Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis.

CD8+ T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8+ T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8+ T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8+ T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8+ T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramer-positive myelin-specific CD8+ T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8+ T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8+ T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20+ CD8+ T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8+ T cells in MS, indicates these cells may be attractive targets in MS therapy

The interaction of class and gender in illness narratives

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2008 BSA Publications Ltd.Perspectives on gender and identity that emphasize variability of performance, local context and individual agency have displaced earlier paradigms.These are now perceived to have supported gender stereotypes and language ideologies by emphasizing gender difference and homogeneity within genders. In a secondary analysis of health and illness narratives we explore the interaction of class and gender in individuals' constructions of gendered identity. High social class men perform gender in particularly varied ways and we speculate that this variable repertoire, including the use of what was once termed `women's language', is linked to a capacity to maintain social distinction and authority. Men's performance of conventional masculinity is often threatened by both the experience of illness and being interviewed about personal experience. Lower social class women in particular demonstrate an intensification of a pre-existing informal family and support group culture, marking successful members by awarding them the accolade of being `lovely'.ESR

A Numerical Relativity Waveform Surrogate Model for Generically Precessing Binary Black Hole Mergers

A generic, non-eccentric binary black hole (BBH) system emits gravitational waves (GWs) that are completely described by 7 intrinsic parameters: the black hole spin vectors and the ratio of their masses. Simulating a BBH coalescence by solving Einstein's equations numerically is computationally expensive, requiring days to months of computing resources for a single set of parameter values. Since theoretical predictions of the GWs are often needed for many different source parameters, a fast and accurate model is essential. We present the first surrogate model for GWs from the coalescence of BBHs including all $7$ dimensions of the intrinsic non-eccentric parameter space. The surrogate model, which we call NRSur7dq2, is built from the results of $744$ numerical relativity simulations. NRSur7dq2 covers spin magnitudes up to $0.8$ and mass ratios up to $2$, includes all $\ell \leq 4$ modes, begins about $20$ orbits before merger, and can be evaluated in $\sim~50\,\mathrm{ms}$. We find the largest NRSur7dq2 errors to be comparable to the largest errors in the numerical relativity simulations, and more than an order of magnitude smaller than the errors of other waveform models. Our model, and more broadly the methods developed here, will enable studies that would otherwise require millions of numerical relativity waveforms, such as parameter inference and tests of general relativity with GW observations.Comment: 10 pages, 5 figures; Added report numbe

Generic local distinguishability and completely entangled subspaces

A subspace of a multipartite Hilbert space is completely entangled if it contains no product states. Such subspaces can be large with a known maximum size, S, approaching the full dimension of the system, D. We show that almost all subspaces with dimension less than or equal to S are completely entangled, and then use this fact to prove that n random pure quantum states are unambiguously locally distinguishable if and only if n does not exceed D-S. This condition holds for almost all sets of states of all multipartite systems, and reveals something surprising. The criterion is identical for separable and for nonseparable states: entanglement makes no difference.Comment: 12 page

Introduction to the Frontiers Research Topic: Optimization of Exercise Countermeasures for Human Space Flight – Lessons From Terrestrial Physiology and Operational Considerations

Exercise in space has evolved from rudimental testing into the multi-modal countermeasure (CM) program used on the International Space Station (ISS). However, with the constraints of future exploration missions, replicating this program will be a significant challenge. Recent ISS data suggest that crew now experience only relatively moderate levels of microgravity (μG)-induced adaptation, although significant variation remains, with some crew displaying marked changes despite significant time/effort investment. This suggests that the efficacy of exercise CMs is yet to be optimized for all individuals. With the current suite of exercise devices operational for almost a decade, and with exploration approaching, it is timely to re-visit the terrestrial literature to identify new knowledge relevant to the management of μG adaptation. As such, the aim of the Frontiers Research Topic Optimization of Exercise Countermeasures for Human Space Flight – Lessons from Terrestrial Physiology and Operational Considerations, is to synthesize current terrestrial exercise physiology knowledge and consider how this might be employed to optimize the use of exercise CM. The purpose of this Perspective, which serves as a preface to the Research Topic is threefold: to briefly review the use and apparent efficacy of exercise in space, to consider the impact of the transition from ISS to exploration mission vehicles and habitats, and to identify areas of terrestrial exercise physiology where current knowledge might contribute to the optimization of CM exercise for exploration. These areas include individual variation, high intensity interval training, strength development/maintenance, concurrent training, plyometric/impact exercise, and strategies to enhance exercise efficacy

Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF.

IntroductionPatient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.MethodsROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).ResultsA total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.ConclusionsStudy drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.FundingThe ROCKET AF trial was funded by Johnson & Johnson and Bayer

Cultural and economic complementarities of spatial agglomeration in the British television broadcasting industry: Some explorations.

This paper considers the processes supporting agglomeration in the British television broadcasting industry. It compares and contrasts the insights offered by the cultural turn in geography and more conventionally economic approaches. It finds that culture and institutions are fundamental to the constitution of production and exchange relationships and also that they solve fundamental economic problems of coordinating resources under conditions of uncertainty and limited information. Processes at a range of spatial scales are important, from highly local to global, and conventional economics casts some light on which firms are most active and successful