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153. Bulklike behavior of magnetoelasticity in epitaxial Fe 1 − x Ga x thin films

Author

Barturen, M., Sander, D., Milano, J., Premper, J., Helman, C., Eddrief, M., Kirschner, J., marangolo, massimiliano, Croissance et propriétés de systèmes hybrides en couches minces (INSP-E8), Institut des Nanosciences de Paris (INSP), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Instituto Balseiro [Bariloche], Universidad Nacional de Cuyo [Mendoza] (UNCUYO)-Comisión Nacional de Energía Atómica [ARGENTINA] (CNEA), Universidad Argentina de la Empresa [Buenos Aires] (UADE), Max-Planck-Institut für Mikrostrukturphysik (MPI-HALLE), Max-Planck-Gesellschaft, Departamento de Fisica CNEA, and Comision Nacional de Energia Atomica

Subjects
[PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2019
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154. Bulklike behavior of magnetoelasticity in epitaxial Fe1-xGax thin films

Author

Barturen, Mariana, Sander, D., Milano, Julian, Premper, J., Helman, Christian, Eddrief, M., Kirschner, J., and Marangolo, M.

Subjects
purl.org/becyt/ford/1 [https], Cantilever method, purl.org/becyt/ford/1.3 [https], Magnetoelasticity
Abstract

Bulk Fe1-xGax alloys present a strong sensitivity of the magnetostrictive properties with Ga content with maximum magnetostriction near x=0.19. Here, we present magnetoelastic coefficients measured by the cantilever method on Fe1-xGax thin films grown by molecular beam epitaxy on GaAs(001). We find that Ga-dependent magnetoelastic coefficients in nanometer thin films are comparable in magnitude to the respective bulk values. Moreover, we compare thin films with a tetragonal structure due to a slightly preferential alignment of Ga pairs along the growth direction with and a cubic structure. It turns out that magnetoelastic coefficients are unaffected by a preferential alignment of Ga pairs along the growth direction. Fil: Barturen, Mariana. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Universidad Argentina de la Empresa; Argentina. Université Pierre et Marie Curie; Francia. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sander, D.. Max Planck Institute For Microstructure Physics; Alemania Fil: Milano, Julian. Centre National de la Recherche Scientifique; Francia. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche | Comisión Nacional de Energía Atómica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche; Argentina Fil: Premper, J.. Max Planck Institute For Microstructure Physics; Alemania Fil: Helman, Christian. Comisión Nacional de Energía Atómica; Argentina Fil: Eddrief, M.. Universite de Paris VI. Institut des Nanosciences de Paris; Francia Fil: Kirschner, J.. Max Planck Institute For Microstructure Physics; Alemania Fil: Marangolo, M.. Universite de Paris VI. Institut des Nanosciences de Paris; Francia

Published
2019

155. Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy

Author

Conrado, D. J., Larkindale, J., Berg, A., Hill, M., Burton, J., Abrams, K. R., Abresch, R. T., Bronson, A., Chapman, D., Crowther, M., Duong, T., Gordish-Dressman, H., Harnisch, L., Henricson, E., Kim, S., Mcdonald, C. M., Schmidt, S., Vong, C., Wang, X., Wong, B. L., Yong, F., Romero, K., Vishwanathan, V., Chidambaranathan, S., Douglas Biggar, W., Mcadam, L. C., Mah, J. K., Tulinius, M., Cnaan, A., Morgenroth, L. P., Leshner, R., Tesi-Rocha, C., Thangarajh, M., Kornberg, A., Ryan, M., Nevo, Y., Dubrovsky, A., Clemens, P. R., Abdel-Hamid, H., Connolly, A. M., Pestronk, A., Teasley, J., Bertorini, T. E., Webster, R., Kolski, H., Kuntz, N., Driscoll, S., Bodensteiner, J. B., Gorni, K., Lotze, T., Day, J. W., Karachunski, P., Henricson, E. K., Joyce, N. C., Campbell, C., Torricelli, R. E., Finkel, R. S., Flanigan, K. M., Goemans, N., Heydemann, P., Kaminska, A., Kirschner, J., Muntoni, F., Osorio, A. N., Schara, U., Sejersen, T., Shieh, P. B., Sweeney, H. L., Topaloglu, H., Vilchez, J. J., Voit, T., Wong, B., Alfano, L. N., Eagle, M., James, M. K., Lowes, L., Mayhew, A., Mazzone, E. S., Nelson, L., Rose, K. J., Abdel-Hamid, H. Z., Apkon, S. D., Barohn, R. J., Bertini, E., Bloetzer, C., Devaud, L. C., Butterfield, R. J., Chabrol, B., Chae, J. H., Jongno-Gu, D. R., Comi, G. P., Darras, B. T., Dastgir, J., Desguerre, I., Escobar, R. G., Finanger, E., Guglieri, M., Hughes, I., Iannaccone, S. T., Jones, K. J., Kudr, M., Mathews, K., Parsons, J., Pereon, Y., de Queiroz Campos Araujo, A. P., Renfroe, J. B., de Resende, M. B. D., Selby, K., Tennekoon, G., Vita, G., Apkon, S., Barohn, R., Belousova, E., Brandsema, J., Bruno, C., Burnette, W., Butterfield, R., Byrne, B., Carlo, J., Chandratre, S., Comi, G., Connolly, A., De Groot I, I., Deconinck, N., Dooley, J., Durigneux, J., Finkel, R., Frank, L. M., Harper, A., Hattori, A., Herguner, O., Iannaccone, S., Janas, J., Jong, Y. J., Komaki, H., Lee, W. T., Leung, E., Mah, J., Mercuri, E., Mcmillan, H., Mueller-Felber, W., de Munain A, L., Nakamura, A., Niks, E., Ogata, K., Pascual, S., Pegoraro, E., Renfroe, B., Sanka, R. B., Schallner, J., Sendra, I. I., Servais, L., Smith, E., Sparks, S., Victor, R., Wicklund, M., Wilichoswki, E., Carter, G. T., and Servais, LJP

Subjects
Orphan Drug Production, Duchenne muscular dystrophy, Pharmacy, Model-informed drug development, 030226 pharmacology & pharmacy, Models, Biological, Food and drug administration, 03 medical and health sciences, 0302 clinical medicine, Models, medicine, Humans, Regulatory science, Computer Simulation, Muscular Dystrophy, Drug development tools, Duchenne muscular dystrophy consortium (D-RSC), Rare diseases, Regulatory endorsement, Clinical Trials as Topic, Muscular Dystrophy, Duchenne, United States, United States Food and Drug Administration, Pharmacology, Protocol (science), business.industry, Duchenne, Biological, medicine.disease, Clinical trial, Risk analysis (engineering), Drug development, 030220 oncology & carcinogenesis, Aggregate data, Business
Abstract

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

Published
2019

156. The Multiple Sclerosis Inventory of Cognition for Adolescents (MUSICADO) : A brief screening instrument to assess cognitive dysfunction, fatigue and loss of health-related quality of life in pediatric-onset multiple sclerosis

Author

Storm van's Gravesande, K., Calabrese, P., Blaschek, A., Rostásy, K., Huppke, P., Rothe, L., Mall, V., Kessler, J., Kalbe, E., Kraus, V., Dornfeld, E., Elpers, C., Lohmann, H., Weddige, A., Hagspiel, S., Kirschner, J., Brehm, M., Blank, C., Schubert, J., Schimmel, M., Pacheè, S., Mohrbach, M., Karenfort, M., Kamp, G., Lücke, T., Neumann, H., Lutz, Sabine, Gierse, A., Sievers, S., Schiffmann, H., de Soye, I., Trollmann, R., Candova, A., Rosner, M., Neu, A., Romer, G., Seidel, U., John, R., Hofmann, C., Schulz, Kinder, S., Bertolatus, A., Scheidtmann, K., Lasogga, R., Leiz, S., Alber, M., Kranz, J., Bajer-Kornek, B., Seidl, R., Novak, A., and Storm van’s Gravesande, K.

Subjects
Male, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Trail Making Test, Medizin, Neuropsychological Tests, 03 medical and health sciences, 0302 clinical medicine, Quality of life, 030225 pediatrics, medicine, Memory span, Verbal fluency test, Humans, Cognitive Dysfunction, Fatigue, Health related quality of life, business.industry, Multiple sclerosis, Cognition, General Medicine, medicine.disease, 3. Good health, Cognitive test, Pediatrics, Perinatology and Child Health, Physical therapy, Quality of Life, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Objective Screening for cognitive impairment (CI), fatigue and also Health-related quality of life (HRQoL) in patients with pediatric-onset multiple sclerosis (POMS) is of utmost importance in clinical practice. The aim of this study was to establish a new and validated pediatric screening tool “MUSICADO” that is easy to use and time economical. Methods 106 patients with POMS aged 12–18 years and 210 healthy controls (HCs) stratified for age and education underwent neuropsychological testing including a screening test “Multiple Sclerosis Inventory of Cognition” for adults and 8 standardized cognitive tests and established scales to assess fatigue and HRQoL. Results The phonemic verbal fluency task (RWT “s-words”), the Trail Making Test A (TMT-A), and the Digit Span Forward discriminated significantly between patients and HCs (p = 0.000, respectively) and showed the highest proportion of test failure in patients (24.5%, 17.9%; 15.1%, respectively). Therefore, they were put together to form the cognitive part of the “MUSICADO”. After applying a scoring algorithm with balanced weighting of the subtests and age and education correction and a cut-off score for impairment, 35.8% of patients were categorized to be cognitively impaired (specificity: 88.6%). Fatigue was detected in 37.1% of the patients (specificity: 94.0%) and loss of HRQoL in 41.8% (specificity 95.7%) with the screening version, respectively. Conclusion The MUSICADO is a newly designed brief and easy to use screening test to help to early identify CI, fatigue, and loss of HRQoL in patients with POMS as cut scores are provided for all three items. Further studies will have to show its usability in independent samples of patients with POMS.

Published
2019

157. Reversible electrodeposition of ultrathin magnetic Co films

Author

Schindler, W., Koop, Th., Hofmann, D., and Kirschner, J.

Subjects
Thin films -- Magnetic properties, Cobalt -- Magnetic properties, Electroforming -- Research, Business, Electronics, Electronics and electrical industries
Abstract

Ultrapure preparation conditions equivalent to ultrahigh vacuum conditions of 5 x [10.sup.-10] mbar allow the reproducible deposition of magnetic films in the monolayer (ML) range from aqueous electrolytic solutions. We used this cost and time efficient technique to prepare ultrathin Co films on Cu(001) substrates. A unique feature of electrodeposition is its ability to dissolve previously deposited layers. The thickness of deposited films can be adjusted in situ by dissolution without damaging the rest of the film. This might be useful in precisely tailoring film properties, for example in magnetic multilayers. In situ magneto-optical Kerr effect (MOKE) measurements are a simple and efficient tool for such a purpose and provide a thickness resolution of better than 0.2 ML. The magnetic properties and anisotropies of the electrodeposited films as derived from our in situ MOKE measurements are mainly determined by their epitaxial growth on Cu(001). Index terms - Co, electrodeposition, magnetic thin films, ultrathin films

Published
1998

158. Modifying diffusion anisotropies: cap layer induced changes in spreading anisotropies

Author

Reuter, D., Gerth, G., and Kirschner, J.

Subjects
Anisotropy -- Research, Diffusion -- Research, Ferromagnetic materials -- Research, Physics
Abstract

A study was conducted on the spreading of Fe, Co and Ni from a dot deposited onto a W(110) substrate. The results indicate that a Cu cap layer covering a dot and surface can change the fast spreading directions for all three metals to . Moreover, the structure in the alloy layer formed during the spreading process may have caused the cap layer induced spreading anisotropy.

Published
1997

174. Health-Related Quality of Life in Patients with Adult-Onset Myotonic Dystrophy Type 1: A Systematic Review

Author

Landfeldt, E., Edstrom, J., Jimenez-Moreno, C., Engelen, B.G.M. van, Kirschner, J., Lochmuller, H., Landfeldt, E., Edstrom, J., Jimenez-Moreno, C., Engelen, B.G.M. van, Kirschner, J., and Lochmuller, H.

Abstract

Contains fulltext : 207160.pdf (publisher's version ) (Open Access), BACKGROUND: Adult-onset myotonic dystrophy type 1 (DM1) is a chronic, multisystem disorder that leads to disability and premature death. OBJECTIVES: The objective of our study was to conduct a systematic literature review of the health-related quality of life (HRQoL) of patients with DM1. METHODS: We searched Embase, Web of Science, and PubMed for English language full-text articles reporting results from studies of HRQoL in patients with adult-onset DM1 published between 1 January 2000 and 21 February 2018. We excluded reviews, editorials, and studies reporting results for a sample with fewer than five patients (to allow for meaningful inference). RESULTS: The search identified 266 unique publications. Of these, 231 were excluded following title and abstract screening and 16 after full-text review, leaving 19 articles for data synthesis. We found 15 articles measuring the HRQoL of patients with adult-onset DM1 using the 36-Item Short Form Health Survey (SF-36), six using the Individualized Neuromuscular Quality of Life Questionnaire (INQoL), and one using Cantril's Ladder. Available evidence shows that patient HRQoL is impaired in DM1, mainly due to compromised physical health, but also reveals that substantial heterogeneity exists in estimates across studies. CONCLUSIONS: HRQoL in adult-onset DM1 has been extensively studied using the SF-36 and the INQoL, but current estimates are inconclusive, and little is known of the impact of the disease as measured using other instruments. Our data synthesis should help characterize the patient burden of DM1 and inform future studies of HRQoL in this indication.

Published
2019

175. Interim report on the safety and efficacy of longer-term treatment with nusinersen in later-onset spinal muscular atrophy (SMA): results from the SHINE study

Author

Kirschner, J, Darras, B, Farrar, M, Mercuri, E, Chiriboga, C, Kuntz, N, Shieh, P, Tulinius, M, Montes, J, Reyna, S, Gambino, G, Foster, R, Bhan, I, Wong, J, Farwell, W, Kirschner, J, Darras, B, Farrar, M, Mercuri, E, Chiriboga, C, Kuntz, N, Shieh, P, Tulinius, M, Montes, J, Reyna, S, Gambino, G, Foster, R, Bhan, I, Wong, J, and Farwell, W

Published
2019

176. Fatigue and depression predict health-related quality of life in patients with pediatric-onset multiple sclerosis

Author

Gravesande, Karin Storm Van's, Blaschek, Astrid, Calabrese, Pasquale, Rostasy, Kevin, Huppke, Peter, Kessler, Josef J., Kalbe, Elke, Mall, Volker, Kraus, V, Dornfeld, E., Elpers, C., Lohmann, H., Weddige, A., Hagspiel, S., Kirschner, J., Brehm, M., Blank, C., Schubert, J., Schimmel, M., Pachee, S., Mohrbach, M., Karenfort, M., Kamp, G., Luecke, T., Neumann, H., Lutz, S., Gierse, A., Sievers, S., Schiffinann, H., de Soye, I, Trollmann, R., Candova, A., Rosner, M., Neu, A., Romer, G., Seidel, U., John, R., Hofmann, C., Kinder, S., Bertolatus, A., Scheidtmann, K., Lasogga, R., Leiz, S., Alber, M., Kranz, J., Bajer-Kornek, B., Seidl, R., Novak, A., Gravesande, Karin Storm Van's, Blaschek, Astrid, Calabrese, Pasquale, Rostasy, Kevin, Huppke, Peter, Kessler, Josef J., Kalbe, Elke, Mall, Volker, Kraus, V, Dornfeld, E., Elpers, C., Lohmann, H., Weddige, A., Hagspiel, S., Kirschner, J., Brehm, M., Blank, C., Schubert, J., Schimmel, M., Pachee, S., Mohrbach, M., Karenfort, M., Kamp, G., Luecke, T., Neumann, H., Lutz, S., Gierse, A., Sievers, S., Schiffinann, H., de Soye, I, Trollmann, R., Candova, A., Rosner, M., Neu, A., Romer, G., Seidel, U., John, R., Hofmann, C., Kinder, S., Bertolatus, A., Scheidtmann, K., Lasogga, R., Leiz, S., Alber, M., Kranz, J., Bajer-Kornek, B., Seidl, R., and Novak, A.

Abstract

Background: Fatigue, depression and loss in health-related quality of life (HRQoL) have been reported to occur in a substantial amount of patients with pediatric-onset MS (POMS). This study aims to evaluate depression, fatigue and HRQoL and its relationship in a cohort of patients with POMS and matched healthy controls (HCs). Methods: In a multicenter cross-sectional study, Beck Depression Inventory II, Depressionstest fur Kinder, the Pediatric Quality of Life Inventory (PedsQL (TM)) 4.0 Generic Core Scale and the PedsQL (TM) Multidimensional Fatigue Scale were performed. Results: In a cohort of 106 patients with POMS and 210 matched HCs, patients were significantly more often depressed (21.7% vs. 11.4%, p = 0.014) experienced greater fatigue (40.6% vs. 17.3%, p < 0.001) and a greater loss of HRQoL (43.4% vs. 15%, p < 0.001) than controls. Depression predicted 51.8% of variance of fatigue. Fatigue was also predicted by female gender. Loss of HRQoL was predicted by EDSS, depression and fatigue. Depression and fatigue together explained 67.7% of variance of HRQoL. Conclusion: Patients with POMS are at a significant increased risk for depression, fatigue and loss of HRQoL. Furthermore, fatigue and depression significantly predict reduced HRQoL in POMS, suggesting that testing for these symptoms and early therapy is of utmost importance in all patients with POMS.

Published
2019

177. The Multiple Sclerosis Inventory of Cognition for Adolescents (MUSICADO): A brief screening instrument to assess cognitive dysfunction, fatigue and loss of health-related quality of life in pediatric-onset multiple sclerosis

Author

Gravesande, K. Storm Van's, Calabrese, P., Blaschek, A., Rostasy, K., Huppke, P., Rothe, L., Mall, V, Kessler, J., Kalbe, E., Kraus, V, Dornfeld, E., Elpers, C., Lohmann, H., Weddige, A., Hagspiel, S., Kirschner, J., Brehm, M., Blank, C., Schubert, J., Schimmel, M., Pachee, S., Mohrbach, M., Karenfort, M., Kamp, G., Luecke, T., Neumann, H., Lutz, S., Gierse, A., Sievers, S., Schiffmann, H., de Soye, I, Trollmann, R., Candova, A., Rosner, M., Neu, A., Romer, G., Seidel, U., John, R., Hofmann, C., Kinder, S., Bertolatus, A., Scheidtmann, K., Lasogga, R., Leiz, S., Alber, M., Kranz, J., Bajer-Kornek, B., Seidl, R., Novak, A., Gravesande, K. Storm Van's, Calabrese, P., Blaschek, A., Rostasy, K., Huppke, P., Rothe, L., Mall, V, Kessler, J., Kalbe, E., Kraus, V, Dornfeld, E., Elpers, C., Lohmann, H., Weddige, A., Hagspiel, S., Kirschner, J., Brehm, M., Blank, C., Schubert, J., Schimmel, M., Pachee, S., Mohrbach, M., Karenfort, M., Kamp, G., Luecke, T., Neumann, H., Lutz, S., Gierse, A., Sievers, S., Schiffmann, H., de Soye, I, Trollmann, R., Candova, A., Rosner, M., Neu, A., Romer, G., Seidel, U., John, R., Hofmann, C., Kinder, S., Bertolatus, A., Scheidtmann, K., Lasogga, R., Leiz, S., Alber, M., Kranz, J., Bajer-Kornek, B., Seidl, R., and Novak, A.

Abstract

Objective: Screening for cognitive impairment (CI), fatigue and also Health-related quality of life (HRQoL) in patients with pediatric-onset multiple sclerosis (POMS) is of utmost importance in clinical practice. The aim of this study was to establish a new and validated pediatric screening tool MUSICADO that is easy to use and time economical. Methods: 106 patients with POMS aged 12-18 years and 210 healthy controls (HCs) stratified for age and education underwent neuropsychological testing including a screening test Multiple Sclerosis Inventory of Cognition for adults and 8 standardized cognitive tests and established scales to assess fatigue and HRQoL. Results: The phonemic verbal fluency task (RWT s-words), the Trail Making Test A (TMTA), and the Digit Span Forward discriminated significantly between patients and HCs (p = 0.000, respectively) and showed the highest proportion of test failure in patients 24.5%, 17.9%; 15.1%, respectively). Therefore, they were put together to form the cognitive part of the MUSICADO. After applying a scoring algorithm with balanced weighting of the subtests and age and education correction and a cut-off score for impairment, 35.8% of patients were categorized to be cognitively impaired (specificity: 88.6%). Fatigue was detected in 37.1% of the patients (specificity: 94.0%) and loss of HRQoL in 41.8% (specificity 95.7%) with the screening version, respectively. Conclusion: The MUSICADO is a newly designed brief and easy to use screening test to help to early identify CI, fatigue, and loss of HRQoL in patients with POMS as cut scores are provided for all three items. Further studies will have to show its usability in independent samples of patients with POMS. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Published
2019

178. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study

Author

De Vivo, DC, Bertini, E, Swoboda, KJ, Hwu, W-L, Crawford, TO, Finkel, RS, Kirschner, J, Kuntz, NL, Parsons, JA, Ryan, MM, Butterfield, RJ, Topaloglu, H, Ben-Omran, T, Sansone, VA, Jong, Y-J, Shu, F, Staropoli, JF, Kerr, D, Sandrock, AW, Stebbins, C, Petrillo, M, Braley, G, Johnson, K, Foster, R, Gheuens, S, Bhan, I, Reyna, SP, Fradette, S, Farwell, W, De Vivo, DC, Bertini, E, Swoboda, KJ, Hwu, W-L, Crawford, TO, Finkel, RS, Kirschner, J, Kuntz, NL, Parsons, JA, Ryan, MM, Butterfield, RJ, Topaloglu, H, Ben-Omran, T, Sansone, VA, Jong, Y-J, Shu, F, Staropoli, JF, Kerr, D, Sandrock, AW, Stebbins, C, Petrillo, M, Braley, G, Johnson, K, Foster, R, Gheuens, S, Bhan, I, Reyna, SP, Fradette, S, and Farwell, W

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Published
2019

179. Bookreviews

Author

Slavíková, Zdeňka, Herben, Tomáš, Kolbek, Jiří, Kirschnerová, L., Kirschner, J., Dostálek, Jiří, Samek, Věroslav, Bíba, Milan, Kovářová, Marcela, Holubová-Jechová, Věra, Hadač, Emil, Chytrý, Milan, and Jehlík, Vladimír

Published
1992
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188. Treatment with Ataluren for Duchene Muscular Dystrophy

Author

Mercuri, E, Muntoni, F, Osorio, An, Tulinius, M, Buccella, F, Morgenroth, Lp, Gordish-Dressman, H, Jiang, J, Trifillis, P, Zhu, J, Kristensen, A, Santos, Cl, Henricson, Ek, Mcdonald, Cm, Desguerre, I, Bernert, G, Gosk-Tomek, M, Ille, A, Kellersmann, A, Weiss, S, Pilshofer, V, Balintovà, Z, Danhofer, P, Fabulovà, P, Jurıkovà, L, Fuchsovà, P, Haberlovà, J, Laffargue, F, Sarret, C, Pontier, B, Bellance, R, Sarrazin, E, Sabouraud, P, Magot, A, Mercier, S, Péréon, Y, Cuisset, J-M, Coopman-Degryse, S, Enaud, E, Jacquemont, M-L, Perville, A, Renouil, M, Trommsdorff, V, Verheulpen, D, Fontaine-Carbonnel, S, Vuillerot, C, Peudenier, S, Ropars, J, Audic, F, Chabrol, B, Chabrier, S, Gousse, G, Lagrue, E, Aragon, K, Barnerias, C, Brande, Lv, De Lucia, S, Gidaro, T, Seferian, A, Servais, L, Laugel, V, Espil-Taris, C, Mecili, H, Raffo, E, Ragot-Mandry, S, Borrell, S, Kirschner, J, Gangfuss, A, Henrich, M, Kolbel, H, Schara, U, Sponemann, N, Temme, E, Seeger, J, Hirsch, A, Denecke, J, Johannsen, J, Neu, A, Osinski, D, Rugner, S, Schussler, S, Trollmann, R, Kaindl, A, Schneider, Jb, Stoltenburg, C, Weiss, C, Schreiber, G, Hahn, A, Grzybowski, M, Pavlidou, E, Pavlou, E, Dobner, S, Liptai, Z, Dor, T, Brogna, C, Catteruccia, M, D’Amico, A, Pane, E, Bello, L, Pegoraro, E, Semplicini, C, Albamonte, E, Baranello, G, Comi, G, Govoni, A, Lerario, A, Magri, F, Masson, R, Mauri, E, Sansone, V, Brusa, C, Mongini, T, Ricci, F, Vacchetti, M, Bruno, C, Paniucci, C, Pedemonte, M, Giannotta, M, Pini, A, Messina, S, Sframeli, M, Vita, Gl, Vita, G, Ruggiero, L, Santoro, L, Craiu, D, Motoescu, C, Sandu, C, Teleanu, R, Vasile, D, Hughes, I, Childs, A-M, Alhaswani, Z, Roper, H, Parasuraman, D, Degoede, C, Gowda, V, Manzur, A, Munot, P, Sarkokzy, A, Charlesworth, C, Lemon, J, Turner, L, Spinty, S, Dubrovsky, A, Kornberg, A, Ryan, M, Webster, R, Biggar, Wd, Mcadam, Lc, Mah, Jh, Kolski, H, Vishwanathan, V, Chidambaranathan, S, Nevo, Y, Gorni, K, Carlo, J, Abresch, Rt, Joyce, Nc, Cnaan, A, Leshner, R, Tesi-Rocha, C, Thangarajh, M, Duong, T, Clemens, Pr, Abdel-Hamid, H, Connolly, Am, Pestronk, A, Teasley, J, Harper, A, Bertorini, Te, Kuntz, N, Driscoll, S, Day, Jw, Karachunski, P, and Lotze, T.

Subjects
safety, medicine.medical_specialty, nonsense mutation Duchenne muscular dystrophy, Duchenne muscular dystrophy, Neurosurgery, STRIDE, effectiveness, Duchenne Muscular Dystrophy, Pediatrics, Dystrophin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Child Development, STRIDE Registry, International database, Internal medicine, medicine, Humans, In patient, Registries, Child, 030304 developmental biology, Pediatric, 0303 health sciences, Brain Diseases, Oxadiazoles, business.industry, Health Policy, Disease progression, Infant, ataluren, medicine.disease, Ataluren, Muscular Dystrophy, Duchenne, Treatment Outcome, chemistry, Neurology, Muscle Disorders, Codon, Nonsense, Neuromuscular, Propensity score matching, dystrophin, Nervous System Diseases, business, 030217 neurology & neurosurgery, Natural history study, Research Article
Abstract

Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype–phenotype/–ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan–Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p ≤ 0.05). There were no DMD genotype–phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731. ClinicalTrials.gov identifier: NCT02369731.

Published
2020

189. Nusinersen versus sham control in later-onset spinal muscular atrophy

Author

Vogt, Sibylle, Krueger, Marcus, Pechmann, Astrid, Rippberger, Bianca, Eckenweiler, Matthias, Schara, Ulrike, Koelbel, Heike, Andres, Barbara, Rupprich, Katrin, Gangfuss, Andrea, Jachertz, Philipp, Della Marina, Adela, Sponemann, Nina, Pane, Markia, Palermo, Concetta, Piastra, Marco, Fanelli, Lavinia, de Sanctis, Roberto, Genovese, Orazio, Antonaci, Laura, Pera, Maria Carmela, Lamendola, Priscilla, Messina, Sonia, Vita, Gianluca, Di Bella, Vincenzo, Sframeli, Maria, Rosa, Matteo, Barcellona, Costanza, Distefano, Maria Grazia, Cavallaro, Filippo, Versaci, Antonio, de Luca, Francesco, Vita, Giuseppe, Nacimento Osorio, Andres, Tizzano, Eduardo, Ortez Gonzalez, Carlos Ignacio, Ortigoza Escobar, Juan Dario, Colomer Oferil, Juame, Medina Cantillo, Julita, Febrer Rotger, Anna, Vigo Morancho, Meritxell, Eldblom, Johanneh, Darin, Niklas, Kroksmark, Anna Karin, Lindstedt, Asa, Michael, Eva, Kimber, Eva, Wahlgren, Lisa, Chan, Sophelia Hoi-Shan, Chim, Stella, Chiu, Joseph, Ho, Alvin Chi Chung, Ip, Jing Kun Janice, Lam, Wendy Wai Man, Ng, Maggie Chui-San, Wan, Connie, Wong, Virginia Chun Nei, Yue, Yvonne, Arakawa, Reiko, Yamauchi, Akemi, Nagata, Satoru, Ito, Yasushi, Nakatsukasa, Hidetsugu, Takeshita, Akiko, Hirasawa, Kyoko, Ikai, Tetsuo, Eto, Kaoru, Otamni, Yui, Takeshima, Yasuhiro, Fukuda, Noroki, Tanaka, Yasuhiro, Shimomura, Hideki, Lee, Tomoko, Shibano, Takayuki, Mercuri, E., Tachikawa, Tomohiro, Darras, B. T., Chae, Jong-Hee, Chiriboga, C. A., Lim, Byung Chan, Day, J. W., Shin, Hyung-Ik, Campbell, C., Kim, Soo Yeon, Connolly, A. M., Choi, Sun Ah, Iannaccone, S. T., Son, Woo Sung, Kirschner, J., Jo, Hyemi, Kuntz, N. L., Chun, Seong Min, Saito, K., Kim, Hyuna, Shieh, P. B., Tulinius, M., Mazzone, E. S., Montes, J., Bishop, K. M., Yang, Q., Foster, R., Gheuens, S., Bennett, C. F., Farwell, W., Schneider, E., de Vivo, D. C., Finkel, R. S., Bradley, Walter G., Kaufmann, Petra, Dickson, Patricia I., Reingold, Stephen C., Davis, Charles S., Arredondo, Kristen, Castro, Diana, Cowie, Margaret, Farrow-Gillespie, Alan, Hebert, Andrew, Kauk, Melissa, Miller, Nancy, Nelson, Leslie, Spain, Thomas, Cappell, Joshua, Constantinescu, Andrei, Cruz, Rosangel, Dastgir, Jahannaz, de Vivo, Darryl, Dunaway, Sally, Engelstad, Kristin, Khandji, Alexander G., Kramer, Samantha, Marra, Jonathan, Popolizio, Molly, Salazar, Rachel, Weimer, Louis H., Aziz-Zaman, Sonya, Lamarca, Nicole, Ghosh, Partha, Al-Ghamdi, Fouad, Liew, Wendy, Graham, Robert, Berde, Charles, Sethna, Navil, Koka, Anjali, Wang, Luke, Laine, Regina, Souris, Michelle, Ordonez, Grace, Harrington, Timothy, Szelag, Heather, Pasternak, Amy, Mirek, Elizabeth, Quigley, Janet, Finkel, Richard, Berry, Debbie, Civitello, Matthew, Endsley, Julie Duke, Eden, Candace, Leon, Wendy, O'Reardon, Kathleen, Sigurdardottir, Laufey, Johnson, Craig, Turner, Jenna, Vega, Melisa, Weber-Guzman, Fabiola, Zinn, Matthias, Rocha, Ana Carolina Tesi, Watson, Karolina, d'Souza, Genevieve, Ramamurthi, R. J., Gee, Richard, Kitsuwa-Lowe, Janis, Hagerman, Katharine, Crasta, Sheela, Welsh, Lesly, Paulose, Shirley, Mcfall, Danielle, Perez, Jennifer, Patnaik, Swetapadma, Sanjanwala, Bharati, Sakamuri, Sarada, Proud, Crystal, Purse, Bona Park, Duong, Trinh Tina, Sampson, Jacinda, Tennekoon, Gihan, Brandsema, John, Glanzman, Allan, Flickinger, Jean, Toms, Michele, Adang, Laura, Stanford, Delores, Mayer, Oscar, Zigmont, Joshua, Chadehumbe, Madeline, Kichula, Elizabeth, Finanger, Erika, Russman, Barry, Roberts, Colin, Frank, Andrea, Benjamin, Danielle, Zilke, Kirsten, Golumbek, Paul T., Zaidman, Craig M., Anand, Pallavi, Gadeken, Rebecca, Siener, Catherine, Kuntz, Nancy, Epstein, Leon, Krueger, Jena, Goldman, Stewart, Krosschell, Kristin, Blomgren, Colleen, Choi, Hyoung Won, Kurz, Jonathan, Parsons, Julie, Janas, Joanne, Yang, Michele, Ballard, Alison, Carry, Terri, Shea, Stephanie, Bielsky, Alan, Booker, Kaylee, Camuto, Alicia, Lord-Halvorson, Sierra, Gibbons, Melissa, Zimmerman, Carl, Allen, Victoria, Fuhr, Peter, Johnson, Hannah, Tran, Vi, Vanderveen, Gina, Shieh, Perry, Fowler, Eileen, Parziale, Nicholas, Rao, Lekha, Skura, Christy, Kelley, Carolyn, Shu, Francy, Oskoui, Maryam, Zielinski, David, Poulin, Chantal, Ingelmo, Pablo Mauricio, Desilets, Sarah Turgeon, Dinunzio, Pamela, Rivera, Gonzalo, Srour, Myriam, Arpin, Stephanie, Goobie, Sharan, Gibson, Paul, Scholtes, Cheryl, Mcdonald, Wendy, Zapata, Eugenio, Nguyen, Cam-Tu Emilie, Servais, Laurent, Gargaun, Elena, Le Moing, Anne-Gaelle, Gidaro, Teresa, Vialle, Raphael, Guye, Marie-Laurence, Lilien, Charlotte, Olliver, Gwenn, Gilabert, Stephanie, Borell, Sabine, Wider, Sabine, Stein, Sabine, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Department of Paediatrics, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Vall d'Hebron University Hospital [Barcelona], CIBER de Enfermedades Raras (CIBERER), Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Seoul National University Hospital, Max-Planck-Institut für Mikrostrukturphysik (MPI-HALLE), Max-Planck-Gesellschaft, The University of Tokyo (UTokyo), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institute of Plasma Physics, Chinese Academy of Sciences (ASIPP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de mécanique des solides (LMS), École polytechnique (X)-Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), CureSMA [Elk Grove Village, IL, USA], Harvard Medical School [Boston] (HMS), Institute for Marine and Antarctic Studies [Hobart] (IMAS), University of Tasmania [Hobart, Australia] (UTAS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, The Open University [Milton Keynes] (OU), Department of Pediatrics, Feinberg School of Medicine, Northwestern University [Evanston]-Northwestern University [Evanston]-Northwestern University, University Hospital Basel [Basel], McGill University Health Center [Montreal] (MUHC), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service of Clinical Trials and Databases, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Oxford, Schara, Ulrike (Beitragende*r), Koelbel, Heike (Beitragende*r), Rupprich, Katrin (Beitragende*r), Gangfuss, Andrea (Beitragende*r), Della Marina, Adela (Beitragende*r), and Sponemann, Nina (Beitragende*r)

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], spinal, Medizin, Oligonucleotides, Spinal Muscular Atrophies of Childhood, Pediatrics, law.invention, Age of Onset, Child, Child, Preschool, Double-Blind Method, Female, Humans, Infant, Injections, Spinal, Least-Squares Analysis, Motor Skills, Oligonucleotides, Antisense, Medicine (all), 0302 clinical medicine, age of onset, Randomized controlled trial, law, Clinical endpoint, inglese, injections, Motor skill, motor skills, General Medicine, SMA, Settore MED/26 - NEUROLOGIA, medicine.anatomical_structure, female, Anesthesia, Nusinersen, Spinal, antisense, preschool, Injections, 03 medical and health sciences, least-squares analysis, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Settore MED/41 - ANESTESIOLOGIA, medicine, Antisense, Preschool, business.industry, Spinal muscular atrophy, Motor neuron, medicine.disease, 030104 developmental biology, Age of onset, business, 030217 neurology & neurosurgery
Abstract

Background: Nusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). Methods: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. Results: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by –1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P Conclusions: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537. opens in new tab.)

Published
2018
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190. Nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA): Interim results from the phase 2 nurture study

Author

Ryan, M.M., primary, De Vivo, D.C., additional, Bertini, E., additional, Hwu, W.L., additional, Crawford, T.O., additional, Swoboda, K.J., additional, Finkel, R.S., additional, Kirschner, J., additional, Kuntz, N.L., additional, Parsons, J., additional, Butterfield, R.J., additional, Topaloglu, H., additional, Omran, T. Ben, additional, Sansone, V.A., additional, Jong, Y.J., additional, Shu, F., additional, Foster, R., additional, Bhan, I., additional, Fradette, S., additional, and Farwell, W., additional

Published
2019
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192. O.41Sunfish part 1: 18-month safety and exploratory outcomes of risdiplam (RG7916) treatment in patients with type 2 or 3 spinal muscular atrophy

Author

Mercuri, E., primary, Baranello, G., additional, Kirschner, J., additional, Servais, L., additional, Goemans, N., additional, Pera, M., additional, Tichy, M., additional, Yeung, W., additional, Kletzl, H., additional, Gerber, M., additional, Czech, C., additional, Annoussamy, M., additional, Cleary, Y., additional, and Gorni, K., additional

Published
2019
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193. Interim report on the safety and efficacy of longer-term treatment with nusinersen in later-onset spinal muscular atrophy (SMA): Results from the shine study

Author

Kirschner, J., primary, Darras, B.T., additional, Farrar, M.A., additional, Mercuri, E., additional, Chiriboga, C.A., additional, Kuntz, N.L., additional, Shieh, P.B., additional, Tulinius, M., additional, Montes, J., additional, Reyna, S.P., additional, Gambino, G., additional, Foster, R., additional, Bhan, I., additional, Wong, J., additional, and Farwell, W., additional

Published
2019
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196. REGISTRIES

Author

Servais, L., primary, Day, J., additional, De Vivo, D., additional, Kirschner, J., additional, Mercuri, E., additional, Muntoni, F., additional, Shieh, P., additional, Tizzano, E., additional, Droege, M., additional, Dabbous, O., additional, Khan, F., additional, Anderson, F., additional, and Finkel, R., additional

Published
2019
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199. P.390Pulmonary function in patients with Duchenne muscular dystrophy from the STRIDE registry and the CINRG natural history study: a matched cohort analysis

Author

Tulinius, M., primary, Buccella, F., additional, Desguerre, I., additional, Kirschner, J., additional, Mercuri, E., additional, Muntoni, F., additional, Nascimento Osorio, A., additional, Delage, A., additional, Zhu, J., additional, Kristensen, A., additional, Trifillis, P., additional, Santos, C., additional, and McDonald, C., additional

Published
2019
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200. P.352Interim report on the safety and efficacy of longer-term treatment with nusinersen in later-onset spinal muscular atrophy (SMA): results from the SHINE study

Author

Kirschner, J., primary, Darras, B., additional, Farrar, M., additional, Mercuri, E., additional, Chiriboga, C., additional, Kuntz, N., additional, Shieh, P., additional, Tulinius, M., additional, Montes, J., additional, Reyna, S., additional, Gambino, G., additional, Foster, R., additional, Bhan, I., additional, Wong, J., additional, and Farwell, W., additional

Published
2019
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