The distribution of blood eosinophil levels in a Japanese COPD clinical trial database and in the rest of the world.

Background: Blood eosinophil measurements may help to guide physicians on the use of inhaled corticosteroids (ICS) for patients with chronic obstructive pulmonary disease (COPD). Emerging data suggest that COPD patients with higher blood eosinophil counts may be at higher risk of exacerbations and more likely to benefit from combined ICS/long-acting beta2-agonist (LABA) treatment than therapy with a LABA alone. This analysis describes the distribution of blood eosinophil count at baseline in Japanese COPD patients in comparison with non-Japanese COPD patients. Methods: A post hoc analysis of eosinophil distribution by percentage and absolute cell count was performed across 12 Phase II-IV COPD clinical studies (seven Japanese studies [N=848 available absolute eosinophil counts] and five global studies [N=5,397 available eosinophil counts] that included 246 Japanese patients resident in Japan with available counts). Blood eosinophil distributions were assessed at baseline, before blinded treatment assignment. Findings: Among Japanese patients, the median (interquartile range) absolute eosinophil count was 170 cells/mm3(100-280 cells/mm3). Overall, 612/1,094 Japanese patients (56%) had an absolute eosinophil count ≥150 cells/mm3and 902/1,304 Japanese patients (69%) had a percentage eosinophil ≥2%. Among non-Japanese patients, these values were 160 (100-250) cells/mm3, 2,842/5,151 patients (55%), and 2,937/5,155 patients (57%), respectively. The eosinophil distribution among Japanese patients was similar to that among non-Japanese patients. Within multi-country studies with similar inclusion criteria, the eosinophil count was numerically lower in Japanese compared with non-Japanese patients (median 120 vs 160 cells/mm3). Interpretation: The eosinophil distribution in Japanese patients seems comparable to that of non-Japanese patients; although within multi-country studies, there was a slightly lower median eosinophil count for Japanese patients compared with non-Japanese patients. These findings suggest that blood eosinophil data from global studies are of relevance in Japan

Longitudinal observational study investigating outcome measures for clinical trials in inclusion body myositis.

OBJECTIVE: To describe decline in muscle strength and physical function in patients with sporadic inclusion body myositis (IBM). METHODS: Manual muscle testing (MMT), quantitative muscle testing (QMT) and disability scoring using the IBM Functional Rating Scale (IBMFRS) were undertaken for 181 patients for up to 7.3 years. The relationship between MMT, QMT and IBMFRS composite scores and time from onset were examined using linear mixed effects models adjusted for gender and age of disease onset. Adaptive LASSO regression analysis was used to identify muscle groups that best predicted the time elapsed from onset. Cox proportional hazards regression was used to evaluate time to use of a mobility aid. RESULTS: Multilevel modelling of change in percentage MMT, QMT and IBMFRS score over time yielded an average decline of 3.7% (95% CI 3.1% to 4.3%), 3.8% (95% CI 2.7% to 4.9%) and 6.3% (95% CI 5.5% to 7.2%) per year, respectively. The decline, however, was not linear, with steeper decline in the initial years. Older age of onset was associated with a more rapid IBMFRS decline (p=0.007), but did not influence the rate of MMT/QMT decline. Combination of selected muscle groups allowed for generation of single measures of patient progress (MMT and QMT factors). Median (IQR) time to using a mobility aid was 5.4 (3.6-9.2) years, significantly affected by greater age of onset (HR 1.06, 95% CI 1.04 to 1.09, p<0.001). CONCLUSION: This prospective observational study represents the largest IBM cohort to date. Measures of patient progress evaluated in this study accurately predict disease progression in a reliable and useful way to be used in trial design

Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry

Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a "Global FSHD registry". We suggest that the registry's ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally

The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis.

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in "translocase of outer mitochondrial membrane 40" (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. To further investigate the influence of these genetic factors in sIBM, we analyzed a large sIBM cohort of 158 cases as part of an International sIBM Genetics Study. No significant association was found between APOE or TOMM40 genotypes and the risk of developing sIBM. We found that the presence of at least 1 VL polyT repeat allele in TOMM40 was significantly associated with about 4 years later onset of sIBM symptoms. The age of onset was delayed by 5 years when the patients were also carriers of the APOE genotype ε3/ε3. In addition, males were likely to have a later age of onset than females. Therefore, the TOMM40 VL polyT repeat, although not influencing disease susceptibility, has a disease-modifying effect on sIBM, which can be enhanced by the APOE genotype ε3/ε3

Physical Properties of (2) Pallas

We acquired and analyzed adaptive-optics imaging observations of asteroid (2) Pallas from Keck II and the Very Large Telescope taken during four Pallas oppositions between 2003 and 2007, with spatial resolution spanning 32-88 km (image scales 13-20 km/pix). We improve our determination of the size, shape, and pole by a novel method that combines our AO data with 51 visual light-curves spanning 34 years of observations as well as occultation data. The shape model of Pallas derived here reproduces well both the projected shape of Pallas on the sky and light-curve behavior at all the epochs considered. We resolved the pole ambiguity and found the spin-vector coordinates to be within 5 deg. of [long, lat] = [30 deg., -16 deg.] in the ECJ2000.0 reference frame, indicating a high obliquity of ~84 deg., leading to high seasonal contrast. The best triaxial-ellipsoid fit returns radii of a=275 km, b= 258 km, and c= 238 km. From the mass of Pallas determined by gravitational perturbation on other minor bodies [(1.2 +/- 0.3) x 10-10 Solar Masses], we derive a density of 3.4 +/- 0.9 g.cm-3 significantly different from the density of C-type (1) Ceres of 2.2 +/- 0.1 g.cm-3. Considering the spectral similarities of Pallas and Ceres at visible and near-infrared wavelengths, this may point to fundamental differences in the interior composition or structure of these two bodies. We define a planetocentric longitude system for Pallas, following IAU guidelines. We also present the first albedo maps of Pallas covering ~80% of the surface in K-band. These maps reveal features with diameters in the 70-180 km range and an albedo contrast of about 6% wrt the mean surface albedo.Comment: 16 pages, 8 figures, 6 table

SPIDER: a balloon-borne CMB polarimeter for large angular scales

We describe SPIDER, a balloon-borne instrument to map the polarization of the millimeter-wave sky with degree angular resolution. Spider consists of six monochromatic refracting telescopes, each illuminating a focal plane of large-format antenna-coupled bolometer arrays. A total of 2,624 superconducting transition-edge sensors are distributed among three observing bands centered at 90, 150, and 280 GHz. A cold half-wave plate at the aperture of each telescope modulates the polarization of incoming light to control systematics. Spider's first flight will be a 20-30-day Antarctic balloon campaign in December 2011. This flight will map \sim8% of the sky to achieve unprecedented sensitivity to the polarization signature of the gravitational wave background predicted by inflationary cosmology. The Spider mission will also serve as a proving ground for these detector technologies in preparation for a future satellite mission.Comment: 12 pages, 6 figures; as published in the conference proceedings for SPIE Millimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy V (2010

Design and construction of a carbon fiber gondola for the SPIDER balloon-borne telescope

We introduce the light-weight carbon fiber and aluminum gondola designed for the SPIDER balloon-borne telescope. SPIDER is designed to measure the polarization of the Cosmic Microwave Background radiation with unprecedented sensitivity and control of systematics in search of the imprint of inflation: a period of exponential expansion in the early Universe. The requirements of this balloon-borne instrument put tight constrains on the mass budget of the payload. The SPIDER gondola is designed to house the experiment and guarantee its operational and structural integrity during its balloon-borne flight, while using less than 10% of the total mass of the payload. We present a construction method for the gondola based on carbon fiber reinforced polymer tubes with aluminum inserts and aluminum multi-tube joints. We describe the validation of the model through Finite Element Analysis and mechanical tests.Comment: 16 pages, 11 figures. Presented at SPIE Ground-based and Airborne Telescopes V, June 23, 2014. To be published in Proceedings of SPIE Volume 914

Spider Optimization: Probing the Systematics of a Large Scale B-Mode Experiment

Spider is a long-duration, balloon-borne polarimeter designed to measure large scale Cosmic Microwave Background (CMB) polarization with very high sensitivity and control of systematics. The instrument will map over half the sky with degree angular resolution in I, Q and U Stokes parameters, in four frequency bands from 96 to 275 GHz. Spider's ultimate goal is to detect the primordial gravity wave signal imprinted on the CMB B-mode polarization. One of the challenges in achieving this goal is the minimization of the contamination of B-modes by systematic effects. This paper explores a number of instrument systematics and observing strategies in order to optimize B-mode sensitivity. This is done by injecting realistic-amplitude, time-varying systematics in a set of simulated time-streams. Tests of the impact of detector noise characteristics, pointing jitter, payload pendulations, polarization angle offsets, beam systematics and receiver gain drifts are shown. Spider's default observing strategy is to spin continuously in azimuth, with polarization modulation achieved by either a rapidly spinning half-wave plate or a rapidly spinning gondola and a slowly stepped half-wave plate. Although the latter is more susceptible to systematics, results shown here indicate that either mode of operation can be used by Spider.Comment: 15 pages, 12 figs, version with full resolution figs available here http://www.astro.caltech.edu/~lgg/spider_front.ht