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3. Factors associated with the severity of COVID-19 outcomes in people with neuromuscular diseases: Data from the International Neuromuscular COVID-19 Registry

Author

Pizzamiglio, C., Pitceathly, R.D.S., Lunn, M.P., Brady, S., Marchi, F. De, Galan, L., Heckmann, J.M., Horga, A., Molnar, M.J., Oliveira, A.S.B., Pinto, W., Primiano, G., Santos, E., Schoser, B., Servidei, S., Souza, P.V. Sgobbi, Venugopalan, V., Hanna, M.G., Groothuis, J.T., Janssen, M.C.H., Dimachkie, M.M., Machado, P.M., Pizzamiglio, C., Pitceathly, R.D.S., Lunn, M.P., Brady, S., Marchi, F. De, Galan, L., Heckmann, J.M., Horga, A., Molnar, M.J., Oliveira, A.S.B., Pinto, W., Primiano, G., Santos, E., Schoser, B., Servidei, S., Souza, P.V. Sgobbi, Venugopalan, V., Hanna, M.G., Groothuis, J.T., Janssen, M.C.H., Dimachkie, M.M., and Machado, P.M.

Abstract

Item does not contain fulltext, BACKGROUND AND PURPOSE: Clinical outcome information on patients with neuromuscular diseases (NMDs) who have been infected with SARS-CoV-2 is limited. The aim of this study was to determine factors associated with the severity of COVID-19 outcomes in people with NMDs. METHODS: Cases of NMD, of any age, and confirmed/presumptive COVID-19, submitted to the International Neuromuscular COVID-19 Registry up to 31 December 2021, were included. A mutually exclusive ordinal COVID-19 severity scale was defined as follows: (1) no hospitalization; (2) hospitalization without oxygenation; (3) hospitalization with ventilation/oxygenation; and (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs) for severe outcome, adjusting for age, sex, race/ethnicity, NMD, comorbidities, baseline functional status (modified Rankin scale [mRS]), use of immunosuppressive/immunomodulatory medication, and pandemic calendar period. RESULTS: Of 315 patients from 13 countries (mean age 50.3 [±17.7] years, 154 [48.9%] female), 175 (55.5%) were not hospitalized, 27 (8.6%) were hospitalized without supplemental oxygen, 91 (28.9%) were hospitalized with ventilation/supplemental oxygen, and 22 (7%) died. Higher odds of severe COVID-19 outcomes were observed for: age ≥50 years (50-64 years: OR 2.4, 95% confidence interval [CI] 1.33-4.31; >64 years: OR 4.16, 95% CI 2.12-8.15; both vs. <50 years); non-White race/ethnicity (OR 1.81, 95% CI 1.07-3.06; vs. White); mRS moderately severe/severe disability (OR 3.02, 95% CI 1.6-5.69; vs. no/slight/moderate disability); history of respiratory dysfunction (OR 3.16, 95% CI 1.79-5.58); obesity (OR 2.24, 95% CI 1.18-4.25); ≥3 comorbidities (OR 3.2, 95% CI 1.76-5.83; vs. ≤2; if comorbidity count used instead of specific comorbidities); glucocorticoid treatment (OR 2.33, 95% CI 1.14-4.78); and Guillain-Barré syndrome (OR 3.1, 95% CI 1.35-7.13; vs. mitochondrial disease). CONCLUSIONS: Among people with NMDs, there is a diffe

Published
2023

4. Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: a report of the international immuno-oncology biomarker working group.

Author

Thagaard, J., Broeckx, G., Page, D.B., Jahangir, C.A., Verbandt, S., Kos, Z., Gupta, R., Khiroya, R., AbdulJabbar, K., Haab, G.A., Acs, B., Akturk, G., Almeida, J.S., Alvarado-Cabrero, I., Amgad, M., Azmoudeh-Ardalan, F., Badve, S., Baharun, N.B., Balslev, E., Bellolio, E.R., Bheemaraju, V., Blenman, K.R., Botinelly Mendonça Fujimoto, L., Bouchmaa, N., Burgues, O., Chardas, A., Chon U Cheang, M., Ciompi, F., Cooper, L.A., Coosemans, A., Corredor, G., Dahl, A.B., Dantas Portela, F.L., Deman, F., Demaria, S., Doré Hansen, J., Dudgeon, S.N., Ebstrup, T., Elghazawy, M., Fernandez-Martín, C., Fox, S.B., Gallagher, W.M., Giltnane, J.M., Gnjatic, S., Gonzalez-Ericsson, P.I., Grigoriadis, A., Halama, N., Hanna, M.G., Harbhajanka, A., Hart, S.N., Hartman, J., Hauberg, S., Hewitt, S., Hida, A.I., Horlings, H.M., Husain, Z., Hytopoulos, E., Irshad, S., Janssen, E.a, Kahila, M., Kataoka, T.R., Kawaguchi, K., Kharidehal, D., Khramtsov, A.I., Kiraz, U., Kirtani, P., Kodach, L.L., Korski, K., Kovács, A., Laenkholm, A.V., Lang-Schwarz, C., Larsimont, D., Lennerz, J.K., Lerousseau, M., Li, Xiaoxian, Ly, Amy, Madabhushi, A., Maley, S.K., Manur Narasimhamurthy, V., Marks, D.K., McDonald, E.S., Mehrotra, R., Michiels, S., Minhas, F.U.A.A., Mittal, S., Moore, D.A., Mushtaq, S., Nighat, H., Papathomas, T., Penault-Llorca, F., Perera, R.D., Pinard, C.J., Pinto-Cardenas, J.C., Pruneri, G., Pusztai, L., Rahman, A., Rajpoot, N.M., Rapoport, B.L., Rau, T.T., Reis-Filho, J.S., Ribeiro, J.M., Rimm, D., Roslind, A., Vincent-Salomon, A., Salto-Tellez, M., Saltz, J., Sayed, S., Scott, E., Siziopikou, K.P., Sotiriou, C., Stenzinger, A., Sughayer, M.A., Sur, D., Fineberg, S., Symmans, F., Tanaka, S., Taxter, T., Tejpar, S., Teuwen, J., Thompson, E.A., Tramm, T., Tran, W.T., Laak, J.A.W.M. van der, Diest, P.J. van, Verghese, G.E., Viale, G., Vieth, M., Wahab, N., Walter, T., Waumans, Y., Wen, H.Y., Yang, W, Yuan, Y., Zin, R.M., Adams, S., Bartlett, J., Loibl, S., Denkert, C., Savas, P., Loi, S., Salgado, R., Specht Stovgaard, E., Thagaard, J., Broeckx, G., Page, D.B., Jahangir, C.A., Verbandt, S., Kos, Z., Gupta, R., Khiroya, R., AbdulJabbar, K., Haab, G.A., Acs, B., Akturk, G., Almeida, J.S., Alvarado-Cabrero, I., Amgad, M., Azmoudeh-Ardalan, F., Badve, S., Baharun, N.B., Balslev, E., Bellolio, E.R., Bheemaraju, V., Blenman, K.R., Botinelly Mendonça Fujimoto, L., Bouchmaa, N., Burgues, O., Chardas, A., Chon U Cheang, M., Ciompi, F., Cooper, L.A., Coosemans, A., Corredor, G., Dahl, A.B., Dantas Portela, F.L., Deman, F., Demaria, S., Doré Hansen, J., Dudgeon, S.N., Ebstrup, T., Elghazawy, M., Fernandez-Martín, C., Fox, S.B., Gallagher, W.M., Giltnane, J.M., Gnjatic, S., Gonzalez-Ericsson, P.I., Grigoriadis, A., Halama, N., Hanna, M.G., Harbhajanka, A., Hart, S.N., Hartman, J., Hauberg, S., Hewitt, S., Hida, A.I., Horlings, H.M., Husain, Z., Hytopoulos, E., Irshad, S., Janssen, E.a, Kahila, M., Kataoka, T.R., Kawaguchi, K., Kharidehal, D., Khramtsov, A.I., Kiraz, U., Kirtani, P., Kodach, L.L., Korski, K., Kovács, A., Laenkholm, A.V., Lang-Schwarz, C., Larsimont, D., Lennerz, J.K., Lerousseau, M., Li, Xiaoxian, Ly, Amy, Madabhushi, A., Maley, S.K., Manur Narasimhamurthy, V., Marks, D.K., McDonald, E.S., Mehrotra, R., Michiels, S., Minhas, F.U.A.A., Mittal, S., Moore, D.A., Mushtaq, S., Nighat, H., Papathomas, T., Penault-Llorca, F., Perera, R.D., Pinard, C.J., Pinto-Cardenas, J.C., Pruneri, G., Pusztai, L., Rahman, A., Rajpoot, N.M., Rapoport, B.L., Rau, T.T., Reis-Filho, J.S., Ribeiro, J.M., Rimm, D., Roslind, A., Vincent-Salomon, A., Salto-Tellez, M., Saltz, J., Sayed, S., Scott, E., Siziopikou, K.P., Sotiriou, C., Stenzinger, A., Sughayer, M.A., Sur, D., Fineberg, S., Symmans, F., Tanaka, S., Taxter, T., Tejpar, S., Teuwen, J., Thompson, E.A., Tramm, T., Tran, W.T., Laak, J.A.W.M. van der, Diest, P.J. van, Verghese, G.E., Viale, G., Vieth, M., Wahab, N., Walter, T., Waumans, Y., Wen, H.Y., Yang, W, Yuan, Y., Zin, R.M., Adams, S., Bartlett, J., Loibl, S., Denkert, C., Savas, P., Loi, S., Salgado, R., and Specht Stovgaard, E.

Abstract

01 augustus 2023, Contains fulltext : 296181.pdf (Publisher’s version ) (Open Access), The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Published
2023

5. Spatial analyses of immune cell infiltration in cancer: current methods and future directions. A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Author

Page, D.B., Broeckx, G., Jahangir, C.A., Verbandt, S., Gupta, R.R., Thagaard, J., Khiroya, R., Kos, Z., AbdulJabbar, K., Acosta Haab, G., Acs, B., Akturk, G., Almeida, J.S., Alvarado-Cabrero, I., Azmoudeh-Ardalan, F., Badve, S., Baharun, N.B., Bellolio, E.R., Bheemaraju, V., Blenman, K.R., Botinelly Mendonça Fujimoto, L., Bouchmaa, N., Burgues, O., Cheang, M.C.U., Ciompi, F., Cooper, L.A., Coosemans, A., Corredor, G., Dantas Portela, F.L., Deman, F., Demaria, S., Dudgeon, S.N., Elghazawy, M., Ely, S., Fernandez-Martín, C., Fineberg, S., Fox, S.B., Gallagher, W.M., Giltnane, J.M., Gnjatic, S., Gonzalez-Ericsson, P.I., Grigoriadis, A., Halama, N., Hanna, M.G., Harbhajanka, A., Hardas, A., Hart, S.N., Hartman, J., Hewitt, S., Hida, A.I., Horlings, H.M., Husain, Z., Hytopoulos, E., Irshad, S., Janssen, E.a, Kahila, M., Kataoka, T.R., Kawaguchi, K., Kharidehal, D., Khramtsov, A.I., Kiraz, U., Kirtani, P., Kodach, L.L., Korski, K., Kovács, A., Laenkholm, A.V., Lang-Schwarz, C., Larsimont, D., Lennerz, J.K., Lerousseau, M., Li, Xiaoxian, Ly, Amy, Madabhushi, A., Maley, S.K., Manur Narasimhamurthy, V., Marks, D.K., McDonald, E.S., Mehrotra, R., Michiels, S., Minhas, F.U.A.A., Mittal, S., Moore, D.A., Mushtaq, S., Nighat, H., Papathomas, T., Penault-Llorca, F., Perera, R.D., Pinard, C.J., Pinto-Cardenas, J.C., Pruneri, G., Pusztai, L., Rahman, A., Rajpoot, N.M., Rapoport, B.L., Rau, T.T., Reis-Filho, J.S., Ribeiro, J.M., Rimm, D., Vincent-Salomon, A., Salto-Tellez, M., Saltz, J., Sayed, S., Siziopikou, K.P., Sotiriou, C., Stenzinger, A., Sughayer, M.A., Sur, D., Symmans, F., Tanaka, S., Taxter, T., Tejpar, S., Teuwen, J., Thompson, E.A., Tramm, T., Tran, W.T., Laak, J.A.W.M. van der, Diest, P.J. van, Verghese, G.E., Viale, G., Vieth, M., Wahab, N., Walter, T., Waumans, Y., Wen, H.Y., Yang, W, Yuan, Y., Adams, S., Bartlett, J.M.S., Loibl, S., Denkert, C., Savas, P., Loi, S., Salgado, R., Specht Stovgaard, E., Page, D.B., Broeckx, G., Jahangir, C.A., Verbandt, S., Gupta, R.R., Thagaard, J., Khiroya, R., Kos, Z., AbdulJabbar, K., Acosta Haab, G., Acs, B., Akturk, G., Almeida, J.S., Alvarado-Cabrero, I., Azmoudeh-Ardalan, F., Badve, S., Baharun, N.B., Bellolio, E.R., Bheemaraju, V., Blenman, K.R., Botinelly Mendonça Fujimoto, L., Bouchmaa, N., Burgues, O., Cheang, M.C.U., Ciompi, F., Cooper, L.A., Coosemans, A., Corredor, G., Dantas Portela, F.L., Deman, F., Demaria, S., Dudgeon, S.N., Elghazawy, M., Ely, S., Fernandez-Martín, C., Fineberg, S., Fox, S.B., Gallagher, W.M., Giltnane, J.M., Gnjatic, S., Gonzalez-Ericsson, P.I., Grigoriadis, A., Halama, N., Hanna, M.G., Harbhajanka, A., Hardas, A., Hart, S.N., Hartman, J., Hewitt, S., Hida, A.I., Horlings, H.M., Husain, Z., Hytopoulos, E., Irshad, S., Janssen, E.a, Kahila, M., Kataoka, T.R., Kawaguchi, K., Kharidehal, D., Khramtsov, A.I., Kiraz, U., Kirtani, P., Kodach, L.L., Korski, K., Kovács, A., Laenkholm, A.V., Lang-Schwarz, C., Larsimont, D., Lennerz, J.K., Lerousseau, M., Li, Xiaoxian, Ly, Amy, Madabhushi, A., Maley, S.K., Manur Narasimhamurthy, V., Marks, D.K., McDonald, E.S., Mehrotra, R., Michiels, S., Minhas, F.U.A.A., Mittal, S., Moore, D.A., Mushtaq, S., Nighat, H., Papathomas, T., Penault-Llorca, F., Perera, R.D., Pinard, C.J., Pinto-Cardenas, J.C., Pruneri, G., Pusztai, L., Rahman, A., Rajpoot, N.M., Rapoport, B.L., Rau, T.T., Reis-Filho, J.S., Ribeiro, J.M., Rimm, D., Vincent-Salomon, A., Salto-Tellez, M., Saltz, J., Sayed, S., Siziopikou, K.P., Sotiriou, C., Stenzinger, A., Sughayer, M.A., Sur, D., Symmans, F., Tanaka, S., Taxter, T., Tejpar, S., Teuwen, J., Thompson, E.A., Tramm, T., Tran, W.T., Laak, J.A.W.M. van der, Diest, P.J. van, Verghese, G.E., Viale, G., Vieth, M., Wahab, N., Walter, T., Waumans, Y., Wen, H.Y., Yang, W, Yuan, Y., Adams, S., Bartlett, J.M.S., Loibl, S., Denkert, C., Savas, P., Loi, S., Salgado, R., and Specht Stovgaard, E.

Abstract

01 augustus 2023, Contains fulltext : 296131.pdf (Publisher’s version ) (Closed access), Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

Published
2023

7. Single particle profiler for measuring content and properties of nano-sized bioparticles

Author

Taras Sych, Jan Schlegel, Hanna M.G. Barriga, Miina Ojansivu, Leo Hanke, Florian Weber, R. Beklem Bostancioglu, Kariem Ezzat, Herbert Stangl, Birgit Plochberger, Jurga Laurencikiene, Samir El Andaloussi, Daniel Fürth, Molly M. Stevens, and Erdinc Sezgin

Abstract

It is technically challenging to study the content and properties of nanoscale bioparticles in a high-throughput and single-molecule manner. We developed a high-throughput analysis method, called single particle profiler (SPP) that provides single-particle information on content and biophysical properties of thousands of particles. We applied SPP to measure the mRNA encapsulation efficiency of lipid nanoparticles, viral binding efficiency of different nanobodies and biophysical heterogeneity of liposomes, lipoproteins, exosomes and viruses.

Published
2022
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8. Concurrent sodium channelopathies and amyotrophic lateral sclerosis supports shared pathogenesis

Author

Franklin, J.P., Cooper-Knock, J., Baheerathan, A., Moll, T., Männikkö, R., Heverin, M., Hardiman, O., Shaw, P.J., and Hanna, M.G.

Abstract

Amyotrophic lateral sclerosis (ALS) is an invariably fatal adult-onset neurodegenerative disorder; approximately 10% of ALS is monogenic but all ALS exhibits significant heritability. The skeletal muscle sodium channelopathies are a group of inherited, non-dystrophic ion channel disorders caused by heterozygous point mutations in the SCN4A gene, leading to clinical manifestations of congenital myotonia, paramyotonia, and periodic paralysis syndromes. We provide clinical and genetic evidence of concurrence of these two rare disorders which implies a possible shared underlying pathophysiology in two patients. We then identify an enrichment of ALS-associated mutations in another sodium channel, SCN7A, from whole genome sequencing data of 4495 ALS patients and 1925 controls passing multiple testing correction (67 variants, p = 0.0002, Firth logistic regression). These findings suggest dysfunctional sodium channels may play a role upstream in the pathogenesis of ALS in a subset of patients, potentially opening the door to novel personalized medicine approaches.

Published
2020

9. Efficacy and safety of Bimagrumab in sporadic inclusion body myositis

Author

Amato, A.A., Hanna, M.G., Machado, P.M., Badrising, U.A., Chinoy, H., Benveniste, O., Karanam, A.K., Wu, M., Tankó, L.B., Schubert-Tennigkeit, A.A., Papanicolaou, D.A., Lloyd, T.E., Needham, M., Liang, C., Reardon, K.A., de Visser, M., Ascherman, D.P., Barohn, R.J., Dimachkie, M.M., Miller, J.A.L., Kissel, J.T., Oskarsson, B., Joyce, N.C., Van den Bergh, P., Baets, J., De Bleecker, J.L., Karam, C., David, W.S., Mirabella, M., Nations, S.P., Jung, H.H., Pegoraro, E., Maggi, L., Rodolico, C., Filosto, M., Shaibani, A.I., Sivakumar, K., Goyal, N.A., Mori-Yoshimura, M., Yamashita, S., Suzuki, N., Aoki, M., Katsuno, M., Morihata, H., Murata, K., Nodera, H., Nishino, I., Romano, C.D., Williams, V.S.L., Vissing, J., Zhang Auberson, L., Amato, A.A., Hanna, M.G., Machado, P.M., Badrising, U.A., Chinoy, H., Benveniste, O., Karanam, A.K., Wu, M., Tankó, L.B., Schubert-Tennigkeit, A.A., Papanicolaou, D.A., Lloyd, T.E., Needham, M., Liang, C., Reardon, K.A., de Visser, M., Ascherman, D.P., Barohn, R.J., Dimachkie, M.M., Miller, J.A.L., Kissel, J.T., Oskarsson, B., Joyce, N.C., Van den Bergh, P., Baets, J., De Bleecker, J.L., Karam, C., David, W.S., Mirabella, M., Nations, S.P., Jung, H.H., Pegoraro, E., Maggi, L., Rodolico, C., Filosto, M., Shaibani, A.I., Sivakumar, K., Goyal, N.A., Mori-Yoshimura, M., Yamashita, S., Suzuki, N., Aoki, M., Katsuno, M., Morihata, H., Murata, K., Nodera, H., Nishino, I., Romano, C.D., Williams, V.S.L., Vissing, J., and Zhang Auberson, L.

Abstract

Objective To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). Methods Participants (aged 36–85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co–primary outcome measures were 6-minute walk distance (6MWD) and safety. Results Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24–104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). Conclusion Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.

Published
2021

10. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author

Kos, Z., Roblin, E., Kim, R.S., Michiels, S., Gallas, B.D., Chen, W, Vijver, K.K. van de, Goel, S., Adams, S., Demaria, S., Viale, G., Nielsen, T.O., Badve, S.S., Symmans, W.F., Sotiriou, C., Rimm, D.L., Hewitt, S., Denkert, C., Loibl, S., Luen, S.J., Bartlett, J.M.S., Savas, P., Pruneri, G., Dillon, D.A., Cheang, M.C.U., Tutt, A., Hall, J.A., Kok, M., Horlings, H.M., Madabhushi, A., Laak, J.A.W.M. van der, Ciompi, F., Laenkholm, A.V., Bellolio, E., Gruosso, T., Fox, S.B., Araya, J.C., Floris, G., Hudecek, J., Voorwerk, L., Beck, A.H., Kerner, J., Larsimont, D., Declercq, S., Eynden, G. Van den, Pusztai, L., Ehinger, A., Yang, W, AbdulJabbar, K., Yuan, Y., Singh, R., Hiley, C., Bakir, M.A., Lazar, A.J., Naber, S., Wienert, S., Castillo, M., Curigliano, G., Dieci, M.V., Andre, F., Swanton, C., Reis-Filho, J., Sparano, J., Balslev, E., Chen, I.C., Stovgaard, E.I.S., Pogue-Geile, K., Blenman, K.R.M., Penault-Llorca, F., Schnitt, S., Lakhani, S.R., Vincent-Salomon, A., Rojo, F., Braybrooke, J.P., Hanna, M.G., Soler-Monso, M.T., Bethmann, D., Castaneda, C.A., Willard-Gallo, K., Sharma, A., Lien, H.C., Fineberg, S., Thagaard, J., Comerma, L., Gonzalez-Ericsson, P., Brogi, E., Loi, S., Saltz, J., Klaushen, F., Cooper, L., Amgad, M., Moore, D.A.J., Salgado, R., Kos, Z., Roblin, E., Kim, R.S., Michiels, S., Gallas, B.D., Chen, W, Vijver, K.K. van de, Goel, S., Adams, S., Demaria, S., Viale, G., Nielsen, T.O., Badve, S.S., Symmans, W.F., Sotiriou, C., Rimm, D.L., Hewitt, S., Denkert, C., Loibl, S., Luen, S.J., Bartlett, J.M.S., Savas, P., Pruneri, G., Dillon, D.A., Cheang, M.C.U., Tutt, A., Hall, J.A., Kok, M., Horlings, H.M., Madabhushi, A., Laak, J.A.W.M. van der, Ciompi, F., Laenkholm, A.V., Bellolio, E., Gruosso, T., Fox, S.B., Araya, J.C., Floris, G., Hudecek, J., Voorwerk, L., Beck, A.H., Kerner, J., Larsimont, D., Declercq, S., Eynden, G. Van den, Pusztai, L., Ehinger, A., Yang, W, AbdulJabbar, K., Yuan, Y., Singh, R., Hiley, C., Bakir, M.A., Lazar, A.J., Naber, S., Wienert, S., Castillo, M., Curigliano, G., Dieci, M.V., Andre, F., Swanton, C., Reis-Filho, J., Sparano, J., Balslev, E., Chen, I.C., Stovgaard, E.I.S., Pogue-Geile, K., Blenman, K.R.M., Penault-Llorca, F., Schnitt, S., Lakhani, S.R., Vincent-Salomon, A., Rojo, F., Braybrooke, J.P., Hanna, M.G., Soler-Monso, M.T., Bethmann, D., Castaneda, C.A., Willard-Gallo, K., Sharma, A., Lien, H.C., Fineberg, S., Thagaard, J., Comerma, L., Gonzalez-Ericsson, P., Brogi, E., Loi, S., Saltz, J., Klaushen, F., Cooper, L., Amgad, M., Moore, D.A.J., and Salgado, R.

Abstract

Contains fulltext : 220827.pdf (publisher's version ) (Open Access), Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.

Published
2020

11. Guidelines on clinical presentation and management of nondystrophic myotonias

Author

Stunnenberg, B.C., LoRusso, S., Arnold, W.D., Barohn, R.J., Cannon, S.C., Fontaine, B., Griggs, R.C., Hanna, M.G., Matthews, E., Meola, G., Sansone, V.A., Trivedi, J.R., Engelen, B.G.M. van, Vicart, S., Statland, J.M., Stunnenberg, B.C., LoRusso, S., Arnold, W.D., Barohn, R.J., Cannon, S.C., Fontaine, B., Griggs, R.C., Hanna, M.G., Matthews, E., Meola, G., Sansone, V.A., Trivedi, J.R., Engelen, B.G.M. van, Vicart, S., and Statland, J.M.

Abstract

Contains fulltext : 229739.pdf (Publisher’s version ) (Closed access), The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.

Published
2020

12. Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients

Author

Molenaar, J.P.F., Verhoeven, J.I., Rodenburg, R.J.T., Kamsteeg, E.J., Erasmus, C.E., Vicart, S., Behin, A., Bassez, G., Magot, A., Pereon, Y., Brandom, B.W., Guglielmi, V., Vattemi, G., Chevessier, F., Mathieu, J., Franques, J., Suetterlin, K., Hanna, M.G., Guyant-Marechal, L., Snoeck, M.M., Roberts, M.E., Kuntzer, T., Fernandez-Torron, R., Martinez-Arroyo, A., Seeger, J., Kusters, B., Treves, S., Engelen, B.G.M. van, Eymard, B., Voermans, N.C., Sternberg, D., Molenaar, J.P.F., Verhoeven, J.I., Rodenburg, R.J.T., Kamsteeg, E.J., Erasmus, C.E., Vicart, S., Behin, A., Bassez, G., Magot, A., Pereon, Y., Brandom, B.W., Guglielmi, V., Vattemi, G., Chevessier, F., Mathieu, J., Franques, J., Suetterlin, K., Hanna, M.G., Guyant-Marechal, L., Snoeck, M.M., Roberts, M.E., Kuntzer, T., Fernandez-Torron, R., Martinez-Arroyo, A., Seeger, J., Kusters, B., Treves, S., Engelen, B.G.M. van, Eymard, B., Voermans, N.C., and Sternberg, D.

Abstract

Contains fulltext : 218262.pdf (publisher's version ) (Open Access), Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequenc

Published
2020

13. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, M., Stovgaard, E.S., Balslev, E., Thagaard, J., Chen, W, Dudgeon, S., Sharma, A., Kerner, J.K., Denkert, C., Yuan, Y., AbdulJabbar, K., Wienert, S., Savas, P., Voorwerk, L., Beck, A.H., Madabhushi, A., Hartman, J., Sebastian, M.M., Horlings, H.M., Hudecek, J., Ciompi, F., Moore, D.A.J., Singh, R., Roblin, E., Balancin, M.L., Mathieu, M.C., Lennerz, J.K., Kirtani, P., Chen, I.C., Braybrooke, J.P., Pruneri, G., Demaria, S., Adams, S., Schnitt, S.J., Lakhani, S.R., Rojo, F., Comerma, L., Badve, S.S., Khojasteh, M., Symmans, W.F., Sotiriou, C., Gonzalez-Ericsson, P., Pogue-Geile, K.L., Kim, R.S., Rimm, D.L., Viale, G., Hewitt, S.M., Bartlett, J.M.S., Penault-Llorca, F., Goel, S., Lien, H.C., Loibl, S., Kos, Z., Loi, S., Hanna, M.G., Michiels, S., Kok, M., Nielsen, T.O., Lazar, A.J., Bago-Horvath, Z., Kooreman, L.F., Laak, J.A.W.M. van der, Saltz, J., Gallas, B.D., Kurkure, U., Barnes, M., Salgado, R., Cooper, L.A.D., Amgad, M., Stovgaard, E.S., Balslev, E., Thagaard, J., Chen, W, Dudgeon, S., Sharma, A., Kerner, J.K., Denkert, C., Yuan, Y., AbdulJabbar, K., Wienert, S., Savas, P., Voorwerk, L., Beck, A.H., Madabhushi, A., Hartman, J., Sebastian, M.M., Horlings, H.M., Hudecek, J., Ciompi, F., Moore, D.A.J., Singh, R., Roblin, E., Balancin, M.L., Mathieu, M.C., Lennerz, J.K., Kirtani, P., Chen, I.C., Braybrooke, J.P., Pruneri, G., Demaria, S., Adams, S., Schnitt, S.J., Lakhani, S.R., Rojo, F., Comerma, L., Badve, S.S., Khojasteh, M., Symmans, W.F., Sotiriou, C., Gonzalez-Ericsson, P., Pogue-Geile, K.L., Kim, R.S., Rimm, D.L., Viale, G., Hewitt, S.M., Bartlett, J.M.S., Penault-Llorca, F., Goel, S., Lien, H.C., Loibl, S., Kos, Z., Loi, S., Hanna, M.G., Michiels, S., Kok, M., Nielsen, T.O., Lazar, A.J., Bago-Horvath, Z., Kooreman, L.F., Laak, J.A.W.M. van der, Saltz, J., Gallas, B.D., Kurkure, U., Barnes, M., Salgado, R., and Cooper, L.A.D.

Abstract

Contains fulltext : 220833.pdf (publisher's version ) (Open Access), Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

Published
2020

14. Cytosolic 5 '-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis

Author

Lilleker, J.B., Rietveld, A., Pye, S.R., Mariampillai, K., Benveniste, O., Peeters, M.T.J., Miller, J.A.L., Hanna, M.G., Machado, P.M., Parton, M.J., Gheorghe, K.R., Badrising, U.A., Lundberg, I.E., Sacconi, S., Herbert, M.K., McHugh, N.J., Lecky, B.R.F., Brierley, C., Hilton-Jones, D., Lamb, J.A., Roberts, M.E., Cooper, R.G., Saris, C.G.J., Pruijn, G., Chinoy, H., and Engelen, B.G.M. van

Subjects
Bio-Molecular Chemistry, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

Contains fulltext : 174409.pdf (Publisher’s version ) (Open Access)

Published
2017

15. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, V. Dixon, C.L. Guo, H. Bello, O.D. Vandrovcova, J. Efthymiou, S. Maroofian, R. Heimer, G. Burglen, L. Valence, S. Torti, E. Hacke, M. Rankin, J. Tariq, H. Colin, E. Procaccio, V. Striano, P. Mankad, K. Lieb, A. Chen, S. Pisani, L. Bettencourt, C. Männikkö, R. Manole, A. Brusco, A. Grosso, E. Ferrero, G.B. Armstrong-Moron, J. Gueden, S. Bar-Yosef, O. Tzadok, M. Monaghan, K.G. Santiago-Sim, T. Person, R.E. Cho, M.T. Willaert, R. Yoo, Y. Chae, J.-H. Quan, Y. Wu, H. Wang, T. Bernier, R.A. Xia, K. Blesson, A. Jain, M. Motazacker, M.M. Jaeger, B. Schneider, A.L. Boysen, K. Muir, A.M. Myers, C.T. Gavrilova, R.H. Gunderson, L. Schultz-Rogers, L. Klee, E.W. Dyment, D. Osmond, M. Parellada, M. Llorente, C. Gonzalez-Peñas, J. Carracedo, A. Van Haeringen, A. Ruivenkamp, C. Nava, C. Heron, D. Nardello, R. Iacomino, M. Minetti, C. Skabar, A. Fabretto, A. Hanna, M.G. Bugiardini, E. Hostettler, I. O’Callaghan, B. Khan, A. Cortese, A. O’Connor, E. Yau, W.Y. Bourinaris, T. Kaiyrzhanov, R. Chelban, V. Madej, M. Diana, M.C. Vari, M.S. Pedemonte, M. Bruno, C. Balagura, G. Scala, M. Fiorillo, C. Nobili, L. Malintan, N.T. Zanetti, M.N. Krishnakumar, S.S. Lignani, G. Jepson, J.E.C. Broda, P. Baldassari, S. Rossi, P. Fruscione, F. Madia, F. Traverso, M. De-Marco, P. Pérez-Dueñas, B. Munell, F. Kriouile, Y. El-Khorassani, M. Karashova, B. Avdjieva, D. Kathom, H. Tincheva, R. Van-Maldergem, L. Nachbauer, W. Boesch, S. Gagliano, A. Amadori, E. Goraya, J.S. Sultan, T. Kirmani, S. Ibrahim, S. Jan, F. Mine, J. Banu, S. Veggiotti, P. Zuccotti, G.V. Ferrari, M.D. Van Den Maagdenberg, A.M.J. Verrotti, A. Marseglia, G.L. Savasta, S. Soler, M.A. Scuderi, C. Borgione, E. Chimenz, R. Gitto, E. Dipasquale, V. Sallemi, A. Fusco, M. Cuppari, C. Cutrupi, M.C. Ruggieri, M. Cama, A. Capra, V. Mencacci, N.E. Boles, R. Gupta, N. Kabra, M. Papacostas, S. Zamba-Papanicolaou, E. Dardiotis, E. Maqbool, S. Rana, N. Atawneh, O. Lim, S.Y. Shaikh, F. Koutsis, G. Breza, M. Coviello, D.A. Dauvilliers, Y.A. AlKhawaja, I. AlKhawaja, M. Al-Mutairi, F. Stojkovic, T. Ferrucci, V. Zollo, M. Alkuraya, F.S. Kinali, M. Sherifa, H. Benrhouma, H. Turki, I.B.Y. Tazir, M. Obeid, M. Bakhtadze, S. Saadi, N.W. Zaki, M.S. Triki, C.C. Benfenati, F. Gustincich, S. Kara, M. Belcastro, V. Specchio, N. Capovilla, G. Karimiani, E.G. Salih, A.M. Okubadejo, N.U. Ojo, O.O. Oshinaike, O.O. Oguntunde, O. Wahab, K. Bello, A.H. Abubakar, S. Obiabo, Y. Nwazor, E. Ekenze, O. Williams, U. Iyagba, A. Taiwo, L. Komolafe, M. Senkevich, K. Shashkin, C. Zharkynbekova, N. Koneyev, K. Manizha, G. Isrofilov, M. Guliyeva, U. Salayev, K. Khachatryan, S. Rossi, S. Silvestri, G. Haridy, N. Ramenghi, L.A. Xiromerisiou, G. David, E. Aguennouz, M. Fidani, L. Spanaki, C. Tucci, A. Raspall-Chaure, M. Chez, M. Tsai, A. Fassi, E. Shinawi, M. Constantino, J.N. De Zorzi, R. Fortuna, S. Kok, F. Keren, B. Bonneau, D. Choi, M. Benzeev, B. Zara, F. Mefford, H.C. Scheffer, I.E. Clayton-Smith, J. Macaya, A. Rothman, J.E. Eichler, E.E. Kullmann, D.M. Houlden, H. SYNAPS Study Group

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).

Published
2019

16. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial

Author

Hanna, M.G., Badrising, U.A., Benveniste, O., Lloyd, T.E., Needham, M., Chinoy, H., Aoki, M., Machado, P.M., Liang, C., Reardon, K.A., Visser, M. de, Ascherman, D.P., Barohn, R.J., Dimachkie, M.M., Miller, J.A.L., Kissel, J.T., Oskarsson, B., Joyce, N.C., Bergh, P. van den, Baets, J., Bleecker, J.L. de, Karam, C., David, W.S., Mirabella, M., Nations, S.P., Jung, H.H., Pegoraro, E., Maggi, L., Rodolico, C., Filosto, M., Shaibani, A.I., Sivakumar, K., Goyal, N.A., Mori-Yoshimura, M., Yamashita, S., Suzuki, N., Katsuno, M., Murata, K., Nodera, H., Romano, C.D., Williams, V.S.L., Vissing, J., Auberson, L.Z., Wu, M., Vera, A. de, Papanicolaou, D.A., Amato, A.A., Nishino, I., RESILIENT Study Grp, Neurology, ANS - Neuroinfection & -inflammation, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, and RESILIENT Study Grp

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Myostatin, Guidelines, Population, Guidelines, Antibodies, Monoclonal, Humanized, Placebo, Myositis, Inclusion Body, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, medicine, Humans, education, Adverse effect, Bimagrumab, Aged, Aged, 80 and over, education.field_of_study, business.industry, Repeated measures design, Middle Aged, Myostatin, Settore MED/26 - NEUROLOGIA, Treatment Outcome, 030104 developmental biology, Blood chemistry, Tolerability, Female, Human medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. Methods We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 3685 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. Findings Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17.6 m, SE 14.3, 99% CI -19.6 to 54.8; p=0.22; for 3 mg/kg group, 18.6 m, 14.2, -18.2 to 55.4; p=0.19; and for 1 mg/kg group, 1.3 m, 14.1, -38.0 to 35.4; p=0.93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. Interpretation Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Published
2019
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21. Translating discovery science into treatments for patients: observational cohort studies at the MRC Centre for Neuromuscular Diseases

Author

Bellin, A., primary, Bushby, K.M., additional, Chinnery, P., additional, Germain, L., additional, Kozyra, D., additional, Holton, J., additional, Houlden, H., additional, Laurá, M., additional, Lochmüller, H., additional, Lunn, M., additional, McFarland, B., additional, Matthews, E., additional, Miller, J., additional, Morrow, J., additional, Muntoni, F., additional, Parton, M., additional, Pitceathly, R., additional, Quinlivan, R., additional, Ramdharry, G., additional, Rossor, A., additional, Skorupinska, I., additional, Skorupinska, M., additional, Straub, V., additional, Thornton, J., additional, Turnbull, D.M., additional, Turner, C., additional, Yousry, T., additional, Machado, P., additional, Reilly, M.M., additional, and Hanna, M.G., additional

Published
2018
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24. Mitochondrial ribosomal protein S25 (MRPS25) mutations impair ribosomal assembly and cause mitochondrial encephalomyopathy with partial agenesis of the corpus callosum

Author

Bugiardini, E., primary, Mitchell, A., additional, Dalla Rosa, I., additional, Menunni, M., additional, Pittmann, A., additional, Poole, O., additional, Holton, J., additional, Quinlivan, R., additional, Holt, I., additional, Houlden, H., additional, Hanna, M.G., additional, Spinazzola, A., additional, and Pitceathly, R.D.S., additional

Published
2018
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28. MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load

Author

Ng, Y.S., Lax, N.Z., Maddison, P., Alston, C.L., Blakely, E.L., Hepplewhite, P.D., Riordan, G., Meldau, S., Chinnery, P.F., Pierre, G., Chronopoulou, E., Du, A., Hughes, I., Morris, A.A., Kamakari, S., Chrousos, G., Rodenburg, R.J.T., Saris, C.G.J., Feeney, C., Hardy, S.A., Sakakibara, T., Sudo, A., Okazaki, Y., Murayama, K., Mundy, H., Hanna, M.G., Ohtake, A., Schaefer, A.M., Champion, M.P., Turnbull, D.M., Taylor, R.W., Pitceathly, R.D.S., McFarland, R., Gorman, G.S., Ng, Y.S., Lax, N.Z., Maddison, P., Alston, C.L., Blakely, E.L., Hepplewhite, P.D., Riordan, G., Meldau, S., Chinnery, P.F., Pierre, G., Chronopoulou, E., Du, A., Hughes, I., Morris, A.A., Kamakari, S., Chrousos, G., Rodenburg, R.J.T., Saris, C.G.J., Feeney, C., Hardy, S.A., Sakakibara, T., Sudo, A., Okazaki, Y., Murayama, K., Mundy, H., Hanna, M.G., Ohtake, A., Schaefer, A.M., Champion, M.P., Turnbull, D.M., Taylor, R.W., Pitceathly, R.D.S., McFarland, R., and Gorman, G.S.

Abstract

Contains fulltext : 191175.pdf (publisher's version ) (Open Access), Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5.4months-37years, IQR=17.9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C.

Published
2018

33. Myostatin inhibition for neuromuscular disorders: defining the good candidate

Author

Mariot, V., primary, Joubert, R., additional, Hourdé, C., additional, Servais, L., additional, Hanna, M.G., additional, Maisonobe, T., additional, Muntoni, F., additional, Féasson, L., additional, Le Panse, R., additional, Benvensite, O., additional, Stojkovic, T., additional, Buj-Bello, A., additional, Machado, P., additional, Voit, T., additional, and Dumonceaux, J., additional

Published
2017
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37. A feasibility study of bezafibrate in mitochondrial myopathy

Author

Steele, H.E., primary, Newman, J., additional, Jakovljevic, D.G., additional, Scadeng, A.J., additional, Clark, S.K., additional, Jimenez-Moreno, A.C., additional, Trenell, M.I., additional, Parikh, J.D., additional, Hollingsworth, K.G., additional, Blamire, A.M., additional, Pitceathly, R.D.S., additional, Hanna, M.G., additional, Gorman, G.S., additional, McFarland, R., additional, Turnbull, D.M., additional, Taylor, R.W., additional, Horvath, R., additional, and Chinnery, P.F., additional

Published
2017
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43. Next generation sequencing in inherited myopathies

Author

Bugiardini, E., primary, Lynch, D., additional, Pittman, A., additional, Pihlstrom, L., additional, Morrow, J.M., additional, Turner, C., additional, Parton, M., additional, Holton, J.L., additional, Houlden, H., additional, Matthews, E., additional, and Hanna, M.G., additional

Published
2017
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46. Evaluating the benefits of community based aerobic training on the physical health and well-being of people with neuromuscular disease

Author

Wallace, A., primary, Pietrusz, A., additional, Dewar, E., additional, Dudziec, M., additional, Jones, K., additional, Hennis, P., additional, Sterr, A., additional, Baio, G., additional, Butcher, K., additional, Machado, P., additional, Laurá, M., additional, Skorupinska, I., additional, Skorupinska, M., additional, Trenell, M.I., additional, Hanna, M.G., additional, Reilly, M.M., additional, and Ramdharry, G.M., additional

Published
2017
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47. Cause of death in a cohort of mitochondrial patients

Author

Skorupinska, I., primary, Bugiardini, E., additional, Ng, Y.S., additional, Horga, A., additional, Poole, O.V., additional, McFarland, R., additional, Pitceathly, R.D.S., additional, Turnbull, D.M., additional, and Hanna, M.G., additional

Published
2017
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50. Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

Author

Rothwell, S., Cooper, R.G., Lundberg, I.E., Gregersen, P.K., Hanna, M.G., Machado, P.M., Herbert, M.K., Pruijn, G.J.M., Lilleker, J.B., Roberts, M, Bowes, J., Seldin, M.F., Vencovsky, J., Danko, K., Limaye, V., Selva-O'Callaghan, A., Platt, H., Molberg, O., Benveniste, O., Radstake, T.R., Doria, A., De Bleecker, J., De Paepe, B., Gieger, C., Meitinger, T., Winkelmann, J., Amos, C.I., Ollier, W.E., Padyukov, L., Lee, A.T van der, Lamb, J.A., Chinoy, H., Rothwell, S., Cooper, R.G., Lundberg, I.E., Gregersen, P.K., Hanna, M.G., Machado, P.M., Herbert, M.K., Pruijn, G.J.M., Lilleker, J.B., Roberts, M, Bowes, J., Seldin, M.F., Vencovsky, J., Danko, K., Limaye, V., Selva-O'Callaghan, A., Platt, H., Molberg, O., Benveniste, O., Radstake, T.R., Doria, A., De Bleecker, J., De Paepe, B., Gieger, C., Meitinger, T., Winkelmann, J., Amos, C.I., Ollier, W.E., Padyukov, L., Lee, A.T van der, Lamb, J.A., and Chinoy, H.

Abstract

Contains fulltext : 169069.pdf (publisher's version ) (Open Access)

Published
2017

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