Direct Oral Anticoagulants and Their Use in Treatment and Secondary Prevention of Acute Symptomatic Venous Thromboembolism.

Direct oral anticoagulants (DOACs) have been compared with standard therapy in large phase III studies to assess their safety and efficacy in the treatment of deep vein thrombosis and/or pulmonary embolism and in the secondary prevention of recurrent venous thromboembolism. Although the mean population age and the gross inclusion and exclusion criteria were similar across these studies, they differed in other aspects such as overall study design and acute treatment strategies. The 4 DOACs examined in phase III trials (apixaban, edoxaban, rivaroxaban, and dabigatran) showed noninferiority compared with standard therapy for the treatment of deep vein thrombosis and/or pulmonary embolism and for the prevention of recurrent venous thromboembolism. Furthermore, these DOACs exhibited a similar safety profile to standard therapy, with the risk of major bleeding significantly reduced in some of these studies. Rivaroxaban and apixaban were tested as a single-drug approach, whereas in the dabigatran and edoxaban studies, initial bridging with parenteral agents was employed. The purpose of this review is to compare the phase III studies of DOACs in this indication, to highlight the differences, and to discuss a series of clinically relevant issues, including the management of key patient subgroups (eg, fragile patients, those with cancer or renal impairment), extended treatment, use of comedications, heparin pretreatment versus a single-drug approach, and the bleeding profiles of the DOACs

Automatic and Intentional Number Processing Both Rely on Intact Right Parietal Cortex: A Combined fMRI and Neuronavigated TMS Study

Practice and training usually lead to performance increase in a given task. In addition, a shift from intentional toward more automatic processing mechanisms is often observed. It is currently debated whether automatic and intentional processing is subserved by the same or by different mechanism(s), and whether the same or different regions in the brain are recruited. Previous correlational evidence provided by behavioral, neuroimaging, modeling, and neuropsychological studies addressing this question yielded conflicting results. Here we used transcranial magnetic stimulation (TMS) to compare the causal influence of disrupting either left or right parietal cortex during automatic and intentional numerical processing, as reflected by the size congruity effect and the numerical distance effect, respectively. We found a functional hemispheric asymmetry within parietal cortex with only the TMS-induced right parietal disruption impairing both automatic and intentional numerical processing. In contrast, disrupting the left parietal lobe with TMS, or applying sham stimulation, did not affect performance during automatic or intentional numerical processing. The current results provide causal evidence for the functional relevance of right, but not left, parietal cortex for intentional, and automatic numerical processing, implying that at least within the parietal cortices, automatic, and intentional numerical processing rely on the same underlying hemispheric lateralization

Lagrangian and Hamiltonian two-scale reduction

Studying high-dimensional Hamiltonian systems with microstructure, it is an important and challenging problem to identify reduced macroscopic models that describe some effective dynamics on large spatial and temporal scales. This paper concerns the question how reasonable macroscopic Lagrangian and Hamiltonian structures can by derived from the microscopic system. In the first part we develop a general approach to this problem by considering non-canonical Hamiltonian structures on the tangent bundle. This approach can be applied to all Hamiltonian lattices (or Hamiltonian PDEs) and involves three building blocks: (i) the embedding of the microscopic system, (ii) an invertible two-scale transformation that encodes the underlying scaling of space and time, (iii) an elementary model reduction that is based on a Principle of Consistent Expansions. In the second part we exemplify the reduction approach and derive various reduced PDE models for the atomic chain. The reduced equations are either related to long wave-length motion or describe the macroscopic modulation of an oscillatory microstructure.Comment: 40 page

Complex Networks on Hyperbolic Surfaces

We explore a novel method to generate and characterize complex networks by means of their embedding on hyperbolic surfaces. Evolution through local elementary moves allows the exploration of the ensemble of networks which share common embeddings and consequently share similar hierarchical properties. This method provides a new perspective to classify network-complexity both on local and global scale. We demonstrate by means of several examples that there is a strong relation between the network properties and the embedding surface.Comment: 8 Pages 3 Figure

Using VO tools to investigate distant radio starbursts hosting obscured AGN in the HDF(N) region

A 10-arcmin field around the HDF(N) contains 92 radio sources >40 uJy, resolved by MERLIN+VLA at 0".2-2".0 resolution. 55 have Chandra X-ray counterparts including 18 with a hard X-ray photon index and high luminosity characteristic of a type-II (obscured) AGN. >70% of the radio sources have been classified as starbursts or AGN using radio morphologies, spectral indices and comparisons with optical appearance and MIR emission. Starbursts outnumber radio AGN 3:1. This study extends the VO methods previously used to identify X-ray-selected obscured type-II AGN to investigate whether very luminous radio and X-ray emission originates from different phenomena in the same galaxy. The high-redshift starbursts have typical sizes of 5--10 kpc and star formation rates of ~1000 Msun/yr. There is no correlation between radio and X-ray luminosities nor spectral indices at z>~1.3. ~70% of both the radio-selected AGN and the starburst samples were detected by Chandra. The X-ray luminosity indicates the presence of an AGN in at least half of the 45 cross-matched radio starbursts, of which 11 are type-II AGN including 7 at z>1.5. This distribution overlaps closely with the X-ray detected radio sources which were also detected by SCUBA. Stacked 1.4-GHz emission at the positions of radio-faint X-ray sources is correlated with X-ray hardness. Most extended radio starbursts at z>1.3 host X-ray selected obscured AGN. Radio emission from most of these ultra-luminous objects is dominated by star formation but it contributes less than 1/3 of their X-ray luminosity. Our results support the inferences from SCUBA and IR data, that at z>1.5, star formation is an order of magnitude more extended and more copious, it is closely linked to AGN activity and it is triggered differently, compared with star formation at lower redshifts.Comment: 24 pages, 12 figures, uses graphicx, rotating, natbib, supertabular packages and aa.cls. Accepted for publication in A&

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

Inflating magnetically charged braneworlds

Numerical solutions of Einstein, scalar, and gauge field equations are found for static and inflating defects in a higher-dimensional spacetime. The defects have $(3+1)$-dimensional core and magnetic monopole configuration in $n=3$ extra dimensions. For symmetry-breaking scale $\eta$ below the critical value $\eta_c$, the defects are characterized by a flat worldsheet geometry and asymptotically flat extra dimensions. The critical scale $\eta_c$ is comparable to the higher-dimensional Planck scale and has some dependence on the gauge and scalar couplings. For $\eta=\eta_c$, the extra dimensions degenerate into a `cigar', and for $\eta>\eta_c$ all static solutions are singular. The singularity can be removed if the requirement of staticity is relaxed and defect cores are allowed to inflate. The inflating solutions have de Sitter worldsheets and cigar geometry in the extra dimensions. Exact analytic solutions describing the asymptotic behavior of these inflating monopoles are found and the parameter space of these solutions is analyzed.Comment: 35 pages, revtex, 18 eps figure

Probing SUSY-induced CP violations at B factories

In the minimal supersymmetric standard model (MSSM), the \mu-parameter and the trilinear coupling A_t may be generically complex and can affect various observables at B factories. Imposing the edm constraints, we find that there is no new large phase shift in the B^0 - \bar{B^0} mixing, CP violating dilepton asymmetry is smaller than 0.1 %, and the direct CP violation in B\to X_s \gamma can be as large as \sim \pm 16 %.Comment: 4 pages, 2 figures. Version to appear in Phys. Rev. Let

Cost-of-Illness Analysis of Long-Term Health Care Resource Use and Disease Burden in Patients With Pulmonary Embolism: Insights From the PREFER in VTE Registry

Background As mortality from pulmonary embolism (PE) decreases, the personal and societal costs among survivors are receiving increasing attention. Detailing this burden would support an efficient public health resource allocation. We aimed to provide estimates for the economic and disease burden of PE also accounting for long-term health care use and both direct and indirect costs beyond the acute phase. Methods and Results This is a cost-of-illness analysis with a bottom-up approach based on data from the PREFER in VTE registry (Prevention of Thromboembolic Events-European Registry in Venous Thromboembolism). We calculated direct (clinical events and anticoagulation) and indirect costs (loss of productivity) of an acute PE event and its 12-month follow-up in 2020 Euros. We estimated a disability weight for the 12-month post-PE status and corresponding disability adjusted life years presumably owing to PE. Disease-specific costs in the first year of follow-up after an incident PE case ranged between 9135 Euros and 10 620 Euros. The proportion of indirect costs was 42% to 49% of total costs. Costs were lowest in patients with ongoing cancer, mainly because productivity loss was less evident in this already burdened population. The calculated disability weight for survivors who were cancer free 12 months post-PE was 0.017, and the estimated disability adjusted life years per incident case were 1.17. Conclusions The economic burden imposed by PE to society and affected patients is considerable, and productivity loss is its main driver. The disease burden from PE is remarkable and translates to the loss of roughly 1.2 years of healthy life per incident PE case