A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80\% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios

Laboratory Diagnosis Of Bovine Leptospirosis

In issue no. 2 1951 the Iowa State College Veterinarian published an article by Dr. K. R. Reinhard entitled Bovine Leptospirosis. Since that time, the Iowa Veterinary Diagnostic Laboratory has received several cases which were diagnosed as leptospirosis. Following is the history and laboratory finding of three herds

Linear continuous interior penalty finite element method for Helmholtz equation With High Wave Number: One-Dimensional Analysis

This article addresses the properties of continuous interior penalty (CIP) finite element solutions for the Helmholtz equation. The h-version of the CIP finite element method with piecewise linear approximation is applied to a one-dimensional (1D) model problem. We first show discrete well posedness and convergence results, using the imaginary part of the stabilization operator, for the complex Helmholtz equation. Then we consider a method with real valued penalty parameter and prove an error estimate of the discrete solution in the H1-norm, as the sum of best approximation error plus a pollution term that is the order of the phase difference. It is proved that the pollution effect can be eliminated by selecting the penalty parameter appropriately. As a result of this analysis, thorough and rigorous understanding of the error behavior throughout the range of convergence is gained. Numerical results are presented that show sharpness of the error estimates and highlight some phenomena of the discrete solution behavior. In particular, we give numerical evidence that the optimal penalty parameter obtained in the 1D case also works very well for the CIP-FEM on two-dimensional Cartesian grids

A finite element data assimilation method for the wave equation

We design a primal-dual stabilized finite element method for the numerical approximation of a data assimilation problem subject to the acoustic wave equation. For the forward problem, piecewise affine, continuous, finite element functions are used for the approximation in space and backward differentiation is used in time. Stabilizing terms are added on the discrete level. The design of these terms is driven by numerical stability and the stability of the continuous problem, with the objective of minimizing the computational error. Error estimates are then derived that are optimal with respect to the approximation properties of the numerical scheme and the stability properties of the continuous problem. The effects of discretizing the (smooth) domain boundary and other perturbations in data are included in the analysis

Physician Aid in Dying: A Humane Option, a Constitutionally Protected Choice

This Article presents the argument that the Fourteenth Amendment protects the individual decision to hasten death with physician-prescribed medication and that statutes prohibiting physician-assisted suicide deny equal protection, guaranteed by the Fourteenth Amendment, to competent, terminally-ill adults who are not on life support

Weakly Consistent Regularisation Methods for Ill-Posed Problems

This Chapter takes its origin in the lecture notes for a 9 h course at the Institut Henri Poincaré in September 2016. The course was divided in three parts. In the first part, which is not included herein, the aim was to first recall some basic aspects of stabilised finite element methods for convection-diffusion problems. We focus entirely on the second and third parts which were dedicated to ill-posed problems and their approximation using stabilised finite element methods. First we introduce the concept of conditional stability. Then we consider the elliptic Cauchy-problem and a data assimilation problem in a unified setting and show how stabilised finite element methods may be used to derive error estimates that are consistent with the stability properties of the problem and the approximation properties of the finite element space. Finally, we extend the result to a data assimilation problem subject to the heat equation

A priori and a posteriori analysis of non-conforming finite elements with face penalty for advection-diffusion equations

We analyse a non-conforming finite-element method to approximate advection-diffusion-reaction equations. The method is stabilized by penalizing the jumps of the solution and those of its advective derivative across mesh interfaces. The a priori error analysis leads to (quasi-)optimal estimates in the mesh size (sub-optimal by order ½ in the L2-norm and optimal in the broken graph norm for quasi-uniform meshes) keeping the Péclet number fixed. Then, we investigate a residual a posteriori error estimator for the method. The estimator is semi-robust in the sense that it yields lower and upper bounds of the error which differ by a factor equal at most to the square root of the Péclet number. Finally, to illustrate the theory we present numerical results including adaptively generated meshe

Is there a link between treatments with exogenous corticosteroids and dog behaviour problems?

Possible side effects of exogenous corticosteroids have been described in both humans and laboratory animals, with recent studies highlighting this issue in dogs. In this paper the behaviour of 345 dogs drawn from the caseload of a behaviour clinic based in the north of Italy between February 2012 and November 2014 were analysed. Possible relationships between dogs that received treatment with corticosteroids versus dogs that received treatment with drugs other than corticosteroids and positive or negative affective states, aggression towards people, other behaviour problems apart from aggression, occurrence of severe bites, and prescription of psychoactive drugs were initially assessed using a Pearson's chi-squared test. Regression analysis was then performed in order to evaluate the best predictors of the investigated items. The goal of this retrospective survey was to investigate possible relationships between the affective states associated with the behavioural complaint of dogs and their previous history of treatment with corticosteroids. Results showed that a history of corticosteroid treatment was a significant predictor of a range of behaviour problems associated with negative affective state, but this result may be confounded by age-related effects

Results from the LSND Neutrino Oscillation Search

The Liquid Scintillator Neutrino Detector (LSND) at the Los Alamos Meson Physics Facility sets bounds on neutrino oscillations in the appearance channel nu_mu_bar --> nu_e_bar by searching for the signature of the reaction nu_e_bar p --> e^+ n: an e$^+$ followed by a 2.2MeV gamma ray from neutron capture. Five e^{+/-} -- gamma coincidences are observed in time with the LAMPF beam, with an estimated background of 6.2 events. The 90\% confidence limits obtained are: Delta (m^2) < 0.07eV^2 for sin^2 (2theta) = 1, and sin^2(2theta) < 6 10^{-3} for Delta (m^2) > 20 eV^2.Comment: 10 pages, uses REVTeX and epsf macro