AplusB: A Web Application for Investigating A + B Designs for Phase I Cancer Clinical Trials.

In phase I cancer clinical trials, the maximum tolerated dose of a new drug is often found by a dose-escalation method known as the A + B design. We have developed an interactive web application, AplusB, which computes and returns exact operating characteristics of A + B trial designs. The application has a graphical user interface (GUI), requires no programming knowledge and is free to access and use on any device that can open an internet browser. A customised report is available for download for each design that contains tabulated operating characteristics and informative plots, which can then be compared with other dose-escalation methods. We present a step-by-step guide on how to use this application and provide several illustrative examples of its capabilities.GMW and APM are supported by the UK Medical Research Council (www.mrc.ac.uk; grant number G0800860). MJS is supported by a European Research Council Advanced Investigator Award: EPIC-Heart (https://erc.europa.eu; grant number 268834), the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation (www.bhf.org.uk), and the Cambridge National Institute for Health Research Biomedical Research Centre (http://www.cambridge-brc.org.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLOS at http://dx.doi.org/10.1371/journal.pone.0159026

Curvature contraction of convex hypersurfaces by nonsmooth speeds

We consider contraction of convex hypersurfaces by convex speeds, homogeneous of degree one in the principal curvatures, that are not necessarily smooth. We show how to approximate such a speed by a sequence of smooth speeds for which behaviour is well known. By obtaining speed and curvature pinching estimates for the flows by the approximating speeds, independent of the smoothing parameter, we may pass to the limit to deduce that the flow by the nonsmooth speed converges to a point in finite time that, under a suitable rescaling, is round in the C^2 sense, with the convergence being exponential

Modelling semi-attributable toxicity in dual-agent phase I trials with non-concurrent drug administration.

In oncology, combinations of drugs are often used to improve treatment efficacy and/or reduce harmful side effects. Dual-agent phase I clinical trials assess drug safety and aim to discover a maximum tolerated dose combination via dose-escalation; cohorts of patients are given set doses of both drugs and monitored to see if toxic reactions occur. Dose-escalation decisions for subsequent cohorts are based on the number and severity of observed toxic reactions, and an escalation rule. In a combination trial, drugs may be administered concurrently or non-concurrently over a treatment cycle. For two drugs given non-concurrently with overlapping toxicities, toxicities occurring after administration of the first drug yet before administration of the second may be attributed directly to the first drug, whereas toxicities occurring after both drugs have been given some present ambiguity; toxicities may be attributable to the first drug only, the second drug only or the synergistic combination of both. We call this mixture of attributable and non-attributable toxicity semi-attributable toxicity. Most published methods assume drugs are given concurrently, which may not be reflective of trials with non-concurrent drug administration. We incorporate semi-attributable toxicity into Bayesian modelling for dual-agent phase I trials with non-concurrent drug administration and compare the operating characteristics to an approach where this detail is not considered. Simulations based on a trial for non-concurrent administration of intravesical Cabazitaxel and Cisplatin in early-stage bladder cancer patients are presented for several scenarios and show that including semi-attributable toxicity data reduces the number of patients given overly toxic combinations. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.G.M. Wheeler and A.P. Mander are supported by the Medical Research Council (grant number G0800860). M.J. Sweeting is supported by a European Research Council Advanced Investigator Award: EPIC-Heart (grant number 268834), the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation and the Cambridge National Institute for Health Research Biomedical Research Centre. S.M. Lee is supported by the American Cancer Society (grant number MRSG-13-146-01-CPHPS).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/sim.691

Supersymmetric minisuperspace with non-vanishing fermion number

The Lagrangean of $N=1$ supergravity is dimensionally reduced to one (time-like) dimension assuming spatial homogeneity of any Bianchi type within class A of the classification of Ellis and McCallum. The algebra of the supersymmetry generators, the Lorentz generators, the diffeomorphism generators and the Hamiltonian generator is determined and found to close. In contrast to earlier work, infinitely many physical states with non-vanishing even fermion number are found to exist in these models, indicating that minisuperspace models in supergravity may be just as useful as in pure gravity.Comment: 4 page

Evolution of genomes, host shifts and the geographic spread of SARS-CoV and related coronaviruses

Severe acute respiratory syndrome (SARS) is a novel human illness caused by a previously unrecognized coronavirus (CoV) termed SARS-CoV. There are conflicting reports on the animal reservoir of SARS-CoV. Many of the groups that argue carnivores are the original reservoir of SARS-CoV use a phylogeny to support their argument. However, the phylogenies in these studies often lack outgroup and rooting criteria necessary to determine the origins of SARS-CoV. Recently, SARS-CoV has been isolated from various species of Chiroptera from China (e.g., Rhinolophus sinicus) thus leading to reconsideration of the original reservoir of SARS-CoV. We evaluated the hypothesis that SARS-CoV isolated from Chiroptera are the original zoonotic source for SARS-CoV by sampling SARS-CoV and non-SARS-CoV from diverse hosts including Chiroptera, carnivores, artiodactyls and humans. Regardless of alignment parameters, optimality criteria, or isolate sampling, the resulting phylogenies clearly show that the SARS-CoV was transmitted to small carnivores well after the epidemic of SARS in humans that began in late 2002. The SARS-CoV isolates from small carnivores in Shenzhen markets form a terminal clade that emerged recently from within the radiation of human SARS-CoV. There is evidence of subsequent exchange of SARS-CoV between humans and carnivores. In addition SARS-CoV was transmitted independently from humans to farmed pigs (Sus scrofa). The position of SARS-CoV isolates from Chiroptera are basal to the SARS-CoV clade isolated from humans and carnivores. Although sequence data indicate that Chiroptera are a good candidate for the original reservoir of SARS-CoV, the structural biology of the spike protein of SARS-CoV isolated from Chiroptera suggests that these viruses are not able to interact with the human variant of the receptor of SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In SARS-CoV study, both visually and statistically, labile genomic fragments and, putative key mutations of the spike protein that may be associated with host shifts. We display host shifts and candidate mutations on trees projected in virtual globes depicting the spread of SARS-CoV. These results suggest that more sampling of coronaviruses from diverse hosts, especially Chiroptera, carnivores and primates, will be required to understand the genomic and biochemical evolution of coronaviruses, including SARS-CoV.Fil: Janies, Daniel. Ohio State University; Estados UnidosFil: Habib, Farhat. Ohio State University; Estados UnidosFil: Alexandrov, Boyan. Ohio State University; Estados UnidosFil: Hill, Andrew. University of Colorado; Estados UnidosFil: Pol, Diego. Museo Paleontológico Egidio Feruglio; Argentina. Ohio State University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Quantum states on supersymmetric minisuperspace with a cosmological constant

Spatially homogeneous models in quantum supergravity with a nonvanishing cosmological constant are studied. A class of exact nontrivial solutions of the supersymmetry and Lorentz constraints is obtained in terms of the Chern-Simons action on the spatially homogeneous 3-manifold, both in Ashketar variables where the solution is explicit up to reality conditions, and, more concretely, in the tetrad-representation, where the solutions are given as integral representations differing only by the contours of integration. In the limit of a vanishing cosmological constant earlier exact solutions for Bianchi type IX models in the tetrad-representation are recovered and additional asymmetric solutions are found.Comment: 14 pages, late

A Bayesian model‐free approach to combination therapy phase I trials using censored time‐to‐toxicity data

The product of independent beta probabilities escalation design for dual agent phase I dose escalation trials is a Bayesian model‐free approach for identifying multiple maximum tolerated dose combinations of novel combination therapies. Despite only being published in 2015, the design has been implemented in at least two oncology trials. However, these trials require patients to have completed follow‐up before clinicians can make dose escalation decisions. For trials of radiotherapy or advanced therapeutics, this may lead to impractically long trial durations due to late‐onset treatment‐related toxicities. We extend the product of independent probabilities escalation design to use censored time‐to‐event toxicity outcomes for making dose escalation decisions. We show via comprehensive simulation studies and sensitivity analyses that trial duration can be reduced by up to 35%, particularly when recruitment is faster than expected, without compromising on other operating characteristics

Supersymmetric Homogeneous Quantum Cosmologies Coupled to a Scalar Field

Recent work on $N=2$ supersymmetric Bianchi type IX cosmologies coupled to a scalar field is extended to a general treatment of homogeneous quantum cosmologies with explicitely solvable momentum constraints, i.e. Bianchi types I, II, VII, VIII besides the Bianchi type IX, and special cases, namely the Friedmann universes, the Kantowski-Sachs space, and Taub-NUT space. Besides the earlier explicit solution of the Wheeler DeWitt equation for Bianchi type IX, describing a virtual wormhole fluctuation, an additional explicit solution is given and identified with the `no-boundary state'.Comment: 23 PAGE

Decoherence Functional and Probability Interpretation

We confirm that the diagonal elements of the Gell-Mann and Hartle's decoherence decoherence functional are equal to the relative frequencies of the results of many identical experiments, when a set of alternative histories decoheres. We consider both cases of the pure and mixed initial states.Comment: 9 pages, UCSBTH-92-40 and MMC-M-