35 results on '"Seegobin, S."'
Search Results
2. The influence of gender and haemoglobin on TPMT activity
- Author
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KARIYAWASAM, V, WARD, M, BLAKER, P A, MOGAN, S B, KUBOTA, Y, SEEGOBIN, S, IRVING, P M, MARINAKI, A M, and SANDERSON, J D
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- 2013
3. CT-based intravenous thrombolysis for acute ischaemic stroke in people aged 80 years and older: a systematic review
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Seegobin, S
- Published
- 2013
4. Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02
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Tziotzios, C., Petridis, C., Dand, N., Ainali, C., Saklatvala, J.R., Pullabhatla, V., Onoufriadis, A., Pramanik, R., Baudry, D., Lee, S.H., Wood, K., Liu, L., Seegobin, S., Michelotti, G.A., Lwin, S.M., Christou, E.A.A., Curtis, C.J.., de Rinaldis, E., Saxena, A., Holmes, S., Harries, M., Palamaras, I., Cunningham, F., Parkins, G., Kaur, M., Farrant, P., McDonagh, A., Messenger, A., Jones, J., Jolliffe, V., Ali, I., Ardern-Jones, M., Mitchell, C., Burrows, N., Atkar, R., Banfield, C., Alexandroff, A., Champagne, C., Cooper, H.L., Vano-Galvan, S., Maria Molina-Ruiz, A., Ormaechea Perez, N., Patel, G.K., Macbeth, A., Page, M., Bryden, A., Mowbray, M., Wahie, S., Armstrong, K., Cooke, N., Goodfield, M., Man, I., de Berker, D., Dunnill, G., Takwale, A., Rao, A., Siah, T.-W., Sinclair, R., Wade, M.S., Dlova, N.C., Setterfield, J., Lewis, F., Bhargava, K., Kirkpatrick, N., Estivill, X., Stefanato, C.M., Flohr, C., Spector, T., Watt, F.M., Smith, C.H., Barker, J.N., Fenton, D.A., Simpson, M.A., and McGrath, J.A.
- Abstract
Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.
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- 2019
5. Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02
- Author
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Tziotzios, C, Petridis, C, Dand, N, Ainali, C, Saklatvala, JR, Pullabhatla, V, Onoufriadis, A, Pramanik, R, Baudry, D, Lee, SH, Wood, K, Liu, L, Seegobin, S, Michelotti, GA, Lwin, SM, Christou, EAA, Curtis, CJ, de Rinaldis, E, Saxena, A, Holmes, S, Harries, M, Palamaras, I, Cunningham, F, Parkins, G, Kaur, M, Farrant, P, McDonagh, A, Messenger, A, Jones, J, Jolliffe, V, Ali, I, Ardern-Jones, M, Mitchell, C, Burrows, N, Atkar, R, Banfield, C, Alexandroff, A, Champagne, C, Cooper, HL, Vano-Galvan, S, Maria Molina-Ruiz, A, Ormaechea Perez, N, Patel, GK, Macbeth, A, Page, M, Bryden, A, Mowbray, M, Wahie, S, Armstrong, K, Cooke, N, Goodfield, M, Man, I, de Berker, D, Dunnill, G, Takwale, A, Rao, A, Siah, T-W, Sinclair, R, Wade, MS, Dlova, NC, Setterfield, J, Lewis, F, Bhargava, K, Kirkpatrick, N, Estivill, X, Stefanato, CM, Flohr, C, Spector, T, Watt, FM, Smith, CH, Barker, JN, Fenton, DA, Simpson, MA, McGrath, JA, Tziotzios, C, Petridis, C, Dand, N, Ainali, C, Saklatvala, JR, Pullabhatla, V, Onoufriadis, A, Pramanik, R, Baudry, D, Lee, SH, Wood, K, Liu, L, Seegobin, S, Michelotti, GA, Lwin, SM, Christou, EAA, Curtis, CJ, de Rinaldis, E, Saxena, A, Holmes, S, Harries, M, Palamaras, I, Cunningham, F, Parkins, G, Kaur, M, Farrant, P, McDonagh, A, Messenger, A, Jones, J, Jolliffe, V, Ali, I, Ardern-Jones, M, Mitchell, C, Burrows, N, Atkar, R, Banfield, C, Alexandroff, A, Champagne, C, Cooper, HL, Vano-Galvan, S, Maria Molina-Ruiz, A, Ormaechea Perez, N, Patel, GK, Macbeth, A, Page, M, Bryden, A, Mowbray, M, Wahie, S, Armstrong, K, Cooke, N, Goodfield, M, Man, I, de Berker, D, Dunnill, G, Takwale, A, Rao, A, Siah, T-W, Sinclair, R, Wade, MS, Dlova, NC, Setterfield, J, Lewis, F, Bhargava, K, Kirkpatrick, N, Estivill, X, Stefanato, CM, Flohr, C, Spector, T, Watt, FM, Smith, CH, Barker, JN, Fenton, DA, Simpson, MA, and McGrath, JA
- Abstract
Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.
- Published
- 2019
6. Cannabinoids in attention-deficit/hyperactivity disorder: a randomised-controlled trial
- Author
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Cooper, R.E., primary, Williams, E., additional, Seegobin, S., additional, Tye, C., additional, Kuntsi, J., additional, and Asherson, P., additional
- Published
- 2016
- Full Text
- View/download PDF
7. P.3.031 The effects of combined delta-9-tetrahydrocannabinol and cannabidiol on neurocognitive and behavioural function in attention-deficit/hyperactivity disorder
- Author
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Cooper, R.E., primary, Williams, E., additional, Seegobin, S., additional, Tye, C., additional, and Asherson, P., additional
- Published
- 2016
- Full Text
- View/download PDF
8. PREDICTING THE RISK OF RHEUMATOID ARTHRITIS AND ITS AGE OF ONSET: MODELLING GENETIC RISK VARIANTS WITH SMOKING
- Author
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Scott, I, Steer, S, Seegobin, S, Hinks, A, Eyre, S, Morgan, A, Wilson, A, Hocking, L, Wordsworth, B, Barton, A, Worthington, J, Cope, A, and Lewis, C
- Abstract
The improved characterisation of risk factors for rheumatoid arthritis (RA) suggests they could be combined to identify individuals at increased disease risks in whom preventive strategies may be evaluated. We aimed to develop an RA prediction model capable of generating clinically relevant predictive data and to determine if it better predicted younger onset RA (YORA). Our novel modelling approach combined odds ratios for 15 four-digit/10 two-digit HLA-DRB1 alleles, 31 single nucleotide polymorphisms (SNPs) and ever-smoking status in males to determine risk using computer simulation and confidence interval based risk categorisation. Only males were evaluated in our models incorporating smoking as ever-smoking is a significant risk factor for RA in men but not women. We developed multiple models to evaluate each risk factor's impact on prediction. Each model's ability to discriminate anti-citrullinated protein antibody (ACPA)-positive RA from controls was evaluated in two cohorts: Wellcome Trust Case Control Consortium (WTCCC: 1,516 cases; 1,647 controls); UK RA Genetics Group Consortium (UKRAGG: 2,623 cases; 1,500 controls). HLA and smoking provided strongest prediction with good discrimination evidenced by an HLA-smoking model area under the curve (AUC) value of 0.813 in both WTCCC and UKRAGG. SNPs provided minimal prediction (AUC 0.660 WTCCC/0.617 UKRAGG). Whilst high individual risks were identified, with some cases having estimated lifetime risks of 86%, only a minority overall had substantially increased odds for RA. High risks from the HLA model were associated with YORA (P
- Published
- 2013
9. S.12.08 - Cannabinoids in attention-deficit/hyperactivity disorder: a randomised-controlled trial
- Author
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Cooper, R.E., Williams, E., Seegobin, S., Tye, C., Kuntsi, J., and Asherson, P.
- Published
- 2016
- Full Text
- View/download PDF
10. Basic Science * 208. Stem Cell Factor Expression is Increased in the Skin of Patients with Systemic Sclerosis and Promotes Proliferation and Migration of Fibroblasts in vitro
- Author
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Karrar, S., primary, Shiwen, X., additional, Nikotorowicz-Buniak, J., additional, Abraham, D. J., additional, Denton, C., additional, Stratton, R., additional, Bayley, R., additional, Kite, K. A., additional, Clay, E., additional, Smith, J. P., additional, Kitas, G. D., additional, Buckley, C., additional, Young, S. P., additional, Ye, L., additional, Zhang, L., additional, Goodall, J., additional, Gaston, H., additional, Xu, H., additional, Lutalo, P. M., additional, Zhao, Y., additional, Meng Choong, L., additional, Sangle, S., additional, Spencer, J., additional, D'Cruz, D., additional, Rysnik, O. J., additional, McHugh, K., additional, Bowness, P., additional, Rump-Goodrich, L., additional, Mattey, D., additional, Kehoe, O., additional, Middleton, J., additional, Cartwright, A., additional, Schmutz, C., additional, Askari, A., additional, Gardner, D. H., additional, Jeffery, L. E., additional, Raza, K., additional, Sansom, D. M., additional, Fitzpatrick, M., additional, Wallace, G., additional, Young, S., additional, Shaw, J., additional, Hatano, H., additional, Cauli, A., additional, Giles, J. L., additional, Mathieu, A., additional, Kollnberger, S., additional, Webster, S., additional, Ellis, L., additional, O'Brien, L. M., additional, Fitzmaurice, T. J., additional, Nazeer Moideen, A., additional, Evans, L., additional, Osgood, L., additional, Williams, A., additional, Jones, S., additional, Thomas, C., additional, O'Donnell, V., additional, Nowell, M., additional, Ouboussad, L., additional, Savic, S., additional, Dickie, L. J., additional, Hintze, J., additional, Wong, C. H., additional, Cook, G. P., additional, Buch, M., additional, Emery, P., additional, McDermott, M. F., additional, Hardcastle, S. A., additional, Gregson, C. L., additional, Deere, K., additional, Davey Smith, G., additional, Dieppe, P., additional, Tobias, J. H., additional, Dennison, E., additional, Edwards, M., additional, Bennett, J., additional, Coggon, D., additional, Palmer, K., additional, Cooper, C., additional, McWilliams, D., additional, Young, A., additional, Kiely, P. D., additional, Walsh, D., additional, Taylor, H. J., additional, Harding, I., additional, Hutchinson, J., additional, Nelson, I., additional, Blom, A., additional, Tobias, J., additional, Clark, E., additional, Parker, J., additional, Bukhari, M., additional, Jayakumar, K., additional, Kiely, P., additional, Diffin, J., additional, Lunt, M., additional, Marshall, T., additional, Chipping, J., additional, Symmons, D., additional, Verstappen, S., additional, Bluett, J., additional, Bowes, J., additional, Ho, P., additional, McHugh, N., additional, Buden, D., additional, Fitzgerald, O., additional, Barton, A., additional, Glossop, J. R., additional, Nixon, N. B., additional, Emes, R. D., additional, Dawes, P. T., additional, Farrell, W. E., additional, Mattey, D. L., additional, Scott, I. C., additional, Steer, S., additional, Seegobin, S., additional, Hinks, A. M., additional, Eyre, S., additional, Morgan, A., additional, Wilson, A. G., additional, Hocking, L., additional, Wordsworth, P., additional, Worthington, J., additional, Cope, A., additional, Lewis, C. M., additional, Guerra, S., additional, Ahmed, B. A., additional, Abraham, D., additional, Fonseca, C., additional, Robinson, J., additional, Taylor, J., additional, Haroon Rashid, L., additional, Flynn, E., additional, Isaacs, J., additional, Barrett, J. H., additional, Kingston, B., additional, Ahmed, M., additional, Kirwan, J. R., additional, Marshall, R., additional, Chapman, K., additional, Pearson, R., additional, Heycock, C., additional, Kelly, C., additional, Rynne, M., additional, Saravanan, V., additional, Hamilton, J., additional, Saeed, A., additional, Coughlan, R., additional, Carey, J. J., additional, Farah, Z., additional, Matthews, W., additional, Bell, C., additional, Petford, S., additional, Tibbetts, L.-M., additional, Douglas, K. M. J., additional, Holden, W., additional, Ledingham, J., additional, Fletcher, M., additional, Winfield, R., additional, Price, Z., additional, Mackay, K., additional, Dixon, C., additional, Oppong, R., additional, Jowett, S., additional, Nicholls, E., additional, Whitehurst, D., additional, Hill, S., additional, Hammond, A., additional, Hay, E., additional, Dziedzic, K., additional, Righetti, C., additional, Lebmeier, M., additional, Manning, V. L., additional, Hurley, M., additional, Scott, D. L., additional, Choy, E., additional, Bearne, L., additional, Nikiphorou, E., additional, Morris, S., additional, James, D., additional, Wong, E. C., additional, Long, J., additional, Fletcher, A., additional, Holmes, S., additional, Hockey, P., additional, Abbas, M., additional, Chattopadhyay, C., additional, Flint, J., additional, Gayed, M., additional, Schreiber, K., additional, Arthanari, S., additional, Nisar, M., additional, Khamashta, M., additional, Gordon, C., additional, Giles, I., additional, Robson, J., additional, Kiran, A., additional, Maskell, J., additional, Arden, N., additional, Hutchings, A., additional, Emin, A., additional, Culliford, D., additional, Dasgupta, B., additional, Hamilton, W., additional, Luqmani, R., additional, Jethwa, H., additional, Rowczenio, D., additional, Trojer, H., additional, Russell, T., additional, Loeffler, J., additional, Hawkins, P., additional, Lachmann, H., additional, Verma, I., additional, Syngle, A., additional, Krishan, P., additional, Garg, N., additional, McGowan, S. P., additional, Gerrard, D. T., additional, Chinoy, H., additional, Ollier, W. E., additional, Cooper, R. G., additional, Lamb, J. A., additional, Taborda, L., additional, Correia Azevedo, P., additional, Isenberg, D., additional, Leyland, K. M., additional, Judge, A., additional, Hunter, D., additional, Hart, D., additional, Javaid, M. K., additional, Edwards, M. H., additional, Litwic, A. E., additional, Jameson, K. A., additional, Deeg, D., additional, Cushnaghan, J., additional, Aihie Sayer, A., additional, Jagannath, D., additional, Parsons, C., additional, Stoppiello, L., additional, Mapp, P., additional, Ashraf, S., additional, Wilson, D., additional, Hill, R., additional, Scammell, B., additional, Wenham, C., additional, Shore, P., additional, Hodgson, R., additional, Grainger, A., additional, Aaron, J., additional, Hordon, L., additional, Conaghan, P., additional, Bar-Ziv, Y., additional, Beer, Y., additional, Ran, Y., additional, Benedict, S., additional, Halperin, N., additional, Drexler, M., additional, Mor, A., additional, Segal, G., additional, Lahad, A., additional, Haim, A., additional, Rath, U., additional, Morgensteren, D. M., additional, Salai, M., additional, Elbaz, A., additional, Vasishta, V. G., additional, Derrett-Smith, E., additional, Hoyles, R., additional, Khan, K., additional, Ezeonyeji, A., additional, Takhar, G., additional, Ong, V., additional, Loughrey, L., additional, Bissell, L.-A., additional, Hensor, E., additional, Abignano, G., additional, Redmond, A., additional, Del Galdo, F., additional, Hall, F. C., additional, Malaviya, A., additional, Baker, S., additional, Furlong, A., additional, Mitchell, A., additional, Godfrey, A. L., additional, Ruddlesden, M., additional, Hadjinicolaou, A., additional, Hughes, M., additional, Moore, T., additional, O'Leary, N., additional, Tracey, A., additional, Ennis, H., additional, Dinsdale, G., additional, Roberts, C., additional, Herrick, A., additional, Denton, C. P., additional, Guillevin, L., additional, Hunsche, E., additional, Rosenberg, D., additional, Schwierin, B., additional, Scott, M., additional, Krieg, T., additional, Anderson, M., additional, Matucci-Cerinic, M., additional, Alade, R., additional, Xu, S., additional, Nihtyanova, S., additional, Clark, K. E., additional, Tam, F. W. K., additional, Unwin, R., additional, Stratton, R. J., additional, Schreiber, B., additional, Seng Edwin Lim, C., additional, Corsiero, E., additional, Sutcliffe, N., additional, Wardemann, H., additional, Pitzalis, C., additional, Bombardieri, M., additional, Tahir, H., additional, Donnelly, S., additional, Greenwood, M., additional, Smith, T. O., additional, Easton, V., additional, Bacon, H., additional, Jerman, E., additional, Armon, K., additional, Poland, F., additional, Macgregor, A., additional, van der Heijde, D., additional, Sieper, J., additional, Elewaut, D., additional, Pangan, A. L., additional, Nguyen, D., additional, Badenhorst, C., additional, Kirby, S., additional, White, D., additional, Harrison, A., additional, Garcia, J. A., additional, Stebbings, S., additional, MacKay, J. W., additional, Aboelmagd, S., additional, Gaffney, K., additional, Deodhar, A., additional, Braun, J., additional, Mack, M., additional, Hsu, B., additional, Gathany, T., additional, Han, C., additional, Inman, R. D., additional, Cooper-Moss, N., additional, Packham, J., additional, Strauss, V., additional, Freeston, J. E., additional, Coates, L., additional, Nam, J., additional, Moverley, A. R., additional, Helliwell, P., additional, Wakefield, R., additional, Mease, P., additional, Fleischmann, R., additional, Wollenhaupt, J., additional, Kielar, D., additional, Woltering, F., additional, Stach, C., additional, Hoepken, B., additional, Arledge, T., additional, Gladman, D., additional, Coteur, G., additional, Kavanaugh, A., additional, Purcaru, O., additional, McInnes, I., additional, Gottlieb, A. B., additional, Puig, L., additional, Rahman, P., additional, Ritchlin, C., additional, Li, S., additional, Wang, Y., additional, Mendelsohn, A., additional, Doyle, M., additional, Tillett, W., additional, Jadon, D., additional, Shaddick, G., additional, Cavill, C., additional, Robinson, G., additional, Sengupta, R., additional, Korendowych, E., additional, de Vries, C., additional, Thomas, R. C., additional, Shuto, T., additional, Busquets-Perez, N., additional, Marzo-Ortega, H., additional, McGonagle, D., additional, Richards, G., additional, Bingham, S., additional, John Hamlin, P., additional, Adshead, R., additional, Cambridge, S., additional, Suppiah, P., additional, Cullinan, M., additional, Nolan, A., additional, Thompson, W. M., additional, Mathieson, H. R., additional, Mackie, S. L., additional, Bryer, D., additional, Krutikov, M., additional, Gray, L., additional, Bruce, E., additional, Keat, A., additional, Innes, W., additional, Pandit, R., additional, Kay, L., additional, Lapshina, S., additional, Myasoutova, L., additional, Erdes, S., additional, Wallis, D., additional, Waldron, N., additional, Thorne, I., additional, Harris, C., additional, Vohra, K., additional, Khinchi, D., additional, Kaur, L., additional, Jones, A., additional, Harrison, N., additional, Harris, D., additional, Jones, T., additional, Rees, J., additional, Bennett, A., additional, Fazal, S., additional, Tugnet, N., additional, Barkham, N., additional, Basu, N., additional, McClean, A., additional, Harper, L., additional, Amft, E. N., additional, Dhaun, N., additional, Luqmani, R. A., additional, Little, M. A., additional, Jayne, D. R., additional, Flossmann, O., additional, McLaren, J., additional, Kumar, V., additional, Reid, D. M., additional, Macfarlane, G. J., additional, Jones, G., additional, Yates, M., additional, Watts, R. A., additional, Igali, L., additional, Mukhtyar, C., additional, Doll, H., additional, Yew, S., additional, Suppiah, R., additional, Hoglund, P., additional, Jayne, D., additional, Westman, K., additional, Win Maw, W., additional, Patil, P., additional, Williams, M., additional, Adizie, T., additional, Christidis, D., additional, Borg, F., additional, Robertson, A., additional, Croft, A. P., additional, Smith, S., additional, Carr, S., additional, Youssouf, S., additional, Salama, A., additional, Pusey, C., additional, and Morgan, M., additional
- Published
- 2013
- Full Text
- View/download PDF
11. Impact of eribulin on overall survival in patients with metastatic breast cancer with visceral disease.
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Vahdat, L. T., primary, Cortes, J., additional, Twelves, C., additional, Wanders, J., additional, Seegobin, S., additional, Dutcus, C., additional, and O'Shaughnessy, J., additional
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- 2011
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- View/download PDF
12. 5006 ORAL Eribulin Mesylate EMBRACE Study – Survival Analysis Excluding Patients Re-challenged With Therapies of the Same Class
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Cardoso, F., primary, Twelves, C., additional, Vahdat, L.T., additional, Dutcus, C., additional, Seegobin, S., additional, Wanders, J., additional, Cortes, J., additional, and O'Shaughnessy, J., additional
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- 2011
- Full Text
- View/download PDF
13. The relationship between age and survival outcomes for eribulin in metastatic breast cancer.
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Twelves, C., primary, Vahdat, L. T., additional, Cortes, J., additional, Wanders, J., additional, Dutcus, C. E., additional, Seegobin, S., additional, and Muss, H. B., additional
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- 2011
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- View/download PDF
14. Abstract P6-13-01: Impact of the Number of Prior Chemotherapy Regimens on Overall Survival (OS) among Subjects with Locally Recurrent or Metastatic Breast Cancer Treated with Eribulin Mesylate: Results from the Phase III EMBRACE Study
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Blum, JL, primary, Twelves, CJ, additional, Akerele, C, additional, Seegobin, S, additional, Wanders, J, additional, and Cortes, J., additional
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- 2010
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- View/download PDF
15. Abstract P6-13-02: Survival Outcomes with Eribulin Mesylate vs. Treatment of the Physician's Choice (TPC) in Heavily Pretreated Subjects with Locally Recurrent or Metastatic Breast Cancer in North America, Western Europe, and Australia: Results of the Phase III EMBRACE Study
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Vahdat, LT, primary, Twelves, CJ, additional, Seegobin, S, additional, Akerele, C, additional, Wanders, J, additional, and Cortes, J., additional
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- 2010
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16. Abstract P6-14-18: Updated Survival Analysis of a Phase III Study (EMBRACE) of Eribulin Mesylate Versus Treatment of Physician's Choice in Subjects with Locally Recurrent or Metastatic Breast Cancer Previously Treated with an Anthracycline and a Taxane
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Twelves, C, primary, Loesch, D, additional, Blum, J, additional, Vahdat, L, additional, Petrakova, K, additional, Durando, X, additional, Seegobin, S, additional, Akerele, C, additional, Wanders, J, additional, and Cortes, J., additional
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- 2010
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17. Immunogenicity and safety of beta variant COVID-19 vaccine AZD2816 and AZD1222 (ChAdOx1 nCoV-19) as primary-series vaccination for previously unvaccinated adults in Brazil, South Africa, Poland, and the UK: a randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study.
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Costa Clemens SA, Jepson B, Bhorat QE, Ahmad A, Akhund T, Aley PK, Bansal H, Bibi S, Kelly EJ, Khan M, Lambe T, Lombaard JJ, Matthews S, Pipolo Milan E, Olsson U, Ramasamy MN, Moura de Oliveira Paiva MS, Seegobin S, Shoemaker K, Szylak A, Villafana T, Pollard AJ, and Green JA
- Subjects
- Humans, Male, Female, Adult, Middle Aged, Double-Blind Method, United Kingdom, Brazil, South Africa, Poland, Antibodies, Viral blood, Antibodies, Neutralizing blood, Aged, Vaccination methods, Young Adult, ChAdOx1 nCoV-19, COVID-19 prevention & control, COVID-19 immunology, SARS-CoV-2 immunology, COVID-19 Vaccines immunology, COVID-19 Vaccines adverse effects, COVID-19 Vaccines administration & dosage, Immunogenicity, Vaccine
- Abstract
Background: AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated., Methods: In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed., Findings: Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28 days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2., Interpretation: Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants., Funding: AstraZeneca., Competing Interests: Declaration of interests SACC declares participation in the clinical development, with University of Oxford, of the vaccines described in this Article, membership on CureVac and Clover advisory boards, and institutional research grants from AstraZeneca. BJ is an employee of Cytel and is currently on assignment to AstraZeneca. QEB declares institutional funding, the provision of study materials, or both from the Wits Health Consortium, the Bill & Melinda Gates Foundation, the South African Medical Research Council, and AstraZeneca, as well as research grants or contracts from Regeneron, Novo Nordisk, Avillion, GlaxoSmithKline, Novavax, Sinovac, Johnson & Johnson, and Pfizer pharmaceuticals. PKA declares institutional grants to support the conduct of the study from AstraZeneca and the UK Vaccine Taskforce via the UK National Institute for Health Research (NIHR). HB is an employee of Bogier consulting and is currently on assignment to AstraZeneca. EJK is an employee of Sanofi. SM is an employee of Exploristics and is currently on assignment to AstraZeneca. EPM declares no competing interests. TL declares consulting fees from Vaccitech on an unrelated project, an honorarium from Seqirus on an unrelated project, an institutional grant from the UK Vaccine Taskforce via the NIHR, work-related investments, and is a named inventor on a patent application for a vaccine against SARS-CoV-2. JJL declares no competing interests. MNR declares institutional support for the study from AstraZeneca. AJP is Chair of the UK Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee. AJP also declares membership of the WHO’s Strategic Advisory Group of Experts on Immunization until January, 2022; provision of advice to Shionogi on COVID-19; and funding from the NIHR, AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the UK Research and Innovation Medical Research Council, the Serum Institute of India, and the Coalition for Epidemic Preparedness Innovations. University of Oxford has entered a partnership with AstraZeneca for the development of COVID-19 vaccines; TL, MNR, SB, PKA, and AJP are contributors to the intellectual property licensed by Oxford University Innovation to AstraZeneca. AA, TA, EJK, MK, UO, SS, KS, AS, TV, and JAG are, or were, employees of and may hold (or have held) stock or stock options in AstraZeneca. MSMdOP declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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18. Serum AZD7442 (tixagevimab-cilgavimab) concentrations and in vitro IC 50 values predict SARS-CoV-2 neutralising antibody titres.
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Clegg LE, Stepanov O, Matthews S, White T, Seegobin S, Thomas S, Tuffy KM, Någård M, Esser MT, Streicher K, Cohen TS, and Aksyuk AA
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Objectives: The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.g. storing infectious viruses and testing at biosafety level-3 facilities). Here, we demonstrate the utility of pseudovirus neutralisation assay data in conjunction with serum mAb concentrations to robustly predict nAb titres in serum., Methods: SARS-CoV-2 nAb titres were determined via authentic- and lentiviral pseudovirus-based neutralisation assays using serological data from three AZD7442 (tixagevimab-cilgavimab) studies: PROVENT (NCT04625725), TACKLE (NCT04723394) and a phase 1 dose-ranging study (NCT04507256). AZD7442 serum concentrations were assessed using immunocapture. Serum-based half-maximal inhibitory concentration (IC
50 ) values were derived from pseudovirus nAb titres and serum mAb concentrations, and compared with in vitro IC50 measurements., Results: nAb titres measured via authentic- and lentiviral pseudovirus-based neutralisation assays were strongly correlated for the ancestral SARS-CoV-2 virus and SARS-CoV-2 Alpha. Serum AZD7442 concentrations and pseudovirus nAb titres were strongly correlated for multiple SARS-CoV-2 variants with all Spearman correlation coefficients ≥ 0.78. Serum-based IC50 values were similar to in vitro IC50 values for AZD7442, for ancestral SARS-CoV-2 and Alpha, Delta, Omicron BA.2 and Omicron BA.4/5 variants., Conclusions: These data highlight that serum mAb concentrations and pseudovirus in vitro IC50 values can be used to rapidly predict nAb titres in serum for emerging and historical SARS-CoV-2 variants., Competing Interests: The authors of this report are all current employees of AstraZeneca and may own AstraZeneca stock or stock options. SM is a contractor to AstraZeneca via Exploristics (Belfast, UK). MTE is a named inventor on patents planned, issued or pending relating to AZD7442., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
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19. Efficacy, Safety, and Pharmacokinetics of AZD7442 (Tixagevimab/Cilgavimab) for Prevention of Symptomatic COVID-19: 15-Month Final Analysis of the PROVENT and STORM CHASER Trials.
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Levin MJ, Ustianowski A, De Wit S, Beavon R, Thissen J, Seegobin S, Dey K, Near KA, Streicher K, Kiazand A, and Esser MT
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Introduction: The phase 3 PROVENT and STORM CHASER studies evaluated AZD7442 (tixagevimab/cilgavimab) for pre-exposure and post-exposure prophylaxis of symptomatic coronavirus disease 2019 (COVID-19). We report the final 15-month results of both studies., Methods: In PROVENT, participants were randomized 2:1 to receive 300 mg AZD7442 (n = 3460) or placebo (n = 1737). In STORM CHASER, participants were enrolled within 8 days of exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individual and randomized 2:1 to receive 300 mg AZD7442 (n = 749) or placebo (n = 372)., Results: In PROVENT, the relative risk reduction (RRR) in symptomatic COVID-19 for AZD7442 versus placebo was 76.7% at primary analysis [95% confidence interval (CI) 46.1, 90.0; p < 0.001], 83.0% at day 183 (95% CI 67.3, 91.2; nominal p < 0.001), and 46.3% at day 366 (95% CI 23.1, 62.4; nominal p < 0.001). Severe/critical COVID-19 was reduced by 91.4% with AZD7442 versus placebo by day 366 (95% CI 61.3, 98.1; nominal p < 0.0001). Adverse events (AEs) occurred in 58.2% and 58.0% of participants administered AZD7442 or placebo, respectively; serious AEs (SAEs) occurred in 6.2% and 5.6%, respectively. In STORM CHASER, the RRR in symptomatic COVID-19 for AZD7442 versus placebo was 33.3% at primary analysis (95% CI - 25.9, 64.7; p = 0.212), 43.3% at day 183 (95% CI 1.4, 67.4; nominal p = 0.044) and 3.4% at day 366 (95% CI - 35.6, 31.2; nominal p = 0.842). Severe/critical COVID-19 did not occur in participants receiving AZD7442 versus 0.5% of participants receiving placebo by day 366. AEs occurred in 46.5% and 51.9% of participants administered AZD7442 or placebo, respectively; SAEs occurred in 2.7% and 4.3%, respectively. In both studies, serum concentration-time profiles over 457 days were similar for tixagevimab and cilgavimab and consistent with the extended half-life reported for AZD7442 (approximately 90 days)., Conclusion: This analysis provides proof of concept supporting long-term safety of intramuscularly administered AZD7442 for prevention of symptomatic/severe COVID-19. A graphical abstract is available with this article., Gov Identifiers: PROVENT (NCT04625725) and STORM CHASER (NCT04625972)., (© 2024. The Author(s).)
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20. Safety, Efficacy and Pharmacokinetics of AZD7442 (Tixagevimab/Cilgavimab) for Treatment of Mild-to-Moderate COVID-19: 15-Month Final Analysis of the TACKLE Trial.
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Hobbs FDR, Montgomery H, Padilla F, Simón-Campos JA, Arbetter D, Seegobin S, Kiazand A, Streicher K, Martinez-Alier N, Cohen TS, and Esser MT
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Introduction: In the phase 3 TACKLE study, outpatient treatment with AZD7442 (tixagevimab/cilgavimab) was well tolerated and significantly reduced progression to severe disease or death through day 29 in adults with mild-to-moderate coronavirus disease 2019 (COVID-19) at the primary analysis. Here, we report data from the final analysis of the TACKLE study, performed after approximately 15 months' follow-up., Methods: Eligible participants were randomized 1:1 and dosed within 7 days of symptom onset with 600 mg intramuscular AZD7442 (n = 456; 300 mg tixagevimab/300 mg cilgavimab) or placebo (n = 454)., Results: Severe COVID-19 or death through day 29 occurred in 4.4% and 8.8% of participants who received AZD7442 or placebo, a relative risk reduction (RRR) of 50.4% [95% confidence interval (CI) 14.4, 71.3; p = 0.0096]; among participants dosed within 5 days of symptom onset, the RRR was 66.9% (95% CI 31.1, 84.1; p = 0.002). Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 occurred in 5.0% of participants receiving AZD7442 versus 9.7% receiving placebo, an RRR of 49.2% (95% CI 14.7, 69.8; p = 0.009). Adverse events occurred in 55.5% and 55.9% of participants who received AZD7442 or placebo, respectively, and were mostly mild or moderate in severity. Serious adverse events occurred in 10.2% and 14.4% of participants who received AZD7442 or placebo, respectively, and deaths occurred in 1.8% of participants in both groups. Serum concentration-time profiles recorded over 457 days were similar for AZD7442, tixagevimab, and cilgavimab, and were consistent with the extended half-life reported for AZD7442 (approx. 90 days)., Conclusions: AZD7442 reduced the risk of progression to severe COVID-19, hospitalization, and death, was well tolerated through 15 months, and exhibited predictable pharmacokinetics in outpatients with mild-to-moderate COVID-19. These data support the long-term safety of using long-acting monoclonal antibodies to treat COVID-19., Trial Registration: Clinicaltrials.gov, NCT04723394. ( https://clinicaltrials.gov/study/NCT04723394 ., (© 2024. The Author(s).)
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21. Immunogenicity and safety of AZD2816, a beta (B.1.351) variant COVID-19 vaccine, and AZD1222 (ChAdOx1 nCoV-19) as third-dose boosters for previously vaccinated adults: a multicentre, randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study in the UK and Poland.
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Ramasamy MN, Kelly EJ, Seegobin S, Dargan PI, Payne R, Libri V, Adam M, Aley PK, Martinez-Alier N, Church A, Jepson B, Khan M, Matthews S, Townsend GT, Vekemans J, Bibi S, Swanson PA 2nd, Lambe T, Pangalos MN, Villafana T, Pollard AJ, and Green JA
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- Adult, Humans, COVID-19 Vaccines adverse effects, SARS-CoV-2, Poland, Antibodies, Neutralizing, RNA, Messenger, United Kingdom, ChAdOx1 nCoV-19, COVID-19 prevention & control
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Background: This study aimed to evaluate AZD2816, a variant-updated COVID-19 vaccine expressing the full-length SARS-CoV-2 beta (B.1.351) variant spike protein that is otherwise similar to AZD1222 (ChAdOx1 nCoV-19), and AZD1222 as third-dose boosters., Methods: This phase 2/3, partly double-blinded, randomised, active-controlled study was done at 19 sites in the UK and four in Poland. Adult participants who had received a two-dose AZD1222 or mRNA vaccine primary series were randomly assigned by means of an Interactive Response Technology-Randomisation and Trial Supply Management system (1:1 within each primary-series cohort, stratified by age, sex, and comorbidities) to receive AZD1222 or AZD2816 (intramuscular injection; 5 × 10
10 viral particles). Participants, investigators, and all sponsor staff members involved in study conduct were masked to randomisation. AZD1222 and AZD2816 doses were prepared by unmasked study staff members. The primary objectives were to evaluate safety and humoral immunogenicity (non-inferiority of day-29 pseudovirus neutralising antibody geometric mean titre [GMT] against ancestral SARS-CoV-2: AZD1222 booster vs AZD1222 primary series [historical controls]; margin 0·67; SARS-CoV-2-seronegative participants). This study is registered with ClinicalTrials.gov, NCT04973449, and is completed., Findings: Between June 27 and Sept 30, 2021, 1394 participants of the 1741 screened were randomly assigned to AZD1222 or AZD2816 following an AZD1222 (n=373, n=377) or mRNA vaccine (n=322, n=322) primary series. In SARS-CoV-2-seronegative participants receiving AZD1222 or AZD2816, 78% and 80% (AZD1222 primary series) and 90% and 93%, respectively (mRNA vaccine primary series) reported solicited adverse events to the end of day 8; 2%, 2%, 1%, and 1% had serious adverse events and 12%, 12%, 10%, and 11% had adverse events of special interest, respectively, to the end of day 180. The primary immunogenicity non-inferiority endpoint was met: day-29 neutralising antibody GMT ratios (ancestral SARS-CoV-2) were 1·02 (95% CI 0·90-1·14) and 3·47 (3·09-3·89) with AZD1222 booster versus historical controls (AZD1222 and mRNA vaccine primary series, respectively). Responses against beta were greater with AZD2816 versus AZD1222 (GMT ratios, AZD1222, mRNA vaccine primary series 1·84 [1·63-2·08], 2·22 [1·99-2·47])., Interpretation: Both boosters were well tolerated, with immunogenicity against ancestral SARS-CoV-2 similar to AZD1222 primary-series vaccination. AZD2816 gave greater immune responses against beta versus AZD1222., Funding: AstraZeneca., Competing Interests: Declaration of interests MNR declares institutional support for the study from AstraZeneca. EJK, SS, AC, MK, GTT, JV, PAS, MNP, TV, NM-A, and JAG are, or were, employees of and may hold (or have held) stock or stock options in AstraZeneca. PID declares institutional support for the study from AstraZeneca, and institutional grants from AstraZeneca, Janssen, Moderna, and Atea. RP declares institutional support for the study from AstraZeneca. MA declares support for the study from AstraZeneca and IQVIA to the Clinical Infection Research Group. PKA declares institutional grants to support the conduct of the study from AstraZeneca and the UK Vaccine Taskforce via National Institute for Health Research (NIHR). BJ is an employee of Cytel and is currently on assignment to AstraZeneca. SM is an employee of Exploristics and is currently on assignment to AstraZeneca. TL reports consulting fees from Vaccitech on an unrelated project, an honorarium from Seqirus, grant support from the Vaccine Taskforce for this trial, work-related investments, and is named as an inventor on a patent application for a vaccine against SARS-CoV-2. AJP was a member of WHO's Strategic Advisory Group of Experts on Immunization until January, 2022 and remains chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee; and reports providing advice to Shionogi on COVID-19, and funding from the NIHR, AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, and the Coalition for Epidemic Preparedness Innovations. Oxford University has entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. VL and SB declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
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22. Outpatient Treatment with AZD7442 (Tixagevimab/Cilgavimab) Prevented COVID-19 Hospitalizations over 6 Months and Reduced Symptom Progression in the TACKLE Randomized Trial.
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Hobbs FDR, Montgomery H, Padilla F, Simón-Campos JA, Kim K, Arbetter D, Padilla KW, Reddy VP, Seegobin S, Streicher K, Templeton A, Viani RM, Johnsson E, Koh GCKW, and Esser MT
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Introduction: We assessed effects of AZD7442 (tixagevimab/cilgavimab) on deaths from any cause or hospitalizations due to coronavirus disease 2019 (COVID-19) and symptom severity and longer-term safety in the TACKLE adult outpatient treatment study., Methods: Participants received 600 mg AZD7442 (n = 452) or placebo (n = 451) ≤ 7 days of COVID-19 symptom onset., Results: Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 (key secondary endpoint) occurred in 20/399 (5.0%) participants receiving AZD7442 versus 40/407 (9.8%) receiving placebo [relative risk reduction (RRR) 49.1%; 95% confidence interval (CI) 14.5, 69.7; p = 0.009] or 50.7% (95% CI 17.5, 70.5; p = 0.006) after excluding participants unblinded before day 169 for consideration of vaccination). AZD7442 reduced progression of COVID-19 symptoms versus placebo through to day 29 (RRR 12.5%; 95% CI 0.5, 23.0) and improved most symptoms within 1-2 weeks. Over median safety follow-up of 170 days, adverse events occurred in 174 (38.5%) and 196 (43.5%) participants receiving AZD7442 or placebo, respectively. Cardiac serious adverse events occurred in two (0.4%) and three (0.7%) participants receiving AZD7442 or placebo, respectively., Conclusions: AZD7442 was well tolerated and reduced hospitalization and mortality through 6 months, and symptom burden through 29 days, in outpatients with mild-to-moderate COVID-19., Clinical Trial Registration: Clinicaltrials.gov, NCT04723394. ( https://beta., Clinicaltrials: gov/study/NCT04723394 )., (© 2023. The Author(s).)
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23. Lithium-Induced Hypercalcemia Presenting as Catatonia in a Patient With Schizoaffective Disorder.
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Seegobin S, Williams S, Hyder M, and Peteru S
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Catatonia, a relatively rare and less explored consequence of lithium-induced hypercalcemia, represents a notable yet understudied side effect. Lithium is utilized in the management of acute mania and as a maintenance therapy for bipolar disorder. However, the specific catatonic presentation resulting from hypercalcemia remains poorly understood. Here, we present a case study involving a 55-year-old male with a history of schizoaffective disorder, bipolar type, who had been receiving lithium therapy. The patient presented with catatonia and altered mental status. Manifesting as mutism, rigidity, immobility, and staring, these symptoms were subsequently attributed to hyperparathyroidism-induced hypercalcemia. Markedly elevated levels of both calcium and parathyroid hormone (PTH) were detected in the patient's laboratory results. The patient's lithium therapy was promptly discontinued. Serum calcium and PTH levels began to decrease gradually and returned to normal limits over 29 days. The patient returned to his baseline level of functionality. There was a notable improvement in his mental status and his ability to communicate using simple sentences. This case underscores the significance of recognizing uncommon clinical presentations of hypercalcemia in patients undergoing chronic lithium therapy. Given the broad range of neuropsychiatric manifestations associated with hypercalcemia, it is crucial to enhance our understanding of this phenomenon and develop the capacity to differentiate it from primary psychiatric disturbances., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Seegobin et al.)
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24. Safety, Tolerability and Pharmacokinetics of Half-Life Extended Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Monoclonal Antibodies AZD7442 (Tixagevimab-Cilgavimab) in Healthy Adults.
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Forte-Soto P, Albayaty M, Brooks D, Arends RH, Tillinghast J, Aksyuk AA, Bouquet J, Chen C, Gebre A, Kubiak RJ, Pilla Reddy V, Seegobin S, Streicher K, Templeton A, and Esser MT
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- Humans, Adult, Half-Life, Antibodies, Monoclonal, Antibodies, Neutralizing, Double-Blind Method, Antibodies, Viral, SARS-CoV-2, COVID-19
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Background: AZD7442 is a combination of extended half-life, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing monoclonal antibodies (tixagevimab and cilgavimab)., Methods: This phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study evaluated AZD7442 administered intramuscularly (300 mg) or intravenously (300, 1000, or 3000 mg) in healthy adults (aged 18-55 years). The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and antidrug antibodies., Results: Between 18 August and 16 October 2020, a total of 60 participants were enrolled; 50 received AZD7442, and 10 received placebo. Adverse events (all of mild or moderate intensity) occurred in 26 participants (52.0%) in the AZD7442 groups and 8 (80.0%) in the placebo group. No infusion or injection site or hypersensitivity reactions occurred. Tixagevimab and cilgavimab had mean half-lives of approximately 90 days (range, 87.0-95.3 days for tixagevimab and 79.8--91.1 days for cilgavimab) and similar pharmacokinetic profiles over the 361-day study period. SARS-CoV-2-specific neutralizing antibody titers provided by AZD7442 were maintained above those in plasma from convalescent patients with coronavirus disease 2019 (COVID-19)., Conclusions: AZD7442 was well tolerated in healthy adults, showing a favorable safety profile across all doses. Depending on the SARS-CoV-2 variant, pharmacokinetic analyses suggest the AZD7442 could offer protection for ≥6 months against symptomatic COVID-19 after a single 300-mg intramuscular administration., Clinical Trials Registration: NCT04507256., Competing Interests: Potential conflicts of interest. P. F. S. is an employee of Parexel International and does not hold stock in AstraZeneca. M. A., D. B., R. H. A., J. T., A. A. A., J. B., C. C., A. G., R. J. K., V. P. R., S. S., K. S., A. T., and M. T. E. were employees of, and hold or may have held stock in, AstraZeneca at the time of study. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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25. AZD7442 (Tixagevimab/Cilgavimab) for Post-Exposure Prophylaxis of Symptomatic Coronavirus Disease 2019.
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Levin MJ, Ustianowski A, Thomas S, Templeton A, Yuan Y, Seegobin S, Houlihan CF, Menendez-Perez I, Pollett S, Arends RH, Beavon R, Dey K, Garbes P, Kelly EJ, Koh GCKW, Ivanov S, Near KA, Sharbaugh A, Streicher K, Pangalos MN, and Esser MT
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- Adult, Humans, SARS-CoV-2, Post-Exposure Prophylaxis, COVID-19 Vaccines, COVID-19 prevention & control
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Background: This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis against symptomatic coronavirus disease 2019 (COVID-19)., Methods: Adults without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab) or placebo. Primary end points were safety and first post-dose SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)-positive symptomatic COVID-19 event before day 183., Results: A total of 1121 participants were randomized and dosed (AZD7442, n = 749; placebo, n = 372). Median (range) follow-up was 49 (5-115) and 48 (20-113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of 749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19 occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction, 33.3%; 95% confidence interval [CI], -25.9 to 64.7; P = .21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR-negative (n = 974, 87%) or missing an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR-positive symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo., Conclusions: This study did not meet the primary efficacy end point of post-exposure prevention of symptomatic COVID-19. However, analysis of participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical Trials Registration. NCT04625972., Competing Interests: Potential conflicts of interest. M. J. L. reports research support from GSK, Johnson & Johnson, Moderna, and Novavax; consultancy for Dynavax, GSK, Merck & Co, Pfizer, and Seqirus; and participation on a data and safety monitoring board (DSMB)/advisory board for GSK. A. U. reports honoraria/speaker fees from Sanofi, Merck, Janssen, GSK, Roche, ViiV, and Gilead; advisory boards for Gilead, Merck, and ViiV/GSK; and participation on a DSMB for COV-Boost study, Flare study, and for Vicore. S. D. P. reports that the USU Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and HJF were funded under a cooperative research and development agreement to help conduct the STORM CHASER study, sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was also funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase 3 vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US government COVID-19 response. M. T. E. reports patents planned, issued, or pending by AstraZeneca on AZD7442. P. G. reports consulting fees from Medicago and Takeda Vaccines as senior medical director; a leadership or fiduciary role as a full member of the Academy of Medicine in Rio de Janeiro, Brazil; and stock or stock options in Takeda Pharmaceuticals, AstraZeneca. All authors report medical writing assistance provided by Prime Global. S. T., A. T., Y. Y., S. S., R. H. A., R. B., K. D., P. G., E. J. K., G. C. K. W. K., S. I., K. A. N., A. S., K. S., M. N. P., and M. T. E. are employees of and hold or may hold stock in AstraZeneca. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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26. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial.
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Montgomery H, Hobbs FDR, Padilla F, Arbetter D, Templeton A, Seegobin S, Kim K, Campos JAS, Arends RH, Brodek BH, Brooks D, Garbes P, Jimenez J, Koh GCKW, Padilla KW, Streicher K, Viani RM, Alagappan V, Pangalos MN, and Esser MT
- Subjects
- Adult, Antibodies, Monoclonal therapeutic use, Double-Blind Method, Humans, Middle Aged, Outpatients, SARS-CoV-2, Treatment Outcome, COVID-19 Drug Treatment
- Abstract
Background: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab-cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab-cilgavimab in preventing progression to severe COVID-19 or death., Methods: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab-cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394., Findings: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab-cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab-cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6-71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1-8·0; p<0·0001). Adverse events occurred in 132 (29%) of 452 participants in the tixagevimab-cilgavimab group and 163 (36%) of 451 participants in the placebo group, and were mostly of mild or moderate severity. There were three COVID-19-reported deaths in the tixagevimab-cilgavimab group and six in the placebo group., Interpretation: A single intramuscular tixagevimab-cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab-cilgavimab might lead to more favourable outcomes., Funding: AstraZeneca., Competing Interests: Declaration of interests HM has received consultation fees from AstraZeneca and is supported by the UK National Institute for Health Research's Comprehensive Biomedical Research Centre at University College London Hospitals. He has consulted for Millfield Medical Ltd on the development of a new continuous positive airway pressure machine. JASC reports serving on advisory boards for Pfizer and Eli Lilly; and serving on advisory boards and as a speaker for AstraZeneca and Roche. FDRH reports funding from AstraZeneca to cover meeting attendances and operationalisation of TACKLE in the UK as UK principal investigator. He has received funding by UK Research and Innovation and National Institute for Health and Care Research (NIHR) for national Urgent Public Health COVID-19 trials, and as Director of the NIHR Applied Research Collaboration, Oxford Thames Valley, and investigator on the Oxford Biomedical Research Centre and NIHR MedTech. FP has received personal fees and grants from Amgen, AstraZeneca, Boehringer Ingelheim, Ferrer, Kowa, Medix, Merck, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, Servier, and Silanes. KK has received research grants for the conduct of the TACKLE trial, reports funding from Regeneron, Eli Lilly, Merck, Pfizer, and Adagio, and serves as a speaker for Regeneron. DA, AT, SS, RHA, BHB, DB, PG, JJ, GCKWK, KWP, RMV, KS, VA, MNP, and MTE are employees of, and hold or may hold stock in, AstraZeneca., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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27. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19.
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Levin MJ, Ustianowski A, De Wit S, Launay O, Avila M, Templeton A, Yuan Y, Seegobin S, Ellery A, Levinson DJ, Ambery P, Arends RH, Beavon R, Dey K, Garbes P, Kelly EJ, Koh GCKW, Near KA, Padilla KW, Psachoulia K, Sharbaugh A, Streicher K, Pangalos MN, and Esser MT
- Subjects
- Adult, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal therapeutic use, Antibodies, Neutralizing administration & dosage, Antibodies, Neutralizing therapeutic use, Double-Blind Method, Drug Combinations, Humans, Injections, Intramuscular, SARS-CoV-2, Antiviral Agents administration & dosage, Antiviral Agents therapeutic use, COVID-19 prevention & control
- Abstract
Background: The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days., Methods: In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183., Results: A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group., Conclusions: A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.)., (Copyright © 2022 Massachusetts Medical Society.)
- Published
- 2022
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28. Efficacy and Safety of Bimekizumab in Moderate to Severe Hidradenitis Suppurativa: A Phase 2, Double-blind, Placebo-Controlled Randomized Clinical Trial.
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Glatt S, Jemec GBE, Forman S, Sayed C, Schmieder G, Weisman J, Rolleri R, Seegobin S, Baeten D, Ionescu L, Zouboulis CC, and Shaw S
- Subjects
- Adalimumab adverse effects, Adult, Antibodies, Monoclonal, Humanized, Bayes Theorem, Double-Blind Method, Drug Administration Schedule, Female, Humans, Infant, Severity of Illness Index, Treatment Outcome, Hidradenitis Suppurativa diagnosis, Hidradenitis Suppurativa drug therapy
- Abstract
Importance: Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a high burden for patients and limited existing therapeutic options., Objective: To evaluate the efficacy and safety of bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin 17A and 17F in individuals with moderate to severe HS., Design, Setting, and Participants: This phase 2, double-blind, placebo-controlled randomized clinical trial with an active reference arm was performed from September 22, 2017, to February 21, 2019. The study included a 2- to 4-week screening period, a 12-week treatment period, and a 20-week safety follow-up. Of 167 participants screened at multiple centers, 90 were enrolled. Eligible participants were 18 to 70 years of age with a diagnosis of moderate to severe HS 12 months or more before baseline., Interventions: Participants with HS were randomized 2:1:1 to receive bimekizumab (640 mg at week 0, 320 mg every 2 weeks), placebo, or reference arm adalimumab (160 mg at week 0, 80 mg at week 2, and 40 mg every week for weeks 4-10)., Main Outcomes and Measures: The prespecified primary efficacy variable was the proportion of participants with a 50% or greater reduction from baseline in the total abscess and inflammatory nodule count with no increase in abscess or draining fistula count (Hidradenitis Suppurativa Clinical Response [HiSCR] at week 12. Exploratory variables included proportion achieving a modified HiSCR with 75% reduction of HiSCR criteria (HiSCR75) or a modified HiSCR with 90% reduction of HiSCR criteria (HiSCR90), change in Patient's Global Assessment of Pain, and Dermatology Life Quality Index total scores., Results: Eighty-eight participants received at least 1 dose of study medication (61 [69%] female; median age, 36 years; range, 18-69 years). Seventy-three participants completed the study, including safety follow-up. Bimekizumab demonstrated a higher HiSCR rate vs placebo at week 12 (57.3% vs 26.1%; posterior probability of superiority equaled 0.998, calculated using bayesian analysis). Bimekizumab demonstrated greater clinical improvements compared with placebo. Improvements in the International Hidradenitis Suppurativa Severity Score (IHS4) were seen at week 12 with bimekizumab (mean [SD] IHS4, 16.0 [18.0]) compared with placebo (mean [SD] IHS4, 40.2 [32.6]). More bimekizumab-treated participants achieved positive results on stringent outcome measures compared with placebo. At week 12, 46% of bimekizumab-treated participants achieved HiSCR75 and 32% achieved HiSCR90, whereas 10% of placebo-treated participants achieved HiSCR75 and none achieved HiSCR90; in adalimumab-treated participants, 35% achieved HiSCR75 and 15% achieved HiSCR90. One participant withdrew because of adverse events. Serious adverse events occurred in 2 of 46 bimekizumab-treated participants (4%), 2 of 21 placebo-treated participants (10%), and 1 of 21 adalimumab-treated participants (5%)., Conclusions and Relevance: In this phase 2 randomized clinical trial, bimekizumab demonstrated clinically meaningful improvements across all outcome measures, including stringent outcomes. Bimekizumab's safety profile was consistent with studies of other indications, supporting further evaluation in participants with HS., Trial Registration: ClinicalTrials.gov Identifier: NCT03248531.
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- 2021
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29. Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.
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Tziotzios C, Petridis C, Dand N, Ainali C, Saklatvala JR, Pullabhatla V, Onoufriadis A, Pramanik R, Baudry D, Lee SH, Wood K, Liu L, Seegobin S, Michelotti GA, Lwin SM, Christou EAA, Curtis CJ, de Rinaldis E, Saxena A, Holmes S, Harries M, Palamaras I, Cunningham F, Parkins G, Kaur M, Farrant P, McDonagh A, Messenger A, Jones J, Jolliffe V, Ali I, Ardern-Jones M, Mitchell C, Burrows N, Atkar R, Banfield C, Alexandroff A, Champagne C, Cooper HL, Vañó-Galván S, Molina-Ruiz AM, Perez NO, Patel GK, Macbeth A, Page M, Bryden A, Mowbray M, Wahie S, Armstrong K, Cooke N, Goodfield M, Man I, de Berker D, Dunnill G, Takwale A, Rao A, Siah TW, Sinclair R, Wade MS, Dlova NC, Setterfield J, Lewis F, Bhargava K, Kirkpatrick N, Estivill X, Stefanato CM, Flohr C, Spector T, Watt FM, Smith CH, Barker JN, Fenton DA, Simpson MA, and McGrath JA
- Subjects
- Adaptive Immunity, Alopecia diagnosis, Alopecia genetics, Alopecia physiopathology, Case-Control Studies, Cohort Studies, Cytochrome P-450 CYP1B1 genetics, Cytochrome P-450 CYP1B1 immunology, Female, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-B7 Antigen immunology, Humans, Immunity, Innate, Polymorphism, Single Nucleotide, Alopecia congenital, Genetic Loci, Genetic Predisposition to Disease, HLA-B7 Antigen genetics, Transcriptome immunology
- Abstract
Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.
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- 2019
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30. Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial.
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Cooper RE, Williams E, Seegobin S, Tye C, Kuntsi J, and Asherson P
- Subjects
- Adolescent, Adult, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Retrospective Studies, Treatment Outcome, Young Adult, Attention Deficit Disorder with Hyperactivity drug therapy, Cannabinoids therapeutic use
- Abstract
Adults with ADHD describe self-medicating with cannabis, with some reporting a preference for cannabis over ADHD medications. A small number of psychiatrists in the US prescribe cannabis medication for ADHD, despite there being no evidence from randomised controlled studies. The EMA-C trial (Experimental Medicine in ADHD-Cannabinoids) was a pilot randomised placebo-controlled experimental study of a cannabinoid medication, Sativex Oromucosal Spray, in 30 adults with ADHD. The primary outcome was cognitive performance and activity level using the QbTest. Secondary outcomes included ADHD and emotional lability (EL) symptoms. From 17.07.14 to 18.06.15, 30 participants were randomly assigned to the active (n=15) or placebo (n=15) group. For the primary outcome, no significant difference was found in the ITT analysis although the overall pattern of scores was such that the active group usually had scores that were better than the placebo group (Est=-0.17, 95%CI-0.40 to 0.07, p=0.16, n=15/11 active/placebo). For secondary outcomes Sativex was associated with a nominally significant improvement in hyperactivity/impulsivity (p=0.03) and a cognitive measure of inhibition (p=0.05), and a trend towards improvement for inattention (p=0.10) and EL (p=0.11). Per-protocol effects were higher. Results did not meet significance following adjustment for multiple testing. One serious (muscular seizures/spasms) and three mild adverse events occurred in the active group and one serious (cardiovascular problems) adverse event in the placebo group. Adults with ADHD may represent a subgroup of individuals who experience a reduction of symptoms and no cognitive impairments following cannabinoid use. While not definitive, this study provides preliminary evidence supporting the self-medication theory of cannabis use in ADHD and the need for further studies of the endocannabinoid system in ADHD., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2017
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31. Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin.
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Brocks T, Fedorchenko O, Schliermann N, Stein A, Moll UM, Seegobin S, Dewor M, Hallek M, Marquardt Y, Fietkau K, Heise R, Huth S, Pfister H, Bernhagen J, Bucala R, Baron JM, and Fingerle-Rowson G
- Subjects
- Animals, Anthracenes toxicity, Antigens, CD genetics, Antigens, CD metabolism, Carcinogenesis, Gene Expression Regulation physiology, Inflammation metabolism, Keratinocytes metabolism, Macrophage Migration-Inhibitory Factors genetics, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Piperidines toxicity, Pyridines toxicity, Receptors, CXCR genetics, Receptors, CXCR metabolism, Macrophage Migration-Inhibitory Factors metabolism, Skin cytology, Skin immunology, Skin Neoplasms chemically induced
- Abstract
The response of the skin to harmful environmental agents is shaped decisively by the status of the immune system. Keratinocytes constitutively express and secrete the chemokine-like mediator, macrophage migration inhibitory factor (MIF), more strongly than dermal fibroblasts, thereby creating a MIF gradient in skin. By using global and epidermis-restricted Mif-knockout (Mif
-/- and K14-Cre+/tg ; Miffl/fl ) mice, we found that MIF both recruits and maintains antigen-presenting cells in the dermis/epidermis. The reduced presence of antigen-presenting cells in the absence of MIF was associated with accelerated and increased formation of nonmelanoma skin tumors during chemical carcinogenesis. Our results demonstrate that MIF is essential for maintaining innate immunity in skin. Loss of keratinocyte-derived MIF leads to a loss of control of epithelial skin tumor formation in chemical skin carcinogenesis, which highlights an unexpected tumor-suppressive activity of MIF in murine skin.-Brocks, T., Fedorchenko, O., Schliermann, N., Stein, A., Moll, U. M., Seegobin, S., Dewor, M., Hallek, M., Marquardt, Y., Fietkau, K., Heise, R., Huth, S., Pfister, H., Bernhagen, J., Bucala, R., Baron, J. M., Fingerle-Rowson, G. Macrophage migration inhibitory factor protects from nonmelanoma epidermal tumors by regulating the number of antigen-presenting cells in skin., (© FASEB.)- Published
- 2017
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32. Frontal fibrosing alopecia: there is no statistically significant association with leave-on facial skin care products and sunscreens.
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Seegobin SD, Tziotzios C, Stefanato CM, Bhargava K, Fenton DA, and McGrath JA
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- Face, Fibrosis, Humans, Skin Care, Alopecia, Sunscreening Agents
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- 2016
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33. Validation of the standardised assessment of personality--abbreviated scale in a general population sample.
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Fok ML, Seegobin S, Frissa S, Hatch SL, Hotopf M, Hayes RD, and Moran P
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- Adult, Female, Humans, Male, Middle Aged, ROC Curve, Sensitivity and Specificity, Mental Status Schedule, Personality Assessment, Personality Disorders diagnosis
- Abstract
Background: Personality disorder (PD) is associated with important health outcomes in the general population. However, the length of diagnostic interviews poses a significant barrier to obtaining large scale, population-based data on PD. A brief screen for the identification of people at high risk of PD in the general population could be extremely valuable for both clinicians and researchers., Aim: We set out to validate the Standardised Assessment of Personality - Abbreviated Scale (SAPAS), in a general population sample, using the Structured Clinical Interviews for DSM-IV Personality Disorders (SCID-II) as a gold standard., Method: One hundred and ten randomly selected, community-dwelling adults were administered the SAPAS screening interview. The SCID-II was subsequently administered by a clinical interviewer blind to the initial SAPAS score. Receiver operating characteristic analysis was used to assess the discriminatory performance of the SAPAS, relative to the SCID-II., Results: Area under the curve for the SAPAS was 0.70 (95% CI = 0.60 to 0.80; p < 0.001), indicating moderate overall discriminatory accuracy. A cut point score of 4 on the SAPAS correctly classified 58% of participants. At this cut point, the sensitivity and specificity were 0.69 and 0.53 respectively., Conclusion: The SAPAS operates less efficiently as a screen in general population samples and is probably most usefully applied in clinical populations., (© 2015 The Authors Personality and Mental Health published by John Wiley & Sons Ltd.)
- Published
- 2015
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34. Eribulin monotherapy in patients aged 70 years and older with metastatic breast cancer.
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Muss H, Cortes J, Vahdat LT, Cardoso F, Twelves C, Wanders J, Dutcus CE, Yang J, Seegobin S, and O'Shaughnessy J
- Subjects
- Age Factors, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Breast Neoplasms mortality, Disease-Free Survival, Female, Humans, Middle Aged, Neoplasm Metastasis drug therapy, Retrospective Studies, Treatment Outcome, Aging, Breast Neoplasms drug therapy, Furans adverse effects, Furans therapeutic use, Ketones adverse effects, Ketones therapeutic use
- Abstract
Purpose: Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients., Methods: Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m(2) as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), clinical benefit rate (CBR), and incidence of adverse events (AEs) was calculated for four age groups (<50 years, 50-59 years, 60-69 years, ≥ 70 years). RESULTS. Overall, 827 patients were included in the analysis (<50 years, n = 253; 50-59 years, n = 289; 60-69 years, n = 206; ≥ 70 years, n = 79). Age had no significant impact on OS (11.8 months, 12.3 months, 11.7 months, and 12.5 months, respectively; p = .82), PFS (3.5 months, 2.9 months, 3.8 months, and 4.0 months, respectively; p = .42), ORR (12.7%, 12.5%, 6.3%, and 10.1%, respectively), or CBR (20.2%, 20.8%, 20.4%, and 21.5%, respectively). Although some AEs had higher incidence in either the youngest or the oldest subgroup, there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia)., Conclusion: Eribulin monotherapy in these selected older patients with good baseline performance status led to OS, PFS, ORR, CBR, and tolerability similar to those of younger patients with metastatic breast cancer. The benefits and risks of eribulin appear to be similar across age groups.
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- 2014
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35. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
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Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, and Twelves C
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Breast Neoplasms mortality, Disease-Free Survival, Female, Furans adverse effects, Humans, Ketones adverse effects, Middle Aged, Neoplasm Metastasis drug therapy, Survival Rate, Antineoplastic Agents therapeutic use, Breast Neoplasms pathology, Furans therapeutic use, Ketones therapeutic use
- Abstract
Background: Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments., Methods: In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1·4 mg/m(2) administered intravenously during 2-5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726., Findings: 762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13·1 months, 95% CI 11·8-14·3) compared with TPC (10·6 months, 9·3-12·5; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients., Interpretation: Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting., Funding: Eisai., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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