The impact of personalised therapies on respiratory medicine

Stratified approaches to treating disease are very attractive, as efficacy is maximised by identifying responders using a companion diagnostic or by careful phenotyping. This approach will spare non-responders form potential side-effects. This has been pioneered in oncology where single genes or gene signatures indicate tumours that will respond to specific chemotherapies. Stratified approaches to the treatment of asthma with biological therapies are currently being extensively studied. In cystic fibrosis (CF), therapies have been developed that are targeted at specific functional classes of mutations. Ivacaftor, the first of such therapies, potentiates dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein Class III mutations and is now available in the USA and some European countries. Pivotal studies in patients with a G551D mutation, the most common Class III mutation, have demonstrated significant improvements in clinically important outcomes such as spirometry and exacerbations. Sweat chloride was significantly reduced demonstrating a functional effect on the dysfunctional CFTR protein produced by the G551D mutation. Symptom scores are also greatly improved to a level that indicates that this is a transformational treatment for many patients. This stratified approach to the development of therapies based on the functional class of the mutations in CF is likely to lead to new drugs or combinations that will correct the basic defect in many patients with CF. © ERS 2013.

Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids

OBJECTIVE - To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy. RESEARCH DESIGN AND METHODS - This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) froma diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non-HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed. RESULTS - Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16-0.94], highest versus lowest quartile; P = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59-0.98]), whereas apoB (per SD increase, 1.31 [1.02-1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13-1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%. CONCLUSIONS - ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures. © 2011 by the American Diabetes Association.

Personalized medicine: Has it started yet? A reconstruction of the early history

Within the last few years the field personalized medicine entered the stage. Accompanied with great hopes and expectations it is believed that this field may have the potential to revolutionize medical and clinical care by utilizing genomics information about the individual patients themselves. In this paper, we reconstruct the early footprints of personalized medicine as reflected by information retrieved from PubMed and Google Scholar. That means we are providing a data-driven perspective of this field to estimate its current status and potential problems.

“Do You Want to See My Hornpipe?”: The Traditional Irish Dancing Body at Play in the Work of Jean Butler and Colin Dunne.

This chapter considers the radical re-imaginings of traditional Irish step dance in the recent works of Jean Butler and Colin Dunne. In Butler's Does She Take Sugar (2007) and Dunne's Out of Time (2008), the Irish step dancing body is separated from its historical roots in nationalism, from the exhibitionism required by the competitive form, and from the spectacularization of the commercialized theatrical format. In these works, which are both solo pieces performed by the choreographers themselves, the traditional form undergoes a critical interrogation in which the dancers attempt to depart from the determinacy of the traditional technique, while acknowledging its formation of their corporealities; the Irish step dance technique becomes a springboard for creative experimentation. In order to consider the importance of the creative potential revealed by these works, this chapter will contextualize them within the dance background from which they emerged, outlining the history of competitive step dancing in Ireland, the "modernization" of traditional Irish dance with the emergence of Riverdance (1994), and the experiments of Ireland's national folk theatre, Siamsa Tíre.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Developing mathematics support for first-year engineering students with non-traditional mathematics backgrounds

A maths support system for first-year engineering students with non-traditional entry qualifications has involved students working through practice questions structured to correspond with the maths module which runs in parallel. The setting was informal and there was significant one-to-one assistance. The non-traditional students (who are known to be less well prepared mathematically) were explicitly contacted in the first week of their university studies regarding the maths support and they generally seemed keen to participate. However, attendance at support classes was relatively low, on average, but varied greatly between students. Students appreciated the personal help and having time to ask questions. It seemed that having a small group of friends within the class promoted attendance – perhaps the mutual support or comfort that they all had similar mathematical difficulties was a factor. The classes helped develop confidence. Attendance was hindered by the class being timetabled too soon after the relevant lecture and students were reluctant to come with no work done beforehand. Although students at risk due to their mathematical unpreparedness can easily be identified at an early stage of their university career, encouraging them to partake of the maths support is an ongoing, major problem.

Expert opinion on the cough hypersensitivity syndrome in respiratory medicine

In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area.

"...and they won land among the Picts by friendly treaty or the sword": How a re-examination of early historical sources and an analysis of early medieval settlement in north Co. Antrim confirms the validity of traditional accounts of Dál Riatic migration to Scotland from Ulster

Much recent scholarship has been critical of the concept of a Dál Riatic migration to, or colonisation of, Argyll. Scepticism of the accuracy of the early medieval accounts of this population movement, arguing that these are late amendments to early sources, coupled with an apparent lack of archaeological evidence for such a migration have led to its rejection. It is argued here, however, that this rejection has been based on too narrow a reading of historical sources and that there are several early accounts which, while differing in detail, agree on one point of substance, that the origin of Scottish Dál Riata lies in Ireland. Also, the use of archaeological evidence to suggest no migration to Argyll by the Dál Riata is flawed, misunderstanding the nature of early migrations and how they might be archaeologically identified, and it's proposed that there is actually quite a lot of evidence for migration to Argyll by the Dál Riata, in the form of settlement and artefactural evidence, but that it is to be found in Ireland through the mechanism of counterstream migration, rather than in Scotland.