Bayesian comparison of cost-effectiveness of different clinical approaches to diagnose coronary artery disease

The objective of this study was to compare the cost-effectiveness of four clinical policies (policies I to IV) in the diagnosis of the presence or absence of coronary artery disease. A model based on Bayes' theorem and published clinical data was constructed to make these comparisons. Effectiveness was denned as either the number of patients with coronary disease diagnosed or as the number of quality-adjusted life years extended by therapy after the diagnosis of coronary disease.The following conclusions arise strictly from analysis of the model and may not necessarily be applicable to all situations. 1) As prevalence of coronary disease in the population increased, it caused a linear increase in cost per patient tested, but a hyperbolic decrease in cost per effect, that is, increased cost-effectiveness. Thus, cost-effectiveness of all policies (I to IV) was poor in populations with a prevalence of disease below 10%, for example, asymptomatic people with no risk factors. 2) Analysis of the model also indicates that at prevalences less than 80%, exercise thallium scintigraphy alone as a first test (policy II) is a more cost-effective initial test than is exercise electrocardiography alone as a first test (policy I) or exercise electrocardiography first combined with thallium imaging as a second test (policy IV). 3) Exercise electrocardiography before thallium imaging (policy IV) is more cost-effective than exercise electrocardiography alone (policy I) at prevalences less than 80%. 4) Noninvasive exercise testing before angiography (policies I, II and IV) is more cost-effective than using coronary angiography as the first and only test (policy III) at prevalences less than 80%. 5) Above a threshold value of prevalence of 80% (for example patients with typical angina), proceeding to angiography as the first test (policy III) was more cost-effective than initial noninvasive exercise tests (policies I, II and IV).One advantage of this quantitative model is that it estimates a threshold value of prevalence (80%) at which the rank order of policies changes. The model also allows substitution of different values for any variable as a way of accounting for the uncertainty inherent in the data. In conclusion, it is essential to consider the prevalence of disease when selecting the most cost-effective clinical approach to making a diagnosis

High Energy Colliders as Black Hole Factories: The End of Short Distance Physics

If the fundamental Planck scale is of order a TeV, as the case in some extra-dimensions scenarios, future hadron colliders such as the Large Hadron Collider will be black hole factories. The non-perturbative process of black hole formation and decay by Hawking evaporation gives rise to spectacular events with up to many dozens of relatively hard jets and leptons, with a characteristic ratio of hadronic to leptonic activity of roughly 5:1. The total transverse energy of such events is typically a sizeable fraction of the beam energy. Perturbative hard scattering processes at energies well above the Planck scale are cloaked behind a horizon, thus limiting the ability to probe short distances. The high energy black hole cross section grows with energy at a rate determined by the dimensionality and geometry of the extra dimensions. This dependence therefore probes the extra dimensions at distances larger than the Planck scale.Comment: Latex, 28 pages. v4: minor changes, largely to agree with published version; appendix added comparing convention

Maxwell-Chern-Simons Vortices and Holographic Superconductors

We investigate probe limit vortex solutions of a charged scalar field in Einstein-Maxwell theory in 3+1 dimensions, for an asymptotically AdS Schwarzschild black hole metric with the addition of an axionic coupling to the Maxwell field. We show that the inclusion of such a term, together with a suitable potential for the axion field, can induce an effective Chern-Simons term on the 2+1 dimensional boundary. We obtain numerical solutions of the equations of motion and find Maxwell-Chern-Simons like magnetic vortex configurations, where the magnetic field profile varies with the size of the effective Chern-Simons coupling. The axion field has a non-trivial profile inside the AdS bulk but does not condense at spatial infinity.Comment: 17 pages, 5 figures, version accepted for publication in JHE

Scales and hierarchies in warped compactifications and brane worlds

Warped compactifications with branes provide a new approach to the hierarchy problem and generate a diversity of four-dimensional thresholds. We investigate the relationships between these scales, which fall into two classes. Geometrical scales, such as thresholds for Kaluza-Klein, excited string, and black hole production, are generically determined soley by the spacetime geometry. Dynamical scales, notably the scale of supersymmetry breaking and moduli masses, depend on other details of the model. We illustrate these relationships in a class of solutions of type IIB string theory with imaginary self-dual fluxes. After identifying the geometrical scales and the resulting hierarchy, we determine the gravitino and moduli masses through explicit dimensional reduction, and estimate their value to be near the four-dimensional Planck scale. In the process we obtain expressions for the superpotential and Kahler potential, including the effects of warping. We identify matter living on certain branes to be effectively sequestered from the supersymmetry breaking fluxes: specifically, such "visible sector" fields receive no tree-level masses from the supersymmetry breaking. However, loop corrections are expected to generate masses, at the phenomenologically viable TeV scale.Comment: 33 pages, LaTeX. v2: reference added v3: reference added, typos correcte

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Conditions for Generating Scale-Invariant Density Perturbations

We analyze the general conditions on the equation of state $w$ required for quantum fluctuations of a scalar field to produce a scale-invariant spectrum of density perturbations, including models which (in the four dimensional effective description) bounce from a contracting to an expanding phase. We show that there are only two robust cases: $w\approx -1$ (inflation) and $w \gg 1$ (the ekpyrotic/cyclic scenario). All other cases, including the $w \approx 0$ case considered by some authors, require extreme fine-tuning of initial conditions and/or the effective potential. For the ekpyrotic/cyclic ($w \gg 1$) case, we also analyze the small deviations from scale invariance.Comment: 6 pages, no figure

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin