A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

Arduous implementation: Does the Normalisation Process Model explain why it's so difficult to embed decision support technologies for patients in routine clinical practice

Background: decision support technologies (DSTs, also known as decision aids) help patients and professionals take part in collaborative decision-making processes. Trials have shown favorable impacts on patient knowledge, satisfaction, decisional conflict and confidence. However, they have not become routinely embedded in health care settings. Few studies have approached this issue using a theoretical framework. We explained problems of implementing DSTs using the Normalization Process Model, a conceptual model that focuses attention on how complex interventions become routinely embedded in practice.Methods: the Normalization Process Model was used as the basis of conceptual analysis of the outcomes of previous primary research and reviews. Using a virtual working environment we applied the model and its main concepts to examine: the 'workability' of DSTs in professional-patient interactions; how DSTs affect knowledge relations between their users; how DSTs impact on users' skills and performance; and the impact of DSTs on the allocation of organizational resources.Results: conceptual analysis using the Normalization Process Model provided insight on implementation problems for DSTs in routine settings. Current research focuses mainly on the interactional workability of these technologies, but factors related to divisions of labor and health care, and the organizational contexts in which DSTs are used, are poorly described and understood.Conclusion: the model successfully provided a framework for helping to identify factors that promote and inhibit the implementation of DSTs in healthcare and gave us insights into factors influencing the introduction of new technologies into contexts where negotiations are characterized by asymmetries of power and knowledge. Future research and development on the deployment of DSTs needs to take a more holistic approach and give emphasis to the structural conditions and social norms in which these technologies are enacte

Blurred digital mammography images : an analysis of technical recall and observer detection performance

Background: Blurred images in Full Field Digital Mammography (FFDM) are a problem in the UK Breast Screening Programme. Technical recalls may be due to blurring not being seen on lower resolution monitors used for review. Objectives: This study assesses the visual detection of blurring on a 2.3 megapixel (MP) monitor and a 5 MP report grade monitor and proposes an observer standard for the visual detection of blurring on a 5 MP reporting grade monitor. Method: Twenty-eight observers assessed 120 images for blurring; 20 had no blurring present whilst 100 had blurring imposed through mathematical simulation at 0.2, 0.4, 0.6, 0.8 and 1.0 mm levels of motion. Technical recall rate for both monitors and angular size at each level of motion were calculated. Chi-squared (X2) tests were used to test whether significant differences in blurring detection existed between 2.3 and 5 MP monitors. Results: The technical recall rate for 2.3 and 5 MP monitors are 20.3 % and 9.1% respectively. Angular size for 0.2 to 1 mm motion varied from 55 to 275 arc seconds. The minimum amount of motion for visual detection of blurring in this study is 0.4 mm. For 0.2 mm simulated motion, there was no significant difference X2 (1, N=1095) =1.61, p=0.20) in blurring detection between the 2.3 and 5 MP monitors. Conclusion: According to this study monitors equal or below 2.3 MP are not suitable for technical review of FFDM images for the detection of blur. Advances in knowledge: This research proposes the first observer standard for the visual detection of blurring. Key words: Simulated motion; technical recall; monitor resolution; observer standard; blurring detectio

The effects of an afterschool STEM program on students’ motivation and engagement

Background: One significant factor in facilitating students’ career intentions and persistence in STEM (science, technology, engineering, and mathematics) fields is targeting their interests and motivation before eighth grade. To reach students at this critical stage, a design-based afterschool STEM program, titled Studio STEM, was implemented to foster motivation and engagement in STEM topics and activities. The purpose of this study is twofold: (a) to investigate how Studio STEM affected students’ beliefs about science and whether these beliefs differed from their peers who did not participate in the program, and (b) to examine a case study of one Studio STEM implementation to investigate elements of the curriculum that motivated students to engage in the program. Results: After completing two Studio STEM programs, participants’ ratings of their values for science and science competence were higher than those of non participants. In addition, the Studio STEM participants’ motivational beliefs about science and intentions to pursue a college degree were more resilient over time than their peers. We also found that students could be motivated in a voluntary afterschool program (Studio STEM) in which they grappled with STEM concepts and activities, and could verbalize specific program elements that motivated them. Conclusions: Through this study, we found that students could be motivated in Studio STEM and that the experience had a positive impact on their perceptions about science as a field. Importantly, Studio STEM appeared to halt the decline in these students’ motivational beliefs about science that typically occurs during the middle school years, indicating that after school programs can be one way to help students maintain their motivation in science. Studying the program features that the students found motivating may help educators to make connections between research and theory, and their classroom instruction to motivate their students.ECU Open Access Publishing Support Fun

Articulating ‘public interest’ through complexity theory

The ‘Public interest’, even if viewed with ambiguity or scepticism, has been one of the primary means by which various professional roles of planners have been justified. Many objections to the concept have been advanced by writers in planning academia. Notwithstanding these, ‘public interest’ continues to be mobilised, to justify, defend or argue for planning interventions and reforms. This has led to arguments that planning will have to adopt and recognise some form of public interest in practice to legitimise itself.. This paper explores current debates around public interest and social justice and advances a vision of the public interest informed by complexity theory. The empirical context of the paper is the poverty alleviation programme, the Kudumbashree project in Kerala, India

Is social stress in the first half of life detrimental to later physical and mental health in both men and women?

This study examined gender differences in the associations between affection- and status-related stressors encountered in the first half of life and physical and mental health problems later on. Based on the theory of Social Production Functions (SPF) two hypotheses have been formulated, which were tested in a representative sample of 446 men and 514 women (aged 40–79). Main outcome measures were number of chronic somatic diseases and level of psychological distress. As expected, regression analyses showed no gender differences in the associations between affection-related stressors and physical and mental health problems later on. In contrast, but as also expected, status-related stressors encountered in the first half of life were associated with later physical and mental health for men only. It is concluded that the gender differences in the associations between earlier social stressors and later health problems may be more complex than the common assumption that men are only affected by status stress and women only by affection stress. This study contributes to the knowledge on gender differences concerning the link between social stress and health, and it indicates that social experiences encountered earlier in life are of importance for being healthy and happy in later life

Beyond price: individuals' accounts of deciding to pay for private healthcare treatment in the UK

<p>Abstract</p> <p>Background</p> <p>Delivering appropriate and affordable healthcare is a concern across the globe. As countries grapple with the issue of delivering healthcare with finite resources and populations continue to age, more health-related care services or treatments may become an optional 'extra' to be purchased privately. It is timely to consider how, and to what extent, the individual can act as both a 'patient' and a 'consumer'. In the UK the majority of healthcare treatments are free at the point of delivery. However, increasingly some healthcare treatments are being made available via the private healthcare market. Drawing from insights from healthcare policy and social sciences, this paper uses the exemplar of private dental implant treatment provision in the UK to examine what factors people considered when deciding whether or not to pay for a costly healthcare treatment for a non-fatal condition.</p> <p>Methods</p> <p>Qualitative interviews with people (n = 27) who considered paying for dental implants treatments in the UK. Data collection and analysis processes followed the principles of the constant comparative methods, and thematic analysis was facilitated through the use of NVivo qualitative data software.</p> <p>Results</p> <p>Decisions to pay for private healthcare treatments are not simply determined by price. Decisions are mediated by: the perceived 'status' of the healthcare treatment as either functional or aesthetic; how the individual determines and values their 'need' for the treatment; and, the impact the expenditure may have on themselves and others. Choosing a private healthcare provider is sometimes determined simply by personal rapport or extant clinical relationship, or based on the recommendation of others.</p> <p>Conclusions</p> <p>As private healthcare markets expand to provide more 'non-essential' services, patients need to develop new skills and to be supported in their new role as consumers.</p

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research