Adjusting Overall Survival Estimates after Treatment Switching: a Case Study in Metastatic Castration-Resistant Prostate Cancer

Background If patients in oncology trials receive subsequent therapy, standard intention-to-treat (ITT) analyses may inaccurately estimate the overall survival (OS) effect of the investigational product. In this context, a post-hoc analysis of the phase 3 PREVAIL study was performed with the aim to compare enzalutamide with placebo in terms of OS, adjusting for potential confounding from switching to antineoplastic therapies that are not part of standard metastatic castration-resistant prostate cancer (mCRPC) treatment pathways in some jurisdictions. Methods The PREVAIL study, which included 1717 chemotherapy-naïve men with mCRPC randomized to treatment with enzalutamide 160 mg/day or placebo, was stopped after a planned interim survival analysis revealed a benefit in favor of enzalutamide. Data from this cutoff point were confounded by switching from both arms and so were evaluated in terms of OS using two switching adjustment methods: the two-stage accelerated failure time model (two-stage method) and inverse probability of censoring weights (IPCW). Results Following adjustment for switching to nonstandard antineoplastic therapies by 14.8 (129/872 patients) and 21.3% (180/845 patients) of patients initially randomized to enzalutamide and placebo, respectively, the two-stage and IPCW methods both resulted in numerical reductions in the hazard ratio (HR) for OS [HR 0.66, 95% confidence interval (CI) 0.57–0.81 and HR 0.63, 95% CI 0.52–0.75, respectively] for enzalutamide compared to placebo versus the unadjusted ITT analysis (HR 0.71, 95% CI 0.60–0.84). These results suggest a slightly greater effect of enzalutamide on OS than originally reported. Conclusion In the PREVAIL study, switching to nonstandard antineoplastic mCRPC therapies resulted in the ITT analysis of primary data underestimating the benefit of enzalutamide on OS

Corporate Hierarchies and the Size of Nations: Theory and Evidence

Corporate organization varies within a country and across countries with country size. The paper starts by establishing some facts about corporate organization based on unique data of 660 Austrian and German corporations. The larger country (Germany) has larger firms with flatter more decentral corporate hierarchies compared to the smaller country (Austria). Firms in the larger country change their organization less fast than firms in the smaller country. Over time firms have been introducing less hierarchical organizations by delegating power to lower levels of the corporation. We develop a theory which explains these facts and which links these features to the trade environment that countries and firms face. We introduce firms with internal hierarchies in a Krugman (1980) model of trade. We show that international trade and the toughness of competition in international markets induce a power struggle in firms which eventually leads to decentralized corporate hierarchies. We offer econometric evidence which is consistent with the models predictions

Search for the Lepton-Number-Violating Decay Ξ−→pμ−μ−\Xi^- \to p \mu^- \mu^-

A sensitive search for the lepton-number-violating decay $\Xi^-\to p \mu^-\mu^-$ has been performed using a sample of $\sim10^9$ $\Xi^-$ hyperons produced in 800 GeV/$c$ $p$-Cu collisions. We obtain $\mathcal{B}(\Xi^-\to p \mu^-\mu^-)< 4.0\times 10^{-8}$ at 90% confidence, improving on the best previous limit by four orders of magnitude.Comment: 9 pages, 5 figures, to be published in Phys. Rev. Let

delta S = 2 nonleptonic hyperon decays

A sensitive search for the rare decays \Omega^- \to \Lambda \pi^- and \Xi^0 \to p \pi^- has been performed using data from the 1997 run of the HyperCP (Fermilab E871) experiment. Limits on other such processes do not exclude the possibility of observable rates for |\Delta S| = 2 nonleptonic hyperon decays, provided the decays occur through parity-odd operators. We obtain the branching-fraction limits B(\Omega^- \to \Lambda \pi^-)< 2.9 x 10^{-6} and B(\Xi^0 \to p \pi^-)< 8.2 x 10^{-6}, both at 90% confidence level.Comment: 4 pages, 5 figures, PRL pape

Implementing telephone triage in general practice: a process evaluation of a cluster randomised controlled trial

Background: Telephone triage represents one strategy to manage demand for face-to-face GP appointments in primary care. However, limited evidence exists of the challenges GP practices face in implementing telephone triage. We conducted a qualitative process evaluation alongside a UK-based cluster randomised trial (ESTEEM) which compared the impact of GP-led and nurse-led telephone triage with usual care on primary care workload, cost, patient experience, and safety for patients requesting a same-day GP consultation. The aim of the process study was to provide insights into the observed effects of the ESTEEM trial from the perspectives of staff and patients, and to specify the circumstances under which triage is likely to be successfully implemented. Here we report perspectives of staff. Methods: The intervention comprised implementation of either GP-led or nurse-led telephone triage for a period of 2-3 months. A qualitative evaluation was conducted using staff interviews recruited from eight general practices (4 GP triage, 4 Nurse triage) in the UK, implementing triage as part of the ESTEEM trial. Qualitative interviews were undertaken with 44 staff members in GP triage and nurse triage practices (16 GPs, 8 nurses, 7 practice managers, 13 administrative staff). Results: Staff reported diverse experiences and perceptions regarding the implementation of telephone triage, its effects on workload, and on the benefits of triage. Such diversity were explained by the different ways triage was organised, the staffing models used to support triage, how the introduction of triage was communicated across practice staff, and by how staff roles were reconfigured as a result of implementing triage. Conclusion: The findings from the process evaluation offer insight into the range of ways GP practices participating in ESTEEM implemented telephone triage, and the circumstances under which telephone triage can be successfully implemented beyond the context of a clinical trial. Staff experiences and perceptions of telephone triage are shaped by the way practices communicate with staff, prepare for and sustain the changes required to implement triage effectively, as well as by existing practice culture, and staff and patient behaviour arising in response to the changes made. Trial registration: Current Controlled Trials ISRCTN20687662. Registered 28 May 2009

JLab Measurement of the 4^4He Charge Form Factor at Large Momentum Transfers

The charge form factor of ^4He has been extracted in the range 29 fm$^{-2}$ $\le Q^2 \le 77$ fm$^{-2}$ from elastic electron scattering, detecting $^4$He nuclei and electrons in coincidence with the High Resolution Spectrometers of the Hall A Facility of Jefferson Lab. The results are in qualitative agreement with realistic meson-nucleon theoretical calculations. The data have uncovered a second diffraction minimum, which was predicted in the $Q^2$ range of this experiment, and rule out conclusively long-standing predictions of dimensional scaling of high-energy amplitudes using quark counting.Comment: 4 pages, 2 figure

Measurement of the 12C(e,e'p)11B Two-Body Breakup Reaction at High Missing Momentum Values

The five-fold differential cross section for the 12C(e,e'p)11B reaction was determined over a missing momentum range of 200-400 MeV/c, in a kinematics regime with Bjorken x > 1 and Q2 = 2.0 (GeV/c)2. A comparison of the results and theoretical models and previous lower missing momentum data is shown. The theoretical calculations agree well with the data up to a missing momentum value of 325 MeV/c and then diverge for larger missing momenta. The extracted distorted momentum distribution is shown to be consistent with previous data and extends the range of available data up to 400 MeV/c.Comment: 12 pages, 1 table and 3 figures for submission to Journal Physics

Search for a new gauge boson in the A′A' Experiment (APEX)

We present a search at Jefferson Laboratory for new forces mediated by sub-GeV vector bosons with weak coupling $\alpha'$ to electrons. Such a particle $A'$ can be produced in electron-nucleus fixed-target scattering and then decay to an $e^+e^-$ pair, producing a narrow resonance in the QED trident spectrum. Using APEX test run data, we searched in the mass range 175--250 MeV, found no evidence for an $A'\to e^+e^-$ reaction, and set an upper limit of $\alpha'/\alpha \simeq 10^{-6}$. Our findings demonstrate that fixed-target searches can explore a new, wide, and important range of masses and couplings for sub-GeV forces.Comment: 5 pages, 5 figures, references adde