Methodological pluralism in qualitative research: Reflections on a meta-study

A short report is provided of a meta-study of methodological pluralism in qualitative research; that is, of the use of two or more qualitative methods to analyse the same data set. Ten eligible papers were identified and assessed. Their contents are described with respect to theory, methods and findings, and their possible implications discussed in relation to a series of wider debates in qualitative research more generally

Synthesis of novel and potent vorapaxar analogues

Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM

Identification of an active metabolite of PAR-1 antagonist RWJ-58259 and synthesis of analogues to enhance its metabolic stability

The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259

TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells.

The major high-affinity thrombin receptor, proteinase activated receptor-1 (PAR-1) is expressed at low levels by the normal epithelium but is upregulated in many types of cancer, including lung cancer. The thrombin-PAR-1 signalling axis contributes to the activation of latent TGFβ in response to tissue injury via an αvβ6 integrin-mediated mechanism. TGFβ is a pleiotropic cytokine that acts as a tumour suppressor in normal and dysplastic cells but switches into a tumour promoter in advanced tumours. In this study we demonstrate that TGFβ is a positive regulator of PAR-1 expression in A549 lung adenocarcinoma cells, which in turn increases the sensitivity of these cells to thrombin signalling. We further demonstrate that this effect is Smad3-, ERK1/2- and Sp1-dependent. We also show that TGFβ-mediated PAR-1 upregulation is accompanied by increased expression of integrin αv and β6 subunits. Finally, TGFβ pre-stimulation promotes increased migratory potential of A549 to thrombin. These data have important implications for our understanding of the interplay between coagulation and TGFβ signalling responses in lung cancer.Medical Research Council UK (MRC) CASE studentship with Novartis awarded to RCC, MRC Centenary Award awarded to NS and RCC, and MRC Career Development Award G0800340 to CJS

Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis

Disulfide bridging offers a convenient approach to generate site-selective antibody conjugates from native antibodies. To optimise the reagents available to achieve this strategy, we describe here the use of dibromomaleimides designed to undergo accelerated post-conjugation hydrolysis. Conjugation and hydrolysis, which serve to 'lock' the conjugates as robustly stable maleamic acids, is achieved in just over 1 h. This dramatic acceleration is also shown to infer significant improvements in homogeneity, as demonstrated by mass spectrometry analysis

San Francisco Bar Pilot Fatigue Study

The purpose of this study was to evaluate the extent of fatigue among San Francisco Bar Pilots (Maritime Pilots) and its potential impact on safety, and to make recommendations concerning how the risk of fatigue could be managed. Information was gathered via a literature review, observations of Bar Pilots at work, surveys, a task analysis, and an analysis of dispatch records.The work of San Francisco Bar Pilots involves an unusual mix of activities and job demands. Their work calls for situational awareness, reasoning, communication, and perceptual abilities comparable to those required by airline pilots and air traffic controllers. Errors can have severe consequences for public safety and the environment, as well as significant financial costs. Fatigue is increasingly recognized as a hazard that must be managed by the transportation industry. The reduced sleep quality and quantity experienced by personnel who work at night, in conjunction with human circadian rhythms can lead to an operationally significant level of cognitive impairment. The cognitive impact of fatigue includes functions that are critical to safe maritime piloting, such as vigilance, judgment, reaction time and communication. The surveys distributed to Bar Pilots did not uncover evidence of widespread fatigue. The survey results also suggested that fatigue was not a major concern of Bar Pilots. Bar Pilots had overall low scores on the subjective fatigue measures used in the survey, and generally assessed the safety risk due to fatigue as low. Compared to air traffic controllers, Bar Pilots gave significantly lower ratings on questions concerning the prevalence and impact of fatigue. The application of fatigue modeling software to Bar Pilot dispatch records identified that in most cases, pilot's cognitive effectiveness was predicted to be acceptable during their duty periods. However, these results could not be verified with objective data.The study identified a number of fatigue issues that deserve attention. These include Bar Pilot work periods that frequently infringe on the circadian low, consecutive work periods without a significant break, consecutive periods of night work, unpredictable work schedules, start time variability, the potential for sleep inertia, and the number of pilots on the board at any given time

mTORC1 is essential for early steps during Schwann cell differentiation of amniotic fluid stem cells and regulates lipogenic gene expression.

Schwann cell development is hallmarked by the induction of a lipogenic profile. Here we used amniotic fluid stem (AFS) cells and focused on the mechanisms occurring during early steps of differentiation along the Schwann cell lineage. Therefore, we initiated Schwann cell differentiation in AFS cells and monitored as well as modulated the activity of the mechanistic target of rapamycin (mTOR) pathway, the major regulator of anabolic processes. Our results show that mTOR complex 1 (mTORC1) activity is essential for glial marker expression and expression of Sterol Regulatory Element-Binding Protein (SREBP) target genes. Moreover, SREBP target gene activation by statin treatment promoted lipogenic gene expression, induced mTORC1 activation and stimulated Schwann cell differentiation. To investigate mTORC1 downstream signaling we expressed a mutant S6K1, which subsequently induced the expression of the Schwann cell marker S100b, but did not affect lipogenic gene expression. This suggests that S6K1 dependent and independent pathways downstream of mTORC1 drive AFS cells to early Schwann cell differentiation and lipogenic gene expression. In conclusion our results propose that future strategies for peripheral nervous system regeneration will depend on ways to efficiently induce the mTORC1 pathway

‘You’re just chopped off at the end’: Retired servicemen’s identity work struggles in the military to civilian transition

Promoting positive transition to retirement and cultural adaption for ex-service personnel has been identified as a priority for both social-science research and for public health policy in the UK. The Royal British Legion (RBL) aims to provide support to service and retired service personnel, but to date the transition to retirement experiences of older (60-plus) ex- service personnel remain under-researched. In this article, we employ a symbolic interactionist theoretical framework to examine older servicemen’s experiences and identity challenges post-retirement from the British armed forces. Data were collected primarily through semi-structured, focus-group interviews with 20 former servicemen. Here, we focus specifically upon the challenges encountered by these ex-servicemen in the retirement transition from military to civilian life, a time of identity flux of sociological interest. To navigate this period of identity change and challenge, many participants constructed a ‘modified military self’ through involvement with the RBL as a key social support network. For many retired personnel the RBL offered a form of identification and group identity that resonated strongly with earlier experiences of comradeship in the military

Adjusting to Retirement from Sport: Narratives of Former Competitive Rhythmic Gymnasts

This study used narrative inquiry to understand the retirement experiences of rhythmic gymnasts. Eight female former competitive gymnasts (M age = 24.5, SD = 8.33) each participated in four life-history interviews. Following dialogical narrative analysis, three narrative typologies were outlined: Entangled Narrative, Going Forward Narrative, and Making Sense Narrative. The entangled narrative shows an individual with a monological athletic identity, who is unable to develop a new identity following her retirement to the detriment of her well-being, and wishes to return to being a gymnast. The going-forward narrative describes those former gymnasts who were able to develop multiple identities during their gymnastics career, and are now flourishing in their life post-retirement. The making-sense narrative is an emergent narrative, which transcends the previous two narratives. Findings expand narrative research by providing new narrative resources to understand the experience of retirement from gymnastics. These narrative resources might assist gymnasts to expand their narrative repertoire by raising awareness of different narratives available in their culture