28 results on '"Alice Garrett"'
Search Results
2. Demonstrating the Use of Optical Fibres in Biomedical Sensing: A Collaborative Approach for Engagement and Education
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Katjana Ehrlich, Helen E. Parker, Duncan K. McNicholl, Peter Reid, Mark Reynolds, Vincent Bussiere, Graham Crawford, Angela Deighan, Alice Garrett, András Kufcsák, Dominic R. Norberg, Giulia Spennati, Gregor Steele, Helen Szoor-McElhinney, and Melanie Jimenez
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endoscopic imaging ,fluorescence imaging ,fiber optics ,medical imaging ,medical optics instrumentation ,lung disease diagnostics ,public understanding/outreach ,high school/introduction medicine ,interdisciplinary/multidisciplinary ,Chemical technology ,TP1-1185 - Abstract
This paper demonstrates how research at the intersection of physics, engineering, biology and medicine can be presented in an interactive and educational way to a non-scientific audience. Interdisciplinary research with a focus on prevalent diseases provides a relatable context that can be used to engage with the public. Respiratory diseases are significant contributors to avoidable morbidity and mortality and have a growing social and economic impact. With the aim of improving lung disease understanding, new techniques in fibre-based optical endomicroscopy have been recently developed. Here, we present a novel engagement activity that resembles a bench-to-bedside pathway. The activity comprises an inexpensive educational tool (
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- 2020
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3. The nature and prevalence of chronic pain in homeless persons: an observational study [v1; ref status: indexed, http://f1000r.es/o6]
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Rebecca Fisher, Judith Ewing, Alice Garrett, E Katherine Harrison, Kimberly KT Lwin, and Daniel W Wheeler
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Pain Management: Chronic Clinical ,Social & Behavioral Determinants of Health ,Medicine ,Science - Abstract
Background: Homeless people are known to suffer disproportionately with health problems that reduce physical functioning and quality of life, and shorten life expectancy. They suffer from a wide range of diseases that are known to be painful, but little information is available about the nature and prevalence of chronic pain in this vulnerable group. This study aimed to estimate the prevalence of chronic pain among homeless people, and to examine its location, effect on activities of daily living, and relationship with alcohol and drugs. Methods: We conducted face-to-face interviews with users of homeless shelters in four major cities in the United Kingdom, in the winters of 2009-11. Participants completed the Brief Pain Inventory, Short Form McGill Pain questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, and detailed their intake of prescribed and unprescribed medications and alcohol. We also recorded each participant’s reasons for homelessness, and whether they slept rough or in shelters. Findings: Of 168 shelter users approached, 150 (89.3%) participated: 93 participants (63%) reported experiencing pain lasting longer than three months; the mean duration of pain experienced was 82.2 months. The lower limbs were most frequently affected. Opioids appeared to afford a degree of analgesia for some, but whilst many reported symptoms suggestive of neuropathic pain, very few were taking anti-neuropathic drugs. Interpretation: The prevalence of chronic pain in the homeless appears to be substantially higher than the general population, is poorly controlled, and adversely affects general activity, walking and sleeping. It is hard to discern whether chronic pain is a cause or effect of homelessness, or both. Pain is a symptom, but in this challenging group it might not always be possible to treat the underlying cause. Exploring the diagnosis and treatment of neuropathic pain may offer a means of improving the quality of these vulnerable people’s lives.
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- 2013
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4. Reason and emotion in policy making : an ethnographic study
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Anderson, Rosemary Alice Garrett, Freeman, Richard, and Bondi, Liz
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361.6 ,emotion ,policy ,psychosocial research ,storytelling ,power - Abstract
Recent policy analysis has had a growing interest in examining the everyday practices of policy work. Despite this, conceptions of what policy can and should encompass tend to be focused on its tangible outputs and products, in particular the texts and documents of policy and governance. Policy’s legitimacy is commonly considered to rest on its participants’ ability to make rational decisions motivated not by private reasons but by the public good. This has had serious implications for scholars’ ability to discuss the non-purposive, nonverbal and non-rational content in policy work. This thesis presents an ethnographic study of emotion in the context of policy work. Starting from informants’ own understandings of what emotion means in policy and politics, it focuses on a fifteen month period in the policy practices of a Scottish NGO and its stakeholders and participants. From the perspective of a participant observer policy worker, it uses observation, documents, and interviews to explore the way traditionally “rational” models of governance based on apparently objective knowledge and other non-rational, “caring” ways of knowing are brought to bear upon policy work through detailed examination of practice. Analysis of these practices begins by examining the way that informants described the anxieties caused by competing understandings of “good” governance. Emotion and rationality were considered mutually exclusive but equally essential components of policy making. This thesis proposes that the way these anxieties were managed by the Partnership’s policy participants was to split these incommensurable expectations of governance between two self-identifying groups: activists such as community organisers and professionals such as civil servants. Splitting knowledge in this way helped the wider policy making community to maintain their own sense of legitimacy and moral integrity while making use of “dangerous” knowledge.
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- 2015
5. Results from London Regional Clinical Genetics services over a 5-year period on germline TP53 testing in women diagnosed with breast cancer at <30 years
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Munaza Ahmed, Dara Vakili, Li Shan Guillemot, Angela F. Brady, Sabrina Talukdar, Monisha Shanmugasundaram, Shevaun Ey, Sinead Whyte, Katherine S Josephs, Louise Izatt, and Alice Garrett
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Cancer ,medicine.disease ,Germline ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Germline mutation ,Breast cancer ,030220 oncology & carcinogenesis ,Internal medicine ,Genetics ,medicine ,Medical genetics ,Detection rate ,Family history ,business ,Genetics (clinical) ,Genetic testing - Abstract
BackgroundThe most common cancer diagnosed in germline TP53 pathogenic variant (PV) carriers is premenopausal breast cancer. An increased rate of breast tumour HER2 positivity has been reported in this group. Screening for breast/other cancers is recommended in PV carriers.Objectives1. To assess the frequency of germline TP53 PVs reported diagnostically in women with breast cancer at 2. To evaluate the impact of personal/family history and HER2 status on the likelihood of germline TP53 pathogenic/likely pathogenic variant (PV/LPV) identification.MethodsGenetic test results from patients undergoing diagnostic germline TP53 tests between 2012 and 2017 in the four London Regional Clinical Genetics Services were reviewed. Clinical/pathology data and family history were extracted from genetics files for women diagnosed with breast cancer at ResultsThe overall germline TP53 PV/LPV variant detection rate was 9/270=3.3% in all women diagnosed with breast cancer at TP53-spectrum cancers. Breast cancers were significantly more likely to be HER2-positive in TP53 PV/LPV carriers than in non-carriers (p=0.00006).ConclusionsGermline TP53 PVs/LPVs are uncommon among women diagnosed with breast cancer aged
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- 2021
6. Reclassification of clinically-detected sequence variants:Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK)
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Lucy Loong, Alice Garrett, Sophie Allen, Subin Choi, Miranda Durkie, Alison Callaway, James Drummond, George J. Burghel, Rachel Robinson, Beth Torr, Ian R. Berry, Andrew J. Wallace, Diana M. Eccles, Sian Ellard, Emma Baple, D. Gareth Evans, Emma R. Woodward, Anjana Kulkarni, Fiona Lalloo, Marc Tischkowitz, Anneke Lucassen, Helen Hanson, and Clare Turnbull
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Neoplasms ,Genetic Variation ,Humans ,Reclassification ,Recontact ,Genetic Predisposition to Disease ,Reinterpretation ,Genetic Testing ,Variant ,Laboratories ,Classification ,Genetics (clinical) - Abstract
PURPOSE: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely.METHODS: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification.RESULTS: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score.CONCLUSION: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings.
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- 2022
7. A digital pathway for genetic testing in UK NHS patients with cancer:BRCA-DIRECT randomised study internal pilot
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Bethany Torr, Christopher Jones, Subin Choi, Sophie Allen, Grace Kavanaugh, Monica Hamill, Alice Garrett, Suzanne MacMahon, Lucy Loong, Alistair Reay, Lina Yuan, Mikel Valganon Petrizan, Kathryn Monson, Nicky Perry, Lesley Fallowfield, Valerie Jenkins, Rochelle Gold, Amy Taylor, Rhian Gabe, Jennifer Wiggins, Anneke Lucassen, Ranjit Manchanda, Ashu Gandhi, Angela George, Michael Hubank, Zoe Kemp, D Gareth Evans, Stephen Bremner, and Clare Turnbull
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Manchester Cancer Research Centre ,ResearchInstitutes_Networks_Beacons/mcrc ,Genetics ,Humans ,Female ,Breast Neoplasms ,Genetic Testing ,Referral and Consultation ,State Medicine ,United Kingdom ,Genetics (clinical) ,Telephone - Abstract
BackgroundGermline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing.MethodsWe designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing ofBRCA1/BRCA2/PALB2(BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway).ResultsUptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with ConclusionPilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses.Trial registration numberISRCTN87845055.
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- 2022
8. Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records
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Lucy Loong, Catherine Huntley, Fiona McRonald, Francesco Santaniello, Joanna Pethick, Bethany Torr, Sophie Allen, Oliver Tulloch, Shilpi Goel, Brian Shand, Tameera Rahman, Margreet Luchtenborg, Alice Garrett, Richard Barber, Tina Bedenham, David Bourn, Kirsty Bradshaw, Claire Brooks, Jonathan Bruty, George J Burghel, Samantha Butler, Chris Buxton, Alison Callaway, Jonathan Callaway, James Drummond, Miranda Durkie, Joanne Field, Lucy Jenkins, Terri P McVeigh, Roger Mountford, Rodney Nyanhete, Evgenia Petrides, Rachel Robinson, Tracy Scott, Victoria Stinton, James Tellez, Andrew J Wallace, Laura Yarram-Smith, Kate Sahan, Nina Hallowell, Diana M Eccles, Paul Pharoah, Marc Tischkowitz, Antonis C Antoniou, D Gareth Evans, Fiona Lalloo, Gail Norbury, Eva Morris, John Burn, Steven Hardy, Clare Turnbull, Huntley, Catherine [0000-0002-3797-7398], Torr, Bethany [0000-0003-3487-9749], Garrett, Alice [0000-0001-8942-283X], Burghel, George J [0000-0001-9360-8194], Eccles, Diana M [0000-0002-9935-3169], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis C [0000-0001-9223-3116], Evans, D Gareth [0000-0002-8482-5784], and Apollo - University of Cambridge Repository
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Genetics, Population ,Genetics, Medical ,Neoplasms ,Databases, Genetic ,Genetics ,Humans ,Genetic Testing ,Genomics ,Laboratories ,DNA Mismatch Repair ,Genetics (clinical) ,State Medicine - Abstract
Peer reviewed: True, OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.
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- 2022
9. Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network
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Andrew J Wallace, Diana Eccles, Lucy Side, Diana Baralle, Gail Norbury, Marc Tischkowitz, Helen Hanson, Rachel Robinson, D. Gareth Evans, George J Burghel, Cankut Çubuk, Alice Garrett, Treena Cranston, Sabrina Talukdar, Sheila Palmer-Smith, Emma R. Woodward, Alison Callaway, Fiona Lalloo, James Drummond, Ian R. Berry, Sian Ellard, Louise Izatt, Miranda Durkie, Clare Turnbull, Mary Alikian, Garrett, Alice [0000-0001-8942-283X], Burghel, George J [0000-0001-9360-8194], Berry, Ian R [0000-0002-9710-4724], Eccles, Diana M [0000-0002-9935-3169], Evans, D Gareth [0000-0002-8482-5784], Turnbull, Clare [0000-0002-1734-5772], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,medicine.medical_specialty ,Service (systems architecture) ,Subspecialty ,03 medical and health sciences ,0302 clinical medicine ,Multidisciplinary approach ,Neoplasms ,medicine ,Cancer Genetics ,Humans ,genetics ,guidelines ,Genetic Testing ,Genetics (clinical) ,business.industry ,Interpretation (philosophy) ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Geneticist ,Genomics ,United Kingdom ,Data sharing ,030104 developmental biology ,030220 oncology & carcinogenesis ,Family medicine ,molecular genetics ,oncology ,Medical genetics ,Female ,Personalized medicine ,business ,Psychology ,Ireland ,clinical genetics - Abstract
Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic–high risk and benign–no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease–gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that ‘national subspecialist multidisciplinary meetings’ (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.
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- 2020
10. Paper microfluidic implementation of loop mediated isothermal amplification for early diagnosis of hepatitis C virus
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Jonathan M. Cooper, Pawel Jajesniak, Alice Garrett, Suleman R. Sabir, Amanda Bradley-Stewart, Julien Reboud, Rory Gunson, Gaolian Xu, Chris Davis, E. Thomson, Weronika Witkowska McConnell, and Zhugen Yang
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medicine.medical_specialty ,Genotype ,Point-of-Care Systems ,Science ,Hepatitis C virus ,Microfluidics ,Biomedical Engineering ,Loop-mediated isothermal amplification ,General Physics and Astronomy ,Hepacivirus ,World Health Organization ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Virus ,World health ,Patient care ,Blood Urea Nitrogen ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Intensive care medicine ,Active hepatitis ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Diagnostic Tests, Routine ,business.industry ,Infectious-disease diagnostics ,Diagnostic test ,General Chemistry ,Viral Load ,Hepatitis C ,3. Good health ,Early Diagnosis ,Molecular Diagnostic Techniques ,030211 gastroenterology & hepatology ,Laboratories ,business ,Nucleic Acid Amplification Techniques ,Nucleic acid detection - Abstract
The early diagnosis of active hepatitis C virus (HCV) infection remains a significant barrier to the treatment of the disease and to preventing the associated significant morbidity and mortality seen, worldwide. Current testing is delayed due to the high cost, long turnaround times and high expertise needed in centralised diagnostic laboratories. Here we demonstrate a user-friendly, low-cost pan-genotypic assay, based upon reverse transcriptase loop mediated isothermal amplification (RT-LAMP). We developed a prototype device for point-of-care use, comprising a LAMP amplification chamber and lateral flow nucleic acid detection strips, giving a visually-read, user-friendly result in, Current HCV nucleic acid-based diagnosis is largely performed in centralised laboratories. Here, the authors present a pan-genotypic RNA assay, based on reverse transcriptase loop mediated isothermal amplification and develop a low-cost prototype paper-based lateral flow device for point-of-care use, providing a visually read result within 40 min.
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- 2021
11. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants
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Lucy Loong, Cankut Cubuk, Subin Choi, Sophie Allen, Beth Torr, Alice Garrett, Chey Loveday, Miranda Durkie, Alison Callaway, George J. Burghel, James Drummond, Rachel Robinson, Ian R. Berry, Andrew Wallace, Diana M. Eccles, Marc Tischkowitz, Sian Ellard, James S. Ware, Helen Hanson, Clare Turnbull, S. Samant, A. Lucassen, A. Znaczko, A. Shaw, A. Ansari, A. Kumar, A. Donaldson, A. Murray, A. Ross, A. Taylor-Beadling, A. Taylor, A. Innes, A. Brady, A. Kulkarni, A.-C. Hogg, A. Ramsay Bowden, A. Hadonou, B. Coad, B. McIldowie, B. Speight, B. DeSouza, B. Mullaney, C. McKenna, C. Brewer, C. Olimpio, C. Clabby, C. Crosby, C. Jenkins, C. Armstrong, C. Bowles, C. Brooks, C. Byrne, C. Maurer, D. Baralle, D. Chubb, D. Stobo, D. Moore, D. O'Sullivan, D. Donnelly, D. Randhawa, D. Halliday, E. Atkinson, E. Baple, E. Rauter, E. Johnston, E. Woodward, E. Maher, E. Sofianopoulou, E. Petrides, F. Lalloo, F. McRonald, F. Pelz, I. Frayling, G. Evans, G. Corbett, G. Rea, H. Clouston, H. Powell, H. Williamson, H. Carley, H.J.W. Thomas, I. Tomlinson, J. Cook, J. Hoyle, J. Tellez, J. Whitworth, J. Williams, J. Murray, J. Campbell, J. Tolmie, J. Field, J. Mason, J. Burn, J. Bruty, J. Callaway, J. Grant, J. Del Rey Jimenez, J. Pagan, J. VanCampen, J. Barwell, K. Monahan, K. Tatton-Brown, K.-R. Ong, K. Murphy, K. Andrews, K. Mokretar, K. Cadoo, K. Smith, K. Baker, K. Brown, K. Reay, K. McKay Bounford, K. Bradshaw, K. Russell, K. Stone, K. Snape, L. Crookes, L. Reed, L. Taggart, L. Yarram, L. Cobbold, L. Walker, L. Hawkes, L. Busby, L. Izatt, L. Kiely, L. Hughes, L. Side, L. Sarkies, K.-L. Greenhalgh, M. Shanmugasundaram, M. Duff, M. Bartlett, M. Watson, M. Owens, M. Bradford, M. Huxley, M. Slean, M. Ryten, M. Smith, M. Ahmed, N. Roberts, C. O'Brien, O. Middleton, P. Tarpey, P. Logan, P. Dean, P. May, P. Brace, R. Tredwell, R. Harrison, R. Hart, R. Kirk, R. Martin, R. Nyanhete, R. Wright, R. Davidson, R. Cleaver, S. Talukdar, S. Butler, J. Sampson, S. Ribeiro, S. Dell, S. Mackenzie, S. Hegarty, S. Albaba, S. McKee, S. Palmer-Smith, S. Heggarty, S. MacParland, S. Greville-Heygate, S. Daniels, S. Prapa, S. Abbs, S. Tennant, S. Hardy, S. MacMahon, T. McVeigh, T. Foo, T. Bedenham, T. Cranston, T. McDevitt, V. Clowes, V. Tripathi, V. McConnell, N. Woodwaer, Y. Wallis, Z. Kemp, G. Mullan, L. Pierson, L. Rainey, C. Joyce, A. Timbs, A.-M. Reuther, B. Frugtniet, C. Husher, C. Lawn, C. Corbett, D. Nocera-Jijon, D. Reay, E. Cross, F. Ryan, H. Lindsay, J. Oliver, J. Dring, J. Spiers, J. Harper, K. Ciucias, L. Connolly, M. Tsang, R. Brown, S. Shepherd, S. Begum, T. Tadiso, T. Linton-Willoughby, H. Heppell, K. Sahan, L. Worrillow, Z. Allen, M. Barlett, C. Watt, M. Hegarty, British Heart Foundation, and Wellcome Trust
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Concordance ,Mutation, Missense ,Biology ,PM5 ,CanVIG-UK ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Variant ,Codon ,Genetics (clinical) ,Genetics ,Genetics & Heredity ,0604 Genetics ,BRCA1 Protein ,Genetic Variation ,1103 Clinical Sciences ,Pathogenicity ,Classification ,MutS Homolog 2 Protein ,Genetic Variation/genetics ,Mutation, Missense/genetics ,MSH2 ,ACMG ,BRCA1 Protein/genetics ,MutS Homolog 2 Protein/genetics - Abstract
Purpose: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.
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- 2021
12. Clinical likelihood ratios and balanced accuracy for 44 in silico tools against multiple large-scale functional assays of cancer susceptibility genes
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A. Callaway, George J Burghel, Chey Loveday, James S. Ware, Alice Garrett, Subin Choi, Helen Hanson, J. Drummond, Ian R. Berry, CanVIG-UK, Diana Eccles, C. Cubuk, Marc Tischkowitz, Rachel Robinson, Bethany Torr, Andrew J Wallace, Clare Turnbull, Nicola Whiffin, Laura King, Miranda Durkie, Wellcome Trust, Rosetrees Trust, British Heart Foundation, National Heart & Lung Institute Foundation, Cubuk, C [0000-0002-1734-5772], and Apollo - University of Cambridge Repository
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medicine.medical_specialty ,Computer science ,In silico ,Mutation, Missense ,PROTEIN ,Genomics ,Scale (descriptive set theory) ,Computational biology ,Article ,PREDICT ,03 medical and health sciences ,Neoplasms ,medicine ,Humans ,Computer Simulation ,Gene ,Genetics (clinical) ,030304 developmental biology ,Genetics & Heredity ,0604 Genetics ,0303 health sciences ,Science & Technology ,Molecular pathology ,Benignity ,030305 genetics & heredity ,MISSENSE VARIANTS ,Genetic Variation ,1103 Clinical Sciences ,Weighting ,Medical genetics ,Life Sciences & Biomedicine ,PATHOGENICITY - Abstract
Purpose: Where multiple in silico tools are concordant, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework affords supporting evidence toward pathogenicity or benignity, equivalent to a likelihood ratio of ~2. However, limited availability of “clinical truth sets” and prior use in tool training limits their utility for evaluation of tool performance. Methods: We created a truth set of 9,436 missense variants classified as deleterious or tolerated in clinically validated high-throughput functional assays for BRCA1, BRCA2, MSH2, PTEN, and TP53 to evaluate predictive performance for 44 recommended/commonly used in silico tools. Results: Over two-thirds of the tool–threshold combinations examined had specificity of 0.7. For Meta-SNP, the equivalent PLR = 42.9 (14.4–406) and NLR = 19.4 (15.6–24.9). Conclusion: Against these clinically validated “functional truth sets," there was wide variation in the predictive performance of commonly used in silico tools. Overall, REVEL and Meta-SNP had best balanced accuracy and might potentially be used at stronger evidence weighting than current ACMG/AMP prescription, in particular for predictions of benignity.
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- 2021
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13. Smartphone-based DNA diagnostics for malaria detection using deep learning for local decision support and blockchain technology for security
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Anna Lito Michala, Diana Ajambo, Edridah M. Tukahebwa, Xin Guo, Jonathan M. Cooper, Alice Garrett, Ivo Domingos, Moses Adriko, Shantimoy Kar, Xiaoxiang Yan, Muhammad Khalid, Julien Reboud, and Candia Rowel
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Diagnostic information ,Decision support system ,Blockchain ,business.industry ,Computer science ,Deep learning ,medicine.disease ,Data science ,Electronic, Optical and Magnetic Materials ,Infectious disease diagnosis ,Infectious disease (medical specialty) ,medicine ,Artificial intelligence ,Electrical and Electronic Engineering ,Dna diagnosis ,business ,Instrumentation ,Malaria - Abstract
In infectious disease diagnosis, results need to be communicated rapidly to healthcare professionals once testing has been completed so that care pathways can be implemented. This represents a particular challenge when testing in remote, low-resource rural communities, in which such diseases often create the largest burden. Here, we report a smartphone-based end-to-end platform for multiplexed DNA diagnosis of malaria. The approach uses a low-cost paper-based microfluidic diagnostic test, which is combined with deep learning algorithms for local decision support and blockchain technology for secure data connectivity and management. We validated the approach via field tests in rural Uganda, where it correctly identified more than 98% of tested cases. Our platform also provides secure geotagged diagnostic information, which creates the possibility of integrating infectious disease data within surveillance frameworks. A smartphone-based system that uses deep learning algorithms for local decision support, and incorporates blockchain technology to provide secure data connectivity and management, can be used for multiplexed DNA diagnosis of malaria.
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- 2021
14. Paper-based microfluidics for DNA diagnostics of malaria in low resource underserved rural communities
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Edridah M. Tukahebwa, Julien Reboud, Zhugen Yang, Jonathan M. Cooper, Alice Garrett, Candia Rowell, Gaolian Xu, and Moses Adriko
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Paper ,Rural Population ,Adolescent ,Low resource ,Computer science ,low-resource settings ,Point-of-care testing ,Microfluidics ,Loop-mediated isothermal amplification ,malaria ,Medically Underserved Area ,02 engineering and technology ,Computational biology ,01 natural sciences ,Biochemistry ,Polymerase Chain Reaction ,law.invention ,Engineering ,nucleic acid-based tests ,law ,medicine ,Humans ,Medical diagnosis ,Malaria, Falciparum ,Child ,Polymerase chain reaction ,Multidisciplinary ,010401 analytical chemistry ,Reproducibility of Results ,Biological Sciences ,DNA, Protozoan ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,0104 chemical sciences ,Diagnosis of malaria ,PNAS Plus ,Molecular Diagnostic Techniques ,Physical Sciences ,Health Resources ,paper microfluidics ,0210 nano-technology ,point-of-care diagnostics ,Malaria - Abstract
Significance Populations living in remote rural communities would benefit from rapid, highly sensitive molecular, DNA-based diagnostics to inform the correct and timely treatment of infectious diseases. Such information is also becoming increasingly relevant in global efforts for disease elimination, where the testing of asymptomatic patients is now seen as being important for the identification of disease reservoirs. However, healthcare workers face practical and logistical problems in the implementation of such tests, which often involve complex instrumentation and centralized laboratories. Here we describe innovations in paper microfluidics that enable low-cost, multiplexed DNA-based diagnostics for malaria, delivered, in a first-in-human study, in schools in rural Uganda., Rapid, low-cost, species-specific diagnosis, based upon DNA testing, is becoming important in the treatment of patients with infectious diseases. Here, we demonstrate an innovation that uses origami to enable multiplexed, sensitive assays that rival polymerase chain reactions (PCR) laboratory assays and provide high-quality, fast precision diagnostics for malaria. The paper-based microfluidic technology proposed here combines vertical flow sample-processing steps, including paper folding for whole-blood sample preparation, with an isothermal amplification and a lateral flow detection, incorporating a simple visualization system. Studies were performed in village schools in Uganda with individual diagnoses being completed in
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- 2019
15. Results from London Regional Clinical Genetics services over a 5-year period on germline
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Alice, Garrett, Sabrina, Talukdar, Louise, Izatt, Angela F, Brady, Sinead, Whyte, Katherine S, Josephs, Monisha, Shanmugasundaram, Li Shan, Guillemot, Dara, Vakili, Shevaun, Ey, and Munaza, Ahmed
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Adult ,Germ Cells ,London ,Humans ,Breast Neoplasms ,Female ,Genetic Predisposition to Disease ,Genetic Testing ,Tumor Suppressor Protein p53 ,Germ-Line Mutation - Abstract
The most common cancer diagnosed in germline1. To assess the frequency of germlineGenetic test results from patients undergoing diagnostic germlineThe overall germlineGermline
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- 2021
16. Contributors
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Ana Catarina Alves, Christina Anne Austin-Tse, Mafalda Bourbon, Marcelo A. Carvalho, Ozge Ceyhan-Birsoy, George S. Charames, Joana Rita Chora, Mara Colombo, Xavier de la Cruz, Johan T. den Dunnen, Niels de Wind, Orland Diez, Anna B.R. Elias, D Gareth Evans, Lidia Feliubadaló, Vanessa C. Fernandes, Ivo F.A.C. Fokkema, Cristina Fortuno, Alice Garrett, Paolo Gasparini, Giorgia Girotto, Anna González-Neira, Karen W. Gripp, Sara Gutiérrez-Enríquez, Steven M. Harrison, Miguel de la Hoya, Jodie Ingles, Renee Johnson, Jordan Lerner-Ellis, Harvey Levy, Conxi Lázaro, Heather Mason-Suares, Ana Margarida Medeiros, Jessica L. Mester, Alejandro Moles-Fernández, Alvaro N.A. Monteiro, Anna Morgan, Thales C. Nepomuceno, Rocío Núñez-Torres, Selen Özkan, Natàlia Padilla, Michael T. Parsons, Tina F. Pesaran, Marta Pineda, Paolo Radice, Farrah Rajabi, Ebony Richardson, Peter Sabatini, Stephanie Sacharow, Amanda Spurdle, Bryony A. Thompson, Emma Tudini, Clare Turnbull, Lisa M. Vincent, Michael F. Walsh, and Nicholas Watkins
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- 2021
17. Sepsis: when a simple infection becomes deadly
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Jessie Howell, William J. Peveler, Michael E. Murphy, Carl S. Goodyear, Jennifer Gracie, Tansy C. Hammarton, Simon Pybus, Mohammad Saiful Islam Sajib, Colin Graham, J. Kenneth Baillie, Melanie Jimenez, Gill Thomson, Taya Forde, Andrew G. Farthing, and Alice Garrett
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Sepsis ,Immune system ,business.industry ,Inflammatory response ,Immunology ,medicine ,food and beverages ,Inflammation ,General Medicine ,medicine.symptom ,business ,medicine.disease ,Shut down - Abstract
The immune system plays a crucial role in maintaining a healthy body by working around the clock to recognize and respond to infection. Inflammation is part of the immune system’s protective response to an infection. The inflammatory response is incredibly powerful, so much so that it can damage the body’s cells if it is not tightly controlled. Sometimes, inflammation affects the whole body—this is called sepsis. The powerful and complex mechanisms in place to wipe out the infection can cause serious damage to healthy cells and tissues. Uncontrolled inflammation can cause irreversible damage to the body’s organs, such as the kidneys, eventually causing organs to shut down. If sepsis is not treated rapidly, it can lead to death. In this article, we describe the symptoms and diagnosis of sepsis and some of the current research being performed to better understand this dangerous process.
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- 2021
18. The nature and prevalence of chronic pain in homeless persons: an observational study [version 1; referees: 2 approved]
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Rebecca Fisher, Judith Ewing, Alice Garrett, E Katherine Harrison, Kimberly KT Lwin, and Daniel W Wheeler
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Short Research Article ,Articles ,Pain Management: Chronic Clinical ,Social & Behavioral Determinants of Health ,Homeless ,chronic pain - Abstract
Background: Homeless people are known to suffer disproportionately with health problems that reduce physical functioning and quality of life, and shorten life expectancy. They suffer from a wide range of diseases that are known to be painful, but little information is available about the nature and prevalence of chronic pain in this vulnerable group. This study aimed to estimate the prevalence of chronic pain among homeless people, and to examine its location, effect on activities of daily living, and relationship with alcohol and drugs. Methods: We conducted face-to-face interviews with users of homeless shelters in four major cities in the United Kingdom, in the winters of 2009-11. Participants completed the Brief Pain Inventory, Short Form McGill Pain questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, and detailed their intake of prescribed and unprescribed medications and alcohol. We also recorded each participant’s reasons for homelessness, and whether they slept rough or in shelters. Findings: Of 168 shelter users approached, 150 (89.3%) participated: 93 participants (63%) reported experiencing pain lasting longer than three months; the mean duration of pain experienced was 82.2 months. The lower limbs were most frequently affected. Opioids appeared to afford a degree of analgesia for some, but whilst many reported symptoms suggestive of neuropathic pain, very few were taking anti-neuropathic drugs. Interpretation: The prevalence of chronic pain in the homeless appears to be substantially higher than the general population, is poorly controlled, and adversely affects general activity, walking and sleeping. It is hard to discern whether chronic pain is a cause or effect of homelessness, or both. Pain is a symptom, but in this challenging group it might not always be possible to treat the underlying cause. Exploring the diagnosis and treatment of neuropathic pain may offer a means of improving the quality of these vulnerable people’s lives.
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- 2013
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19. Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic
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Alice Garrett, Chey Loveday, Amit Sud, John Broggio, Y-E. Suh, James Larkin, Bethany Torr, Matthew Williams, Stephen Scott, Christopher Abbosh, Michael Jones, David Nicol, Georgios Lyratzopoulos, Stephen A. Boyce, J.M. Handy, F. Gronthoud, Nadia Yousaf, P. Ward, Clare Turnbull, Charles Swanton, Richard S. Houlston, Pharoah Pd, Shaman Jhanji, Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Male ,CYSTECTOMY ,medicine.medical_treatment ,MUSCLE INVASION ,0302 clinical medicine ,Neoplasms ,Pandemic ,Health care ,diagnostics ,Aged, 80 and over ,Hazard ratio ,Hematology ,Middle Aged ,TIME ,Hospitalization ,Treatment Outcome ,030220 oncology & carcinogenesis ,oncology ,Female ,Coronavirus Infections ,Life Sciences & Biomedicine ,Adult ,medicine.medical_specialty ,delay ,Pneumonia, Viral ,DIAGNOSIS ,survival ,Article ,Time-to-Treatment ,Cystectomy ,03 medical and health sciences ,Betacoronavirus ,Breast cancer ,medicine ,BREAST-CANCER ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Pandemics ,Aged ,Science & Technology ,business.industry ,SARS-CoV-2 ,Public health ,Cancer ,COVID-19 ,medicine.disease ,030104 developmental biology ,Emergency medicine ,Observational study ,business - Abstract
Background Cancer diagnostics and surgery have been disrupted by the response of healthcare services to the COVID-19 pandemic. Progression of cancers during delay will impact on patient long-term survival. Methods We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of three months and six months and periods of disruption of one year and two years. Using healthcare resource costing, we contextualise attributable lives saved and life-years gained from cancer surgery to equivalent volumes of COVID-19 hospitalisations. Findings Per year, 94,912 resections for major cancers result in 80,406 long-term survivors and 1,717,051 life years gained. Per-patient delay of three/six months would cause attributable death of 4,755/10,760 of these individuals with loss of 92,214/208,275 life-years. For cancer surgery, average life-years gained (LYGs) per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of three/six months (an average loss of 0.97/2.19 LYG per patient). Taking into account units of healthcare resource (HCRU), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of three/six months. For 94,912 hospital COVID-19 admissions, there are 482,022 LYGs requiring of 1,052,949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs. Interpretation Modest delays in surgery for cancer incur significant impact on survival. Delay of three/six months in surgery for incident cancers would mitigate 19%/43% of life-years gained by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59% when considering resource-adjusted life-years gained. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued., Highlights • Lockdown and re-deployment due to the COVID-19 pandemic is causing significant disruption to cancer diagnosis and management. • 3-month delay to surgery across all Stage 1-3 cancers is estimated to cause >4,700 attributable deaths per year in England. • The impact on life years lost of 3-6 month to surgery for Stage 1-3 disease varies widely between tumour types. • Strategic prioritisation of patients for diagnostics and surgery has potential to mitigate deaths attributable to delays. • The resource-adjusted benefit in avoiding delay in cancer management compares favourably to admission for COVID-19 infection.
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- 2020
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20. Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study
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Amit Sud, Mark Lawler, John Broggio, Elio Riboli, David C. Muller, Alice Garrett, Muti Abulafi, Firza Gronthound, Ethna McFerran, Emma Kipps, Stephen Scott, Matthew Williams, Clare Turnbull, Richard S. Houlston, Beth Torr, David Nicol, Stephen A. Boyce, Michael Jones, Georgios Lyratzopoulos, Claire Barry, Chey Loveday, Shaman Jhanji, and Cancer Research UK
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medicine.medical_specialty ,Delayed Diagnosis ,Referral ,Colorectal cancer ,Colonoscopy ,colorectal cancer ,colorectal cancer screening ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,Infection control ,Life Tables ,Mortality ,Early Detection of Cancer ,Cross Infection ,Infection Control ,Gastroenterology & Hepatology ,medicine.diagnostic_test ,SARS-CoV-2 ,business.industry ,Immunochemistry ,Gastroenterology ,COVID-19 ,Cancer ,1103 Clinical Sciences ,medicine.disease ,Triage ,United Kingdom ,GI cancer ,Occult Blood ,030220 oncology & carcinogenesis ,Emergency medicine ,Critical Pathways ,1114 Paediatrics and Reproductive Medicine ,030211 gastroenterology & hepatology ,Observational study ,Colorectal Neoplasms ,Risk assessment ,business - Abstract
ObjectiveTo evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic.DesignWe modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2–6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19–related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008–2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval.ResultsDelay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk–benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%.ConclusionsDelays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.
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- 2020
21. Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study
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Shaman Jhanji, Stephen Scott, Amit Sud, Neal Navani, Elio Riboli, Matthew Williams, Charles Swanton, Richard S. Houlston, Mark Lawler, John Broggio, Ethna McFerran, Michael Jones, James Larkin, Georgios Lyratzopoulos, Chey Loveday, Stephen A. Boyce, David Nicol, Alice Garrett, David C. Muller, Firza Gronthoud, Clare Turnbull, Bethany Torr, and Emma Kipps
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Adult ,Male ,medicine.medical_specialty ,Referral ,Waiting Lists ,Pneumonia, Viral ,Disease ,03 medical and health sciences ,Betacoronavirus ,0302 clinical medicine ,Breast cancer ,SDG 3 - Good Health and Well-being ,Neoplasms ,Medicine ,Humans ,030212 general & internal medicine ,Pandemics ,Pneumonia, Viral/epidemiology ,Referral and Consultation ,Survival analysis ,Aged ,Aged, 80 and over ,Models, Statistical ,business.industry ,SARS-CoV-2 ,Public health ,Hazard ratio ,Cancer ,COVID-19 ,Articles ,Middle Aged ,medicine.disease ,Survival Analysis ,Oncology ,England ,030220 oncology & carcinogenesis ,Emergency medicine ,Observational study ,Coronavirus Infections/epidemiology ,Female ,Coronavirus Infections ,business ,Neoplasms/diagnosis - Abstract
Summary Background During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2. Methods In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008–17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013–16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I–III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1–6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred. Findings Across England in 2013–16, an average of 6281 patients with stage I–III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1–3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3–8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14 873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22 635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type. Interpretation Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer. Funding None.
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- 2020
22. Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations
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Alison Callaway, Rachel Robinson, Cankut Çubuk, Sian Ellard, Bethany Torr, Clare Turnbull, George J Burghel, Diana Eccles, Miranda Durkie, Helen Hanson, Marc Tischkowitz, James Drummond, Ian R. Berry, Alice Garrett, Andrew J Wallace, Garrett, Alice [0000-0001-8942-283X], Burghel, George J [0000-0001-9360-8194], Berry, Ian R [0000-0002-9710-4724], Eccles, Diana M [0000-0002-9935-3169], and Apollo - University of Cambridge Repository
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0301 basic medicine ,medicine.medical_specialty ,Genomics ,Computational biology ,030105 genetics & heredity ,Biology ,medical ,genetic testing ,03 medical and health sciences ,Neoplasms ,medicine ,genomics ,Humans ,genetics ,Genetic Predisposition to Disease ,Gene ,Genetics (clinical) ,Genetic testing ,Evidence-Based Medicine ,medicine.diagnostic_test ,Cancer susceptibility ,Cancer ,Genetic Variation ,Geneticist ,medicine.disease ,Pathogenicity ,030104 developmental biology ,Medical genetics ,Genes, Neoplasm - Abstract
Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical ‘exponent score’ (2) new combinations of evidence elements constituting likely pathogenic’ and ‘pathogenic’ classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.
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- 2020
23. Collateral damage: the impact on cancer outcomes of the COVID-19 pandemic
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Christopher Abbosh, Jonathan M. Handy, Nadia Yousaf, Bethany Torr, Stephen A. Boyce, Yae-Eun Suh, Alice Garrett, Clare Turnbull, Paul D.P. Pharoah, David Nicol, Charles Swanton, Shaman Jhanji, Richard S. Houlston, John Broggio, Stephen Scott, Michael Jones, Georgios Lyratzopoulos, Amit Sud, James Larkin, Chey Loveday, Phillip Ward, and Matthew Williams
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Receipt ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Public health ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Hazard ratio ,Cancer ,medicine.disease_cause ,medicine.disease ,Virology ,Breast cancer ,Family medicine ,Health care ,Pandemic ,medicine ,Collateral damage ,Observational study ,business ,Coronavirus Infections ,Coronavirus - Abstract
Background: Cancer diagnostics and surgery have been disrupted by the response of healthcare services to the COVID-19 pandemic. Progression of cancers during delay will impact on patient long-term survival. Methods: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of three months and six months and periods of disruption of one year and two years. Using healthcare resource costing, we contextualise attributable lives saved and life years gained from cancer surgery to equivalent volumes of COVID-19 hospitalisations. Findings: Per year, 94,912 resections for major cancers result in 80,406 long-term survivors and 1,717,051 life years gained. Per-patient delay of six months would cause attributable death of 10,555 of these individuals with loss of 205,024 life years. For cancer surgery, average life years gained (LYGs) per patient are 18·1 under standard conditions and 15·9 with a delay of six months (a loss of 2·3 LYG per patient). Taking into account units of healthcare resource (HCRU), surgery results on average per patient in 2·25 resource-adjusted life years gained (RALYGs) under standard conditions and 1·98 RALYGs following delay of six months. For 94,912 hospital COVID-19 admissions, there are 474,505 LYGs requiring of 1,097,937 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5·0 LYG and 0·43 RALYGs. Interpretation: Delay of six months in surgery for incident cancers would mitigate 43% of life years gained by hospitalisation of an equivalent volume of admissions for community acquired COVID-19. This rises to 62% when considering resource-adjusted life-years gained. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued. Funding Statement: MEJ additionally received funding from Breast Cancer Now.GL is supported by a Cancer Research UK Advanced Clinician Scientist Fellowship Award [C18081/A18180] and is Associate Director of the multi-institutional CanTest Collaborative funded by Cancer Research UK [C8640/A23385]. B.T and A.G. are supported by Cancer Research UK award C61296/A27223. R.S.H. is supported by Cancer Research UK (C1298/A8362) and Bobby Moore Fund for Cancer Research UK). A.S. is in receipt of an Academic Clinical Lectureship from National Institute for Health Research (NIHR) and Biomedical Research Centre (BRC) post-doctoral support. This is a summary of independent research supported by the NIHR BRC at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research. Declaration of Interests: The authors declare no competing interests.
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- 2020
24. Quantifying and Mitigating the Impact of the COVID-19 Pandemic on Outcomes in Colorectal Cancer
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John Broggio, Stephen Scott, Bethany Torr, Alice Garrett, Emma Kipps, Mark Lawler, Amit Sud, Elio Riboli, Clare Turnbull, Richard S. Houlston, David C. Muller, Ethna McFerran, Muti Abulafi, Chey Loveday, Matthew Williams, Shaman Jhanji, David L. Nicol, Michael Jones, Georgios Lyratzopoulos, Stephen A. Boyce, and Claire Barry
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medicine.medical_specialty ,medicine.diagnostic_test ,Referral ,Colorectal cancer ,business.industry ,Hazard ratio ,Cancer ,Colonoscopy ,Disease ,medicine.disease ,Triage ,Breast cancer ,Emergency medicine ,medicine ,Observational study ,business - Abstract
Background: The COVID-19 pandemic has caused disruption across cancer pathways for diagnosis and treatment. In England, 32% of colorectal cancer (CRC) is diagnosed via urgent symptomatic referral from primary care, the “2-week-wait” (2WW) pathway. Access to routine endoscopy is likely to be a critical bottleneck causing delays in CRC management due to chronic limitation in capacity, acute competition for physician time, and safety concerns. Methods: We used age-specific, stage-specific 10 year CRC survival for England 2007-2017 and 2WW CRC cases volumes. We used per-day hazard ratios of CRC survival generated from observational studies of CRC diagnosis-to-treatment interval to model the effect of different durations of per-patient delay. We utilised data from a large London observational study of faecal immunochemical testing (FIT) in symptomatic patients to model FIT-triage to mitigate delay to colonoscopy. Findings: Modest delays result in significant reduction in survival from CRC with a 4-month delay resulting across age groups in ≥20% reduction in survival in Stage 3 disease and in total over a year, 1,419 attributable deaths across the 11,266 CRC patients diagnosed via the 2WW pathway. FIT triage of >10 ug Hb/g would salvage 1,292/1,419 of the attributable deaths and reduce colonoscopy requirements by >80%. Diagnostic colonoscopy offers net survival in all age groups, providing nosocomial COVID-19 infection rates are kept low (
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- 2020
25. The impact of artificial intelligence on the current and future practice of clinical cancer genomics
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Katie Snape, Olivia Greatbatch, and Alice Garrett
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Opposition (planets) ,media_common.quotation_subject ,Genomics ,Review ,03 medical and health sciences ,0302 clinical medicine ,Optimism ,Artificial Intelligence ,Neoplasms ,Health care ,Genetics ,medicine ,Humans ,030212 general & internal medicine ,Speculation ,media_common ,Physician-Patient Relations ,Apprehension ,business.industry ,General Medicine ,Harm ,030220 oncology & carcinogenesis ,Unemployment ,Artificial intelligence ,medicine.symptom ,business ,Psychology ,Delivery of Health Care - Abstract
Artificial intelligence (AI) is one of the most significant fields of development in the current digital age. Rapid advancements have raised speculation as to its potential benefits in a wide range of fields, with healthcare often at the forefront. However, amidst this optimism, apprehension and opposition continue to strongly persist. Oft-cited concerns include the threat of unemployment, harm to the doctor–patient relationship and questions of safety and accuracy. In this article, we review both the current and future medical applications of AI within the sub-speciality of cancer genomics.
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- 2019
26. First Trimester Circulating MicroRNA Biomarkers Predictive of Subsequent Preterm Delivery and Cervical Shortening
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Lynne Sykes, L Kindinger, Alice Garrett, T. G. Teoh, Phillip R. Bennett, Reem Binkhamis, Vasso Terzidou, Joanna R. Cook, Sung Hye Kim, David A. MacIntyre, Medical Research Council (MRC), Imperial College Healthcare NHS Trust- BRC Funding, Action Medical Research, Seattle ChildrensHospital Research Foundation, and Genesis Research Trust
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0301 basic medicine ,EXPRESSION ,Adult ,medicine.medical_specialty ,BIRTH ,lcsh:Medicine ,Cervix Uteri ,Asymptomatic ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,medicine ,LENGTH ,Humans ,lcsh:Science ,Preterm delivery ,RISK ,Multidisciplinary ,Science & Technology ,Obstetrics ,business.industry ,lcsh:R ,PROLIFERATION ,medicine.disease ,Cervical shortening ,3. Good health ,Multidisciplinary Sciences ,body regions ,First trimester ,Circulating MicroRNA ,MicroRNAs ,Pregnancy Trimester, First ,030104 developmental biology ,ROC Curve ,Area Under Curve ,embryonic structures ,Gestation ,Science & Technology - Other Topics ,Premature Birth ,lcsh:Q ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Biomarkers ,Cohort study - Abstract
Preterm birth (PTB) is the leading cause of infant death and disability worldwide. The onset of preterm uterine contractions is preceded by asymptomatic cervical remodelling and ripening, which can be seen on trans-vaginal ultrasound as cervical shortening. This study aimed to identify plasma miRNA biomarkers that predict preterm birth and/or cervical shortening. We collected serial plasma samples from pregnant women prospectively from 12 to 22 weeks gestation. The nCounter miRNA assay was used to identify differentially expressed miRNAs associated with spontaneous PTB and/or cervical shortening (n = 16 term no short, n = 13 preterm, n = 24 short). Predictive values of the miRNA biomarkers were confirmed in an independent validation cohort consisting of 96 women who delivered at term, 14 preterm and 21 early cervical shortening at P
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- 2019
27. Demonstrating the Use of Optical Fibres in Biomedical Sensing: A Collaborative Approach for Engagement and Education
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Duncan K. McNicholl, Giulia Spennati, Mark Reynolds, András Kufcsák, Katjana Ehrlich, Graham Crawford, Helen E. Parker, Peter Reid, Helen Szoor-McElhinney, Gregor Steele, Melanie Jimenez, Alice Garrett, Angela Deighan, Vincent Bussiere, and Dominic Norberg
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Lung Diseases ,Biomedical Research ,high school/introduction medicine ,Process (engineering) ,medical imaging ,Context (language use) ,Biosensing Techniques ,lcsh:Chemical technology ,01 natural sciences ,Biochemistry ,Article ,Analytical Chemistry ,Translational Research, Biomedical ,010309 optics ,Endoscopic imaging ,fluorescence imaging ,interdisciplinary/multidisciplinary ,0103 physical sciences ,Endomicroscopy ,Humans ,lcsh:TP1-1185 ,Economic impact analysis ,Cooperative Behavior ,Electrical and Electronic Engineering ,medical optics instrumentation ,Instrumentation ,Optical Fibers ,fiber optics ,Microscopy ,public understanding/outreach ,4. Education ,010401 analytical chemistry ,Science teachers ,Atomic and Molecular Physics, and Optics ,lung disease diagnostics ,3. Good health ,0104 chemical sciences ,Lung disease ,endoscopic imaging ,Engineering ethics - Abstract
This paper demonstrates how research at the intersection of physics, engineering, biology and medicine can be presented in an interactive and educational way to a non-scientific audience. Interdisciplinary research with a focus on prevalent diseases provides a relatable context that can be used to engage with the public. Respiratory diseases are significant contributors to avoidable morbidity and mortality and have a growing social and economic impact. With the aim of improving lung disease understanding, new techniques in fibre-based optical endomicroscopy have been recently developed. Here, we present a novel engagement activity that resembles a bench-to-bedside pathway. The activity comprises an inexpensive educational tool (<, $70) adapted from a clinical optical endomicroscopy system and tutorials that cover state-of-the-art research. The activity was co-created by high school science teachers and researchers in a collaborative way that can be implemented into any engagement development process.
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- 2020
28. The nature and prevalence of chronic pain in homeless persons: an observational study
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E. Katherine Harrison, Kimberly Kt Lwin, Alice Garrett, Daniel W. Wheeler, Rebecca Fisher, and Judith Ewing
- Subjects
Gerontology ,medicine.medical_specialty ,education.field_of_study ,Activities of daily living ,General Immunology and Microbiology ,business.industry ,Population ,Chronic pain ,Articles ,General Medicine ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Pain Management: Chronic Clinical ,Social & Behavioral Determinants of Health ,Short-Form McGill Pain Questionnaire ,Quality of life (healthcare) ,Neuropathic pain ,medicine ,Short Research Article ,Pain catastrophizing ,General Pharmacology, Toxicology and Pharmaceutics ,Brief Pain Inventory ,Psychiatry ,education ,business - Abstract
Background: Homeless people are known to suffer disproportionately with health problems that reduce physical functioning and quality of life, and shorten life expectancy. They suffer from a wide range of diseases that are known to be painful, but little information is available about the nature and prevalence of chronic pain in this vulnerable group. This study aimed to estimate the prevalence of chronic pain among homeless people, and to examine its location, effect on activities of daily living, and relationship with alcohol and drugs.Methods: We conducted face-to-face interviews with users of homeless shelters in four major cities in the United Kingdom, in the winters of 2009-11. Participants completed the Brief Pain Inventory, Short Form McGill Pain questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, and detailed their intake of prescribed and unprescribed medications and alcohol. We also recorded each participant’s reasons for homelessness, and whether they slept rough or in shelters.Findings: Of 168 shelter users approached, 150 (89.3%) participated: 93 participants (63%) reported experiencing pain lasting longer than three months; the mean duration of pain experienced was 82.2 months. The lower limbs were most frequently affected. Opioids appeared to afford a degree of analgesia for some, but whilst many reported symptoms suggestive of neuropathic pain, very few were taking anti-neuropathic drugs.Interpretation: The prevalence of chronic pain in the homeless appears to be substantially higher than the general population, is poorly controlled, and adversely affects general activity, walking and sleeping. It is hard to discern whether chronic pain is a cause or effect of homelessness, or both. Pain is a symptom, but in this challenging group it might not always be possible to treat the underlying cause. Exploring the diagnosis and treatment of neuropathic pain may offer a means of improving the quality of these vulnerable people’s lives.
- Published
- 2013
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