Plausibility functions and exact frequentist inference

In the frequentist program, inferential methods with exact control on error rates are a primary focus. The standard approach, however, is to rely on asymptotic approximations, which may not be suitable. This paper presents a general framework for the construction of exact frequentist procedures based on plausibility functions. It is shown that the plausibility function-based tests and confidence regions have the desired frequentist properties in finite samples---no large-sample justification needed. An extension of the proposed method is also given for problems involving nuisance parameters. Examples demonstrate that the plausibility function-based method is both exact and efficient in a wide variety of problems.Comment: 21 pages, 5 figures, 3 table

The efficacy of recombinant thrombopoietin in murine and nonhuman primate models for radiation-induced myelosuppression and stem cell transplantation

Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed

Finite element analysis of embedded optical fibre sensors

Micromechanical Finite Element (FE) analysis was used to model stress and strain fields in and around embedded optical fibres EOF'S) in flexural test coupons of carbon fibre composite. The coupons were used in studies of EOF effects on macroscopic laminate properties. The FE method allows complex material inhomogeneities, laminate boundaries and load conditions to be modelled

Thermoelastic Investigation of Damage Evolution in Small Stainless Steel Pipework

This paper describes work on damage studies in small cold worked pipe sections. The effect of material heat treatment on the sensitivity of the thermoelastic constant to exposure to plastic strain is assessed. It is shown that strain hardening plays an important role in modifying the thermoelastic constant. X-ray computed tomography has been use to assess the geometry of the deformed cross-section of pipe and to identify the presence of damage. Finally the potential of thermoelastic stress analysis for damage assessment in the pipe work is established

Quantum Mechanics from Focusing and Symmetry

A foundation of quantum mechanics based on the concepts of focusing and symmetry is proposed. Focusing is connected to c-variables - inaccessible conceptually derived variables; several examples of such variables are given. The focus is then on a maximal accessible parameter, a function of the common c-variable. Symmetry is introduced via a group acting on the c-variable. From this, the Hilbert space is constructed and state vectors and operators are given a clear interpretation. The Born formula is proved from weak assumptions, and from this the usual rules of quantum mechanics are derived. Several paradoxes and other issues of quantum theory are discussed.Comment: 26 page

The evolution of plasmid stability: Are infectious transmission and compensatory evolution competing evolutionary trajectories?

Conjugative plasmids are widespread and play an important role in bacterial evolution by accelerating adaptation through horizontal gene transfer. However, explaining the long-term stability of plasmids remains challenging because segregational loss and the costs of plasmid carriage should drive the loss of plasmids though purifying selection. Theoretical and experimental studies suggest two key evolutionary routes to plasmid stability: First, the evolution of high conjugation rates would allow plasmids to survive through horizontal transmission as infectious agents, and second, compensatory evolution to ameliorate the cost of plasmid carriage can weaken purifying selection against plasmids. How these two evolutionary strategies for plasmid stability interact is unclear. Here, we summarise the literature on the evolution of plasmid stability and then use individual based modelling to investigate the evolutionary interplay between the evolution of plasmid conjugation rate and cost amelioration. We find that, individually, both strategies promote plasmid stability, and that they act together to increase the likelihood of plasmid survival. However, due to the inherent costs of increasing conjugation rate, particularly where conjugation is unlikely to be successful, our model predicts that amelioration is the more likely long-term solution to evolving stable bacteria-plasmid associations. Our model therefore suggests that bacteria-plasmid relationships should evolve towards lower plasmid costs that may forestall the evolution of highly conjugative, 'infectious' plasmids

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR