Uncertain hierarchical modeling

For modeling complex systems, it is natural to reduce the system into subsystems and model each subsystem. The approach taken in this paper is that it is desired that a model should be consistent with the modeling methodology. Further it is important to explicitly represent the inaccuracies of the model as part of the model. Within this paper, uncertain hierarchical modeling is further motivated. A hierarchy, interconnection structure, and a fundamental component data type are proposed and the choices motivated. The framework is proposed with the intention of being implemented on a computer and having a family of models of different resolution representing a system

Approximate behaviors

The motivation for this paper is to contribute to a unified approach to modeling, realization, approximation and analysis for systems with a rich class of uncertainty structures. The specific focus is on what is the appropriate framework to model components with uncertainty, and what is the appropriate notion of approximation for such components. Components and systems are conceptualized in terms of their behaviors, which can be specified by parametrized equations. More questions are posed than are answered

Uncertain hierarchical modeling

For modeling complex systems, it is natural to reduce the system into subsystems and model each subsystem. The approach taken in this paper is that it is desired that a model should be consistent with the modeling methodology. Further it is important to explicitly represent the inaccuracies of the model as part of the model. Within this paper, uncertain hierarchical modeling is further motivated. A hierarchy, interconnection structure, and a fundamental component data type are proposed and the choices motivated. The framework is proposed with the intention of being implemented on a computer and having a family of models of different resolution representing a system

REDD+, transformational change and the promise of performance-based payments: a qualitative comparative analysis

Reducing emissions from deforestation and forest degradation (REDD+) has emerged as a promising climate change mitigation mechanism in developing countries. This paper examines the national political context in 13 REDD+ countries in order to identify the enabling conditions for achieving progress with the implementation of countries REDD+ policies and measures. The analysis builds on a qualitative comparative analysis (QCA) of various countries' progress with REDD+, conducted in 12 REDD+ countries in 2012, which highlighted the importance of factors such as already initiated policy change, and the presence of coalitions calling for broader policy change A follow-up survey in 2014 was considered timely because the REDD+ policy arena, at international and at country levels, is highly dynamic and undergoes constant evolution, which affects progress with REDD+ policy making and implementation. Furthermore, we will now examine whether the 'promise' of performance-based funds has played a role in enabling the establishment of REDD+. The results show a set of enabling conditions and characteristics of the policy process under which REDD+ policies can be established. The study finds that the existence of broader policy change, and availability of performance-based funding in combination with strong national ownership of the REDD+ policy process may help guide other countries seeking to formulate REDD+ policies that are likely to deliver efficient, effective, and equitable outcomes

Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy

Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5–4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML–IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Extensions to the structured singular value

NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document. There are two basic approaches to robustness analysis. The first is Monte Carlo analysis which randomly samples parameter space to generate a profile for the typical behavior of the system. The other approach is fundamentally worst case, where the objective is to determine the worst behavior in a set of models. The structured singular value, [...], is a powerful frame work for worst case analysis. Where [...] is a measure of the distance to singularity using the co-norm. Under the appropriate projection, the uncertainty sets in the standard [...] framework that admit analysis are hypercubes. In this work, [...] and the computation of the bounds is extended to spherical sets or equivalently measuring the distance to singularity using the 2-norm. The upper bound is constructed by converting the spherical set of operators into a quadratic form relating the input and output vectors. Using a separating hyperplane or the S-procedure, a linear matrix inequality (LMI) upper bound can be constructed which is tighter than and consistent with the standard p upper bound. This new upper bound has special structure that can be exploited for efficient computation and the standard power algorithm is extended to compute lower bounds for spherical [...]. The upper bound construction is further generalized to more exotic regions like arbitrary ellipsoids, the Cartesian product of ellipsoids, and the intersection of ellipsoids. These generalizations are unified with the standard structures. These new tools enable the analysis of more exotic descriptions of uncertain models. For many real world problems, the worst case paradigm leads to overly pessimistic answers and Monte Carlo methods are computationally expensive to obtain reasonable probabilistic descriptions for rare events. A few natural probabilistic robustness analysis questions are posed within the [...] framework. The proper formulation is as a mixed probabilistic and worst case uncertainty structure. Using branch and bound algorithms, an upper bound can be computed for probabilistic robustness. Motivated by this approach, a purely probabilistic [...] problem is posed and bounds are computed. Using the existing machinery, the branch and bound computation cost grows exponentially in the average case for questions of probabilistic robustness. This growth is due to gridding an n-dimensional surface with hypercubes. A motivation for the extensions of [...] to other uncertainty descriptions which admit analysis is to enable more efficient gridding techniques than just hypercubes. The desired fundamental region is a hypercube with a linear constraint. The motivation for this choice is the rank one problem. For rank one, the boundary of singularity is a hyperplane, but the conventional branch and bound tools still result in exponential gridding growth. The generalization of the [...] framework is used to formulate an LMI upper bound for [...] with the linear constraint on uncertainty space. This is done by constructing the upper bound for the intersection of an eccentric ellipsoid with the standard uncertainty set. A more promising approach to this computation is the construction of an implicit [...] problem where the linear constraints on the uncertainty can be generically rewritten as an algebraic constraint on signals. This may lead to improvements on average to the branch and bound algorithms for probabilistic robustness analysis

Exposure–Response Relationship for Ombitasvir and Paritaprevir/Ritonavir in Hepatitis C Virus Subgenotype 1b-Infected Japanese Patients in the Phase 3 Randomized GIFT-I Study

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s12325-016-0320-y">https://link.springer.com/article/10.1007/s12325-016-0320-y</a></p><p></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p