Toward a Functional Definition of a “Rare Disease” for Regulatory Authorities and Funding Agencies

AbstractBackgroundThe designation of a disease as “rare” is associated with some substantial benefits for companies involved in new drug development, including expedited review by regulatory authorities and relaxed criteria for reimbursement. How “rare disease” is defined therefore has major financial implications, both for pharmaceutical companies and for insurers or public drug reimbursement programs. All existing definitions are based, somewhat arbitrarily, on disease incidence or prevalence.ObjectivesWhat is proposed here is a functional definition of rare based on an assessment of the feasibility of measuring the efficacy of a new treatment in conventional randomized controlled trials, to inform regulatory authorities and funding agencies charged with assessing new therapies being considered for public funding.MethodsIt involves a five-step process, involving significant negotiations between patient advocacy groups, pharmaceutical companies, physicians, and public drug reimbursement programs, designed to establish the feasibility of carrying out a randomized controlled trial with sufficient statistical power to show a clinically significant treatment effect.Results and ConclusionsThe steps are as follows: 1) identification of a specific disease, including appropriate genetic definition; 2) identification of clinically relevant outcomes to evaluate efficacy; 3) establishment of the inherent variability of measurements of clinically relevant outcomes; 4) calculation of the sample size required to assess the efficacy of a new treatment with acceptable statistical power; and 5) estimation of the difficulty of recruiting an adequate sample size given the estimated prevalence or incidence of the disorder in the population and the inclusion criteria to be used

Reflecting tidal wave beams and local generation of solitary waves in the ocean thermocline

It is generally accepted that ocean internal solitary waves can arise from the interaction of the barotropic tide with the continental shelf, which generates an internal tide that in turn steepens and forms solitary waves as it propagates shorewards. Some field observations, however, reveal large-amplitude internal solitary waves in deep water, hundreds of kilometers away from the continental shelf, suggesting an alternative generation mechanism: tidal flow over steep topography forces a propagating beam of internal tidal wave energy which impacts the thermocline at a considerable distance from the forcing site and gives rise to internal solitary waves there. Motivated by this possibility, a simple nonlinear long-wave model is proposed for the interaction of a tidal wave beam with the thermocline and the ensuing local generation of solitary waves. The thermocline is modelled as a density jump across the interface of a shallow homogeneous fluid layer on top of a deep uniformly stratified fluid, and a finite-amplitude propagating internal wave beam of tidal frequency in the lower fluid is assumed to be incident and reflected at the interface. The induced weakly nonlinear long-wave disturbance on the interface is governed in the far field by an integral–differential equation which accounts for nonlinear and dispersive effects as well as energy loss owing to radiation into the lower fluid. Depending on the intensity of the incident beam, nonlinear wave steepening can overcome radiation damping so a series of solitary waves may arise in the thermocline. Sample numerical solutions of the governing evolution equation suggest that this mechanism is quite robust for typical oceanic conditions

An Introduction to Data Analysis in Asteroseismology

A practical guide is presented to some of the main data analysis concepts and techniques employed contemporarily in the asteroseismic study of stars exhibiting solar-like oscillations. The subjects of digital signal processing and spectral analysis are introduced first. These concern the acquisition of continuous physical signals to be subsequently digitally analyzed. A number of specific concepts and techniques relevant to asteroseismology are then presented as we follow the typical workflow of the data analysis process, namely, the extraction of global asteroseismic parameters and individual mode parameters (also known as peak-bagging) from the oscillation spectrum.Comment: Lecture presented at the IVth Azores International Advanced School in Space Sciences on "Asteroseismology and Exoplanets: Listening to the Stars and Searching for New Worlds" (arXiv:1709.00645), which took place in Horta, Azores Islands, Portugal in July 201

The landscape of gifted and talented education in England and Wales: How are teachers implementing policy?

This is an Author's Accepted Manuscript of an article published in Research Papers in Education, 27(2), 167-186, 2012, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/02671522.2010.509514.This paper explores the evidence relating to how primary schools are responding to the ‘gifted and talented’ initiative in England and Wales. A questionnaire survey which invited both closed and open-ended responses was carried out with a national sample of primary schools. The survey indicated an increasing proportion of coordinators, compared with a survey carried out in 1996, were identifying their gifted and talented children as well as having associated school policies. However, the survey also highlighted a number of issues which need addressing if the initiative is to achieve its objective of providing the best possible educational opportunities for children. For example, it was found that a significant number of practitioners were not aware of the existence of the National Quality Standards for gifted and talented education, provided by the UK government in 2007, and the subject-specific criteria provided by the UK’s Curriculum Authority for identification and provision have been largely ignored. The process of identifying children to be placed on the ‘gifted and talented’ register seems haphazard and based on pragmatic reasons. Analysis of teachers’ responses also revealed a range of views and theoretical positioning held by them, which have implications for classroom practice. As the ‘gifted and talented’ initiative in the UK is entering a second decade, and yet more significant changes in policy are introduced, pertinent questions need to be raised and given consideration

Numerical analysis of the radio-frequency single-electron transistor operation

We have analyzed numerically the response and noise-limited charge sensitivity of a radio-frequency single-electron transistor (RF-SET) in a non-superconducting state using the orthodox theory. In particular, we have studied the performance dependence on the quality factor Q of the tank circuit for Q both below and above the value corresponding to the impedance matching between the coaxial cable and SET.Comment: 14 page

Large-scale magnetic fields from inflation in dilaton electromagnetism

The generation of large-scale magnetic fields is studied in dilaton electromagnetism in inflationary cosmology, taking into account the dilaton's evolution throughout inflation and reheating until it is stabilized with possible entropy production. It is shown that large-scale magnetic fields with observationally interesting strength at the present time could be generated if the conformal invariance of the Maxwell theory is broken through the coupling between the dilaton and electromagnetic fields in such a way that the resultant quantum fluctuations in the magnetic field has a nearly scale-invariant spectrum. If this condition is met, the amplitude of the generated magnetic field could be sufficiently large even in the case huge amount of entropy is produced with the dilution factor $\sim 10^{24}$ as the dilaton decays.Comment: 28 pages, 5 figures, the version accepted for publication in Phys. Rev. D; some references are adde

A complete 3D numerical study of the effects of pseudoscalar-photon mixing on quasar polarizations

We present the results of three-dimensional simulations of quasar polarizations in the presence of pseudoscalar-photon mixing in the intergalactic medium. The intergalactic magnetic field is assumed to be uncorrelated in wave vector space but correlated in real space. Such a field may be obtained if its origin is primordial. Furthermore we assume that the quasars, located at cosmological distances, have negligible initial polarization. In the presence of pseudoscalar-photon mixing we show, through a direct comparison with observations, that this may explain the observed large scale alignments in quasar polarizations within the framework of big bang cosmology. We find that the simulation results give a reasonably good fit to the observed data.Comment: 15 pages, 8 figures, significant changes, to appear in EPJ