Selective loss of TGFbeta Smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines.

In cancer, Transforming Growth Factor beta (TGFbeta) increases proliferation and promotes invasion via selective loss of signalling pathways. Oesophageal adenocarcinoma arises from Barrett's oesophagus, progresses rapidly and is usually fatal. The contribution of perturbed TGFbeta signalling in the promotion of metastasis in this disease has not been elucidated. We therefore investigated the role of TGFbeta in Barrett's associated oesophageal adenocarcinoma using a panel of cell lines (OE33, TE7, SEG, BIC, FLO). 4/5 adenocarcinoma cell lines failed to cell cycle arrest, down-regulate c-Myc or induce p21 in response to TGFbeta, and modulation of a Smad3/4 specific promoter was inhibited. These hyperproliferative adenocarcinoma cell lines displayed a TGFbeta induced increase in the expression of the extracellular matrix degrading proteinases, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1), which correlated with an invasive cell phenotype as measured by in vitro migration, invasion and cell scattering assays. Inhibiting ERK and JNK pathways significantly reduced PAI and uPA induction and inhibited the invasive cell phenotype. These results suggest that TGFbeta Smad-dependent signalling is perturbed in Barrett's carcinogenesis, resulting in failure of growth-arrest. However, TGFbeta can promote PAI and uPA expression and invasion through MAPK pathways. These data would support a dual role for TGFbeta in oesophageal adenocarcinoma

Influential factors of aligning Spotify squads in mission-critical and offshore projects – a longitudinal embedded case study

Changing the development process of an organization is one of the toughest and riskiest decisions. This is particularly true if the known experiences and practices of the new considered ways of working are relative and subject to contextual assumptions. Spotify engineering culture is deemed as a new agile software development method which increasingly attracts large-scale organizations. The method relies on several small cross-functional self-organized teams (i.e., squads). The squad autonomy is a key driver in Spotify method, where a squad decides what to do and how to do it. To enable effective squad autonomy, each squad shall be aligned with a mission, strategy, short-term goals and other squads. Since a little known about Spotify method, there is a need to answer the question of: How can organizations work out and maintain the alignment to enable loosely coupled and tightly aligned squads? In this paper, we identify factors to support the alignment that is actually performed in practice but have never been discussed before in terms of Spotify method. We also present Spotify Tailoring by highlighting the modified and newly introduced processes to the method. Our work is based on a longitudinal embedded case study which was conducted in a real-world large-scale offshore software intensive organization that maintains mission-critical systems. According to the confidentiality agreement by the organization in question, we are not allowed to reveal a detailed description of the features of the explored project

Understanding innovators' experiences of barriers and facilitators in implementation and diffusion of healthcare service innovations: A qualitative study

This article is made available through the Brunel Open Access Publishing Fund - Copyright @ 2011 Barnett et al.Background: Healthcare service innovations are considered to play a pivotal role in improving organisational efficiency and responding effectively to healthcare needs. Nevertheless, healthcare organisations encounter major difficulties in sustaining and diffusing innovations, especially those which concern the organisation and delivery of healthcare services. The purpose of the present study was to explore how healthcare innovators of process-based initiatives perceived and made sense of factors that either facilitated or obstructed the innovation implementation and diffusion. Methods: A qualitative study was designed. Fifteen primary and secondary healthcare organisations in the UK, which had received health service awards for successfully generating and implementing service innovations, were studied. In-depth, semi structured interviews were conducted with the organisational representatives who conceived and led the development process. The data were recorded, transcribed and thematically analysed. Results: Four main themes were identified in the analysis of the data: the role of evidence, the function of inter-organisational partnerships, the influence of human-based resources, and the impact of contextual factors. "Hard" evidence operated as a proof of effectiveness, a means of dissemination and a pre-requisite for the initiation of innovation. Inter-organisational partnerships and people-based resources, such as champions, were considered an integral part of the process of developing, establishing and diffusing the innovations. Finally, contextual influences, both intra-organisational and extra-organisational were seen as critical in either impeding or facilitating innovators' efforts. Conclusions: A range of factors of different combinations and co-occurrence were pointed out by the innovators as they were reflecting on their experiences of implementing, stabilising and diffusing novel service initiatives. Even though the innovations studied were of various contents and originated from diverse organisational contexts, innovators' accounts converged to the significant role of the evidential base of success, the inter-personal and inter-organisational networks, and the inner and outer context. The innovators, operating themselves as important champions and being often willing to lead constructive efforts of implementation to different contexts, can contribute to the promulgation and spread of the novelties significantly.This research was supported financially by the Multidisciplinary Assessment of Technology Centre for Healthcare (MATCH)

Phase manipulation and the harmonic components of ringing forces on a surface-piercing column

The Stokes-type expansion for the hydrodynamic force on a column in a regular wave can be written to 4th order as φφφφφφ 2coscos4cos3cos2coscos 44233122044433322211 afafafafafafafF ++++++= where the coefficients f represent wave to force transfer functions (including implicit phase shifts) and a is the incoming linear wave amplitude. Note the structure of the terms multiplying coefficients such as f33 where the power of the amplitude term is the same as the frequency harmonic (here both 3), and the terms multiplying terms such as f42 where the power of the amplitude is greater than that of the frequency harmonic by 2. In the notation of Stokes expansions, these correspond to sum and difference components respectively. For ringing we are mostly concerned with the sum harmonics. Whilst these individual harmonic components are easy to extract for regular wave forcing, this is much more difficult for broadbanded waves trains, either random or wave groups, where the simple Stokes terms are replaced by summations of products of linear terms and each net higher harmonic contributes across an increasingly broad range of frequencies. There are then strict limits as to what can be achieved by simple frequency filtering. Here we are concerned with the nonlinear force components generated by isolated compact wave group

Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science

Abstract Background Many interventions found to be effective in health services research studies fail to translate into meaningful patient care outcomes across multiple contexts. Health services researchers recognize the need to evaluate not only summative outcomes but also formative outcomes to assess the extent to which implementation is effective in a specific setting, prolongs sustainability, and promotes dissemination into other settings. Many implementation theories have been published to help promote effective implementation. However, they overlap considerably in the constructs included in individual theories, and a comparison of theories reveals that each is missing important constructs included in other theories. In addition, terminology and definitions are not consistent across theories. We describe the Consolidated Framework For Implementation Research (CFIR) that offers an overarching typology to promote implementation theory development and verification about what works where and why across multiple contexts. Methods We used a snowball sampling approach to identify published theories that were evaluated to identify constructs based on strength of conceptual or empirical support for influence on implementation, consistency in definitions, alignment with our own findings, and potential for measurement. We combined constructs across published theories that had different labels but were redundant or overlapping in definition, and we parsed apart constructs that conflated underlying concepts. Results The CFIR is composed of five major domains: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation. Eight constructs were identified related to the intervention (e.g., evidence strength and quality), four constructs were identified related to outer setting (e.g., patient needs and resources), 12 constructs were identified related to inner setting (e.g., culture, leadership engagement), five constructs were identified related to individual characteristics, and eight constructs were identified related to process (e.g., plan, evaluate, and reflect). We present explicit definitions for each construct. Conclusion The CFIR provides a pragmatic structure for approaching complex, interacting, multi-level, and transient states of constructs in the real world by embracing, consolidating, and unifying key constructs from published implementation theories. It can be used to guide formative evaluations and build the implementation knowledge base across multiple studies and settings.http://deepblue.lib.umich.edu/bitstream/2027.42/78272/1/1748-5908-4-50.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/2/1748-5908-4-50-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/3/1748-5908-4-50-S3.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/4/1748-5908-4-50-S4.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/5/1748-5908-4-50.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/6/1748-5908-4-50-S2.PDFPeer Reviewe

Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus

abstract: Surveillance of Barrett’s oesophagus allows us to study the evolutionary dynamics of a human neoplasm over time. Here we use multicolour fluorescence in situ hybridization on brush cytology specimens, from two time points with a median interval of 37 months in 195 non-dysplastic Barrett's patients, and a third time point in a subset of 90 patients at a median interval of 36 months, to study clonal evolution at single-cell resolution. Baseline genetic diversity predicts progression and remains in a stable dynamic equilibrium over time. Clonal expansions are rare, being detected once every 36.8 patient years, and growing at an average rate of 1.58 cm[superscript 2] (95% CI: 0.09–4.06) per year, often involving the p16 locus. This suggests a lack of strong clonal selection in Barrett’s and that the malignant potential of ‘benign’ Barrett’s lesions is predetermined, with important implications for surveillance programs.The final version of this article, as published in Nature Communications, can be viewed online at: https://www.nature.com/articles/ncomms1215

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Improving the sensitivity of the hop index in patients with an ACL deficient knee by transforming the hop distance scores

BACKGROUND: The one leg hop for distance is one of the most commonly employed functional tests utilized in the evaluation of the ACL deficient and reconstructed patient. While the reliability of the hop test scores has been well established, validity studies have revealed low sensitivity rates in detecting functional limitations using the hop index (the ratio or percentage of limb performance). However, the impact of the inherent limitations associated with the hop index have not been investigated to date. One specific limitation relates to the impact of the differences in the underlying hop distance scores. Therefore, this pilot study set out to determine: 1) the impact that between limb differences in hop distance has on the sensitivity of the hop index in detecting functional limitations and; 2) whether a logarithmic transformation of the underlying hop distance scores improves the sensitivity of the hop index. METHODS: A cross sectional design involving the evaluation of one leg hop for distance performance in a consecutive sample of 10 ACL deficient males with an isolated ACL tear awaiting reconstructive surgery and nine gender, age-matched controls. RESULTS: In the ACL deficient, the hop index was associated with the distance hopped on the non-injured limb (r = -0.66, p = 0.04) but not on the injured limb. Transformation (logarithmic) of the hop distance scores and re-calculation of the hop index using the transformed scores increased the sensitivity of the hop index in the detection of functional limitations from 20 to 60% and 50 to 70% using the normal limb symmetry reference norms of ≥ 85% and 90% respectively. CONCLUSION: The distance hopped on the non-injured limb is a critical factor in detecting functional limitations using the hop index in patients with an ACL deficient knee. Logarithmic transformation of the hop distance scores minimizes the effect of the arithmetic differences between limbs however; the sensitivity of the hop index in detecting abnormal limb symmetry remains low

Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis

Background: Although meta-analyses have shown that placebo responses are large in Major Depressive Disorder (MDD) trials; the placebo response of devices such as repetitive transcranial magnetic stimulation (rTMS) has not been systematically assessed. We proposed to assess placebo responses in two categories of MDD trials: pharmacological (antidepressant drugs) and non-pharmacological (device- rTMS) trials. Methodology/Principal Findings: We performed a systematic review and meta-analysis of the literature from April 2002 to April 2008, searching MEDLINE, Cochrane, Scielo and CRISP electronic databases and reference lists from retrieved studies and conference abstracts. We used the keywords placebo and depression and escitalopram for pharmacological studies; and transcranial magnetic stimulation and depression and sham for non-pharmacological studies. All randomized, double-blinded, placebo-controlled, parallel articles on major depressive disorder were included. Forty-one studies met our inclusion criteria - 29 in the rTMS arm and 12 in the escitalopram arm. We extracted the mean and standard values of depression scores in the placebo group of each study. Then, we calculated the pooled effect size for escitalopram and rTMS arm separately, using Cohen's d as the measure of effect size. We found that placebo response are large for both escitalopram (Cohen's d - random-effects model - 1.48; 95%C.I. 1.26 to 1.6) and rTMS studies (0.82; 95%C.I. 0.63 to 1). Exploratory analyses show that sham response is associated with refractoriness and with the use of rTMS as an add-on therapy, but not with age, gender and sham method utilized. Conclusions/Significance: We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself

Experiences of the implementation of a tool for lifestyle intervention in primary health care: a qualitative study among managers and professional groups

<p>Abstract</p> <p>Background</p> <p>In recent years there has been increasing interest in transferring new knowledge into health care practices, a process often referred to as implementation. The various subcultures that exist among health care workers may be an obstacle in this process. The aim of this study was to explore how professional groups and managers experienced the implementation of a new tool for lifestyle intervention in primary health care (PHC). The computer-based tool was introduced with the intention of facilitating the delivery of preventive services.</p> <p>Methods</p> <p>Focus group interviews with staff and individual interviews with managers at six PHC units in the southeast of Sweden were performed 9 months after the introduction of the new working tool. Staff interviews were conducted in groups according to profession, and were analysed using manifest content analysis. Experiences and opinions from the different staff groups and from managers were analysed.</p> <p>Results</p> <p>Implementation preconditions, opinions about the lifestyle test, and opinions about usage were the main areas identified. In each of the groups, managers and professionals, factors related to the existing subcultures seemed to influence their experiences of the implementation. Managers were visionary, GPs were reluctant, nurses were open, and nurse assistants were indifferent.</p> <p>Conclusion</p> <p>This study indicates that the existing subcultures in PHC influence how the implementation of an innovation is perceived by managers and the different professionals. In PHC, an organization with several subcultures and an established hierarchical structure, an implementation strategy aimed at all groups did not seem to result in a successful uptake of the new method.</p