The TRACTISS protocol: a randomised double blind placebo controlled clinical trial of anti-B-cell therapy in patients with primary Sjögren's Syndrome.

Background: Primary Sjögren's Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes. Methods/design: TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition. Discussion: The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity. Trial registration: UKCRN Portfolio ID: 9809 ISRCTN65360827

Adding omega-3 fatty acids to a protein-based supplement during pre-season training results in reduced muscle soreness and the better maintenance of explosive power in professional Rugby Union players

Evidence suggests that omega-3 fatty acid supplementation could reduce muscle soreness and maintain muscle function following eccentric exercise-induced muscle damage. The aim of this applied field study was to investigate the effectiveness of consuming a protein-based supplement containing 1546 mg of omega-3 polyunsaturated fatty acid (PUFA) (551 mg eicosapentaenoic acid (EPA) and 551 mg docosahexaenoic acid (DHA)) twice daily (FO) compared to a protein-based placebo (P) on muscle soreness, countermovement jump (CMJ) performance and psychological well-being in 20 professional Rugby Union players during 5 weeks of pre-season training. Players completed a 5-point-Likert soreness scale with 5 indicating “no soreness” and a questionnaire assessing fatigue, sleep, stress and mood each morning of training, plus they performed CMJ tests once or twice per week. Data were analysed using magnitude-based inferential statistics and are presented as percent beneficial/trivial/harmful. On day 35, there was a likely (% beneficial/trivial/harmful: 94/5/1) moderate (0.75, standardized mean difference (SMD)) beneficial effect of FO vs. P on the change in lower body muscle soreness compared with day 0 (FO: −3.8 ± 21.7%; P: −19.4 ± 11.2%). There was a likely (92/7/0) moderate (SMD: 0.60) beneficial effect of FO vs. P on CMJ performance (change from baseline to day 35, FO: +4.6 ± 5.9%; P: −3.4 ± 8.6%). From day 20, a moderate beneficial effect of FO on fatigue was observed. In terms of practical relevance, the moderate beneficial effect of adding fish oil to a protein-based supplement on muscle soreness translated into the better maintenance of explosive power in elite Rugby Union players during pre-season training

The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes

Aims: Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies. Methods: We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). Results: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies; randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH‐I/II). Within the discriminated favourable‐risk iMBSHH DN/MBEN patient group, iMBSHH‐II had significantly better progression‐free survival than iMBSHH‐I, offering opportunities for risk‐adapted stratification of upfront therapies. Both iMBSHH‐I and iMBSHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Conclusions: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies

Rings and bars: unmasking secular evolution of galaxies

Secular evolution gradually shapes galaxies by internal processes, in contrast to early cosmological evolution which is more rapid. An important driver of secular evolution is the flow of gas from the disk into the central regions, often under the influence of a bar. In this paper, we review several new observational results on bars and nuclear rings in galaxies. They show that these components are intimately linked to each other, and to the properties of their host galaxy. We briefly discuss how upcoming observations, e.g., imaging from the Spitzer Survey of Stellar Structure in Galaxies (S4G), will lead to significant further advances in this area of research.Comment: Invited review at "Galaxies and their Masks", celebrating Ken Freeman's 70-th birthday, Sossusvlei, Namibia, April 2010. To be published by Springer, New York, editors D.L. Block, K.C. Freeman, & I. Puerari; minor change

Biology ideology and pastiche hegemony

As knowledge about the biological foundation of the modern patriarchal gender order is increasingly challenged within late-modern social worlds enclaves persist in which men and women can attempt to recreate understandings of the "natural" basis of sex difference. Within "Power Gym," male boxers were able to symbolize their bodies and behaviors in such a manner. The language and logic of popular scientific discourses authored and authorized notions of an "innate" manhood. The ability to instrumentally deploy one's manliness in symbolically legitimate ways could then be represented and emotionally experienced as a man's biological right and obligation. Through scripted performances of "mimetic" violence and self-bullying, the boxers were able to experience this discursive naturalness and carve out a masculinity-validating social enclave. As such, they accessed a "patriarchal dividend" by securing a local pastiche hegemony in which discourses surrounding men's natural place as physically and psychologically dominant remained largely uncontested. Through the reflexive appropriation of "science," within appropriate subcultural codes, these men could negotiate taboos and restrictions that are characteristic of late-modern social worlds. When considered in this way, the power of "scientific" truth claims to explain and justify a certain level of violence, aggression, and behaviors coded as masculine, comes to the fore

Interferometric observations of the Mira star o Ceti with the VLTI/VINCI instrument in the near-infrared

We present K-band commissioning observations of the Mira star prototype o Cet obtained at the ESO Very Large Telescope Interferometer (VLTI) with the VINCI instrument and two siderostats. The observations were carried out between 2001 October and December, in 2002 January and December, and in 2003 January. Rosseland angular radii are derived from the measured visibilities by fitting theoretical visibility functions obtained from center-to-limb intensity variations (CLVs) of Mira star models (Bessel et al. 1996, Hofmann et al. 1998, Tej et al. 2003). Using the derived Rosseland angular radii and the SEDs reconstructed from available photometric and spectrophotometric data, we find effective temperatures ranging from T_eff=3192 +/- 200 K at phase phi=0.13 to 2918 +/- 183 K at phi=0.26. Comparison of these Rosseland radii, effective temperatures, and the shape of the observed visibility functions with model predictions suggests that o Cet is a fundamental mode pulsator. Furthermore, we investigated the variation of visibility function and diameter with phase. The Rosseland angular diameter of o Cet increased from 28.9 +/- 0.3 mas (corresponding to a Rosseland radius of 332 +/- 38 R_sun for a distance of D=107 +/- 12 pc) at phi=0.13 to 34.9 +/- 0.4 mas (402 +/- 46 R_sun) at phi=0.4. The error of the Rosseland linear radius almost entirely results from the error of the parallax, since the error of the angular diameter is only approximately 1 %.Comment: 12 pages, 8 figures, accepted for publication in Astronomy & Astrophysic

Ultrafast force-clamp spectroscopy of single molecules reveals load dependence of myosin working stroke

n/

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. / Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. / Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. / Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. / Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201