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1. Estimation of kidney doses from [177Lu]Lu-DOTA-TATE PRRT using single time point post-treatment SPECT/CT

Author

Safia Spink, Daniel Gillett, Sarah Heard, Ines Harper, Ruth Casey, and Luigi Aloj

Subjects
Dota-tate, PRRT, Dosimetry, STP, Single time point, Lutate, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background Dosimetry after [177Lu]Lu-DOTA-TATE therapy can be demanding for both patients and the clinical service due to the need for imaging at several time points. In this work we compare three methods of single time point (STP) kidney dosimetry after [177Lu]Lu-DOTA-TATE therapy with a multiple time point (MTP) dosimetry method. Method Method 1 (MTP): Kidney doses were calculated from 31 patients including 107 therapy cycles. Post-therapy SPECT images were acquired on day 0, 4 and 7 along with a CT scan on day 4. A mono-exponential fit was used to calculate kidney doses using cycle specific data. Method 2 (Consistent effective half-life): The effective half-life $$\left({\text{T}}_{\text{e}\text{f}\text{f}}\right)$$ calculated in cycle 1 was assumed consistent for subsequent cycles of therapy and the activity scaled using a single day 3–5 SPECT/CT. Methods 3 and 4 (Hänscheid and Madsen approximations): The Hänscheid approximation and Madsen approximation were both evaluated using a single SPECT/CT acquired on day 0, 4 and 7. All STP methods were compared to the MTP method for accuracy. Results Using the MTP method, mean right and left kidney doses were calculated to be 2.9 ± 1.1 Gy and 2.8 ± 0.9 Gy respectively and the population $${\text{T}}_{\text{e}\text{f}\text{f}}$$ was 56 ± 13 h. For the consistent $${\text{T}}_{\text{e}\text{f}\text{f}}$$ , Hänscheid and Madsen methods, the percentage of results within ± 20% of MTP method were 96% (n = 70), 95% (n = 80) and 94% (n = 80) respectively. Conclusion All three single time point methods had > 94% of results within ± 20% of the MTP method, however the consistent $${\text{T}}_{\text{e}\text{f}\text{f}}$$ method resulted in the highest alignment with the MTP method and is the only method which allows for calculation of the patient-specific $${\text{T}}_{\text{e}\text{f}\text{f}}$$ . If only a single scan can be performed, day 4 is optimal for kidney dosimetry where the Hänscheid or Madsen approximation can be implemented with good accuracy.

Published
2024
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2. Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD)

Author

Jennifer Hague, Ruth Casey, Jonathan Bruty, Tom Legerton, Stephen Abbs, Susan Oddy, Andrew S Powlson, Mohamed Majeed, Mark Gurnell, Soo-Mi Park, and Helen Simpson

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Activating mutations in AVPR2 are associated with nephrogenic syndrome of inappropriate antidiuresis (NSIAD). NSIAD causes hyponatremia, decreased serum osmolality and clinical symptoms, which may present from birth or in infancy and include hypotonia, irritability, vomiting and/or seizures. Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache. NSIAD is a rare X-linked condition, which is associated with a variable phenotype in males, of whom some present in infancy but others do not become symptomatic until adulthood, or occasionally, never. Female carriers may present with episodes of hyponatremia, usually found incidentally. Literature in this field is limited; namely, two clinical reports describing a female proband, both diagnosed in infancy. We describe, for the first time, the case of an adult female proband with NSIAD, who had longstanding associated symptoms of tiredness, headache, temporary memory loss and mood changes as well as hyponatremia and decreased serum osmolality. A water load test demonstrated an inability to dilute urine and gene sequencing confirmed a recurrent activating mutation in AVPR2. The variant was inherited from the proband’s mother who had had longstanding episodes of transient asymptomatic hyponatremia. This is the third report of a female proband with NSIAD and is the first female reported who sought medical treatment for chronic symptoms from adulthood. This case acts as a reminder of the importance of considering NSIAD as a diagnosis in females of all ages with unexplained hyponatremia.

Published
2018
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3. Corrigendum to ‘Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes’ [Surgery 171 (2021) 77–87]

Author

Omair A. Shariq, Kate E. Lines, Katherine A. English, Bahram Jafar-Mohammadi, Philippa Prentice, Ruth Casey, Benjamin G. Challis, Andreas Selberherr, Hannah Boon, Treena Cranston, Fiona J. Ryan, Radu Mihai, Ultan Healy, Tom Kurzawinski, Mehul T. Dattani, Irina Bancos, Benzon M. Dy, Melanie L. Lyden, William F. Young, Travis J. McKenzie, Duncan Richards, and Rajesh V. Thakker

Subjects
Surgery
Published
2022

4. UK recommendations forSDHAgermline genetic testing and surveillance in clinical practice

Author

Helen Hanson, Miranda Durkie, Fiona Lalloo, Louise Izatt, Terri P McVeigh, Jackie A Cook, Carole Brewer, James Drummond, Samantha Butler, Treena Cranston, Ruth Casey, Tricia Tan, Daniel Morganstein, Diana M Eccles, Marc Tischkowitz, Clare Turnbull, Emma Roisin Woodward, and Eamonn R Maher

Subjects
Genetics, Genetics (clinical)
Abstract

SDHApathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. MostSDHAPGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies ofSDHAPGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance forSDHAPGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely moreSDHAPGV carriers will be identified in patients with tumours not strongly associated withSDHA,or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expertSDHAworking group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management ofSDHAPGV carriers in clinical practice.

Published
2022

5. Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study

Author

Zhigang Liu, Kaixing Le, Xin Zhou, James L Alexander, Simeng Lin, Claire Bewshea, Neil Chanchlani, Rachel Nice, Timothy J McDonald, Christopher A Lamb, Shaji Sebastian, Klaartje Kok, Charlie W Lees, Ailsa L Hart, Richard C Pollok, Rosemary J Boyton, Daniel M Altmann, Katrina M Pollock, James R Goodhand, Nicholas A Kennedy, Tariq Ahmad, Nick Powell, Madiha Islam, Nick Croft, Bessie Cipriano, Caroline Francia, Nosheen Khalid, Ashley Kingston, Irish Lee, Anouk Lehmann, Kinnari Naik, Kevin Samuels, Nicolene Plaatjies, Hafiza Khatun, Farjana Bokth, Elise Pabriaga, Rebecca Saich, Hayley Cousins, Wendy Fraser, Rachel Thomas, Matthew Brown, Benjamin White, Nikolaos Kirkineziadis, Bernadette Tilley, Pennie Porter, Rachel Bryant, Natalia Robaczewska, Rafeeq Muhammed, Rehana Bi, Catherine Cotter, Jayne Grove, Kate Hong, Ruth Howman, Monica Mitchell, Sophie Clayton, Louise Rogers, Sugrah Sultan, Melanie Rooney, Charlotte Cottrill, Salil Singh, Chris Dawe, Robert Hull, Natalie Silva, Julie Chadwick, Laura Robertson, Jonathan Manning, Lauren Finlayson, Allison Roebuck, Joy Dawson, Sunil Sonwalkar, Naomi Chambers, Matthew Robinson, Andrew Haigh, Lear Matapure, Tim Raine, Varun George, Christina Kapizioni, Konstantina Strongili, Tina Thompson, Mohamed Ahmed, Christos Kontos, Claire Dawson, Christophe Bourges, Isabella Barbutti, Megan E Gozzard, Philip Hendy, Rhian Bull, Patricia Costa, Lisa Davey, Hayley Hannington, Kribashnie Nundlall, Catarina Martins, Laura Avanzi, Jaime Carungcong, Sabrina Barr, Richard Appleby, Emma Johnson, Eathar Shakweh, Kath Phillis, Rachel Gascoyne, Amanda Crowder, Amanda Whileman, Ian London, Jenny Grounds, Emmeline Martin, Susie Pajak, Jude Price, Kathryn Cawley, Sandra Powell, Nichola Kearsley, Anjan Dhar, Ellen Brown, Amanda Cowton, Kimberley Stamp, Ben Warner, Carmel Stuart, Louise Lacey, Shanika de Silva, Clare Allcock, Philip Harvey, Lesley Jones, Elise Cooke, Jayne Slater, Dominic King, Johanne Brooks, Pearl Baker, Hannah Beadle, Carina Cruz, Debbie Potter, Joe Collum, Farzana Masters, Aashish Kumar, Samantha Coetzee, Mihaela Peiu, Becky Icke, Jill Williams, Meena Raj, Edward Gaynor, Sibongile Chadokufa, Bonita Huggett, Hamza Meghari, Sara El-Khouly, Fevronia Kiparissi, Waffa Girshab, Lynda Russell-Walker, Christopher Jackson, Sara Sidler, Andrew Claridge, Emily Fowler, Laura McCafferty, Lesley Haxton, Peter Irving, Karolina Christodoulides, Angela Clifford, Patrick Dawson, Sailish Honap, Samuel Lim, Raphael Luber, Karina Mahiouz, Susanna Meade, Parizade Raymode, Rebecca Reynolds, Anna Stanton, Sherill Tripoli, Naomi Hare, Sopuluchukwu Odukwe, Senthuran Balachandran, Emma North, Jessica North, Bria Browne, Jessica Cordle, Ella Jameson, Yih Harn Siaw, Lane Manzano, Jonathan Segal, Ibrahim Al-Bakir, Imran Khakoo, Sofiya Portukhay, Nora Thoua, Katherine Davidson, Jagrul Miah, Lisa Canclini, Alex Hall, Hassina Furreed, Christine Mitchell-Inwang, Melony Hayes, Sally Myers, Alison Talbot, Jack Turnbull, Emma Whitehead, Katie Stamp, Alison Pattinson, Verghese Mathew, Leanne Sherris, Julie Wilcox, Sankaranarayanan Ramachandran, Hayley Robertson, Angela Harvey, Lucy Hicks, Tara-Marie Byrne, Leilani Cabreros, Hannah Downing-Wood, Sophie Hunter, Mohammad Aamir Saifuddin, Hemanth Prabhudev, Sharmili Balarajah, Jan Krucznski, Kalliopi Driva, Andrea D'Mello, Parith Shah, Rocio Castro-Seoane, Hajir Ibraheim, Laura E Constable, Jonathan W Lo, Melissa Torkizadeh, Sherine K Hermangild, Helen Sutherland, Elva Wilhelmsen, Katherine Mackintosh, Ajay M Verma, Juliemol Sebastian, Mohammad Farhad Peerally, Anne-marie Guerdette, Susan Coburn, Ching Yee Novem lam, Donna Durrant, Belinda Schaefer, Solange Serna, Muhammad Shahzad, Alexandra Kent, Lee Meng Choong, Benedetta Pantaloni, Pantelis Ravdas, Babu Vadamalayan, Stephen Foley, Becky Arnold, Cheryl Heeley, Wayne Lovegrove, Donna Sowton, Lynne Allsop, Heidi Gregory, Mandy Gill, Megan Holmes, Valeria Balan, Susan Smith, Sarah Turner, Philip J Smith, Alan Steel, Giovanna Bretland, Sarah King, Martina Lofthouse, Lindsey Rigby, Sreedhar Subramanian, David Tyrer, Kate Martin, Christopher Probert, Nikolaos Kamperidis, Temi Adedoyin, Manisha Baden, Jeannette Brown, Feba Chacko, Lisa Young, Michela Cicchetti, Mohammad Saifuddin, Priya Yesupatham, Rohit Gowda, Maureen Williams, Karen Kemp, Rima Akhand, Glaxy Gray, Anu John, Maya John, Tasnim Mohammed, Diamond Sathe, Natasha Jones, Jennifer Soren, Michael Sprakes, Julie Burton, Patricia Kane, Stephanie Lupton, Jacqueline Bartholomew, Elizabeth Denis, Alison Daniels, George MacFaul, Diane Scaletta, Loria Siamia, Felicity Williams, Chloe Green, Zeljka Ver, Chris Lamb, Mary Doona, Ashleigh Hogg, Lesley Jeffrey, Andrew King, R Alexander Speight, Jennifer Doyle, Ruth Owen, Jenny Haworth, Linda Patterson, Vithusa Varnaulasingam, Craig Mowat, Debbie Rice, Susan MacFarlane, Anne MacLeod, Samera Mohammed, Shona Murray, Anne Elliott, Mary Anne Morris, Louise Coke, Grace Hindle, Eirini Kolokouri, Catherine Wright, Claire Lee, Nicola Ward, Adele Dann, Melanie Lockett, Charlotte Cranfield, Louise Jennings, Ankur Srivastava, Lana Ward, Nouf Jeynes, Poonam Ranga, Praveen Rajasekhar, Lisa Gallagher, Jill Ward, Rae Basnett, Judy Murphy, Lauren Parking, Emma Lawson, Stacey Short, David Devadason, Gordon Moran, Neelam Khan, Lauren Tarr, Charmaine Olivia, Samantha Warbarton, Sian Kelly, Jimmy Limdi, Kay Goulden, Asad Javed, Lauren McKenzie, Julie Melville, Eleanor Liu, Joseph Sabine, Patricia Jacob, Denise McSorland, Nick Schofield, Lisa Cornwall, James Quirke, Emma Crook, Anne Turner, Pradeep Bhandari, Michelle Baker-Moffatt, Joanne Dash, Alison Le Poidevin, Hayley Downe, Lucille Bombeo, Helen Blackman, Rebecca Smith, Alan Wiles, Hannah Bloxham, Jose Dias, Evelyn Nadar, Hollie Curgenven, Ellie Gilham, Jonathan Macdonald, Shona Finan, Faye McMeeken, Misbah Mahmood, Stephanie Shields, John Paul Seenan, Des DeSilva, Susanna Malkakorpi, Rachel Carson, Holly Lawrence, Ofori Boateng, Felix Kpodo, Simon Whiteoak, Kelli Edger-Earley, Luke Vamplew, Joanna Samways, Sue Roffe, Sarah Ingram, Joel James, Sharon Botfield, Fiona Hammonds, Clare James, Zoe Berry, Gemma Aspinall, Sarah Hawkins, Marian Parkinson, Helen Gardner-Thorpe, Suzie Marriott, Clare Redstone, Halina Windak, Ana-Marie Adam, Hannah Mabb, Emma Stevenson, Jessica Record, Charles Murray, Cynthia Diaba, Fexy Joseph, Glykeria Pakou, Yvonne Gleeson, Annalyn Nunag, James Berrill, Natalie Stroud, Carla Pothecary, Lisa Roche, Keri Turner, Lisa Deering, Lynda Israel, Evelyn Baker, Maxine Nash, Andrew Fagbemi, Felicia Jennings, Imelda Mayor, Jill Wilson, Alice Wheeler, Nicola Phillips, John Gordon, Emma Levell, Silvia Zagalo, Ina Hoad, Bindu Anil, Richard Russell, Paul Henderson, Margaret Millar, Christopher Alexakis, Natalia Michalak, Cheryl Marriott, Sarah Stone, Veronika Pristopan, John Saunders, Helen Burton, Vanessa Cambridge, Tonia Clark, Charlotte Ekblad, Sarah Hierons, Joyce Katebe, Emma Saunsbury, Rachel Perry, Matthew Brookes, Kathryn Davies, Marie Green, Ann Plumbe, Clare Ormerod, Helen Christensen, Hannah Howlett, Anne Keen, Jonathan Ogor, Marie Greenhaigh, Karen Knowles, Shanzi Yin, Maria Poulaka, Alpha Anthony, Emily Newitt, Fiona Trim, Ruth Casey, Katherine Seymour, Catherine Reed, Lijo Joy, Edward Fogden, Kalisha Russell, Samia Hussain, Anne Phillips, Muaad Abdulla, Jeff Butterworth, Colene Adams, Mandy Carnahan, Elizabeth Buckingham, Danielle Childs, Alison Magness, Jo Stickley, Nichola Motherwell, Louise Tonks, Hannah Gibson, Kate Wistance, Caradog Thomas, Elaine Brinkworth, Lynda Connor, Amanda Cook, Tabitha Rees, Rachel Harford, Sean Farley, Marie Jones, Emma Wesley, Alison Moss, Jacob Lucas, Claire Lorimer, Maria Oleary, Maxine Dixon, Fiona Goodchild, Rebecca Twenlow, Corinne Pawley, Arvind Ramadas, Julie Tregonning, Olaku Okeke, Wendy Jackson, Ioannis Koumoutsos, Viji George, Swapna Kunhunny, Sophie Laverick, Isla Anderson, Sophie Smith, Joan Joyce, Sarala Janarthan, Kamal Patel, Mariam Ali, Hilda Mhandu, Aleem Rana, Katherine Spears, Joana Teixeira, Mark Mencias, Abigail Seaward, Jessica Sousa, Nooria Said, Mark Soomaroo, Valentina Raspa, Asha Tacouri, Nicholas Reps, Rebecca Martin, Tinashe Samakomva, Christian Selinger, Jenelyn Carbonell, Felicia Onovira, Doris Quartey, Alice L'Anson, Andrew Ashworth, Jessica Bailey, Angie Dunn, Gjuzel Bespaloi, Harold Rasalan, Zahid Mahmood, Racheal Campbell, Liane Marsh, Tricia Coughlan, Wisam Jafar, Janet Marrs, Christopher McPheat, Monira Rahman, Sarah Davies, Ruth Habibi, Ellen Jessup-Dunton, Teishel Joefield, Reina Layug, Vinod Patel, Joanne Vere, Victoria Turner, Susan Kilroy, Martina Coulding, Martyn Clark, Jacqueline McCormick, Attiya Nisar, Gareth Walker, Stacey Atkins, Jasmine Growdon, Becky George, Charlotte McNeill, Bryony Reed, Angela Foulds, Catherine Marshall, Michele Allison, Briony Dillon, Rachel Cooney, Lillie Bennett, Louise Bowlas, Sharafaath Shariff, Aileen Fraser, Dwayne Punnette, Rebecca Lambert, Charlotte Bishop-Hurman, Elizabeth Undrell, Katherine Belfield, Said Din, Catherine Addleton, Marie Appleby, Johanna Brown, Kathleen Holding, Catherine Fraser, Janice Birkenshaw, Jodie Williams, Kamille Maulion, Meg Lane, Arita Kravale, Claud Smith, Patricia Hooper, John deCaestecker, Olivia Watchorn, Ellie Clarke, Chris Hayward, Susan Inniss, Lucy Pritchard, Karen Rudge, Amanda Carney, Sarah Griffee, Jervoise Andreyev, Sathish Babu, Caroline Hayhurst, Carol Lockwood, Lynn Osborne, Amanda Roper, Karen Warner, Julia Hindle, Tara Lawrence, Kimberley Netherton, Caroline Watt, Kinga Szymiczek, Shameer Mehta, James Bell, William Blad, Lisa Whitley, Roman Jastrub, Dhamaraj Durai, Mark Baker, Elizabeth John Sivamurugan, Mim Evans, Fraser Cummings, Clare Harris, Amy Jones, Liga Krauze, Sohail Rahmany, Michelle Earl, Jenny Vowles, Audrey Torokwa, Mirela Petrova, Andrew Procter, Jo Stanley, Claudia Silvamoniz, Marion Bettey, Amar Wahid, Zoe Morrison, Rhian Thomas-Turner, Louise Yendle, Jennifer Muller, Marcus Mitchell, John Kirkwood, Anna Barnes, Rakesh Chaudhary, Melanie Claridge, Chiara Ellis, Cheryl Kemp, Ogwa Tobi, Jentus Milton, Emma Johnston, Metod Oblak, Carmen Winpenny, Marie-Louise Svensson, Jo Godden, Marium Ashhar, Debbie Alexander, Kate Covil, Lauranne Derikx, Sryros Siakavellas, Helen Baxter, Scott Robertson, Linda Smith, Beena Poulose, Anne Colemam, Margareta Balint, Gareth Rhys-Jones, Helen Watters, Susan Begg, Beatriz Grosalcalde, Judy Coyle, Kerrie Johns, Rachel Hughes, Janet Phipps, Abigail Taylor, Catherine MacPhee, Suzanne Brooks, Jolene John, Michelle Edwards, Katie Smith, Linda Howard, Dianne Wood, Ajay Muddu, Laura Barman, Janine Mallinson, Tania Neale, Diana Ionita, Kerry Elliot, Alison Turnball, Iola Thomas, Alice Thomas, Kelly Andrews, Jonathon Sutton, Caroline Mulvaney Jones, Julia Roberts, and Jeannie Bishop

Subjects
Hepatology, Gastroenterology, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract

Contains fulltext : 291657.pdf (Publisher’s version ) (Open Access) BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p

Published
2023

12. 4DCT as first line imaging during Covid pandeminc

Author

Katerina Karamali, Eniola Salau, Tilak Das, Daniel Scoffings, Ruth Casey, Liam Masterson, and Brian Fish

Subjects
Surgery
Abstract

Aim The Covid-19 pandemic encouraged prompt modification to clinical practice to minimise hospital attendances in an aim to minimize exposure and protection of the NHS whilst maintaining the standards of patient care. Current literature advocates that Four-Dimensional Computerised Tomography (4DCT) has equal diagnostic value as ultrasound alone or a combination of ultrasound and Sestamibi scan in the identification of abnormal parathyroid glands in the work up for surgical management of hyperparathyroidism. In response to the evolving pandemic at Addenbrookes we modified our practice and escalated 4DCT as our first line imaging. In light of this we had a unique opportunity to evaluate the diagnostic value of the currently used imaging modalities. Methods This is a retrospective study of 270 parathyroidectomies who underwent pre-operative 4DCT (n=270), ultrasound (n= 254) and sestamibi scan (n=253). Subsequently, we assessed the accuracy of these three modalities with the of intra-operative findings, histology, post-operative calcium and PTH. Results The sensitivity of the 4DCT was 77% in comparison to 43% sensitivity of the ultrasound alone. (p>0.05). The combined sensitivity of ultrasound and Sestamibi scan was found to be 69%. Conclusion The implementation of 4DCT as a single modality diagnostic imaging can be considered equally effective and accurate in the diagnosis of parathyroid abnormality. Implementing this would reduce the number of diagnostic tests improving the likelihood of successful operative planning and reduce financial cost.

Published
2022

13. UK recommendations for

Author

Helen, Hanson, Miranda, Durkie, Fiona, Lalloo, Louise, Izatt, Terri P, McVeigh, Jackie A, Cook, Carole, Brewer, James, Drummond, Samantha, Butler, Treena, Cranston, Ruth, Casey, Tricia, Tan, Daniel, Morganstein, Diana M, Eccles, Marc, Tischkowitz, Clare, Turnbull, Emma Roisin, Woodward, Eamonn R, Maher, and Lucy, Side

Published
2021

14. RF19 | PSUN367 Urinary bladder Paragangliomas – A Case series

Author

Sadia Nasir, Eunice Lau, James MacFarlane, Ben Challis, Anum Sheikh, Deborah Pitfield, Helen Bolton, Arthur McPhee, William Turner, Alexandra Cloquhoun, Ines Harper, and Ruth Casey

Subjects
Endocrinology, Diabetes and Metabolism
Abstract

Introduction Paragangliomas (PGL) are rare neuroendocrine tumours and account for approximately 10% of all chromaffin tumours. They may occur in the retroperitoneum, mediastinum, skull and the urinary bladder. Paragangliomas of the urinary bladder are rare entities accounting for 10% of all paragangliomas and 0.06% of all bladder tumours. Approximately 10% of urinary bladder paragangliomas are malignant. Bladder paragangliomas can be either functional or non-functional. Main symptoms of functional PGLs are due to catecholamine excess with palpitations, paroxysmal hypertension during micturition, sweating and headaches. Functional bladder PGL are diagnosed on biochemical analysis. Non-functional bladder PGLs present with haematuria and are often misdiagnosed as bladder cancer as they may cystoscopically and histologically resemble a urothelial neoplasm. Clinical cases: We present a case series of 4 surgically treated patients with urinary bladder paragangliomas who presented to Cambridge University Hospital over the last 3 years. All patients were female with an age range between 21 and 44 years. All four patients had SDHB deficient tumours, and all four patients were diagnosed with a pathogenic variant in the SDHB gene. Three patients had no family history of SDHx associated neoplasia whereas one had a paternal aunt who died from a metastatic pheochromocytoma. Three patients had presented with palpitations and hypertensive episodes, one of whom experienced symptoms while micturating. Biochemical analysis revealed elevated plasma normetadrenaline levels in all patients. On presentations, one patient had a synchronous paratracheal paraganglioma while two patients had lymph node metastasis. All patients were surgically treated with two patients undergoing fertility preserving cystectomy and bladder substitution, one undergoing partial cystectomy, radical hysterectomy and ureteric implantation and one managed with robot-assisted partial cystectomy. None of the patients have evidence of biochemical or radiological tumour recurrence on follow-up with a mean follow-up time of 23 months (range 12 to 40 months). Conclusion and points for discussion The diagnosis of urinary bladder PGL is challenging. Biochemical assessment to assess catecholamine production and imaging studies like CT, MRI and NM Ga68 DOTATATE PET CT are helpful modalities in diagnosis. Patients presenting with extra adrenal paragangliomas including bladder paragangliomas require genetic testing because of the strong hereditary predisposition, with mutations in the SDHx genes being most common with this clinical phenotype. The surgical approach should be tailored to the individual patient, agreed by a multi-disciplinary team and the risk of malignancy should be weighed against the potential morbidity associated with a curative oncological surgery. As urinary bladder PGLs have malignant potential and are frequently hereditary (as demonstrated in this series), lifelong follow-up is required to screen for synchronous tumours and tumour recurrence. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m.

Published
2022

15. Endocrine and metabolic complications of advanced cancer

Author

Richella Ryan and Ruth Casey

Subjects
endocrine system diseases
Abstract

This chapter reviews the epidemiology, pathogenesis, clinical features, and management of endocrine and metabolic complications of advanced cancer. Broadly, these complications may arise in three ways due to (1) direct tumour invasion of organs or tissues; (2) non-metastatic systemic effects resulting from secretion of hormones, cytokines, or growth factors either by the tumour itself or by normal cells in response to tumour invasion (‘paraneoplastic effects’); and (3) treatments targeted at cancer or its symptoms. The chapter is divided into four sections. First, it describes the three most common endocrine manifestations of advanced cancer, including hypercalcaemia, Cushing’s syndrome, and syndrome of inappropriate antidiuresis. Second, it discusses the endocrine manifestations resulting from rare but important secretory endocrine tumours, including hypoglycaemia secondary to islet-cell and non-islet cell tumours, enteropancreatic hormone syndromes, carcinoid syndrome, phaeochromocytoma, adrenocortical carcinoma, and medullary thyroid carcinoma. Third, it briefly describes miscellaneous rare endocrine manifestations of cancer, including gynaecomastia, hypo- and hyperthyroidism, hypothalamic–pituitary dysfunction, and adrenal insufficiency. Finally, it concludes with a brief discussion of metabolic complications that may arise in association with malignancy, including paraneoplastic pyrexia, hyperglycaemia, and metabolic bone disease. Renal failure and hepatic failure are dealt with separately in the volume.

Published
2021

16. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences

Subjects
0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Published
2020

21. Genetic testing in hyperparathyroidism - who to test and why

Author

Edward Thompson, Katrina A. Andrews, Ruth Casey, Ruth Armstrong, Helen Simpson, Sashi Mariathasan, and Soo-Mi Park

Subjects
Hyperparathyroidism, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Medicine, business, medicine.disease, Genetic testing, Test (assessment)
Published
2019

23. Breast cancer in MEN1: coincidence or association?

Author

Olivier Giger, Soo-Mi Park, Deborah Pitfield, Jose Ezequiel Martin, Seong Keat Cheah, Craig Parkinson, Ruth Casey, Chad Bisambar, Bejamin Challis, Rogier ten Hoopen, and Graeme R Clark

Subjects
Oncology, medicine.medical_specialty, Breast cancer, business.industry, Internal medicine, Association (object-oriented programming), Medicine, MEN1, business, medicine.disease, Coincidence
Published
2019

24. Genetic testing for hereditary hyperparathyroidism in a large UK cohort

Author

Ruth Casey, Soo-Mi Park, Katrina A. Andrews, Sashi Mariathasan, Ruth Armstrong, and Edward Thompson

Subjects
Pediatrics, medicine.medical_specialty, Hyperparathyroidism, medicine.diagnostic_test, business.industry, Cohort, medicine, medicine.disease, business, Genetic testing
Published
2019

26. New types of localization methods for adrenocorticotropic hormone-dependent Cushing’s syndrome

Author

Russell Senanayake, Waiel Bashari, Daniel Gillett, Olympia Koulouri, Andrew S. Powlson, Merel Van de Meulen, Ruth Casey, James MacFarlane, and Mark Gurnell

Subjects
Adenoma, Diagnostic Imaging, 0301 basic medicine, Pathology, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Adrenocorticotropic hormone, Diagnosis, Differential, Diagnostic Techniques, Endocrine, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Adrenocorticotropic Hormone, Inventions, Pituitary adenoma, medicine, Humans, Pituitary ACTH Hypersecretion, Cushing Syndrome, medicine.diagnostic_test, business.industry, Inferior petrosal sinus, Magnetic resonance imaging, Cushing's disease, medicine.disease, Magnetic Resonance Imaging, Functional imaging, ACTH Syndrome, Ectopic, ACTH-Secreting Pituitary Adenoma, 030104 developmental biology, Positron emission tomography, Pituitary Gland, Positron-Emission Tomography, Corticotropic cell, business
Abstract

The management of endogenous Cushing's syndrome (CS) typically involves two key steps: (i) confirmation of autonomous hypercortisolism and (ii) localization of the cause to guide treatment. Adrenocorticotropic hormone (ACTH)-dependent CS is most commonly due to a pituitary corticotrope tumor which may be so small as to evade detection on conventional magnetic resonance imaging (MRI). Although biochemical testing (e.g., corticotropin stimulation; dexamethasone suppression) can provide an indication of the likely origin of ACTH excess, bilateral inferior petrosal sinus catheterization offers greater accuracy to distinguish pituitary-driven CS [Cushing's Disease (CD)] from the ectopic ACTH syndrome [EAS, e.g., due to a bronchial or pancreatic neuroendocrine tumor (NET)]. In patients with CD, 40-50% may not have a pituitary adenoma (PA) readily visualized on standard clinical MRI. In these subjects, alternative MR sequences (e.g., dynamic, volumetric, fluid attenuation inversion recovery) and higher magnetic field strength (7T > 3T > 1.5T) may aid tumor localization but carry a risk of identifying coincidental (non-causative) pituitary lesions. Molecular imaging is therefore increasingly being deployed to detect small ACTH-secreting PA, with hybrid imaging [e.g., positron emission tomography (PET) combined with MRI] allowing precise anatomical localization of sites of radiotracer (e.g., 11C-methionine) uptake. Similarly, small ACTH-secreting NETs, missed on initial cross-sectional imaging, may be detected using PET tracers targeting abnormal glucose metabolism (e.g., 18F-fluorodeoxyglucose), somatostatin receptor (SSTR) expression (e.g., 68Ga-DOTATATE), amine precursor (e.g., 18F-DOPA) or amino acid (e.g., 11C-methionine) uptake. Therefore, modern management of ACTH-dependent CS should ideally be undertaken in specialist centers which have an array of cross-sectional and functional imaging techniques at their disposal.

Published
2021

27. The Rise of Calcium and Control of its Fall

Author

Ruth Casey, Larissa Higgins, and Tara Tarmey

Subjects
medicine.medical_specialty, Endocrinology, chemistry, business.industry, Internal medicine, medicine, chemistry.chemical_element, Calcium, business
Published
2016

31. Activating mutation in the arginine vasopressin receptor AVPR2 resulting in nephrogenic syndrome of inappropriate antidiuresis in a female

Author

Mark Gurnell, Andrew S Powlson, Ruth Casey, Mohamed Ashif Majeed, Helen Simpson, Sue Oddy, Julia Hale, Jennifer Hague, and Soo-Mi Park

Subjects
Arginine vasopressin receptor 1B, medicine.medical_specialty, Endocrinology, Chemistry, Internal medicine, Arginine vasopressin receptor 2, Arginine Vasopressin Receptor, medicine, Activating mutation
Published
2017

32. The role of in vivo metabolomics using H-MRS in SDH deficient disease

Author

Helen Simpson, Madhu Bassetti, Ferdia Gallagher, Krishna Chatterjee, Ruth Casey, Eamonn R. Maher, Alison Marker, Olivier Giger, Kieran Allinson, Mary A. McLean, Ben Challis, Ramesh Bulusu, and Mark Gurnell

Subjects
Metabolomics, Biochemistry, In vivo, business.industry, Medicine, Disease, business
Published
2017

33. The effect of peptide receptor radionuclide therapy (PRRT) on symptoms and tumour burden in patients with metastatic neuroendocrine tumour (NET)

Author

John R. Buscombe, Helen Simpson, Sarah Heard, Ashley Shaw, Stalin Abraham, Ruth Casey, Zia Saad, Deborah Pitfield, Ben Challis, and Siobhan Whitley

Subjects
Oncology, medicine.medical_specialty, Pathology, Peptide receptor, business.industry, Internal medicine, Radionuclide therapy, medicine, In patient, business, Neuroendocrine tumour
Published
2016

35. Is there an optimal preoperative management strategy for phaeochromocytoma/paraganglioma?

Author

Mark Gurnell, Ruth Casey, Helen Simpson, and Benjamin G. Challis

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, MEDLINE, Pheochromocytoma, Preoperative care, Paraganglioma, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Postoperative Complications, Internal medicine, Preoperative Care, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Stroke, Adrenergic alpha-Antagonists, business.industry, medicine.disease, Blockade, Management strategy, 030220 oncology & carcinogenesis, business
Abstract

Phaeochromocytomas and paragangliomas (PPGLs) are catecholamine secreting neuroendocrine tumours that predispose to haemodynamic instability. Currently, surgery is the only available curative treatment, but carries potential risks including hypertensive and hypotensive crises, cardiac arrhythmias, myocardial infarction and stroke, due to tumoral release of catecholamines during anaesthetic induction and tumour manipulation. The mortality associated with surgical resection of PPGL has significantly improved from 20-45% in the early 20th century (Apgar & Papper, AMA Archives of Surgery, 1951, 62, 634) to 0-2·9% in the early 21st century (Kinney et al. Journal of Cardiothoracic and Vascular Anesthesia, 2002, 16, 359), largely due to availability of effective pharmacological agents and advances in surgical and anaesthetic practice. However, surgical resection of PPGL still poses significant clinical management challenges. Preoperatively, alpha-adrenoceptor blockade is the mainstay of management, although various pharmacological strategies have been proposed, based largely on reports derived from retrospective data sets. To date, no consensus has been reached regarding the 'ideal' preoperative strategy due, in part, to a paucity of data from high-quality evidence-based studies comparing different treatment regimens. Here, based on the available literature, we address the Clinical Question: Is there an optimal preoperative management strategy for PPGL?

Published
2016

37. Clinical and biochemical outcomes during pregnancy in patients with acromegaly

Author

Triona O'Shea, Saket Guptha, Audrey Melvin, Karen McGurran, Ruth Casey, Donal O'Halloran, James Gibney, Christopher Thompson, and Mark Sherlock

Subjects
medicine.medical_specialty, Pediatrics, Pregnancy, Endocrinology, business.industry, Internal medicine, Acromegaly, medicine, In patient, medicine.disease, business
Published
2015

38. Hypercalcaemia; a silent indolent course?

Author

Ruth Casey, Conal Dennedy, Aoife Lowery, Larissa Higgins, and Michael J. Kerin

Subjects
Pediatrics, medicine.medical_specialty, Hypercalcaemia, business.industry, Medicine, business, medicine.disease
Published
2015

40. First reported case in Ireland of MEN2A due to a rare mutation in exon 8 of the RET oncogene

Author

Domhnall J O'Halloran, Caroline Joyce, Susan Prendeville, and Ruth Casey

Subjects
Genetics, endocrine system, Insight into Disease Pathogenesis or Mechanism of Therapy, Mutation, endocrine system diseases, business.industry, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Thyroidectomy, Gene mutation, Hyperplasia, medicine.disease, medicine.disease_cause, Genetic analysis, Exon, C-Cell Hyperplasia, Internal Medicine, medicine, business, Genetic screen
Abstract

Summary We present the case of a 30-year-old female who was diagnosed with hereditary phaeochromocytoma secondary to a rare gene mutation in exon 8 of the RET oncogene. This genetic mutation was picked up as part of an extended genetic screen using a method known as next generation sequencing. Detection of this genetic mutation prompted further screening for the manifestation of multiple endocrine neoplasia type 2A (MEN2A). The patient subsequently underwent a thyroidectomy with histology confirming C-cell hyperplasia. Learning points Genetic analysis is an important step in the diagnostic work up of phaeochromocytoma. Extended genetic analysis is important when there is a strong suspicion of hereditary phaeochromocytoma. Mutations in exon 8 of the RET gene are associated with phaeochromocytoma as part of MEN2A syndrome.

Published
2013

44. SDHB gene positive metastatic paraganglioma associated with lesions which demonstrate both positive and negative uptake of 18FDG PET and 131MIBG

Author

Michael Moore, Susan Prendeville, Domhnall J O'Halloran, Ruth Casey, Michael M. Maher, and David Slattery

Subjects
Male, medicine.medical_specialty, Genotype, SDHB, Bone Neoplasms, Disease, Gene mutation, Inflammatory bowel disease, Paraganglioma, Fluorodeoxyglucose F18, medicine, Humans, Pelvis, business.industry, Sacroiliitis, General Medicine, Gold standard (test), medicine.disease, Succinate Dehydrogenase, 3-Iodobenzylguanidine, medicine.anatomical_structure, Positron-Emission Tomography, Radiology, Radiopharmaceuticals, business, Ireland
Abstract

Learning Points for Clinicians Paragangliomas are rare caetacholamine secreting neuroendocrine tumours. The diagnosis and management of these tumours is often difficult, particularly as a diagnosis of metastases is often made retrospectively when disease recurrence occurs. In recent years, the role of genotyping has allowed us to better predict which tumours are more likely to be metastatic. Mutations in the SDHB gene have been associated with higher rates of metastatic disease.1 Unfortunately, mutations in this gene can also lower the sensitivity of radiolabeled metaiodobenzylguanidine (MIBG). MIBG scanning is considered the gold standard imaging modality for the diagnosis of recurrent disease but this case illustrates the potential diagnostic pitfalls associated with this imaging modality in cases of SDHB gene mutations. The case demonstrates the importance of genotyping as a diagnostic and predictive tool and the importance of clinical acumen in the face of negative test results. This gentleman underwent a MRI of pelvis in February 2011 for investigation of possible sacroiliitis on a background of known inflammatory bowel disease. This MRI demonstrated a 2.3 × 2.3 cm nodule posterior to the pubic …

Published
2013

49. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19

Author

Angus, Derek, Derde, Lennie, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen, de Jong, Menno, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Higgins, Alisa, Horvat, Christopher, Hullegie, Sebastiaan, Kruger, Peter, Lamontagne, Francois, Lawler, Patrick, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, Mcauley, Daniel, Mcglothin, Anna, Mcguinness, Shay, Mcverry, Bryan, Montgomery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Rowan, Kathryn, Sanil, Ashish, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Turner, Anne, van de Veerdonk, Frank, Venkatesh, Balasubramanian, Zarychanski, Ryan, Berry, Scott, Lewis, Roger, Mcarthur, Colin, Webb, Steven, Gordon, Anthony, NIHR, Hôpital Raymond Poincaré [AP-HP], Writing Committee for the REMAP-CAP Investigators, Farah Al-Beidh, Derek Angus, Djillali Annane, Yaseen Arabi, Wilma van Bentum-Puijk, Scott Berry, Abigail Beane, Zahra Bhimani, Marc Bonten, Charlotte Bradbury, Frank Brunkhorst, Meredith Buxton, Allen Cheng, Menno De Jong, Lennie Derde, Lise Estcourt, Herman Goossens, Anthony Gordon, Cameron Green, Rashan Haniffa, Francois Lamontagne, Patrick Lawler, Edward Litton, John Marshall, Colin McArthur, Daniel McAuley, Shay McGuinness, Bryan McVerry, Stephanie Montgomery, Paul Mouncey, Srinivas Murthy, Alistair Nichol, Rachael Parke, Kathryn Rowan, Christopher Seymour, Anne Turner, Frank van de Veerdonk, Steve Webb, Ryan Zarychanski, Lewis Campbell, Andrew Forbes, David Gattas, Stephane Heritier, Lisa Higgins, Peter Kruger, Sandra Peake, Jeffrey Presneill, Ian Seppelt, Tony Trapani, Paul Young, Sean Bagshaw, Nick Daneman, Niall Ferguson, Cheryl Misak, Marlene Santos, Sebastiaan Hullegie, Mathias Pletz, Gernot Rohde, Kathy Rowan, Brian Alexander, Kim Basile, Timothy Girard, Christopher Horvat, David Huang, Kelsey Linstrum, Jennifer Vates, Richard Beasley, Robert Fowler, Steve McGloughlin, Susan Morpeth, David Paterson, Bala Venkatesh, Tim Uyeki, Kenneth Baillie, Eamon Duffy, Rob Fowler, Thomas Hills, Katrina Orr, Asad Patanwala, Steve Tong, Mihai Netea, Shilesh Bihari, Marc Carrier, Dean Fergusson, Ewan Goligher, Ghady Haidar, Beverley Hunt, Anand Kumar, Mike Laffan, Patrick Lawless, Sylvain Lother, Peter McCallum, Saskia Middeldopr, Zoe McQuilten, Matthew Neal, John Pasi, Roger Schutgens, Simon Stanworth, Alexis Turgeon, Alexandra Weissman, Neill Adhikari, Matthew Anstey, Emily Brant, Angelique de Man, Francois Lamonagne, Marie-Helene Masse, Andrew Udy, Donald Arnold, Phillipe Begin, Richard Charlewood, Michael Chasse, Mark Coyne, Jamie Cooper, James Daly, Iain Gosbell, Heli Harvala-Simmonds, Tom Hills, Sheila MacLennan, David Menon, John McDyer, Nicole Pridee, David Roberts, Manu Shankar-Hari, Helen 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Marroquin, Edvin Music, Kevin Quinn, Heidi Cate, Karen Pearson, Joanne Collins, Jane Hanson, Penny Williams, Shane Jackson, Adeeba Asghar, Sarah Dyas, Mihaela Sutu, Sheenagh Murphy, Dawn Williamson, Nhlanhla Mguni, Alison Potter, David Porter, Jayne Goodwin, Clare Rook, Susie Harrison, Hannah Williams, Hilary Campbell, Kaatje Lomme, James Williamson, Jonathan Sheffield, Willian van’t Hoff, Phobe McCracken, Meredith Young, Jasmin Board, Emma Mart, Cameron Knott, Julie Smith, Catherine Boschert, Julia Affleck, Mahesh Ramanan, Ramsy D’Souza, Kelsey Pateman, Arif Shakih, Winston Cheung, Mark Kol, Helen Wong, Asim Shah, Atul Wagh, Joanne Simpson, Graeme Duke, Peter Chan, Brittney Cartner, Stephanie Hunter, Russell Laver, Tapaswi Shrestha, Adrian Regli, Annamaria Pellicano, James McCullough, Mandy Tallott, Nikhil Kumar, Rakshit Panwar, Gail Brinkerhoff, Cassandra Koppen, Federica Cazzola, Matthew Brain, Sarah Mineall, Roy Fischer, Vishwanath Biradar, Natalie Soar, Hayden White, Kristen 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Francia, Stephen Brett, Sonia Sousa Arias, Rebecca Elin Hall, Joanna Budd, Charlotte Small, Janine Birch, Emma Collins, Jeremy Henning, Stephen Bonner, Keith Hugill, Emanuel Cirstea, Dean Wilkinson, Michal Karlikowski, Helen Sutherland, Elva Wilhelmsen, Jane Woods, Julie North, Dhinesh Sundaran, Laszlo Hollos, Susan Coburn, Joanne Walsh, Margaret Turns, Phil Hopkins, John Smith, Harriet Noble, Maria Theresa Depante, Emma Clarey, Shondipon Laha, Mark Verlander, Alexandra Williams, Abby Huckle, Andrew Hall, Jill Cooke, Caroline Gardiner-Hill, Carolyn Maloney, Hafiz Qureshi, Neil Flint, Sarah Nicholson, Sara Southin, Andrew Nicholson, Barbara Borgatta, Ian Turner-Bone, Amie Reddy, Laura Wilding, Loku Chamara Warnapura, Ronan Agno Sathianathan, David Golden, Ciaran Hart, Jo Jones, Jonathan Bannard-Smith, Joanne Henry, Katie Birchall, Fiona Pomeroy, Rachael Quayle, Arystarch Makowski, Beata Misztal, Iram Ahmed, Thyra KyereDiabour, Kevin Naiker, Richard Stewart, Esther Mwaura, Louise Mew, 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David Shaw, Zudin Puthucheary, Timothy Martin, Filipa Santos, Ruzena Uddin, Alastair Somerville, Kate Colette Tatham, Shaman Jhanji, Ethel Black, Arnold Dela Rosa, Ryan Howle, Redmond Tully, Andrew Drummond, Joy Dearden, Jennifer Philbin, Sheila Munt, Alain Vuylsteke, Charles Chan, Saji Victor, Ramprasad Matsa, Minerva Gellamucho, Ben Creagh-Brown, Joe Tooley, Laura Montague, Fiona De Beaux, Laetitia Bullman, Ian Kersiake, Carrie Demetriou, Sarah Mitchard, Lidia Ramos, Katie White, Phil Donnison, Maggie Johns, Ruth Casey, Lehentha Mattocks, Sarah Salisbury, Paul Dark, Andrew Claxton, Danielle McLachlan, Kathryn Slevin, Stephanie Lee, Jonathan Hulme, Sibet Joseph, Fiona Kinney, Ho Jan Senya, Aneta Oborska, Abdul Kayani, Bernard Hadebe, Rajalakshmi Orath Prabakaran, Lesley Nichols, Matt Thomas, Ruth Worner, Beverley Faulkner, Emma Gendall, Kati Hayes, Colin Hamilton-Davies, Carmen Chan, Celina Mfuko, Hakam Abbass, Vineela Mandadapu, Susannah Leaver, Daniel Forton, Kamal Patel, Elankumaran Paramasivam, Matthew Powell, Richard Gould, Elizabeth Wilby, Clare Howcroft, Dorota Banach, Ziortza Fernández de Pinedo Artaraz, Leilani Cabreros, Ian White, Maria Croft, Nicky Holland, Rita Pereira, Ahmed Zaki, David Johnson, Matthew Jackson, Hywel Garrard, Vera Juhaz, Alistair Roy, Anthony Rostron, Lindsey Woods, Sarah Cornell, Suresh Pillai, Rachel Harford, Tabitha Rees, Helen Ivatt, Ajay Sundara Raman, Miriam Davey, Kelvin Lee, Russell Barber, Manish Chablani, Farooq Brohi, Vijay Jagannathan, Michele Clark, Sarah Purvis, Bill Wetherill, Ahilanandan Dushianthan, Rebecca Cusack, Kim de Courcy-Golder, Simon Smith, Susan Jackson, Ben Attwood, Penny Parsons, Valerie Page, Xiao Bei Zhao, Deepali Oza, Jonathan Rhodes, Tom Anderson, Sheila Morris, Charlotte Xia Le Tai, Amy Thomas, Alexandra Keen, Stephen Digby, Nicholas Cowley, Laura Wild, David Southern, Harsha Reddy, Andy Campbell, Claire Watkins, Sara Smuts, Omar Touma, Nicky Barnes, Peter Alexander, Tim Felton, Susan Ferguson, Katharine Sellers, Joanne Bradley-Potts, David Yates, Isobel Birkinshaw, Kay Kell, Nicola Marshall, Lisa Carr-Knott, Charlotte Summers, and Mégarbane, Bruno

Subjects
[SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, General Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Writing Committee for the REMAP-CAP Investigators, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, General & Internal Medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 11 Medical and Health Sciences
Abstract

Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Published
2020

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