Cost-Effectiveness Analysis of Apixaban Versus Edoxaban in Patients with Atrial Fibrillation for Stroke Prevention

OBJECTIVE: Our objective was to assess the cost effectiveness of apixaban versus edoxaban in the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF) in Spain. METHODS: We customized a Markov model with ten health states to estimate the lifetime economic and clinical outcomes in 6-week cycles. The efficacy (clinical event rates per 100 patient-years) and safety data were derived from a pairwise indirect treatment comparison. The analysis was conducted from both the national health service (NHS) and societal perspectives, and included pharmaceutical costs (retail price plus value-added tax (VAT) and applicable national deductions) according to daily dosages (apixaban 10 mg (5 mg twice daily (bid)) and edoxaban 60 or 30 mg) and complications and disease-management costs, obtained from national databases. Utilities for quality-adjusted life-year (QALY) calculations reflected EuroQoL 5-Dimension scores in patients with AF. An annual discount rate of 3% was applied for costs (euro, year 2019 values) and outcomes. RESULTS: In a 1000-patient cohort, apixaban 5 mg bid versus edoxaban 60 mg could avoid five strokes, six major bleedings and 29 clinically relevant non-major bleedings (CRNMBs). Compared with edoxaban 30 mg, apixaban could avoid 21 strokes and two SEs. An increase in bleedings was observed with apixaban (seven haemorrhagic strokes, 48 major bleedings and 17 CRNMBs). Apixaban yielded 0.04 additional QALYs compared with edoxaban 60 mg or 30 mg. Incremental costs/QALY were euro9639.33 and euro354.22 for apixaban versus edoxaban 60 mg and edoxaban 30 mg, respectively, from the NHS perspective and euro7756.62 for apixaban versus edoxaban 60 mg from the societal perspective. Apixaban was dominant versus edoxaban 30 mg from the societal perspective. Sensitivity analyses confirmed the robustness of the model. CONCLUSIONS: This study suggests that apixaban 5 mg bid is a cost-effective alternative to edoxaban for stroke prevention in the AF population in Spain

Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer

PURPOSE: The purpose of our study was to determine the maximum-tolerated\n dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the\n polyamine synthesis inhibitor SAM486A given in combination with\n 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients. EXPERIMENTAL\n DESIGN: Patients with advanced colorectal cancer were treated with 5-FU\n [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV\n (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3\n days. Plasma sampling was performed to characterize the pharmacokinetics\n and pharmacodynamics of the combination RESULTS: Twenty-seven patients\n with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were\n treated. Twenty-six patients received SAM486A in the combination at doses\n ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of\n fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included\n neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and\n constipation. Fifteen of 26 patients evaluable for best response according\n to the Southwest Oncology Group criteria achieved a partial response [8\n (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence\n the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that\n when used as a single agent. CONCLUSIONS: The novel molecular agent\n SAM486A is tolerable and safe in combination with a standard 5-FU regimen\n in patients with advanced colorectal cancer. The dose of SAM486A\n recommended for additional studies with this combination is 125\n mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen\n is warranted

Kinetics of magnetic ageing of 2%Si non-oriented grain electrical steel.

The effect of carbon content on the magnetic ageing index and Vickers hardness evolution on annealed samples of 2%Si non-oriented grain electrical steel was studied. Samples with 40 and 60ppm carbon content were subjected at ageing temperatures of 200 and 225?C, respectively. During the ageing treatment, the cycle was interrupted on several time intervals in order to obtain the core loss and to determine Vickers hardness. The precipitates were characterized using scanning electron microscope (SEM). Using the software MatCalc, computer simulations of ?-carbide precipitation were performed and compared with experimental data from literature. The results for both carbon contents showed that the maximum hardness value was achieved in shorter time than that to achieve the maximum magnetic ageing, indicating that the critical size of precipitates more harmful to the magnetic properties is larger than the ones that maximize the hardness

Measurement of the multi-TeV neutrino cross section with IceCube using Earth absorption

Neutrinos interact only very weakly, so they are extremely penetrating. However, the theoretical neutrino-nucleon interaction cross section rises with energy such that, at energies above 40 TeV, neutrinos are expected to be absorbed as they pass through the Earth. Experimentally, the cross section has been measured only at the relatively low energies (below 400 GeV) available at neutrino beams from accelerators \cite{Agashe:2014kda, Formaggio:2013kya}. Here we report the first measurement of neutrino absorption in the Earth, using a sample of 10,784 energetic upward-going neutrino-induced muons observed with the IceCube Neutrino Observatory. The flux of high-energy neutrinos transiting long paths through the Earth is attenuated compared to a reference sample that follows shorter trajectories through the Earth. Using a fit to the two-dimensional distribution of muon energy and zenith angle, we determine the cross section for neutrino energies between 6.3 TeV and 980 TeV, more than an order of magnitude higher in energy than previous measurements. The measured cross section is $1.30^{+0.21}_{-0.19}$ (stat.) $^{+0.39}_{-0.43}$ (syst.) times the prediction of the Standard Model \cite{CooperSarkar:2011pa}, consistent with the expectation for charged and neutral current interactions. We do not observe a dramatic increase in the cross section, expected in some speculative models, including those invoking new compact dimensions \cite{AlvarezMuniz:2002ga} or the production of leptoquarks \cite{Romero:2009vu}.Comment: Preprint version of Nature paper 10.1038/nature2445

The AMANDA Neutrino Telescope and the Indirect Search for Dark Matter

With an effective telescope area of order 10^4 m^2, a threshold of ~50 GeV and a pointing accuracy of 2.5 degrees, the AMANDA detector represents the first of a new generation of high energy neutrino telescopes, reaching a scale envisaged over 25 years ago. We describe its performance, focussing on the capability to detect halo dark matter particles via their annihilation into neutrinos.Comment: Latex2.09, 16 pages, uses epsf.sty to place 15 postscript figures. Talk presented at the 3rd International Symposium on Sources and Detection of Dark Matter in the Universe (DM98), Santa Monica, California, Feb. 199

Ionize Hard: Interstellar PO+ Detection

We report the first detection of the phosphorus monoxide ion (PO+) in the interstellar medium. Our unbiased and very sensitive spectral survey toward the G+0.693–0.027 molecular cloud covers four different rotational transitions of this molecule, two of which (J = 1–0 and J = 2–1) appear free of contamination from other species. The fit performed, assuming local thermodynamic equilibrium conditions, yields a column density of N=(6.0 \ub1 0.7) 7 1011\ua0cm−2. The resulting molecular abundance with respect to molecular hydrogen is 4.5 7 10–12. The column density of PO+ normalized by the cosmic abundance of P is larger than those of NO+ and SO+, normalized by N and S, by factors of 3.6 and 2.3, respectively. The N(PO+)/N(PO) ratio is 0.12 \ub1 0.03, more than one order of magnitude higher than that of N(SO+)/N(SO) and N(NO+)/N(NO). These results indicate that P is more efficiently ionized than N and S in the ISM. We have performed new chemical models that confirm that the PO+ abundance is strongly enhanced in shocked regions with high values of cosmic-ray ionization rates (10–15 − 10–14 s−1), as occurring in the G+0.693–0.027 molecular cloud. The shocks sputter the interstellar icy grain mantles, releasing into the gas phase most of their P content, mainly in the form of PH3, which is converted into atomic P, and then ionized efficiently by cosmic rays, forming P+. Further reactions with O2 and OH produces PO+. The cosmic-ray ionization of PO might also contribute significantly, which would explain the high N(PO+)/N(PO) ratio observed. The relatively high gas-phase abundance of PO+ with respect to other P-bearing species stresses the relevance of this species in the interstellar chemistry of P

Authoritarian Regime Learning: Comparative Insights from the Arab Uprisings

This paper examines the learning of authoritarian regimes in the early phase of the Arab uprisings. Differentiating conceptually between learning and policy change, we analyze and compare the authoritarian regimes of Algeria, Bahrain, Jordan, and Syria and their reactions to the challenge of "late riser" oppositional protests. We first show that the four regimes initiated very diverse measures in the domains of repression, material co-optation, and legal reforms. With regard to the sources of learning, we find that proximity is a determining factor, in terms of both geography and political similarity. Using the case of Bahrain, we then demonstrate that structural factors such as internal power structures, regional and international pressures, or state capacity can decisively constrain the implementation of learning-induced policy change. Overall, the paper aims to contribute to the emerging research on the international dimension of authoritarian regimes in the Middle East and beyond

Renovascular hypertension increases serum TNF and CX3CL1 in experimental Trypanosoma cruzi infection.

Trypanosoma cruzi triggers a progressive inflammatory response affecting cardiovascular functions in humans and experimental models. Angiotensin II, a key effector of the renin-angiotensin system, plays roles in mediating hypertension, heart failure, and inflammatory responses. T. cruzi and AngII can induce inflammatory responses by releasing inflammatory mediators. The aim of this study was to evaluate systemic AngII, tumor necrosis factor (TNF), and CX3CL1 mediators in a two-kidney one-clip (2K1C) renovascular hypertension model using Wistar rats infected with T. cruzi. Our data showed an increase in serum AngII in uninfected and T. cruzi-infected rats 1 week after 2K1C surgery compared to non-2K1C (Sham) animals. The baseline systolic blood pressure was higher in both uninfected and infected 2K1C rats. Despite no difference in circulating parasites in the acute phase of infection, elevated serum TNF and CX3CL1 were observed at 8 weeks post-infection in 2K1C rats in association with higher cardiac inflammatory infiltration. In summary, AngII-induced hypertension associated with T. cruzi infection may act synergistically to increase TNF and CX3CL1 in the 2K1C rat model, thereby intensifying cardiac inflammatory infiltration and worsening the underlying inflammation triggered by this protozoan