Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin.
In this ...randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding.
A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval CI, 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups.
Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).
Cracking and coalescence behavior has been studied experimentally with prismatic laboratory-molded gypsum and Carrara marble specimens containing two parallel pre-existing open flaws. This was done ...at both the
macroscopic
and the
microscopic
scales, and the results are presented in two separate papers. This paper (the first of two) summarizes the macroscopic experimental results and investigates the influence of the different flaw geometries and material, on the cracking processes. In the companion paper (also in this issue), most of the macroscopic deformation and cracking processes shown in this present paper will be related to the underlying microscopic changes. In the present study, a high speed video system was used, which allowed us to precisely observe the cracking mechanisms. Nine crack coalescence categories with different crack types and trajectories were identified. The flaw inclination angle (
β
), the ligament length (
L
), that is, intact rock length between the flaws, and the bridging angle (
α
), that is, the inclination of a line linking up the inner flaw tips, between two flaws, had different effects on the coalescence patterns. One of the pronounced differences observed between marble and gypsum during the compression loading test was the development of macroscopic white patches prior to the initiation of macroscopic cracks in marble, but not in gypsum. Comparing the cracking and coalescence behaviors in the two tested materials, tensile cracking generally occurred more often in marble than in gypsum for the same flaw pair geometries.
Tunnel reinforcement with rockbolts Bobet, A.; Einstein, H.H.
Tunnelling and underground space technology,
2011, 2011-1-00, 20110101, Volume:
26, Issue:
1
Journal Article
Peer reviewed
Closed-form solutions are presented for a tunnel supported with Discretely Mechanically or Frictionally Coupled (DMFC) and with Continuously Mechanically Coupled (CMC) or Continuously Frictionally ...Coupled (CFC) rockbolts. The formulation is based on the following assumptions: (1) circular cross section; (2) deep tunnel; (3)
K
o
=
1, i.e. axisymmetric problem; (4) homogeneous and isotropic ground; (5) elasto-plastic ground, with brittle failure governed by the Coulomb criterion and non-associated flow rule; (6) elastic reinforcement and (7) construction effects approximated with the
β-method (reduction of internally applied stresses). The analytical solutions are compared with results obtained with a Finite Element Method. The comparisons show that the analytical solutions provide reasonable results for DMFC rockbolts and for CMC/CFC rockbolts with low to moderate spacing. For the same rock properties, tunnel geometry and construction, and reinforcement characteristics, CMC/CFC rockbolts result in slightly smaller convergence but somewhat larger rockbolt stresses than DMFC rockbolts. The behavior of DMFC rockbolts and rock response depends on “average” response of the rock between the two end points, while for CMC/CFC rockbolts the maximum stress in the rockbolt occurs at the location of maximum radial strain in the rock. In both cases the solution strongly depends on the relative stiffness between the rockbolt and the deformed rock. Practically speaking, placement of the reinforcement while the rock undergoes elastic deformations may not result in a substantial reduction of tunnel convergence. Instead, it appears that best results are obtained by placing the rockbolts while the rock undergoes plastic deformations. It has also been observed that when the distribution of rockbolts around the tunnel perimeter is linked to the far-field stresses, smaller convergence and reduced reinforcement stresses are possible.
Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory ...monitoring.
We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.
The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events 2.1%, vs. 51 events with enoxaparin-vitamin K antagonist 3.0%; hazard ratio, 0.68; 95% confidence interval CI, 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events 1.3%, vs. 42 with placebo 7.1%; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).
Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).
Experimental uniaxial compression loading tests were conducted on molded gypsum and Carrara marble prismatic specimens to study the cracking and coalescence processes between pre-existing artificial ...flaws. The study showed that material had an influence on the cracking and coalescence processes (see the companion paper in this issue). As reported in the companion paper, one of the pronounced features as observed in the high-speed video recordings was the development of macroscopic white patches prior to the development of observable cracks in marble, but not in gypsum. This paper (part 2) deals with the
microscopic
aspects of the study. Specifically, the scanning electron microscope (SEM) and the environmental scanning electron microscope (ESEM) imaging techniques were used to study the microscopic development of white patches and their evolution into macroscopic tensile cracks and shear cracks in marble, and the microscopic initiation of hair-line tensile cracks and their evolution into macroscopic tensile cracks in gypsum. The microscopic imaging study in marble showed that the white patches were associated with extensive microcracking zones (process zones), while the extent of process zone development in gypsum was limited. The comparison of the macroscopic and microscopic results indicates that the different extent of microcracking zone development, related to the material textural properties, is a key factor leading to different macroscopic cracking behavior in gypsum and marble.
This paper presents the results of an experimental study in which molded gypsum and Carrara Marble specimens containing a pre-existing flaw were tested in uniaxial compression. The main purpose of ...this study was to observe and characterize the cracks that emanate from a single pre-existing flaw. Seven different crack types were identified based on their geometry and propagation mechanism (tensile/shear). Specifically, they include three types of tensile cracks, three types of shear cracks, and one type of mixed tensile–shear crack. In addition to the geometry and mechanism, it was also possible to determine the temporal sequence of different crack types. These observations form the basis for a re-evaluation of cracking processes reported in the literature. It is possible to apply the classification obtained in the present research to previously conducted experiments by others. This eliminates much of the confusion that has existed when comparing different research results.
A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for ...laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism.
In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding.
Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval CI, 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups.
A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).
Determination of the cracking levels during the crack propagation is one of the key challenges in the field of fracture mechanics of rocks. Acoustic emission (AE) is a technique that has been used to ...detect cracks as they occur across the specimen. Parametric analysis of AE signals and correlating these parameters (e.g., hits and energy) to stress–strain plots of rocks let us detect cracking levels properly. The number of AE hits is related to the number of cracks, and the AE energy is related to magnitude of the cracking event. For a full understanding of the fracture process in brittle rocks, prismatic specimens of granite containing pre-existing flaws have been tested in uniaxial compression tests, and their cracking process was monitored with both AE and high-speed video imaging. In this paper, the characteristics of the AE parameters and the evolution of cracking sequences are analyzed for every cracking level. Based on micro- and macro-crack damage, a classification of cracking levels is introduced. This classification contains eight stages (1) crack closure, (2) linear elastic deformation, (3) micro-crack initiation (white patch initiation), (4) micro-crack growth (stable crack growth), (5) micro-crack coalescence (macro-crack initiation), (6) macro-crack growth (unstable crack growth), (7) macro-crack coalescence and (8) failure.
Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). A novel ...mitochondria-associated peptide, Humanin (HN), has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin resistance and AD, we investigated if HN influences insulin sensitivity.
Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action. Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity. The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling; effects that were negated by co-inhibition of hypothalamic STAT-3. Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN. Inhibition of hypothalamic STAT-3 completely negated the effects of IV HN analog on liver, suggesting that the hepatic actions of HN are centrally mediated. This is consistent with the lack of a direct effect of HN on primary hepatocytes. Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats. Based upon the link of HN with two age-related diseases, we examined if there were age associated changes in HN levels. Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents, and circulating levels of HN were decreased with age in humans and mice.
We conclude that the decline in HN with age could play a role in the pathogenesis of age-related diseases including AD and T2DM. HN represents a novel link between T2DM and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM.
•Real-time visual anisotropic rock cracking processes.•Systematic representation of shale failure mechanisms.•Shale cracking comparison to previous rock crack studies.
Understanding the cracking ...processes of rock is important regarding the fundamental material behavior and in engineering applications. Characterizing and predicting the cracking processes in shale is necessary when assessing unconventional oil and gas reservoirs and designing nuclear waste repositories. Of particular interest is the effect of bedding planes on the cracking processes. For this reason we tested one such shale, Opalinus shale, in this study. A series of unconfined compression tests were conducted on prismatic specimens with two pre-existing flaws and various bedding plane orientations. High speed- and high resolution imagery were used to capture crack initiation, -propagation and -coalescence between the flaw pairs and study the effects of bedding plane orientation and flaw pair geometry. It was found that in specimens with bedding planes aligned perpendicularly to the maximum applied compressive stress, the effects of the flaw angle and flaw pair bridging angle on the cracking processes were similar to those observed in previously tested rocks without bedding planes. However, as the bedding planes became more aligned with the direction of the maximum compressive stress the cracks initiating at the flaw tips propagated more frequently along the bedding planes. This visual observation is unique as previous studies did not characterize, in real-time, cracking along bedding planes (weak surfaces). Hence, the results from this study contribute to the understanding of cracking in anisotropic rocks.
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