Extended thromboprophylaxis with betrixaban in acutely ill medical patients

BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.)

Uptake of new treatment strategies for deep vein thrombosis: an international audit

Objective. Study of the uptake of new medical technologies provides useful information on the transfer of published evidence into usual practice. We conducted an audit of selected hospitals in three countries (Canada, France, and Switzerland) to identify clinical predictors of low-molecular-weight (LMW) heparin use and outpatient treatment, and to compare the pace of uptake of these new therapeutic approaches across hospitals. Design. Historical review of medical records. Setting and participants. We reviewed the medical records of 3043 patients diagnosed with deep vein thrombosis (DVT) in five Canadian, two French, and two Swiss teaching hospitals from 1994 to 1998. Measures. We explored independent clinical variables associated with LMW heparin use and outpatient treatment, and determined crude and adjusted rates of LMW heparin use and outpatient treatment across hospitals. Results. For the years studied, the overall rates of LMW heparin use and outpatient treatment in the study sample were 34.1 and 15.8%, respectively, with higher rates of use in later years. Many comorbidities were negatively associated with outpatient treatment, and risk-adjusted rates of use of these new approaches varied significantly across hospitals. Conclusion. There has been a relatively rapid uptake of LMW heparins and outpatient treatment for DVT in their early years of availability, but the pace of uptake has varied considerably across hospitals and countrie

The IMPROVEDD VTE risk score: Incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification

Background The IMPROVE score is a validated venous thromboembolism (VTE) assessment tool to risk stratify hospitalized, medically ill patients based on clinical variables. It was hypothesized that addition of D-dimer measurement to derive a new IMPROVEDD score would improve identification of at risk of VTE. Methods The association of the IMPROVE score and D-dimer ≥ 2 × the upper limit of normal (ULN) with the risk of symptomatic deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was evaluated in 7,441 hospitalized, medically ill patients randomized in the APEX trial. Based on the Cox regression analysis, the IMPROVEDD score was derived by adding two points to the IMPROVE score if the D-dimer was ≥ 2 × ULN. Results Baseline D-dimer was independently associated with symptomatic VTE through 77 days (adjusted HR: 2.22 [95% CI: 1.38–1.58], p = 0.001). Incorporation of D-dimer into the IMPROVE score improved VTE risk discrimination (ΔAUC: 0.06 [95% CI: 0.02–0.09], p = 0.0006) and reclassification (continuous NRI: 0.34 [95% CI: 0.17–0.51], p = 0.001; categorical NRI: 0.13 [95% CI: 0.03–0.23], p = 0.0159). Patients with an IMPROVEDD score of ≥2 had a greater VTE risk compared with those with an IMPROVEDD score of 0 to 1 (HR: 2.73 [95% CI: 1.52–4.90], p = 0.0007). Conclusion Incorporation of D-dimer into the IMPROVE VTE risk assessment model further improves risk stratification in hospitalized, medically ill patients who received thromboprophylaxis. An IMPROVEDD score of ≥2 identifies hospitalized, medically ill patients with a heightened risk for VTE through 77 days.</jats:p

Weak Lensing with SDSS Commissioning Data: The Galaxy-Mass Correlation Function To 1/h Mpc

(abridged) We present measurements of galaxy-galaxy lensing from early commissioning imaging data from the Sloan Digital Sky Survey (SDSS). We measure a mean tangential shear around a stacked sample of foreground galaxies in three bandpasses out to angular radii of 600'', detecting the shear signal at very high statistical significance. The shear profile is well described by a power-law. A variety of rigorous tests demonstrate the reality of the gravitational lensing signal and confirm the uncertainty estimates. We interpret our results by modeling the mass distributions of the foreground galaxies as approximately isothermal spheres characterized by a velocity dispersion and a truncation radius. The velocity dispersion is constrained to be 150-190 km/s at 95% confidence (145-195 km/s including systematic uncertainties), consistent with previous determinations but with smaller error bars. Our detection of shear at large angular radii sets a 95% confidence lower limit $s>140^{\prime\prime}$, corresponding to a physical radius of $260h^{-1}$ kpc, implying that galaxy halos extend to very large radii. However, it is likely that this is being biased high by diffuse matter in the halos of groups and clusters. We also present a preliminary determination of the galaxy-mass correlation function finding a correlation length similar to the galaxy autocorrelation function and consistency with a low matter density universe with modest bias. The full SDSS will cover an area 44 times larger and provide spectroscopic redshifts for the foreground galaxies, making it possible to greatly improve the precision of these constraints, measure additional parameters such as halo shape, and measure the properties of dark matter halos separately for many different classes of galaxies.Comment: 28 pages, 11 figures, submitted to A

The Multi-Object, Fiber-Fed Spectrographs for SDSS and the Baryon Oscillation Spectroscopic Survey

We present the design and performance of the multi-object fiber spectrographs for the Sloan Digital Sky Survey (SDSS) and their upgrade for the Baryon Oscillation Spectroscopic Survey (BOSS). Originally commissioned in Fall 1999 on the 2.5-m aperture Sloan Telescope at Apache Point Observatory, the spectrographs produced more than 1.5 million spectra for the SDSS and SDSS-II surveys, enabling a wide variety of Galactic and extra-galactic science including the first observation of baryon acoustic oscillations in 2005. The spectrographs were upgraded in 2009 and are currently in use for BOSS, the flagship survey of the third-generation SDSS-III project. BOSS will measure redshifts of 1.35 million massive galaxies to redshift 0.7 and Lyman-alpha absorption of 160,000 high redshift quasars over 10,000 square degrees of sky, making percent level measurements of the absolute cosmic distance scale of the Universe and placing tight constraints on the equation of state of dark energy. The twin multi-object fiber spectrographs utilize a simple optical layout with reflective collimators, gratings, all-refractive cameras, and state-of-the-art CCD detectors to produce hundreds of spectra simultaneously in two channels over a bandpass covering the near ultraviolet to the near infrared, with a resolving power R = \lambda/FWHM ~ 2000. Building on proven heritage, the spectrographs were upgraded for BOSS with volume-phase holographic gratings and modern CCD detectors, improving the peak throughput by nearly a factor of two, extending the bandpass to cover 360 < \lambda < 1000 nm, and increasing the number of fibers from 640 to 1000 per exposure. In this paper we describe the original SDSS spectrograph design and the upgrades implemented for BOSS, and document the predicted and measured performances.Comment: 43 pages, 42 figures, revised according to referee report and accepted by AJ. Provides background for the instrument responsible for SDSS and BOSS spectra. 4th in a series of survey technical papers released in Summer 2012, including arXiv:1207.7137 (DR9), arXiv:1207.7326 (Spectral Classification), and arXiv:1208.0022 (BOSS Overview

Obesity surgery and risk of colorectal and other obesity-related cancers: An English population-based cohort study

Background: The association between obesity surgery (OS) and cancer risk remains unclear. We investigated this association across the English National Health Service. A population-based Swedish study has previously suggested that OS may increase the risk of developing colorectal cancer (CRC). Methods: A retrospective observational study of individuals who underwent OS (surgery cohort) or diagnosed with obesity, but had no OS (no-surgery cohort) (1997–2013) were identified using Hospital Episode Statistics. Subsequent diagnosis of CRC, breast, endometrial, kidney and lung cancer, as well as time ‘at risk’, were determined by linkage to National Cancer Registration & Analysis Service and Office of National Statistics data, respectively. Standardised incidence ratios (SIR) in relation to OS were calculated. Results: 1 002 607 obese patients were identified, of whom 3.9% (n = 39 747) underwent OS. In the no-surgery obese population, 3 237 developed CRC (SIR 1.12 [95% CI 1.08–1.16]). In those who underwent OS, 43 developed CRC (SIR 1.26 [95% CI 0.92–1.71]). The OS cohort demonstrated decreased breast cancer risk (SIR 0.76 [95% CI 0.62–0.92]), unlike the no surgery cohort (SIR 1.08 [95% CI 1.04–1.11]). Increased risk of endometrial and kidney cancer was observed in surgery and no-surgery cohorts. Conclusions: CRC risk is increased in individuals diagnosed as obese. Prior obesity surgery was not associated with an increased CRC risk. However, the OS population was small, with limited follow-up. Risk of breast cancer after OS is reduced compared with the obese no-surgery population, while the risk of endometrial and kidney cancers remained elevated after OS

Circulating C-peptide levels in living children and young people and pancreatic beta cell loss in pancreas donors across type 1 diabetes disease duration.

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record Data Availability: Further information about the data is available from the corresponding author upon request.C-peptide declines in type 1 diabetes although many long-duration patients retain low, but detectable levels. Histological analyses confirm that beta cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N=4,079), with beta cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N=235), stratified by recently reported age at diagnosis endotypes (< 7, 7-12, ≥ 13 years) across increasing diabetes durations. The proportion of individuals with detectable C-peptide declined beyond the first year after diagnosis, but this was most marked in the youngest age group (< 1 year duration: age < 7 years: 18/20 (90%), 7-12 years: 107/110 (97%), ≥ 13 years: 58/61 (95%) versus. 1-5 years post diagnosis: < 7 years: 172/522 (33%), 7-12 years: 604/995 (61%), ≥ 13 years: 225/289 (78%)). A similar profile was observed in beta cell loss, with those diagnosed at younger ages experiencing more rapid loss of islets containing insulin-positive (insulin+) beta cells < 1 year post diagnosis: age < 7 years: 23/26 (88%), 7-12 years: 32/33 (97%), ≥ 13 years: 22/25 (88%) versus. 1-5 years post diagnosis: < 7 years: 1/12 (8.3%) ,7-12 years: 7/13 (54%), ≥ 13 years: 7/8 (88%)). These data should be considered in the planning and interpretation of intervention trials designed to promote beta cell retention and function.Diabetes UKDiabetes UKDiabetes UKThe Leona M. & Harry B. Helmsley Charitable TrustJuvenile Diabetes Research FoundationWellcome Trus

Formalization of the classification pattern: Survey of classification modeling in information systems engineering

Formalization is becoming more common in all stages of the development of information systems, as a better understanding of its benefits emerges. Classification systems are ubiquitous, no more so than in domain modeling. The classification pattern that underlies these systems provides a good case study of the move towards formalization in part because it illustrates some of the barriers to formalization; including the formal complexity of the pattern and the ontological issues surrounding the ‘one and the many’. Powersets are a way of characterizing the (complex) formal structure of the classification pattern and their formalization has been extensively studied in mathematics since Cantor’s work in the late 19th century. One can use this formalization to develop a useful benchmark. There are various communities within Information Systems Engineering (ISE) that are gradually working towards a formalization of the classification pattern. However, for most of these communities this work is incomplete, in that they have not yet arrived at a solution with the expressiveness of the powerset benchmark. This contrasts with the early smooth adoption of powerset by other Information Systems communities to, for example, formalize relations. One way of understanding the varying rates of adoption is recognizing that the different communities have different historical baggage. Many conceptual modeling communities emerged from work done on database design and this creates hurdles to the adoption of the high level of expressiveness of powersets. Another relevant factor is that these communities also often feel, particularly in the case of domain modeling, a responsibility to explain the semantics of whatever formal structures they adopt. This paper aims to make sense of the formalization of the classification pattern in ISE and surveys its history through the literature; starting from the relevant theoretical works of the mathematical literature and gradually shifting focus to the ISE literature. The literature survey follows the evolution of ISE’s understanding of how to formalize the classification pattern. The various proposals are assessed using the classical example of classification; the Linnaean taxonomy formalized using powersets as a benchmark for formal expressiveness. The broad conclusion of the survey is that (1) the ISE community is currently in the early stages of the process of understanding how to formalize the classification pattern, particularly in the requirements for expressiveness exemplified by powersets and (2) that there is an opportunity to intervene and speed up the process of adoption by clarifying this expressiveness. Given the central place that the classification pattern has in domain modeling, this intervention has the potential to lead to significant improvements.The UK Engineering and Physical Sciences Research Council (grant EP/K009923/1)