Rivaroxaban for Preventing Atherothrombotic Events in People with Acute Coronary Syndrome and Elevated Cardiac Biomarkers: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures rivaroxaban (Xarelto, Bayer) to submit evidence of the clinical and cost effectiveness of rivaroxaban for the prevention of adverse outcomes in patients after the acute management of acute coronary syndrome (ACS). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from a randomised, double-blind, phase III, placebo-controlled trial of rivaroxaban (either 2.5 or 5 mg twice daily) in patients with recent ACS [unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI)]. In addition, all patients received antiplatelet therapy [aspirin alone or aspirin and a thienopyridine either as clopidogrel (approximately 99 %) or ticlopidine (approximately 1 %) according to national or local guidelines]. The higher dose of rivaroxaban (5 mg twice daily) did not form part of the marketing authorisation. A post hoc subgroup analysis of the licensed patients who had ACS with elevated cardiac biomarkers (that is, patients with STEMI and NSTEMI) without prior stroke or transient ischaemic stroke showed that compared with standard care, the addition of rivaroxaban (2.5 mg twice daily) to existing antiplatelet therapy reduced the composite endpoint of cardiovascular mortality, myocardial infarction or stroke, but increased the risk of major bleeding and intracranial haemorrhage. However, there were a number of limitations in the evidence base that warrant caution in its interpretation. In particular, the evidence may be confounded because of the post hoc subgroup analysis, modified intention-to-treat analyses, high dropout rates and missing vital status data. Results from the company's economic evaluation showed that the deterministic incremental cost-effectiveness ratio (ICER) for rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone compared with aspirin plus clopidogrel or aspirin alone was £6203 per quality-adjusted life-year (QALY) gained. In contrast, the ERG's preferred base case estimate was £5622 per QALY gained. The ICER did not rise above £10,000 per QALY gained in any of the sensitivity analyses undertaken by the ERG, although the inflexibility of the company's economic model precluded the ERG from formally undertaking all desired exploratory analyses. As such, only a crude exploration of the impact of additional bleeding events could be undertaken. The NICE Appraisal Committee concluded that the ICERs presented were all within the range that could be considered cost effective and that the results of the ERG's exploratory sensitivity and scenario analyses suggested that the ICER was unlikely to increase to the extent that it would become unacceptable. The Appraisal Committee therefore concluded that rivaroxaban in combination with aspirin plus clopidogrel, or with aspirin alone, was a cost-effective use of National Health Service (NHS) resources for preventing atherothrombotic events in people with ACS and elevated cardiac biomarkers

Electron scattering in multi-wall carbon-nanotubes

We analyze two scattering mechanisms that might cause intrinsic electronic resistivity in multi-wall carbon nanotubes: scattering by dopant impurities, and scattering by inter-tube electron-electron interaction. We find that for typically doped multi-wall tubes backward scattering at dopants is by far the dominating effect.Comment: 6 pages, 2 figures, to appear in Phys. Rev.

Size, Shape and Low Energy Electronic Structure of Carbon Nanotubes

A theory of the long wavelength low energy electronic structure of graphite-derived nanotubules is presented. The propagating $\pi$ electrons are described by wrapping a massless two dimensional Dirac Hamiltonian onto a curved surface. The effects of the tubule size, shape and symmetry are included through an effective vector potential which we derive for this model. The rich gap structure for all straight single wall cylindrical tubes is obtained analytically in this theory, and the effects of inhomogeneous shape deformations on nominally metallic armchair tubes are analyzed.Comment: 5 pages, 3 postscript figure

Norovirus Infection and Disease in an Ecuadorian Birth Cohort: Association of Certain Norovirus Genotypes With Host FUT2 Secretor Status.

BACKGROUND: Although norovirus is the most common cause of gastroenteritis, there are few data on the community incidence of infection/disease or the patterns of acquired immunity or innate resistance to norovirus. METHODS: We followed a community-based birth cohort of 194 children in Ecuador with the aim to estimate (1) the incidence of norovirus gastroenteritis from birth to age 3 years, (2) the protective effect of norovirus infection against subsequent infection/disease, and (3) the association of infection and disease with FUT2 secretor status. RESULTS: Over the 3-year period, we detected a mean of 2.26 diarrheal episodes per child (range, 0-12 episodes). Norovirus was detected in 260 samples (18%) but was not found more frequently in diarrheal samples (79 of 438 [18%]), compared with diarrhea-free samples (181 of 1016 [18%]; P = .919). A total of 66% of children had at least 1 norovirus infection during the first 3 years of life, and 40% of children had 2 infections. Previous norovirus infections were not associated with the risk of subsequent infection. All genogroup II, genotype 4 (GII.4) infections were among secretor-positive children (P < .001), but higher rates of non-GII.4 infections were found in secretor-negative children (relative risk, 0.56; P = .029). CONCLUSIONS: GII.4 infections were uniquely detected in secretor-positive children, while non-GII.4 infections were more often found in secretor-negative children

Supporting pruning in tabled LP

This paper analyzes issues which appear when supporting pruning operators in tabled LP. A version of the once/1 control predicate tailored for tabled predicates is presented, and an implementation analyzed and evaluated. Using once/1 with answer-on-demand strategies makes it possible to avoid computing unneeded solutions for problems which can benefit from tabled LP but in which only a single solution is needed, such as model checking and planning. The proposed version of once/1 is also directly applicable to the efficient implementation of other optimizations, such as early completion, cut-fail loops (to, e.g., prune at the top level), if-then-else, and constraint-based branch-and-bound optimization. Although once/1 still presents open issues such as dependencies of tabled solutions on program history, our experimental evaluation confirms that it provides an arbitrarily large efficiency improvement in several application areas

Analysis of quantum conductance of carbon nanotube junctions by the effective mass approximation

The electron transport through the nanotube junctions which connect the different metallic nanotubes by a pair of a pentagonal defect and a heptagonal defect is investigated by Landauer's formula and the effective mass approximation. From our previous calculations based on the tight binding model, it has been known that the conductance is determined almost only by two parameters,i.e., the energy in the unit of the onset energy of more than two channels and the ratio of the radii of the two nanotubes. The conductance is calculated again by the effective mass theory in this paper and a simple analytical form of the conductance is obtained considering a special boundary conditions of the envelop wavefunctions. The two scaling parameters appear naturally in this treatment. The results by this formula coincide fairly well with those of the tight binding model. The physical origin of the scaling law is clarified by this approach.Comment: RevTe

Interference effects in electronic transport through metallic single-wall carbon nanotubes

In a recent paper Liang {\it et al.} [Nature {\bf 411}, 665 (2001)] showed experimentally, that metallic nanotubes, strongly coupled to external electrodes, may act as coherent molecular waveguides for electronic transport. The experimental results were supported by theoretical analysis based on the scattering matrix approach. In this paper we analyze theoretically this problem using a real-space approach, which makes it possible to control quality of interface contacts. Electronic structure of the nanotube is taken into account within the tight-binding model. External electrodes and the central part (sample) are assumed to be made of carbon nanotubes, while the contacts between electrodes and the sample are modeled by appropriate on-site (diagonal) and hopping (off-diagonal) parameters. Conductance is calculated by the Green function technique combined with the Landauer formalism. In the plots displaying conductance {\it vs.} bias and gate voltages, we have found typical diamond structure patterns, similar to those observed experimentally. In certain cases, however, we have found new features in the patterns, like a double-diamond sub-structure.Comment: 15 pages, 4 figures. To apear in Phys. Rev.

Subband population in a single-wall carbon nanotube diode

We observe current rectification in a molecular diode consisting of a semiconducting single-wall carbon nanotube and an impurity. One half of the nanotube has no impurity, and it has a current-voltage (I-V) charcteristic of a typical semiconducting nanotube. The other half of the nanotube has the impurity on it, and its I-V characteristic is that of a diode. Current in the nanotube diode is carried by holes transported through the molecule's one-dimensional subbands. At 77 Kelvin we observe a step-wise increase in the current through the diode as a function of gate voltage, showing that we can control the number of occupied one-dimensional subbands through electrostatic doping.Comment: to appear in Physical Review Letters. 4 pages & 3 figure