Testing two different doses of tiotropium Respimat® in cystic fibrosis: Phase 2 randomized trial results

Background: Tiotropium is a once-daily, long-acting anticholinergic bronchodilator with the potential to alleviate airway obstruction in cystic fibrosis. Our objective was to evaluate the efficacy and safety of 2.5 and 5 μg once-daily tiotropium delivered via the Respimat Soft Mist Inhaler vs. placebo in people with cystic fibrosis. Methods: This phase 2, 12-week, randomized, double-blind, placebo-controlled parallel-group study of tiotropium Respimat as add-on to usual cystic fibrosis maintenance therapy included people with cystic fibrosis with pre-bronchodilator forced expiratory volume in 1 second (FEV₁) ≥25% predicted. Co-primary efficacy end points were change from baseline in percent-predicted FEV₁area under the curve from 0 to 4 hours (FEV₁AUC_0-4h), and trough FEV₁at the end of week 12. Findings: A total of 510 subjects with cystic fibrosis aged 5-69 years were randomized. Both doses of tiotropium resulted in significant improvement compared with placebo in the co-primary efficacy end points at the end of week 12 (change from baseline in percent-predicted FEV₁AUC_0-4h: 2.5 μg: 2.94%, 95% confidence interval 1.19-4.70, p = 0.001; 5 μg: 3.39%, 95% confidence interval 1.67-5.12, p = 0.0001; in percent-predicted trough FEV₁:2.5 μg: 2.24%, p = 0.2; 5 μg: 2.22%, p = 0.02). There was a greater benefit with tiotropium 5 vs. 2.5 μg. No treatment-related adverse events or unexpected safety findings were observed in patients taking tiotropium. Conclusions: Tiotropium significantly improved lung function in people with cystic fibrosis. The improvement was greater with the higher dose than the lower dose, with no difference in adverse events.

Tumor necrosis factor receptor expression and signaling in renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC), a tubular epithelial cell (TEC) malignancy, frequently secretes tumor necrosis factor (TNF). TNF signals via two distinct receptors (TNFRs). TNFR1, expressed in normal kidney primarily on endothelial cells, activates apoptotic signaling kinase 1 and nuclear factor-kappaB (NF-kappaB) and induces cell death, whereas TNFR2, inducibly expressed on endothelial cells and on TECs by injury, activates endothelial/epithelial tyrosine kinase (Etk), which trans-activates vascular endothelial growth factor receptor 2 (VEGFR2) to promote cell proliferation. We investigated TNFR expression in clinical samples and function in short-term organ cultures of ccRCC tissue treated with wild-type TNF or specific muteins selective for TNFR1 (R1-TNF) or TNFR2 (R2-TNF). There is a significant increase in TNFR2 but not TNFR1 expression on malignant TECs that correlates with increasing malignant grade. In ccRCC organ cultures, R1-TNF increases TNFR1, activates apoptotic signaling kinase and NF-kappaB, and promotes apoptosis in malignant TECs. R2-TNF increases TNFR2, activates NF-kappaB, Etk, and VEGFR2 and increases entry into the cell cycle. Wild-type TNF induces both sets of responses. R2-TNF actions are blocked by pretreatment with a VEGFR2 kinase inhibitor. We conclude that TNF, acting through TNFR2, is an autocrine growth factor for ccRCC acting via Etk-VEGFR2 cross-talk, insights that may provide a more effective therapeutic approach to this disease.

Managerial Representations of Achieving Competitive Advantage in Architectural Firms within the United Kingdom

Purpose - The purpose is to unearth managerial representations of achieving competitive advantage in relation to architectural firms operating within the United Kingdom (UK).
Design/Methodology/Approach - A sequential qualitative methodology is applied, underpinned by nine managerial interviews in five architectural practices; all of which are analysed using computer assisted qualitative data analysis software.
Findings - 108 representations are identified with highly rated concepts discussed in detail. Subsequently, the leading concepts include reputation, client satisfaction, fees and staff resources, among others.
Research Limitations/Implications - There are numerous studies conducted on this subject; however, there has been no research done to date documenting managerial representations within the UK on achieving competitive advantage in the context of architectural firms.
Practical Implications – The need for architectural firms to develop a competitive advantage within their market sector is ever more apparent, particularly during times of increased competitiveness.
Originality/Value – This paper fulfils a gap in knowledge by contributing to underlying research on the subject of competitive advantage, but focusing on the managerial representations, specifically within UK practices. The findings are of relevance to architects in both the UK and beyond, as well as perhaps forming the basis of identifying further research with the area.

Obsessive-compulsive symptoms and attentional bias: An eye-tracking methodology

Background and objectives: Cognitive models suggest that attentional biases are integral in the maintenance of obsessive-compulsive symptoms (OCS). Such biases have been established experimentally in anxiety disorders; however, the evidence is unclear in Obsessive Compulsive disorder (OCD). In the present study, an eye-tracking methodology was employed to explore attentional biases in relation to OCS.
Methods: A convenience sample of 85 community volunteers was assessed on OCS using the Yale-Brown Obsessive Compulsive Scale-self report. Participants completed an eye-tracking paradigm where they were exposed to OCD, Aversive and Neutral visual stimuli. Indices of attentional bias were derived from the eye-tracking data.
Results: Simple linear regressions were performed with OCS severity as the predictor and eye-tracking measures of the different attentional biases for each of the three stimuli types were the criterion variables. Findings revealed that OCS severity moderately predicted greater frequency and duration of fixations on OCD stimuli, which reflect the maintenance attentional bias. No significant results were found in support of other biases.
Limitations: Interpretations based on a non-clinical sample limit the generalisability of the conclusions, although use of such samples in OCD research has been found to be comparable to clinical populations. Future research would include both clinical and sub-clinical participants.
Conclusions: Results provide some support for the theory of maintained attention in OCD attentional biases, as opposed to vigilance theory. Individuals with greater OCS do not orient to OCD stimuli any faster than individuals with lower OCS, but once a threat is identified, these individuals allocate more attention to OCS-relevant stimuli.

Shortened Lung Clearance Index is a repeatable and sensitive test in children and adults with cystic fibrosis

Background: Lung clearance index (LCI) derived from sulfur hexafluoride (SF6) multiple breath washout (MBW) is a sensitive measure of lung disease in people with cystic fibrosis (CF). However, it can be time-consuming, limiting its use clinically. Aim: To compare the repeatability, sensitivity and test duration of LCI derived from washout to 1/30th (LCI1/30), 1/20th (LCI1/20) and 1/10th (LCI1/10) to ‘standard’ LCI derived from washout to 1/40th initial concentration (LCI1/40). Methods: Triplicate MBW test results from 30 clinically stable people with CF and 30 healthy controls were analysed retrospectively. MBW tests were performed using 0.2% SF6 and a modified Innocor device. All LCI end points were calculated using SimpleWashout software. Repeatability was assessed using coefficient of variation (CV%). The proportion of people with CF with and without abnormal LCI and forced expiratory volume in 1 s (FEV1) % predicted was compared. Receiver operating characteristic (ROC) curve statistics were calculated. Test duration of all LCI end points was compared using paired t tests. Results: In people with CF, LCI1/40 CV% (p=0.16), LCI1/30 CV%, (p=0.53), LCI1/20 CV% (p=0.14) and LCI1/10 CV% (p=0.25) was not significantly different to controls. The sensitivity of LCI1/40, LCI1/30 and LCI1/20 to the presence of CF was equal (67%). The sensitivity of LCI1/10 and FEV1% predicted was lower (53% and 47% respectively). Area under the ROC curve (95% CI) for LCI1/40, LCI1/30, LCI1/20, LCI1/10 and FEV1% predicted was 0.89 (0.80 to 0.97), 0.87 (0.77 to 0.96), 0.87 (0.78 to 0.96), 0.83 (0.72 to 0.94) and 0.73 (0.60 to 0.86), respectively. Test duration of LCI1/30, LCI1/20 and LCI1/10 was significantly shorter compared with the test duration of LCI1/40 in people with CF (p<0.0001) equating to a 5%, 9% and 15% time saving, respectively. Conclusions: In this study, LCI1/20 was a repeatable and sensitive measure with equal diagnostic performance to LCI1/40. LCI1/20 was shorter, potentially offering a more feasible research and clinical measure.

Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review

Objective: To summarise the findings of an updated Cochrane review of interventions aimed at improving the appropriate use of polypharmacy in older people. Design: Cochrane systematic review. Multiple electronic databases were searched including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (from inception to November 2013). Hand searching of references was also performed. Randomised controlled trials (RCTs), controlled clinical trials, controlled before-and-after studies and interrupted time series analyses reporting on interventions targeting appropriate polypharmacy in older people in any healthcare setting were included if they used a validated measure of prescribing appropriateness. Evidence quality was assessed using the Cochrane risk of bias tool and GRADE (Grades of Recommendation, Assessment, Development and Evaluation).
Setting: All healthcare settings. 
Participants: Older people (≥65 years) with ≥1 long-term condition who were receiving polypharmacy (≥4 regular medicines).
Primary and secondary outcome measures: Primary outcomes were the change in prevalence of appropriate polypharmacy and hospital admissions. Medication-related problems (eg, adverse drug reactions), medication adherence and quality of life were included as secondary outcomes.
Results: 12 studies were included: 8 RCTs, 2 cluster RCTs and 2 controlled before-and-after studies. 1 study involved computerised decision support and 11 comprised pharmaceutical care approaches across various settings. Appropriateness was measured using validated tools, including the Medication Appropriateness Index, Beers’ criteria and Screening Tool of Older Person’s Prescriptions (STOPP)/ Screening Tool to Alert doctors to Right Treatment (START). The interventions demonstrated a reduction in inappropriate prescribing. Evidence of effect on hospital admissions and medication-related problems was conflicting. No differences in health-related quality of life were reported.
Conclusions: The included interventions demonstrated improvements in appropriate polypharmacy based on reductions in inappropriate prescribing. However, it remains unclear if interventions resulted in clinically significant improvements (eg, in terms of hospital admissions). Future intervention studies would benefit from available guidance on intervention development, evaluation and reporting to facilitate replication in clinical practice.

Reasons for non-participation in the Northern Ireland Bowel Cancer Screening Programme: a qualitative study

OBJECTIVES: To identify the reasons why some people do not participate in bowel cancer screening so that steps can be taken to improve informed decision-making.

DESIGN: Qualitative study, using focus groups with thematic analysis of data to identify, analyse and report patterns. Transcripts were repeatedly read and inductively coded using a phenomenological perspective, and organised into key themes.

SETTING: Belfast and Armagh, two areas of Northern Ireland with relatively low uptake of bowel cancer screening.

PARTICIPANTS: Ten women and 18 men in three single-gender focus groups (two male and one female), each with 9-10 participants. Study participants were recruited by convenience sampling from the general public and were eligible for, but had not taken part in, the Northern Ireland Bowel Cancer Screening Programme.

RESULTS: Key themes identified were fear of cancer; the test procedure; social norms; past experience of cancer and screening; lack of knowledge or understanding about bowel cancer screening; and resulting behaviour towards the test. Fear about receiving bad news and reluctance to conduct the test themselves were reactions that participants seemed willing to overcome after taking part in open discussion about the test.

CONCLUSIONS: We identified barriers to participation in bowel cancer screening and used these insights to develop new materials to support delivery of the programme. Some of the issues raised have been identified in other UK settings, suggesting that knowledge about barriers, and strategies to improve uptake, may be generalisable.

Physical activity assessment in cystic fibrosis: A position statement

Background

The aim of this position statement was to inform the choice of physical activity tools for use within CF research and clinical settings.

Methods

A systematic review of physical activity tools to explore evidence for reliability, validity, and responsiveness. Narrative answers to “four key questions” on motion sensors, questionnaires and diaries were drafted by the core writing team and then discussed at the Exercise Working Group in ECFS Lisbon 2013.

Results and summary

Our current position is that activity monitors such as SenseWear or ActiGraph offer informed choices to facilitate a comprehensive assessment of physical activity, and should as a minimum report on dimensions of physical activity including energy expenditure, step count and time spent in different intensities and sedentary time. The DigiWalker pedometer offers an informed choice of a comparatively inexpensive method of obtaining some measurement of physical activity. The HAES represents an informed choice of questionnaire to assess physical activity. There is insufficient data to recommend the use of one diary over another. Future research should focus on providing additional evidence of clinimetric properties of these and new physical activity assessment tools, as well as further exploring the added value of physical activity assessment in CF.

Interventions to increase physical activity in patients with COPD: A comprehensive review

It is unknown how interventions aimed at increasing physical activity (PA), other than traditional pulmonary rehabilitation, are structured and whether they are effective in increasing PA in chronic obstructive pulmonary disease (COPD). The primary aim of this review was to outline the typical components of PA interventions in patients with COPD. This review followed the PRISMA guidelines. A structured literature search of relevant electronic databases from inception to April 2014 was undertaken to outline typical components and examine outcome variables of PA interventions in patients with COPD. Over 12000 articles were screened and 20 relevant studies involving 31 PA interventions were included. Data extracted included patient demographics, components of the PA intervention, PA outcome measures and effects of the intervention. Quality was assessed using the PEDro and CASP scales. There were 13 randomised controlled trials and three randomised trials (PEDro score 5-7/10) and four cohort studies (CASP score 5/10). Interventions varied in duration, number of participant/researcher contacts and mode of delivery. The most common behaviour change techniques included information on when and where (n = 26/31) and how (n = 22/31) to perform PA behaviour and self-monitoring (n = 18/31). Significant between-group differences post-intervention in favour of the PA intervention, compared to a control group or to other PA interventions, in one or more PA assessments were found in 7/16 studies. All seven studies used walking as the main type of PA/exercise. In conclusion, although the components of PA interventions were variable, there is some evidence that PA interventions have the potential to increase PA in patients with COPD

Is the raised volume rapid thoracic compression technique ready for use in clinical trials in infants with cystic fibrosis?

The European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) has established a Standardization Committee to undertake a rigorous evaluation of promising outcome measures with regard to use in multicentre clinical trials in cystic fibrosis (CF). The aim of this article is to present a review of literature on clinimetric properties of the infant raised-volume rapid thoracic compression (RVRTC) technique in the context of CF, to summarise the consensus amongst the group on feasibility and answer key questions regarding the promotion of this technique to surrogate endpoint status.

METHODS: A literature search (from 1985 onwards) identified 20 papers that met inclusion criteria of RVRTC use in infants with CF. Data were extracted and tabulated regarding repeatability, validity, correlation with other outcome measures, responsiveness and reference values. A working group discussed the tables and answered 4 key questions.

RESULTS: Overall, RVRTC in particular forced expiratory volume in 0.5s, showed good clinimetric properties despite presence of individual variability. Few studies showed a relationship between RVRTC and inflammation and infection, and to date, data remains limited regarding the responsiveness of RVRTC after an intervention. Concerns were raised regarding feasibility in multi-centre studies and availability of reference values.

CONCLUSION: The ECFS-CTN Working Group considers that RVRTC cannot be used as a primary outcome in clinical trials in infants with CF before universal standardization of this measurement is achieved and implementation of inter-institutional networking is in place. We advise its use currently in phase I/II trials and as a secondary endpoint in phase III studies. We emphasise the need for (1) more short-term variability and longitudinal 'natural history' studies, and (2) robust reference values for commercially available devices.

Applying the Transtheoretical Model to Physical Activity Behavior in Individuals With Non-Cystic Fibrosis Bronchiectasis

BACKGROUND: The transtheoretical model has been successful in promoting health behavior change in general and clinical populations. However, there is little knowledge about the application of the transtheoretical model to explain physical activity behavior in individuals with non-cystic fibrosis bronchiectasis. The aim was to examine patterns of (1) physical activity and (2) mediators of behavior change (self-efficacy, decisional balance, and processes of change) across stages of change in individuals with non-cystic fibrosis bronchiectasis.

METHODS: Fifty-five subjects with non-cystic fibrosis bronchiectasis (mean age ± SD = 63 ± 10 y) had physical activity assessed over 7 d using an accelerometer. Each component of the transtheoretical model was assessed using validated questionnaires. Subjects were divided into groups depending on stage of change: Group 1 (pre-contemplation and contemplation; n = 10), Group 2 (preparation; n = 20), and Group 3 (action and maintenance; n = 25). Statistical analyses included one-way analysis of variance and Tukey-Kramer post hoc tests.

RESULTS: Physical activity variables were significantly (P < .05) higher in Group 3 (action and maintenance) compared with Group 2 (preparation) and Group 1 (pre-contemplation and contemplation). For self-efficacy, there were no significant differences between groups for mean scores (P = .14). Decisional balance cons (barriers to being physically active) were significantly lower in Group 3 versus Group 2 (P = .032). For processes of change, substituting alternatives (substituting inactive options for active options) was significantly higher in Group 3 versus Group 1 (P = .01), and enlisting social support (seeking out social support to increase and maintain physical activity) was significantly lower in Group 3 versus Group 2 (P = .038).

CONCLUSIONS: The pattern of physical activity across stages of change is consistent with the theoretical predictions of the transtheoretical model. Constructs of the transtheoretical model that appear to be important at different stages of change include decisional balance cons, substituting alternatives, and enlisting social support. This study provides support to explore transtheoretical model-based physical activity interventions in individuals with non-cystic fibrosis bronchiectasis.

PTF11iqb: cool supergiant mass-loss that bridges the gap between Type IIn and normal supernovae

PTF11iqb was initially classified as a TypeIIn event caught very early after explosion. It showed narrow Wolf-Rayet (WR) spectral features on day 2, but the narrow emission weakened quickly and the spectrum morphed to resemble those of Types II-L and II-P. At late times, Halpha emission exhibited a complex, multipeaked profile reminiscent of SN1998S. In terms of spectroscopic evolution, we find that PTF11iqb was a near twin of SN~1998S, although with weaker interaction with circumstellar material (CSM) at early times, and stronger CSM interaction at late times. We interpret the spectral changes as caused by early interaction with asymmetric CSM that is quickly (by day 20) enveloped by the expanding SN ejecta photosphere, but then revealed again after the end of the plateau when the photosphere recedes. The light curve can be matched with a simple model for weak CSM interaction added to the light curve of a normal SN~II-P. This plateau requires that the progenitor had an extended H envelope like a red supergiant, consistent with the slow progenitor wind speed indicated by narrow emission. The cool supergiant progenitor is significant because PTF11iqb showed WR features in its early spectrum --- meaning that the presence of such WR features in an early SN spectrum does not necessarily indicate a WR-like progenitor. [abridged] Overall, PTF11iqb bridges SNe~IIn with weaker pre-SN mass loss seen in SNe II-L and II-P, implying a continuum between these types.

EARLY RADIO AND X-RAY OBSERVATIONS OF THE YOUNGEST NEARBY TYPE Ia SUPERNOVA PTF 11kly (SN 2011fe)

On 2011 August 24 (UT) the Palomar Transient Factory (PTF) discovered PTF11kly (SN 2011fe), the youngest and most nearby Type Ia supernova (SN Ia) in decades. We followed this event up in the radio (centimeter and millimeter bands) and X-ray bands, starting about a day after the estimated explosion time. We present our analysis of the radio and X-ray observations, yielding the tightest constraints yet placed on the pre-explosion mass-loss rate from the progenitor system of this supernova. We find a robust limit of from sensitive X-ray non-detections, as well as a similar limit from radio data, which depends, however, on assumptions about microphysical parameters. We discuss our results in the context of single-degenerate models for SNe Ia and find that our observations modestly disfavor symbiotic progenitor models involving a red giant donor, but cannot constrain systems accreting from main-sequence or sub-giant stars, including the popular supersoft channel. In view of the proximity of PTF11kly and the sensitivity of our prompt observations, we would have to wait for a long time (a decade or longer) in order to more meaningfully probe the circumstellar matter of SNe Ia.