Evidence-based prescribing: combining network meta-analysis with multicriteria decision analysis to choose among multiple drugs

What is the drug of choice for condition x? is among the most commonly asked questions in primary care.1 Reflecting the complexity of prescribing decisions, answering this question requires a difficult trade-off between the benefits and harms of multiple drugs for a given condition. The principles of evidence-based medicine suggest that prescribing decisions should be guided by an objective benchmark, namely scientific evidence.2 Such evidence is particularly important when choosing a first-line treatment among multiple alternatives. Unfortunately, existing clinical evidence on benefits and harms is rarely adequate to inform prescribing decisions. A randomized controlled trial comparing all relevant drugs would provide such information. However, clinical trials are often designed for regulatory purposes and, therefore, include selective patient populations and do not include all available comparator drugs.3,4 To obtain insight into the comparative benefits and harms of multiple drugs, prescribers turn to summaries of evidence to discern the most promising drugs from their less effective comparators. Recent methods used to synthesize existing evidence provide much-needed information on the comparative benefits and harms of multiple drugs. Network meta-analysis is one such method that allows for the combination of direct and indirect evidences from randomized trials, facilitating the comparison of all relevant drugs even when they are not directly compared with each other in clinical trials.5 The recent surge in the number of network meta-analyses in the general medical literature is a testament to the increasing need for comparative evidence in prescribing decisions

Recovering star formation histories: Integrated-light analyses vs stellar colour-magnitude diagrams

Accurate star formation histories (SFHs) of galaxies are fundamental for understanding the build-up of their stellar content. However, the most accurate SFHs - those obtained from colour-magnitude diagrams (CMDs) of resolved stars reaching the oldest main sequence turnoffs (oMSTO) - are presently limited to a few systems in the Local Group. It is therefore crucial to determine the reliability and range of applicability of SFHs derived from integrated light spectroscopy, as this affects our understanding of unresolved galaxies from low to high redshift. To evaluate the reliability of current full spectral fitting techniques in deriving SFHs from integrated light spectroscopy by comparing SFHs from integrated spectra to those obtained from deep CMDs of resolved stars. We have obtained a high signal--to--noise (S/N $\sim$ 36.3 per \AA) integrated spectrum of a field in the bar of the Large Magellanic Cloud (LMC) using EFOSC2 at the 3.6 meter telescope at La Silla Observatory. For this same field, resolved stellar data reaching the oMSTO are available. We have compared the star formation rate (SFR) as a function of time and the age-metallicity relation (AMR) obtained from the integrated spectrum using {\tt STECKMAP}, and the CMD using the IAC-star/MinnIAC/IAC-pop set of routines. For the sake of completeness we also use and discuss other synthesis codes ({\tt STARLIGHT} and {\tt ULySS}) to derive the SFR and AMR from the integrated LMC spectrum. We find very good agreement (average differences $\sim$ 4.1 $\%$) between the SFR(t) and the AMR obtained using {\tt STECKMAP} on the integrated light spectrum, and the CMD analysis. {\tt STECKMAP} minimizes the impact of the age-metallicity degeneracy and has the advantage of preferring smooth solutions to recover complex SFHs by means of a penalized $\chi^2$. [abridged]Comment: 23 pages, 24 figures. Accepted for publication in A&A (6 Sep 2015

Metallic atomically-thin layered silicon epitaxially grown on silicene/ZrB2

Using low energy electron diffraction (LEED) and scanning tunnelling microscopy (STM), we observe a new two-dimensional (2D) silicon crystal that is formed by depositing additional Si atoms onto spontaneously-formed epitaxial silicene on a ZrB2 thin film. From scanning tunnelling spectroscopy (STS) studies, we find that this atomically-thin layered silicon has distinctly different electronic properties. Angle resolved photoelectron spectroscopy (ARPES) reveals that, in sharp contrast to epitaxial silicene, the layered silicon exhibits significantly enhanced density of states at the Fermi level resulting from newly formed metallic bands. The 2D growth of this material could allow for direct contacting to the silicene surface and demonstrates the dramatic changes in electronic structure that can occur by the addition of even a single monolayer amount of material in 2D systems

Quasi-Topological Insulator and Trigonal Warping in Gated Bilayer Silicene

Bilayer silicene has richer physical properties than bilayer graphene due to its buckled structure together with its trigonal symmetric structure. The buckled structure arises from a large ionic radius of silicon, and the trigonal symmetry from a particular way of hopping between two silicenes. It is a topologically trivial insulator since it carries a trivial $\mathbb{Z}_{2}$ topological charge. Nevertheless, its physical properties are more akin to those of a topological insulator than those of a band insulator. Indeed, a bilayer silicene nanoribbon has edge modes which are almost gapless and helical. We may call it a quasi-topological insulator. An important observation is that the band structure is controllable by applying the electric field to a bilayer silicene sheet. We investigate the energy spectrum of bilayer silicene under electric field. Just as monolayer silicene undergoes a phase transition from a topological insulator to a band insulator at a certain electric field, bilayer silicene makes a transition from a quasi-topological insulator to a band insulator beyond a certain critical field. Bilayer silicene is a metal while monolayer silicene is a semimetal at the critical field. Furthermore we find that there are several critical electric fields where the gap closes due to the trigonal warping effect in bilayer silicene.Comment: 8 pages, 11 figures, to be published in J. Phys. Soc. Jp

Topological Phase Transition and Electrically Tunable Diamagnetism in Silicene

Silicene is a monolayer of silicon atoms forming a honeycomb lattice. The lattice is actually made of two sublattices with a tiny separation. Silicene is a topological insulator, which is characterized by a full insulating gap in the bulk and helical gapless edges. It undergoes a phase transition from a topological insulator to a band insulator by applying external electric field. Analyzing the spin Chern number based on the effective Dirac theory, we find their origin to be a pseudospin meron in the momentum space. The peudospin degree of freedom arises from the two-sublattice structure. Our analysis makes clear the mechanism how a phase transition occurs from a topological insulator to a band insulator under increasing electric field. We propose a method to determine the critical electric field with the aid of diamagnetism of silicene. Diamagnetism is tunable by the external electric field, and exhibits a singular behaviour at the critical electric field. Our result is important also from the viewpoint of cross correlation between electric field and magnetism. Our finding will be important for future electro-magnetic correlated devices.Comment: 4 pages,5 figure

Magnetic properties of ultrathin Co(0001) films on vicinal Si(111) substrate

In the present work we report on magnetization reversal process, anisotropy and domain structures in ultrathin Au/Co(0001)/Au films deposited on vicinal Si(111) substrates. The measurements were performed using a magneto-optical Kerr effect based magnetometer, a polarizing optical microscope and a ferromagnetic resonance spectrometer. Co thickness induced spin-reorientation from out-of-plane into in-plane magnetization was studied. Changes of in-plane magnetic anisotropy symmetry were deduced from shapes of magneto-optical hysteresis loops and from analysis of angular dependences of the resonance field. The experimental data have been discussed taking into account both uniaxial out-of-plane anisotropy and step-induced uniaxial in-plane anisotropy. A preferential orientation of domain walls in 3ML thick Co films was observed. The finding is explained by the step-induced magnetic anisotropy

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

Cost effectiveness of first-line oral therapies for pulmonary arterial hypertension: A modelling study

Background: In recent years, a significant number of costly oral therapies have become available for the treatment of pulmonary arterial hypertension (PAH). Funding decisions for these therapies requires weighing up their effectiveness and costs. Objective: The aim of this study was to assess the cost effectiveness of monotherapy with oral PAH-specific therapies versus supportive care as initial therapy for patients with functional class (FC) II and III PAH in Canada. Methods: A cost-utility analysis, from the perspective of a healthcare system and based on a Markov model, was designed to estimate the costs and quality-adjusted life-years (QALYs) associated with bosentan, ambrisentan, riociguat, tadalafil, sildenafil and supportive care for PAH in treatment-naïve patients. Separate analyses were conducted for cohorts of patients commencing therapy at FC II and III PAH. Transition probabilities, based on the relative risk of improving and worsening in FC with treatment versus placebo, were derived from a recent network meta-analysis. Utility values and costs were obtained from published data and clinical expert opinion. Extensive sensitivity analyses were conducted. Results: Analysis suggests that sildenafil is the most cost-effective therapy for PAH in patients with FC II or III. Sildenafil was both the least costly and most effective therapy, thereby dominating all other treatments. Tadalafil was also less costly and more effective than supportive care in FC II and III; however, sildenafil was dominant over tadalafil. Even given the uncertainty within the clinical inputs, the probabilistic sensitivity analysis showed that apart from sildenafil and tadalafil, the other PAH therapies had negligible probability of being the most cost effective. Conclusion: The results show that initiation of therapy with sildenafil is likely the most cost-effective strategy in PAH patients with either FC II or III disease.This research was supported by funds from the Canadian Agency for Drugs and Technologies in Health (CADTH)