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143 results on '"Gunawardena, H."'

1. Mind, Body, Heart and Spirit: Leader Transformation and the Coming into Being of the Leader’s Creative Vision

Author

Gunawardena H. P. G. V., Jayakody J. A. S. K., and Adikaram A.S.

Subjects
creative leadership, organizational transformation leader, creative vision, leader transformation process, generalized theorem of transformation, Management. Industrial management, HD28-70
Abstract

his article aims to explore and discuss how the leader’s creative vision comes into being within the leader and how it triggers the attainment of organizational transformation. Adopting the embedded multiple case study approach, three descriptive cases (organizational transformation initiatives) were selected for the analysis. In-depth interviews were carried out with the leader of the organizational transformation initiatives and fifteen respondents involved in the transformations. Westley and Mintzberg’s Visionary Leadership Theory and Brook’s Theorem on Transformation were used as the theoretical lenses of the study. Findings indicate the transformation process through which the leader’s creative vision comes into being as an outcome of a ‘whole-person’ transformation involving the mind, body, heart, and spirit of the leader, which passes through the states of ‘active desire’, ‘intent’, ‘confidence’, and finally ‘action’ when the leader’s creative vision is shared with the followers. The contribution of these findings to theory and practice are also discussed.

Published
2023
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6. AB0589 TOCILIZUMAB FOR GIANT CELL ARTERITIS: BASELINE AND TWELVE MONTH AUDIT DATA FROM THE UK BRISTOL AND BATH MULTIDISCIPLINARY MEETING.

Author

Jayatilleke, C. N. R., primary, Anilkumar, A., additional, Janagan, S., additional, Marshall, R. W., additional, Skeoch, S., additional, Guly, C., additional, Sin, F. E., additional, Austin, K., additional, Al-Sweedan, L., additional, Bourn, A., additional, Clarke, L., additional, Gunawardena, H., additional, Boyce, B., additional, Knights, S., additional, Pauling, J. D., additional, Reilly, E., additional, Reynolds, T. D., additional, Villar, S., additional, and Robson, J. C., additional

Published
2022
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17. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

Author

Herrick, A, Peytrignet, S, Lunt, M, Pan, X, Hesselstrand, R, Mouthon, L, Silman, A, Dinsdale, G, Brown, E, Czirják, L, Distler, J, Distler, O, Fligelstone, K, Gregory, W, Ochiel, R, Vonk, M, Ancuţa, C, Ong, V, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jobanputra, P, Jordan, A, Stevens, W, Moinzadeh, P, Hall, F, Agard, C, Anderson, M, Diot, E, Madhok, R, Akil, M, Buch, M, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, Macgregor, A, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, P, Fauchais, A, Hachulla, E, Hamilton, J, İnanç, M, McLaren, J, Van Laar, J, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, D, Grange, C, Trad, G, and Denton, C

Subjects
Adult, Male, Skin/pathology, systemic sclerosis, autoantibodies, Severity of Illness Index, Scleroderma, Diffuse/diagnosis, outcomes research, Predictive Value of Tests, Skin Tests/statistics & numerical data, Humans, Prospective Studies, Skin, Skin Tests, RNA Polymerase III, Clinical and Epidemiological Research, Early Diagnosis, Logistic Models, ROC Curve, RNA Polymerase III/analysis, Area Under Curve, Scleroderma, Diffuse, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Disease Progression, Female, Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study
Abstract

ObjectivesOur aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). MethodsThe modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. ConclusionsTwo prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration numberNCT02339441.

Published
2018
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21. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

Author

Herrick, A.L., Peytrignet, S., Lunt, M., Pan, X., Hesselstrand, R., Mouthon, L., Silman, A.J., Dinsdale, G., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jobanputra, P., Jordan, A.C., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N.S., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S.M., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., Denton, C.P., Herrick, A.L., Peytrignet, S., Lunt, M., Pan, X., Hesselstrand, R., Mouthon, L., Silman, A.J., Dinsdale, G., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jobanputra, P., Jordan, A.C., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N.S., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S.M., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., and Denton, C.P.

Abstract

Contains fulltext : 191335.pdf (publisher's version ) (Open Access), OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (+/-3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2018

22. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

Author

Midtvedt O., Veale D.J., Grange C., Trad G.-S., Denton C.P., Herrick A.L., Peytrignet S., Lunt M., Pan X., Hesselstrand R., Mouthon L., Silman A.J., DInsdale G., Brown E., Czirjak L., DIstler J.H.W., DIstler O., Fligelstone K., Gregory W.J., Ochiel R., Vonk M.C., Ancu C., Ong V.H., Farge D., Hudson M., Matucci-Cerinic M., Balbir-Gurman A., Jobanputra P., Jordan A.C., Stevens W., Moinzadeh P., Hall F.C., Agard C., Anderson M.E., DIot E., Madhok R., Akil M., Buch M.H., Chung L., Damjanov N.S., Gunawardena H., Lanyon P., Ahmad Y., Chakravarty K., Jacobsen S., MacGregor A.J., McHugh N., Muller-Ladner U., Riemekasten G., Becker M., Roddy J., Carreira P.E., Fauchais A.L., Hachulla E., Hamilton J., Inanc M., McLaren J.S., Van Laar J.M., Pathare S., Proudman S.M., Rudin A., Sahhar J., Coppere B., Serratrice C., Sheeran T., Midtvedt O., Veale D.J., Grange C., Trad G.-S., Denton C.P., Herrick A.L., Peytrignet S., Lunt M., Pan X., Hesselstrand R., Mouthon L., Silman A.J., DInsdale G., Brown E., Czirjak L., DIstler J.H.W., DIstler O., Fligelstone K., Gregory W.J., Ochiel R., Vonk M.C., Ancu C., Ong V.H., Farge D., Hudson M., Matucci-Cerinic M., Balbir-Gurman A., Jobanputra P., Jordan A.C., Stevens W., Moinzadeh P., Hall F.C., Agard C., Anderson M.E., DIot E., Madhok R., Akil M., Buch M.H., Chung L., Damjanov N.S., Gunawardena H., Lanyon P., Ahmad Y., Chakravarty K., Jacobsen S., MacGregor A.J., McHugh N., Muller-Ladner U., Riemekasten G., Becker M., Roddy J., Carreira P.E., Fauchais A.L., Hachulla E., Hamilton J., Inanc M., McLaren J.S., Van Laar J.M., Pathare S., Proudman S.M., Rudin A., Sahhar J., Coppere B., Serratrice C., and Sheeran T.

Abstract

Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (+/-3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441.Copyright © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Published
2018

23. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

Author

Herrick, AL, Peytrignet, S, Lunt, M, Pan, X, Hesselstrand, R, Mouthon, L, Silman, AJ, Dinsdale, G, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, MC, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jobanputra, P, Jordan, AC, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, NS, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, SM, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, Denton, CP, Herrick, AL, Peytrignet, S, Lunt, M, Pan, X, Hesselstrand, R, Mouthon, L, Silman, AJ, Dinsdale, G, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, MC, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jobanputra, P, Jordan, AC, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, NS, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, SM, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, and Denton, CP

Abstract

OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2018

24. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Author

Herrick, A, Pan, X, Peytrignet, S, Lunt, M, Hesselstrand, R, Mouthon, L, Silman, A, Brown, E, Czirják, L, Distler, J, Distler, O, Fligelstone, K, Gregory, W, Ochiel, R, Vonk, M, Ancuţa, C, Ong, V, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jordan, A, Jobanputra, P, Stevens, W, Moinzadeh, P, Hall, F, Agard, C, Anderson, M, Diot, E, Madhok, R, Akil, M, Buch, M, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, Macgregor, A, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, P, Fauchais, A, Hachulla, E, Hamilton, J, İnanç, M, McLaren, J, Van Laar, J, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, D, Grange, C, Trad, G, and Denton, C

Subjects
Adult, Male, Methotrexate/therapeutic use, RNA Polymerase III/immunology, Antibodies, Antinuclear/immunology, Systemic Sclerosis, Severity of Illness Index, Cohort Studies, Early Medical Intervention, Journal Article, Humans, Prospective Studies, Cyclophosphamide, Autoantibodies, Nuclear Proteins, RNA Polymerase III, Mycophenolic Acid/therapeutic use, Clinical and Epidemiological Research, Middle Aged, Mycophenolic Acid, Scleroderma, Diffuse/drug therapy, Treatment, Europe, Survival Rate, Methotrexate, Treatment Outcome, DNA Topoisomerases, Type I, Cyclophosphamide/therapeutic use, Antibodies, Antinuclear, Scleroderma, Diffuse, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Immunosuppressive Agents/therapeutic use, Nuclear Proteins/immunology, Female, Autoantibodies/immunology, Immunosuppressive Agents
Abstract

Objectives: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. Methods: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Results: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. Conclusions: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. Trial Registration Number: NCT02339441.

Published
2017
Full Text
View/download PDF

26. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Author

Herrick, A.L., Pan, X., Peytrignet, S., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jordan, A.C., Jobanputra, P., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M, Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., Denton, C.P., Herrick, A.L., Pan, X., Peytrignet, S., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jordan, A.C., Jobanputra, P., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M, Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., and Denton, C.P.

Abstract

Contains fulltext : 174691.pdf (publisher's version ) (Open Access), OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2017

27. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS).

Author

Herrick, AL, Pan, X, Peytrignet, S, Lunt, M, Hesselstrand, R, Mouthon, L, Silman, A, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, M, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jordan, AC, Jobanputra, P, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, Denton, CP, Herrick, AL, Pan, X, Peytrignet, S, Lunt, M, Hesselstrand, R, Mouthon, L, Silman, A, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, M, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jordan, AC, Jobanputra, P, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, and Denton, CP

Abstract

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2017

28. Reversible acetylation regulates acetate and propionate metabolism in Mycobacterium smegmatis

Author

Braunstein, M., Hayden, J. D., Chen, X., Gunawardena, H. P., Brown, L. R., and Perkowski, E. F.

Abstract

Carbon metabolic pathways are important to the pathogenesis of Mycobacterium tuberculosis, the causative agent of tuberculosis. However, extremely little is known about metabolic regulation in mycobacteria. There is growing evidence for lysine acetylation being a mechanism of regulating bacterial metabolism. Lysine acetylation is a post-translational modification in which an acetyl group is covalently attached to the side chain of a lysine residue. This modification is mediated by acetyltransferases, which add acetyl groups, and deacetylases, which remove the acetyl groups. Here we set out to test whether lysine acetylation and deacetylation impact acetate metabolism in the model mycobacteria Mycobacterium smegmatis, which possesses 25 candidate acetyltransferases and 3 putative lysine deacetylases. Using mutants lacking predicted acetyltransferases and deacetylases we showed that acetate metabolism in M. smegmatis is regulated by reversible acetylation of acetyl-CoA synthetase (Ms-Acs) through the action of a single pair of enzymes: the acetyltransferase Ms-PatA and the sirtuin deacetylase Ms-SrtN. We also confirmed that the role of Ms-PatA in regulating Ms-Acs regulation depends on cAMP binding. We additionally demonstrated a role for Ms-Acs, Ms-PatA and Ms-SrtN in regulating the metabolism of propionate in M. smegmatis. Finally, along with Ms-Acs, we identified a candidate propionyl-CoA synthetase, Ms5404, as acetylated in whole-cell lysates. This work lays the foundation for studying the regulatory circuit of acetylation and deacetylation in the cellular context of mycobacteria.

Published
2013
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29. Modulation of B-cell exosome proteins by gamma herpesvirus infection

Author

Raab-Traub, N., Dekroon, R. M., Heaton, P. R., Damania, B., Edwards, R. H., Ozgur, S., Gunawardena, H. P., Meckes, D. G., and Griffith, J. D.

Subjects
viruses
Abstract

Exosomes are released from tumor cells at high levels, and multiple studies have determined that the secreted exosomes enter recipient cells and can affect their biologic and biochemical properties. In this study, the specific effects of the oncogenic herpesviruses, EBV and Kaposi sarcoma-associated virus, on the proteomes of B-cell exosomes were determined using global quantitative proteomics. The data indicate that the viruses greatly impact the protein content of exosomes with common and distinct changes induced by both viruses. It is likely that these alterations in exosome content modulate the tumor environment, potentially to enhance viral infection and promote tumorigenesis.

Published
2013
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30. BCLAF1 is a radiation-induced H2AX-interacting partner involved in γH2AX-mediated regulation of apoptosis and DNA repair

Author

Chen, X., Xie, L., Yu, Y. B., Lee, Y. Y., and Gunawardena, H. P.

Subjects
enzymes and coenzymes (carbohydrates), biological phenomena, cell phenomena, and immunity
Abstract

H2AX, a histone H2A variant, has a key role in the cellular response to DNA double-strand breaks (DSBs). H2AX senses DSBs through rapid serine 139 phosphorylation, concurrently leading to the formation of phospho-(γ)H2AX foci with various proteins. However, in the cells with different sensitivity to ionizing radiation (IR)-induced DSBs, still incomplete are those specific proteins selectively recruited by γH2AX to decide different cell fates. Because the abundance of γH2AX indicates the extent of DSBs, we first identified IR-induced dose-dependent H2AX-interacting partners and found that Bcl-2-associated transcription factor 1 (BCLAF1/Btf) showed enhanced association with γH2AX only under high-dose radiation. In acutely irradiated cells, BCLAF1 promoted apoptosis of irreparable cells through disturbing p21-mediated inhibition of Caspase/cyclin E-dependent, mitochondrial-mediated pathways. Meanwhile, BCLAF1 co-localized with γH2AX foci in nuclei and stabilized the Ku70/DNA-PKcs complex therein, facilitating non-homologous end joining (NHEJ)-based DSB repair in surviving cells. In tumor cells, BCLAF1 was intrinsically suppressed, leading to formation of anti-apoptotic Ku70–Bax complexes and disruption of Ku70/DNA-PKcs complexes, all of which contribute to tumor-associated apoptotic resistance and cell survival with defective NHEJ DNA repair. For the first time, our studies reveal that, based on the extent of DNA damage, BCLAF1 is involved in the γH2AX-mediated regulation of apoptosis and DNA repair, and is a γH2AX-interacting tumor suppressor.

Published
2012
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31. The PTPN22 gene is associated with juvenile and adult UK Caucasian idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype

Author

Chinoy, H., Platt, H., Lamb, J.A., Betteridge, Z., Gunawardena, H., Fertig, N., Varsani, H., Davidson, J., Oddis, C.V., McHugh, N.J., Wedderburn, L.R., Ollier, W.E.R., and Cooper, R.G.

Subjects
Adult, Adolescent, Myositis, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Polymorphism, Single Nucleotide, Article, United Kingdom, White People, Gene Frequency, Haplotypes, Case-Control Studies, Humans, Genetic Predisposition to Disease, Autoantibodies
Abstract

To examine single-nucleotide polymorphisms (SNPs) of the protein tyrosine phosphatase N22 gene (PTPN22) and to study the relationship between PTPN22 and the HLA region in patients with idiopathic inflammatory myopathies (IIMs).PTPN22 SNPs were assessed in a large, cross-sectional, case-control study from the UK involving patients with adult or juvenile IIM, comprising patients with polymyositis (PM) (n=114), dermatomyositis (DM) (n=102), myositis associated with another connective tissue disease (myositis-CTD overlap syndrome) (n=64), or juvenile DM (n=101), in comparison with 748 control subjects. Seventeen PTPN22 SNPs were genotyped using the Sequenom MassArray iPLEX platform. Serotyping for myositis-specific/myositis-associated autoantibodies (MSAs/MAAs) was performed by radioimmunoprecipitation.A significant association was noted between the R620W variant (rs2476601) and IIM (corrected P [Pcorr]=0.0009 versus controls), and specifically with the clinical subgroup of PM (Pcorr=0.003 versus controls). A weaker association was noted with juvenile DM (Pcorr=0.009 versus controls). No significant associations were noted after stratification by serologic subgroups. The association with the R620W variant was independent of alleles forming the HLA 8.1 haplotype. No other PTPN22 SNPs were associated with IIM. The PTPN22 haplotype containing the R620W T allele was the only haplotype significantly associated with IIM.The R620W variant is a significant risk factor for IIM, independent of the HLA 8.1 haplotype. Unlike that in the HLA region, risk is not increased in individuals possessing MSAs/MAAs. These results are further evidence that the PTPN22 gene confers autoimmune susceptibility.

Published
2008

34. Oral Abstracts 3: Adolescent and Young Adult * O13. Hypermobility is a Risk Factor for Musculoskeletal Pain in Adolescence: Findings From a Prospective Cohort Study

Author

Tobias, J., primary, Deere, K., additional, Palmer, S., additional, Clark, E., additional, Clinch, J., additional, Fikree, A., additional, Aktar, R., additional, Wellstead, G., additional, Knowles, C., additional, Grahame, R., additional, Aziz, Q., additional, Amaral, B., additional, Murphy, G., additional, Ioannou, Y., additional, Isenberg, D. A., additional, Tansley, S. L., additional, Betteridge, Z. E., additional, Gunawardena, H., additional, Shaddick, G., additional, Varsani, H., additional, Wedderburn, L., additional, McHugh, N., additional, De Benedetti, F., additional, Ruperto, N., additional, Espada, G., additional, Gerloni, V., additional, Flato, B., additional, Horneff, G., additional, Myones, B. L., additional, Onel, K., additional, Frane, J., additional, Kenwright, A., additional, Lipman, T. H., additional, Bharucha, K. N., additional, Martini, A., additional, Lovell, D. J., additional, Baildam, E., additional, Brunner, H., additional, Zuber, Z., additional, Keane, C., additional, Harari, O., additional, Cuttica, R. J., additional, Keltsev, V., additional, Xavier, R., additional, Penades, I. C., additional, Nikishina, I., additional, Rubio-Perez, N., additional, Alekseeva, E., additional, Chasnyk, V., additional, Chavez, J., additional, Opoka-Winiarska, V., additional, Quartier, P., additional, Silva, C. A., additional, Silverman, E. D., additional, Spindler, A., additional, Hendry, G. J., additional, Watt, G. F., additional, Brandon, M., additional, Friel, L., additional, Turner, D., additional, Lorgelly, P. K., additional, Gardner-Medwin, J., additional, Sturrock, R. D., additional, Woodburn, J., additional, Firth, J., additional, Waxman, R., additional, Law, G., additional, Siddle, H., additional, Nelson, A. E., additional, Helliwell, P., additional, Otter, S., additional, Butters, V., additional, Loughrey, L., additional, Alcacer-Pitarch, B., additional, Tranter, J., additional, Davies, S., additional, Hryniw, R., additional, Lewis, S., additional, Baker, L., additional, Dures, E., additional, Hewlett, S., additional, Ambler, N., additional, Clarke, J., additional, Gooberman-Hill, R., additional, Jenkins, R., additional, Wilkie, R., additional, Bucknall, M., additional, Jordan, K., additional, McBeth, J., additional, Norton, S., additional, Walsh, D., additional, Kiely, P., additional, Williams, R., additional, Young, A., additional, Harkess, J. E., additional, McAlarey, K., additional, Chesterton, L., additional, van der Windt, D. A., additional, Sim, J., additional, Lewis, M., additional, Mallen, C. D., additional, Mason, E., additional, Hay, E., additional, Clarson, L. E., additional, Hider, S. L., additional, Belcher, J., additional, Heneghan, C., additional, Roddy, E., additional, Gibson, J., additional, Whiteford, S., additional, Williamson, E., additional, Beatty, S., additional, Hamilton-Dyer, N., additional, Healey, E. L., additional, Ryan, S., additional, McHugh, G. A., additional, Main, C. J., additional, Porcheret, M., additional, Nio Ong, B., additional, Pushpa-Rajah, A., additional, Dziedzic, K. S., additional, MacRae, C. S., additional, Shortland, A., additional, Lewis, J., additional, Morrissey, M., additional, Critchley, D., additional, Muller, S., additional, Helliwell, T., additional, Cole, Z., additional, Parsons, C., additional, Crozier, S., additional, Robinson, S., additional, Taylor, P., additional, Inskip, H., additional, Godfrey, K., additional, Dennison, E., additional, Harvey, N. C., additional, Cooper, C., additional, Prieto Alhambra, D., additional, Lalmohamed, A., additional, Abrahamsen, B., additional, Arden, N., additional, de Boer, A., additional, Vestergaard, P., additional, de Vries, F., additional, Kendal, A., additional, Carr, A., additional, Prieto-Alhambra, D., additional, Judge, A., additional, Chapurlat, R., additional, Bellamy, N., additional, Czerwinski, E., additional, Pierre Devogelaer, J., additional, March, L., additional, Pavelka, K., additional, Reginster, J.-Y., additional, Kiran, A., additional, Javaid, M. K., additional, Sundy, J. S., additional, Baraf, H. S., additional, Becker, M., additional, Treadwell, E. L., additional, Yood, R., additional, and Ottery, F. D., additional

Published
2013
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43. A User's Guide to the Encyclopedia of DNA Elements (ENCODE)

Author

Zhi Lu, Giltae Song, Troy W. Whitfield, Vishwanath R. Iyer, Teresa Vales, Angelika Merkel, Max Libbrecht, David Haussler, Ting Wang, Kristen Lee, Lingyun Song, Richard M. Myers, Alfonso Valencia, Rachel A. Harte, Xiaoqin Xu, Lucas D. Ward, Hazuki Takahashi, Nathan C. Sheffield, Thomas Derrien, Georgi K. Marinov, Eric D. Nguyen, Bernard B. Suh, Brian J. Raney, Richard Sandstrom, Thomas D. Tullius, Benoit Miotto, Alexander Dobin, Youhan Xu, Lukas Habegger, Ian Dunham, Brian A. Risk, Paul G. Giresi, Morgan C. Giddings, Hualin Xi, Anshul Kundaje, Robert S. Harris, Devin Absher, Peter J. Bickel, Yanbao Yu, Browen Aken, Colin Kingswood, Bryan R. Lajoie, Peter J. Good, Katrina Learned, Laura Elnitski, Shirley Pepke, Brandon King, Piero Carninci, Xinqiong Yang, Ghia Euskirchen, Kathryn Beal, Christelle Borel, Michael Muratet, Robert L. Grossman, David G. Knowles, Zarmik Moqtaderi, Veronika Boychenko, Steven P. Wilder, Michael L. Tress, Florencia Pauli, Alan P. Boyle, Andrea Tanzer, Philipp Kapranov, Serafim Batzoglou, Audra K. Johnson, Jun Neri, Nitin Bhardwaj, Elise A. Feingold, Venkat S. Malladi, Michael M. Hoffman, William Stafford Noble, Andrea Sboner, Mark Gerstein, Stephanie L. Parker, Jacqueline Dumais, Felix Schlesinger, Deborah R. Winter, Randall H. Brown, Thanh Truong, Rebecca F. Lowdon, Paolo Ribeca, Brooke Rhead, Peggy J. Farnham, Krista Thibeault, Terrence S. Furey, Donna Karolchik, Alec Victorsen, Xiaoan Ruan, Rehab F. Abdelhamid, Amy S. Nesmith, Jing Wang, Nicholas M. Luscombe, Alina R. Cao, Diane Trout, Teri Slifer, Peter E. Newburger, Cricket A. Sloan, Dimitra Lotakis, Stephen M. J. Searle, Ali Mortazavi, Alexandra Bignell, Alex Reynolds, Orion J. Buske, Chris Zaleski, Theresa K. Canfield, Ian Bell, Jin Lian, Vanessa K. Swing, Katalin Toth Fejes, Catherine Ucla, Robert E. Thurman, Jacqueline Chrast, Wei Lin, Tim Hubbard, Gary Saunders, Minyi Shi, Vihra Sotirova, Sherman M. Weissman, Jason D. Lieb, Richard Humbert, Kevin M. Bowling, Assaf Gordon, Tarjei S. Mikkelsen, Jing Leng, Thomas R. Gingeras, Fabian Grubert, Nader Jameel, Jost Vielmetter, Hannah Monahan, Preti Jain, Lindsay L. Waite, Tony Shafer, Joel Rozowsky, Michael Coyne, Brian Reed, M. Kay, Harsha P. Gunawardena, Ross C. Hardison, Gavin Sherlock, Alexandra Charos, Joseph D. Fleming, Ann S. Zweig, Jason Gertz, Rajinder Kaul, Xianjun Dong, Alexandre Reymond, Carrie A. Davis, Haiyan Huang, Chao Cheng, Marco Mariotti, Phil Lacroute, Jason A. Dilocker, Kenneth McCue, R. Robilotto, Stylianos E. Antonarakis, Sridar V. Chittur, Justin Jee, Barbara J. Wold, Sudipto K. Chakrabortty, Erica Dumais, Amartya Sanyal, Nathan Boley, Tianyuan Wang, Julien Lagarde, Anthony Kirilusha, Jonathan B. Preall, Kevin Roberts, Erika Giste, Hugo Y. K. Lam, Alvis Brazma, Gregory J. Hannon, Eric Rynes, Philippe Batut, Kevin Struhl, Margus Lukk, Manching Ku, Suganthi Balasubramanian, Sonali Jha, Jorg Drenkow, W. James Kent, Michael Snyder, Jie Wang, Anna Battenhouse, Charles B. Epstein, Rami Rauch, Christopher Shestak, John A. Stamatoyannopoulos, Gaurab Mukherjee, Cédric Howald, Tanya Kutyavin, Huaien Wang, Scott A. Tenenbaum, Wan Ting Poh, Kate R. Rosenbloom, Manolis Kellis, Pauline A. Fujita, Linfeng Wu, Anita Bansal, Molly Weaver, Linda L. Grasfeder, Peter J. Sabo, Qiang Li, Melissa S. Cline, Robert M. Kuhn, Darin London, Seth Frietze, Atif Shahab, Shane Neph, Damian Keefe, James B. Brown, Mark Diekhans, Webb Miller, Katherine Aylor Fisher, Jiang Du, Hadar H. Sheffer, Sarah Djebali, Frank Doyle, Nathan Lamarre-Vincent, Chia-Lin Wei, Laura A.L. Dillon, Jennifer Harrow, Robert C. Altshuler, Tyler Alioto, Raymond K. Auerbach, Adam Frankish, Rebekka O. Sprouse, Patrick J. Collins, E. Christopher Partridge, Zheng Liu, Yoichiro Shibata, Elliott H. Margulies, Abigail K. Ebersol, Kimberly A. Showers, Eric D. Green, Krishna M. Roskin, Job Dekker, Barbara N. Pusey, Ekta Khurana, Gilberto DeSalvo, Yijun Ruan, Hao Wang, Jainab Khatun, Henriette O'Geen, Alexej Abyzov, Brian Williams, Ryan M. McDaniell, Maya Kasowski, Manoj Hariharan, Felix Kokocinski, Gloria Despacio-Reyes, Zhancheng Zhang, Subhradip Karmakar, Ewan Birney, Koon-Kiu Yan, Xian Chen, Shinny Vong, Daniel Sobral, Nick Bild, Seul K.C. Kim, Timo Lassmann, Li Wang, Minerva E. Sanchez, Vaughan Roach, Theodore Gibson, Stephen C. J. Parker, Michael F. Lin, Patrick A. Navas, Laurence R. Meyer, Luiz O. F. Penalva, Bradley E. Bernstein, Kevin P. White, Emilie Aït Yahya Graison, Juan M. Vaquerizas, Sushma Iyengar, Kimberly M. Newberry, Akshay Bhinge, Xiaolan Zhang, Kim Bell, Yoshihide Hayashizaki, Lucas Lochovsky, Noam Shoresh, Hagen Tilgner, Philip Cayting, Dorrelyn Patacsil, Timothy E. Reddy, Eric Haugen, Katherine E. Varley, M. van Baren, Nathan D. Trinklein, Bum Kyu Lee, Tristan Frum, Marianne Lindahl-Allen, Timothy Durham, Roderic Guigó, Christopher W. Maier, Micha Sammeth, Debasish Raha, Timothy R. Dreszer, Benedict Paten, Robbyn Issner, Michael R. Brent, Kevin Y. Yip, Kim Blahnik, Jason Ernst, Zhiping Weng, Henry Amrhein, Arend Sidow, Javier Herrero, Hui Gao, Stephen G. Landt, Pouya Kheradpour, Galt P. Barber, Gregory E. Crawford, Toby Hunt, HudsonAlpha Institute for Biotechnology [Huntsville, AL], ENCODE Project Consortium : Myers RM, Stamatoyannopoulos J, Snyder M, Dunham I, Hardison RC, Bernstein BE, Gingeras TR, Kent WJ, Birney E, Wold B, Crawford GE, Bernstein BE, Epstein CB, Shoresh N, Ernst J, Mikkelsen TS, Kheradpour P, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Ward LD, Altshuler RC, Lin MF, Kellis M, Gingeras TR, Davis CA, Kapranov P, Dobin A, Zaleski C, Schlesinger F, Batut P, Chakrabortty S, Jha S, Lin W, Drenkow J, Wang H, Bell K, Gao H, Bell I, Dumais E, Dumais J, Antonarakis SE, Ucla C, Borel C, Guigo R, Djebali S, Lagarde J, Kingswood C, Ribeca P, Sammeth M, Alioto T, Merkel A, Tilgner H, Carninci P, Hayashizaki Y, Lassmann T, Takahashi H, Abdelhamid RF, Hannon G, Fejes-Toth K, Preall J, Gordon A, Sotirova V, Reymond A, Howald C, Graison E, Chrast J, Ruan Y, Ruan X, Shahab A, Ting Poh W, Wei CL, Crawford GE, Furey TS, Boyle AP, Sheffield NC, Song L, Shibata Y, Vales T, Winter D, Zhang Z, London D, Wang T, Birney E, Keefe D, Iyer VR, Lee BK, McDaniell RM, Liu Z, Battenhouse A, Bhinge AA, Lieb JD, Grasfeder LL, Showers KA, Giresi PG, Kim SK, Shestak C, Myers RM, Pauli F, Reddy TE, Gertz J, Partridge EC, Jain P, Sprouse RO, Bansal A, Pusey B, Muratet MA, Varley KE, Bowling KM, Newberry KM, Nesmith AS, Dilocker JA, Parker SL, Waite LL, Thibeault K, Roberts K, Absher DM, Wold B, Mortazavi A, Williams B, Marinov G, Trout D, Pepke S, King B, McCue K, Kirilusha A, DeSalvo G, Fisher-Aylor K, Amrhein H, Vielmetter J, Sherlock G, Sidow A, Batzoglou S, Rauch R, Kundaje A, Libbrecht M, Margulies EH, Parker SC, Elnitski L, Green ED, Hubbard T, Harrow J, Searle S, Kokocinski F, Aken B, Frankish A, Hunt T, Despacio-Reyes G, Kay M, Mukherjee G, Bignell A, Saunders G, Boychenko V, Van Baren M, Brown RH, Khurana E, Balasubramanian S, Zhang Z, Lam H, Cayting P, Robilotto R, Lu Z, Guigo R, Derrien T, Tanzer A, Knowles DG, Mariotti M, James Kent W, Haussler D, Harte R, Diekhans M, Kellis M, Lin M, Kheradpour P, Ernst J, Reymond A, Howald C, Graison EA, Chrast J, Tress M, Rodriguez JM, Snyder M, Landt SG, Raha D, Shi M, Euskirchen G, Grubert F, Kasowski M, Lian J, Cayting P, Lacroute P, Xu Y, Monahan H, Patacsil D, Slifer T, Yang X, Charos A, Reed B, Wu L, Auerbach RK, Habegger L, Hariharan M, Rozowsky J, Abyzov A, Weissman SM, Gerstein M, Struhl K, Lamarre-Vincent N, Lindahl-Allen M, Miotto B, Moqtaderi Z, Fleming JD, Newburger P, Farnham PJ, Frietze S, O'Geen H, Xu X, Blahnik KR, Cao AR, Iyengar S, Stamatoyannopoulos JA, Kaul R, Thurman RE, Wang H, Navas PA, Sandstrom R, Sabo PJ, Weaver M, Canfield T, Lee K, Neph S, Roach V, Reynolds A, Johnson A, Rynes E, Giste E, Vong S, Neri J, Frum T, Johnson EM, Nguyen ED, Ebersol AK, Sanchez ME, Sheffer HH, Lotakis D, Haugen E, Humbert R, Kutyavin T, Shafer T, Dekker J, Lajoie BR, Sanyal A, James Kent W, Rosenbloom KR, Dreszer TR, Raney BJ, Barber GP, Meyer LR, Sloan CA, Malladi VS, Cline MS, Learned K, Swing VK, Zweig AS, Rhead B, Fujita PA, Roskin K, Karolchik D, Kuhn RM, Haussler D, Birney E, Dunham I, Wilder SP, Keefe D, Sobral D, Herrero J, Beal K, Lukk M, Brazma A, Vaquerizas JM, Luscombe NM, Bickel PJ, Boley N, Brown JB, Li Q, Huang H, Gerstein M, Habegger L, Sboner A, Rozowsky J, Auerbach RK, Yip KY, Cheng C, Yan KK, Bhardwaj N, Wang J, Lochovsky L, Jee J, Gibson T, Leng J, Du J, Hardison RC, Harris RS, Song G, Miller W, Haussler D, Roskin K, Suh B, Wang T, Paten B, Noble WS, Hoffman MM, Buske OJ, Weng Z, Dong X, Wang J, Xi H, Tenenbaum SA, Doyle F, Penalva LO, Chittur S, Tullius TD, Parker SC, White KP, Karmakar S, Victorsen A, Jameel N, Bild N, Grossman RL, Snyder M, Landt SG, Yang X, Patacsil D, Slifer T, Dekker J, Lajoie BR, Sanyal A, Weng Z, Whitfield TW, Wang J, Collins PJ, Trinklein ND, Partridge EC, Myers RM, Giddings MC, Chen X, Khatun J, Maier C, Yu Y, Gunawardena H, Risk B, Feingold EA, Lowdon RF, Dillon LA, Good PJ, Harrow J, Searle S., Becker, Peter B, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology. Department of Physics, Kellis, Manolis, Epstein, Charles B., Bernstein, Bradley E., Shoresh, Noam, Ernst, Jason, Mikkelsen, Tarjei Sigurd, Kheradpour, Pouya, Zhang, Xiaolan, Wang, Li, Issner, Robbyn, Coyne, Michael J., Durham, Timothy, Ku, Manching, Truong, Thanh, Ward, Lucas D., Altshuler, Robert Charles, Lin, Michael F., ENCODE Project Consortium, Antonarakis, Stylianos, and Miotto, Benoit

Subjects
RNA, Messenger/genetics, [SDV]Life Sciences [q-bio], Messenger, Genoma humà, Genome, Medical and Health Sciences, 0302 clinical medicine, Models, ddc:576.5, Biology (General), Conserved Sequence, Genetics, 0303 health sciences, General Neuroscience, RNA-Binding Proteins, Genomics, Biological Sciences, Chromatin, 3. Good health, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, Gene Components, 030220 oncology & carcinogenesis, DNA methylation, Encyclopedia, HIV/AIDS, Proteïnes de la sang -- Aspectes genètics, General Agricultural and Biological Sciences, Databases, Nucleic Acid, Human, Research Article, Quality Control, Process (engineering), QH301-705.5, 1.1 Normal biological development and functioning, Computational biology, Biology, ENCODE, General Biochemistry, Genetics and Molecular Biology, Chromatin/metabolism, Vaccine Related, 03 medical and health sciences, Databases, Genetic, Underpinning research, Humans, RNA, Messenger, RNA-Binding Proteins/genetics/metabolism, Vaccine Related (AIDS), Gene, 030304 developmental biology, Internet, General Immunology and Microbiology, Nucleic Acid, Agricultural and Veterinary Sciences, Base Sequence, Models, Genetic, Genome, Human, Prevention, Human Genome, Computational Biology, DNA Methylation, ENCODE Project Consortium, Gene Expression Regulation, DNA-Binding Proteins/genetics/metabolism, RNA, Human genome, Immunization, Generic health relevance, Developmental Biology
Abstract

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome., National Human Genome Research Institute (U.S.), National Institutes of Health (U.S.)

Published
2011
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44. Clinical Characteristics of Anti-Synthetase Syndrome: Analysis from the CLASS project.

Author

Faghihi-Kashani S, Yoshida A, Bozan F, Zanframundo G, Rozza D, Loganathan A, Dourado E, Sambataro G, Ventura IB, Bae SS, Lim D, Gallegos DR, Yamano Y, Selva-O'Callaghan A, Mammen AL, Scirè CA, Montecucco C, Oddis CV, Fiorentino D, Bonella F, Miller FW, Lundberg IE, Schmidt J, Rojas-Serrano J, Hudson M, Kuwana M, González-Gay MA, McHugh N, Corte TJ, Doyle TJ, Werth VP, Gupta L, Roman DIP, Bianchessi LM, Devarasetti PK, Shinjo SK, Luppi F, Cavazzana I, Moghadam-Kia S, Fornaro M, Volkmann ER, Piga M, Loarce-Martos J, De Luca G, Knitza J, Wolff-Cecchi V, Sebastiani M, Schiffenbauer A, Rider LG, Campanilho-Marques R, Marts L, Bravi E, Gunawardena H, Aggarwal R, and Cavagna L

Abstract

Objective: Anti-synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data-driven classification criteria for ASSD., Methods: We utilized a large, international, multi-center "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both ASSD patients and controls with mimicking conditions, namely SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort., Results: Our analysis included 948 ASSD cases and 1077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo-1 and non-Jo-1 anti-synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti-Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/MRI/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between ASSD and controls or were inversely associated with ASSD., Conclusion: We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data-driven classification criteria for ASSD., (This article is protected by copyright. All rights reserved.)

Published
2024
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45. IgG and plasma viscosity as markers of disease activity in primary Sjogren's syndrome-related lymphocytic interstitial pneumonia.

Author

Alawi S, Dixon G, Bhatt N, Adamali HI, and Gunawardena H

Subjects
Humans, Female, Middle Aged, Male, Blood Viscosity physiology, Aged, Sjogren's Syndrome complications, Sjogren's Syndrome blood, Lung Diseases, Interstitial etiology, Lung Diseases, Interstitial blood, Biomarkers blood, Immunoglobulin G blood
Abstract

Competing Interests: Competing interests: None declared.

Published
2024
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46. The diagnosis and management of systemic autoimmune rheumatic disease-related interstitial lung disease: British Society for Rheumatology guideline scope.

Author

Hannah J, Rodziewicz M, Mehta P, Heenan KM, Ball E, Barratt S, Carty S, Conway R, Cotton CV, Cox S, Crawshaw A, Dawson J, Desai S, Fahim A, Fielding C, Garton M, George P, Gunawardena H, Kelly C, Khan F, Koduri G, Morris H, Naqvi M, Perry E, Riddell C, Sieiro Santos C, Spencer LG, Chaudhuri N, and Nisar MK

Abstract

Interstitial lung disease (ILD) is a significant complication of many systemic autoimmune rheumatic diseases (SARDs), although the clinical presentation, severity and outlook may vary widely between individuals. Despite the prevalence, there are no specific guidelines addressing the issue of screening, diagnosis and management of ILD across this diverse group. Guidelines from the ACR and EULAR are expected, but there is a need for UK-specific guidelines that consider the framework of the UK National Health Service, local licensing and funding strategies. This article outlines the intended scope for the British Society for Rheumatology guideline on the diagnosis and management of SARD-ILD developed by the guideline working group. It specifically identifies the SARDs for consideration, alongside the overarching principles for which systematic review will be conducted. Expert consensus will be produced based on the most up-to-date available evidence for inclusion within the final guideline. Key issues to be addressed include recommendations for screening of ILD, identifying the methodology and frequency of monitoring and pharmacological and non-pharmacological management. The guideline will be developed according to methods and processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Published
2024
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47. Teachers as first responders: classroom experiences and mental health training needs of Australian schoolteachers.

Author

Gunawardena H, Leontini R, Nair S, Cross S, and Hickie I

Subjects
Adolescent, Child, Humans, Mental Health, Australia, Anxiety, Mental Disorders, Emergency Responders
Abstract

Background: Schoolteachers are often the first to respond when a student presents with a mental health issue in the classroom. This places a burden on schools that impacts school staff, healthcare workers and teachers. More broadly, it places a responsibility on the education system to address students' mental health. This study examines Australian teachers' classroom experiences and the training areas identified by teachers as necessary to manage these issues., Method: Interviews were undertaken with 18 in-service teachers between 2020 and 2021 from Catholic, Independent and Public schools. Data were gathered via multiple interviews and analysed using thematic content analysis., Results: The major mental health issues identified by teachers related to mental disorders, depression, anxiety, and a complex range of negative emotional states. Teachers requested training in child and adolescent mental health, counselling skills, early detection and intervention, and training skills to manage the complex relationship with parents and external health and community personnel. Teachers also reported the need to access mental health resources, support and training, which were differentially accessed along socioeconomic status and postcodes., Conclusion: The data show that teachers are often placed as first responders when a student has a mental health issue but feel inadequately trained to manage these issues in the classroom. We identified mental health issues presenting in Australian classrooms and documented critical features of mental-health training asked for by teachers in order to address those issues. Given the increasing demands on teachers to address the mental health of children and adolescents, we argue that an urgent review of mental health training for teachers is needed., (© 2024. The Author(s).)

Published
2024
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48. A Phase II randomized controlled trial of oral prednisolone in early diffuse cutaneous systemic sclerosis (PRedSS).

Author

Griffiths-Jones DJ, Garcia YS, Ryder WD, Pauling JD, Hall F, Lanyon P, Bhat S, Douglas K, Gunawardena H, Akil M, Anderson M, Griffiths B, Del Galdo F, Youssef H, Madhok R, Arthurs B, Buch M, Fligelstone K, Zubair M, Mason JC, Denton CP, and Herrick AL

Subjects
Humans, Treatment Outcome, Pandemics, Double-Blind Method, Prednisolone adverse effects, Pain, Scleroderma, Diffuse drug therapy, COVID-19
Abstract

Objectives: Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc., Methods: PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients., Results: Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was -0.10 (97.5% CI: -0.29, 0.10), P = 0.254, and in mRSS -3.90 (97.5% CI: -8.83, 1.03), P = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P = 0.027), anxiety (P = 0.018) and helplessness (P = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small., Conclusion: PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Published
2023
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49. Efficacy and Effectiveness of Universal School-Based Wellbeing Interventions in Australia: A Systematic Review.

Author

Gunawardena H, Voukelatos A, Nair S, Cross S, and Hickie IB

Subjects
Humans, Australia, Early Intervention, Educational, Program Evaluation, Students psychology, Schools
Abstract

The World Health Organisation defines health in terms of wellbeing, and wellbeing has become both a construct and a measure of impact in early intervention and prevention programs in schools. In Australia, schools report on their wellbeing initiatives and there is a plethora of government-funded wellbeing programs already in place in schools. However, education systems and stakeholders worldwide are facing significant challenges with mixed evaluation results of program impact and intervention effect. To better support students, schools, school-based healthcare workers, and community, it is important to know about the effectiveness of school-based programs; yet in the last decade, there has been no national appraisal of these programs in Australia. This systematic review aims to report on the effectiveness of Australian school-based wellbeing programs through a search of 13 databases. Out of 2888 articles, 29 met inclusion criteria. The results found that seventeen interventions comprising 80% of the total number of participants reported no statistically significant intervention effect on wellbeing outcomes. We argue that supporting wellbeing through robust program intervention is important as wellbeing presents both an indication of later onset of more serious mental health issues, and an opportunity for early intervention to break the trajectory leading to full disorder.

Published
2023
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50. A multidisciplinary approach to the diagnosis of antisynthetase syndrome.

Author

Wells M, Alawi S, Thin KYM, Gunawardena H, Brown AR, Edey A, Pauling JD, Barratt SL, and Adamali HI

Abstract

Antisynthetase syndrome is a subtype of idiopathic inflammatory myopathy, strongly associated with the presence of interstitial lung disease. Diagnosis is made by identifying myositis-specific antibodies directed against aminoacyl tRNA synthetase, and relevant clinical and radiologic features. Given the multisystem nature of the disease, diagnosis requires the careful synthesis of subtle clinical and radiological features with the interpretation of specialized autoimmune serological testing. This is provided in a multidisciplinary environment with input from rheumatologists, respiratory physicians, and radiologists. Differentiation from other idiopathic interstitial lung diseases is key; treatment and prognosis differ between patients with antisynthetase syndrome and idiopathic interstitial lung disease. In this review article, we look at the role of the multidisciplinary team and its individual members in the initial diagnosis of the antisynthetase syndrome, including the role of physicians, radiologists, and the wider team., Competing Interests: HG has received speaker and advisory fees from Boehringer-Ingelheim. JDP has received personal support from and undertaken consultancy work for Janssen, Astra Zeneca, Permeatus Inc, Boehringer-Ingelheim and Sojournix Pharma. SLB has undertaken consultancy work and received speaker honoraria from Boehringer-Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wells, Alawi, Thin, Gunawardena, Brown, Edey, Pauling, Barratt and Adamali.)

Published
2022
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