1,643 research outputs found
Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism : a pooled analysis of the EINSTEIN-DVT and PE randomized studies
Background: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects.
Methods: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75.
Results: 8282 patients were enrolled. 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 rivaroxaban-treated patients (2.1%) compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority<0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p=0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban was similar compared with standard-therapy.
Conclusion: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups
Production of α1,3-galactosyltransferase-deficient pigs
The enzyme α1,3-galactosyltransferase (α1,3GT or GGTA1) synthesizes α1,3galactose (α1,3Gal) epitopes (Galα1,3Galβ1,4GlcNAc-R), which are the major xenoantigens causing hyperacute rejection in pig-to-human xenotransplantation. Complete removal of α1,3Gal from pig organs is the critical step toward the success of xenotransplantation. We reported earlier the targeted disruption of one allele of the α1,3GT gene in cloned pigs. A selection procedure based on a bacteria[toxin was used to select for cells in which the second allele of the gene was knocked out. Sequencing analysis demonstrated that knockout of the second allele of the α1,3GT gene was caused by a T-to-G single point mutation at the second base of exon 9, which resulted in inactivation of the α1,3GT protein. Four healthy α1,3GT double-knockout female piglets were produced by three consecutive rounds of cloning. The piglets carrying a point mutation in the α1,3GT gene hold significant value, as they would allow production of α1,3Gal-deficient pigs free of antibiotic-resistance genes and thus have the potential to make a safer product for human use
SN 2005hj: Evidence for Two Classes of Normal-Bright SNe Ia and Implications for Cosmology
HET Optical spectra covering the evolution from about 6 days before to about
5 weeks after maximum light and the ROTSE-IIIb unfiltered light curve of the
"Branch-normal" Type Ia Supernova SN 2005hj are presented. The host galaxy
shows HII region lines at redshift of z=0.0574, which puts the peak unfiltered
absolute magnitude at a somewhat over-luminous -19.6. The spectra show weak and
narrow SiII lines, and for a period of at least 10 days beginning around
maximum light these profiles do not change in width or depth and they indicate
a constant expansion velocity of ~10,600 km/s. We analyzed the observations
based on detailed radiation dynamical models in the literature. Whereas delayed
detonation and deflagration models have been used to explain the majority of
SNe Ia, they do not predict a long velocity plateau in the SiII minimum with an
unvarying line profile. Pulsating delayed detonations and merger scenarios form
shell-like density structures with properties mostly related to the mass of the
shell, M_shell, and we discuss how these models may explain the observed SiII
line evolution; however, these models are based on spherical calculations and
other possibilities may exist. SN 2005hj is consistent with respect to the
onset, duration, and velocity of the plateau, the peak luminosity and, within
the uncertainties, with the intrinsic colors for models with M_shell=0.2 M_sun.
Our analysis suggests a distinct class of events hidden within the
Branch-normal SNe Ia. If the predicted relations between observables are
confirmed, they may provide a way to separate these two groups. We discuss the
implications of two distinct progenitor classes on cosmological studies
employing SNe Ia, including possible differences in the peak luminosity to
light curve width relation.Comment: ApJ accepted, 31 page
Adoption of new health products in low and middle income settings: how product development partnerships can support country decision making
When a new health product becomes available, countries have a choice to adopt the product into their national health systems or to pursue an alternate strategy to address the public health problem. Here, we describe the role for product development partnerships (PDPs) in supporting this decision-making process. PDPs are focused on developing new products to respond to health problems prevalent in low and middle income settings. The impact of these products within public sector health systems can only be realized after a country policy process. PDPs may be the organizations most familiar with the evidence which assists decision making, and this generally translates into involvement in international policy development, but PDPs have limited reach into endemic countries. In a few individual countries, there may be more extensive involvement in tracking adoption activities and generating local evidence. This local PDP involvement begins with geographical prioritization based on disease burden, relationships established during clinical trials, PDP in-country resources, and other factors. Strategies adopted by PDPs to establish a presence in endemic countries vary from the opening of country offices to engagement of part-time consultants or with long-term or ad hoc committees. Once a PDP commits to support country decision making, the approaches vary, but include country consultations, regional meetings, formation of regional, product-specific committees, support of in-country advocates, development of decision-making frameworks, provision of technical assistance to aid therapeutic or diagnostic guideline revision, and conduct of stakeholder and Phase 4 studies. To reach large numbers of countries, the formation of partnerships, particularly with WHO, are essential. At this early stage, impact data are limited. But available evidence suggests PDPs can and do play an important catalytic role in their support of country decision making in a number of target countries
Atomic excitation during recollision-free ultrafast multi-electron tunnel ionization
Modern intense ultrafast pulsed lasers generate an electric field of
sufficient strength to permit tunnel ionization of the valence electrons in
atoms. This process is usually treated as a rapid succession of isolated
events, in which the states of the remaining electrons are neglected. Such
electronic interactions are predicted to be weak, the exception being
recollision excitation and ionization caused by linearly-polarized radiation.
In contrast, it has recently been suggested that intense field ionization may
be accompanied by a two-stage `shake-up' reaction. Here we report a unique
combination of experimental techniques that enables us to accurately measure
the tunnel ionization probability for argon exposed to 50 femtosecond laser
pulses. Most significantly for the current study, this measurement is
independent of the optical focal geometry, equivalent to a homogenous electric
field. Furthermore, circularly-polarized radiation negates recollision. The
present measurements indicate that tunnel ionization results in simultaneous
excitation of one or more remaining electrons through shake-up. From an atomic
physics standpoint, it may be possible to induce ionization from specific
states, and will influence the development of coherent attosecond XUV radiation
sources. Such pulses have vital scientific and economic potential in areas such
as high-resolution imaging of in-vivo cells and nanoscale XUV lithography.Comment: 17 pages, 4 figures, original format as accepted by Nature Physic
Forced vital capacity trajectories in patients with idiopathic pulmonary fibrosis: a secondary analysis of a multicentre, prospective, observational cohort
BACKGROUND: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease with a variable clinical trajectory. Decline in forced vital capacity (FVC) is the main indicator of progression; however, missingness prevents long-term analysis of patterns in lung function. We aimed to identify distinct clusters of lung function trajectory among patients with idiopathic pulmonary fibrosis using machine learning techniques. METHODS: We did a secondary analysis of longitudinal data on FVC collected from a cohort of patients with idiopathic pulmonary fibrosis from the PROFILE study; a multicentre, prospective, observational cohort study. We evaluated the imputation performance of conventional and machine learning techniques to impute missing data and then analysed the fully imputed dataset by unsupervised clustering using self-organising maps. We compared anthropometric features, genomic associations, serum biomarkers, and clinical outcomes between clusters. We also performed a replication of the analysis on data from a cohort of patients with idiopathic pulmonary fibrosis from an independent dataset, obtained from the Chicago Consortium. FINDINGS: 415 (71%) of 581 participants recruited into the PROFILE study were eligible for further analysis. An unsupervised machine learning algorithm had the lowest imputation error among tested methods, and self-organising maps identified four distinct clusters (1-4), which was confirmed by sensitivity analysis. Cluster 1 comprised 140 (34%) participants and was associated with a disease trajectory showing a linear decline in FVC over 3 years. Cluster 2 comprised 100 (24%) participants and was associated with a trajectory showing an initial improvement in FVC before subsequently decreasing. Cluster 3 comprised 113 (27%) participants and was associated with a trajectory showing an initial decline in FVC before subsequent stabilisation. Cluster 4 comprised 62 (15%) participants and was associated with a trajectory showing stable lung function. Median survival was shortest in cluster 1 (2·87 years [IQR 2·29-3·40]) and cluster 3 (2·23 years [1·75-3·84]), followed by cluster 2 (4·74 years [3·96-5·73]), and was longest in cluster 4 (5·56 years [5·18-6·62]). Baseline FEV1 to FVC ratio and concentrations of the biomarker SP-D were significantly higher in clusters 1 and 3. Similar lung function clusters with some shared anthropometric features were identified in the replication cohort. INTERPRETATION: Using a data-driven unsupervised approach, we identified four clusters of lung function trajectory with distinct clinical and biochemical features. Enriching or stratifying longitudinal spirometric data into clusters might optimise evaluation of intervention efficacy during clinical trials and patient management. FUNDING: National Institute for Health and Care Research, Medical Research Council, and GlaxoSmithKline
The circadian clock rephases during lateral root organ initiation in Arabidopsis thaliana
The endogenous circadian clock enables organisms to adapt their growth and development to environmental changes. Here we describe how the circadian clock is employed to coordinate responses to the key signal auxin during lateral root (LR) emergence. In the model plant, Arabidopsis thaliana, LRs originate from a group of stem cells deep within the root, necessitating that new organs emerge through overlying root tissues. We report that the circadian clock is rephased during LR development. Metabolite and transcript profiling revealed that the circadian clock controls the levels of auxin and auxin-related genes including the auxin response repressor IAA14 and auxin oxidase AtDAO2. Plants lacking or overexpressing core clock components exhibit LR emergence defects. We conclude that the circadian clock acts to gate auxin signalling during LR development to facilitate organ emergence
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