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1. Implementing and evaluating group interpersonal therapy for postnatal depression in Lebanon and Kenya—individually randomised superiority trial

Author

Peter Fonagy, Rabih El Chammay, Carol Ngunu, Manasi Kumar, Lena Verdeli, Elizabeth Allison, Ghida Anani, Pasco Fearon, Fouad Fouad, Zoe Hoare, Lucina Koyio, Henrietta Moore, Andrew Nyandigisi, Stephen Pilling, Hannah Sender, Jolene Skordis, Rachel Evans, Gerard Joseph Abou Jaoude, Beatrice Madeghe, Sandra Pardi Arsen Maradian, Ciara O’Donnell, Elizabeth Simes, Alexandra Truscott, Grace Nduku Wambua, and Obadia Yator

Subjects
Post-natal depression, Group interpersonal therapy, Infant development, High-quality standard care, Multisite randomised controlled trial, Randomised controlled trial, Medicine (General), R5-920
Abstract

Abstract Background Depression ranks as the foremost mental health concern among childbearing women. Within low- and middle-income countries (LMICs), between 20 and 25% of women encounter depression during pregnancy or soon after delivery. This condition impacts not only the mothers but also their offspring. Offspring of women suffering from postnatal depression (PND) exhibit suboptimal cognitive development and increased emotional and behavioural issues throughout their growth. This scenario becomes more pronounced in LMICs, where numerous adversities further jeopardise children’s developmental progress. Despite antenatal services providing a pivotal platform to address women’s mental health needs, PND treatment remains inaccessible in many LMICs. The World Health Organization advocates interpersonal psychotherapy (IPT) for treating depression. While research from high-income countries has established the efficacy of IPT and group-IPT (g-IPT) for PND, its effectiveness within the LMIC context and its potential benefits for child development remain uncharted. This study seeks to gauge the potency of g-IPT for women with PND in two LMICs. Methods This multi-site randomised controlled trial is a continuation of two preceding phases—conceptual mapping and a feasibility study executed in Lebanon and Kenya. Insights gleaned from these phases underpin this comprehensive RCT, which contrasts the efficacy and cost-effectiveness of high-quality standard care (HQ-SC) augmented with g-IPT against HQ-SC in isolation. The trial, characterised as an individually randomised superiority assessment, targets women with postnatal depression in Beirut, Lebanon, and Nairobi, Kenya. It aims to determine if culturally tailored g-IPT, administered within community settings in both countries, outperforms HQ-SC in influencing child developmental outcomes, maternal depression, and the quality of the mother–child bond. Discussion The SUMMIT trial, designed with pragmatism, possesses the magnitude to evaluate g-IPT within two LMIC frameworks. It seeks to enlighten policymakers, service commissioners, professionals, and users about g-IPT’s potential to alleviate maternal PND and bolster child developmental outcomes in LMICs. Additionally, the trial will generate valuable data on the clinical and economic merits of high-quality standard care. Trial registration ISRCTN, ISRCTN15154316. Registered on 27 September 2023, https://doi.org/10.1186/ISRCTN15154316

Published
2024
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2. Reducing the treatment burden of keratinocyte cancers requiring referral to plastic surgery: Lessons from lockdown

Author

Ciara Drumm, Sorcha Lynch, Ciara O'Donnell, Catriona Lawlor, Roisin Dolan, Blaithin Moriarty, and Aoife Lally

Subjects
COVID‐19, cutaneous neoplasms, dermatologic surgery, healthcare utilisation, quality of life, skin cancer, Dermatology, RL1-803, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Keratinocyte cancers are increasing in incidence in Ireland and are more common in older age, necessitating multidisciplinary specialist input and treatment often is a greater burden for patients. The coronavirus disease 2019 (COVID‐19) allowed us to restructure our interspecialty treatment pathways to reduce healthcare contact for patients. Objectives The aim of this study was to establish whether a revised interspecialty pathway reduced the time‐to‐treatment completion (days) and treatment burden (defined as total healthcare encounter days). Methods Patients with keratinocyte cancer under the care of dermatology and plastic surgery at St Vincent's University Hospital Dublin from July to December 2020 inclusive were identified in the Hospital‐Inpatient Enquiry database. Treatment burden was captured as the number of total days with a healthcare encounter and time‐to‐treatment completion was captured as the time from initial dermatology review to complete excision by plastic surgery. Results Forty patients with 49 keratinocyte cancers were referred by dermatology to plastic surgery from July to December 2020. Thirty‐nine patients with 48 keratinocyte cancers were included in the analysis. The new referral pathway reduced the time‐to‐treatment completion from a mean of 164 to 75 days (p = 0.04). Treatment burden reduced from a mean of 5.4 to 3.5 (p = 0.002) total healthcare encounter days. Conclusions Multidisciplinary input to establish a more efficient referral pathway for patients with keratinocyte cancer has successfully reduced the time‐to‐treatment completion and the treatment burden for our patients. This approach reduced the risk of exposure to COVID‐19 for patients and frees up valuable healthcare resources to treat these increasingly frequent malignancies.

Published
2023
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3. Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

Author

Lisa Hurler, Ágnes Szilágyi, Federica Mescia, Laura Bergamaschi, Blanka Mező, György Sinkovits, Marienn Réti, Veronika Müller, Zsolt Iványi, János Gál, László Gopcsa, Péter Reményi, Beáta Szathmáry, Botond Lakatos, János Szlávik, Ilona Bobek, Zita Z. Prohászka, Zsolt Förhécz, Dorottya Csuka, Erika Kajdácsi, László Cervenak, Petra Kiszel, Tamás Masszi, István Vályi-Nagy, Reinhard Würzner, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Paul A. Lyons, Erik J. M. Toonen, Zoltán Prohászka, Stephen Baker, John R. Bradley, Patrick F. Chinnery, Daniel J. Cooper, Gordon Dougan, Ian G. Goodfellow, Ravindra K. Gupta, Nathalie Kingston, Paul J. Lehner, Nicholas J. Matheson, Caroline Saunders, Kenneth G. C. Smith, Charlotte Summers, James Thaventhiran, M. Estee Torok, Mark R. Toshner, Michael P. Weekes, Gisele Alvio, Sharon Baker, Areti Bermperi, Karen Brookes, Ashlea Bucke, Jo Calder, Laura Canna, Cherry Crucusio, Isabel Cruz, Rnalie de Jesus, Katie Dempsey, Giovanni Di Stephano, Jason Domingo, Anne Elmer, Julie Harris, Sarah Hewitt, Heather Jones, Sherly Jose, Jane Kennet, Yvonne King, Jenny Kourampa, Emily Li, Caroline McMahon, Anne Meadows, Vivien Mendoza, Criona O’Brien, Charmain Ocaya, Ciro Pascuale, Marlyn Perales, Jane Price, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Phoebe Vargas, Bensi Vergese, Laura Watson, Jieniean Worsley, Julie-Ann Zerrudo, Ariana Betancourt, Georgie Bower, Ben Bullman, Chiara Cossetti, Aloka De Sa, Benjamin J. Dunore, Maddie Epping, Stuart Fawke, Stefan Gräf, Richard Grenfell, Andrew Hinch, Josh Hodgson, Christopher Huang, Oisin Huhn, Kelvin Hunter, Isobel Jarvis, Emma Jones, Maša Josipović, Ekaterina Legchenko, Daniel Lewis, Joe Marsden, Jennifer Martin, Francesca Nice, Ciara O’Donnell, Ommar Omarjee, Marianne Perera, Linda Pointon, Nicole Pond, Nathan Richoz, Nika Romashova, Natalia Savoinykh, Rahul Sharma, Joy Shih, Mateusz Strezlecki, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Lori Turner, Jennifer Wood, Marta Wylot, John Allison, Heather Biggs, Helen Butcher, Daniela Caputo, Debbie Clapham-Riley, Eleanor Dewhurst, Christian Fernandez, Anita Furlong, Barbara Graves, Jennifer Gray, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Mary Kasanicki, Sarah Meloy, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Christopher J. Penkett, Isabel Phelan, Venkatesh Ranganath, Jennifer Sambrook, Katherine Schon, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Julie von Ziegenweidt, Jennifer Webster, Ali Asaripour, Lucy Mwaura, Caroline Patterson, Gary Polwarth, Katherine Bunclark, Michael Mackay, Alice Michael, Sabrina Rossi, Mayurun Selvan, Sarah Spencer, Cissy Yong, and Petra Polgarova

Subjects
mannose binding lectin (MBL), MBL2 genotypes, COVID-19, severe acute respiratory coronavirus 2 (SARS-CoV-2), lectin pathway activation, lectin pathway of complement, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p

Published
2023
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4. Distinction of early complement classical and lectin pathway activation via quantification of C1s/C1-INH and MASP-1/C1-INH complexes using novel ELISAs

Author

Lisa Hurler, Erik J. M. Toonen, Erika Kajdácsi, Bregje van Bree, Ricardo J. M. G. E. Brandwijk, Wieke de Bruin, Paul A. Lyons, Laura Bergamaschi, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, György Sinkovits, László Cervenak, Reinhard Würzner, Zoltán Prohászka, Stephen Baker, John R. Bradley, Patrick F. Chinnery, Daniel J. Cooper, Gordon Dougan, Ian G. Goodfellow, Ravindra K. Gupta, Nathalie Kingston, Paul J. Lehner, Nicholas J. Matheson, Caroline Saunders, Kenneth G. C. Smith, Charlotte Summers, James Thaventhiran, M. Estee Torok, Mark R. Toshner, Michael P. Weekes, Gisele Alvio, Sharon Baker, Areti Bermperi, Karen Brookes, Ashlea Bucke, Jo Calder, Laura Canna, Cherry Crucusio, Isabel Cruz, Rnalie de Jesus, Katie Dempsey, Giovanni Di Stephano, Jason Domingo, Anne Elmer, Julie Harris, Sarah Hewitt, Heather Jones, Sherly Jose, Jane Kennet, Yvonne King, Jenny Kourampa, Emily Li, Caroline McMahon, Anne Meadows, Vivien Mendoza, Criona O’Brien, Charmain Ocaya, Ciro Pascuale, Marlyn Perales, Jane Price, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Phoebe Vargas, Bensi Vergese, Laura Watson, Jieniean Worsley, Julie-Ann Zerrudo, Ariana Betancourt, Georgie Bower, Ben Bullman, Chiara Cossetti, Aloka De Sa, Benjamin J. Dunore, Maddie Epping, Stuart Fawke, Stefan Gräf, Richard Grenfell, Andrew Hinch, Josh Hodgson, Christopher Huang, Oisin Huhn, Kelvin Hunter, Isobel Jarvis, Emma Jones, Maša Josipović, Ekaterina Legchenko, Daniel Lewis, Joe Marsden, Jennifer Martin, Federica Mescia, Francesca Nice, Ciara O’Donnell, Ommar Omarjee, Marianne Perera, Linda Pointon, Nicole Pond, Nathan Richoz, Nika Romashova, Natalia Savoinykh, Rahul Sharma, Joy Shih, Mateusz Strezlecki, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Lori Turner, Jennifer Wood, Marta Wylot, John Allison, Heather Biggs, Helen Butcher, Daniela Caputo, Debbie Clapham-Riley, Eleanor Dewhurst, Christian Fernandez, Anita Furlong, Barbara Graves, Jennifer Gray, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Mary Kasanicki, Sarah Meloy, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Christopher J. Penkett, Isabel Phelan, Venkatesh Ranganath, Jennifer Sambrook, Katherine Schon, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Julie von Ziegenweidt, Jennifer Webster, Ali Asaripour, Lucy Mwaura, Caroline Patterson, Gary Polwarth, Katherine Bunclark, Michael Mackay, Alice Michael, Sabrina Rossi, Mayurun Selvan, Sarah Spencer, Cissy Yong, and Petra Polgarova

Subjects
early complement activation, classical pathway activation, lectin pathway activation, C1-INH complexes, assay development and validation, C1s/C1-INH complex, Immunologic diseases. Allergy, RC581-607
Abstract

The most commonly used markers to assess complement activation are split products that are produced through activation of all three pathways and are located downstream of C3. In contrast, C4d derives from the cleavage of C4 and indicates either classical (CP) or lectin pathway (LP) activation. Although C4d is perfectly able to distinguish between CP/LP and alternative pathway (AP) activation, no well-established markers are available to differentiate between early CP and LP activation. Active enzymes of both pathways (C1s/C1r for the CP, MASP-1/MASP-2 for the LP) are regulated by C1 esterase inhibitor (C1-INH) through the formation of covalent complexes. Aim of this study was to develop validated immunoassays detecting C1s/C1-INH and MASP-1/C1-INH complex levels. Measurement of the complexes reveals information about the involvement of the respective pathways in complement-mediated diseases. Two sandwich ELISAs detecting C1s/C1-INH and MASP-1/C1-INH complex were developed and tested thoroughly, and it was investigated whether C1s/C1-INH and MASP-1/C1-INH complexes could serve as markers for either early CP or LP activation. In addition, a reference range for these complexes in healthy adults was defined, and the assays were clinically validated utilizing samples of 414 COVID-19 patients and 96 healthy controls. The immunoassays can reliably measure C1s/C1-INH and MASP-1/C1-INH complex concentrations in EDTA plasma from healthy and diseased individuals. Both complex levels are increased in serum when activated with zymosan, making them suitable markers for early classical and early lectin pathway activation. Furthermore, measurements of C1-INH complexes in 96 healthy adults showed normally distributed C1s/C1-INH complex levels with a physiological concentration of 1846 ± 1060 ng/mL (mean ± 2SD) and right-skewed distribution of MASP-1/C1-INH complex levels with a median concentration of 36.9 (13.18 - 87.89) ng/mL (2.5-97.5 percentile range), while levels of both complexes were increased in COVID-19 patients (p

Published
2022
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5. Levels of soluble complement regulators predict severity of COVID-19 symptoms

Author

Anna L. Tierney, Wajd Mohammed Alali, Thomas Scott, Karen S. Rees-Unwin, CITIID-NIHR BioResource COVID-19 Collaboration, Simon J. Clark, Richard D. Unwin, Stephen Baker, John Bradley, Patrick Chinnery, Daniel Cooper, Gordon Dougan, Ian Goodfellow, Ravindra Gupta, Nathalie Kingston, Paul J. Lehner, Paul A. Lyons, Nicholas J. Matheson, Caroline Saunders, Kenneth G. C. Smith, Charlotte Summers, James Thaventhiran, M. Estee Torok, Mark R. Toshner, Michael P. Weekes, Gisele Alvio, Sharon Baker, Areti Bermperi, Karen Brookes, Ashlea Bucke, Jo Calder, Laura Canna, Cherry Crucusio, Isabel Cruz, Ranalie de Jesus, Katie Dempsey, Giovanni Di Stephano, Jason Domingo, Anne Elmer, Julie Harris, Sarah Hewitt, Heather Jones, Sherly Jose, Jane Kennet, Yvonne King, Jenny Kourampa, Emily Li, Caroline McMahon, Anne Meadows, Vivien Mendoza, Criona O’Brien, Charmain Ocaya, Ciro Pasquale, Marlyn Perales, Jane Price, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Phoebe Vargas, Bensi Vergese, Laura Watson, Jieniean Worsley, Julie-Ann Zerrudo, Laura Bergamashi, Ariana Betancourt, Georgie Bower, Ben Bullman, Chiara Cossetti, Aloka De Sa, Benjamin J. Dunmore, Maddie Epping, Stuart Fawke, Stefan Gräf, Richard Grenfell, Andrew Hinch, Josh Hodgson, Christopher Huang, Oisin Huhn, Kelvin Hunter, Isobel Jarvis, Emma Jones, Maša Josipović, Ekaterina Legchenko, Daniel Lewis, Joe Marsden, Jennifer Martin, Federica Mescia, Ciara O’Donnell, Ommar Omarjee, Marianne Perera, Linda Pointon, Nicole Pond, Nathan Richoz, Nika Romashova, Natalia Savoinykh, Rahul Sharma, Joy Shih, Mateusz Strezlecki, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Lori Turner, Jennifer Wood, Marta Wylot, John Allison, Heather Biggs, John R. Bradley, Helen Butcher, Daniela Caputo, Matt Chandler, Debbie Clapham-Riley, Eleanor Dewhurst, Christian Fernandez, Anita Furlong, Barbara Graves, Jennifer Gray, Sabine Hein, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Mary Kasanicki, Rebecca King, Sarah Meloy, Alexei Moulton, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Christopher J. Penkett, Isabel Phelan, Venkatesh Ranganath, Roxana Paraschiv, Abigail Sage, Jennifer Sambrook, Ingrid Scholtes, Katherine Schon, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Neil Walker, Jennifer Webster, Mayurun Selvan, Petra Polgarova, Sarah L. Caddy, Laura G. Caller, Yasmin Chaudhry, Martin D. Curran, Theresa Feltwell, Stewart Fuller, Iliana Georgana, Grant Hall, William L. Hamilton, Myra Hosmillo, Charlotte J. Houldcroft, Rhys Izuagbe, Aminu S. Jahun, Fahad A. Khokhar, Anna G. Kovalenko, Luke W. Meredith, Surendra Parmar, Malte L. Pinckert, Anna Yakovleva, Emily C. Horner, Lucy Booth, Alexander Ferreira, Rebecca Boston, Robert Hughes, Juan Carlos Yam Puc, Nonantzin Beristain-Covarrubias, Maria Rust, Thevinya Gurugama, Lihinya Gurugama, Thomas Mulroney, Sarah Spencer, Zhaleh Hosseini, and Kate Williamson

Subjects
COVID-19, SARS-CoV-2, complement, factor H, factor H-related proteins, biomarkers, Immunologic diseases. Allergy, RC581-607
Abstract

The SARS-CoV-2 virus continues to cause significant morbidity and mortality worldwide from COVID-19. One of the major challenges of patient management is the broad range of symptoms observed. While the majority of individuals experience relatively mild disease, a significant minority of patients require hospitalisation, with COVID-19 still proving fatal for some. As such, there remains a desperate need to better understand what drives this severe disease, both in terms of the underlying biology, but also to potentially predict at diagnosis which patients are likely to require further interventions, thus enabling better outcomes for both patients and healthcare systems. Several lines of evidence have pointed to dysregulation of the complement cascade as a major factor in severe COVID-19 outcomes. How this is underpinned mechanistically is not known. Here, we have focussed on the role of the soluble complement regulators Complement Factor H (FH), its splice variant Factor H-like 1 (FHL-1) and five Factor H-Related proteins (FHR1-5). Using a targeted mass spectrometry approach, we quantified these proteins in a cohort of 188 plasma samples from controls and SARS-CoV-2 patients taken at diagnosis. This analysis revealed significant elevations in all FHR proteins, but not FH, in patients with more severe disease, particularly FHR2 and FHR5 (FHR2: 1.97-fold, p

Published
2022
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6. Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Author

Petra Mlcochova, Dami Collier, Allyson Ritchie, Sonny M. Assennato, Myra Hosmillo, Neha Goel, Bo Meng, Krishna Chatterjee, Vivien Mendoza, Nigel Temperton, Leo Kiss, Leo C. James, Katarzyna A. Ciazynska, Xiaoli Xiong, John A.G. Briggs, James A. Nathan, Federica Mescia, Laura Bergamaschi, Hongyi Zhang, Petros Barmpounakis, Nikos Demeris, Richard Skells, Paul A. Lyons, John Bradley, Steven Baker, Jean Pierre Allain, Kenneth G.C. Smith, Rachel Bousfield, Michael Wilson, Dominic Sparkes, Glenn Amoroso, Effrosyni Gkrania-Klotsas, Susie Hardwick, Adrian Boyle, Ian Goodfellow, Ravindra K. Gupta, Stephen Baker, Gordon Dougan, Ravi Gupta, Paul J. Lehner, Paul Lyons, Nicholas J. Matheson, Mark Toshner, Michael P. Weekes, Nick Brown, Martin Curran, Surendra Palmar, David Enoch, Daniel Chapman, Ashley Shaw, Sherly Jose, Areti Bermperi, Julie Ann Zerrudo, Evgenia Kourampa, Laura Watson, Jieniean Worsley, Caroline Saunders, Ranalie de Jesus, Jason Domingo, Ciro Pasquale, Bensi Vergese, Phoebe Vargas, Marivic Fabiculana, Marlyn Perales, Lee Mynott, Elizabeth Blake, Amy Bates, Anne-Laure Vallier, Alexandra Williams, David Phillips, Edmund Chiu, Alex Overhill, Nicola Ramenatte, Jamal Sipple, Steven Frost, Helena Knock, Richard Hardy, Emily Foster, Fiona Davidson, Viona Rundell, Purity Bundi, Richmond Abeseabe, Sarah Clark, Isabel Vicente, Anne Elmer, Carla Ribeiro, Jenny Kourampa, Jane Kennet, Jane Rowlands, Anne Meadows, Criona O’Brien, Rebecca Rastall, Cherry Crucusio, Sarah Hewitt, Jane Price, Jo Calder, Laura Canna, Ashlea Bucke, Hugo Tordesillas, Julie Harris, Valentina Ruffolo, Barbara Graves, Helen Butcher, Daniela Caputo, Emma Le Gresley, Benjamin J. Dunmore, Jennifer Martin, Ekaterina Legchenko, Carmen Treacy, Christopher Huang, Jennifer Wood, Rachel Sutcliffe, Josh Hodgson, Joy Shih, Stefan Graf, Zhen Tong, Tobias Tilly, Ciara O’Donnell, Kelvin Hunter, Linda Pointon, Nicole Pond, Marta Wylot, Emma Jones, Stuart Fawke, Ben Bullman, Lori Turner, Isobel Jarvis, Ommar Omarjee, Aloka De Sa, Joe Marsden, Ariana Betancourt, Marianne Perera, Maddie Epping, Nathan Richoz, Georgie Bower, Rahul Sharma, Francesca Nice, Oisin Huhn, Natalia Savoinykh Yarkoni, Nika Romashova, Daniel Lewis, Andrew Hinch, Chiara Cossetti, Mateusz Strezlecki, Richard Grenfell, Hannah Stark, Neil Walker, Kathy Stirrups, Nigel Ovington, Eleanor Dewhust, Emily Li, Sofia Papadia, Nathalie Kingston, Andrew Lever, Estee Torok, William Hamilton, Grant Hall, Aminu Jahun, Yasmin Chaudhry, Malte Pinckert, Iliana Georgana, Anna Yakovleva, Laura Caller, Sarah Caddy, Theresa Feltwell, Fahad Khokhar, Luke Meredith, Charlotte Holdcroft, and Surendra Parmar

Subjects
SARS-CoV-2, COVID-19, rapid diagnoses, point of care testing, D614G, Medicine (General), R5-920
Abstract

Summary: Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity.

Published
2020
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7. SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Author

Bo Meng, Rawlings Datir, Jinwook Choi, John R. Bradley, Kenneth G.C. Smith, Joo Hyeon Lee, Ravindra K. Gupta, Stephen Baker, Gordon Dougan, Christoph Hess, Nathalie Kingston, Paul J. Lehner, Paul A. Lyons, Nicholas J. Matheson, Willem H. Owehand, Caroline Saunders, Charlotte Summers, James E.D. Thaventhiran, Mark Toshner, Michael P. Weekes, Patrick Maxwell, Ashley Shaw, Ashlea Bucke, Jo Calder, Laura Canna, Jason Domingo, Anne Elmer, Stewart Fuller, Julie Harris, Sarah Hewitt, Jane Kennet, Sherly Jose, Jenny Kourampa, Anne Meadows, Criona O’Brien, Jane Price, Cherry Publico, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Ben Bullman, Benjamin J. Dunmore, Stuart Fawke, Stefan Gräf, Josh Hodgson, Christopher Huang, Kelvin Hunter, Emma Jones, Ekaterina Legchenko, Cecilia Matara, Jennifer Martin, Federica Mescia, Ciara O’Donnell, Linda Pointon, Joy Shih, Rachel Sutcliffe, Tobias Tilly, Carmen Treacy, Zhen Tong, Jennifer Wood, Marta Wylot, Ariana Betancourt, Georgie Bower, Chiara Cossetti, Aloka De Sa, Madeline Epping, Nick Gleadall, Richard Grenfell, Andrew Hinch, Sarah Jackson, Isobel Jarvis, Ben Krishna, Francesca Nice, Ommar Omarjee, Marianne Perera, Martin Potts, Nathan Richoz, Veronika Romashova, Luca Stefanucci, Mateusz Strezlecki, Lori Turner, Eckart M.D.D. De Bie, Katherine Bunclark, Masa Josipovic, Michael Mackay, John Allison, Helen Butcher, Daniela Caputo, Debbie Clapham-Riley, Eleanor Dewhurst, Anita Furlong, Barbara Graves, Jennifer Gray, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Sarah Meloy, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Isabel Phelan, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Neil Walker, Jennifer Webster, Ingrid Scholtes, Sabine Hein, and Rebecca King

Subjects
Organoid, Omicron, SARS-CoV-2, Serine Endopeptidases, CP: Microbiology, COVID-19, spike, Virus Internalization, General Biochemistry, Genetics and Molecular Biology, Spike Glycoprotein, Coronavirus, NTD, Delta, Spike Glycoprotein, Coronavirus, entry, Humans, fusogenicity, TMPRSS2
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs.

Published
2022

9. Combined point-of-care nucleic acid and antibody testing for SARS-CoV-2 following emergence of D614G spike variant

Author

Petra Mlcochova, Dami Collier, Allyson Ritchie, Sonny M. Assennato, Myra Hosmillo, Neha Goel, Bo Meng, Krishna Chatterjee, Vivien Mendoza, Nigel Temperton, Leo Kiss, Leo C. James, Katarzyna A. Ciazynska, Xiaoli Xiong, John A.G. Briggs, James A. Nathan, Federica Mescia, Laura Bergamaschi, Hongyi Zhang, Petros Barmpounakis, Nikos Demeris, Richard Skells, Paul A. Lyons, John Bradley, Steven Baker, Jean Pierre Allain, Kenneth G.C. Smith, Rachel Bousfield, Michael Wilson, Dominic Sparkes, Glenn Amoroso, Effrosyni Gkrania-Klotsas, Susie Hardwick, Adrian Boyle, Ian Goodfellow, Ravindra K. Gupta, Stephen Baker, Gordon Dougan, Ravi Gupta, Paul J. Lehner, Paul Lyons, Nicholas J. Matheson, Mark Toshner, Michael P. Weekes, Nick Brown, Martin Curran, Surendra Palmar, David Enoch, Daniel Chapman, Ashley Shaw, Sherly Jose, Areti Bermperi, Julie Ann Zerrudo, Evgenia Kourampa, Laura Watson, Jieniean Worsley, Caroline Saunders, Ranalie de Jesus, Jason Domingo, Ciro Pasquale, Bensi Vergese, Phoebe Vargas, Marivic Fabiculana, Marlyn Perales, Lee Mynott, Elizabeth Blake, Amy Bates, Anne-Laure Vallier, Alexandra Williams, David Phillips, Edmund Chiu, Alex Overhill, Nicola Ramenatte, Jamal Sipple, Steven Frost, Helena Knock, Richard Hardy, Emily Foster, Fiona Davidson, Viona Rundell, Purity Bundi, Richmond Abeseabe, Sarah Clark, Isabel Vicente, Anne Elmer, Carla Ribeiro, Jenny Kourampa, Jane Kennet, Jane Rowlands, Anne Meadows, Criona O’Brien, Rebecca Rastall, Cherry Crucusio, Sarah Hewitt, Jane Price, Jo Calder, Laura Canna, Ashlea Bucke, Hugo Tordesillas, Julie Harris, Valentina Ruffolo, Barbara Graves, Helen Butcher, Daniela Caputo, Emma Le Gresley, Benjamin J. Dunmore, Jennifer Martin, Ekaterina Legchenko, Carmen Treacy, Christopher Huang, Jennifer Wood, Rachel Sutcliffe, Josh Hodgson, Joy Shih, Stefan Graf, Zhen Tong, Tobias Tilly, Ciara O’Donnell, Kelvin Hunter, Linda Pointon, Nicole Pond, Marta Wylot, Emma Jones, Stuart Fawke, Ben Bullman, Lori Turner, Isobel Jarvis, Ommar Omarjee, Aloka De Sa, Joe Marsden, Ariana Betancourt, Marianne Perera, Maddie Epping, Nathan Richoz, Georgie Bower, Rahul Sharma, Francesca Nice, Oisin Huhn, Natalia Savoinykh Yarkoni, Nika Romashova, Daniel Lewis, Andrew Hinch, Chiara Cossetti, Mateusz Strezlecki, Richard Grenfell, Hannah Stark, Neil Walker, Kathy Stirrups, Nigel Ovington, Eleanor Dewhust, Emily Li, Sofia Papadia, Nathalie Kingston, Andrew Lever, Estee Torok, William Hamilton, Grant Hall, Aminu Jahun, Yasmin Chaudhry, Malte Pinckert, Iliana Georgana, Anna Yakovleva, Laura Caller, Sarah Caddy, Theresa Feltwell, Fahad Khokhar, Luke Meredith, Charlotte Holdcroft, and Surendra Parmar

Subjects
Male, Antibodies, Viral, Serology, 0302 clinical medicine, COVID-19 Testing, 80 and over, Medicine, 030212 general & internal medicine, Viral, Aged, 80 and over, Immunoassay, 0303 health sciences, lcsh:R5-920, biology, Middle Aged, D614G, Spike Glycoprotein, 3. Good health, medicine.anatomical_structure, Point-of-Care Testing, Spike Glycoprotein, Coronavirus, Spike (software development), Female, Antibody, lcsh:Medicine (General), Nucleic Acid Amplification Techniques, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Point-of-care testing, Sensitivity and Specificity, General Biochemistry, Genetics and Molecular Biology, Antibodies, 03 medical and health sciences, rapid diagnoses, Neutralization Tests, Throat, Report, Humans, 030304 developmental biology, Point of care, Aged, QR355, COVID-19, point of care testing, SARS-CoV-2, business.industry, Virology, Coronavirus, biology.protein, Nucleic acid, business
Abstract

Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity., Graphical Abstract, Highlights Combined rapid antibody + nucleic acid detection correctly diagnoses SARS-CoV-2 Rapid antibody tests detect immune responses against SARS-CoV-2 bearing D614G Rapid SARS-CoV-2 antibody tests do not cross-react with antibodies to seasonal CoV False positivity in SARS-CoV-2 finger prick blood antibody tests can be very low, Mlcochova et al. report that combined rapid nucleic acid amplification testing (NAAT) and finger prick blood antibody tests can substantially improve the diagnosis of COVID-19 as compared to NAAT alone and is able to detect the SARS-CoV-2 Spike D614G variant that dominates the pandemic.

Published
2021

10. An expanding manifold in transmodal regions characterizes adolescent reconfiguration of structural connectome organization

Author

Cleo McIntosh, Kalia Cleridou, John Suckling, Aislinn Bowler, E.T. Bullmore, Richard A. I. Bethlehem, Michael Moutoussis, Sara Larivière, Jessica Memarzia, Kirstie Whitaker, Beatrice Kiddle, Ian M. Goodyer, Michelle St Clair, Danae Kokorikou, Ciara O’Donnell, Rafael Romero-Garcia, Sarah Birt, Harriet Mills, Anne-Laura van Harmelen, Raúl Rodríguez-Cruces, Christina Maurice, Petra E. Vértes, Sara Pantaleone, Casey Paquola, Peter B. Jones, Becky Inkster, Daniel Isaacs, Laura Villis, Boris C. Bernhardt, Ela Polek, Samuel R. Chamberlain, Sian Granville, Barry Widmer, Ashlyn Firkins, Peter Fonagy, Elizabeth Harding, Sharon Neufeld, Emma Davies, Umar Toseeb, Bo-yong Park, Alexandra Hopkins, Junaid Bhatti, Janchai King, Gita Prabhu, Pasco Fearon, Ayesha Alrumaithi, Cinly Ooi, Hina Dadabhoy, Jenny Scott, Raymond Dolan, Tobias U. Hauser, Reinder Vos de Wael, Rogier A. Kievit, Edward T. Bullmore, Neuroscience in Psychiatry Network (NSPN) Consortium [Members of the Max Planck UCL Centre for Computational Psychiatry and Ageing Research, London: Raymond J. Dolan, Michael Moutoussis, Tobias Hauser, Alexandra Hopkins, Rogier Kievit], Park, Bo-Yong [0000-0001-7096-337X], Bethlehem, Richard Ai [0000-0002-0714-0685], Paquola, Casey [0000-0002-0190-4103], Bernhardt, Boris C [0000-0001-9256-6041], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, Cognition, 0302 clinical medicine, Cortex (anatomy), Neural Pathways, Longitudinal Studies, Biology (General), 10. No inequality, neuroimaging, neurodevelopment, General Neuroscience, connectome, Age Factors, Brain, Gene Expression Regulation, Developmental, General Medicine, Magnetic Resonance Imaging, Manifold, medicine.anatomical_structure, Connectome, Medicine, Female, Psychology, Research Article, Human, Adult, Adolescent, longitudinal, multi-scale, QH301-705.5, Neurogenesis, Science, Models, Neurological, Thalamus, Nerve Tissue Proteins, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Neuroimaging, medicine, Humans, Association (psychology), General Immunology and Microbiology, Gene Expression Profiling, Nonlinear dimensionality reduction, Adolescent Development, 030104 developmental biology, Adolescent Behavior, adolescence, Transcriptome, ddc:600, Neuroscience, 030217 neurology & neurosurgery
Abstract

Adolescence is a critical time for the continued maturation of brain networks. Here, we assessed structural connectome development in a large longitudinal sample ranging from childhood to young adulthood. By projecting high-dimensional connectomes into compact manifold spaces, we identified a marked expansion of structural connectomes, with strongest effects in transmodal regions during adolescence. Findings reflected increased within-module connectivity together with increased segregation, indicating increasing differentiation of higher-order association networks from the rest of the brain. Projection of subcortico-cortical connectivity patterns into these manifolds showed parallel alterations in pathways centered on the caudate and thalamus. Connectome findings were contextualized via spatial transcriptome association analysis, highlighting genes enriched in cortex, thalamus, and striatum. Statistical learning of cortical and subcortical manifold features at baseline and their maturational change predicted measures of intelligence at follow-up. Our findings demonstrate that connectome manifold learning can bridge the conceptual and empirical gaps between macroscale network reconfigurations, microscale processes, and cognitive outcomes in adolescent development.

Published
2021

11. Decision-making ability, psychopathology, and brain connectivity

Author

Michael Moutoussis, Benjamín Garzón, Sharon Neufeld, Dominik R. Bach, Francesco Rigoli, Ian Goodyer, Edward Bullmore, Marc Guitart-Masip, Raymond J. Dolan, Peter Fonagy, Peter Jones, Tobias Hauser, Rafael Romero-Garcia, Michelle St Clair, Petra Vértes, Kirstie Whitaker, Becky Inkster, Gita Prabhu, Cinly Ooi, Umar Toseeb, Barry Widmer, Junaid Bhatti, Laura Villis, Ayesha Alrumaithi, Sarah Birt, Aislinn Bowler, Kalia Cleridou, Hina Dadabhoy, Emma Davies, Ashlyn Firkins, Sian Granville, Elizabeth Harding, Alexandra Hopkins, Daniel Isaacs, Janchai King, Danae Kokorikou, Christina Maurice, Cleo McIntosh, Jessica Memarzia, Harriet Mills, Ciara O’Donnell, Sara Pantaleone, Jenny Scott, Pasco Fearon, John Suckling, Anne-Laura van Harmelen, Rogier Kievit, and NSPN Consortium

Subjects
Male, 0301 basic medicine, Adolescent, media_common.quotation_subject, Decision Making, Social Interaction, BF, HN, Anxiety, Neuropsychological Tests, Young Adult, 03 medical and health sciences, Cognition, 0302 clinical medicine, Neural Pathways, Humans, Quality (business), media_common, Social functioning, Intelligence Tests, Depressive Disorder, Major, Depression, Functional Neuroimaging, General Neuroscience, Functional connectivity, Brain, Antisocial Personality Disorder, Magnetic Resonance Imaging, Mental health, Self Concept, Affect, Psychosocial Functioning, 030104 developmental biology, RC0321, Female, Factor Analysis, Statistical, Construct (philosophy), Psychology, 030217 neurology & neurosurgery, Cognitive psychology, Psychopathology, Decision making ability
Abstract

Summary Decision-making is a cognitive process of central importance for the quality of our lives. Here, we ask whether a common factor underpins our diverse decision-making abilities. We obtained 32 decision-making measures from 830 young people and identified a common factor that we call “decision acuity,” which was distinct from IQ and reflected a generic decision-making ability. Decision acuity was decreased in those with aberrant thinking and low general social functioning. Crucially, decision acuity and IQ had dissociable brain signatures, in terms of their associated neural networks of resting-state functional connectivity. Decision acuity was reliably measured, and its relationship with functional connectivity was also stable when measured in the same individuals 18 months later. Thus, our behavioral and brain data identify a new cognitive construct that underpins decision-making ability across multiple domains. This construct may be important for understanding mental health, particularly regarding poor social function and aberrant thought patterns.

Published
2021

12. A Modest Increase in 11C-PK11195-Positron Emission Tomography TSPO Binding in Depression Is Not Associated With Serum C-Reactive Protein or Body Mass Index

Author

Julia J. Schubert, Mattia Veronese, Tim D. Fryer, Roido Manavaki, Manfred G. Kitzbichler, Maria A. Nettis, Valeria Mondelli, Carmine M. Pariante, Edward T. Bullmore, Federico E. Turkheimer, Dominika Wlazly, Amber Dickinson, Andy Foster, Clare Knight, Claire Leckey, Paul Morgan, Angharad Morgan, Caroline O'Hagan, Samuel Touchard, Shahid Khan, Phil Murphy, Christine Parker, Jai Patel, Jill Richardson, Paul Acton, Nigel Austin, Anindya Bhattacharya, Nick Carruthers, Peter de Boer, Wayne Drevets, John Isaac, Declan Jones, John Kemp, Hartmuth Kolb, Jeff Nye, Gayle Wittenberg, Gareth Barker, Anna Bogdanova, Heidi Byrom, Diana Cash, Annamaria Cattaneo, Daniela Enache, Tony Gee, Caitlin Hastings, Melisa Kose, Giulia Lombardo, Nicole Mariani, Anna McLaughlin, Maria Nettis, Naghmeh Nikkheslat, Carmine Pariante, Karen Randall, Julia Schubert, Luca Sforzini, Hannah Sheridan, Camilla Simmons, Nisha Singh, Federico Turkheimer, Vicky Van Loo, Marta Vicente Rodriguez, Toby Wood, Courtney Worrell, Zuzanna Zajkowska, Brian Campbell, Jan Egebjerg, Hans Eriksson, Francois Gastambide, Karen Husted Adams, Ross Jeggo, Thomas Moeller, Bob Nelson, Niels Plath, Christian Thomsen, Jan Torleif Pederson, Stevin Zorn, Catherine Deith, Scott Farmer, John McClean, Andrew McPherson, Nagore Penandes, Paul Scouller, Murray Sutherland, Mary Jane Attenburrow, Jithen Benjamin, Helen Jones, Fran Mada, Akintayo Oladejo, Katy Smith, Rita Balice-Gordon, Brendon Binneman, James Duerr, Terence Fullerton, Veeru Goli, Zoe Hughes, Justin Piro, Tarek Samad, Jonathan Sporn, Liz Hoskins, Charmaine Kohn, Lauren Wilcock, Franklin Aigbirhio, Junaid Bhatti, Ed Bullmore, Sam Chamberlain, Marta Correia, Anna Crofts, Tim Fryer, Martin Graves, Alex Hatton, Manfred Kitzbichler, Mary-Ellen Lynall, Christina Maurice, Ciara O'Donnell, Linda Pointon, Peter St George Hyslop, Lorinda Turner, Petra Vertes, Barry Widmer, Guy Williams, Jonathan Cavanagh, Alison McColl, Robin Shaw, Erik Boddeke, Alison Baird, Stuart Clare, Phil Cowen, I-Shu (Dante) Huang, Sam Hurley, Simon Lovestone, Alejo Nevado-Holgado, Elena Ribe, Anviti Vyas, Laura Winchester, Madeleine Cleal, Diego Gomez-Nicola, Renzo Mancuso, Hugh Perry, Mara Cercignani, Charlotte Clarke, Alessandro Colasanti, Neil Harrison, Rosemary Murray, Jason O'Connor, and Howard Mount

Subjects
medicine.medical_specialty, Cognitive Neuroscience, 050105 experimental psychology, Body Mass Index, C-reactive protein, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Receptors, GABA, Interquartile range, Internal medicine, medicine, Translocator protein, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Prefrontal cortex, Biological Psychiatry, Anterior cingulate cortex, Inflammation, Depressive Disorder, Major, biology, business.industry, Depression, 05 social sciences, Microglia, PET, TSPO, medicine.disease, Isoquinolines, Archival Report, Endocrinology, medicine.anatomical_structure, Positron-Emission Tomography, biology.protein, Major depressive disorder, Neurology (clinical), business, Body mass index, 030217 neurology & neurosurgery
Abstract

Background: Immune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)–targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration. Methods: A total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16–22) and 25 healthy control subjects underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (2 p = .09; F 1,71 = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t 74 = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t 54 = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures. Conclusions: Consistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.

Published
2021

13. A nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury: A randomised, placebo-controlled pilot study

Author

Martin O. Shields, Kelly Hardes, Daniel F. McAuley, Andrew Fowler, Joyce Yeung, James M. Ryan, Aili L. Lazaar, Elizabeth McKie, William Powley, Andrew I. Bayliffe, Charlotte Summers, David R Thickett, Phillip A Howells, Gavin D. Perkins, Tracey J. Wright, Ciara O'Donnell, Arlette Vassallo, Rob Wilson, Summers, Charlotte [0000-0002-7269-2873], and Apollo - University of Cambridge Repository

Subjects
Pilot Projects, Lung injury, Placebo, 03 medical and health sciences, Necrosis, 0302 clinical medicine, Double-Blind Method, 030202 anesthesiology, Clinical endpoint, Medicine, Humans, Adverse effect, Lung, medicine.diagnostic_test, business.industry, 030208 emergency & critical care medicine, Bayes Theorem, Lung Injury, Ventilation, Confidence interval, United Kingdom, Clinical trial, Anesthesiology and Pain Medicine, Bronchoalveolar lavage, medicine.anatomical_structure, Treatment Outcome, Anesthesia, business
Abstract

BACKGROUND: Tumour necrosis factor receptor 1 (TNFR1) signalling mediates the cell death and inflammatory effects of TNF-α. OBJECTIVE: The current clinical trial investigated the effects of a nebulised TNFR1 antagonist (GSK2862277) on signs of lung injury in patients undergoing oesophagectomy. DESIGN: Randomised double-blind (sponsor unblind), placebo-controlled, parallel group study. SETTING: Eight secondary care centres, the United Kingdom between April 2015 and June 2017. PATIENTS: Thirty-three patients undergoing elective transthoracic oesophagectomy. INTERVENTIONS: Patients randomly received a single nebulised dose (26 mg) of GSK2862277 (n = 17) or placebo (n = 16), given 1 to 5 h before surgery; 14 and 16, respectively competed the study. MAIN OUTCOME MEASUREMENTS: Physiological and biochemical markers of lung injury, pharmacokinetic and safety endpoints were measured. The primary endpoint was the change from baseline in pulmonary vascular permeability index (PVPI) at completion of surgery, measured using single-indicator transpulmonary thermodilution. Adjusted point estimates and 95% credible intervals (analogous to conventional confidence intervals) were constructed for each treatment using Bayesian statistical models. RESULTS: The mean change (with 95% credible intervals) from baseline in PVPI on completion of surgery was 0.00 (-0.23, 0.39) in the placebo and 0.00 (-0.24, 0.37) in the GSK2862277 treatment groups. There were no significant treatment-related differences in PaO2/FiO2 or Sequential Organ Failure Assessment score. Levels of free soluble TNFR1, Macrophage Inflammatory Protein-1 alpha and total protein were significantly reduced in the bronchoalveolar lavage fluid of patients treated with GSK2862277 (posterior probability of decrease with GSK2862277 vs. placebo:≥0.977; equivalent to P < 0.05). The frequency of adverse events and serious adverse events were distributed evenly across the two treatment arms. CONCLUSION: Pre-operative treatment with a single 26 mg inhaled dose of GSK2862277 did not result in significantly lower postoperative alveolar capillary leak or extra vascular lung water. Unexpectedly small increases in transpulmonary thermodilution-measured PVPI and extra vascular lung water index at completion of surgery suggest less postoperative lung injury than historically reported, which may have also compromised a clear assessment of efficacy in this trial. GSK2862277 was well tolerated, resulted in expected lung exposure and reduced biomarkers of lung permeability and inflammation. TRIAL REGISTRATION: clinicaltrials.gov: NCT02221037.

Published
2020
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14. Author response: Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19

Author

Simone Hargreaves, Francescsa Nice, Naidine Escoffery, Paul J. Lehner, Lucy Rivett, Caroline Saunders, Julie Harris, Neil Bartholomew, Natalia Savoinykh Yarkoni, Anne Meadows, Anne-Laure Vallier, Mary Kasanicki, Joe Marsden, Jo Wright, Charlotte J. Houldcroft, Chris Workman, Mark Ferris, Carmen M. Treacy, Kelvin Hunter, Anita Furlong, Harmeet Gill, Michael P. Weekes, Surendra Parmar, Nika Romashova, Kenneth G. C. Smith, Greg Hannon, Ashlea Bucke, Chris McNicholas, Debbie Read, Myra Hosmillo, Sushmita Sridhar, Linda Pointon, Jane Gray, John Bradley, Josh Hodgson, Emma Le Gresley, Joana Pereira-Dias, Lori Turner, Nicola Ramenatte, Stefan Gräf, Ben Warne, Claire Cormie, Jane Rowlands, Jane Kennet, Penelope-Jane Eames, Christopher Huang, Barbara J. Graves, Sally Forrest, Helen Butcher, Daniela Caputo, Joanna Calder, Anna Yakovleva, Jo Price, Aileen Narcorda, M. Estée Török, Sarah Hewitt, Martin D. Curran, Ian Goodfellow, Valentina Ruffolo, Cordova Jiménez, Michelle Wantoch, Lisa Thake, Zhen Tong, Isobel Jarvis, Laura Canna, Paul A. Lyons, Isabel Cruz, Benjamin J. Dunmore, Anne Roberts, William David Córdova Jiménez, Lucy Worboys, Helen Dolling, Rebecca Rastall, Ommar Omarjee, Sarah L Caddy, Barrie Bailey, William L Hamilton, Ekaterina Legchenko, Debra Clapham-Riley, Rachel Sutcliffe, Ciara O’Donnell, Fahad A Khokhar, Laura G Caller, Kathleen E Stirrups, Fathima Nisha Begum Samad, Hongyi Zhang, Jamie Young, Sofia Papadia, Criona O Brien, Tobias Tilly, Jennifer M. Martin, Nick K Jones, Kirsty Lagadu, Carla Ribeiro, Ailsa Bowring, Nicholas J Matheson, Tim Gould, D. Johnson, Ashley Shaw, Simon McCallum, Tim Raine, Daniel Lewis, Ariana Betancourt, Stewart Fuller, Afzal N. Chaudhry, Lenette Mactavous, Heather F Jones, William David, Rachel Doughton, Theresa Feltwell, Luke W. Meredith, Nathalie Kingston, Hannah Stark, Georgie Bowyer, Gregory J. Hannon, Karen Brookes, Dominic Sparkes, Iain Kean, Ravi Gupta, Cherry Publico, Katie Dempsey, Matthew Routledge, Nicholas K Jones, Aloka De Sa, Giles Wright, Laura Bergamaschi, Claire Mather, Rutendo Nyagumbo, Maddie Epping, Jack Levy, Marianne Perera, Christian Sparke, Fatima Nb Samad, Nicola Reynolds, Michael Gill, Hugo Tordesillas, Oisin Huhn, Anne Elmer, Geraldine Martell, Mateusz Strezlecki, Grant Hall, Andrew Hinch, Gordon Dougan, Jennifer Webster, Helen Murphy, Stephen Baker, Aminu S Jahun, Mark Toshner, Angela Wright, Natalie Quinnell, Joy Shih, Caroline Trotter, Nicholas K. Brown, Federica Mescia, John S. Bradley, and Jennifer Wood

Subjects
medicine.medical_specialty, Transmission (mechanics), Coronavirus disease 2019 (COVID-19), business.industry, law, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Period (gene), Emergency medicine, Health care, Medicine, business, law.invention
Published
2020

15. Author response: Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission

Author

Jennifer Webster, Stephen Baker, Neil Bartholomew, Aminu S Jahun, Rutendo Nyagumbo, Mark Toshner, Julie Harris, Paul J. Lehner, Charlotte J. Houldcroft, Lisa Thake, Sarah L Caddy, Benjamin J. Dunmore, Afzal N. Chaudhry, Theresa Feltwell, Christian Sparke, M. Estée Török, Nick K Jones, Michael P. Weekes, Emma Le Gresley, Simon McCallum, Tim Raine, Josefin Bartholdson Scott, Grant Hall, Myra Hosmillo, Stewart Fuller, Andrew Hinch, Angela Wright, Gordon Dougan, Jane Rowlands, Aileen Narcorda, Sally Forrest, Claire Cormie, Jennifer M. Martin, Kathleen E Stirrups, Sarah Hewitt, Natalie Quinnell, Joy Shih, Katie Dempsey, Geraldine Martell, Helen Murphy, Ashley Shaw, Cherry Publico, Heather F Jones, Carmen M. Treacy, Anne-Laure Vallier, Surendra Parmar, Jennifer Wood, Ariana Betancourt, Ashlea Bucke, Debbie Read, Helen Butcher, Martin D. Curran, Penelope-Jane Eames, Sushmita Sridhar, Chris McNicholas, Dominic Sparkes, Ian Goodfellow, Nicola Reynolds, Ciara O’Donnell, Valentina Ruffolo, Jane Kennet, Fahad A Khokhar, Hannah Stark, Paul A. Lyons, Francescsa Nice, Karen Brookes, Lenette Mactavous, Claire Mather, Maddie Epping, Aloka De Sa, Lucy Warboys, Isabel Cruz, Naidine Escoffery, Carla Ribeiro, Ailsa Bowring, Nicholas J Matheson, Iain Kean, Tobias Tilly, Daniel Lewis, Ravi Gupta, Kelvin Hunter, Giles Wright, Anne Roberts, Hugo Tordesillas, Isobel Jarvis, Nicholas K. Brown, Laura Bergamaschi, Anne Elmer, Harmeet Gill, Oisin Huhn, D. Johnson, Laura G Caller, John Bradley, Caroline Saunders, Federica Mescia, Joanna Calder, Anna Yakovleva, Jo Price, Richard J. Samworth, Kenneth G. C. Smith, Mary Kasanicki, Hongyi Zhang, Laura Canna, Rebecca Rastall, Jo Wright, Ben Warne, Simone Hargreaves, Anita Furlong, Josh Hodgson, Daniela Caputo, Stefan Gräf, Jamie Young, Sofia Papadia, Criona O Brien, Kirsty Lagadu, Georgie Bowyer, Michelle Wantoch, Ekaterina Legchenko, Debra Clapham-Riley, Rachel Sutcliffe, Joe Marsden, Mark Ferris, Tim Gould, Mailis Maes, Luke W. Meredith, Joana Pereira-Dias, Nicola Ramenatte, Matthew Routledge, Nathalie Kingston, Helen Dolling, William L Hamilton, Linda Pointon, Christopher Huang, Barbara J. Graves, Lucy Rivett, Anne Meadows, and Zhen Tong

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Asymptomatic, law.invention, Carriage, Transmission (mechanics), law, Health care, medicine, medicine.symptom, Intensive care medicine, business
Published
2020

16. Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes

Author

Rafael Romero-Garcia, Jakob Seidlitz, Kirstie J. Whitaker, Sarah E. Morgan, Peter Fonagy, Raymond J. Dolan, Peter B. Jones, Ian M. Goodyer, John Suckling, Petra E. Vértes, Edward T. Bullmore, Edward Bullmore, Raymond Dolan, Ian Goodyer, Peter Jones, Matilde Vaghi, Michael Moutoussis, Tobias Hauser, Sharon Neufeld, Michelle St Clair, Kirstie Whitaker, Becky Inkster, Gita Prabhu, Cinly Ooi, Umar Toseeb, Barry Widmer, Junaid Bhatti, Laura Villis, Ayesha Alrumaithi, Sarah Birt, Aislinn Bowler, Kalia Cleridou, Hina Dadabhoy, Emma Davies, Ashlyn Firkins, Sian Granville, Elizabeth Harding, Alexandra Hopkins, Daniel Isaacs, Janchai King, Danae Kokorikou, Christina Maurice, Cleo McIntosh, Jessica Memarzia, Harriet Mills, Ciara O’Donnell, Sara Pantaleone, Jenny Scott, Pasco Fearon, Anne-Laura van Harmelen, Rogier Kievit, Petra Vértes, and the NSPN Consortium

Subjects
0301 basic medicine, Adult, Adolescent, Schizotypy, Allen Human Brain Atlas, Precuneus, Biology, Development, Brain mapping, Article, Schizotypal Personality Disorder, 03 medical and health sciences, Fast-spiking GABAergic interneurons, Myelination, 0302 clinical medicine, Cortex (anatomy), medicine, Multiparameter MRI mapping, Humans, Prefrontal cortex, Biological Psychiatry, Default mode network, 030304 developmental biology, 0303 health sciences, Brain Mapping, Brain, equipment and supplies, medicine.disease, Schizotypal personality disorder, Magnetic Resonance Imaging, Adolescence, 030104 developmental biology, medicine.anatomical_structure, Schizophrenia, Posterior cingulate, biology.protein, human activities, Neuroscience, 030217 neurology & neurosurgery, Parvalbumin
Abstract

BackgroundGenetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behaviour are unclear.MethodsWe assessed schizotypy using a self-reported questionnaire, and measured magnetization transfer (MT), as a putative micro-structural MRI marker of intra-cortical myelination, in 68 brain regions, in 248 healthy young people (aged 14-25 years). We used normative adult brain gene expression data, and partial least squares (PLS) analysis, to find the weighted gene expression pattern that was most co-located with the cortical map of schizotypy-related magnetization (SRM).ResultsMagnetization was significantly correlated with schizotypy in bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy also in medial prefrontal cortex; all FDR-corrected P < 0.05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole genome expression map co-located with SRM were enriched for genes that were significantly down-regulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally up-regulated in schizophrenia. Positively weighted (down-regulated) genes were enriched for neuronal, specifically inter-neuronal, affiliations and coded a network of proteins comprising a few highly interactive “hubs” such as parvalbumin and calmodulin.ConclusionsMicrostructural MRI maps of intracortical magnetization can be linked to both the behavioural traits of schizotypy and to prior histological data on dysregulated gene expression in schizophrenia.

Published
2018
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