49 results on '"Overell J"'
Search Results
2. Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry
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Butzkueven, H, Spelman, T, Horakova, D, Hughes, S, Solaro, C, Izquierdo, G, Kubala Havrdova, E, Grand'Maison, F, Prat, A, Girard, M, Hupperts, R, Onofrj, M, Lugaresi, A, Taylor, B, Giovannoni, G, Kappos, L, Hauser, SL, Montalban, X, Craveiro, L, Freitas, R, Model, F, Overell, J, Muros-Le Rouzic, E, Sauter, A, Wang, Q, Wormser, D, Wolinsky, JS, Butzkueven, H, Spelman, T, Horakova, D, Hughes, S, Solaro, C, Izquierdo, G, Kubala Havrdova, E, Grand'Maison, F, Prat, A, Girard, M, Hupperts, R, Onofrj, M, Lugaresi, A, Taylor, B, Giovannoni, G, Kappos, L, Hauser, SL, Montalban, X, Craveiro, L, Freitas, R, Model, F, Overell, J, Muros-Le Rouzic, E, Sauter, A, Wang, Q, Wormser, D, and Wolinsky, JS
- Abstract
BACKGROUND AND PURPOSE: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662). METHODS: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0-6.5) were investigated in ORATORIO and MSBase. RESULTS: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31-0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: -4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years. CONCLUSIONS: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
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- 2021
3. PND55 Socioeconomic Value of Ocrelizumab in the Treatment of Patients with Primary Progressive Multiple Sclerosis
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Di Maio, D., primary, Liu, C., additional, Marcelli, G., additional, Sanchez Alvarez, J., additional, and Overell, J., additional
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- 2020
- Full Text
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4. PND47 Socioeconomic Value of Ocrelizumab in the Treatment of Patients with Relapsing Forms of Multiple Sclerosis
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Di Maio, D., primary, Liu, C., additional, Marcelli, G., additional, Sanchez Alvarez, J., additional, and Overell, J., additional
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- 2020
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5. Neuro-otological syndromes for the neurologist
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Overell, J. and Lindahl, A.
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Otolaryngology -- Research ,Deafness -- Causes of ,Deafness -- Research ,Neurological research ,Health ,Psychology and mental health - Published
- 2004
6. Diffraction studies of molecular crystals
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Overell, J. S. W.
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530.41 ,Solid-state physics - Published
- 1981
7. Design and rationale of the determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis (DELIVER-MS) trial
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Ontaneda, D, Tallantyre, E, Nakamura, K, Planchon, S, Miller, D, Hersh, C, Chaudhry, B, Bale, C, Alvarez, E, Chataway, J, Craner, M, Freeman, L, Frost, N, Goldman, M, Hobart, J, Hunt, D, Hutton, G, Hyland, M, Joseph, F, Lily, O, Moses, H, Nicholas, J, Nicholas, R, Overell, J, Pearson, O, Pomeroy, I, Smith, A, Zabeti, A, Gerry, S, Gunzler, D, Coles, A, LaRocca, N, Gray, E, Cohen, J, and Evangelou, N
- Published
- 2018
8. International consensus on quality standards for brain health-focused care in multiple sclerosis.
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Hobart, J, Bowen, A, Pepper, G, Crofts, H, Eberhard, L, Berger, T, Boyko, A, Boz, C, Butzkueven, H, Celius, EG, Drulovic, J, Flores, J, Horáková, D, Lebrun-Frénay, C, Marrie, RA, Overell, J, Piehl, F, Rasmussen, PV, Sá, MJ, Sîrbu, C-A, Skromne, E, Torkildsen, Ø, van Pesch, V, Vollmer, T, Zakaria, M, Ziemssen, T, Giovannoni, G, Hobart, J, Bowen, A, Pepper, G, Crofts, H, Eberhard, L, Berger, T, Boyko, A, Boz, C, Butzkueven, H, Celius, EG, Drulovic, J, Flores, J, Horáková, D, Lebrun-Frénay, C, Marrie, RA, Overell, J, Piehl, F, Rasmussen, PV, Sá, MJ, Sîrbu, C-A, Skromne, E, Torkildsen, Ø, van Pesch, V, Vollmer, T, Zakaria, M, Ziemssen, T, and Giovannoni, G
- Abstract
BACKGROUND: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. OBJECTIVES: We sought to develop internationally applicable quality standards for timely, brain health-focused MS care. METHODS: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define 'core', 'achievable' and 'aspirational' time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. RESULTS: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. CONCLUSION: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.
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- 2019
9. Neuro-otological syndromes for the neurologist
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Overell, J and Lindahl, A
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- 2004
10. An aid to predicting prognosis in patients with non-traumatic coma at one day
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Overell, J, Bone, I, and Fuller, G N
- Published
- 2001
11. Ensemble-plus Study Design: An Investigation of Shortened Ocrelizumab Infusion Time on Infusion-related Reactions in Patients with Relapsing Multiple Sclerosis from the Phase Iiib Ensemble-plus Study
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Yamout, B., primary, Brochet, B., additional, Nos, C., additional, Freedman, M.S., additional, Killstein, J., additional, Overell, J., additional, Buffels, R., additional, Fitovski, K., additional, Mehta, L., additional, Wang, Q., additional, and Hartung, H., additional
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- 2018
- Full Text
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12. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
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Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), Terzi M., Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), and Terzi M.
- Abstract
Background: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS. Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative
- Published
- 2018
13. A giant cause of a low pressure headache
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Miller, S, Overell, J, Jampana, R, Gorrie, G, Tyagi, A, Gilles, C, and McKenzie, M
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- 2013
- Full Text
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14. Inhibition of complement in Guillain-Barré syndrome: the ICA-GBS study
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Davidson, A.I. (Amy I.), Halstead, S.K. (Susan), Goodfellow, J.A. (John A.), Chavada, G. (Govind), Mallik, A. (Arup), Overell, J. (James), Lunn, M.P.T. (Michael P. T.), McConnachie, A. (Alex), Doorn, P.A. (Pieter) van, Willison, H.J. (Hugh), Davidson, A.I. (Amy I.), Halstead, S.K. (Susan), Goodfellow, J.A. (John A.), Chavada, G. (Govind), Mallik, A. (Arup), Overell, J. (James), Lunn, M.P.T. (Michael P. T.), McConnachie, A. (Alex), Doorn, P.A. (Pieter) van, and Willison, H.J. (Hugh)
- Abstract
The outcome of Guillain-Barré syndrome (GBS) remains unchanged since plasma exchange and intravenous immunoglobulin (IVIg) were introduced over 20 years ago. Pathogenesis studies on GBS have identified the terminal component of complement cascade as a key disease mediator and therapeutic target. We report the first use of terminal complement pathway inhibition with eculizumab in humans with GBS. In a randomised, double-blind, placebo-controlled trial, 28 subjects eligible on the basis of GBS disability grade of at least 3 were screened, of whom 8 (29%) were randomised. Five received eculizumab for 4 weeks, alongside standard IVIg treatment. The safety outcomes, monitored via adverse events capture, showed eculizumab to be well-tolerated and safe when administered in conjunction with IVIg. Primary and secondary efficacy outcomes in the form of GBS disability scores (GBS DS), MRC sum scores, Rasch overall disability scores, and overall neuropathy limitation scores are reported descriptively. For the primary efficacy outcome at 4 weeks after recruitment, two of two placebo- and two of five eculizumab-treated subjects had improved by one or more grades on the GBS DS. Although the small sample size precludes a statistically meaningful analysis, these pilot data indicate further studies on complement inhibition in GBS are warranted.
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- 2017
- Full Text
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15. Randomized Trial of Thymectomy in Myasthenia Gravis
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Wolfe, Gi, Kaminski, Hj, Aban, Ib, Minisman, G, Kuo, Hc, Marx, A, Ströbel, P, Mazia, C, Oger, J, Cea, Jg, Heckmann, Jm, Evoli, A, Nix, W, Ciafaloni, E, Antonini, G, Witoonpanich, R, King, Jo, Beydoun, Sr, Chalk, Ch, Barboi, Ac, Amato, Aa, Shaibani, Ai, Katirji, B, Lecky, Br, Buckley, C, Vincent, A, Dias Tosta, E, Yoshikawa, H, Waddington Cruz, M, Pulley, Mt, Rivner, Mh, Kostera Pruszczyk, A, Pascuzzi, Rm, Jackson, Ce, Garcia Ramos GS, Verschuuren, Jj, Massey, Jm, Kissel, Jt, Werneck, Lc, Benatar, M, Barohn, Rj, Tandan, R, Mozaffar, T, Conwit, R, Odenkirchen, J, Sonett, Jr, 3rd, Jaretzki A., Newsom Davis, J, Cutter, Gr, MGTX study group including Cutter GR, Feese, M, Saluto, V, Rosenberg, M, Alvarez, V, Rey, L, King, J, Butzkueven, H, Goldblatt, J, Carey, J, Pollard, J, Reddel, S, Handel, N, Mccaughan, B, Pallot, L, Novis, R, Boasquevisque, C, Morato Fernandez, R, Ximenes, M, Werneck, L, Scola, R, Soltoski, P, Chalk, C, Moore, F, Mulder, D, Wadup, L, Mezei, M, Evans, K, Jiwa, T, Schaffar, A, White, C, Toth, C, Gelfand, G, Wood, S, Pringle, E, Zwicker, J, Maziak, D, Shamji, F, Sundaresan, S, Seely, A, Cea, G, Verdugo, R, Aguayo, A, Jander, S, Zickler, P, Klein, M, Weis, Ca, Melms, A, Bischof, F, Aebert, H, Ziemer, G, Thümler, B, Wilhem Schwenkmezger, T, Mayer, E, Schalke, B, Pöschel, P, Hieber, G, Wiebe, K, Clemenzi, A, Ceschin, V, Rendina, E, Venuta, F, Morino, S, Bucci, E, Durelli, Luca, Tavella, A, Clerico, Marinella, Contessa, G, Borasio, P, Servidei, S, Granone, P, Mantegazza, R, Berta, E, Novellino, L, Spinelli, L, Motomura, M, Matsuo, H, Nagayasu, T, Takamori, M, Oda, M, Matsumoto, I, Furukawa, Y, Noto, D, Motozaki, Y, Iwasa, K, Yanase, D, Ramos, Gg, Cacho, B, de la Garza, L, Lipowska, M, Kwiecinski, H, Potulska Chromik, A, Orlowski, T, Silva, A, Feijo, M, Freitas, A, Heckmann, J, Frost, A, Pan, El, Tucker, L, Rossouw, J, Drummond, F, Illa, I, Diaz, J, Leon, C, Yeh, Jh, Chiu, Hc, Hsieh, Ys, Tunlayadechanont, S, Attanavanich, S, Verschuuren, J, Straathof, C, Titulaer, M, Versteegh, M, Pels, A, Krum, Y, Leite, M, Hilton Jones, D, Ratnatunga, C, Farrugia, Me, Petty, R, Overell, J, Kirk, A, Gibson, A, Mcdermott, C, Hopkinson, D, Lecky, B, Watling, D, Marshall, D, Saminaden, S, Davies, D, Dougan, C, Sathasivam, S, Page, R, Sussman, J, Ealing, J, Krysiak, P, Amato, A, Salajegheh, M, Jaklitsch, M, Roe, K, Ashizawa, T, Smith, Rg, Zwischenberg, J, Stanton, P, Barboi, A, Jaradeh, S, Tisol, W, Gasparri, M, Haasler, G, Yellick, M, Dennis, C, Barohn, R, Pasnoor, M, Dimachkie, M, Mcvey, A, Gronseth, G, Dick, A, Kramer, J, Currence, M, Herbelin, L, Belsh, J, Li, G, Langenfeld, J, Mertz, Ma, Harrison, T, Force, S, Usher, S, Beydoun, S, Lin, F, Demeester, S, Akhter, S, Malekniazi, A, Avenido, G, Crum, B, Milone, M, Cassivi, S, Fisher, J, Heatwole, C, Watson, T, Hilbert, J, Smirnow, A, Distad, B, Weiss, M, Wood, D, Haug, J, Ernstoff, R, Cao, J, Chmielewski, G, Welsh, R, Duris, R, Gutmann, L, Pawar, G, Graeber, Gm, Altemus, P, Nance, C, Jackson, C, Grogan, P, Calhoon, J, Kittrell, P, Myers, D, Kaminski, H, Hayat, G, Naunheim, K, Eller, S, Holzemer, E, Alshekhlee, A, Robke, J, Karlinchak, B, Katz, J, Miller, R, Roan, R, Forshew, D, Kissel, J, Elsheikh, B, Ross, P, Chelnick, S, Lewis, R, Acsadi, A, Baciewicz, F, Masse, S, Massey, J, Juel, V, Onaitis, M, Lowe, J, Lipscomb, B, Thai, G, Milliken, J, Martin, V, Karayan, R, Muley, S, Parry, G, Shumway, S, Oh, S, Claussen, G, Lu, L, Cerfolio, R, Young, A, Morgan, M, Pascuzzi, R, Kincaid, J, Kesler, K, Guingrich, S, Michaels, A, Phillips, L, Burns, T, Jones, D, Fischer, C, Pulley, M, Berger, A, D'Agostino, H, Smith, L, Rivner, M, Pruitt, J, Landolfo, K, Hillman, D, Shaibani, A, Sermas, A, Ruel, R, Ismail, F, Sivak, M, Goldstein, M, Camunas, J, Bratton, J, Panitch, H, Leavitt, B, Jones, M, Wolfe, G, Muppidi, S, Vernino, S, Nations, S, Meyer, D, and Gorham, N.
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Male ,medicine ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Medical and Health Sciences ,Severity of Illness Index ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Prednisone ,Adolescent ,Adult ,Aged ,Combined Modality Therapy ,Female ,Glucocorticoids ,Hospitalization ,Humans ,Middle Aged ,Myasthenia Gravis ,Single-Blind Method ,Treatment Outcome ,Young Adult ,Thymectomy ,Medicine (all) ,Young adult ,MGTX Study Group ,General Medicine ,Settore MED/26 - NEUROLOGIA ,6.1 Pharmaceuticals ,medicine.drug ,medicine.medical_specialty ,Clinical Trials and Supportive Activities ,Autoimmune Disease ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,General & Internal Medicine ,Internal medicine ,Severity of illness ,business.industry ,Neurosciences ,Evaluation of treatments and therapeutic interventions ,Retrospective cohort study ,medicine.disease ,Myasthenia gravis ,Surgery ,Clinical research ,adolescent ,adult ,aged ,combined modality therapy ,female ,glucocorticoids ,hospitalization ,humans ,male ,middle aged ,myasthenia gravis ,prednisone ,severity of Illness index ,single-blind method ,treatment outcome ,young adult ,thymectomy ,business ,030217 neurology & neurosurgery - Abstract
BackgroundThymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone.MethodsWe compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period.ResultsA total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P
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- 2016
16. Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study
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Mahdi Rogers, M, Rutterford, C, Hughes, Ra, Léger, Jm, Nobile Orazio, E, Van den Bergh, P, van Doorn, P, van Schaik IN, Hadden, Rd, Choy, E, Reilly, M, Winer, J, Evers, E, van Doorn PA, Créange, A, Gueguen, A, Uzenot, D, Behin, A, Nicolas, G, Pautot, V, Uncini, A, Manzoli, C, Lauria, G, Pareyson, D, Casellato, C, Sabatelli, M, Conte, A, Luigetti, M, Briani, Chiara, Lucchetta, Marta, Schenone, A, Benedetti, L, Fiorina, E, Brusse, E, van der Kooi AJ, Guiloff, Rj, Rakowicz, Wp, Lecky, Br, Dougan, Cf, Marshall, D, Davies, N, Busby, M, Lansbury, A, Overell, J, Willison, Hj, Rajabally, Ya, Kendall, B, Gow, D, Nixon, J, Kulkarni, O, Katifi, H, Hammans, S, Gibson, A, Mcdermott, C, Cornblath, Dr, Chaudry, V., Amsterdam institute for Infection and Immunity, Amsterdam Neuroscience, and Neurology
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Male ,medicine.medical_specialty ,Anti-Inflammatory Agents ,Pilot Projects ,Placebo ,Placebo group ,law.invention ,Disability Evaluation ,Folic Acid ,Randomized controlled trial ,Double-Blind Method ,law ,Adrenal Cortex Hormones ,Internal medicine ,Medicine ,Humans ,Adverse effect ,Aged ,Intention-to-treat analysis ,business.industry ,Immunoglobulins, Intravenous ,Polyradiculoneuropathy ,Odds ratio ,Vitamins ,Middle Aged ,medicine.disease ,Surgery ,Methotrexate ,Treatment Outcome ,Polyradiculoneuropathy, Chronic Inflammatory Demyelinating ,Female ,Neurology (clinical) ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) responds to treatment with corticosteroids, intravenous immunoglobulin, and plasma exchange. We aimed to test whether the standard immunosuppressive drug methotrexate was of use in treatment of CIDP. METHODS: In a pilot, multicentre, randomised, double-blind, controlled trial we compared oral methotrexate 7.5 mg weekly for 4 weeks, then 10 mg weekly for 4 weeks, and finally 15 mg weekly for 32 weeks (40 weeks' total treatment) with placebo in patients with CIDP requiring intravenous immunoglobulin or corticosteroids. After about 16 weeks, the dose of corticosteroids or intravenous immunoglobulin was decreased by 20% every 4 weeks if participants did not deteriorate. Primary outcome was a greater than 20% reduction in mean weekly dose in the last 4 weeks of the trial compared with the first 4 weeks. Secondary outcomes analysed separately at the mid-trial and final visits measured activity limitations and strength. Analyses were done by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN73774524. FINDINGS: 59 of the 60 enrolled participants completed the trial. 14 (52%) of 27 taking methotrexate and 14 (44%) of 32 taking placebo had a greater than 20% reduction in mean weekly dose of corticosteroids or intravenous immunoglobulin (adjusted odds ratio 1.21, 95% CI 0.40-3.70). There were no clinically and statistically significant differences in secondary outcomes. The one serious adverse event in the placebo group and the three in the methotrexate group were not thought to be related to treatment. INTERPRETATION: Oral methotrexate 15 mg weekly showed no significant benefit, but limitations in the trial design and the high rate of response in the placebo group meant that a treatment effect could not be excluded. This study can inform design of future trials in CIDP. FUNDING: The GBS/CIDP Foundation International
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- 2009
17. Peripheral neuropathy: pattern recognition for the pragmatist
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Overell, J. R., primary
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- 2011
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18. POC24 Subspeciality demand in a regional neurology service
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Newman, E., primary, Overell, J., additional, Leach, J. P., additional, Garscadden, R., additional, Farrugia, M. E., additional, Gorrie, G., additional, and Thomas, S. R., additional
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- 2010
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19. Chronic inflammatory demyelinating polyradiculoneuropathy: classification and treatment options
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Overell, J. R, primary and Willison, H. J, additional
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- 2006
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20. Interatrial septal abnormalities and stroke: A meta-analysis of case-control studies
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Overell, J. R., primary, Bone, I., additional, and Lees, K. R., additional
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- 2000
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21. Treatment and secondary prevention of stroke (multiple letters)
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Overell, J. R., Christopher Weir, Walker, A., Lees, K. R., Newcombe, H., Hankey, G., and Warlow, C.
22. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature
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Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, Gunther C, Ritchie D, Daniel Gale, Ys, Kanwar, Challis R, Buist H, Overell J, Weller B, Flossmann O, Blunden M, Ep, Meyer, Krucker T, Sj, Evans, and Il, Campbell
23. An X-ray single-crystal study of the molecular system C6F6.C6D6
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Overell, J. S. W., primary and Pawley, G. S., additional
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- 1982
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24. Powder refinement of carbonyl sulphide
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Overell, J. S. W., primary, Pawley, G. S., additional, and Powell, B. M., additional
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- 1982
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25. An aid to predicting prognosis in patients with non-traumatic coma at one day.
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Overell J, Bone I, Fuller GN, Overell, J, Bone, I, and Fuller, G N
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- 2001
26. Treatment and secondary prevention of stroke.
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Overell, J R, Weir, C J, Walker, A, and Lees, K R
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- 2000
27. Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry
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Montalban, Xavier, Butzkueven, Helmut, Spelman, Tim, Horakova, Dana, Hughes, Stella, Solaro, Claudio Marcello, Izquierdo, Guillermo, Kubala Havrdova, Eva, Grand'Maison, Francois, Prat, Alexandre, Girard, Marc, Hupperts, Raymond, Onofrj, Marco, Lugaresi, Alessandra, Taylor, Bruce, Giovannoni, Gavin, Kappos, Ludwig, Hauser, Stephen L., Craveiro, Licinio, Freitas, Rita, Model, Fabian, Overell, James, Muros-Le Rouzic, Erwan, Sauter, Annette, Wang, Qing, Wormser, David, Wolinsky, Jerry S., MSBase Study Group, Universitat Autònoma de Barcelona, Butzkueven H., Spelman T., Horakova D., Hughes S., Solaro C., Izquierdo G., Kubala Havrdova E., Grand'Maison F., Prat A., Girard M., Hupperts R., Onofrj M., Lugaresi A., Taylor B., Giovannoni G., Kappos L., Hauser S.L., Montalban X., Craveiro L., Freitas R., Model F., Overell J., Muros-Le Rouzic E., Sauter A., Wang Q., Wormser D., and Wolinsky J.S.
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medicine.medical_specialty ,Multiple Sclerosis ,Primary Progressive Multiple Sclerosis ,Placebo ,Placebo group ,03 medical and health sciences ,Primary progressive multiple sclerosis ,0302 clinical medicine ,Wheelchair ,ocrelizumab ,wheelchair ,Internal medicine ,Medicine ,Humans ,Ocrelizumab ,030212 general & internal medicine ,Registries ,Disease progression ,Expanded Disability Status Scale ,business.industry ,Multiple Sclerosis, Chronic Progressive ,primary progressive multiple sclerosi ,Confidence interval ,Neurology ,Wheelchairs ,Cohort ,Disease Progression ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background and purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662). Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0–6.5) were investigated in ORATORIO and MSBase. Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio=0.54, 95% confidence interval [CI]: 0.31–0.92; p=0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: −4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4years. Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
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- 2021
28. Brain reserve and physical disability in secondary progressive multiple sclerosis.
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John N, Li Y, De Angelis F, Stutters J, Prados Carrasco F, Eshaghi A, Doshi A, Calvi A, Williams T, Plantone D, Phan T, Barkhof F, Chataway J, Ourselin S, Braisher M, Beyene T, Bassan V, Zapata A, Chandran S, Connick P, Lyle D, Cameron J, Mollison D, Colville S, Dhillon B, Ross M, Cranswick G, Walker A, Smith L, Giovannoni G, Gnanapavan S, Nicholas R, Rashid W, Aram J, Ford H, Pavitt SH, Overell J, Young C, Arndt H, Duddy M, Guadagno J, Evangelou N, Craner M, Palace J, Hobart J, Sharrack B, Paling D, Hawkins C, Kalra S, McLean B, Stallard N, and Bastow R
- Abstract
Background: The brain reserve hypothesis posits that larger maximal lifetime brain growth (MLBG) may confer protection against physical disability in multiple sclerosis (MS). Larger MLBG as a proxy for brain reserve, has been associated with reduced progression of physical disability in patients with early MS; however, it is unknown whether this association remains once in the secondary progressive phase of MS (SPMS). Our aim was to assess whether larger MLBG is associated with decreased physical disability progression in SPMS., Methods: We conducted a post hoc analysis of participants in the MS-Secondary Progressive Multi-Arm Randomisation Trial (NCT01910259), a multicentre randomised placebo-controlled trial of the neuroprotective potential of three agents in SPMS. Physical disability was measured by Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and 25-foot timed walk test (T25FW) at baseline, 48 and 96 weeks. MLBG was estimated by baseline intracranial volume (ICV). Multivariable time-varying Cox regression models were used to investigate the association between MLBG and physical disability progression., Results: 383 participants (mean age 54.5 years, 298 female) were followed up over 96 weeks. Median baseline EDSS was 6.0 (range 4.0-6.5). Adjusted for covariates, larger MLBG was associated with a reduced risk of EDSS progression (HR 0.84,95% CI:0.72 to 0.99;p=0.04). MLBG was not independently associated with time to progression as measured by 9HPT or T25FW., Conclusion: Larger MLBG is independently associated with physical disability progression over 96 weeks as measured by EDSS in SPMS. This suggests that MLBG as a proxy for brain reserve may continue to confer protection against disability when in the secondary progression phase of MS., Trail Registration Number: NCT01910259., Competing Interests: NJ is a local principal investigator on commercial MS studies funded by Novartis, Roche and Sanofi. He has received speakers honoraria from Merck and congress sponsorship covering registration and travel from Novartis. FB serves on the editorial boards of Brain, European Radiology, Journal of Neurology, Neurosurgery & Psychiatry, Neurology, Multiple Sclerosis and Neuroradiology, and serves as consultant for Bayer Schering Pharma, Sanofi-Aventis, Biogen-Idec, TEVA Pharmaceuticals, Genzyme, Merck-Serono, Novartis, Roche, Synthon, Jansen Research and Lundbeck. CAGW-K has received research grants (PI and co-applicant) from Spinal Research, Craig H. Neilsen Foundation, EPSRC, Wings for Life, UK MS Society, Horizon 2020, NIHR/MRC, MRC and is a shareholder of Queen Square Analytics. In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS Society. A local principal investigator for commercial trials funded by: Actelion, Biogen, Novartis and Roche; has received an investigator grant from Novartis; and has taken part in advisory boards/consultancy for Azadyne, Biogen, Celgene, Janssen, MedDay, Merck, NervGen, Novartis and Roche., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
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- 2024
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29. Innovation and optimization in autoimmune encephalitis trials: the design and rationale for the Phase 3, randomized study of satralizumab in patients with NMDAR-IgG-antibody-positive or LGI1-IgG-antibody-positive autoimmune encephalitis (CIELO).
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Lee ST, Abboud H, Irani SR, Nakajima H, Piquet AL, Pittock SJ, Yeh EA, Wang J, Rajan S, Overell J, Smith J, St Lambert J, El-Khairi M, Gafarova M, and Gelfand JM
- Abstract
Background: Autoimmune encephalitis (AIE) encompasses a spectrum of rare autoimmune-mediated neurological disorders, which are characterized by brain inflammation and dysfunction. Autoantibodies targeting the N -methyl-d-aspartic acid receptor (NMDAR) and leucine-rich glioma-inactivated 1 (LGI1) are the most common subtypes of antibody-positive AIE. Currently, there are no approved therapies for AIE. Interleukin-6 (IL-6) signaling plays a role in the pathophysiology of AIE. Satralizumab, a humanized, monoclonal recycling antibody that specifically targets the IL-6 receptor and inhibits IL-6 signaling, has demonstrated efficacy and safety in another autoantibody-mediated neuroinflammatory disease, aquaporin-4 immunoglobulin G antibody-positive neuromyelitis optica spectrum disorder, and has the potential to be an evidence-based disease modifying treatment in AIE., Objectives: CIELO will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of satralizumab compared with placebo in patients with NMDAR-immunoglobulin G antibody-positive (IgG+) or LGI1-IgG+ AIE., Study Design: CIELO (NCT05503264) is a prospective, Phase 3, randomized, double-blind, multicenter, basket study that will enroll approximately 152 participants with NMDAR-IgG+ or LGI1-IgG+ AIE. Prior to enrollment, participants will have received acute first-line therapy. Part 1 of the study will consist of a 52-week primary treatment period, where participants will receive subcutaneous placebo or satralizumab at Weeks 0, 2, 4, and every 4 weeks thereafter. Participants may continue to receive background immunosuppressive therapy, symptomatic treatment, and rescue therapy throughout the study. Following Part 1, participants can enter an optional extension period (Part 2) to continue the randomized, double-blind study drug, start open-label satralizumab, or stop study treatment and continue with follow-up assessments., Endpoints: The primary efficacy endpoint is the proportion of participants with a ≥1-point improvement in the modified Rankin Scale (mRS) score from study baseline and no use of rescue therapy at Week 24. Secondary efficacy assessments include mRS, Clinical Assessment Scale of Autoimmune Encephalitis (CASE), time to rescue therapy, sustained seizure cessation and no rescue therapy, Montreal Cognitive Assessment, and Rey Auditory Verbal Learning Test (RAVLT) measures. Safety, pharmacokinetics, pharmacodynamics, exploratory efficacy, and biomarker endpoints will be captured., Conclusion: The innovative basket study design of CIELO offers the opportunity to yield prospective, robust evidence, which may contribute to the development of evidence-based treatment recommendations for satralizumab in AIE., Competing Interests: S-TL reports advisory roles for Roche/Genentech, Biofire Diagnostics, GC Pharma, Celltrion, and Advanced Neural Technologies. HA is a consultant and speaker for Biogen, Genentech, BMS, Horizon, and Alexion. HA has served as a consultant and/or advisory board member for Cycle Pharma, Alpine Pharma, and Axonics. HA received honoraria from Neurology Live. HA receives research support from Genentech, BMS, Novartis, Sanofi, UCB, and the Guthy-Jackson Charitable Foundation. HA receives royalties from UpToDate. HA serves as an Assistant Editor for Neurology Journal. SI has received honoraria/research support from UCB, Immunovant, Roche, Janssen, Cerebral Therapeutics, ADC Therapeutics, Brain, CSL Behring, and ONO Pharma. SI receives licensed royalties on patent application WO/2010/046716 entitled ‘Neurological Autoimmune Disorders,’ and has filed two other patents entitled “Diagnostic method and therapy” (WO2019211633 and US-2021-0071249-A1; PCT application WO202189788A1) and “Biomarkers” (PCT/GB2022/050614 and WO202189788A1). HN reports being a consultant/advisor for F. Hoffmann-La Roche Ltd. and has received speaker honoraria from Alexion, Biogen, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Kirin, and Takeda. AP reports research grants from the University of Colorado, Rocky Mountain MS Center, and the Foundation for Sarcoidosis; consulting fees from Genentech/Roche, UCB, EMD Serono, and Alexion; and honoraria from MedLink and publication royalties from Springer as co-editor of a medical textbook. AP serves as an unpaid member of the Medical Advisory Board for the Autoimmune Encephalitis Alliance. SP reports grants, personal fees, and nonfinancial support from Alexion Pharmaceuticals; grants, personal fees, and nonfinancial support from MedImmune, Viela Bio, and Horizon; grants from Adimune; grants, personal fees, and nonfinancial support from Genentech and Roche, and personal fees for consulting from UCB, Astellas, and Arialys. SP has two patents issued (8889102; application 12-678350; Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia; and 9891219B2; application 12-573942; Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an Individual That is Aquaporin-4 [AQP4]-IgG Autoantibody-Positive), for which he has received royalties. SP also has patents pending for IgGs to the following proteins as biomarkers of autoimmune neurological disorders: septin-5, kelch-like protein 11, GFAP, PDE10A, and MAP1B. SP is an employee of Mayo Clinic, which offers commercial NMDAR and LGI1-IgG testing. SP receives no royalties from the sale of tests done at the neuroimmunology laboratory at Mayo Clinic. EY has received research funding from NMSS, CMSC, CIHR, NIH, OIRM, SCN, CBMH Chase an Idea, SickKids Foundation, Rare Diseases Foundation, MS Scientific Foundation, McLaughlin Centre, Leong Center, and Peterson Foundation, and investigator-initiated research funding from Biogen. EY has served on a scientific advisory board for F. Hoffmann-La Roche and a data safety monitoring board for TG Therapeutics and has received speaker honoraria from Biogen, JHU, Saudi Epilepsy Society, NYU, MS-ATL, ACRS, PRIME, and CNPS. JW serves as a trial steering committee member for the CIELO study. JO and MG are employees and shareholders of F. Hoffmann-La Roche Ltd. JS, JSL, and ME-K are employees of Roche Products Ltd. and shareholders of F. Hoffmann-La Roche Ltd. SR is an employee and shareholder of Genentech, Inc. JG receives research support to his institution from F. Hoffmann-La Roche Ltd. for clinical trials and serves as chair of the Trial Steering Committee for the CIELO study. JG has also received research support to his institution for clinical trials from Vigil Neurosciences; and received personal fees for consulting for Arialys and Ventyx Bio. The authors declare that this study received funding from F. Hoffmann-La Roche. The sponsor had the following involvement in the study: study design, collection, analysis and the decision to submit it for publication. Medical writing assistance was provided by Reece Bracewell, MBiolSci and Nicole Ellman, PhD, of Apothecom, London, UK, and was funded by F. Hoffmann-La Roche Ltd. All authors contributed to the conceptualisation, drafting, revising, and critical reviewing of the manuscript for intellectual content, and approved the final version of this manuscript to be published., (Copyright © 2024 Lee, Abboud, Irani, Nakajima, Piquet, Pittock, Yeh, Wang, Rajan, Overell, Smith, St Lambert, El-Khairi, Gafarova and Gelfand.)
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- 2024
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30. Patient-reported outcome parameters and disability worsening in progressive multiple sclerosis.
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Abdelhak A, Antweiler K, Kowarik MC, Senel M, Havla J, Zettl UK, Kleiter I, Hoshi MM, Skripuletz T, Haarmann A, Stahmann A, Huss A, Gingele S, Krumbholz M, Selge C, Friede T, Ludolph AC, Overell J, Koendgen H, Clinch S, Wang Q, Ziemann U, Hauser SL, Kümpfel T, Green AJ, and Tumani H
- Subjects
- Humans, Retrospective Studies, Prospective Studies, Patient Reported Outcome Measures, Disease Progression, Multiple Sclerosis drug therapy, Multiple Sclerosis, Chronic Progressive diagnosis, Multiple Sclerosis, Chronic Progressive drug therapy
- Abstract
Objectives: Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS., Methods: Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated., Results: EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29
physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30th- ], 2.11 [20th- ], and 2.8 [10th percentile], P = 0.007, 0.012 and 0.005, respectively)., Conclusions: PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AA received research funding from DMSG, AMSEL, Bavarian MS Trust. MK received travel funding, speaker honoraria and research support from Bristol Myers Squibb, Merck, Novartis and Roche, all not related to this manuscript. MS received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Roche, and Sanofi Genzyme; none related to this work. JH reports a grant for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees and non-financial support from Merck, Alexion, Novartis, Roche, Celgene, Biogen, Bayer and Horizon and non-financial support of the Sumaira-Foundation and Guthy-Jackson Charitable Foundation, all outside the submitted work. UKZ has received speaking fees, travel support, and financial support for research activities from Alexion, Almirall, Bayer, Biogen, Celgene, Janssen, Merck Serono, Novartis, Octapharm, Roche, Sanofi Genzyme, Teva as well as EU, BMBF, BMWi and DFG. None resulted in a conflict of interest. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Alexion, Almirall, Bayer, Biogen, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi, all outside the submitted work. AS has no personal pecuniary interests to disclose, other than being the lead of the German MS Registry, which receives project funding from a range of public and corporate sponsors, recently including The German Innovation Fund (G-BA), The German Retirement Insurance, The German MS Trust, The German MS Society, Biogen, BMS, Merck, Novartis, Roche, and Sanofi. All outside the submitted work. AH received travel funding, consulting and/or speaker honoraria from Alexion, Argenx and Horizon; none related to this manuscript. MCK has served on advisory boards and received speaker fees / travel grants from Merck, Sanofi-Genzyme, Novartis, Biogen, Jansen, Alexion, Celgene / Bristol-Myers Squibb and Roche and received research grants from Merck, Sanofi-Genzyme and Celgene / Bristol-Myers Squibb. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alnylam Pharmaceuticals and Merck all outside the submitted work. HK was an employee and shareholder of F. Hoffmann–La Roche Ltd during completion of the work related to this manuscript. He is currently an employee and shareholder of UCB Farchim SA, Bulle, Switzerland. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene, Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global and Allergan, employment from Hoffmann La-Roche and is a shareholder of Hoffmann La-Roche. QW, SC are employee and shareholder of F. Hoffmann–La Roche Ltd. TF reports personal fees for consultancies (including data monitoring committees) in the past three years from Bayer, BiosenseWebster, Cardialysis, CSL Behring, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, Janssen, Kyowa Kirin, Lilly, Liva Nova, Minoryx, Mylan, Novartis, Roche, Vifor; all outside the submitted work. UZ received grants from the European Research Council (ERC), German Ministry of Education and Research (BMBF), German Research Foundation (DFG), Takeda Pharmaceutical Company Ltd., and consulting fees from CorTec GmbH, all not related to this work. TK has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche Pharma, Alexion/Astra Zeneca and Biogen as well as grant support from Novartis and Chugai Pharma in the past. HT received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Celgene, GSK, Jannssen, Merck, Novartis, Roche, Sanofi Genzyme and TEVA; none related to this work. All other authors report no conflict of interest in relation to this work., (Copyright © 2023. Published by Elsevier B.V.)- Published
- 2024
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31. Opioid prescribing patterns following common general surgery procedures in the Bay of Plenty, New Zealand.
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Mclaughlin S, Overell J, and Rossaak J
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- Male, Female, Humans, Analgesics, Opioid therapeutic use, Bays, New Zealand epidemiology, Pain, Postoperative drug therapy, Practice Patterns, Physicians', Australia, Retrospective Studies, Opioid-Related Disorders epidemiology, Opioid-Related Disorders prevention & control, Hernia, Inguinal complications
- Abstract
Background: Global increases in opioid prescribing and misuse have prompted calls for closer regulation. Opioid prescription following surgery may lead to long term opioid use. A study was conducted evaluating opioid prescriptions on hospital discharge following common general surgery operations in the Bay of Plenty., Methods: Retrospective observational study over a two-year period in two regional New Zealand hospitals. Six hundred and eleven patients aged 18-64 years were assessed. Patients with complications, readmission, and a prescription of opioids in the preceding 3 months were excluded., Results: A total of 460 patients (165 Laparoscopic Cholecystectomy (LC), 200 Laparoscopic Appendicectomy (LA) and 95 Open Inguinal Hernia Repair (OIHR)) were included in analysis. Opioids were prescribed to 53% of LC, 55% of LA, and 60% of OIHR patients, with a mean of 75.8 Morphine Milligram Equivalents (MMEs), 75.3 MMEs, and 82.8 MMEs respectively. Seven percent of patients (18/254) received a second opioid prescription within 3 months, and of those only 1.6% (4/254) received a further prescription between 3 and 6 months from discharge. Opioid prescribing did not correlate with operation, ethnicity, age, length of stay, or gender, except for males receiving a more MMEs than females following LC (mean 102.0 MMEs versus 65.4 MMEs, P = 0.017)., Conclusion: This study shows a rate of opioid prescribing lower than the USA, and greater than seen in an Australian setting. Substantial amounts of opioids were prescribed following uncomplicated surgery, with significant variability. Improvements in training in post-operative opioid prescribing are needed. Fortunately, rates of ongoing opioid use were low., (© 2023 Royal Australasian College of Surgeons.)
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- 2023
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32. Risk of requiring a walking aid after 6.5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis: Data from the OPERA I and OPERA II trials.
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Giovannoni G, Kappos L, de Seze J, Hauser SL, Overell J, Koendgen H, Manfrini M, Wang Q, and Wolinsky JS
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- Antibodies, Monoclonal, Humanized, Humans, Immunologic Factors adverse effects, Walking, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting drug therapy
- Abstract
Background and Purpose: Requiring a walking aid is a fundamental milestone in multiple sclerosis (MS), represented by an Expanded Disability Status Scale (EDSS) score ≥6.0. In the present study, we assess the effect of ocrelizumab (OCR) on time to EDSS score ≥6.0 in relapsing MS., Methods: Time to EDSS score ≥6.0 confirmed for ≥24 and ≥48 weeks was assessed over the course of 6.5 years (336 weeks) in the double-blind period (DBP) and open-label extension (OLE) period of the OPERA I (NCT01247324) and OPERA II (NCT01412333) studies., Results: Time to reach EDSS score ≥6.0 was significantly delayed in those initially randomized to OCR versus interferon. Over 6.5 years, the risk of requiring a walking aid confirmed for ≥24 weeks was 34% lower among those who initiated OCR earlier versus delayed treatment (average hazard ratio [HR] DBP + OLE 0.66, 95% confidence interval [CI] 0.45-0.95; p = 0.024); the risk of requiring a walking aid confirmed for ≥48 weeks was 46% lower (average HR DBP+OLE 0.54, 95% CI 0.35-0.83; p = 0.004)., Conclusion: The reduced risk of requiring a walking aid in earlier initiators of OCR demonstrates the long-term implications of earlier highly effective treatment., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
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- 2022
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33. Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry.
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Butzkueven H, Spelman T, Horakova D, Hughes S, Solaro C, Izquierdo G, Kubala Havrdová E, Grand'Maison F, Prat A, Girard M, Hupperts R, Onofrj M, Lugaresi A, Taylor B, Giovannoni G, Kappos L, Hauser SL, Montalban X, Craveiro L, Freitas R, Model F, Overell J, Muros-Le Rouzic E, Sauter A, Wang Q, Wormser D, and Wolinsky JS
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- Disease Progression, Humans, Registries, Multiple Sclerosis drug therapy, Multiple Sclerosis, Chronic Progressive drug therapy, Wheelchairs
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Background and Purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662)., Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0-6.5) were investigated in ORATORIO and MSBase., Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31-0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: -4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years., Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
- Published
- 2022
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34. MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis.
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York EN, Martin SJ, Meijboom R, Thrippleton MJ, Bastin ME, Carter E, Overell J, Connick P, Chandran S, Waldman AD, and Hunt DPJ
- Abstract
Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single-molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation and neurite orientation dispersion and density imaging diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 versus 0.57, difference 0.036, 95% CI: 0.029-0.043, P < 0.001). Lesion volume (Spearman's rho r
s = 0.38, P < 0.001) and g-ratio (rs = 0.24, P < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load ( n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) [11/23 (48%) versus 2/15 (13%), P < 0.05]. These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity and help to identify individuals with a high degree of axonal damage at disease onset., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)- Published
- 2021
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35. Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study.
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Brown JWL, Cunniffe NG, Prados F, Kanber B, Jones JL, Needham E, Georgieva Z, Rog D, Pearson OR, Overell J, MacManus D, Samson RS, Stutters J, Ffrench-Constant C, Gandini Wheeler-Kingshott CAM, Moran C, Flynn PD, Michell AW, Franklin RJM, Chandran S, Altmann DR, Chard DT, Connick P, and Coles AJ
- Subjects
- Adult, Bexarotene administration & dosage, Bexarotene adverse effects, Double-Blind Method, Evoked Potentials, Visual physiology, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting diagnostic imaging, Multiple Sclerosis, Relapsing-Remitting physiopathology, Bexarotene pharmacology, Drug-Related Side Effects and Adverse Reactions, Multiple Sclerosis, Relapsing-Remitting drug therapy, Outcome Assessment, Health Care, Remyelination drug effects, Retinoid X Receptors agonists
- Abstract
Background: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis., Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m
2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed., Findings: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55)., Interpretation: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies., Funding: Multiple Sclerosis Society of the United Kingdom., Competing Interests: Declaration of interests JWLB reports personal fees from Biogen for real-world evidence consultation, outside the submitted work. NGC reports grants from the Multiple Sclerosis Society of the United Kingdom, during the conduct of the study. JLJ reports grants and personal fees from Sanofi, outside the submitted work. DR reports grants from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, TG Therapeutics, and Mitsubishi, and personal fees from Merck, Roche, Biogen, MedDay, Sanofi Genzyme, Novartis, Janssen, and Celgene, outside the submitted work. ORP reports personal fees from Biogen, Genzyme, Merck, Novartis, Celegene, and Roche, outside the submitted work. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene, Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global, and Allergan, and employment from Hoffmann La-Roche, outside the submitted work, and is a shareholder of Hoffmann La-Roche. Cf-C reports grants from Roche, outside the submitted work. CM reports personal fees from Sanofi, AstraZeneca, and Apitope, and non-financial support from Sanofi and AstraZeneca, outside the submitted work. RJMF reports grants from Biogen, and personal fees from Biogen, Frequency Therapeutics, and Rewind Therapeutics, outside the submitted work. SC reports funding from Phenotherapeutics, outside the submitted work. DTC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study, and personal fees from Biogen and Hoffmann-La Roche, grants from the International Progressive MS Alliance and the Multiple Sclerosis Society of the United Kingdom, and infrastructure support from the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, outside the submitted work. AJC reports grants from the Multiple Sclerosis Society of the United Kingdom during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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36. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial.
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Wolinsky JS, Arnold DL, Brochet B, Hartung HP, Montalban X, Naismith RT, Manfrini M, Overell J, Koendgen H, Sauter A, Bennett I, Hubeaux S, Kappos L, and Hauser SL
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Double-Blind Method, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Immunologic Factors administration & dosage, Immunologic Factors adverse effects, Male, Middle Aged, Outcome Assessment, Health Care, Young Adult, Antibodies, Monoclonal, Humanized pharmacology, Disease Progression, Immunologic Factors pharmacology, Multiple Sclerosis, Chronic Progressive drug therapy
- Abstract
Background: The safety and efficacy of ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO., Methods: ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18-55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0-6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued ocrelizumab or switched from placebo to ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test [9HPT], ≥20% increase in time to perform the Timed 25-Foot Walk [T25FW], and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov, NCT01194570, and is ongoing., Findings: From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% [95% CI 4·9-21·3]; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% [4·1-20·9]); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% [-0·3 to 15·2]; p=0·058); composite progression, 73·2% vs 83·3% (10·1% [3·6-16·6]; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% [0·8-13·9]; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p<0·0001) and T1 hypointense lesion volume (36·68% vs 60·93%, p<0·0001). Over the entire period, in the ORATORIO all ocrelizumab exposure population, the rate of adverse events was 238·09 (95% CI 232·71-243·57) per 100 patient-years and serious adverse events was 12·63 (95% CI 11·41-13·94) per 100 patient-years; the most common serious adverse events were infections at 4·13 (95% CI 3·45-4·91) per 100 patient-years. No new safety signals emerged compared with the double-blind phase of ORATORIO., Interpretation: Compared with patients switching from placebo, earlier and continuous ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods., Funding: F Hoffmann-La Roche., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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37. Diagnosis and management of multiple sclerosis: MRI in clinical practice.
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Tomassini V, Sinclair A, Sawlani V, Overell J, Pearson OR, Hall J, and Guadagno J
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- Humans, State Medicine, Magnetic Resonance Imaging, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis therapy
- Abstract
Background: Recent changes in the understanding and management of multiple sclerosis (MS) have increased the role of MRI in supporting diagnosis and disease monitoring. However, published guidelines on the use of MRI in MS do not translate easily into different clinical settings and considerable variation in practice remains. Here, informed by published guidelines for the use of MRI in MS, we identified a clinically informative MRI protocol applicable in a variety of clinical settings, from district general hospitals to tertiary centres., Methods: MS specialists geographically representing the UK National Health Service and with expertise in MRI examined existing guidelines on the use of MRI in MS and identification of challenges in their applications in various clinical settings informed the formulation of a feasible MRI protocol., Results: We identified a minimum set of MRI information, based on clinical relevance, as well as on applicability to various clinical settings. This informed the selection of MRI acquisitions for scanning protocols, differentiated on the basis of their purpose and stage of the disease, and indication of timing for scans. Advice on standardisation of MRI requests and reporting, and proposed timing and frequency of MRI scans were generated., Conclusions: The proposed MRI protocol can adapt to a range of clinical settings, aiding the impetus towards standardisation of practice and offering an example of research-informed service improvement to support optimisation of resources. Other neurological conditions, where a gap still exists between published guidelines and their clinical implementation, may benefit from this same approach.
- Published
- 2020
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38. International consensus on quality standards for brain health-focused care in multiple sclerosis.
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Hobart J, Bowen A, Pepper G, Crofts H, Eberhard L, Berger T, Boyko A, Boz C, Butzkueven H, Celius EG, Drulovic J, Flores J, Horáková D, Lebrun-Frénay C, Marrie RA, Overell J, Piehl F, Rasmussen PV, Sá MJ, Sîrbu CA, Skromne E, Torkildsen Ø, van Pesch V, Vollmer T, Zakaria M, Ziemssen T, and Giovannoni G
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- Consensus, Delphi Technique, Humans, Brain pathology, Multiple Sclerosis diagnosis, Multiple Sclerosis pathology, Multiple Sclerosis therapy, Neurology standards
- Abstract
Background: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS., Objectives: We sought to develop internationally applicable quality standards for timely, brain health-focused MS care., Methods: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define 'core', 'achievable' and 'aspirational' time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders., Results: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms., Conclusion: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.
- Published
- 2019
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39. Cerebrospinal fluid neurofilament light chain in multiple sclerosis and its subtypes: a meta-analysis of case-control studies.
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Martin SJ, McGlasson S, Hunt D, and Overell J
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- Case-Control Studies, Humans, Multiple Sclerosis diagnosis, Multiple Sclerosis, Chronic Progressive cerebrospinal fluid, Multiple Sclerosis, Chronic Progressive diagnosis, Multiple Sclerosis, Relapsing-Remitting cerebrospinal fluid, Multiple Sclerosis, Relapsing-Remitting diagnosis, Severity of Illness Index, Multiple Sclerosis cerebrospinal fluid, Neurofilament Proteins cerebrospinal fluid
- Abstract
Objective: Neurofilament is a biomarker of axonal injury proposed as a useful adjunct in the monitoring of patients with multiple sclerosis (MS). We conducted a systematic review and meta-analysis of case-control studies that have measured neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of people with MS (pwMS), in order to determine whether, and to what degree, CSF NfL levels differentiate MS from controls, or the subtypes or stages of MS from each other., Methods: Guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. Electronic databases were searched for published and 'grey' literature, with 151 hits. Of 51 full articles screened, 20 were included in qualitative analysis, and 14 in meta-analysis., Results: CSF NfL was higher in 746 pwMS than 435 (healthy and disease) controls, with a moderate effect size of 0.61 (p < 0.00001). Mean CSF NfL levels were significantly higher in 176 pwMS with relapsing disease than 92 with progressive disease (2124.8 ng/L, SD 3348.9 vs 1121.4 ng/L, SD 947.7, p = 0.0108). CSF NfL in 138 pwMS in relapse (irrespective of MS subtype) was double that seen in 268 pwMS in remission (3080.6 ng/L, SD 4715.9 vs 1541.7 ng/L, SD 2406.5, p < 0.0001)., Conclusions: CSF NfL correlates with MS activity throughout the course of MS, reflecting the axonal damage in pwMS. Relapse is more strongly associated with elevated CSF NfL levels than the development of progression, and NfL may be most useful as a marker of disease 'activity' rather than as a marker of disability or disease stage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2019
- Full Text
- View/download PDF
40. Towards a More User-Friendly Medication Information Delivery to People Living with Multiple Sclerosis: A Case Study with Alemtuzumab.
- Author
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Azman A, Poyade M, and Overell J
- Subjects
- Antibodies, Monoclonal, Humanized, Computer Graphics, Humans, Mobile Applications, User-Computer Interface, Alemtuzumab therapeutic use, Health Literacy, Multiple Sclerosis drug therapy, Patient Education as Topic methods
- Abstract
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system which leads to demyelination and neurodegeneration. The T and B cells, the body's immune cells, start attacking the brain and spinal cord, leading to a variety of symptoms. Alemtuzumab is a recently approved disease-modifying therapy that has been shown to have a very high impact on MS. However, it has many potentially life-threatening side effects which patients are often not aware of. For treatments as effective and risky as Alemtuzumab, patients who are considering it must be well-informed on the process and the potential side effects. Patient education is vital to equip patients with knowledge on their disease and treatment, and has shown to be successful in improving the management of chronic diseases and increasing medication adherence. Unfortunately, the language used is often too complex and at a higher reading level than average patients can comprehend, and available resources such as pamphlets and websites are often disorganized. This research proposes a radically different approach to patient education, using less formal channels such as a mobile application to improve health literacy, using LEMTRADA
® (Alemtuzumab) as an example. MS patients were involved in a co-design process to produce a series of user-friendly, intuitive and interactive graphical interfaces which propose plain language, illustrations, animations, audio and Augmented Reality components that aim to enhance patients' knowledge retention and recall. Finally, nine MS patients along with a senior MS nurse tested the mobile application and answered a usability questionnaire that aimed to compare the delivery of information with typical websites and pamphlets. Results suggested this approach to be highly user-friendly and engaging, improving patients' understanding of medical information considerably. This research illustrates more engaging channels to communicate with MS patients in order to enhance health literacy.- Published
- 2019
- Full Text
- View/download PDF
41. Factors influencing multiple sclerosis disease-modifying treatment prescribing decisions in the United Kingdom: A qualitative interview study.
- Author
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Cameron E, Rog D, McDonnell G, Overell J, Pearson O, and French DP
- Subjects
- Female, Humans, Interviews as Topic, Male, Neurology methods, Qualitative Research, United Kingdom, Clinical Decision-Making, Multiple Sclerosis drug therapy, Practice Patterns, Physicians'
- Abstract
Background: The proportion of people with relapsing-remitting multiple sclerosis prescribed disease modifying treatments (DMTs) in the United Kingdom (UK) is considered low compared with other countries. There are differences in DMT prescription rates between UK nations (England, Wales, Scotland, Northern Ireland). Despite this, there has been little research into decision-making processes and prescribing practices., Objective: To investigate views and experiences of neurologists prescribing DMTs and MS specialist nurses to identify factors influencing prescribing., Methods: Semi-structured interviews with 18 consultant neurologists and 16 specialist nurses from diverse settings across the four UK nations. Data were analysed using thematic framework analysis., Results: Prescribing practices are influenced by organisational prescribing "cultures", informal "benchmarking" within peer networks, and prior experience with different DMTs. Health professionals differ in their perceptions of benefits and risks of DMTs and personal "thresholds" for discerning relapses and determining eligibility for DMTs. Prescribers in England felt most constrained by guidelines., Conclusion: To achieve equity in access to DMTs for people with MS eligible for treatment, there is a need for public discussion acknowledging differences in health professionals' interpretations of "relapses" and guidelines and perceptions of DMTs, variation in organisational prescribing "cultures", and whether the prevailing culture sufficiently meets patients' needs., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2019
- Full Text
- View/download PDF
42. Inhibition of complement in Guillain-Barré syndrome: the ICA-GBS study.
- Author
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Davidson AI, Halstead SK, Goodfellow JA, Chavada G, Mallik A, Overell J, Lunn MP, McConnachie A, van Doorn P, and Willison HJ
- Subjects
- Adult, Aged, Disability Evaluation, Dose-Response Relationship, Drug, Double-Blind Method, Female, Gangliosidoses, GM2 metabolism, Gangliosidosis, GM1 metabolism, Humans, Longitudinal Studies, Male, Middle Aged, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Guillain-Barre Syndrome drug therapy, Immunologic Factors therapeutic use
- Abstract
The outcome of Guillain-Barré syndrome (GBS) remains unchanged since plasma exchange and intravenous immunoglobulin (IVIg) were introduced over 20 years ago. Pathogenesis studies on GBS have identified the terminal component of complement cascade as a key disease mediator and therapeutic target. We report the first use of terminal complement pathway inhibition with eculizumab in humans with GBS. In a randomised, double-blind, placebo-controlled trial, 28 subjects eligible on the basis of GBS disability grade of at least 3 were screened, of whom 8 (29%) were randomised. Five received eculizumab for 4 weeks, alongside standard IVIg treatment. The safety outcomes, monitored via adverse events capture, showed eculizumab to be well-tolerated and safe when administered in conjunction with IVIg. Primary and secondary efficacy outcomes in the form of GBS disability scores (GBS DS), MRC sum scores, Rasch overall disability scores, and overall neuropathy limitation scores are reported descriptively. For the primary efficacy outcome at 4 weeks after recruitment, two of two placebo- and two of five eculizumab-treated subjects had improved by one or more grades on the GBS DS. Although the small sample size precludes a statistically meaningful analysis, these pilot data indicate further studies on complement inhibition in GBS are warranted., (© 2016 Peripheral Nerve Society.)
- Published
- 2017
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43. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature.
- Author
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Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, Gunther C, Ritchie D, Gale DP, Kanwar YS, Challis R, Buist H, Overell J, Weller B, Flossmann O, Blunden M, Meyer EP, Krucker T, Evans SJ, Campbell IL, Jackson AP, Chandran S, and Hunt DP
- Subjects
- Animals, Biopsy, Humans, Kidney drug effects, Kidney pathology, Mice, Transgenic, Microvessels ultrastructure, Multiple Sclerosis pathology, Signal Transduction drug effects, Species Specificity, Interferon Type I adverse effects, Microvessels drug effects, Thrombotic Microangiopathies chemically induced
- Abstract
Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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44. Clinical Reasoning: A 48-year-old man with walking difficulty.
- Author
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Kalladka D, Iqbal A, MacDuff E, and Overell J
- Subjects
- Humans, Male, Middle Aged, POEMS Syndrome physiopathology, Mobility Limitation, POEMS Syndrome diagnosis, Walking physiology
- Published
- 2015
- Full Text
- View/download PDF
45. A pragmatic approach to dealing with fingolimod-related lymphopaenia in Europe.
- Author
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Giovannoni G, de Jong B, Derfuss T, Izquierdo G, Mazibrada G, Molyneux P, Nicholas R, Overell J, Ziemssen T, and Juliusson G
- Subjects
- Europe, Humans, Multiple Sclerosis drug therapy, Fingolimod Hydrochloride adverse effects, Immunosuppressive Agents adverse effects, Lymphopenia chemically induced
- Published
- 2015
- Full Text
- View/download PDF
46. Thrombotic microangiopathy associated with interferon beta.
- Author
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Hunt D, Kavanagh D, Drummond I, Weller B, Bellamy C, Overell J, Evans S, Jackson A, and Chandran S
- Subjects
- Humans, Hypertension, Malignant diagnosis, Interferon beta-1a, Interferon-beta administration & dosage, Kidney pathology, Recombinant Proteins administration & dosage, Scotland, Thrombotic Microangiopathies diagnosis, Thrombotic Microangiopathies pathology, United Kingdom, Hypertension, Malignant etiology, Interferon-beta adverse effects, Multiple Sclerosis drug therapy, Pharmacovigilance, Recombinant Proteins adverse effects, Thrombotic Microangiopathies etiology
- Published
- 2014
- Full Text
- View/download PDF
47. Variant CJD in an individual heterozygous for PRNP codon 129.
- Author
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Kaski D, Mead S, Hyare H, Cooper S, Jampana R, Overell J, Knight R, Collinge J, and Rudge P
- Subjects
- Adult, Codon, Creutzfeldt-Jakob Syndrome diagnosis, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Creutzfeldt-Jakob Syndrome genetics, Prions genetics
- Published
- 2009
- Full Text
- View/download PDF
48. Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders.
- Author
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Overell JR, Hsieh ST, Odaka M, Yuki N, and Willison HJ
- Subjects
- Consciousness Disorders etiology, Consciousness Disorders therapy, Humans, Brain Stem, Encephalitis therapy, Immunotherapy, Miller Fisher Syndrome therapy
- Abstract
Background: Fisher syndrome is one of the regional variants of Guillain-Barré syndrome, characterised by impairment of eye movements (ophthalmoplegia), incoordination (ataxia) and loss of tendon reflexes (areflexia). It can occur in more limited forms, and may overlap with Guillain-Barré syndrome. A further variant is associated with upper motor neuron signs and disturbance of consciousness (Bickerstaff's brainstem encephalitis). All of these variants are associated with anti-GQ1b IgG antibodies. Intravenous immunoglobulin (IVIg) and plasma exchange are often used as treatments in this patient group. This review was undertaken to systematically assess any available randomised controlled data on acute immunomodulatory therapies in Fisher Syndrome or its variants., Objectives: To provide the best available evidence from randomised controlled trials on the role of acute immunomodulatory therapy in the treatment of Fisher Syndrome and related disorders., Search Strategy: We searched the Cochrane Neuromuscular Disease Trials register (March 2004), MEDLINE (from January 1966 to November 2004), EMBASE (from January 1980 to November 2004), CINAHL (from January 1982 to November 2004) and LILACS (from January 1982 to November 2004) for randomised controlled trials, quasi-randomised trials, historically controlled studies and trials with concurrent controls. We adapted this strategy to search MEDLINE from 1966 and EMBASE from 1980 for comparative cohort studies, case-control studies and case series., Selection Criteria: All randomised and quasi-randomised controlled clinical trials (in which allocation was not random but was intended to be unbiased, e.g. alternate allocation, and non-randomised controlled studies were to have been selected. Since no such clinical trials were discovered, all retrospective case series containing five or more patients were assessed and summarised in the discussion section., Data Collection and Analysis: All studies of Fisher Syndrome and its clinical variants were scrutinised for data on patients treated with any form of acute immunotherapy. Information on the outcome was then collated and summarised., Main Results: We found no randomised or non-randomised prospective controlled trials of immunotherapy in Fisher Syndrome or related disorders. We summarised the results of retrospective series containing five or more patients in the discussion section., Authors' Conclusions: There are no randomised controlled trials of immunomodulatory therapy in Fisher Syndrome or related disorders on which to base practice.
- Published
- 2007
- Full Text
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49. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism.
- Author
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Overell JR, Lees KR, and Bone I
- Subjects
- Anticoagulants therapeutic use, Heart Septal Defects, Atrial surgery, Humans, Research Design, Secondary Prevention, Stroke complications, Embolism, Paradoxical complications, Heart Septal Defects, Atrial etiology
- Published
- 2001
- Full Text
- View/download PDF
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