Developing an evidence based approach to follow up in breast cancer

After breast cancer, long term follow up is provided with a view to early detection of locoregional relapse, detection and amelioration of side effects of therapy and provision of psychosocial support to those requiring it. There is pressure within the United Kingdom from the National Institute for Clinical Excellence (NICE) to reduce the amount of follow up provided after breast cancer. There is reluctance on the part of clinicians to adopt the NICE guidelines as they are perceived to be based on limited evidence. At the same time, guidelines in other countries continue to advocate long term follow up, sometimes for life. The evidence base for follow up is explored in the first section of this thesis. In chapter one, a systematic review of the literature is undertaken to establish what evidence exists from randomised controlled trials. The randomised controlled trial is the gold standard for comparing one intervention with another, and any evidence for the benefit of routine clinic visits from randomised trials would be of particular value. Trials which have compared differing frequencies of traditional follow up visits or have compared traditional clinic visits with a novel alternative are included. The impact of these different strategies on relapse detection, survival and quality of life is investigated. In chapters 2 and 3, the pattern and timing of potentially treatable locoregional relapse and the contribution of regular clinical examination to detection of such relapse is explored. This information would help to establish the value of routine clinics in terms of detecting relapse, and whether there was a time after diagnosis and treatment that risk of relapse was low enough to allow safe discharge. In chapter 2, retrospective analyses of two local cohorts is undertaken to explore this issue. A systematic review of the literature is presented in chapter 3 incorporating both the data presented in chapter 2 as well as any other evidence available from previously published retrospective analyses. In section 2 of this thesis, the options for alternative follow up are explored. Very little work has been done to establish what women expect from follow up, either in terms of the amount of follow up they expect to receive or their perceptions of the purpose of follow up. In chapter 4, the results of a survey of a cohort of women undertaken prior to attending for their first review visit after completion of therapy is presented. In the final chapter of this thesis, a prospective cohort study into the acceptability and feasibility of an alternative method of follow up is presented. In this study, an automated computer telephone system was used to deliver a well validated quality of life questionnaire to women in their own homes with the aim of remotely identifying women who were having significant problems with either psychosocial concerns or side effects of treatment and therefore identify those with ongoing problems who required to come back to clinic. In this way, those patients with no ongoing problems would be spared a potentially stressful clinic visit and the number of patients coming back to clinic would be reduced, allowing more time to attend to the needs of the few women brought back with concerns. Summary of Results The analysis in chapter 1 reveals that there are only 5 randomised trials of alternative follow methods, and only 2 trials differing frequencies of visits. None is of sufficient size to establish whether routine clinic visits are necessary for relapse detection or overall survival. All suggest that clinic visits have limited impact on quality of life, and may even be less valuable that some alternative methods of follow up for diagnosing anxiety and depression in these women. Potentially treatable relapse occurs at a constant rate to ten years and beyond. Very few relapses are diagnosed by routine clinical examination, the majority being diagnosed by mammography or symptoms. Mammography is of increasing importance. Patients with clinically detected relapse do no better than those relapses detected in other ways, and there is some evidence that, for some types of relapse, they may do worse. Chapter 4 reveals that most women expect some follow up, but their expectations are that follow up will be more frequent but for a shorter duration than is currently provided in our unit. When informed of the inefficiency of routine follow up in terms of relapse detection, most women still choose to come back to routine follow up, but a large number state that they would be happy not to come back to clinic. An alternative method of follow up is shown to be acceptable to a large proportion of women, and valuable in detecting psychological concerns among women after treatment for breast cancer. The implications of all the findings presented in this thesis for the planning of follow up care in the future are discussed

Apparent suppression of turbulent magnetic dynamo action by a dc magnetic field

Numerical studies of the effect of a dc magnetic field on dynamo action (development of magnetic fields with large spatial scales), due to helically-driven magnetohydrodynamic turbulence, are reported. The apparent effect of the dc magnetic field is to suppress the dynamo action, above a relatively low threshold. However, the possibility that the suppression results from an improper combination of rectangular triply spatially-periodic boundary conditions and a uniform dc magnetic field is addressed: heretofore a common and convenient computational convention in turbulence investigations. Physical reasons for the observed suppression are suggested. Other geometries and boundary conditions are offered for which the dynamo action is expected not to be suppressed by the presence of a dc magnetic field component.Comment: To appear in Physics of Plasma

Low magnetic Prandtl number dynamos with helical forcing

We present direct numerical simulations of dynamo action in a forced Roberts flow. The behavior of the dynamo is followed as the mechanical Reynolds number is increased, starting from the laminar case until a turbulent regime is reached. The critical magnetic Reynolds for dynamo action is found, and in the turbulent flow it is observed to be nearly independent on the magnetic Prandtl number in the range from 0.3 to 0.1. Also the dependence of this threshold with the amount of mechanical helicity in the flow is studied. For the different regimes found, the configuration of the magnetic and velocity fields in the saturated steady state are discussed.Comment: 9 pages, 14 figure

Velocity field distributions due to ideal line vortices

We evaluate numerically the velocity field distributions produced by a bounded, two-dimensional fluid model consisting of a collection of parallel ideal line vortices. We sample at many spatial points inside a rigid circular boundary. We focus on ``nearest neighbor'' contributions that result from vortices that fall (randomly) very close to the spatial points where the velocity is being sampled. We confirm that these events lead to a non-Gaussian high-velocity ``tail'' on an otherwise Gaussian distribution function for the Eulerian velocity field. We also investigate the behavior of distributions that do not have equilibrium mean-field probability distributions that are uniform inside the circle, but instead correspond to both higher and lower mean-field energies than those associated with the uniform vorticity distribution. We find substantial differences between these and the uniform case.Comment: 21 pages, 9 figures. To be published in Physical Review E (http://pre.aps.org/) in May 200

Mutations in the E2 glycoprotein and the 3\u27 untranslated region enhance chikungunya virus virulence in mice

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes debilitating musculoskeletal pain and inflammation and can persist for months to years after acute infection. Although studies of humans and experimentally infected animals suggest that CHIKV infection persists in musculoskeletal tissues, the mechanisms for this remain poorly understood. To evaluate this further, we isolated CHIKV from the serum of persistently infected Rag1 -/- mice at day 28. When inoculated into naive wild-type (WT) mice, this persistently circulating CHIKV strain displayed a capacity for earlier dissemination and greater pathogenicity than the parental virus. Sequence analysis revealed a nonsynonymous mutation in the E2 glycoprotein (E2 K200R) and a deletion within the 3' untranslated region (3'-UTR). The introduction of these changes into the parental virus conferred enhanced virulence in mice, although primary tropism for musculoskeletal tissues was maintained. The E2 K200R mutation was largely responsible for enhanced viral dissemination and pathogenicity, although these effects were augmented by the 3'- UTR deletion. Finally, studies with Irf3/Irf7 -/- and Ifnar1 -/- mice suggest that the E2 K200R mutation enhances viral dissemination from the site of inoculation independently of interferon regulatory factor 3 (IRF3)-, IRF7-, and IFNAR1-mediated responses. As our findings reveal viral determinants of CHIKV dissemination and pathogenicity, their further study should help to elucidate host-virus interactions that determine acute and chronic CHIKV infection

Numerical solutions of the three-dimensional magnetohydrodynamic alpha-model

We present direct numerical simulations and alpha-model simulations of four familiar three-dimensional magnetohydrodynamic (MHD) turbulence effects: selective decay, dynamic alignment, inverse cascade of magnetic helicity, and the helical dynamo effect. The MHD alpha-model is shown to capture the long-wavelength spectra in all these problems, allowing for a significant reduction of computer time and memory at the same kinetic and magnetic Reynolds numbers. In the helical dynamo, not only does the alpha-model correctly reproduce the growth rate of magnetic energy during the kinematic regime, but it also captures the nonlinear saturation level and the late generation of a large scale magnetic field by the helical turbulence.Comment: 12 pages, 19 figure