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2. Safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome: protocol for a multicentre, open-label, prospective, single-arm study

Author

Andrew Bryant, Eoin Moloney, Yemi Oluboyede, Neil Sheerin, David Kavanagh, Thomas J Chadwick, Sally Johnson, Sarah Dunn, Jan Lecouturier, Sonya Carnell, Michal Malina, Victoria Brocklebank, Christopher Weetman, Edwin Kwan Soon Wong, and Len Woodward

Subjects
Medicine
Abstract

Introduction Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disease caused by excessive activation of part of the immune system called complement. Eculizumab is an effective treatment, controlling aHUS in 90% of patients. Due to the risk of relapse, lifelong treatment is currently recommended. Eculizumab treatment is not without problems, foremost being the risk of severe meningococcal infection, the burden of biweekly intravenous injections and the high cost.This paper describes the design of the Stopping Eculizumab Treatment Safely in aHUS trial that aims to establish whether a safety monitoring protocol, including the reintroduction of eculizumab for those who relapse, could be a safe, alternative treatment strategy for patients with aHUS.Methods and analysis This is a multicentre, non-randomised, open-label study of eculizumab withdrawal with continuous monitoring of thrombotic microangiopathy-related serious adverse events using the Bayes factor single-arm design. 30 patients will be recruited to withdraw from eculizumab and have regular blood and urine tests for 24 months, to monitor for disease activity. If relapse occurs, treatment will be restarted within 24 hours of presentation. 20 patients will remain on treatment and complete health economic questionnaires only. An embedded qualitative study will explore the views of participants.Ethics and dissemination A favourable ethical opinion and approval was obtained from the North East-Tyne & Wear South Research Ethics Committee. Outcomes will be disseminated via peer-reviewed articles and conference presentations.Trial registration number EudraCT number: 2017-003916-37 and ISRCTN number: ISRCTN17503205.

Published
2022
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3. Glomerular filtration rate: new age- and gender- specific reference ranges and thresholds for living kidney donation

Author

Anthony Fenton, Emma Montgomery, Peter Nightingale, A. Michael Peters, Neil Sheerin, A. Caroline Wroe, and Graham W. Lipkin

Subjects
Glomerular filtration rate, Living kidney donation, Reference ranges, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background There is a need for a large, contemporary, multi-centre series of measured glomerular filtration rates (mGFR) from healthy individuals to determine age- and gender-specific reference ranges for GFR. We aimed to address this and to use the ranges to provide age- and gender-specific advisory GFR thresholds considered acceptable for living kidney donation. Methods Individual-level data including pre-donation mGFR from 2974 prospective living kidney donors from 18 UK renal centres performed between 2003 and 2015 were amalgamated. Age- and gender-specific GFR reference ranges were determined by segmented multiple linear regression and presented as means ± two standard deviations. Results Males had a higher GFR than females (92.0 vs 88.1 mL/min/1.73m2, P 60 years had a GFR

Published
2018
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4. Acute kidney injury electronic alerts: mixed methods Normalisation Process Theory evaluation of their implementation into secondary care in England

Author

Gregory Maniatopoulos, Tracy Finch, Jason Scott, Mark Bevan, Chris Gibbins, Bryan Yates, Narayanan Kilimangalam, Neil Sheerin, and Nigel Suren Kanagasundaram

Subjects
Medicine
Abstract

Objective Around one in five emergency hospital admissions are affected by acute kidney injury (AKI). To address poor quality of care in relation to AKI, electronic alerts (e-alerts) are mandated across primary and secondary care in England and Wales. Evidence of the benefit of AKI e-alerts remains conflicting, with at least some uncertainty explained by poor or unclear implementation. The objective of this study was to identify factors relating to implementation, using Normalisation Process Theory (NPT), which promote or inhibit use of AKI e-alerts in secondary care.Design Mixed methods combining qualitative (observations, semi-structured interviews) and quantitative (survey) methods.Setting and participants Three secondary care hospitals in North East England, representing two distinct AKI e-alerting systems. Observations (>44 hours) were conducted in Emergency Assessment Units (EAUs). Semi-structured interviews were conducted with clinicians (n=29) from EAUs, vascular or general surgery or care of the elderly. Qualitative data were supplemented by Normalization MeAsure Development (NoMAD) surveys (n=101).Analysis Qualitative data were analysed using the NPT framework, with quantitative data analysed descriptively and using χ2 and Wilcoxon signed-rank test for differences in current and future normalisation.Results Participants reported familiarity with the AKI e-alerts but that the e-alerts would become more normalised in the future (p

Published
2019
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5. Methods for the evaluation of biomarkers in patients with kidney and liver diseases: multicentre research programme including ELUCIDATE RCT

Author

Peter J Selby, Rosamonde E Banks, Walter Gregory, Jenny Hewison, William Rosenberg, Douglas G Altman, Jonathan J Deeks, Christopher McCabe, Julie Parkes, Catharine Sturgeon, Douglas Thompson, Maureen Twiddy, Janine Bestall, Joan Bedlington, Tilly Hale, Jacqueline Dinnes, Marc Jones, Andrew Lewington, Michael P Messenger, Vicky Napp, Alice Sitch, Sudeep Tanwar, Naveen S Vasudev, Paul Baxter, Sue Bell, David A Cairns, Nicola Calder, Neil Corrigan, Francesco Del Galdo, Peter Heudtlass, Nick Hornigold, Claire Hulme, Michelle Hutchinson, Carys Lippiatt, Tobias Livingstone, Roberta Longo, Matthew Potton, Stephanie Roberts, Sheryl Sim, Sebastian Trainor, Matthew Welberry Smith, James Neuberger, Douglas Thorburn, Paul Richardson, John Christie, Neil Sheerin, William McKane, Paul Gibbs, Anusha Edwards, Naeem Soomro, Adebanji Adeyoju, Grant D Stewart, and David Hrouda

Subjects
biomarkers, liver disease, kidney disease, prostate-specific antigen, monitoring trials, simulation of biomarker studies, elf test, elucidate, renal cancer, renal transplantation, diagnosis of cirrhosis, Public aspects of medicine, RA1-1270
Abstract

Background: Protein biomarkers with associations with the activity and outcomes of diseases are being identified by modern proteomic technologies. They may be simple, accessible, cheap and safe tests that can inform diagnosis, prognosis, treatment selection, monitoring of disease activity and therapy and may substitute for complex, invasive and expensive tests. However, their potential is not yet being realised. Design and methods: The study consisted of three workstreams to create a framework for research: workstream 1, methodology – to define current practice and explore methodology innovations for biomarkers for monitoring disease; workstream 2, clinical translation – to create a framework of research practice, high-quality samples and related clinical data to evaluate the validity and clinical utility of protein biomarkers; and workstream 3, the ELF to Uncover Cirrhosis as an Indication for Diagnosis and Action for Treatable Event (ELUCIDATE) randomised controlled trial (RCT) – an exemplar RCT of an established test, the ADVIA Centaur® Enhanced Liver Fibrosis (ELF) test (Siemens Healthcare Diagnostics Ltd, Camberley, UK) [consisting of a panel of three markers – (1) serum hyaluronic acid, (2) amino-terminal propeptide of type III procollagen and (3) tissue inhibitor of metalloproteinase 1], for liver cirrhosis to determine its impact on diagnostic timing and the management of cirrhosis and the process of care and improving outcomes. Results: The methodology workstream evaluated the quality of recommendations for using prostate-specific antigen to monitor patients, systematically reviewed RCTs of monitoring strategies and reviewed the monitoring biomarker literature and how monitoring can have an impact on outcomes. Simulation studies were conducted to evaluate monitoring and improve the merits of health care. The monitoring biomarker literature is modest and robust conclusions are infrequent. We recommend improvements in research practice. Patients strongly endorsed the need for robust and conclusive research in this area. The clinical translation workstream focused on analytical and clinical validity. Cohorts were established for renal cell carcinoma (RCC) and renal transplantation (RT), with samples and patient data from multiple centres, as a rapid-access resource to evaluate the validity of biomarkers. Candidate biomarkers for RCC and RT were identified from the literature and their quality was evaluated and selected biomarkers were prioritised. The duration of follow-up was a limitation but biomarkers were identified that may be taken forward for clinical utility. In the third workstream, the ELUCIDATE trial registered 1303 patients and randomised 878 patients out of a target of 1000. The trial started late and recruited slowly initially but ultimately recruited with good statistical power to answer the key questions. ELF monitoring altered the patient process of care and may show benefits from the early introduction of interventions with further follow-up. The ELUCIDATE trial was an ‘exemplar’ trial that has demonstrated the challenges of evaluating biomarker strategies in ‘end-to-end’ RCTs and will inform future study designs. Conclusions: The limitations in the programme were principally that, during the collection and curation of the cohorts of patients with RCC and RT, the pace of discovery of new biomarkers in commercial and non-commercial research was slower than anticipated and so conclusive evaluations using the cohorts are few; however, access to the cohorts will be sustained for future new biomarkers. The ELUCIDATE trial was slow to start and recruit to, with a late surge of recruitment, and so final conclusions about the impact of the ELF test on long-term outcomes await further follow-up. The findings from the three workstreams were used to synthesise a strategy and framework for future biomarker evaluations incorporating innovations in study design, health economics and health informatics. Trial registration: Current Controlled Trials ISRCTN74815110, UKCRN ID 9954 and UKCRN ID 11930. Funding: This project was funded by the NIHR Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 6, No. 3. See the NIHR Journals Library website for further project information.

Published
2018
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7. Safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome: protocol for a multicentre, open-label, prospective, single-arm study

Author

Sarah Dunn, Victoria Brocklebank, Andrew Bryant, Sonya Carnell, Thomas J Chadwick, Sally Johnson, David Kavanagh, Jan Lecouturier, Michal Malina, Eoin Moloney, Yemi Oluboyede, Christopher Weetman, Edwin Kwan Soon Wong, Len Woodward, and Neil Sheerin

Subjects
Recurrence, Humans, Multicenter Studies as Topic, Bayes Theorem, General Medicine, Prospective Studies, Antibodies, Monoclonal, Humanized, Atypical Hemolytic Uremic Syndrome
Abstract

IntroductionAtypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening disease caused by excessive activation of part of the immune system called complement. Eculizumab is an effective treatment, controlling aHUS in 90% of patients. Due to the risk of relapse, lifelong treatment is currently recommended. Eculizumab treatment is not without problems, foremost being the risk of severe meningococcal infection, the burden of biweekly intravenous injections and the high cost.This paper describes the design of the Stopping Eculizumab Treatment Safely in aHUS trial that aims to establish whether a safety monitoring protocol, including the reintroduction of eculizumab for those who relapse, could be a safe, alternative treatment strategy for patients with aHUS.Methods and analysisThis is a multicentre, non-randomised, open-label study of eculizumab withdrawal with continuous monitoring of thrombotic microangiopathy-related serious adverse events using the Bayes factor single-arm design. 30 patients will be recruited to withdraw from eculizumab and have regular blood and urine tests for 24 months, to monitor for disease activity. If relapse occurs, treatment will be restarted within 24 hours of presentation. 20 patients will remain on treatment and complete health economic questionnaires only. An embedded qualitative study will explore the views of participants.Ethics and disseminationA favourable ethical opinion and approval was obtained from the North East-Tyne & Wear South Research Ethics Committee. Outcomes will be disseminated via peer-reviewed articles and conference presentations.Trial registration numberEudraCT number: 2017-003916-37 and ISRCTN number: ISRCTN17503205.

Published
2022

9. Urinary tract infection

Author

Charles Tomson and Neil Sheerin

Subjects
urologic and male genital diseases, female genital diseases and pregnancy complications
Abstract

Urinary tract infection (UTI) is a common condition, accounting for 1 to 3% of all primary care consultations in the United Kingdom. It affects patients of both sexes and all ages. The commonest organism causing uncomplicated community-acquired bacterial UTI is Escherichia coli. The occurrence and course of a UTI is influenced by the integrity of the host defence and by bacterial virulence factors. Disruption of the highly specialized transitional cell epithelium which lines the urinary tract, incomplete bladder emptying, anatomical abnormalities, and the presence of a foreign body, such as a urinary catheter, can all contribute to disruption of the host defence and increase the likelihood of infection. Sexual intercourse and use of spermicides increase the risk, and genetic factors influence the susceptibility of some people. Diagnosis—acute uncomplicated UTI can often be diagnosed on symptoms alone, with urinalysis increasing diagnostic accuracy. Submission of a sample for microbiological testing is unnecessary in most cases. Differential diagnoses (‘culture-negative syndromes’) include chlamydial infection, urethral syndrome, and painful bladder syndrome (interstitial cystitis). Investigation—beyond microbiological testing, further investigation of women with uncomplicated UTI is seldom justified. In men, and those women with features indicating complicated infection, investigation for an underlying cause should be considered. Management: antibiotics—trimethoprim and nitrofurantoin remain the first choice for community-acquired UTI in the United Kingdom. Complicated UTI is caused by a wider spectrum of organisms, and recommendations for treatment differ. This chapter discusses the prevention of recurrent uncomplicated UTI and management of complicated UTIs due to urethral catheterization, urinary tract stones, anatomically abnormal kidneys, and pregnancy, and other causes such as fungal infections, tuberculosis, and schistosomiasis.

Published
2020
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10. List of Contributors

Author

Sophoclis Alexopoulos, Tarek Alhamed, Radica Z. Alicic, Amatur Amarah, Shubha Ananthakrishnan, Matthew J. Arduino, Deborah S. Rosenthal Asher, David Axelrod, Rasheed Abiodun Balogun, Joanne M. Bargman, Gerald A. Beathard, Monica C. Beaulieu, Justin M. Belcher, Jeffrey S. Berns, Scott D. Bieber, Roy D. Bloom, Emily A. Blumberg, Brendan Bowman, Juan J. Carrero, Esteban Cedillo-Couvert, Christopher T. Chan, Anil Chandraker, Tushar Chopra, Gabriela Cobo, Lewis M. Cohen, Allan J. Collins, Beatrice P. Concepcion, Michael J. Connor, Josef Coresh, Daniel Cukor, Solomon Dawson, Ian de Boer, Michelle Denburg, Thomas A. Depner, Vikas R. Dharnidharka, Michael J. Germain, John S. Gill, Simin Goral, Monica Grafals, Judi M. Graham, Gentzon Hall, Olof Heimbürger, Sangeeta R. Hingorani, Joanna Q. Hudson, Lesley A. Inker, Magdalena Jankowska, Emily J. Johnson, Olwyn Johnston, Clare B. Jones, Anna Jovanovich, Philip Kam-Tao Li, Seth J. Karp, Jessica Kendrick, Paul L. Kimmel, Derk C.F. Klatte, Greg Knoll, Michael A. Kraus, James P. Lash, Krista L. Lentine, Andrew S. Levey, Adeera Levin, Mary Ann Lim, Bengt Lindhom, Kathleen Liu, Helen MacLaughlin, Nicola Marsh, Lea Matsuoka, Habib Mawad, Rajnish Mehrotra, Sharon Moe, Nadar Najafian, Melissa Nataatmadja, Duc B. Nguyen, Mark Douglas Okusa, Matthew J. Oliver, Paul M. Palevsky, Chirag R. Parikh, Priti R. Patel, Anna C. Porter, Robert R. Quinn, Leonardo V. Riella, Eugene P. Rhee, Matthew B. Rivara, Mitchell H. Rosner, Maria-Eleni Roumelioti, Athanasios K. Roumeliotis, Mark J. Sarnak, Deirdre Sawinski, Heidi Schaefer, Tariq Shafi, Neil Sheerin, Edward D. Siew, Anand Srivastava, Michelle C. Starr, Peter Stenvinkel, Wendy L. St. Peter, Cheuk-Chun Szeto, Ashita J. Tolwani, Emilie Trinh, Katherine R. Tuttle, Mark L. Unruh, John P. Vella, Sushrut S. Waikar, Angela Yee-Moon Wang, Monnie Wasse, Lori Wazny, Daniel E. Weiner, Eric Weinhandl, Jessica W. Weiss, James B. Wetmore, Tiffany C. Wong, Tyler B. Woodell, Hong Xu, Jane Y. Yeun, and Nadia Zalunardo

Published
2019
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12. Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study

Author

Maria P, Hernandez-Fuentes, Christopher, Franklin, Irene, Rebollo-Mesa, Jennifer, Mollon, Florence, Delaney, Esperanza, Perucha, Caragh, Stapleton, Richard, Borrows, Catherine, Byrne, Gianpiero, Cavalleri, Brendan, Clarke, Menna, Clatworthy, John, Feehally, Susan, Fuggle, Sarah A, Gagliano, Sian, Griffin, Abdul, Hammad, Robert, Higgins, Alan, Jardine, Mary, Keogan, Timothy, Leach, Iain, MacPhee, Patrick B, Mark, James, Marsh, Peter, Maxwell, William, McKane, Adam, McLean, Charles, Newstead, Titus, Augustine, Paul, Phelan, Steve, Powis, Peter, Rowe, Neil, Sheerin, Ellen, Solomon, Henry, Stephens, Raj, Thuraisingham, Richard, Trembath, Peter, Topham, Robert, Vaughan, Steven H, Sacks, Peter, Conlon, Gerhard, Opelz, Nicole, Soranzo, Michael E, Weale, and Graham M, Lord

Subjects
Adult, DNA Replication, Male, basic (laboratory) research/science, Genotype, Histocompatibility Testing, Graft Survival, kidney transplantation/nephrology, kidney (allograft) function/dysfunction, Middle Aged, clinical research/practice, Kidney Transplantation, Polymorphism, Single Nucleotide, Tissue Donors, Transplant Recipients, immunogenetics, Humans, Transplantation, Homologous, informatics, Female, organ transplantation in general, rejection, Letters to the Editor, Letter to the Editor, Genome-Wide Association Study
Abstract

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

Published
2017

13. Urinary tract infection in the adult

Author

Neil Sheerin

Subjects
medicine.medical_specialty, business.industry, Urinary system, Internal medicine, Medicine, business, Gastroenterology
Abstract

Infection of the urinary tract is one of the commonest human infections. It can vary in severity from asymptomatic colonization, through self-limiting but distressing lower tract infection, to life-threatening sepsis. Any site in the urinary tract can be affected. The site of infection determines the pattern of symptoms, but this is also influenced by the age at presentation. The age at presentation and the nature of symptoms will not only suggest a clinical diagnosis, but also guide investigation and treatment. This chapter acts as an introduction to others in this section which address the different presentations of infections of the lower and upper urinary tracts in adults.

Published
2015
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14. A genome-wide association study of anorexia nervosa

Author

Boraska, V., Franklin, C. S., Floyd, J. A. B., Thornton, L. M., Huckins, L. M., Southam, L., Rayner, N. W., Tachmazidou, I., Klump, K. L., Treasure, J., Lewis, C. M., Schmidt, U., Tozzi, F., Kiezebrink, K., Hebebrand, J., Gorwood, P., Adan, R. A. H., Kas, M. J. H., Favaro, Angela, Santonastaso, Paolo, Fernández Aranda, F., Gratacos, M., Rybakowski, F., Dmitrzak Weglarz, M., Kaprio, J., Keski Rahkonen, A., Raevuori, A., Van Furth, E. F., Slof Op 't Landt, M. C. T., Hudson, J. I., Reichborn Kjennerud, T., Knudsen, G. P. S., Monteleone, P., Kaplan, A. S., Karwautz, A., Hakonarson, H., Berrettini, W. H., Guo, Y., Li, D., Schork, N. J., Komaki, G., Ando, T., Inoko, H., Esko, T., Fischer, K., Männik, K., Metspalu, A., Baker, J. H., Cone, R. D., Dackor, J., Desocio, J. E., Hilliard, C. E., O'Toole, J. K., Pantel, J., Szatkiewicz, J. P., Taico, C., Zerwas, S., Trace, S. E., Davis, O. S. P., Helder, S., Bühren, K., Burghardt, R., de Zwaan, M., Egberts, K., Ehrlich, S., Herpertz Dahlmann, B., Herzog, W., Imgart, H., Scherag, A., Scherag, S., Zipfel, S., Boni, C., Ramoz, N., Versini, A., Brandys, M. K., Danner, U. N., de Kovel, C., Hendriks, J., Koeleman, B. P. C., Ophoff, R. A., Strengman, E., van Elburg, A. A., Bruson, Alice, Clementi, Maurizio, Degortes, Daniela, Forzan, Monica, Tenconi, Elena, Docampo, E., Escaramís, G., Jiménez Murcia, S., Lissowska, J., Rajewski, A., Szeszenia Dabrowska, N., Slopien, A., Hauser, J., Karhunen, L., Meulenbelt, I., Slagboom, P. E., Tortorella, A., Maj, M., Dedoussis, G., Dikeos, D., Gonidakis, F., Tziouvas, K., Tsitsika, A., Papezova, H., Slachtova, L., Martaskova, D., Kennedy, J. L., Levitan, R. D., Yilmaz, Z., Huemer, J., Koubek, D., Merl, E., Wagner, G., Lichtenstein, P., Breen, G., Cohen Woods, S., Farmer, A., Mcguffin, P., Cichon, S., Giegling, I., Herms, S., Rujescu, D., Schreiber, S., Wichmann, H. E., Dina, C., Sladek, R., Gambaro, G., Soranzo, N., Julia, A., Marsal, S., Rabionet, R., Gaborieau, V., Dick, D. M., Palotie, A., Ripatti, S., Widén, E., Andreassen, O. A., Espeseth, T., Lundervold, A., Reinvang, I., Steen, V. M., Le Hellard, S., Mattingsdal, M., Ntalla, I., Bencko, V., Foretova, L., Janout, V., Navratilova, M., Gallinger, S., Pinto, D., Scherer, S. W., Aschauer, H., Carlberg, L., Schosser, A., Alfredsson, L., Ding, B., Klareskog, L., Padyukov, L., Courtet, P., Guillaume, S., Jaussent, I., Finan, C., Kalsi, G., Roberts, M., Logan, D. W., Peltonen, L., Ritchie, G. R. S., Barrett, J. C., Anderson, Carl A., Barrett, Jeffrey C., Floyd, James A. B., Franklin, Christopher S., Ralph, Mcginnis, Nicole, Soranzo, Eleftheria, Zeggini, Jennifer, Sambrook, Jonathan, Stephens, Ouwehand, Willem H., Mcardle, Wendy L., Ring, Susan M., Strachan, David P., Graeme, Alexander, Bulik, Cynthia M., Collier, David A., Conlon, Peter J., Anna, Dominiczak, Audrey, Duncanson, Adrian, Hill, Cordelia, Langford, Graham, Lord, Maxwell, Alexander P., Linda, Morgan, Leena, Peltonen, Sandford, Richard N., Neil, Sheerin, Vannberg, Fredrik O., Hannah, Blackburn, Wei Min Chen, Sarah, Edkins, Mathew, Gillman, Emma, Gray, Hunt, Sarah E., Suna Onengut Gumuscu, Simon, Potter, Rich, Stephen S., Douglas, Simpkin, Pamela, Whittaker, Estivill, X., Hinney, A., Sullivan, P. F., Collier, D. A., Zeggini, E., Bulik, C. M., Boraska, V., Franklin, Christopher S., Floyd, James A. B., Thornton, L. M., Huckins, L. M., Southam, L., Rayner, N. W., Tachmazidou, I., Klump, K. L., Treasure, J., Lewis, C. M., Schmidt, U., Tozzi, F., Kiezebrink, K., Hebebrand, J., Gorwood, P., Adan, R. A. H., Kas, M. J. H., Favaro, A., Santonastaso, P., Fernández-Aranda, F., Gratacos, M., Rybakowski, F., Dmitrzak-Weglarz, M., Kaprio, J., Keski-Rahkonen, A., Raevuori, A., Van Furth, E. F., Slof-Op 't Landt, M. C. T., Hudson, J. I., Reichborn-Kjennerud, T., Knudsen, G. P. S., Monteleone, P., Kaplan, A. S., Karwautz, A., Hakonarson, H., Berrettini, W. H., Guo, Y., Li, D., Schork, N. J., Komaki, G., Ando, T., Inoko, H., Esko, T., Fischer, K., Männik, K., Metspalu, A., Baker, J. H., Cone, R. D., Dackor, J., Desocio, J. E., Hilliard, C. E., O'Toole, J. K., Pantel, J., Szatkiewicz, J. P., Taico, C., Zerwas, S., Trace, S. E., Davis, O. S. P., Helder, S., Bühren, K., Burghardt, R., De Zwaan, M., Egberts, K., Ehrlich, S., Herpertz-Dahlmann, B., Herzog, W., Imgart, H., Scherag, A., Scherag, S., Zipfel, S., Boni, C., Ramoz, N., Versini, A., Brandys, M. K., Danner, U. N., De Kovel, C., Hendriks, J., Koeleman, B. P. C., Ophoff, R. A., Strengman, E., Van Elburg, A. A., Bruson, A., Clementi, M., Degortes, D., Forzan, M., Tenconi, E., Docampo, E., Escaramís, G., Jiménez-Murcia, S., Lissowska, J., Rajewski, A., Szeszenia-Dabrowska, N., Slopien, A., Hauser, J., Karhunen, L., Meulenbelt, I., Slagboom, P. E., Tortorella, A., Maj, M., Dedoussis, G., Dikeos, D., Gonidakis, F., Tziouvas, K., Tsitsika, A., Papezova, H., Slachtova, L., Martaskova, D., Kennedy, J. L., Levitan, R. D., Yilmaz, Z., Huemer, J., Koubek, D., Merl, E., Wagner, G., Lichtenstein, P., Breen, G., Cohen-Woods, S., Farmer, A., Mcguffin, P., Cichon, S., Giegling, I., Herms, S., Rujescu, D., Schreiber, S., Wichmann, H. -E., Dina, C., Sladek, R., Gambaro, G., Soranzo, Nicole, Julia, A., Marsal, S., Rabionet, R., Gaborieau, V., Dick, D. M., Palotie, A., Ripatti, S., Widén, E., Andreassen, O. A., Espeseth, T., Lundervold, A., Reinvang, I., Steen, V. M., Le Hellard, S., Mattingsdal, M., Ntalla, I., Bencko, V., Foretova, L., Janout, V., Navratilova, M., Gallinger, S., Pinto, D., Scherer, S. W., Aschauer, H., Carlberg, L., Schosser, A., Alfredsson, L., Ding, B., Klareskog, L., Padyukov, L., Courtet, P., Guillaume, S., Jaussent, I., Finan, C., Kalsi, G., Roberts, M., Logan, D. W., Peltonen, Leena, Ritchie, G. R. S., Barrett, Jeffrey C., Anderson, Carl A., Mcginnis, Ralph, Zeggini, Eleftheria, Sambrook, Jennifer, Stephens, Jonathan, Ouwehand, Willem H., Mcardle, Wendy L., Ring, Susan M., Strachan, David P., Alexander, Graeme, Bulik, C. M., Collier, David A., Conlon, Peter J., Dominiczak, Anna, Duncanson, Audrey, Hill, Adrian, Langford, Cordelia, Lord, Graham, Maxwell, Alexander P., Morgan, Linda, Sandford, Richard N., Sheerin, Neil, Vannberg, Fredrik O., Blackburn, Hannah, Chen, Wei-Min, Edkins, Sarah, Gillman, Mathew, Gray, Emma, Hunt, Sarah E., Onengut-Gumuscu, Suna, Potter, Simon, Rich, Stephen S., Simpkin, Dougla, Whittaker, Pamela, Estivill, X., Hinney, A., Sullivan, P. F., Martaskova D., Wellcome Trust Case Control Consortium 3, Anderson, CA., Barrett, JC., Floyd, JA., Franklin, CS., McGinnis, R., Soranzo, N., Zeggini, E., Sambrook, J., Stephens, J., Ouwehand, WH., McArdle, WL., Ring, SM., Strachan, DP., Alexander, G., Bulik, CM., Collier, DA., Conlon, PJ., Dominiczak, A., Duncanson, A., Hill, A., Langford, C., Lord, G., Maxwell, AP., Morgan, L., Peltonen, L., Sandford, RN., Sheerin, N., Vannberg, FO., Blackburn, H., Chen, WM., Edkins, S., Gillman, M., Gray, E., Hunt, SE., Onengut-Gumuscu, S., Potter, S., Rich, SS., Simpkin, D., and Whittaker, P.

Subjects
Male, Candidate gene, Anorexia Nervosa, Medizin, Genome-wide association study, anorexia nervosa, body mass index, eating disorders, genome-wide association study, GWAS, metabolic, Japan, Settore MED/14 - NEFROLOGIA, Guanine Nucleotide Exchange Factors, genome wide association study, Nuclear Protein, Genetics, Calcineurin, Eating disorder, Anorèxia nerviosa, Nuclear Proteins, Genomics, Cullin Proteins, 3. Good health, Anorexia, VDP::Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714, Anorexia nervosa (differential diagnoses), Psychiatry and Mental Health, Female, Case-Control Studie, Human, Asian Continental Ancestry Group, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Cellular and Molecular Neuroscience, Asian People, Meta-Analysis as Topic, Genetic linkage, Humans, Genotyping, Molecular Biology, anorexia nervosa, body mass index, eating disorders, genome wide association study, GWAS, metabolic, Cullin Protein, Case-control study, Anorexia nervosa, VDP::Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Guanine Nucleotide Exchange Factor, Genòmica, Case-Control Studies, Carrier Protein, Carrier Proteins, Body mass index, Genome-Wide Association Study
Abstract

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P = 3.01 x 10(-7)) in SOX2OT and rs17030795 (P = 5.84 x 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P = 5.76 x 10(-6)) between CUL3 and FAM124B and rs1886797 (P = 8.05 x 10(-6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4x10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Published
2014

16. Calcium homeostasis

Author

TREPICCIONE, Francesco, CAPASSO, Giovambattista, N. Turner, Norbert Lameire, David J. Goldsmith, Christopher G. Winearls, Jonathan Himmelfarb, Giuseppe Remuzzi, and William G. Bennet, Mark E. de Broe, Jeremy R. Chapman, Adrian Covic, Vivekanad Jha, Neil Sheerin, Robert Unwin, and Adrian Woolf, Trepiccione, Francesco, and Capasso, Giovambattista

Published
2015

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