The structure of economic models used in CEAs of DMTs for RRMS has converged over time. However, variation remains in terms of model approach, inputs, and assumptions. Though some recommendations from previous reviews have been incorporated in later models, areas for improvement remain.

Polyomavirus and papillomavirus (papovavirus) capsids are composed of 72 capsomeres of their major capsid proteins, VP1 and L1, respectively. After translation in the cytoplasm, L1 and VP1 pentamerize into capsomeres and are then imported into the nucleus using the cellular ␣ and ␤ karyopherins. Virion assembly only occurs in the nucleus, and cellular mechanisms exist to prevent premature capsid assembly in the cytosol. We have identified the karyopherin family of nuclear import factors as possible "chaperones" in preventing the cytoplasmic assembly of papovavirus capsomeres. Recombinant murine polyomavirus (mPy) VP1 and human papillomavirus type 11 (HPV11) L1 capsomeres bound the karyopherin heterodimer ␣2␤1 in vitro in a nuclear localization signal (NLS)-dependent manner. Because the amino acid sequence comprising the NLS of VP1 and L1 overlaps the previously identified DNA binding domain, we examined the relationship between karyopherin and DNA binding of both mPy VP1 and HPV11 L1. Capsomeres of L1, but not VP1, bound by karyopherin ␣2␤1 or ␤1 alone were unable to bind DNA. VP1 and L1 capsomeres could bind both karyopherin ␣2 and DNA simultaneously. Both VP1 and L1 capsomeres bound by karyopherin ␣2␤1 were unable to assemble into capsids, as shown by in vitro assembly reactions. These results support a role for karyopherins as chaperones in the in vivo regulation of viral capsid assembly.The virus families Polyomaviridae and Papillomaviridae, collectively referred to as papovaviruses, have a nonenveloped icosahedral capsid surrounding a double-stranded circular DNA genome. The structural proteins of polyomavirus (VP1, VP2, and VP3) and papillomavirus (L1 and L2) are synthesized late in viral infection and imported into the nucleus, where they assemble around newly synthesized viral genomes. Viral capsids are constructed from 72 capsomeres (pentamers) of L1 or VP1, arranged on a Tϭ7 icosahedral lattice (1). The carboxyl terminus of VP1 or L1 mediates contacts between the pentamers in the assembled capsid (14,26,27,32). Disulfide bonds stabilize the interpentamer contacts for L1 (25,30,42), while both disulfide bonds and calcium bridges stabilize these contacts for VP1 (2,4,21,28,44,45).The papillomavirus L1 and polyomavirus VP1 capsid proteins each have a well-defined, canonical nuclear localization signal (NLS) (3,12,20,31,35,38,40,49). In the cytoplasm, NLScontaining proteins bind the adaptor protein karyopherin ␣, which has at its amino terminus a karyopherin ␤-binding domain and at its carboxyl terminus the NLS binding domain (8). Karyopherin ␣ binds karyopherin ␤, which then docks the protein complex at the nuclear pore (19,36). After translocation through the nuclear pore, RanGTP dissociates karyopherin ␤ from the complex, resulting in the accumulation of karyopherin ␣ plus NLS protein in the nucleus (15,36). Once in the nucleus, factors such as nucleoporin Nup2 and the export receptor for karyopherin ␣, CAS, may facilitate the dissociation of karyopherin ␣ from the NLS (24,29). An alternative model for ...

Background Decision-analytic models used in economic evaluations of disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) have characterized disease progression and accrue quality-adjusted life-years from utility values based on the Expanded Disability Status Scale (EDSS), the occurrence of relapses, and progression to secondary-progressive multiple sclerosis (SPMS). The EDSS, used to characterize disability progression, has several limitations. If the EDSS is the only disability measure used in economic evaluations, the long-term clinical and economic implications of disease-modifying therapies may not be properly assessed. Objective The objective of this study was to explore if supplementary disability measures including the Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test (PASAT) significantly contribute additional information on health utility in RRMS and SPMS otherwise not captured by the EDSS and relapses and, therefore, should be considered in future economic evaluations of disease-modifying therapies. Methods Short-Form Six-Dimension utility scores were derived from the RAND 36-Item Health Survey 1.0 individual-level data available in the Multiple Sclerosis Outcome Assessment Consortium (MSOAC) Placebo Database. Repeated-measures mixed-effects models were conducted to estimate the effects of EDSS, T25FW, 9HPT (dominant and non-dominant hand), PASAT, and relapses on changes in utility over time, controlling for demographics. Results A higher level of EDSS, longer time to complete the T25FW test, and a recent relapse were significant predictors of lower utility in people with RRMS and SPMS. 9HPT and PASAT were not significant predictors. Conclusions This study suggests that in addition to EDSS and recent relapses, T25FW significantly predicts utility in RRMS and SPMS. These findings support the use of T25FW to supplement the EDSS and the occurrence of relapses to characterize the course of disease progression and to more accurately accrue quality-adjusted life-years in future economic evaluations of disease-modifying therapies for the treatment of RRMS. Data used in the preparation of this article were obtained from the Multiple Sclerosis Outcome Assessment Consortium (MSOAC). As such, the investigators within MSOAC contributed to the design and implementation of the MSOAC Placebo Database and/ or provided placebo data but did not participate in the analysis of the data or the writing of this report.