ratiometric power variation in a few-mode optical waveguide, is proposed. To demonstrate its feasibility, a sensor exploiting a Bragg grating, approximately aligned to the neutral axis, is designed, fabricated and characterized. The reduced thickness of the proposed planar photonic sensor is uniquely limited by optical confinement requirements, enabling for an ultra-thin and highly flexible planar device, based on all-glass platform. Finite Element Method, Beam Propagation Method and Coupled Mode Theory are employed in the design to model the electromagnetic and mechanical phenomena occurring during the three-point bending test. The experiment demonstrates that the planar device withstands tight curvature without mechanical failure. The device shows that by increasing the bending the reflected power from the fundamental mode decreases and the reflected power from the higher order mode increases. The measured ratiometric power sensitivity versus displacement is $K_{P_{R}}=-0.78 \mathrm {dB/mm}$ with negligible variation over a 40°C thermal range. Therefore, exploiting both the Bragg wavelength shift and the mode optical power change, the proposed sensor can be employed for multiparameter sensing purposes, e.g. simultaneous temperature and curvature monitoring.

Published
2024
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3. Airway management in the paediatric difficult intubation registry: a propensity score matched analysis of outcomes over timeResearch in context

Author

Mary Lyn Stein, Lina Andrea Sarmiento Argüello, Steven J. Staffa, Julia Heunis, Chinyere Egbuta, Stephen G. Flynn, Sabina A. Khan, Stefano Sabato, Brad M. Taicher, Franklin Chiao, Adrian Bosenberg, Angela C. Lee, H. Daniel Adams, Britta S. von Ungern-Sternberg, Raymond S. Park, James M. Peyton, Patrick N. Olomu, Agnes I. Hunyady, Annery Garcia-Marcinkiewicz, John E. Fiadjoe, Pete G. Kovatsis, Benjamin Bruins, Paul Stricker, Elizabeth Laverriere, Justin L. Lockman, Brian Struyk, Christopher Ward, Akira Nishisaki, Ramesh Kodavatiganti, Rodrigo Daly Guris, Luis Sequera-Ramos, Mark Teen, Ayodele Oke, Grace Hsu, Arul Lingappan, Rhae Battles, Ashley Bocanegra, Tally Goldfarb, Edgar Kiss, Peter Szmuk, Sam Mireles, Andrea Murray, Simon Whyte, Ranu Jain, Maria Matuszczak, Christopher Holmes, Alexander McCann, Clyde Matava, Nicholas Dalesio, Robert Greenberg, Angela Lucero, Sapna Desai, Sondra Rosander, Sindhu Samba, Charles Schrock, Sydney Nykiel-Bailey, Jennifer Marsh, Melissa Brooks Peterson, Amy Lee, Somaletha Bhattacharya, Nicholas Burjek, Narasimhan Jagannathan, David Lardner, Christy Crockett, Sara Robetson, Jasmine Patel, Aarti Sharma, Thomas Templeton, Piedad Echeverry Marín, Carolina Pérez-Pradilla, Neeta Singh, David Sommerfield, Neil Hauser, Emily Hesselink, Hilana Lewkowitz-Shpuntoff, Pilar Castro, N. Ricardo Riveros Perez, Eduardo Vega, Alejandro González, Paola Ostermann, Kasia Rubin, Jonathan Meserve, Charles Lord, Angela Lee, Songyos Valairucha, Priti Dalal, Thanh Tran, Taylor Anspach, Lisa K. Lee, Ihab Ayad, Mohamed Rehman, Allison Fernandez, Lillian Zamora, Niroop Ravula, Sadiq Shaik, Judit Szolnoki, Preethy Mathew, Sandhya Yaddanapudi, Indu Sen, Aakriti Gupta, Kathryn Handlogten, J. Michael Sroka, Vinícius Caldeira Quintão, Ricardo Vieira Carlos, and Fernanda Leite

Subjects
Paediatric airway, Difficult airway, Intubation, Video laryngoscopy, Outcomes, Complications, Medicine (General), R5-920
Abstract

Summary: Background: The Paediatric Difficult Intubation Collaborative identified multiple attempts and persistence with direct laryngoscopy as risk factors for complications in children with difficult tracheal intubations and subsequently engaged in initiatives to reduce repeated attempts and persistence with direct laryngoscopy in children. We hypothesised these efforts would lead to fewer attempts, fewer direct laryngoscopy attempts and decrease complications. Methods: Paediatric patients less than 18 years of age with difficult direct laryngoscopy were enrolled in the Paediatric Difficult Intubation Registry. We define patients with difficult direct laryngoscopy as those in whom (1) an attending or consultant obtained a Cormack Lehane Grade 3 or 4 view on direct laryngoscopy, (2) limited mouth opening makes direct laryngoscopy impossible, (3) direct laryngoscopy failed in the preceding 6 months, and (4) direct laryngoscopy was deferred due to perceived risk of harm or poor chance of success. We used a 5:1 propensity score match to compare an early cohort from the initial Paediatric Difficult Intubation Registry analysis (August 6, 2012–January 31, 2015, 785 patients, 13 centres) and a current cohort from the Registry (March 4, 2017–March 31, 2023, 3925 patients, 43 centres). The primary outcome was first attempt success rate between cohorts. Success was defined as confirmed endotracheal intubation and assessed by the treating clinician. Secondary outcomes were eventual success rate, number of attempts at intubation, number of attempts with direct laryngoscopy, the incidence of persistence with direct laryngoscopy, use of supplemental oxygen, all complications, and severe complications. Findings: First-attempt success rate was higher in the current cohort (42% vs 32%, OR 1.5 95% CI 1.3–1.8, p

Published
2024
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4. Effect of second booster vaccinations and prior infection against SARS-CoV-2 in the UK SIREN healthcare worker cohortResearch in context

Author

Peter D. Kirwan, Victoria J. Hall, Sarah Foulkes, Ashley D. Otter, Katie Munro, Dominic Sparkes, Anna Howells, Naomi Platt, Jonathan Broad, David Crossman, Chris Norman, Diane Corrigan, Christopher H. Jackson, Michelle Cole, Colin S. Brown, Ana Atti, Jasmin Islam, Anne M. Presanis, Andre Charlett, Daniela De Angelis, Susan Hopkins, Tracy Lewis, Steve Bain, Rebeccah Thomas, John Geen, Carla Pothecary, Sean Cutler, John Northfield, Cathy Price, Johanne Tomlinson, Sarah Knight, Emily Macnaughton, Ekaterina Watson, Rajeka Lazarus, Aaran Sinclair, Joanne Galliford, Bridgett Masunda, Tabitha Mahungu, Alison Rodger, Esther Hanison, Simon Warren, Swati Jain, Mariyam Mirfenderesky, Natasha Mahabir, Rowan Pritchard-Jones, Diane Wycherley, Claire Gabriel, Elijah Matovu, Philippa Bakker, Simantee Guha, S. Gormley, James Pethick, Georgina Butt, Stacey Pepper, Luke Bedford, Paul Ridley, Jane Democratis, Manjula Meda, Anu Chawla, Fran Westwell, Nagesh Kalakonda, Sheena Khanduri, Allison Doel, Sumita Pai, Christian Hacon, Davis Nwaka, Veronica Mendez Moro, A. Moody, Cressida Auckland, Stephanie Prince, Thushan de Silva, Helen Shulver, A. Shah, C. Jones, Banerjee Subhro-Osuji, Angela Houston, Tim Planche, Martin Booth, Christopher Duff, Jonnie Aeron-Thomas, Ray Chaudhuri, David Hilton, Hannah Jory, Zehra'a Al-Khafaji, Philippa Kemsley, Ruth Longfellow, David Boss, Simon Brake, Louise Coke, Ngozi Elumogo, Scott Latham, Chinari Subudhi, Ina Hoad, Claire Thomas, Nihil Chitalia, Tracy Edmunds, Helen Ashby, John Elliott, Beverley Wilkinson, Abby Rand, Catherine Thompson, K. Agwuh, Anna Grice, Kelly Moran, Vijayendra Waykar, Yvonne Lester, Lauren Sach, Kathryn Court, Nikki White, Clair Favager, Kyra Holliday, Jayne Harwood, Brendan Payne, Karen Burns, Lynda Fothergill, Alejandro Arenas-Pinto, Abigail Severn, Kerryanne Brown, Katherine Gray, Jane Dare, Qi Zheng, Kathryn Hollinshead, Robert Shorten, Alun Roebuck, Christopher Holmes, Martin Wiselka, Barzo Faris, Liane Marsh, Clare McAdam, Lisa Ditchfield, Zaman Qazzafi, G. Boyd, N. Wong, Sarah Brand, Jack Squires, John Ashcroft, Ismaelette Del Rosario, Joanne Howard, Emma Ward, Gemma Harrison, Joely Morgan, Claire Corless, Ruth Penn, Nick Wong, Manny Bagary, Nadezda Starkova, Mandy Beekes, Mandy Carnahan, Shivani Khan, Shekoo Mackay, Keneisha Lewis, Graham Pickard, Joy Dawson, Lauren Finlayson, Euan Cameron, Anne Todd, Sebastien Fagegaltier, Sally Mavin, Alexandra Cochrane, Andrew Gibson, Sam Donaldson, Kate Templeton, Martin Malcolm, Beth Smith, Devesh Dhasmana, Susan Fowler, Antonia Ho, Michael Murphy, Claire Beith, Manish Patel, Elizabeth Boyd, Val Irvine, Alison Grant, Rebecca Temple-Purcell, Clodagh Loughrey, Elinor Hanna, Frances Johnston, Angel Boulos, Fiona Thompson, Yuri Protaschik, Susan Regan, Tracy Donaghy, Maurice O'Kane, Omolola Akinbami, Paola Barbero, Tim Brooks, Meera Chand, Ferdinando Insalata, Palak Joshi, Anne-Marie O'Connell, Mary Ramsay, Ayoub Saei, Maria Zambon, Ezra Linley, Simon Tonge, Enemona Adaji, Omoyeni Adebiyi, Nick Andrews, Joanna Conneely, Paul Conneely, Angela Dunne, Simone Dyer, Hannah Emmett, Nipunadi Hettiarachchi, Nishanthan Kapirial, Jameel Khawam, Edward Monk, Sophie Russell, Andrew Taylor-Kerr, Jean Timeyin, Silvia D'Arcangelo, Cathy Rowe, Amanda Semper, Eileen Gallagher, Robert Kyffin, Lisa Cromey, Desmond Areghan, Jennifer Bishop, Melanie Dembinsky, Laura Dobbie, Josie Evans, David Goldberg, Lynne Haahr, Annelysse Jorgenson, Ayodeji Matuluko, Laura Naismith, Desy Nuryunarsih, Alexander Olaoye, Caitlin Plank, Lesley Price, Nicole Sergenson, Sally Stewart, Andrew Telfer, Jennifer Weir, Ellen De Lacy, Yvette Ellis, Susannah Froude, Guy Stevens, Linda Tyson, Susanna Dunachie, Paul Klenerman, Chris Duncan, Rebecca Payne, Lance Turtle, Alex Richter, Thushan De Silva, Eleanor Barnes, Daniel Wootton, Oliver Galgut, Jonathan Heeney, Helen Baxendale, Javier Castillo-Olivares, Rupert Beale, Edward Carr, Wendy Barclay, Maya Moshe, Massimo Palmarini, Brian Willett, John Kenneth Baillie, Jennie Evans, and Erika Aquino

Subjects
SARS-CoV-2, Vaccine effectiveness, Asymptomatic, Symptomatic, Healthcare worker, Cohort study, Public aspects of medicine, RA1-1270
Abstract

Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Published
2024
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5. Flexible photonics in carbon and glass fiber reinforced polymers for new multifunctionality: Exploring the advances, challenges, and opportunities

Author

Christopher Holmes and Janice Dulieu-Barton

Subjects
Flexible photonics, Laminated composites, Sensors, planar optics, Applied optics. Photonics, TA1501-1820, Optics. Light, QC350-467
Abstract

Flexible photonics, characterized by their planar design and integrated features, have surfaced as a promising technology to unlock new possibilities for multifunctionality within fiber reinforced polymer composite materials. A comprehensive review of current progress, challenges, and opportunities associated with flexible photonic integration into carbon and glass fiber reinforced polymers is provided. A systematic examination of the literature has revealed several flexible photonic technologies that have demonstrated potential for integration in composite components to monitor performance in manufacture, service, and reuse. The review highlights the advantages and limitations of the current state-of-the-art in flexible integrated photonics for making assessments of compatibility with carbon and glass fiber reinforced polymer structures. By examining proof-of-concept demonstrations, the improved performance and novel functionalities that can be achieved for industrial applications are identified. The challenges associated with the integration process, such as durability and scalability are discussed in the context of the manufacturing processes required to create composite components. The concept of integrating flexible photonics in composite structures is relatively new, hence the paper closes by highlighting opportunities for further research and development in this field.

Published
2023
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6. Compact high-resolution FBG strain interrogator based on laser-written 3D scattering structure in flat optical fiber

Author

Przemyslaw Falak, Timothy Lee, Shahrzad Zahertar, Bo Shi, Bruno Moog, Gilberto Brambilla, Christopher Holmes, and Martynas Beresna

Subjects
Medicine, Science
Abstract

Abstract We demonstrate a fiber Bragg grating (FBG) strain interrogator based on a scattering medium to generate stable and deterministic speckle patterns, calibrated with applied strain, which are highly dependent on the FBG back-reflection spectral components. The strong wavelength-dependency of speckle patterns was previously used for high resolution wavemeters where scattering effectively folds the optical path, but instability makes practical realization of such devices difficult. Here, a new approach is demonstrated by utilizing femtosecond laser-written scatterers inside flat optical fiber, to enhance mechanical stability. By inscribing 15 planes of pseudo-randomized nanovoids (714 $$\times$$ × 500 voids per plane) as a 3D array in a 1 $$\times$$ × 0.7 $$\times$$ × 0.16 mm volume, the intrinsic stability and compactness of the device was improved. Operating as a wavemeter, it remained stable for at least 60 h with 45 pm resolution over the wavelength range of 1040–1056 nm. As a reflection mode FBG interrogator, after calibrating speckle patterns by applying tensile strain to the FBG, the device is capable of detecting microstrain changes in the range of 0–200 $$\mu \epsilon$$ μ ϵ with a standard error of 4 $$\mu \epsilon$$ μ ϵ , limited by the translation stage step size. All these characteristics make it an interesting technology for filling the niche of low-cost, high-resolution wavemeters and interrogators which offer the best available trade-off between resolution, compactness, price and stability.

Published
2023
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7. Optical Coherence Tomography Angiography as a Diagnostic Tool for Diabetic Retinopathy

Author

Naomi Wijesingha, Wei-Shan Tsai, Ayse Merve Keskin, Christopher Holmes, Dimitrios Kazantzis, Swati Chandak, Heena Kubravi, and Sobha Sivaprasad

Subjects
artefacts, choriocapillaris, diabetic macular ischaemia, diabetic macular oedema, diabetic retinopathy, fundus fluorescein angiography, Medicine (General), R5-920
Abstract

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus, leading to visual impairment if left untreated. This review discusses the use of optical coherence tomography angiography (OCTA) as a diagnostic tool for the early detection and management of DR. OCTA is a fast, non-invasive, non-contact test that enables the detailed visualisation of the macular microvasculature in different plexuses. OCTA offers several advantages over fundus fluorescein angiography (FFA), notably offering quantitative data. OCTA is not without limitations, including the requirement for careful interpretation of artefacts and the limited region of interest that can be captured currently. We explore how OCTA has been instrumental in detecting early microvascular changes that precede clinical signs of DR. We also discuss the application of OCTA in the diagnosis and management of various stages of DR, including non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), diabetic macular oedema (DMO), diabetic macular ischaemia (DMI), and pre-diabetes. Finally, we discuss the future role of OCTA and how it may be used to enhance the clinical outcomes of DR.

Published
2024
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8. Design of Polarization-Maintaining FBGs Using Polyimide Films to Improve Strain-Temperature Sensing in CFRP Laminates

Author

Andrea Annunziato, Francesco Anelli, James Gates, Christopher Holmes, and Francesco Prudenzano

Subjects
Modeling, fiber gratings, theory and design, sensors, Applied optics. Photonics, TA1501-1820, Optics. Light, QC350-467
Abstract

Uniform Fiber Bragg Grating sensors based on Polarization-Maintaining fibers are designed for simultaneous longitudinal strain and temperature measurement of Carbon Fiber Reinforced Polymer laminates. Panda, Bow tie and Pseudo-rectangle optical fiber shape sections are investigated employing three different embedding methods, for each optical fiber. The simulation accurately takes into account that the fibers are embedded in unidirectional Carbon Fiber Reinforced Polymer and covered between two adhesive polyimide films. An exhaustive, accurate and robust investigation of the mechanisms originating Bragg wavelength shift is developed by considering a complete multiphysical model including: the propagation modes and their interaction, the birefringence, the optomechanical and thermal behaviour of both the optical fiber and the embedding composite material. For the first time, the use of polyimide films is proposed to obtain an increase of temperature sensor sensitivity, reducing the stress-transfer, due to thermal expansion, between the composite laminate and the sensing element. The designed Fiber Bragg Grating sensors are compared and their potential application, for simultaneous strain and temperature measurement of Carbon Fiber Reinforced Polymer is discussed.

Published
2021
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10. Direct UV written waveguides and Bragg gratings in doped planar silica using a 213 nm laser

Author

Q. Salman Ahmed, Paul C. Gow, Christopher Holmes, Paolo L. Mennea, James W. Field, Rex H.S. Bannerman, Devin H. Smith, Corin B.E. Gawith, Peter G.R. Smith, and James C. Gates

Subjects
Other optical materials, Gratings, echelles, Optical beam modulators, Optical waveguides and couplers, Integrated optics, Optical fabrication, surface grinding, Electrical engineering. Electronics. Nuclear engineering, TK1-9971
Abstract

Abstract In this paper, the first demonstration of simultaneous UV written Bragg gratings and waveguides in germanium and boron‐doped planar silica is presented using a 5th harmonic solid‐state nanosecond laser operating at 213 nm wavelength. The fabrication of high‐quality gratings by using a high peak power density, yielding sufficient uniformity and without any surface damage is demonstrated. The photosensitivity of the doped silica layer is investigated by measuring the local effective refractive index of the optical modes. The written gratings are used to measure grating refractive index modulation, grating detuning bandwidth and the waveguide propagation loss with a minimum value of 0.28 ± 0.07 dB cm−1. This paper shows that this new generation of pulsed UV lasers is a promising alternative for conventional longer wavelength CW laser sources used in small spot direct grating writing in doped silica.

Published
2021
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11. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Author

Bo Meng, Steven A. Kemp, Guido Papa, Rawlings Datir, Isabella A.T.M. Ferreira, Sara Marelli, William T. Harvey, Spyros Lytras, Ahmed Mohamed, Giulia Gallo, Nazia Thakur, Dami A. Collier, Petra Mlcochova, Lidia M. Duncan, Alessandro M. Carabelli, Julia C. Kenyon, Andrew M. Lever, Anna De Marco, Christian Saliba, Katja Culap, Elisabetta Cameroni, Nicholas J. Matheson, Luca Piccoli, Davide Corti, Leo C. James, David L. Robertson, Dalan Bailey, Ravindra K. Gupta, Samuel C. Robson, Nicholas J. Loman, Thomas R. Connor, Tanya Golubchik, Rocio T. Martinez Nunez, Catherine Ludden, Sally Corden, Ian Johnston, David Bonsall, Colin P. Smith, Ali R. Awan, Giselda Bucca, M. Estee Torok, Kordo Saeed, Jacqui A. Prieto, David K. Jackson, William L. Hamilton, Luke B. Snell, Catherine Moore, Ewan M. Harrison, Sonia Goncalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Rich Livett, Samuel Moses, Roberto Amato, Sam Nicholls, Matthew Bull, Darren L. Smith, Jeff Barrett, David M. Aanensen, Martin D. Curran, Surendra Parmar, Dinesh Aggarwal, James G. Shepherd, Matthew D. Parker, Sharon Glaysher, Matthew Bashton, Anthony P. Underwood, Nicole Pacchiarini, Katie F. Loveson, Kate E. Templeton, Cordelia F. Langford, John Sillitoe, Thushan I. de Silva, Dennis Wang, Dominic Kwiatkowski, Andrew Rambaut, Justin O’Grady, Simon Cottrell, Matthew T.G. Holden, Emma C. Thomson, Husam Osman, Monique Andersson, Anoop J. Chauhan, Mohammed O. Hassan-Ibrahim, Mara Lawniczak, Alex Alderton, Meera Chand, Chrystala Constantinidou, Meera Unnikrishnan, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Inigo Martincorena, Erik M. Volz, Andrew J. Page, Oliver G. Pybus, Andrew R. Bassett, Cristina V. Ariani, Michael H. Spencer Chapman, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yusri Taha, Martin P. McHugh, Rebecca Dewar, Aminu S. Jahun, Claire McMurray, Sarojini Pandey, James P. McKenna, Andrew Nelson, Gregory R. Young, Clare M. McCann, Scott Elliott, Hannah Lowe, Ben Temperton, Sunando Roy, Anna Price, Sara Rey, Matthew Wyles, Stefan Rooke, Sharif Shaaban, Mariateresa de Cesare, Laura Letchford, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Myra Hosmillo, Áine O’Toole, Andrew R. Hesketh, Richard Stark, Louis du Plessis, Chris Ruis, Helen Adams, Yann Bourgeois, Stephen L. Michell, Dimitris Gramatopoulos, Jonathan Edgeworth, Judith Breuer, John A. Todd, Christophe Fraser, David Buck, Michaela John, Gemma L. Kay, Steve Palmer, Sharon J. Peacock, David Heyburn, Danni Weldon, Esther Robinson, Alan McNally, Peter Muir, Ian B. Vipond, John Boyes, Venkat Sivaprakasam, Tranprit Salluja, Samir Dervisevic, Emma J. Meader, Naomi R. Park, Karen Oliver, Aaron R. Jeffries, Sascha Ott, Ana da Silva Filipe, David A. Simpson, Chris Williams, Jane A.H. Masoli, Bridget A. Knight, Christopher R. Jones, Cherian Koshy, Amy Ash, Anna Casey, Andrew Bosworth, Liz Ratcliffe, Li Xu-McCrae, Hannah M. Pymont, Stephanie Hutchings, Lisa Berry, Katie Jones, Fenella Halstead, Thomas Davis, Christopher Holmes, Miren Iturriza-Gomara, Anita O. Lucaci, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Kathryn Ann Harris, Julianne Rose Brown, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Steven Liggett, Clive Graham, Emma Swindells, Jennifer Collins, Gary Eltringham, Sharon Campbell, Patrick C. McClure, Gemma Clark, Tim J. Sloan, Carl Jones, Jessica Lynch, Ben Warne, Steven Leonard, Jillian Durham, Thomas Williams, Sam T. Haldenby, Nathaniel Storey, Nabil-Fareed Alikhan, Nadine Holmes, Christopher Moore, Matthew Carlile, Malorie Perry, Noel Craine, Ronan A. Lyons, Angela H. Beckett, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, Robert Davies, Beth Blane, Sophia T. Girgis, Mathew A. Beale, Katherine L. Bellis, Matthew J. Dorman, Eleanor Drury, Leanne Kane, Sally Kay, Samantha McGuigan, Rachel Nelson, Liam Prestwood, Shavanthi Rajatileka, Rahul Batra, Rachel J. Williams, Mark Kristiansen, Angie Green, Anita Justice, Adhyana I.K. Mahanama, Buddhini Samaraweera, Nazreen F. Hadjirin, Joshua Quick, Radoslaw Poplawski, Leanne M. Kermack, Nicola Reynolds, Grant Hall, Yasmin Chaudhry, Malte L. Pinckert, Iliana Georgana, Robin J. Moll, Alicia Thornton, Richard Myers, Joanne Stockton, Charlotte A. Williams, Wen C. Yew, Alexander J. Trotter, Amy Trebes, George MacIntyre-Cockett, Alec Birchley, Alexander Adams, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Ember Hilvers, Hannah Jones, Hibo Asad, Jason Coombes, Johnathan M. Evans, Laia Fina, Lauren Gilbert, Lee Graham, Michelle Cronin, Sara Kumziene-Summerhayes, Sarah Taylor, Sophie Jones, Danielle C. Groves, Peijun Zhang, Marta Gallis, Stavroula F. Louka, Igor Starinskij, Chris Jackson, Marina Gourtovaia, Gerry Tonkin-Hill, Kevin Lewis, Jaime M. Tovar-Corona, Keith James, Laura Baxter, Mohammad T. Alam, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Olivia Boyd, Lily Geidelberg, Alex E. Zarebski, Jayna Raghwani, Moritz U.G. Kraemer, Joel Southgate, Benjamin B. Lindsey, Timothy M. Freeman, Jon-Paul Keatley, Joshua B. Singer, Leonardo de Oliveira Martins, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, John Danesh, Wendy Hogsden, Sahar Eldirdiri, Anita Kenyon, Jenifer Mason, Trevor I. Robinson, Alison Holmes, James Price, John A. Hartley, Tanya Curran, Alison E. Mather, Giri Shankar, Rachel Jones, Robin Howe, Sian Morgan, Elizabeth Wastenge, Michael R. Chapman, Siddharth Mookerjee, Rachael Stanley, Wendy Smith, Timothy Peto, David Eyre, Derrick Crook, Gabrielle Vernet, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Declan T. Bradley, Tim Wyatt, Charlotte Beaver, Luke Foulser, Sophie Palmer, Carol M. Churcher, Ellena Brooks, Kim S. Smith, Katerina Galai, Georgina M. McManus, Frances Bolt, Francesc Coll, Lizzie Meadows, Stephen W. Attwood, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Garry P. Scarlett, Sarah Jeremiah, Nikki Smith, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Michelle Wantoch, Dorota Jamrozy, Stephanie Lo, Minal Patel, Verity Hill, Claire M. Bewshea, Sian Ellard, Cressida Auckland, Ian Harrison, Chloe Bishop, Vicki Chalker, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Richard Hopes, Patawee Asamaphan, Marc O. Niebel, Rory N. Gunson, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Holli Carden, Nicholas W. Machin, Kathryn A. Jackson, Shazaad S.Y. Ahmad, Ryan P. George, Lance Turtle, Elaine O’Toole, Joanne Watts, Cassie Breen, Angela Cowell, Adela Alcolea-Medina, Themoula Charalampous, Amita Patel, Lisa J. Levett, Judith Heaney, Aileen Rowan, Graham P. Taylor, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adam P. Westhorpe, Riaz Jannoo, Helen L. Lowe, Angeliki Karamani, Leah Ensell, Wendy Chatterton, Monika Pusok, Ashok Dadrah, Amanda Symmonds, Graciela Sluga, Zoltan Molnar, Paul Baker, Stephen Bonner, Sarah Essex, Edward Barton, Debra Padgett, Garren Scott, Jane Greenaway, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Veena Raviprakash, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Jonathan Moore, Susanne Stonehouse, Louise Smith, Rose K. Davidson, Luke Bedford, Lindsay Coupland, Victoria Wright, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Nichola Duckworth, Sarah Walsh, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Stephen Kidd, Rebecca Williams, Laura Gifford, Kelly Bicknell, Sarah Wyllie, Allyson Lloyd, Robert Impey, Cassandra S. Malone, Benjamin J. Cogger, Nick Levene, Lynn Monaghan, Alexander J. Keeley, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Emma Betteridge, Ben W. Farr, Scott Goodwin, Michael A. Quail, Carol Scott, Lesley Shirley, Scott A.J. Thurston, Diana Rajan, Iraad F. Bronner, Louise Aigrain, Nicholas M. Redshaw, Stefanie V. Lensing, Shane McCarthy, Alex Makunin, Carlos E. Balcazar, Michael D. Gallagher, Kathleen A. Williamson, Thomas D. Stanton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Hassan Hartman, Nikos Manesis, Vineet Patel, Juan Ledesma, Katherine A. Twohig, Elias Allara, Clare Pearson, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Paul E. Brown, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Katherine L. Smollett, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Seema Nickbakhsh, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J. Webster, Chloe L. Fisher, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Gaia Nebbia, Flavia Flaviani, Alberto C. Cerda, Tammy V. Merrill, Rebekah E. Wilson, Marius Cotic, Nadua Bayzid, Thomas Thompson, Erwan Acheson, Steven Rushton, Sarah O’Brien, David J. Baker, Steven Rudder, Alp Aydin, Fei Sang, Johnny Debebe, Sarah Francois, Tetyana I. Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, Angela Marchbank, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Mari Morgan, Robert Beer, Safiah Afifi, Trudy Workman, William Fuller, Catherine Bresner, Adrienn Angyal, Luke R. Green, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Max Whiteley, James Bonfield, Christoph Puethe, Andrew Whitwham, Jennifier Liddle, Will Rowe, Igor Siveroni, Thanh Le-Viet, Amy Gaskin, Rob Johnson, Irina Abnizova, Mozam Ali, Laura Allen, Ralph Anderson, Cristina Ariani, Siobhan Austin-Guest, Sendu Bala, Jeffrey Barrett, Andrew Bassett, Kristina Battleday, James Beal, Mathew Beale, Sam Bellany, Tristram Bellerby, Katie Bellis, Duncan Berger, Matt Berriman, Paul Bevan, Simon Binley, Jason Bishop, Kirsty Blackburn, Nick Boughton, Sam Bowker, Timothy Brendler-Spaeth, Iraad Bronner, Tanya Brooklyn, Sarah Kay Buddenborg, Robert Bush, Catarina Caetano, Alex Cagan, Nicola Carter, Joanna Cartwright, Tiago Carvalho Monteiro, Liz Chapman, Tracey-Jane Chillingworth, Peter Clapham, Richard Clark, Adrian Clarke, Catriona Clarke, Daryl Cole, Elizabeth Cook, Maria Coppola, Linda Cornell, Clare Cornwell, Craig Corton, Abby Crackett, Alison Cranage, Harriet Craven, Sarah Craw, Mark Crawford, Tim Cutts, Monika Dabrowska, Matt Davies, Joseph Dawson, Callum Day, Aiden Densem, Thomas Dibling, Cat Dockree, David Dodd, Sunil Dogga, Matthew Dorman, Gordon Dougan, Martin Dougherty, Alexander Dove, Lucy Drummond, Monika Dudek, Laura Durrant, Elizabeth Easthope, Sabine Eckert, Pete Ellis, Ben Farr, Michael Fenton, Marcella Ferrero, Neil Flack, Howerd Fordham, Grace Forsythe, Matt Francis, Audrey Fraser, Adam Freeman, Anastasia Galvin, Maria Garcia-Casado, Alex Gedny, Sophia Girgis, James Glover, Oliver Gould, Andy Gray, Emma Gray, Coline Griffiths, Yong Gu, Florence Guerin, Will Hamilton, Hannah Hanks, Ewan Harrison, Alexandria Harrott, Edward Harry, Julia Harvison, Paul Heath, Anastasia Hernandez-Koutoucheva, Rhiannon Hobbs, Dave Holland, Sarah Holmes, Gary Hornett, Nicholas Hough, Liz Huckle, Lena Hughes-Hallet, Adam Hunter, Stephen Inglis, Sameena Iqbal, Adam Jackson, David Jackson, Carlos Jimenez Verdejo, Matthew Jones, Kalyan Kallepally, Keely Kay, Jon Keatley, Alan Keith, Alison King, Lucy Kitchin, Matt Kleanthous, Martina Klimekova, Petra Korlevic, Ksenia Krasheninnkova, Greg Lane, Cordelia Langford, Adam Laverack, Katharine Law, Stefanie Lensing, Amanah Lewis-Wade, Jennifer Liddle, Quan Lin, Sarah Lindsay, Sally Linsdell, Rhona Long, Jamie Lovell, Jon Lovell, James Mack, Mark Maddison, Aleksei Makunin, Irfan Mamun, Jenny Mansfield, Neil Marriott, Matt Martin, Matthew Mayho, Jo McClintock, Sandra McHugh, Liz MapcMinn, Carl Meadows, Emily Mobley, Robin Moll, Maria Morra, Leanne Morrow, Kathryn Murie, Sian Nash, Claire Nathwani, Plamena Naydenova, Alexandra Neaverson, Ed Nerou, Jon Nicholson, Tabea Nimz, Guillaume G. Noell, Sarah O’Meara, Valeriu Ohan, Charles Olney, Doug Ormond, Agnes Oszlanczi, Yoke Fei Pang, Barbora Pardubska, Naomi Park, Aaron Parmar, Gaurang Patel, Maggie Payne, Sharon Peacock, Arabella Petersen, Deborah Plowman, Tom Preston, Michael Quail, Richard Rance, Suzannah Rawlings, Nicholas Redshaw, Joe Reynolds, Mark Reynolds, Simon Rice, Matt Richardson, Connor Roberts, Katrina Robinson, Melanie Robinson, David Robinson, Hazel Rogers, Eduardo Martin Rojo, Daljit Roopra, Mark Rose, Luke Rudd, Ramin Sadri, Nicholas Salmon, David Saul, Frank Schwach, Phil Seekings, Alison Simms, Matt Sinnott, Shanthi Sivadasan, Bart Siwek, Dale Sizer, Kenneth Skeldon, Jason Skelton, Joanna Slater-Tunstill, Lisa Sloper, Nathalie Smerdon, Chris Smith, Christen Smith, James Smith, Katie Smith, Michelle Smith, Sean Smith, Tina Smith, Leighton Sneade, Carmen Diaz Soria, Catarina Sousa, Emily Souster, Andrew Sparkes, Michael Spencer-Chapman, Janet Squares, Robert Stanley, Claire Steed, Tim Stickland, Ian Still, Mike Stratton, Michelle Strickland, Allen Swann, Agnieszka Swiatkowska, Neil Sycamore, Emma Swift, Edward Symons, Suzanne Szluha, Emma Taluy, Nunu Tao, Katy Taylor, Sam Taylor, Stacey Thompson, Mark Thompson, Mark Thomson, Nicholas Thomson, Scott Thurston, Dee Toombs, Benjamin Topping, Jaime Tovar-Corona, Daniel Ungureanu, James Uphill, Jana Urbanova, Philip Jansen Van, Valerie Vancollie, Paul Voak, Danielle Walker, Matthew Walker, Matt Waller, Gary Ward, Charlie Weatherhogg, Niki Webb, Alan Wells, Eloise Wells, Luke Westwood, Theo Whipp, Thomas Whiteley, Georgia Whitton, Sara Widaa, Mia Williams, Mark Wilson, and Sean Wright

Subjects
SARS-CoV-2, COVID-19, antibody escape, neutralizing antibodies, infectivity, spike mutation, Biology (General), QH301-705.5
Abstract

Summary: We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

Published
2021
Full Text
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12. Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Author

Mark S Graham, PhD, Carole H Sudre, PhD, Anna May, MA, Michela Antonelli, PhD, Benjamin Murray, MSc, Thomas Varsavsky, MSc, Kerstin Kläser, MSc, Liane S Canas, PhD, Erika Molteni, PhD, Marc Modat, PhD, David A Drew, PhD, Long H Nguyen, MD, Lorenzo Polidori, MSc, Somesh Selvachandran, MSc, Christina Hu, MA, Joan Capdevila, PhD, Alexander Hammers, ProfPhD, Andrew T Chan, ProfMD, Jonathan Wolf, MA, Tim D Spector, ProfPhD, Claire J Steves, PhD, Sebastien Ourselin, ProfPhD, Cherian Koshy, Amy Ash, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Jessica Lynch, Stephen Kidd, Derek J Fairley, Tanya Curran, James P McKenna, Helen Adams, Christophe Fraser, Tanya Golubchik, David Bonsall, Mohammed O Hassan-Ibrahim, Cassandra S Malone, Benjamin J Cogger, Michelle Wantoch, Nicola Reynolds, Ben Warne, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Michaela John, Robert Beer, Safiah Afifi, Sian Morgan, Angela Marchbank, Anna Price, Christine Kitchen, Huw Gulliver, Ian Merrick, Joel Southgate, Martyn Guest, Robert Munn, Trudy Workman, Thomas R Connor, William Fuller, Catherine Bresner, Luke B Snell, Amita Patel, Themoula Charalampous, Gaia Nebbia, Rahul Batra, Jonathan Edgeworth, Samuel C Robson, Angela H Beckett, David M Aanensen, Anthony P Underwood, Corin A Yeats, Khalil Abudahab, Ben EW Taylor, Mirko Menegazzo, Gemma Clark, Wendy Smith, Manjinder Khakh, Vicki M Fleming, Michelle M Lister, Hannah C Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Carl Jones, Christopher Holmes, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Veena Raviprakash, Sharon Campbell, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Matthew W Loose, Nadine Holmes, Christopher Moore, Matthew Carlile, Victoria Wright, Fei Sang, Johnny Debebe, Francesc Coll, Adrian W Signell, Gilberto Betancor, Harry D Wilson, Sahar Eldirdiri, Anita Kenyon, Thomas Davis, Oliver G Pybus, Louis du Plessis, Alex E Zarebski, Jayna Raghwani, Moritz UG Kraemer, Sarah Francois, Stephen W Attwood, Tetyana I Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, M. Estee Torok, William L Hamilton, Ian G Goodfellow, Grant Hall, Aminu S Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L Pinckert, Iliana Georgana, Samuel Moses, Hannah Lowe, Luke Bedford, Jonathan Moore, Susanne Stonehouse, Chloe L Fisher, Ali R Awan, John BoYes, Judith Breuer, Kathryn Ann Harris, Julianne Rose Brown, Divya Shah, Laura Atkinson, Jack CD Lee, Nathaniel Storey, Flavia Flaviani, Adela Alcolea-Medina, Rebecca Williams, Gabrielle Vernet, Michael R Chapman, Lisa J Levett, Judith Heaney, Wendy Chatterton, Monika Pusok, Li Xu-McCrae, Darren L Smith, Matthew Bashton, Gregory R Young, Alison Holmes, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Frances Bolt, James Price, Siddharth Mookerjee, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Igor Siveroni, Rob Johnson, Olivia Boyd, Lily Geidelberg, Erik M Volz, Aileen Rowan, Graham P Taylor, Katherine L Smollett, Nicholas J Loman, Joshua Quick, Claire McMurray, Joanne Stockton, Sam Nicholls, Will Rowe, Radoslaw Poplawski, Alan McNally, Rocio T Martinez Nunez, Jenifer Mason, Trevor I Robinson, Elaine O'Toole, Joanne Watts, Cassie Breen, Angela Cowell, Graciela Sluga, Nicholas W Machin, Shazaad S Y Ahmad, Ryan P George, Fenella Halstead, Venkat Sivaprakasam, Wendy Hogsden, Chris J Illingworth, Chris Jackson, Emma C Thomson, James G Shepherd, Patawee Asamaphan, Marc O Niebel, Kathy K Li, Rajiv N Shah, Natasha G Jesudason, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N Carmichael, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Igor Starinskij, Ana da Silva Filipe, David L Robertson, Richard J Orton, Joseph Hughes, Sreenu Vattipally, Joshua B Singer, Seema Nickbakhsh, Antony D Hale, Louissa R Macfarlane-Smith, Katherine L Harper, Holli Carden, Yusri Taha, Brendan AI Payne, Shirelle Burton-Fanning, Sheila Waugh, Jennifer Collins, Gary Eltringham, Steven Rushton, Sarah O'Brien, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Kate E Templeton, Martin P McHugh, Rebecca Dewar, Elizabeth Wastenge, Samir Dervisevic, Rachael Stanley, Emma J Meader, Lindsay Coupland, Louise Smith, Clive Graham, Edward Barton, Debra Padgett, Garren Scott, Emma Swindells, Jane Greenaway, Andrew Nelson, Clare M McCann, Wen C Yew, Monique Andersson, Timothy Peto, Anita Justice, David Eyre, Derrick Crook, Tim J Sloan, Nichola Duckworth, Sarah Walsh, Anoop J Chauhan, Sharon Glaysher, Kelly Bicknell, Sarah Wyllie, Scott Elliott, Allyson Lloyd, Robert Impey, Nick Levene, Lynn Monaghan, Declan T Bradley, Tim Wyatt, Elias Allara, Clare Pearson, Husam Osman, Andrew Bosworth, Esther Robinson, Peter Muir, Ian B Vipond, Richard Hopes, Hannah M Pymont, Stephanie Hutchings, Martin D Curran, Surendra Parmar, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Meera Chand, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Alicia Thornton, Richard Myers, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Ian Harrison, Hassan Hartman, Nikos Manesis, Vineet Patel, Chloe Bishop, Vicki Chalker, Juan Ledesma, Katherine A Twohig, Matthew T.G. Holden, Sharif Shaaban, Alec Birchley, Alexander Adams, Alisha Davies, Amy Gaskin, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Catherine Moore, Chris Williams, David Heyburn, Elen De Lacy, Ember Hilvers, Fatima Downing, Giri Shankar, Hannah Jones, Hibo Asad, Jason Coombes, Joanne Watkins, Johnathan M Evans, Laia Fina, Laura Gifford, Lauren Gilbert, Lee Graham, Malorie Perry, Mari Morgan, Matthew Bull, Michelle Cronin, Nicole Pacchiarini, Noel Craine, Rachel Jones, Robin Howe, Sally Corden, Sara Rey, Sara Kumziene-SummerhaYes, Sarah Taylor, Simon Cottrell, Sophie Jones, Sue Edwards, Justin O'Grady, Andrew J Page, Alison E Mather, David J Baker, Steven Rudder, Alp Aydin, Gemma L Kay, Alexander J Trotter, Nabil-Fareed Alikhan, Leonardo de Oliveira Martins, Thanh Le-Viet, Lizzie Meadows, Anna Casey, Liz Ratcliffe, David A Simpson, Zoltan Molnar, Thomas Thompson, Erwan Acheson, Jane AH Masoli, Bridget A Knight, Sian Ellard, Cressida Auckland, Christopher R Jones, Tabitha W Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Ashok Dadrah, Amanda Symmonds, Tranprit Saluja, Yann Bourgeois, Garry P Scarlett, Katie F Loveson, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, David G Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Steven Liggett, Paul Baker, Stephen Bonner, Sarah Essex, Ronan A Lyons, Kordo Saeed, Adhyana I.K Mahanama, Buddhini Samaraweera, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Rachel J Williams, Mark Kristiansen, Sunando Roy, Charlotte A Williams, Marius Cotic, Nadua Bayzid, Adam P Westhorpe, John A Hartley, Riaz Jannoo, Helen L Lowe, Angeliki Karamani, Leah Ensell, Jacqui A Prieto, Sarah Jeremiah, Dimitris Grammatopoulos, Sarojini Pandey, Lisa Berry, Katie Jones, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Colin P Smith, Giselda Bucca, Andrew R Hesketh, Beth Blane, Sophia T Girgis, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K Gill, Joana Dias, Ellen E Higginson, Mailis Maes, Jamie Young, Leanne M Kermack, Ravi Kumar Gupta, Catherine Ludden, Sharon J Peacock, Sophie Palmer, Carol M Churcher, Nazreen F Hadjirin, Alessandro M Carabelli, Ellena Brooks, Kim S Smith, Katerina Galai, Georgina M McManus, Chris Ruis, Rose K Davidson, Andrew Rambaut, Thomas Williams, Carlos E Balcazar, Michael D Gallagher, Áine O'Toole, Stefan Rooke, Verity Hill, Kathleen A Williamson, Thomas D Stanton, Stephen L Michell, Claire M Bewshea, Ben Temperton, Michelle L Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W Harrison, Christine M Sambles, David J Studholme, Aaron R Jeffries, Alistair C Darby, Julian A Hiscox, Steve Paterson, Miren Iturriza-Gomara, Kathryn A Jackson, Anita O Lucaci, Edith E Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Lance Turtle, Sam T Haldenby, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J Webster, Thushan I de Silva, Nikki Smith, Adrienn Angyal, Benjamin B Lindsey, Danielle C Groves, Luke R Green, Dennis Wang, Timothy M Freeman, Matthew D Parker, Alexander J Keeley, Paul J Parsons, Rachel M Tucker, Rebecca Brown, Matthew Wyles, Max Whiteley, Peijun Zhang, Marta Gallis, Stavroula F Louka, Chrystala Constantinidou, Meera Unnikrishnan, Sascha Ott, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Richard Stark, Laura Baxter, Mohammad T. Alam, Paul E Brown, Dinesh Aggarwal, Alberto C Cerda, Tammy V Merrill, Rebekah E Wilson, Patrick C McClure, Joseph G Chappell, Theocharis Tsoleridis, Jonathan Ball, David Buck, John A Todd, Angie Green, Amy Trebes, George MacIntyre-Cockett, Mariateresa de Cesare, Alex Alderton, Roberto Amato, Cristina V Ariani, Mathew A Beale, Charlotte Beaver, Katherine L Bellis, Emma Betteridge, James Bonfield, John Danesh, Matthew J Dorman, Eleanor Drury, Ben W Farr, Luke Foulser, Sonia Goncalves, Scott Goodwin, Marina Gourtovaia, Ewan M Harrison, David K Jackson, Dorota Jamrozy, Ian Johnston, Leanne Kane, Sally Kay, Jon-Paul Keatley, Dominic Kwiatkowski, Cordelia F Langford, Mara Lawniczak, Laura Letchford, Rich Livett, Stephanie Lo, Inigo Martincorena, Samantha McGuigan, Rachel Nelson, Steve Palmer, Naomi R Park, Minal Patel, Liam Prestwood, Christoph Puethe, Michael A Quail, Shavanthi Rajatileka, Carol Scott, Lesley Shirley, John Sillitoe, Michael H Spencer Chapman, Scott AJ Thurston, Gerry Tonkin-Hill, Danni Weldon, Diana Rajan, Iraad F Bronner, Louise Aigrain, Nicholas M Redshaw, Stefanie V Lensing, Robert Davies, Andrew Whitwham, Jennifier Liddle, Kevin Lewis, Jaime M Tovar-Corona, Steven Leonard, Jillian Durham, Andrew R Bassett, Shane McCarthy, Robin J Moll, Keith James, Karen Oliver, Alex Makunin, Jeff Barrett, and Rory N Gunson

Subjects
Public aspects of medicine, RA1-1270
Abstract

Summary: Background: The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods: We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings: From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation: The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding: Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society.

Published
2021
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13. Reporting guidelines for clinical trial reports for interventions involving artificial intelligence: the CONSORT-AI extension

Author

Xiaoxuan Liu, MBChB, Samantha Cruz Rivera, PhD, David Moher, PhD, Melanie J Calvert, ProfPhD, Alastair K Denniston, ProfPhD, Hutan Ashrafian, Andrew L Beam, An-Wen Chan, Gary S Collins, Ara DarziJonathan J Deeks, M Khair ElZarrad, Cyrus Espinoza, Andre Esteva, Livia Faes, Lavinia Ferrante di Ruffano, John Fletcher, Robert Golub, Hugh Harvey, Charlotte Haug, Christopher Holmes, Adrian Jonas, Pearse A Keane, Christopher J Kelly, Aaron Y Lee, Cecilia S Lee, Elaine Manna, James Matcham, Melissa McCradden, Joao Monteiro, Cynthia Mulrow, Luke Oakden-Rayner, Dina Paltoo, Maria Beatrice Panico, Gary Price, Samuel Rowley, Richard Savage, Rupa Sarkar, Sebastian J Vollmer, and Christopher Yau

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Summary: The CONSORT 2010 statement provides minimum guidelines for reporting randomised trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders), and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human–AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret, and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes.

Published
2020
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14. Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI extension

Author

Samantha Cruz Rivera, PhD, Xiaoxuan Liu, MBChB, An-Wen Chan, MD, Alastair K Denniston, ProfPhD, Melanie J Calvert, ProfPhD, Hutan Ashrafian, Andrew L Beam, Gary S Collins, Ara Darzi, Jonathan J Deeks, M Khair ElZarrad, Cyrus Espinoza, Andre Esteva, Livia Faes, Lavinia Ferrante di Ruffano, John Fletcher, Robert Golub, Hugh Harvey, Charlotte Haug, Christopher Holmes, Adrian Jonas, Pearse A Keane, Christopher J Kelly, Aaron Y Lee, Cecilia S Lee, Elaine Manna, James Matcham, Melissa McCradden, David Moher, Joao Monteiro, Cynthia Mulrow, Luke Oakden-Rayner, Dina Paltoo, Maria Beatrice Panico, Gary Price, Samuel Rowley, Richard Savage, Rupa Sarkar, Sebastian J Vollmer, and Christopher Yau

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Summary: The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes. The SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trial protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 26 candidate items, which were consulted upon by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The SPIRIT-AI extension includes 15 new items that were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations for the handling of input and output data, the human–AI interaction and analysis of error cases. SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer reviewers, as well as the general readership, to understand, interpret, and critically appraise the design and risk of bias for a planned clinical trial.

Published
2020
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15. Effects of Sea Salt Aerosol Emissions for Marine Cloud Brightening on Atmospheric Chemistry: Implications for Radiative Forcing

Author

Hannah M. Horowitz, Christopher Holmes, Alicia Wright, Tomás Sherwen, Xuan Wang, Mat Evans, Jiayue Huang, Lyatt Jaeglé, Qianjie Chen, Shuting Zhai, and Becky Alexander

Subjects
geoengineering, atmospheric chemistry, sea salt aerosols, reactive halogens, marine cloud brightening, Geophysics. Cosmic physics, QC801-809
Abstract

Abstract Marine cloud brightening (MCB) is proposed to offset global warming by emitting sea salt aerosols to the tropical marine boundary layer, which increases aerosol and cloud albedo. Sea salt aerosol is the main source of tropospheric reactive chlorine (Cly) and bromine (Bry). The effects of additional sea salt on atmospheric chemistry have not been explored. We simulate sea salt aerosol injections for MCB under two scenarios (212–569 Tg/a) in the GEOS‐Chem global chemical transport model, only considering their impacts as a halogen source. Globally, tropospheric Cly and Bry increase (20–40%), leading to decreased ozone (−3 to −6%). Consequently, OH decreases (−3 to −5%), which increases the methane lifetime (3–6%). Our results suggest that the chemistry of the additional sea salt leads to minor total radiative forcing compared to that of the sea salt aerosol itself (~2%) but may have potential implications for surface ozone pollution in tropical coastal regions.

Published
2020
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16. Recycling and Reprocessing of Thermoplastic Polyurethane Materials towards Nonwoven Processing

Author

Bastian Wölfel, Andreas Seefried, Vincent Allen, Joachim Kaschta, Christopher Holmes, and Dirk W. Schubert

Subjects
recycling, reprocessing, TPU, thermoplastic elastomers, TPE, thermoplastic, Organic chemistry, QD241-441
Abstract

Thermoplastic Polyurethane (TPU) is a unique tailorable material due to the interactions of hard and soft segments within the block-copolymer chain. Therefore, various products can be created out of this material. A general trend towards a circular economy with regards to sustainability in combination with TPU being comparably expensive is of high interest to recycle production as well as post-consumer wastes. A systematic study investigating the property changes of TPU is provided, focusing on two major aspects. The first aspect focuses on characterizing the change of basic raw material properties through recycling. Gel permeation chromatography (GPC) and processing load during extrusion indicate a decrease in molar mass and consequently viscosity with an increasing number of recycling cycles. This leads to a change in morphology at lower molar mass, characterized by differential scanning calorimetry (DSC) and visualized by atomic force microscope (AFM). The change in molar mass and morphology with increasing number of recycling cycles has an impact on the material performance under tensile stress. The second aspect describes processing of the recycled TPU to nonwoven fabrics utilizing melt blowing, which are evaluated with respect to relevant mechanical properties and related to molecular characteristics. The molar mass turns out to be the governing factor regarding mechanical performance and processing conditions for melt blown products.

Published
2020
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17. Galectin-8 as an immunosuppressor in experimental autoimmune encephalomyelitis and a target of human early prognostic antibodies in multiple sclerosis.

Author

Evelyn Pardo, Claudia Cárcamo, Reinaldo Uribe-San Martín, Ethel Ciampi, Fabián Segovia-Miranda, Cristobal Curkovic-Peña, Fabián Montecino, Christopher Holmes, Juan Enrique Tichauer, Eric Acuña, Francisco Osorio-Barrios, Marjorie Castro, Priscilla Cortes, Claudia Oyanadel, David M Valenzuela, Rodrigo Pacheco, Rodrigo Naves, Andrea Soza, and Alfonso González

Subjects
Medicine, Science
Abstract

Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac-Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide-induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. β-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune-surveillance circuit. In addition, we show that MS patients generate function-blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal-8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS.

Published
2017
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18. Photonic Microcantilevers With Interferometric Bragg Grating Interrogation

Author

Lewis G. Carpenter, Christopher Holmes, Benjamin D. Snow, James C. Gates, and Peter G. R. Smith

Subjects
Micro and nano opto-electro-mechanical systems (MOEMS), sensors, waveguide devices, Applied optics. Photonics, TA1501-1820, Optics. Light, QC350-467
Abstract

Germanosilicate glass microcantilevers are fabricated featuring an integrated Fabry-Pérot interferometer. Direct UV writing of single-mode planar waveguides and Bragg gratings is combined with physical micromachining, using a precision dicing saw, to realize glass microcantilevers on a silicon platform. The device presented here has a wavelength shift force sensitivity of 330 nm/N, which is calibrated using a surface profilometer measurement and is an order of magnitude better than current state-of-the-art Bragg-grating-based sensors. The device also shows an approximately tenfold increase in amplitude modulation compared with a similar device architecture utilizing a single Gaussian-apodized Bragg grating. By forming the Fabry-Pérot cavity around the point of greatest strain, we reduce the unwanted effects of grating chirp as the cantilever is deflected and relate the performance to a mechanical model that relates cavity phase shift to deflection.

Published
2012
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19. Complete Mode Structure Analysis of Tilted Bragg Grating Refractometers in Planar Waveguides Toward Absolute Index Measurement

Author

Keith R. Daly, Christopher Holmes, James C. Gates, Peter G. R. Smith, and Giampaolo D'Alessandro

Subjects
Waveguides, plasmonics, gratings, sensors, Applied optics. Photonics, TA1501-1820, Optics. Light, QC350-467
Abstract

Tilted Bragg grating refractometers are ideal devices for sensing applications. They work by diffracting light from a confined core mode into a series of well-defined cladding modes that are sensitive to the refractive index of an adjacent fluid. Using the Cauchy integral method, we find the modes of a ridge waveguide refractometer. To gain good agreement with the experiment, the method requires us to take into account the dispersion and the 2-D geometry of the waveguide. The resulting modes are then used to predict the coupling dips in the reflection spectrum. Comparison with experimental measurements verifies the ability of this method to accurately determine the mode structure in the waveguide and, with minimal calibration, the refractive index of the adjacent fluid with error less than 2 ×10-4.

Published
2011
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20. Elusive copy number variation in the mouse genome.

Author

Avigail Agam, Binnaz Yalcin, Amarjit Bhomra, Matthew Cubin, Caleb Webber, Christopher Holmes, Jonathan Flint, and Richard Mott

Subjects
Medicine, Science
Abstract

Array comparative genomic hybridization (aCGH) to detect copy number variants (CNVs) in mammalian genomes has led to a growing awareness of the potential importance of this category of sequence variation as a cause of phenotypic variation. Yet there are large discrepancies between studies, so that the extent of the genome affected by CNVs is unknown. We combined molecular and aCGH analyses of CNVs in inbred mouse strains to investigate this question.Using a 2.1 million probe array we identified 1,477 deletions and 499 gains in 7 inbred mouse strains. Molecular characterization indicated that approximately one third of the CNVs detected by the array were false positives and we estimate the false negative rate to be more than 50%. We show that low concordance between studies is largely due to the molecular nature of CNVs, many of which consist of a series of smaller deletions and gains interspersed by regions where the DNA copy number is normal.Our results indicate that CNVs detected by arrays may be the coincidental co-localization of smaller CNVs, whose presence is more likely to perturb an aCGH hybridization profile than the effect of an isolated, small, copy number alteration. Our findings help explain the hitherto unexplored discrepancies between array-based studies of copy number variation in the mouse genome.

Published
2010
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21. The role of demography and markets in determining deforestation rates near Ranomafana National Park, Madagascar.

Author

Christopher P Brooks, Christopher Holmes, Karen Kramer, Barry Barnett, and Timothy H Keitt

Subjects
Medicine, Science
Abstract

The highland forests of Madagascar are home to some of the world's most unique and diverse flora and fauna and to some of its poorest people. This juxtaposition of poverty and biodiversity is continually reinforced by rapid population growth, which results in increasing pressure on the remaining forest habitat in the highland region, and the biodiversity therein. Here we derive a mathematical expression for the subsistence of households to assess the role of markets and household demography on deforestation near Ranomafana National Park. In villages closest to urban rice markets, households were likely to clear less land than our model predicted, presumably because they were purchasing food at market. This effect was offset by the large number of migrant households who cleared significantly more land between 1989-2003 than did residents throughout the region. Deforestation by migrant households typically occurred after a mean time lag of 9 years. Analyses suggest that while local conservation efforts in Madagascar have been successful at reducing the footprint of individual households, large-scale conservation must rely on policies that can reduce the establishment of new households in remaining forested areas.

Published
2009
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27. Effects of Curvature on Flexible Bragg Grating in Off-Axis Core: Theory and Experiment

Author

Francesco Anelli, Andrea Annunziato, Mike Godfrey, Antonella Maria Loconsole, Christopher Holmes, and Francesco Prudenzano

Subjects
Electromagnetic waveguides, Bragg sensor, Bragg gratings, optical fiber devices, Refractive index, Atomic and Molecular Physics, and Optics, Optical waveguides, gratings, Optical variables control, curvature, Optical fibers, Optical refraction, Electromagnetic analysis
Published
2023

29. Difficult or impossible facemask ventilation in children with difficult tracheal intubation: a retrospective analysis of the PeDI registry

Author

Annery G. Garcia-Marcinkiewicz, Lisa K. Lee, Bishr Haydar, John E. Fiadjoe, Clyde T. Matava, Pete G. Kovatsis, James Peyton, Mary L. Stein, Raymond Park, Brad M. Taicher, Thomas W. Templeton, Benjamin B. Bruins, Paul Stricker, Elizabeth K. Laverriere, Justin L. Lockman, Brian Struyk, Christopher Ward, Akira Nishisaki, Ramesh Kodavatiganti, Rodrigo J. Daly Guris, Luis Sequera-Ramos, Mark S. Teen, Ayodele Oke, Grace Hsu, Arul Lingappan, Chinyere Egbuta, Stephen Flynn, Lina Sarmiento, Tally Goldfarb, Edgar E. Kiss, Patrick N. Olomu, Peter Szmuk, Sam Mireles, Andrea Murray, Simon Whyte, Ranu Jain, Maria Matuszczak, Agnes Hunyady, Adrian Bosenberg, See Tham, Daniel Low, Christopher Holmes, Stefan Sabato, Nicholas Dalesio, Robert Greenberg, Angela Lucero, Paul Reynolds, Ian Lewis, Charles Schrock, Sydney Nykiel-Bailey, Elizabeth Starker, Judit Szolnoki, Melissa Brooks-Peterson, Somaletha Bhattacharya, Nicholas E. Burjek, Narasimhan Jagannathan, David Lardner, Scott Watkins, Christy Crockett, John Moore, Sara Robertson, Madhankumar Sathyamoorthy, Franklin Chiao, Jasmine Patel, Aarti Sharma, Piedad Echeverry Marin, Carolina Pérez-Pradilla, Neeta Singh, Britta S. von Ungern-Sternberg, David Sommerfield, Guelay Bilen-Rosas, Hilana Lewkowitz-Shpuntoff, Pilar Castro, N. Ricardo Riveros Perez, Jurgen C. de Graaff, Eduardo Vega, Alejandro González, Paola Ostermann, Kasia Rubin, Charles (Ted) Lord, Angela Lee, Eugenie Heitmiller, Songyos Valairucha, Priti Dalal, Thanh Tran, Ihab Ayad, Mohamed Rehman, Allison Fernandez, Lillian Zamora, Niroop Ravula, Sadiq Shaik, and Anesthesiology

Subjects
Anesthesiology and Pain Medicine
Abstract

Background: Difficult facemask ventilation is perilous in children whose tracheas are difficult to intubate. We hypothesised that certain physical characteristics and anaesthetic factors are associated with difficult mask ventilation in paediatric patients who also had difficult tracheal intubation. Methods: We queried a multicentre registry for children who experienced “difficult” or “impossible” facemask ventilation. Patient and case factors known before mask ventilation attempt were included for consideration in this regularised multivariable regression analysis. Incidence of complications, and frequency and efficacy of rescue placement of a supraglottic airway device were also tabulated. Changes in quality of mask ventilation after injection of a neuromuscular blocking agent were assessed. Results: The incidence of difficult mask ventilation was 9% (483 of 5453 patients). Infants and patients having increased weight, being less than 5th percentile in weight for age, or having Treacher-Collins syndrome, glossoptosis, or limited mouth opening were more likely to have difficult mask ventilation. Anaesthetic induction using facemask and opioids was associated with decreased risk of difficult mask ventilation. The incidence of complications was significantly higher in patients with “difficult” mask ventilation than in patients without. Rescue placement of a supraglottic airway improved ventilation in 71% (96 of 135) of cases. Administration of neuromuscular blocking agents was more frequently associated with improvement or no change in quality of ventilation than with worsening. Conclusions: Certain abnormalities on physical examination should increase suspicion of possible difficult facemask ventilation. Rescue use of a supraglottic airway device in children with difficult or impossible mask ventilation should be strongly considered.

Published
2023

30. Advancing data science in drug development through an innovative computational framework for data sharing and statistical analysis

Author

Thomas E. Nichols, Piet Aarden, E. Straiton, Sibylle Haemmerle, Aimee Readie, Greg Ligozio, Karine Lheritier, M.-C. Laramee, K. El Emam, Janice Branson, Daniel J. Delbarre, Christopher Holmes, Habib Ganjgahi, Soroosh Afyouni, C. H. Kwok, Stephen Gardiner, D. M. West, Peter Krusche, D. A. Haering, T. F. Hofmann, L. F. Kelly, Luis Santos, Ann-Marie Mallon, Frank Dahlke, and Adam Huffman

Subjects
Medicine (General), Databases, Factual, Epidemiology, Computer science, Relational database, Data management, Big data, Health Informatics, R5-920, Drug Development, Machine learning, Humans, Modalities, Information Dissemination, business.industry, Data Science, Data science, Data anonymisation, Data set, Clinical trial, Data sharing, Technical Advance, Research Design, Informatics, business
Abstract

Background Novartis and the University of Oxford’s Big Data Institute (BDI) have established a research alliance with the aim to improve health care and drug development by making it more efficient and targeted. Using a combination of the latest statistical machine learning technology with an innovative IT platform developed to manage large volumes of anonymised data from numerous data sources and types we plan to identify novel patterns with clinical relevance which cannot be detected by humans alone to identify phenotypes and early predictors of patient disease activity and progression. Method The collaboration focuses on highly complex autoimmune diseases and develops a computational framework to assemble a research-ready dataset across numerous modalities. For the Multiple Sclerosis (MS) project, the collaboration has anonymised and integrated phase II to phase IV clinical and imaging trial data from ≈35,000 patients across all clinical phenotypes and collected in more than 2200 centres worldwide. For the “IL-17” project, the collaboration has anonymised and integrated clinical and imaging data from over 30 phase II and III Cosentyx clinical trials including more than 15,000 patients, suffering from four autoimmune disorders (Psoriasis, Axial Spondyloarthritis, Psoriatic arthritis (PsA) and Rheumatoid arthritis (RA)). Results A fundamental component of successful data analysis and the collaborative development of novel machine learning methods on these rich data sets has been the construction of a research informatics framework that can capture the data at regular intervals where images could be anonymised and integrated with the de-identified clinical data, quality controlled and compiled into a research-ready relational database which would then be available to multi-disciplinary analysts. The collaborative development from a group of software developers, data wranglers, statisticians, clinicians, and domain scientists across both organisations has been key. This framework is innovative, as it facilitates collaborative data management and makes a complicated clinical trial data set from a pharmaceutical company available to academic researchers who become associated with the project. Conclusions An informatics framework has been developed to capture clinical trial data into a pipeline of anonymisation, quality control, data exploration, and subsequent integration into a database. Establishing this framework has been integral to the development of analytical tools.

Published
2021

32. Design of microstructured flat optical fiber for multiaxial strain monitoring in composite materials

Author

Francesco Anelli, Andrea Annunziato, Alessia Erario, Christopher Holmes, Caterina Ciminelli, and Francesco Prudenzano

Subjects
Fiber gratings, strain control, Monitoring, Optical fiber sensors, optical fiber devices, modeling, Composite materials, Strain, Optical waveguides, Atmospheric modeling, Electromagnetic analysis, gratings, Atomic and Molecular Physics, and Optics
Abstract

An innovative microstructured flat optical fiber is designed to obtain a multiaxial strain sensor for composite material monitoring. The sensing regions are constituted by the two eyelets where Bragg gratings are written. To achieve multiaxial sensing, a suitable microstructure is designed close to only one of the eyelets. The effect of the strain field, evaluated via a 3D finite element method approach, is considered to obtain the change of the refractive index distribution. The electromagnetic modal analysis and the coupled mode theory are exploited to evaluate the Bragg wavelength shift for the slow and fast axis fundamental modes, guided in the two eyelets and affecting the sensor response. The designed microstructured flat optical fiber is technologically feasible and promises sensing performance higher than that obtainable with the conventional optical fibers. In addition, flat optical fiber can be embedded in composite materials reducing the drawbacks related to both orientation and excess resin.

Published
2022

35. The Novel at the Limit

Author

Thom Dancer and Christopher Holmes

Subjects
Literature and Literary Theory, Economics, Limit (mathematics), Neoclassical economics, Comedy
Abstract

Despite its 18th century origins, the novel appears remarkably resilient in adapting to the global demands of the 21st century. Largely distanced from concerns of the domestic comedy, studies of th...

Published
2021

36. Development of a photosynthetic hydrogel as potential wound dressing for the local delivery of oxygen and bioactive molecules

Author

Rocío Corrales-Orovio, Felipe Carvajal, Christopher Holmes, Miguel Miranda, Sergio González-Itier, Camila Cárdenas, Constanza Vera, Thilo L. Schenck, and José Tomás Egaña

Subjects
Biomaterials, Biomedical Engineering, General Medicine, Molecular Biology, Biochemistry, Biotechnology
Abstract

The development of biomaterials to improve wound healing is a critical clinical challenge and an active field of research. As it is well described that oxygen plays a critical role in almost each step of the wound healing process, in this work, an oxygen producing photosynthetic biomaterial was generated, characterized, and further modified to additionally release other bioactive molecules. Here, alginate hydrogels were loaded with the photosynthetic microalgae Chlamydomonas reinhardtii, showing high integration as well as immediate oxygen release upon illumination. Moreover, the photosynthetic hydrogel showed high biocompatibility in vitro and in vivo, and the capacity to sustain the metabolic oxygen requirements of zebrafish larvae and skin explants. In addition, the photosynthetic dressings were evaluated in 20 healthy human volunteers following the ISO-10993-10-2010 showing no skin irritation, mechanical stability of the dressings, and survival of the photosynthetic microalgae. Finally, hydrogels were also loaded with genetically engineered microalgae to release human VEGF, or pre-loaded with antibiotics, showing sustained release of both bioactive molecules. Overall, this work shows that photosynthetic hydrogels represent a feasible approach for the local delivery of oxygen and other bioactive molecules to promote wound healing. STATEMENT OF SIGNIFICANCE: As oxygen plays a key role in almost every step of the tissue regeneration process, the development of oxygen delivering therapies represents an active field of research, where photosynthetic biomaterials have risen as a promising approach for wound healing. Therefore, in this work a photosynthetic alginate hydrogel-based wound dressing containing C. reinhardtii microalgae was developed and validated in healthy skin of human volunteers. Moreover, hydrogels were modified to additionally release other bioactive molecules such as recombinant VEGF or antibiotics. The present study provides key scientific data to support the use of photosynthetic hydrogels as customizable dressings to promote wound healing.

Published
2022

37. Technical note: Entrainment-limited kinetics of bimolecular reactions in clouds

Author

Christopher Holmes

Subjects
Reaction rate, Atmospheric Science, Range (particle radiation), business.industry, Numerical analysis, Atmospheric chemistry, Kinetics, Thermodynamics, Cloud computing, Technical note, Entrainment (meteorology), business
Abstract

The method of entrainment-limited kinetics enables atmospheric chemistry models that do not resolve clouds to simulate heterogeneous (surface and multiphase) cloud chemistry more accurately and efficiently than previous numerical methods. The method, which was previously described for reactions with first-order kinetics in clouds, incorporates cloud entrainment into the kinetic rate coefficient. This technical note shows how bimolecular reactions with second-order kinetics in clouds can also be treated with entrainment-limited kinetics, enabling efficient simulations of a wider range of cloud chemistry reactions. Accuracy is demonstrated using oxidation of SO2 to S(VI) – a key step in the formation of acid rain – as an example. Over a large range of reaction rates, cloud fractions, and initial reactant concentrations, the numerical errors in the entrainment-limited bimolecular reaction rates are typically ≪1 % and always %; thus, they are far smaller than the errors found in several commonly used methods of simulating cloud chemistry with fractional cloud cover.

Published
2022

38. Design optimisation of C-shaped optical fibre sensor

Author

Nazirah Mohd Razali, Sumiaty Ambran, Christopher Holmes, Siti Nur Fatin Zuikafly, Muhammad Quisar Lokman, Ali Yuzir, and Husni Hani Jameela Sapingi

Subjects
Electrical and Electronic Engineering, Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials
Abstract

Optical fibre sensors have attracted a lot of interest in the field of sensors. However, the limitation of conventional optical fibre sensors such as high fragility and low sensitivity need to be considered. This work demonstrated a simulation of a new optical sensor design, a C–shaped optical fibre sensor to overcome these limitations. The design optimization of the sensor was conducted by changing the remaining cladding thickness ranging from 5 to 0 µm and opening angle ranging from 70 to 110°. The change in refractive index ranging from 1.30 to 1.40 has been performed to evaluate the simulated sensing performance. The simulation results showed that reducing the cladding thickness and wider opening angle can improve the sensor’s sensitivity. In cladding thickness optimization, the sensor showed the highest sensitivity with no remaining cladding thickness. In the opening angle optimization, the highest sensitivity can be achieved at the maximum opening angle of 110°, but the sensitivity changes due to the the opening angle range were minimal compared to cladding thickness optimization. The best C–shaped sensing performance with 0 µm remaining cladding thickness and 110° opening angle was selected to be compared to the closest in term of design which is the D—shaped optical fibre sensor. Overall, the C–shaped design has more cladding sector region left providing better physical robustness and has high potential to act as a new refractive index sensor with an estimated sensitivity of up to 2.77893, higher than the simulated D–shaped optical fibre sensor with an estimated sensitivity of 2.77468.

Published
2022

41. Efficient production of carbonyl sulfide in the low-NOx oxidation of dimethyl sulfide

Author

Anna Novelli, Christopher Jernigan, Charles Fite, Luc Vereecken, Max Berkelhammer, Andrew Rollins, Pamela Rickly, Domenico Taraborelli, Christopher Holmes, and Timothy Bertram

Abstract

The oxidation of carbonyl sulfide (OCS) is the primary, continuous source of stratospheric sulfate aerosol particles, which can scatter shortwave radiation and catalyze heterogeneous reactions in the stratosphere. While it has been estimated that the oxidation of dimethyl sulfide (DMS), emitted from the surface ocean, accounts for 8-20% of the global OCS source, there is no existing DMS oxidation mechanism relevant to the marine atmosphere that is consistent with an OCS source of this magnitude. We describe new laboratory measurements and theoretical analyses of DMS oxidation that provide a mechanistic description for OCS production from hydroperoxymethyl thioformate (HPMTF), an ubiquitous, soluble DMS oxidation product.The mechanism for OCS formation from DMS + OH is found to proceed through several intermediate stages, including secondary OH-initiated oxidation of hydroperoxymethyl thioformate (HOOCH2SCH=O), thioperformic anhydride (O=CHSCH=O), and thioperformic acid (HOOCH=S and HOSCH=O). Several of these reactions are affected by chemical activation, leading to prompt product formation. A theoretical kinetic analysis of these reactions and of conditions representative of the marine boundary layer shows several potential OCS formation channels, which combined lead to a high yield of OCS under OH-initiated oxidation of DMS.We incorporate this chemical mechanism into a global chemical transport model, showing that OCS production from DMS is a factor of 3 smaller than current estimates and displays a maximum in the tropics consistent with field observations. A critical factor in the conversion of DMS to OCS is the heterogeneous loss of the soluble intermediates, making the OCS yield sensitive to multiphase cloud chemistry and reducing the total OCS formation.

Published
2022

42. A Rapid RT-LAMP SARS-CoV-2 Screening Assay for Collapsing Asymptomatic COVID-19 Transmission

Author

Rebecca Allsopp, Caroline Cowley, Ruth Barber, Carolyn Jones, Christopher Holmes, Paul Bird, Shailesh Gohil, Claire Blackmore, Martin Tobin, Nigel Brunskill, Philip Baker, and Jacqui Shaw

Subjects
genetic structures
Abstract

Purpose: Todemonstrate the diagnostic performance of rapid SARS-CoV-2 RT-LAMP assays, comparing the performance of genomic versus sub-genomic sequence target with subsequent application in an asymptomatic screening population. Methods: RT-LAMP diagnostic sensitivity (DSe) and specificity (DSp) was determined using 114 RT-PCR clinically positive and 88 RT-PCR clinically negative swab samples processed through the diagnostic RT-PCR service within the University Hospitals of Leicester NHS Trust. A swab-based RT-LAMP SARS-CoV-2 screening programme was subsequently made available to all staff and students at the University of Leicester (Autumn 2020), implemented to ISO 15189:2012 standardsusing NHS IT infrastructure and supported by University Hospital Leicester via confirmatory NHS diagnostic laboratory testing of RT-LAMP ‘positive’ samples. Results: Validation samples reporting a Ct < 20 were detected at 100% DSe and DSp, reducing to 95% DSe (100% DSp) for all samples reporting a Ct < 30 (both genomicdual sub-genomic assays). Advisory screening identified nine positive cases in 1680 symptom free individuals (equivalent to 540 cases per 100,000) with results reported back to participants and feed into national statisticswithin 48 hours.Conclusion: This work demonstrates the utility of a rapid RT-LAMP assay for collapsing transmission of SARS-CoV-2 in an asymptomatic screening population.

Published
2022

43. Guidelines for clinical trial protocols for interventions involving artificial intelligence: the SPIRIT-AI extension

Author

R Sarkar, Alastair K Denniston, Robert M. Golub, J Monteiro, C Haug, D Paltoo, C Mulrow, Hutan Ashrafian, A Jonas, A Y Lee, Xiaoxuan Liu, Livia Faes, M B Panico, Pearse A. Keane, Gary Price, Christopher Yau, L Oakden-Rayner, M K ElZarrad, A L Beam, Gary S. Collins, Hugh Harvey, J Fletcher, David Moher, An-Wen Chan, S Cruz Rivera, Melanie Calvert, Christopher Kelly, L Ferrante di Ruffano, Ara Darzi, Jon Deeks, R Savage, C Espinoza, J Matcham, E Manna, Sebastian J. Vollmer, S Rowley, Christopher Holmes, C S Lee, Andre Esteva, Melissa D McCradden, and National Institute of Health Research

Subjects
Research Report, 0301 basic medicine, Research design, Technology, Delphi Technique, PREDICTION, SPIRIT-AI and CONSORT-AI Steering Group, Psychological intervention, Delphi method, Medicine (miscellaneous), 0302 clinical medicine, Clinical Protocols, Health Information Management, 030212 general & internal medicine, 11 Medical and Health Sciences, Clinical Trials as Topic, STATEMENT, General Medicine, CANCER, Checklist, Clinical trial design, 3. Good health, Audience measurement, Research Design, 030220 oncology & carcinogenesis, Standard protocol, lcsh:R858-859.7, Psychology, Life Sciences & Biomedicine, Consensus, SPIRIT-AI and CONSORT-AI Consensus Group, Immunology, education, MEDLINE, Guidelines as Topic, Health Informatics, Disclosure, lcsh:Computer applications to medicine. Medical informatics, Health outcomes, Article, General Biochemistry, Genetics and Molecular Biology, 1117 Public Health and Health Services, 03 medical and health sciences, Medicine, General & Internal, Artificial Intelligence, General & Internal Medicine, Intervention (counseling), Humans, Research Methods & Reporting, Decision Sciences (miscellaneous), Publishing, Protocol (science), Science & Technology, business.industry, Clinical study design, Consensus Statement, 1103 Clinical Sciences, Guideline, Clinical trial, 030104 developmental biology, Artificial intelligence, business, SYSTEM, 030217 neurology & neurosurgery, SPIRIT-AI and CONSORT-AI Working Group
Abstract

The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes. The SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials–Artificial Intelligence) extension is a new reporting guideline for clinical trial protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI (Consolidated Standards of Reporting Trials–Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 26 candidate items, which were consulted upon by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The SPIRIT-AI extension includes 15 new items that were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations for the handling of input and output data, the human–AI interaction and analysis of error cases. SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial., The CONSORT-AI and SPIRIT-AI extensions improve the transparency of clinical trial design and trial protocol reporting for artificial intelligence interventions.

Published
2020

44. Graphing and reporting heterogeneous treatment effects through reference classes

Author

James A Watson and Christopher Holmes

Subjects
Multivariate statistics, Computer science, Average treatment effect, Population, Medicine (miscellaneous), Randomised controlled trials, 030204 cardiovascular system & hematology, Overfitting, Interaction, law.invention, External validity, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Treatment trial, law, Covariate, Statistics, Medicine, Pharmacology (medical), Treatment effect, 030212 general & internal medicine, Internal validity, education, Heterogeneous treatment effects, education.field_of_study, lcsh:R5-920, Framingham Risk Score, business.industry, Absolute risk reduction, Methodology, Prognostic risk score, Multiple comparisons problem, business, lcsh:Medicine (General), Reference class forecasting
Abstract

Background Exploration and modelling of heterogeneous treatment effects as a function of baseline covariates is an important aspect of precision medicine in randomised controlled trials (RCTs). Randomisation generally guarantees the internal validity of an RCT, but heterogeneity in treatment effect can reduce external validity. Estimation of heterogeneous treatment effects is usually done via a predictive model for individual outcomes, where one searches for interactions between treatment allocation and important patient baseline covariates. However, such models are prone to overfitting and multiple testing and typically demand a transformation of the outcome measurement, for example, from the absolute risk in the original RCT to log-odds of risk in the predictive model. Methods We show how reference classes derived from baseline covariates can be used to explore heterogeneous treatment effects via a two-stage approach. We first estimate a risk score which captures on a single dimension some of the heterogeneity in outcomes of the trial population. Heterogeneity in the treatment effect can then be explored via reweighting schemes along this axis of variation. This two-stage approach bypasses the search for interactions with multiple covariates, thus protecting against multiple testing. It also allows for exploration of heterogeneous treatment effects on the original outcome scale of the RCT. This approach would typically be applied to multivariable models of baseline risk to assess the stability of average treatment effects with respect to the distribution of risk in the population studied. Case study We illustrate this approach using the single largest randomised treatment trial in severe falciparum malaria and demonstrate how the estimated treatment effect in terms of absolute mortality risk reduction increases considerably in higher risk strata. Conclusions ‘Local’ and ‘tilting’ reweighting schemes based on ranking patients by baseline risk can be used as a general approach for exploring, graphing and reporting heterogeneity of treatment effect in RCTs. Trial registration ISRCTN clinical trials registry: ISRCTN50258054. Prospectively registered on 22 July 2005.

Published
2020

46. Machine learning analysis plans for randomised controlled trials: detecting treatment effect heterogeneity with strict control of type I error

Author

James A Watson and Christopher Holmes

Subjects
Adult, Test strategy, Asia, Subgroup statistical analysis plan, Randomised trials, Plasmodium falciparum, Artesunate, Medicine (miscellaneous), Machine learning, computer.software_genre, 01 natural sciences, law.invention, Antimalarials, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, False positive paradox, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, p-value, Malaria, Falciparum, 0101 mathematics, Statistical theory, Heterogeneous treatment effects, Randomized Controlled Trials as Topic, Retrospective Studies, Statistical hypothesis testing, lcsh:R5-920, Quinine, business.industry, Methodology, Statistical model, Treatment Outcome, Artificial intelligence, business, lcsh:Medicine (General), computer, Algorithms, Type I and type II errors
Abstract

Background Retrospective exploratory analyses of randomised controlled trials (RCTs) seeking to identify treatment effect heterogeneity (TEH) are prone to bias and false positives. Yet the desire to learn all we can from exhaustive data measurements on trial participants motivates the inclusion of such analyses within RCTs. Moreover, widespread advances in machine learning (ML) methods hold potential to utilise such data to identify subjects exhibiting heterogeneous treatment response. Methods We present a novel analysis strategy for detecting TEH in randomised data using ML methods, whilst ensuring proper control of the false positive discovery rate. Our approach uses random data partitioning with statistical or ML-based prediction on held-out data. This method can test for both crossover TEH (switch in optimal treatment) and non-crossover TEH (systematic variation in benefit across patients). The former is done via a two-sample hypothesis test measuring overall predictive performance. The latter is done via ‘stacking’ the ML predictors alongside a classical statistical model to formally test the added benefit of the ML algorithm. An adaptation of recent statistical theory allows for the construction of a valid aggregate p value. This testing strategy is independent of the choice of ML method. Results We demonstrate our approach with a re-analysis of the SEAQUAMAT trial, which compared quinine to artesunate for the treatment of severe malaria in Asian adults. We find no evidence for any subgroup who would benefit from a change in treatment from the current standard of care, artesunate, but strong evidence for significant TEH within the artesunate treatment group. In particular, we find that artesunate provides a differential benefit to patients with high numbers of circulating ring stage parasites. Conclusions ML analysis plans using computational notebooks (documents linked to a programming language that capture the model parameter settings, data processing choices, and evaluation criteria) along with version control can improve the robustness and transparency of RCT exploratory analyses. A data-partitioning algorithm allows researchers to apply the latest ML techniques safe in the knowledge that any declared associations are statistically significant at a user-defined level.

Published
2020

48. Investigation into multi-pass exposure of 213 nm pulsed UV writing for improved writing response

Author

Q. Salman Ahmed, James W. Field, Paul C. Gow, Christopher Holmes, Rex H.S. Bannerman, Paolo L. Mennea, Corin B. E. Gawith, Peter G.R. Smith, and James C. Gates

Abstract

We demonstrate an increase in achievable refractive index change of 1.2×10-3 in Gedoped silica in writing waveguides and gratings using pulsed 213 nm light to deposit the same total fluence over multiple writing passes.

Published
2022

49. Holographically fabricated blazed gratings for out-of-plane coupling in integrated optics

Author

Q. Salman Ahmed, James W. Field, Paul C. Gow, Christopher Holmes, Dong-Woo Ko, Peter Horak, Corin B. E. Gawith, Peter G.R. Smith, and James C. Gates

Subjects
Physics::Optics, Physics::Atomic Physics
Abstract

We report the development of 45° blazed gratings in integrated waveguides using a holographic UV laser inscription technique for out-of-plane free-space coupling of beams.

Published
2022

50. Photosensitivity response of pulsed 213 nm light in planar Bragg grating writing

Author

Q. Salman Ahmed, James W. Field, Paul C. Gow, Swe Zin Oo, Christopher Holmes, Rex H.S. Bannerman, Paolo L. Mennea, Corin B. E. Gawith, Peter G.R. Smith, and James C. Gates

Abstract

We investigate the dynamics of pulsed 213 nm planar Bragg grating writing for a range of powers and fluences. We report the regime for achieving high index contrast, and where damage is likely to occur.

Published
2022

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