X-ray Observations of the Compact Source in CTA 1

The point source RX J0007.0+7302, at the center of supernova remnant CTA 1, was studied using the X-Ray Multi-mirror Mission. The X-ray spectrum of the source is consistent with a neutron star interpretation, and is well described by a power law with the addition of a soft thermal component that may correspond to emission from hot polar cap regions or to cooling emission from a light element atmosphere over the entire star. There is evidence of extended emission on small spatial scales which may correspond to structure in the underlying synchrotron nebula. No pulsations are observed. Extrapolation of the nonthermal spectrum of RX J0007.0+7302 to gamma-ray energies yields a flux consistent with that of EGRET source 3EG J0010+7309, supporting the proposition that there is a gamma-ray emitting pulsar at the center of CTA 1. Observations of the outer regions of CTA 1 with the Advanced Satellite for Cosmology and Astrophysics confirm earlier detections of thermal emission from the remnant and show that the synchrotron nebula extends to the outermost reaches of the SNR.Comment: 5 pages, including 4 postscript figs.LaTex. Accepted for publication by Ap

Transcranial direct current stimulation of the motor cortex in the treatment of chronic non-specific low back pain. A randomised, double-blind exploratory study

This exploratory study aimed to test the proof of principle that active anodal transcranial direct current stimulation (tDCS) applied to the motor cortex reduces pain significantly more than sham stimulation in a group of participants with chronic non-specific low back pain

Turbulent Magnetic Field Amplification from Spiral SASI Modes: Implications for Core-Collapse Supernovae and Proto-Neutron Star Magnetization

We extend our investigation of magnetic field evolution in three-dimensional flows driven by the stationary accretion shock instability (SASI) with a suite of higher-resolution idealized models of the post-bounce core-collapse supernova environment. Our magnetohydrodynamic simulations vary in initial magnetic field strength, rotation rate, and grid resolution. Vigorous SASI-driven turbulence inside the shock amplifies magnetic fields exponentially; but while the amplified fields reduce the kinetic energy of small-scale flows, they do not seem to affect the global shock dynamics. The growth rate and final magnitude of the magnetic energy are very sensitive to grid resolution, and both are underestimated by the simulations. Nevertheless our simulations suggest that neutron star magnetic fields exceeding $10^{14}$ G can result from dynamics driven by the SASI, \emph{even for non-rotating progenitors}.Comment: 28 pages, 17 figures, accepted for publication in the Ap

Meta-analysis of individual registry results enhances international registry collaboration

Background and purpose — Although common in medical research, meta-analysis has not been widely adopted in registry collaborations. A meta-analytic approach in which each registry conducts a standardized analysis on its own data followed by a meta-analysis to calculate a weighted average of the estimates allows collaboration without sharing patient-level data. The value of meta-analysis as an alternative to individual patient data analysis is illustrated in this study by comparing the risk of revision of porous tantalum cups versus other uncemented cups in primary total hip arthroplasties from Sweden, Australia, and a US registry (2003–2015).Patients and methods — For both individual patient data analysis and meta-analysis approaches a Cox proportional hazard model was fit for time to revision, comparing porous tantalum (n = 23,201) with other uncemented cups (n = 128,321). Covariates included age, sex, diagnosis, head size, and stem fixation. In the meta-analysis approach, treatment effect size (i.e., Cox model hazard ratio) was calculated within each registry and a weighted average for the individual registries’ estimates was calculated.Results — Patient-level data analysis and meta-analytic approaches yielded the same results with the porous tantalum cups having a higher risk of revision than other uncemented cups (HR (95% CI) 1.6 (1.4–1.7) and HR (95% CI) 1.5 (1.4–1.7), respectively). Adding the US cohort to the meta-analysis led to greater generalizability, increased precision of the treatment effect, and similar findings (HR (95% CI) 1.6 (1.4–1.7)) with increased risk of porous tantalum cups.Interpretation — The meta-analytic technique is a viable option to address privacy, security, and data ownership concerns allowing more expansive registry collaboration, greater generalizability, and increased precision of treatment effects.</p

Standard requirements for GCP-compliant data management in multinational clinical trials

<p>Abstract</p> <p>Background</p> <p>A recent survey has shown that data management in clinical trials performed by academic trial units still faces many difficulties (e.g. heterogeneity of software products, deficits in quality management, limited human and financial resources and the complexity of running a local computer centre). Unfortunately, no specific, practical and open standard for both GCP-compliant data management and the underlying IT-infrastructure is available to improve the situation. For that reason the "Working Group on Data Centres" of the European Clinical Research Infrastructures Network (ECRIN) has developed a standard specifying the requirements for high quality GCP-compliant data management in multinational clinical trials.</p> <p>Methods</p> <p>International, European and national regulations and guidelines relevant to GCP, data security and IT infrastructures, as well as ECRIN documents produced previously, were evaluated to provide a starting point for the development of standard requirements. The requirements were produced by expert consensus of the ECRIN Working group on Data Centres, using a structured and standardised process. The requirements were divided into two main parts: an IT part covering standards for the underlying IT infrastructure and computer systems in general, and a Data Management (DM) part covering requirements for data management applications in clinical trials.</p> <p>Results</p> <p>The standard developed includes 115 IT requirements, split into 15 separate sections, 107 DM requirements (in 12 sections) and 13 other requirements (2 sections). Sections IT01 to IT05 deal with the basic IT infrastructure while IT06 and IT07 cover validation and local software development. IT08 to IT015 concern the aspects of IT systems that directly support clinical trial management. Sections DM01 to DM03 cover the implementation of a specific clinical data management application, i.e. for a specific trial, whilst DM04 to DM12 address the data management of trials across the unit. Section IN01 is dedicated to international aspects and ST01 to the competence of a trials unit's staff.</p> <p>Conclusions</p> <p>The standard is intended to provide an open and widely used set of requirements for GCP-compliant data management, particularly in academic trial units. It is the intention that ECRIN will use these requirements as the basis for the certification of ECRIN data centres.</p

Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 study

Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages

The relativistic pulsar-white dwarf binary PSR J1738+0333 II. The most stringent test of scalar-tensor gravity

(abridged) We report the results of a 10-year timing campaign on PSR J1738+0333, a 5.85-ms pulsar in a low-eccentricity 8.5-hour orbit with a low-mass white dwarf companion (...) The measurements of proper motion and parallax allow for a precise subtraction of the kinematic contribution to the observed orbital decay; this results in a significant measurement of the intrinsic orbital decay: (-25.9 +/- 3.2) \times 10^{-15} s/s. This is consistent with the orbital decay from the emission of gravitational waves predicted by general relativity, (-27.7 +1.5/-1.9) \times 10^{-15} s/s (...). This agreement introduces a tight upper limit on dipolar gravitational wave emission, a prediction of most alternative theories of gravity for asymmetric binary systems such as this. We use this limit to derive the most stringent constraints ever on a wide class of gravity theories, where gravity involves a scalar field contribution. When considering general scalar-tensor theories of gravity, our new bounds are more stringent than the best current solar-system limits over most of the parameter space, and constrain the matter-scalar coupling constant {\alpha}_0^2 to be below the 10^{-5} level. For the special case of the Jordan-Fierz-Brans-Dicke, we obtain the one-sigma bound {\alpha}_0^2 < 2 \times 10^{-5}, which is within a factor two of the Cassini limit. We also use our limit on dipolar gravitational wave emission to constrain a wide class of theories of gravity which are based on a generalization of Bekenstein's Tensor-Vector-Scalar gravity (TeVeS), a relativistic formulation of Modified Newtonian Dynamics (MOND).Comment: Accepted for publication in MNRAS. 18 pages in emulate MNRAS format, 9 figures and 1 tabl

SAD phasing using iodide ions in a high-throughput structural genomics environment

The Seattle Structural Genomics Center for Infectious Disease (SSGCID) focuses on the structure elucidation of potential drug targets from class A, B, and C infectious disease organisms. Many SSGCID targets are selected because they have homologs in other organisms that are validated drug targets with known structures. Thus, many SSGCID targets are expected to be solved by molecular replacement (MR), and reflective of this, all proteins are expressed in native form. However, many community request targets do not have homologs with known structures and not all internally selected targets readily solve by MR, necessitating experimental phase determination. We have adopted the use of iodide ion soaks and single wavelength anomalous dispersion (SAD) experiments as our primary method for de novo phasing. This method uses existing native crystals and in house data collection, resulting in rapid, low cost structure determination. Iodide ions are non-toxic and soluble at molar concentrations, facilitating binding at numerous hydrophobic or positively charged sites. We have used this technique across a wide range of crystallization conditions with successful structure determination in 16 of 17 cases within the first year of use (94% success rate). Here we present a general overview of this method as well as several examples including SAD phasing of proteins with novel folds and the combined use of SAD and MR for targets with weak MR solutions. These cases highlight the straightforward and powerful method of iodide ion SAD phasing in a high-throughput structural genomics environment

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis