Targeted therapies to improve CFTR function in cystic fibrosis

Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis

Multiplicative random walk Metropolis-Hastings on the real line

In this article we propose multiplication based random walk Metropolis Hastings (MH) algorithm on the real line. We call it the random dive MH (RDMH) algorithm. This algorithm, even if simple to apply, was not studied earlier in Markov chain Monte Carlo literature. The associated kernel is shown to have standard properties like irreducibility, aperiodicity and Harris recurrence under some mild assumptions. These ensure basic convergence (ergodicity) of the kernel. Further the kernel is shown to be geometric ergodic for a large class of target densities on $\mathbb{R}$. This class even contains realistic target densities for which random walk or Langevin MH are not geometrically ergodic. Three simulation studies are given to demonstrate the mixing property and superiority of RDMH to standard MH algorithms on real line. A share-price return data is also analyzed and the results are compared with those available in the literature

Rising to the challenge: acute stress appraisals and selection centre performance in applicants to postgraduate specialty training in anaesthesia

AcceptedArticle in Press© 2015 Springer Science+Business Media Dordrecht The ability to work under pressure is a vital non-technical skill for doctors working in acute medical specialties. Individuals who evaluate potentially stressful situations as challenging rather than threatening may perform better under pressure and be more resilient to stress and burnout. Training programme recruitment processes provide an important opportunity to examine applicants’ reactions to acute stress. In the context of multi-station selection centres for recruitment to anaesthesia training programmes, we investigated the factors influencing candidates’ pre-station challenge/threat evaluations and the extent to which their evaluations predicted subsequent station performance. Candidates evaluated the perceived stress of upcoming stations using a measure of challenge/threat evaluation—the cognitive appraisal ratio (CAR)—and consented to release their demographic details and station scores. Using regression analyses we determined which candidate and station factors predicted variation in the CAR and whether, after accounting for these factors, the CAR predicted candidate performance in the station. The CAR was affected by the nature of the station and candidate gender, but not age, ethnicity, country of training or clinical experience. Candidates perceived stations involving work related tasks as more threatening. After controlling for candidates’ demographic and professional profiles, the CAR significantly predicted station performance: ‘challenge’ evaluations were associated with better performance, though the effect was weak. Our selection centre model can help recruit prospective anaesthetists who are able to rise to the challenge of performing in stressful situations but results do not support the direct use of challenge/threat data for recruitment decisions.Funding was granted as a pilot for selection to acute specialities from the Department of Health (England). M.J.R.’s research post was funded through this grant, as were sessional time allocations for T.C.E.G. All opinions in the manuscript are those of the authors only and recommendations or policy from the DH should not be inferred from this work

Is translation semantically mediated? Evidence from Welsh-English bilingual aphasia

The involvement of the semantic system in picture naming is undisputed. However, it has been proposed that translation could take place via direct lexical links between L1 and L2 word forms in addition to or instead of via semantics(i.e., with translation going from a spoken word in L1 accessing its meaning and this meaning then leading to the retrieval of the translation equivalent in L2). There is conflicting evidence in the psycholinguistic literature as to the extent of semantic mediation in translation vs. picture naming tasks (Potter et al, 1984; Kroll and Stewart, 1994). More recently, Hernandez et al (2010) investigated this question in a case study of JFF, a proficient bilingual Spanish-Catalan speaker with Alzheimer’s disease and naming difficulties due to a semantic deficit. As JFF’s semantic deficit did not only affect picture naming but also translation tasks, the authors concluded against the existence of functional direct lexical links to support translation. The goal of our study was to explore this issue further in a larger sample of proficient bilingual patients with aphasia and word finding difficulties in both languages. More specifically, we compare the rate of semantic errors produced in naming vs. translation tasks

Ozone and alkyl nitrate formation from the Deepwater Horizon oil spill atmospheric emissions

Ozone (O3), alkyl nitrates (RONO2), and other photochemical products were formed in the atmosphere downwind from the Deepwater Horizon (DWH) oil spill by photochemical reactions of evaporating hydrocarbons with NOx (=NO+NO2) emissions from spill response activities. Reactive nitrogen species and volatile organic compounds (VOCs) were measured from an instrumented aircraft during daytime flights in the marine boundary layer downwind from the area of surfacing oil. A unique VOC mixture, where alkanes dominated the hydroxyl radical (OH) loss rate, was emitted into a clean marine environment, enabling a focused examination of O3 and RONO 2 formation processes. In the atmospheric plume from DWH, the OH loss rate, an indicator of potential O3 formation, was large and dominated by alkanes with between 5 and 10 carbons per molecule (C 5-C10). Observations showed that NOx was oxidized very rapidly with a 0.8h lifetime, producing primarily C6-C10 RONO2 that accounted for 78% of the reactive nitrogen enhancements in the atmospheric plume 2.5h downwind from DWH. Both observations and calculations of RONO2 and O3 production rates show that alkane oxidation dominated O3 formation chemistry in the plume. Rapid and nearly complete oxidation of NOx to RONO2 effectively terminated O3 production, with O3 formation yields of 6.0±0.5 ppbv O3 per ppbv of NOx oxidized. VOC mixing ratios were in large excess of NOx, and additional NOx would have formed additional O3 in this plume. Analysis of measurements of VOCs, O3, and reactive nitrogen species and calculations of O3 and RONO2 production rates demonstrate that NOx-VOC chemistry in the DWH plume is explained by known mechanisms. Copyright 2012 by the American Geophysical Union

Media coverage and public understanding of sentencing policy in relation to crimes against children

This research examines how the media report on sentences given to those who commit serious crimes against children and how this impacts on public knowledge and attitudes. Three months of press and television coverage were analysed in order to establish the editorial lines that are taken in different sections of the media and how they are promoted by selective reporting of sentencing. Results indicate that a small number of very high profile crimes account for a significant proportion of reporting in this area and often, particularly in the tabloid press, important information regarding sentencing rationale is sidelined in favour of moral condemnation and criticism of the judiciary. Polling data indicate that public attitudes are highly critical of sentencing but also confused about the meaning of tariffs. The article concludes by discussing what can be done to promote a more informed public debate over penal policy in this area

On the flexibility of the design of Multiple Try Metropolis schemes

The Multiple Try Metropolis (MTM) method is a generalization of the classical Metropolis-Hastings algorithm in which the next state of the chain is chosen among a set of samples, according to normalized weights. In the literature, several extensions have been proposed. In this work, we show and remark upon the flexibility of the design of MTM-type methods, fulfilling the detailed balance condition. We discuss several possibilities and show different numerical results

Novel ulcerative leg lesions in yearling lambs: Clinical features, microbiology and histopathology

Here we report an outbreak of an atypical, ulcerative dermatitis in North Country mule lambs, located in South Gloucestershire, UK. The lesions, which appeared to be contagious, occured between the coronary band and the carpal joint as a focal, well demarcated, circular, ulcerative dermatitis. Histopathological examination of the lesion biopsies revealed areas of ulceration, epidermal hyperplasia, suppurative dermatitis and granulation tissue. Clumped keratohyalin granules and intracellular keratinocyte oedema (ballooning degeneration) were evident within lesion biopsies, consistent with an underlying viral aetiology. A PCR-based microbiological investigation failed to detect bovine digital dermatitis-associated treponeme phylogroups, Dichelobacter nodosus, Staphylococcus aureus, Dermatophilus congolensis or Chordopoxvirinae virus DNA. However, 3 of the 10 (30 %) and 6 of 10 (60 %) lesion samples were positive for Fusobacterium necrophorum and Streptococcus dysgalactiae DNA, respectively. Contralateral limb swabs were negative by all standard PCR assays. To better define the involvement of F. necrophorum in the aetiology of these lesions, a qPCR targeting the rpoB gene was employed and confirmed the presence of F. necrophorum DNA in both the control and lesions swab samples, although the mean F. necrophorum genome copy number detected in the lesion swab samples was ∼19-fold higher than detected in the contralateral control swab samples (245 versus 4752 genome copies/μl, respectively; P < 0.001). Although we have not been able to conclusively define an aetiological agent, the presence of both F. necrophorum and S. dysgalactiae in the majority of lesions assayed supports their role in the aetiopathogenesis of these lesions

Seeing the baby, doing family: commercial ultrasound as family practice?

Medical sociologists and anthropologists have studied the social significance of obstetric ultrasound for families but little is known about how women and families make use of commercially available ultrasound scans. This article draws on interviews with women who booked a scan with a commercial company in the UK. For some women, commercial ultrasound can be understood as a family practice. We investigate this theme by examining who accompanies women to commercial scan appointments, how scan images are shared and how sonograms are used as prompts to resemblance talk. We argue that commercial scans are more than an additional opportunity to acquire ‘baby’s first picture’ and offer a flexible resource to do family, creating and affirming family relationships and rehearsing roles as parents, siblings and grandparents. Our findings confirm the importance of imagination in doing family and raise questions about the role of technology and commercial interests in shaping family practices