803 results on '"Mccombe P."'
Search Results
2. Transformer-based Model for Oral Epithelial Dysplasia Segmentation
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Shephard, Adam J, Mahmood, Hanya, Raza, Shan E Ahmed, Araujo, Anna Luiza Damaceno, Santos-Silva, Alan Roger, Lopes, Marcio Ajudarte, Vargas, Pablo Agustin, McCombe, Kris, Craig, Stephanie, James, Jacqueline, Brooks, Jill, Nankivell, Paul, Mehanna, Hisham, Khurram, Syed Ali, and Rajpoot, Nasir M
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Electrical Engineering and Systems Science - Image and Video Processing ,Computer Science - Computer Vision and Pattern Recognition ,Computer Science - Machine Learning - Abstract
Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. OED grading is subject to large inter/intra-rater variability, resulting in the under/over-treatment of patients. We developed a new Transformer-based pipeline to improve detection and segmentation of OED in haematoxylin and eosin (H&E) stained whole slide images (WSIs). Our model was trained on OED cases (n = 260) and controls (n = 105) collected using three different scanners, and validated on test data from three external centres in the United Kingdom and Brazil (n = 78). Our internal experiments yield a mean F1-score of 0.81 for OED segmentation, which reduced slightly to 0.71 on external testing, showing good generalisability, and gaining state-of-the-art results. This is the first externally validated study to use Transformers for segmentation in precancerous histology images. Our publicly available model shows great promise to be the first step of a fully-integrated pipeline, allowing earlier and more efficient OED diagnosis, ultimately benefiting patient outcomes., Comment: 5 pages, 2 figures, 4 tables
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- 2023
3. Families' Perspectives on the Process of Community Transitions of Individuals with Severe Intellectual and Developmental Disabilities
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Maria Baranowski, Margherita Cameranesi, Javier Mignone, Lindsay McCombe, Kayla Kostal, Jenna Heschuk, and Shahin Shooshtari
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Background: Deinstitutionalisation refers to the transition of individuals with intellectual and developmental disabilities from large institutions to smaller homes in the community. The purpose of this study was to explore how family members of persons with intellectual and developmental disabilities perceived their loved ones' community transition process. Method: Eight family members of persons with severe or profound intellectual and developmental disabilities formerly residing at the complex care facility of St.Amant participated in semi-structured interviews. Interview transcripts were analysed thematically using an iterative inductive process and constant comparative method. Results: Three main themes emerged from the family members' accounts of their loved ones' community transitions process: 1) families' initial reactions, 2) strengths, and 3) challenges. Conclusions: Initial reactions of family members to learning about the community transitions process were varied. Family members' perspectives inform deinstitutionalisation efforts by highlighting facilitators such as adequate involvement, and barriers such as, unanticipated delays, to the community transitions process.
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- 2024
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4. A Fully Automated and Explainable Algorithm for the Prediction of Malignant Transformation in Oral Epithelial Dysplasia
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Shephard, Adam J, Bashir, Raja Muhammad Saad, Mahmood, Hanya, Jahanifar, Mostafa, Minhas, Fayyaz, Raza, Shan E Ahmed, McCombe, Kris D, Craig, Stephanie G, James, Jacqueline, Brooks, Jill, Nankivell, Paul, Mehanna, Hisham, Khurram, Syed Ali, and Rajpoot, Nasir M
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Quantitative Biology - Quantitative Methods ,Computer Science - Computer Vision and Pattern Recognition ,Electrical Engineering and Systems Science - Image and Video Processing - Abstract
Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. Its grading suffers from significant inter-/intra- observer variability, and does not reliably predict malignancy progression, potentially leading to suboptimal treatment decisions. To address this, we developed a novel artificial intelligence algorithm that can assign an Oral Malignant Transformation (OMT) risk score, based on histological patterns in the in Haematoxylin and Eosin stained whole slide images, to quantify the risk of OED progression. The algorithm is based on the detection and segmentation of nuclei within (and around) the epithelium using an in-house segmentation model. We then employed a shallow neural network fed with interpretable morphological/spatial features, emulating histological markers. We conducted internal cross-validation on our development cohort (Sheffield; n = 193 cases) followed by independent validation on two external cohorts (Birmingham and Belfast; n = 92 cases). The proposed OMTscore yields an AUROC = 0.74 in predicting whether an OED progresses to malignancy or not. Survival analyses showed the prognostic value of our OMTscore for predicting malignancy transformation, when compared to the manually-assigned WHO and binary grades. Analysis of the correctly predicted cases elucidated the presence of peri-epithelial and epithelium-infiltrating lymphocytes in the most predictive patches of cases that transformed (p < 0.0001). This is the first study to propose a completely automated algorithm for predicting OED transformation based on interpretable nuclear features, whilst being validated on external datasets. The algorithm shows better-than-human-level performance for prediction of OED malignant transformation and offers a promising solution to the challenges of grading OED in routine clinical practice.
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- 2023
5. A fully automated and explainable algorithm for predicting malignant transformation in oral epithelial dysplasia
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Shephard, Adam J., Bashir, Raja Muhammad Saad, Mahmood, Hanya, Jahanifar, Mostafa, Minhas, Fayyaz, Raza, Shan E. Ahmed, McCombe, Kris D., Craig, Stephanie G., James, Jacqueline, Brooks, Jill, Nankivell, Paul, Mehanna, Hisham, Khurram, Syed Ali, and Rajpoot, Nasir M.
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- 2024
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6. Transient binocular vision loss and pain insensitivity in Klippel–Feil syndrome: a case report
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Ullah, Zeeshan, Zafar, Ayesha, Ishaq, Hira, Umar, Zainab, Khan, Amir, Badar, Yaseen, Din, Nizamud, Khan, Muhammad Fawad, McCombe, Pamela, and Khan, Nemat
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- 2024
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7. Irish general practitioner (GP) perspectives on impact of direct access radiology on patient care in the community: results from a mixed-methods study
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O’Callaghan, Michael Edmund, Fawsitt, Ronan, Gao, Jiaran, Broughan, John, McCombe, Geoff, Phelan, Amy, Quinlan, Diarmuid, Collins, Claire, Stanley, Fintan, and Cullen, Walter
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- 2024
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8. A fully automated and explainable algorithm for predicting malignant transformation in oral epithelial dysplasia
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Adam J. Shephard, Raja Muhammad Saad Bashir, Hanya Mahmood, Mostafa Jahanifar, Fayyaz Minhas, Shan E. Ahmed Raza, Kris D. McCombe, Stephanie G. Craig, Jacqueline James, Jill Brooks, Paul Nankivell, Hisham Mehanna, Syed Ali Khurram, and Nasir M. Rajpoot
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. Its grading suffers from significant inter-/intra-observer variability, and does not reliably predict malignancy progression, potentially leading to suboptimal treatment decisions. To address this, we developed an artificial intelligence (AI) algorithm, that assigns an Oral Malignant Transformation (OMT) risk score based on the Haematoxylin and Eosin (H&E) stained whole slide images (WSIs). Our AI pipeline leverages an in-house segmentation model to detect and segment both nuclei and epithelium. Subsequently, a shallow neural network utilises interpretable morphological and spatial features, emulating histological markers, to predict progression. We conducted internal cross-validation on our development cohort (Sheffield; n = 193 cases) and independent validation on two external cohorts (Birmingham and Belfast; n = 89 cases). On external validation, the proposed OMTscore achieved an AUROC = 0.75 (Recall = 0.92) in predicting OED progression, outperforming other grading systems (Binary: AUROC = 0.72, Recall = 0.85). Survival analyses showed the prognostic value of our OMTscore (C-index = 0.60, p = 0.02), compared to WHO (C-index = 0.64, p = 0.003) and binary grades (C-index = 0.65, p
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- 2024
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9. 3018 A multi-centre longitudinal study analysing disease modifying therapy prescribing patterns during the COVID-19 pandemic
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Nevin John, Steve Vucic, Riadh Gouider, Tomas Kalincik, Guillermo Izquierdo, Alexandre Prat, Marc Girard, Pierre Duquette, Pierre Grammond, Serkan Ozakbas, Jeannette Lechner-Scott, Cavit Boz, Julie Prevost, Recai Turkoglu, Vincent Van Pesch, Cristina Ramo-Tello, Mark Slee, Raed Alroughani, Vahid Shaygannejad, Daniele Spitaleri, José Luis Sánchez-Menoyo, Suzanne Hodgkinson, Rana Karabudak, Tim Spelman, Helmut Butzkueven, Noriko Isobe, Paul G Sanfilippo, Michael Barnett, Orla Gray, Maria José Sá, Allan Kermode, Guy Laureys, Richard Macdonell, Anneke Van Der Walt, Ayse Altintas, Mario Habek, Pamela McCombe, Seyed Mohammad Baghbanian, Yi Chao Foong, Riki Matsumoto, Abdullah Al-Asmi, Bruce Taylor, Samia J Khoury, Todd Hardy, Katherine Buzzard, Marzena Fabis-Pedrini, Louise Rath, Olga Skibina, Jiwon Oh, William M Carroll, Katrin Gross-Paju, Jan Schepel, Sara Eichau, Elisabetta Cartechini, Aysun Soysal, Davide Maimone, Anoushka Lal, Masoud Etemadifar, Oliver Gerlach, Saloua Mrabet, Emanuele D'Amico, Yolanda Blanco, Matteo Foschi, Melissa Cambron, Andrea Surcinelli, David Levitz, Liesbeth Van Hijfte, Mehmet Fatih Yetkin, Simón Cárdenas-Robledo, Emmanuelle Lapointe, Abdorreza Naser Moghadasi, Gregor Brecl Jakob, and Talal Al-Harbi
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
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10. 3149 Real-world Australian experience with Ofatumumab in the MSBase registry
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Nevin John, Tomas Kalincik, Jeannette Lechner-Scott, Mark Slee, Suzanne Hodgkinson, Tim Spelman, Helmut Butzkueven, Michael Barnett, Allan Kermode, Richard Macdonell, Anneke Van Der Walt, Pamela McCombe, Marzena Fabis-Pedrini, William M Carroll, Margaret Migocki, and Birte Schmitt
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
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11. 2967 Utilisation of high efficacy therapy for managing multiple sclerosis in Australia
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Helmut Butzkueven, Simon Broadley, Martin Merschhemke, Nicholas Riley, Michael Barnett, Anneke Van Der Walt, Pamela McCombe, Rob Walker, Nicholas Adlard, Naomi Burke, and Imtiaz Samjoo
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
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12. 3207 Case series of multisystem proteinopathy due to valosin-containing protein (VCP) gene variants: an inconsistent phenotype
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Mark Davis, Robert Henderson, Merrilee Needham, Pamela McCombe, Emily Watson, and Susannah Gattas
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
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13. Generation of human induced pluripotent stem cell lines from sporadic, sporadic frontotemporal dementia, familial SOD1, and familial C9orf72 amyotrophic lateral sclerosis (ALS) patients
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Leanne Jiang, Timothy J. Tracey, Melinder K. Gill, Stephanie L. Howe, Dominique T. Power, Vanda Bharti, Pamela A. McCombe, Robert D. Henderson, Frederik J. Steyn, and Shyuan T. Ngo
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Biology (General) ,QH301-705.5 - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics.
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- 2024
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14. Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies
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Li, Ying, Saul, Alice, Taylor, Bruce, Ponsonby, Anne-Louise, Simpson-Yap, Steve, Blizzard, Leigh, Broadley, Simon, Lechner-Scott, Jeannette, Karabudak, Rana, Patti, Francesco, Eichau, Sara, Onofrj, Marco, Ozakbas, Serkan, Horakova, Dana, Kubala Havrdova, Eva, Grand’Maison, Francois, Alroughani, Raed, Gerlach, Oliver, Amato, Maria Pia, Altintas, Ayse, Girard, Marc, Duquette, Pierre, Blanco, Yolanda, Ramo-Tello, Cristina, Laureys, Guy, Kalincik, Tomas, Khoury, Samia J., Shaygannejad, Vahid, Etemadifar, Masoud, Singhal, Bhim, Mrabet, Saloua, Foschi, Matteo, Habek, Mario, John, Nevin, Hughes, Stella, McCombe, Pamela, Ampapa, Radek, van der Walt, Anneke, Butzkueven, Helmut, de Gans, Koen, McGuigan, Chris, Oreja-Guevara, Celia, Sa, Maria Jose, Petersen, Thor, Al-Harbi, Talal, Sempere, Angel Perez, Van Wijmeersch, Bart, Grigoriadis, Nikolaos, Prevost, Julie, Gray, Orla, Castillo-Triviño, Tamara, Macdonell, Richard, Lugaresi, Alessandra, Sajedi, Seyed Aidin, and van der Mei, Ingrid
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- 2024
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15. Development and validation of a multivariable model for prediction of malignant transformation and recurrence of oral epithelial dysplasia
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Mahmood, Hanya, Shephard, Adam, Hankinson, Paul, Bradburn, Mike, Araujo, Anna Luiza Damaceno, Santos-Silva, Alan Roger, Lopes, Marcio Ajudarte, Vargas, Pablo Agustin, McCombe, Kris D., Craig, Stephanie G., James, Jacqueline, Brooks, Jill, Nankivell, Paul, Mehanna, Hisham, Rajpoot, Nasir, and Khurram, Syed Ali
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- 2023
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16. Examining the Changes in Problem Behaviours and Communication of Persons with Intellectual and Developmental Disabilities after Transitioning from an Institutional Setting to the Community
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Kayla Kostal, Maria Baranowski, Hygiea Casiano, Margherita Cameranesi, Lindsay McCombe, and Shahin Shooshtari
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intellectual and developmental disabilities ,community living ,community transitions ,challenging behaviours ,deinstitutionalization ,adult ,Vocational rehabilitation. Employment of people with disabilities ,HD7255-7256 - Abstract
Worldwide, the community transition process away from institutions has increased in the past 30–50 years among persons with severe intellectual and developmental disabilities. This process, also known as “deinstitutionalization”, could potentially impact problem behaviors and communication. This study examined the impacts of community transitions on behavioural and communication outcomes in Canadians with intellectual and developmental disabilities. Data were collected using the Comprehensive Health Assessment Program and medical chart reviews. Descriptive, aggregate-level, and individual-level analyses were conducted for 32 adults who transitioned to community living. Descriptive analyses and the McNemar Chi-Square Test were conducted. Following community transitions, the study group experienced a significant decrease in problem behaviours and changes in communication. The study findings suggest that deinstitutionalization could provide effective strategies for addressing problem behaviors and fostering improvements in communication, promoting the well-being and quality of life of persons with intellectual and developmental disabilities.
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- 2024
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17. Transient binocular vision loss and pain insensitivity in Klippel–Feil syndrome: a case report
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Zeeshan Ullah, Ayesha Zafar, Hira Ishaq, Zainab Umar, Amir Khan, Yaseen Badar, Nizamud Din, Muhammad Fawad Khan, Pamela McCombe, and Nemat Khan
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Case report ,Cervical vertebral abnormalities ,Congenital insensitivity to pain (CIP) ,Klippel–Feil syndrome (KFS) ,Optic disc edema ,Rare congenital disorder ,Medicine - Abstract
Abstract Background Klippel–Feil syndrome is a rare congenital bone disorder characterized by an abnormal fusion of two or more cervical spine vertebrae. Individuals with Klippel–Feil syndrome exhibit diverse clinical manifestations, including skeletal irregularities, visual and hearing impairments, orofacial anomalies, and anomalies in various internal organs, such as the heart, kidneys, genitourinary system, and nervous system. Case presentation This case report describes a 12-year-old Pashtun female patient who presented with acute bilateral visual loss. The patient had Klippel–Feil syndrome, with the typical clinical triad symptoms of Klippel–Feil syndrome, along with Sprengel’s deformity. She also exhibited generalized hypoalgesia, which had previously resulted in widespread burn-related injuries. Upon examination, bilateral optic disc swelling was observed, but intracranial pressure was found to be normal. Extensive investigations yielded normal results, except for hypocalcemia and low vitamin D levels, while parathyroid function remained within the normal range. Visual acuity improved following 2 months of calcium and vitamin D supplementation, suggesting that the visual loss and optic nerve swelling were attributed to hypocalcemia. Given the normal parathyroid function, it is possible that hypocalcemia resulted from low vitamin D levels, which can occur after severe burn scarring. Furthermore, the patient received a provisional diagnosis of congenital insensitivity to pain on the basis of the detailed medical history and the findings of severe and widespread loss of the ability to perceive painful stimuli, as well as impaired temperature sensation. However, due to limitations in genetic testing, confirmation of the congenital insensitivity to pain diagnosis could not be obtained. Conclusion This case highlights a rare presentation of transient binocular vision loss and pain insensitivity in a patient with Klippel–Feil syndrome, emphasizing the importance of considering unusual associations in symptom interpretation.
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- 2024
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18. Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1
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Restuadi, Restuadi, Steyn, Frederik J, Kabashi, Edor, Ngo, Shyuan T, Cheng, Fei-Fei, Nabais, Marta F, Thompson, Mike J, Qi, Ting, Wu, Yang, Henders, Anjali K, Wallace, Leanne, Bye, Chris R, Turner, Bradley J, Ziser, Laura, Mathers, Susan, McCombe, Pamela A, Needham, Merrilee, Schultz, David, Kiernan, Matthew C, van Rheenen, Wouter, van den Berg, Leonard H, Veldink, Jan H, Ophoff, Roel, Gusev, Alexander, Zaitlen, Noah, McRae, Allan F, Henderson, Robert D, Wray, Naomi R, Giacomotto, Jean, and Garton, Fleur C
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Biological Sciences ,Genetics ,Rare Diseases ,Neurosciences ,Neurodegenerative ,Biotechnology ,Human Genome ,Brain Disorders ,ALS ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Amyotrophic Lateral Sclerosis ,Animals ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Neurodegenerative Diseases ,Polymorphism ,Single Nucleotide ,Zebrafish ,Motor neurone disease ,MND ,Genome-wide association study ,Computational biology ,Neurodegenerative diseases ,Quantitative trait loci ,Genes ,Regulator ,Disease progression ,Clinical Sciences - Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this.MethodsThe Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO).ResultsSMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10-6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10-3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all
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- 2022
19. Rationale and design of the multi organ inflammation with serial testing study: a comprehensive assessment of functional and structural abnormalities in patients with recovered COVID-19
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D. Ian Paterson, James A. White, Christian Beaulieu, Rachel Sherrington, Carla M. Prado, Puneeta Tandon, Kieran Halloran, Stephanie Smith, Jennifer A. McCombe, Bruce Ritchie, Edith Pituskin, Mark J. Haykowsky, Richard Coulden, Derek Emery, Albert K. Tsui, Kai Y. Wu, Gavin Y. Oudit, Justin A. Ezekowitz, and Richard B. Thompson
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recovered COVID-19 ,long COVID ,MRI ,circulating biomarkers ,functional assessment ,Medicine (General) ,R5-920 - Abstract
IntroductionShort-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15–20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear.MethodsA multicenter, observational study of 215 vaccine-naïve patients with clinically recovered COVID-19, studied at 3–6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized.DiscussionLong-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease.Study registrationclinicaltrials.gov (MOIST late cross-sectional study; NCT04525404).
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- 2024
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20. Crisis Stabilisation Services for People with Intellectual Disabilities: A Systematic Review
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McCombe, Lindsay H. A., Martin, Toby L., Curtis, Hannah, Ediger, James, and Temple, Beverley
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People with intellectual and developmental disabilities sometimes engage in challenging behaviours. When behaviours escalate to the point where they pose imminent risk to the safety of people and environments, a crisis occurs that jeopardises community living and participation. In these situations, timely access to crisis stabilisation services is required. We conducted a systematic review of the literature to synthesise evidence on effective crisis stabilisation service models for challenging behaviours. A total of 46 publications met the inclusion criteria. The literature describes a spectrum of crisis stabilisation services of varying intensities including: outreach, outpatient, inpatient, respite, and capacity building through education and training. However, there is limited guidance on how to best structure service models. This review highlights the need for comprehensive and person-centred programme evaluations.
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- 2022
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21. Early rapid tissue expansion of a free microvascular flap in head–neck reconstruction as salvage option: a case report
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Dilip Gahankari, Alistair McCombe, and Thomas Meares
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Surgery ,RD1-811 - Published
- 2024
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22. Comparative efficacy of ofatumumab oral therapies for relapsing multiple sclerosis patients using propensity score analyses and simulated treatment comparisons
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Nicholas Riley, Christopher Drudge, Morag Nelson, Anja Haltner, Michael Barnett, Simon Broadley, Helmut Butzkueven, Pamela McCombe, Anneke Van der Walt, Erin O. Y. Wong, Martin Merschhemke, Nicholas Adlard, Rob Walker, and Imtiaz A. Samjoo
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.
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- 2024
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23. The structural repertoire of Fusarium oxysporum f. sp. lycopersici effectors revealed by experimental and computational studies
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Daniel S Yu, Megan A Outram, Ashley Smith, Carl L McCombe, Pravin B Khambalkar, Sharmin A Rima, Xizhe Sun, Lisong Ma, Daniel J Ericsson, David A Jones, and Simon J Williams
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fungal effectors ,Fusarium oxysporum ,secreted in xylem effectors ,FOLD ,tomato ,structural biology ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Plant pathogens secrete proteins, known as effectors, that function in the apoplast or inside plant cells to promote virulence. Effector recognition by cell-surface or cytosolic receptors results in the activation of defence pathways and plant immunity. Despite their importance, our general understanding of fungal effector function and recognition by immunity receptors remains poor. One complication often associated with effectors is their high sequence diversity and lack of identifiable sequence motifs precluding prediction of structure or function. In recent years, several studies have demonstrated that fungal effectors can be grouped into structural classes, despite significant sequence variation and existence across taxonomic groups. Using protein X-ray crystallography, we identify a new structural class of effectors hidden within the secreted in xylem (SIX) effectors from Fusarium oxysporum f. sp. lycopersici (Fol). The recognised effectors Avr1 (SIX4) and Avr3 (SIX1) represent the founding members of the Fol dual-domain (FOLD) effector class, with members containing two distinct domains. Using AlphaFold2, we predicted the full SIX effector repertoire of Fol and show that SIX6 and SIX13 are also FOLD effectors, which we validated experimentally for SIX6. Based on structural prediction and comparisons, we show that FOLD effectors are present within three divisions of fungi and are expanded in pathogens and symbionts. Further structural comparisons demonstrate that Fol secretes effectors that adopt a limited number of structural folds during infection of tomato. This analysis also revealed a structural relationship between transcriptionally co-regulated effector pairs. We make use of the Avr1 structure to understand its recognition by the I receptor, which leads to disease resistance in tomato. This study represents an important advance in our understanding of Fol-tomato, and by extension plant–fungal interactions, which will assist in the development of novel control and engineering strategies to combat plant pathogens.
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- 2024
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24. Use of telemedicine in general practice in Europe since the COVID-19 pandemic: A scoping review of patient and practitioner perspectives
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David Walley, Geoff McCombe, John Broughan, Conor O’Shea, Des Crowley, Diarmuid Quinlan, Catherine Wann, Tadhg Crowley, and Walter Cullen
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Computer applications to medicine. Medical informatics ,R858-859.7 - Published
- 2024
25. Eculizumab for the treatment of glycine receptor antibody associated stiff-person syndrome
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McCombe, Jennifer A., Klassen, Bryan T., Flanagan, Eoin P., Teener, James W., Zekeridou, Anastasia, Pittock, Sean J., and McKeon, Andrew
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- 2023
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26. Enhancing long COVID care in general practice: A qualitative study.
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John Broughan, Emīls Sietiņš, Ka Yuet Emily Siu, Nia Clendennen, Claire Collins, Ronan Fawsitt, John S Lambert, Stefano Savinelli, Stephanie Skeffington, Geoff McCombe, and Walter Cullen
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Medicine ,Science - Abstract
IntroductionResearch suggests that general practice can play an important role in managing long COVID. However, studies investigating the perspectives of general practitioners (GPs) and patients are lacking and knowledge regarding optimal long COVID care in general practice is therefore limited.AimTo investigate GPs' and patients' perspectives on the topic of long COVID and its management in general practice.MethodsBrief questionnaires (GP n = 11, Patient n = 7) and in-depth semi-structured interviews (GP n = 10, Patient n = 7) were conducted with GPs and patients from Irish general practices during July 2022-January 2023. Interviews were conducted via telephone and audio recordings were transcribed. A phenomenological analysis involving reflexive thematic analysis and constant comparison techniques was adopted.ResultsAnalysis of interviews with GPs (male = 7, female = 3; median age = 50yrs (IQR = 39.5-56)) and patients (males = 2, female = 5; median age = 58yrs (IQR = 45-62yrs) generated four themes. These were (1) Complex presentations (2) the value of standardising care, (3) choosing the right path, and (4) supportive and collaborative doctor-patient relationships. Strong agreement was observed among GPs and patients regarding the need for holistic and integrated multidisciplinary care. Supportive and collaborative doctor-patient relationships were largely well received by GPs and patients also. GPs strongly endorsed standardising long COVID care operations.ConclusionGPs and patients indicated that structured, integrated, and collaborative care can help optimise long COVID management in general practice. GPs are advised to incorporate these elements into their long COVID care practices going forward. Future research examining stakeholder's perspectives using larger and longitudinal samples is advised to enhance the generalisability of evidence in this area.
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- 2024
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27. Predicting feature imputability in the absence of ground truth
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McCombe, Niamh, Ding, Xuemei, Prasad, Girijesh, Finn, David P., Todd, Stephen, McClean, Paula L., and Wong-Lin, KongFatt
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Statistics - Methodology ,Computer Science - Machine Learning - Abstract
Data imputation is the most popular method of dealing with missing values, but in most real life applications, large missing data can occur and it is difficult or impossible to evaluate whether data has been imputed accurately (lack of ground truth). This paper addresses these issues by proposing an effective and simple principal component based method for determining whether individual data features can be accurately imputed - feature imputability. In particular, we establish a strong linear relationship between principal component loadings and feature imputability, even in the presence of extreme missingness and lack of ground truth. This work will have important implications in practical data imputation strategies., Comment: 5 pages, 3 figures, 1 table. In: Proceedings of the 37th International Conference on Machine Learning (ICML), 2020
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- 2020
28. Computational neurology: Computational modeling approaches in dementia
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Wong-Lin, KongFatt, Sanchez-Bornot, Jose M., McCombe, Niamh, Kaur, Daman, McClean, Paula L., Zou, Xin, Youssofzadeh, Vahab, Ding, Xuemei, Bucholc, Magda, Yang, Su, Prasad, Girijesh, Coyle, Damien, Maguire, Liam P., Wang, Haiying, Wang, Hui, Atiya, Nadim A. A., and Joshi, Alok
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Quantitative Biology - Neurons and Cognition ,Quantitative Biology - Quantitative Methods - Abstract
Dementia is a collection of symptoms associated with impaired cognition and impedes everyday normal functioning. Dementia, with Alzheimer's disease constituting its most common type, is highly complex in terms of etiology and pathophysiology. A more quantitative or computational attitude towards dementia research, or more generally in neurology, is becoming necessary - Computational Neurology. We provide a focused review of some computational approaches that have been developed and applied to the study of dementia, particularly Alzheimer's disease. Both mechanistic modeling and data-drive, including AI or machine learning, approaches are discussed. Linkage to clinical decision support systems for dementia diagnosis will also be discussed., Comment: Accepted manuscript as a book chapter in Systems Medicine: Integrative, Qualitative and Computational Approaches. Wolkenhauer, O. (ed.). Elsevier Inc
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- 2020
29. Predictors of treatment switching in the Big Multiple Sclerosis Data Network
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Tim Spelman, Melinda Magyari, Helmut Butzkueven, Anneke Van Der Walt, Sandra Vukusic, Maria Trojano, Pietro Iaffaldano, Dana Horáková, Jirí Drahota, Fabio Pellegrini, Robert Hyde, Pierre Duquette, Jeannette Lechner-Scott, Seyed Aidin Sajedi, Patrice Lalive, Vahid Shaygannejad, Serkan Ozakbas, Sara Eichau, Raed Alroughani, Murat Terzi, Marc Girard, Tomas Kalincik, Francois Grand'Maison, Olga Skibina, Samia J. Khoury, Bassem Yamout, Maria Jose Sa, Oliver Gerlach, Yolanda Blanco, Rana Karabudak, Celia Oreja-Guevara, Ayse Altintas, Stella Hughes, Pamela McCombe, Radek Ampapa, Koen de Gans, Chris McGuigan, Aysun Soysal, Julie Prevost, Nevin John, Jihad Inshasi, Leszek Stawiarz, Ali Manouchehrinia, Lars Forsberg, Finn Sellebjerg, Anna Glaser, Luigi Pontieri, Hanna Joensen, Peter Vestergaard Rasmussen, Tobias Sejbaek, Mai Bang Poulsen, Jeppe Romme Christensen, Matthias Kant, Morten Stilund, Henrik Mathiesen, Jan Hillert, and The Big MS Data Network: a collaboration of the Czech MS Registry, the Danish MS Registry, Italian MS Registry, Swedish MS Registry, MSBase Study Group, and OFSEP
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multiple sclerosis ,disease modifying treatment (DMT) ,treatment switching ,disease registry ,real world evidence (RWE) ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
BackgroundTreatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods.ObjectiveThe objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry.MethodsIn this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect.ResultsEvery one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07–1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08–1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48–2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79–8.41; reference = 1996–2006).ConclusionSwitching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.
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- 2023
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30. Gut Symptoms, Gut Dysbiosis and Gut-Derived Toxins in ALS
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Aven Lee, Robert Henderson, James Aylward, and Pamela McCombe
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amyotrophic lateral sclerosis ,gut microbiota ,dysbiosis ,excitotoxicity ,formaldehyde ,D-serine ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Many pathogenetic mechanisms have been proposed for amyotrophic lateral sclerosis (ALS). Recently, there have been emerging suggestions of a possible role for the gut microbiota. Gut microbiota have a range of functions and could influence ALS by several mechanisms. Here, we review the possible role of gut-derived neurotoxins/excitotoxins. We review the evidence of gut symptoms and gut dysbiosis in ALS. We then examine a possible role for gut-derived toxins by reviewing the evidence that these molecules are toxic to the central nervous system, evidence of their association with ALS, the existence of biochemical pathways by which these molecules could be produced by the gut microbiota and existence of mechanisms of transport from the gut to the blood and brain. We then present evidence that there are increased levels of these toxins in the blood of some ALS patients. We review the effects of therapies that attempt to alter the gut microbiota or ameliorate the biochemical effects of gut toxins. It is possible that gut dysbiosis contributes to elevated levels of toxins and that these could potentially contribute to ALS pathogenesis, but more work is required.
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- 2024
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31. Alzheimer's disease classification using cluster‐based labelling for graph neural network on heterogeneous data
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Niamh McCombe, Jake Bamrah, Jose M. Sanchez‐Bornot, David P. Finn, Paula L. McClean, KongFatt Wong‐Lin, and Alzheimer's Disease Neuroimaging Initiative (ADNI)
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Medical technology ,R855-855.5 - Abstract
Abstract Biomarkers for Alzheimer's disease (AD) diagnosis do not always correlate reliably with cognitive symptoms, making clinical diagnosis inconsistent. In this study, the performance of a graphical neural network (GNN) classifier based on data‐driven diagnostic classes from unsupervised clustering on heterogeneous data is compared to the performance of a classifier using clinician diagnosis as an outcome. Unsupervised clustering on tau‐positron emission tomography (PET) and cognitive and functional assessment data was performed. Five clusters embedded in a non‐linear uniform manifold approximation and project (UMAP) space were identified. The individual clusters revealed specific feature characteristics with respect to clinical diagnosis of AD, gender, family history, age, and underlying neurological risk factors (NRFs). In particular, one cluster comprised mainly diagnosed AD cases. All cases within this cluster were re‐labelled AD cases. The re‐labelled cases are characterized by high cerebrospinal fluid amyloid beta (CSF Aβ) levels at a younger age, even though Aβ data was not used for clustering. A GNN model was trained using the re‐labelled data with a multiclass area‐under‐the‐curve (AUC) of 95.2%, higher than the AUC of a GNN trained on clinician diagnosis (91.7%; p = 0.02). Overall, our work suggests that more objective cluster‐based diagnostic labels combined with GNN classification may have value in clinical risk stratification and diagnosis of AD.
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- 2022
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32. Interventions to Optimise Mental Health Outcomes During the COVID-19 Pandemic: A Scoping Review
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Safieh, Jacqueline, Broughan, John, McCombe, Geoff, McCarthy, Niamh, Frawley, Timothy, Guerandel, Allys, Lambert, John S., and Cullen, Walter
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- 2022
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33. Is it feasible to learn research skills in addition to audit skills through clinical audit? A mixed methods study in general practice
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Carberry, Crea, Callanan, Ian, McCombe, Geoff, Tobin, Helen, Bury, Gerard, Last, Jason, and Cullen, Walter
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- 2022
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34. A common statement on anthropogenic hybridization of the European wildcat (Felis silvestris)
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Beatrice Nussberger, Soraia Barbosa, Mark Beaumont, Mathias Currat, Sébastien Devillard, Marco Heurich, Jo Howard-McCombe, Federica Mattucci, Carsten Nowak, Claudio Sebastián Quilodrán, Helen Senn, Paulo Célio Alves, EUROWILDCAT Consortium, Malte Götz, Pablo Ferreras, Dominik Fischer, Luisa Fischer, Lorenzo Frangini, René Janssen, Saskia Jerosch, Andrew Kitchener, Miha Krofel, Jarmila Krojerová-Prokešová, Johannes Lang, József Lanszki, Jenny MacPherson, Dime Melovski, Johan Michaux, Despina Migli, Marc Moes, Pedro Monterroso, Carolina Nogueira, Henryk Okarma, Dominique Pontier, Joe Premier, Héctor Ruiz-Villar, Ferran Sayol, Vinciane Schockert, Lara Semple, Andrea Sforzi, Olaf Simon, Magda Sindičić, Anil Soyumert, Arianna Spada, Sabrina Streif, and Manfred Trinzen
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introgression ,Felis silvestris ,Felis catus ,domestic cat ,wildlife management ,Evolution ,QH359-425 ,Ecology ,QH540-549.5 - Abstract
Preserving natural genetic diversity and ecological function of wild species is a central goal in conservation biology. As such, anthropogenic hybridization is considered a threat to wild populations, as it can lead to changes in the genetic makeup of wild species and even to the extinction of wild genomes. In European wildcats, the genetic and ecological impacts of gene flow from domestic cats are mostly unknown at the species scale. However, in small and isolated populations, it is known to include genetic swamping of wild genomes. In this context, it is crucial to better understand the dynamics of hybridization across the species range, to inform and implement management measures that maintain the genetic diversity and integrity of the European wildcat. In the present paper, we aim to provide an overview of the current scientific understanding of anthropogenic hybridization in European wildcats, to clarify important aspects regarding the evaluation of hybridization given the available methodologies, and to propose guidelines for management and research priorities.
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- 2023
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35. Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia
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Restuadi, Restuadi, Garton, Fleur C., Benyamin, Beben, Lin, Tian, Williams, Kelly L., Vinkhuyzen, Anna, van Rheenen, Wouter, Zhu, Zhihong, Laing, Nigel G., Mather, Karen A., Sachdev, Perminder S., Ngo, Shyuan T., Steyn, Frederik J., Wallace, Leanne, Henders, Anjali K., Visscher, Peter M., Needham, Merrilee, Mathers, Susan, Nicholson, Garth, Rowe, Dominic B., Henderson, Robert D., McCombe, Pamela A., Pamphlett, Roger, Blair, Ian P., Wray, Naomi R., and McRae, Allan F.
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- 2022
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36. Optical control of carrier wavefunction in magnetic quantum dots
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Zhang, P., Norden, T., Pientka, J. M., Oszwałdowski, R., Najafi, A., Barman, B., Tsai, Y., Fan, W-C., Chou, W-C., Han, J. E., Žutić, I., McCombe, B. D., and Petrou, A.
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Condensed Matter - Mesoscale and Nanoscale Physics - Abstract
Spatially indirect Type-II band alignment in magnetically-doped quantum dot (QD) structures provides unexplored opportunities to control the magnetic interaction between carrier wavefunction in the QD and magnetic impurities. Unlike the extensively studied, spatially direct, QDs with Type-I band alignment where both electrons and holes are confined in the QD, in ZnTe QDs embedded in a (Zn,Mn)Se matrix only the holes are confined in the QDs. Photoexcitation with photon energy 3.06 eV (2.54 eV) generates electron-hole pairs predominantly in the (Zn,Mn)Se matrix (ZnTe QDs). The photoluminescence (PL) at 7 K in the presence of an external magnetic field exhibits an up to three-fold increase in the saturation red shift with the 2.54 eV excitation compared to the shift observed with 3.06 eV excitation. This unexpected result is attributed to multiple hole occupancy of the QD and the resulting increased penetration of the hole wavefunction tail further into the (Zn,Mn)Se matrix. The proposed model is supported by microscopic calculations which accurately include the role of hole-hole Coulomb interactions as well as the hole-Mn spin exchange interactions., Comment: 12 pages, 9 figures
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- 2018
37. Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis
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M. Lefort, S. Sharmin, J. B. Andersen, S. Vukusic, R. Casey, M. Debouverie, G. Edan, J. Ciron, A. Ruet, J. De Sèze, E. Maillart, H. Zephir, P. Labauge, G. Defer, C. Lebrun-Frenay, T. Moreau, E. Berger, P. Clavelou, J. Pelletier, B. Stankoff, O. Gout, E. Thouvenot, O. Heinzlef, A. Al-Khedr, B. Bourre, O. Casez, P. Cabre, A. Montcuquet, A. Wahab, J. P. Camdessanché, A. Maurousset, H. Ben Nasr, K. Hankiewicz, C. Pottier, N. Maubeuge, D. Dimitri-Boulos, C. Nifle, D. A. Laplaud, D. Horakova, E. K. Havrdova, R. Alroughani, G. Izquierdo, S. Eichau, S. Ozakbas, F. Patti, M. Onofrj, A. Lugaresi, M. Terzi, P. Grammond, F. Grand’Maison, B. Yamout, A. Prat, M. Girard, P. Duquette, C. Boz, M. Trojano, P. McCombe, M. Slee, J. Lechner-Scott, R. Turkoglu, P. Sola, D. Ferraro, F. Granella, V. Shaygannejad, J. Prevost, D. Maimone, O. Skibina, K. Buzzard, A. Van der Walt, R. Karabudak, B. Van Wijmeersch, T. Csepany, D. Spitaleri, S. Vucic, N. Koch-Henriksen, F. Sellebjerg, P. S. Soerensen, C. C. Hilt Christensen, P. V. Rasmussen, M. B. Jensen, J. L. Frederiksen, S. Bramow, H. K. Mathiesen, K. I. Schreiber, H. Butzkueven, M. Magyari, T. Kalincik, and E. Leray
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Effectiveness ,Multiple sclerosis ,Propensity score ,Indication bias ,Causal contrasts ,Censoring ,Medicine (General) ,R5-920 - Abstract
Abstract Background Natalizumab and fingolimod are used as high-efficacy treatments in relapsing–remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. Methods Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. Results Overall, 5,148 relapsing–remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. Conclusions This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.
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- 2022
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38. Identification of a prognostic signature in colorectal cancer using combinatorial algorithm‐driven analysis
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Abdo Alnabulsi, Tiehui Wang, Wei Pang, Marius Ionescu, Stephanie G Craig, Matthew P Humphries, Kris McCombe, Manuel Salto Tellez, Ayham Alnabulsi, and Graeme I Murray
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biomarker ,colorectal cancer ,combinatorial analysis ,combinatorial algorithm ,immunohistochemistry ,prognosis ,Pathology ,RB1-214 - Abstract
Abstract Colorectal carcinoma is one of the most common types of malignancy and a leading cause of cancer‐related death. Although clinicopathological parameters provide invaluable prognostic information, the accuracy of prognosis can be improved by using molecular biomarker signatures. Using a large dataset of immunohistochemistry‐based biomarkers (n = 66), this study has developed an effective methodology for identifying optimal biomarker combinations as a prognostic tool. Biomarkers were screened and assigned to related subsets before being analysed using an iterative algorithm customised for evaluating combinatorial interactions between biomarkers based on their combined statistical power. A signature consisting of six biomarkers was identified as the best combination in terms of prognostic power. The combination of biomarkers (STAT1, UCP1, p‐cofilin, LIMK2, FOXP3, and ICOS) was significantly associated with overall survival when computed as a linear variable (χ2 = 53.183, p
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- 2022
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39. Some home-based self-managed rehabilitation interventions can improve arm activity after stroke: A systematic review and narrative synthesis
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Kelly Westlake, Ruth Akinlosotu, Jean Udo, Andrea Goldstein Shipper, Sandy McCombe Waller, and Jill Whitall
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stroke ,rehabilitation ,home-based ,self-managed ,systematic review ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
BackgroundThere is an increased need for home-based, self-managed, and low maintenance stroke rehabilitation as well as interest in targeting the arm, which often lags behind leg recovery. Previous reviews have not controlled for concurrent standard of care and the ratio of self-managed care to therapist input.ObjectivesTo determine the effectiveness of home-based, self-managed and low maintenance programs for upper-limb motor recovery in individuals after stroke. A secondary objective explored the adherence to home-based self-managed programs.Data sourcesWe searched PubMed (1809-present), Embase (embase.com, 1974-present), Cochrane CENTRAL Register of Controlled Trials (Wiley), CINAHL (EBSCOhost, 1937-present), Physiotherapy Evidence Database (pedro.org.au), OTseeker (otseeker.com), and REHABDATA (National Rehabilitation Information Center). All searches were completed on June 9, 2022. Bibliographic references of included articles also were searched.Eligibility criteriaRandomized controlled trials (RCT) in adults after stroke, where both intervention and control were home-based, at least 75% self-managed and did not involve concurrent therapy as a confounding factor. Primary outcome was performance in functional motor activities after training. Secondary outcome was sensorimotor impairment. All outcomes after a retention period were also considered secondary outcomes.Data collection and analysisTwo review authors independently screened titles/abstracts, three review authors screened full papers and extracted data, and two review authors undertook assessment of risk of bias (i.e., allocation bias, measurement bias, confounding factors) using the NHLBI Study Quality Assessment Tool.Main resultsWe identified seven heterogenous studies, including five with fair to good quality. All studies had an alternative treatment, dose-equivalent control. Only one trial reported a positive, sustained, between-group effect on activity for the experimental group. The remaining studies reported seven interventions having a within-group training effect with three interventions having sustained effects at follow up. One study reported a between group effect on an impairment measure with no follow-up. Overall adherence rates were high, but three studies reported differential group rates. Compliance with daily logs was higher when the logs were collected on a weekly basis.LimitationsBy excluding studies that allowed concurrent therapy, we likely minimized the number of studies that included participants in the early sub-acute post-stroke stage. By focusing on RCTs, we are unable to comment on other potentially promising home-based, self-managed single cohort programs. By including only published and English language studies, we may have included publication bias.Conclusions and implicationsThere is some evidence that a variety of home-based, self-managed training program can be beneficial after stroke. Future research could compare such programs with natural history controls. Clinicians might utilize home exercise programs with explicit directions and some form of weekly contact to aid compliance.
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- 2023
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40. Anti-complement Agents for Autoimmune Neurological Disease
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McCombe, Jennifer A. and Pittock, Sean J.
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- 2022
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41. Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease
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Ding, Qiao, Kesavan, Kaamini, Lee, Kah Meng, Wimberger, Elyse, Robertson, Thomas, Gill, Melinder, Power, Dominique, Chang, Jeryn, Fard, Atefeh T., Mar, Jessica C., Henderson, Robert D., Heggie, Susan, McCombe, Pamela A., Jeffree, Rosalind L., Colditz, Michael J., Hilliard, Massimo A., Ng, Dominic C. H., Steyn, Frederik J., Phillips, William D., Wolvetang, Ernst J., Ngo, Shyuan T., and Noakes, Peter G.
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- 2022
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42. Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis
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Lefort, M., Sharmin, S., Andersen, J. B., Vukusic, S., Casey, R., Debouverie, M., Edan, G., Ciron, J., Ruet, A., De Sèze, J., Maillart, E., Zephir, H., Labauge, P., Defer, G., Lebrun-Frenay, C., Moreau, T., Berger, E., Clavelou, P., Pelletier, J., Stankoff, B., Gout, O., Thouvenot, E., Heinzlef, O., Al-Khedr, A., Bourre, B., Casez, O., Cabre, P., Montcuquet, A., Wahab, A., Camdessanché, J. P., Maurousset, A., Ben Nasr, H., Hankiewicz, K., Pottier, C., Maubeuge, N., Dimitri-Boulos, D., Nifle, C., Laplaud, D. A., Horakova, D., Havrdova, E. K., Alroughani, R., Izquierdo, G., Eichau, S., Ozakbas, S., Patti, F., Onofrj, M., Lugaresi, A., Terzi, M., Grammond, P., Grand’Maison, F., Yamout, B., Prat, A., Girard, M., Duquette, P., Boz, C., Trojano, M., McCombe, P., Slee, M., Lechner-Scott, J., Turkoglu, R., Sola, P., Ferraro, D., Granella, F., Shaygannejad, V., Prevost, J., Maimone, D., Skibina, O., Buzzard, K., Van der Walt, A., Karabudak, R., Van Wijmeersch, B., Csepany, T., Spitaleri, D., Vucic, S., Koch-Henriksen, N., Sellebjerg, F., Soerensen, P. S., Hilt Christensen, C. C., Rasmussen, P. V., Jensen, M. B., Frederiksen, J. L., Bramow, S., Mathiesen, H. K., Schreiber, K. I., Butzkueven, H., Magyari, M., Kalincik, T., and Leray, E.
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- 2022
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43. Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease
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Qiao Ding, Kaamini Kesavan, Kah Meng Lee, Elyse Wimberger, Thomas Robertson, Melinder Gill, Dominique Power, Jeryn Chang, Atefeh T. Fard, Jessica C. Mar, Robert D. Henderson, Susan Heggie, Pamela A. McCombe, Rosalind L. Jeffree, Michael J. Colditz, Massimo A. Hilliard, Dominic C. H. Ng, Frederik J. Steyn, William D. Phillips, Ernst J. Wolvetang, Shyuan T. Ngo, and Peter G. Noakes
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Amyotrophic Lateral Sclerosis ,ALS ,Neuromuscular junction ,MuSK ,Agrin ,Motor neurons ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin (n-agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n-agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n-agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n-agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND.
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- 2022
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44. Alzheimer’s Disease Assessments Optimized for Diagnostic Accuracy and Administration Time
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Niamh Mccombe, Xuemei Ding, Girijesh Prasad, Paddy Gillespie, David P. Finn, Stephen Todd, Paula L. Mcclean, and Kongfatt Wong-Lin
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Cost-sensitive feature selection ,dementia and Alzheimer’s disease diagnosis ,assessment speed-accuracy trade-off ,cognitive and functional assessments ,sandbox GUI application ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Medical technology ,R855-855.5 - Abstract
Objective: Despite the potential of machine learning techniques to improve dementia diagnostic processes, research outcomes are often not readily translated to or adopted in clinical practice. Importantly, the time taken to administer diagnostic assessment has yet to be taken into account in feature-selection based optimisation for dementia diagnosis. We address these issues by considering the impact of assessment time as a practical constraint for feature selection of cognitive and functional assessments in Alzheimer’s disease diagnosis. Methods: We use three different feature selection algorithms to select informative subsets of dementia assessment items from a large open-source dementia dataset. We use cost-sensitive feature selection to optimise our feature selection results for assessment time as well as diagnostic accuracy. To encourage clinical adoption and further evaluation of our proposed accuracy-vs-cost optimisation algorithms, we also implement a sandbox-like toolbox with graphical user interface to evaluate user-chosen subsets of assessment items. Results: We find that there are subsets of accuracy-cost optimised assessment items that can perform better in terms of diagnostic accuracy and/or total assessment time than most other standard assessments. Discussion: Overall, our analysis and accompanying sandbox tool can facilitate clinical users and other stakeholders to apply their own domain knowledge to analyse and decide which dementia diagnostic assessment items are useful, and aid the redesigning of dementia diagnostic assessments. Clinical Impact (Clinical Research): By optimising diagnostic accuracy and assessment time, we redesign predictive and efficient dementia diagnostic assessments and develop a sandbox interface to facilitate evaluation and testing by clinicians and non-specialists.
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- 2022
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45. Impact of enhancing GP access to diagnostic imaging: A scoping review.
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Amy Phelan, John Broughan, Geoff McCombe, Claire Collins, Ronan Fawsitt, Mike O'Callaghan, Diarmuid Quinlan, Fintan Stanley, and Walter Cullen
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Medicine ,Science - Abstract
BackgroundDirect access to diagnostic imaging in General Practice provides an avenue to reduce referrals to hospital-based specialities and emergency departments, and to ensure timely diagnosis. Enhanced GP access to radiology imaging could potentially reduce hospital referrals, hospital admissions, enhance patient care, and improve disease outcomes. This scoping review aims to demonstrate the value of direct access to diagnostic imaging in General Practice and how it has impacted on healthcare delivery and patient care.MethodsA search was conducted of 'PubMed', 'Cochrane Library', 'Embase' and 'Google Scholar' for papers published between 2012-2022 using Arksey and O'Malley's scoping review framework. The search process was guided by the PRISMA extension for Scoping Reviews checklist (PRISMA-ScR).ResultsTwenty-three papers were included. The studies spanned numerous geographical locations (most commonly UK, Denmark, and Netherlands), encompassing several study designs (most commonly cohort studies, randomised controlled trials and observational studies), and a range of populations and sample sizes. Key outcomes reported included the level of access to imaging serves, the feasibility and cost effectiveness of direct access interventions, GP and patient satisfaction with direct access initiatives, and intervention related scan waiting times and referral process.ConclusionDirect access to imaging for GPs can have many benefits for healthcare service delivery, patient care, and the wider healthcare ecosystem. GP focused direct access initiatives should therefore be considered as a desirable and viable health policy directive. Further research is needed to more closely examine the impacts that access to imaging studies have on health system operations, especially those in General Practice. Research examining the impacts of access to multiple imaging modalities is also warranted.
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- 2023
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46. Case report: Adult-onset limb girdle muscular dystrophy in sibling pair due to novel homozygous LAMA2 missense variant
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Matthew Katz, Leigh B. Waddell, Michaela Yuen, Samantha J. Bryen, Emily Oates, Fleur C. Garton, Thomas Robertson, Robert David Henderson, Sandra T. Cooper, and Pamela A. McCombe
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limb girdle muscular dystrophy ,genotype ,phenotype ,LAMA2 ,whole exome sequencing ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Recessive pathogenic variants in the laminin subunit alpha 2 (LAMA2) gene cause a spectrum of disease ranging from severe congenital muscular dystrophy to later-onset limb girdle muscular dystrophy (LGMDR23). The phenotype of LGMDR23 is characterized by slowly progressive proximal limb weakness, contractures, raised creatine kinase, and sometimes distinctive cerebral white matter changes and/or epilepsy. We present two siblings, born to consanguineous parents, who developed adult-onset LGMDR23 associated with typical cerebral white matter changes and who both later developed dementia. The male proband also had epilepsy and upper motor neuron signs when he presented at age 72. Merosin immunohistochemistry and Western blot on muscle biopsies taken from both subjects was normal. Whole exome sequencing revealed a previously unreported homozygous missense variant in LAMA2 [Chr6(GRCh38):g.129297734G>A; NM_000426.3:c.2906G>A; p.(Cys969Tyr)] in the proband. The same homozygous LAMA2 variant was confirmed by Sanger sequencing in the proband's affected sister. These findings expand the genotypic and phenotypic spectrum of LGMDR23.
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- 2023
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47. Phenotypic variability within the desminopathies: A case series of three patients
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Dennis Yeow, Matthew Katz, Robert Henderson, Sandhir Prasad, Russell Denman, Stefan Blum, Mark Davis, Thomas Robertson, and Pamela McCombe
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desmin ,desminopathy ,cardiomyopathy ,myofibrillar myopathy ,splice-site mutation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The DES gene encodes desmin, a key intermediate filament of skeletal, cardiac and smooth muscle. Pathogenic DES variants produce a range of skeletal and cardiac muscle disorders collectively known as the desminopathies. We report three desminopathy cases which highlight the phenotypic heterogeneity of this disorder and discuss various factors that may contribute to the clinical differences seen between patients with different desmin variants and also between family members with the same variant.
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- 2023
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48. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Jr., Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.
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- 2021
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49. Disability progression in multiple sclerosis is associated with plasma neuroactive steroid profile
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Cheng, C., Gomez, D., McCombe, J. A., Smyth, P., Giuliani, F., Blevins, G., Baker, G. B., and Power, C.
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- 2021
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50. Integrating diabetes, hypertension and HIV care in sub-Saharan Africa: a Delphi consensus study on international best practice
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Geoff McCombe, Sara Murtagh, Jeffrey V. Lazarus, Marie Claire Van Hout, Max Bachmann, Shabbar Jaffar, Anupam Garrib, Kaushik Ramaiya, Nelson K. Sewankambo, Sayoki Mfinanga, and Walter Cullen
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HIV ,Healthcare utilization ,Noncommunicable diseases ,Integration ,Service delivery ,Sub-Saharan Africa ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background Although HIV continues to have a high prevalence among adults in sub-Saharan Africa (SSA), the burden of noncommunicable diseases (NCD) such as diabetes and hypertension is increasing rapidly. There is an urgent need to expand the capacity of healthcare systems in SSA to provide NCD services and scale up existing chronic care management pathways. The aim of this study was to identify key components, outcomes, and best practice in integrated service provision for the prevention, identification and treatment of HIV, hypertension and diabetes. Methods An international, multi stakeholder e-Delphi consensus study was conducted over two successive rounds. In Round 1, 24 participants were asked to score 27 statements, under the headings ‘Service Provision’ and ‘Benefits of Integration’, by importance. In Round 2, the 16 participants who completed Round 1 were shown the distribution of scores from other participants along with the score that they attributed to an outcome and were asked to reflect on the score they gave, based on the scores of the other participants and then to rescore if they wished to. Nine participants completed Round 2. Results Based on the Round 1 ranking, 19 of the 27 outcomes met the 70% threshold for consensus. Four additional outcomes suggested by participants in Round 1 were added to Round 2, and upon review by participants, 22 of the 31 outcomes met the consensus threshold. The five items participants scored from 7 to 9 in both rounds as essential for effective integrated healthcare delivery of health services for chronic conditions were improved data collection and surveillance of NCDs among people living with HIV to inform integrated NCD/HIV programme management, strengthened drug procurement systems, availability of equipment and access to relevant blood tests, health education for all chronic conditions, and enhanced continuity of care for patients with multimorbidity. Conclusions This study highlights the outcomes which may form key components of future complex interventions to define a model of integrated healthcare delivery for diabetes, hypertension and HIV in sub-Saharan Africa.
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- 2021
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