The information specialist in the clinical team: Building expertise in evidence-based healthcare

The Clinician Development Program (CDP) is an initiative of Queensland Health’s Quality Improvement and Enhancement Program. At the Royal Brisbane & Royal Women's Hospital Health Service Districts, evidence-base practice (EBP) is an important CDP area in which several projects were carried out in 2002. This paper describes one such project. A medical librarian was invited to accompany the clinical team on morning rounds in the Medical Assessment & Planning Unit (MAPU). The librarian conducted information skills training in the ward and helped clinicians to answer questions directly related to patient care. Questions not answered during the round were followed-up, usually within 48 hours, and responses emailed to the consultant who led the rounds. At the project’s conclusion the librarian was invited to continue as a member of the MAPU clinical team, thus acknowledging the valuable role an information specialist can play in incorporating research evidence into patient care. Clinical librarianship (CL) creates a space, albeit a contentious one, for the health librarian at the bedside. This paper describes an Australian CL project and attempts to demystify the role of an information specialist in EBP. It also highlights some of the challenges facing librarians and clinicians attempting to embed EBP in clinical settings.

Developing a scalable model of recombinant protein yield from Pichia pastoris:the influence of culture conditions, biomass and induction regime

Background The optimisation and scale-up of process conditions leading to high yields of recombinant proteins is an enduring bottleneck in the post-genomic sciences. Typical experiments rely on varying selected parameters through repeated rounds of trial-and-error optimisation. To rationalise this, several groups have recently adopted the 'design of experiments' (DoE) approach frequently used in industry. Studies have focused on parameters such as medium composition, nutrient feed rates and induction of expression in shake flasks or bioreactors, as well as oxygen transfer rates in micro-well plates. In this study we wanted to generate a predictive model that described small-scale screens and to test its scalability to bioreactors. Results Here we demonstrate how the use of a DoE approach in a multi-well mini-bioreactor permitted the rapid establishment of high yielding production phase conditions that could be transferred to a 7 L bioreactor. Using green fluorescent protein secreted from Pichia pastoris, we derived a predictive model of protein yield as a function of the three most commonly-varied process parameters: temperature, pH and the percentage of dissolved oxygen in the culture medium. Importantly, when yield was normalised to culture volume and density, the model was scalable from mL to L working volumes. By increasing pre-induction biomass accumulation, model-predicted yields were further improved. Yield improvement was most significant, however, on varying the fed-batch induction regime to minimise methanol accumulation so that the productivity of the culture increased throughout the whole induction period. These findings suggest the importance of matching the rate of protein production with the host metabolism. Conclusion We demonstrate how a rational, stepwise approach to recombinant protein production screens can reduce process development time.

Design and synthesis of potential antimicrobial agents

Chorismate mutase is one of the essential enzymes in the shikimate pathway and is key to the survival of the organism Mycobacterium tuberculosis. The x-ray crystal structure of this enzyme from Mycobacterium tuberculosis was manipulated to prepare an initial set of in silico protein models of the active site. Known inhibitors of the enzyme were docked into the active site using the flexible ligand / flexible active site side chains approach implemented in CAChe Worksystem (Fujitsu Ltd). The resulting complexes were refined by molecular dynamics studies in explicit water using Amber 9. This yielded a further set of protein models that were used for additional rounds of ligand docking. A binding hypothesis was established for the enzyme and this was used to screen a database of commercially available drug-like compounds. From these results new potential ligands were designed that fitted appropriately into the active site and matched the functional groups and binding motifs founds therein. Some of these compounds and close analogues were then synthesized and submitted for biological evaluation. As a separate part of this thesis, analogues of very active anti-tuberculosis pyridylcarboxamidrazone were also prepared. This was carried out by the addition and the deletion of the substitutions from the lead compound thereby preparing heteroaryl carboxamidrazone derivatives and related compounds. All these compounds were initially evaluated for biological activity against various gram positive organisms and then sent to the TAACF (USA) for screening against Mycobacterium tuberculosis. Some of the new compounds proved to be at least as potent as the original lead compound but less toxic.

Altering the ribosomal subunit ratio in yeast maximizes recombinant protein yield

Background The production of high yields of recombinant proteins is an enduring bottleneck in the post-genomic sciences that has yet to be addressed in a truly rational manner. Typically eukaryotic protein production experiments have relied on varying expression construct cassettes such as promoters and tags, or culture process parameters such as pH, temperature and aeration to enhance yields. These approaches require repeated rounds of trial-and-error optimization and cannot provide a mechanistic insight into the biology of recombinant protein production. We published an early transcriptome analysis that identified genes implicated in successful membrane protein production experiments in yeast. While there has been a subsequent explosion in such analyses in a range of production organisms, no one has yet exploited the genes identified. The aim of this study was to use the results of our previous comparative transcriptome analysis to engineer improved yeast strains and thereby gain an understanding of the mechanisms involved in high-yielding protein production hosts. Results We show that tuning BMS1 transcript levels in a doxycycline-dependent manner resulted in optimized yields of functional membrane and soluble protein targets. Online flow microcalorimetry demonstrated that there had been a substantial metabolic change to cells cultured under high-yielding conditions, and in particular that high yielding cells were more metabolically efficient. Polysome profiling showed that the key molecular event contributing to this metabolically efficient, high-yielding phenotype is a perturbation of the ratio of 60S to 40S ribosomal subunits from approximately 1:1 to 2:1, and correspondingly of 25S:18S ratios from 2:1 to 3:1. This result is consistent with the role of the gene product of BMS1 in ribosome biogenesis. Conclusion This work demonstrates the power of a rational approach to recombinant protein production by using the results of transcriptome analysis to engineer improved strains, thereby revealing the underlying biological events involved.

The impact of the post-1993 economic reforms on Chinese state-owned enterprises:evidence from the electronics industry

Since 1979, China has embarked on a series of economic reform programmes, leading its socialist economy away from a Soviet planning model towards a much greater reliance on the market. In the course of the last twenty years, the Chinese economy has enjoyed a phenomenally high economic growth rate. However, earlier research suggests that Chinese state-owned enterprises remain a financial 'black hole' for the Chinese economy, in spite of various enterprise reform measures. This thesis tries to assess the impact of the reforms after 1993, especially the so-called Modern Enterprise System, on the behaviour and management practices of state firms. The central research question is whether the new rounds of economic reform have changed state firms into commercial entities operating according to market signals, as intended. In order to explore this question, an institutional approach is employed. More specifically, the thesis examines how the behaviour and management practices of state enterprises have changed with changes in the institutional environmental resulting from the introduction of new reform measures and especially the MES. The main evidence used in this research comes from the Chinese electronics industry (CEI). Non-state firms, namely collectives and joint ventures, are involved in the study to provide a benchmark against which changes in the behaviour of state firms in the mid and late 1990s are compared. A comparative statistical analysis shows that state-owned firms, both traditional and corporatised ones, still lag behind collectives and joint ventures in terms of both labour and total factor productivity. The further empirical work of this research consists of a questionnaire survey and case studies that are based on interviews with senior managers of 17 firms in the CEI. The findings of these analyses suggest that there has been little fundamental change in the behaviour pattern of state firms in the 1990s, despite the introduction of the Modern Enterprise System, and that the economic reforms after 1993 so far seem to have failed to transform the state firms into commercial entities operating according to market signals.

The effectiveness of an innovative intervention aimed at reducing binge drinking among young people:results from a pilot study

Aims: To assess the effectiveness of a digital-story intervention (short videos made by young people) seeking to reduce the prevalence of young people's binge drinking in Caerphilly. Method: A quasi-experimental design was adopted with three intervention sites and one control site providing the sample (mainly aged 1415 years). Three rounds of self-completion questionnaires, completed prior (T1), immediately after (T2) and 6 months after the intervention (T3). Findings: A total of 1031 questionnaires completed across the three time-points. Two-factor ANOVAs revealed a positive effect on knowledge for the intervention sample. The intervention group results showed stable attitudes towards drinking at the three time-points whilst the control group showed increasing positive attitudes towards drunkenness over the same time period. Intentions towards drunkenness were higher in the control group than the intervention group at T2 (ControlT1 Mean 3.37, T2 Mean 3.90; interventionT1 Mean 3.26, T2 Mean 3.29). Intervention participants got drunk on fewer occasions in the last week (mean occasions last week 1.57) compared to control participants (mean occasions last week 2.00), with the difference approaching statistical significance (F 1.90, p 0.07). Conclusions: Promoting negative attitudes towards drunkenness, alongside a greater sense of control and potential regret about drunkenness are likely to be important factors when considering how to change people's intentions to drink. The study shows the potential to reduce the frequency of drinking behaviour when intentions are changed, and provides recommendations for future interventions of this nature. © 2010 Informa UK Ltd.

Relieving the first bottleneck in the drug discovery pipeline:using array technologies to rationalize membrane protein production

The slow down in the drug discovery pipeline is, in part, owing to a lack of structural and functional information available for new drug targets. Membrane proteins, the targets of well over 50% of marketed pharmaceuticals, present a particular challenge. As they are not naturally abundant, they must be produced recombinantly for the structural biology that is a prerequisite to structure-based drug design. Unfortunately, however, obtaining high yields of functional, recombinant membrane proteins remains a major bottleneck in contemporary bioscience. While repeated rounds of trial-and-error optimization have not (and cannot) reveal mechanistic details of the biology of recombinant protein production, examination of the host response has provided new insights. To this end, we published an early transcriptome analysis that identified genes implicated in high-yielding yeast cell factories, which has enabled the engineering of improved production strains. These advances offer hope that the bottleneck of membrane protein production can be relieved rationally.

A sequential mechanism for clathrin cage disassembly by 70-kDa heat-shock cognate protein (Hsc70) and auxilin

An essential stage in endocytic coated vesicle recycling is the dissociation of clathrin from the vesicle coat by the molecular chaperone, 70-kDa heat-shock cognate protein (Hsc70), and the J-domain-containing protein, auxilin, in an ATP-dependent process. We present a detailed mechanistic analysis of clathrin disassembly catalyzed by Hsc70 and auxilin, using loss of perpendicular light scattering to monitor the process. We report that a single auxilin per clathrin triskelion is required for maximal rate of disassembly, that ATP is hydrolyzed at the same rate that disassembly occurs, and that three ATP molecules are hydrolyzed per clathrin triskelion released. Stopped-flow measurements revealed a lag phase in which the scattering intensity increased owing to association of Hsc70 with clathrin cages followed by serial rounds of ATP hydrolysis prior to triskelion removal. Global fit of stopped-flow data to several physically plausible mechanisms showed the best fit to a model in which sequential hydrolysis of three separate ATP molecules is required for the eventual release of a triskelion from the clathrin-auxilin cage.

Internationalization in a business school:co-existing and entwined professional and organizational narratives

This empirical paper adopts a narrative approach to explain how a strategic goal of internationalization within a UK business school developed over a three year period and in particular how two conflicting institutional logics - a market logic and a professional logic - were given meaning and played out within a specific organizational context. The paper is in four parts. First, the theoretical framework explains the business school as characteristic of a professional organization, with a professional academic workforce, ambiguous strategic goals and multiple competing but legitimate demands. We then frame our methodological approach of narrative as a means of understanding how professional actors are co-opted into enabling organizational goals, even where these are perceived as antithetical to professional interests. We do this by showing how actors within organizations that exist with multiple, potentially competing institutional logics draw upon those logics and embed them in narratives to give meaning to their actions. Second, the research design, which followed the pursuit of an internationalization goal within a UK business school over three years, based on a dataset of three rounds of interviews, documentary analysis and meeting observations is explained, showing how we used a narrative approach for analysis. Third the results are presented as a series of co-existing and entwined narratives: organizational/managerial narratives, professional narratives of resistance, and professional narratives of engagement. Finally our findings show that narrative is a useful theoretical lens for explaining how multiple, ambiguous and conflicting strategic goals within professional organizations may coexist, enabling the organization to act both as a collective unit and also to fulfil the sometimes contradictory professional interests of its constituents. These findings contribute to understanding about strategy in professional organizations and also to narrative theory by showing how organizations may comprise multiple, entwined narratives, in which actors change roles according to their varying interests in the 'central' narrative.

Marine Le Pen and the 'New' FN:a change of style or of substance?

The electoral challenge of the far right is an enduringly problematic feature of contemporary French politics. In the first rounds of the 2012 presidential and parliamentary elections, the Front National (FN) under new leader Marine Le Pen attracted a combined total of ten million votes, bringing its ultra-nationalist policies to the centre of national political debate. This article examines the FN's impact on these elections and its implications for French politics. Drawing on official FN programmes, detailed election results and a range of opinion polling data, it assesses the strength of support for Le Pen and her party and seeks to explain their electoral appeal. In particular, it subjects to analysis the claim that the new leader has ‘de-demonised’ the FN, transforming it from perennial outsider to normal participant in mainstream French politics; and it reflects on the strategic dilemma posed for the centre-right by this newly invigorated far-right challenge.

Physicians' perceptions, attitudes and expectations regarding the role of hospital-based pharmacists in the West Bank, Palestine

Objective - To evaluate the perceptions, expectations and experiences of physicians with regard to hospital-based pharmacists in the West Bank, Palestine. Methods - A self-administered questionnaire was distributed to 250 physicians practising in four general hospitals in the West Bank, Palestine. The main sections of the questionnaire comprised a series of statements pertaining to physicians' perceptions, expectations and experiences with pharmacists. Key findings - One hundred and fifty seven questionnaires were completed and returned (response rate, 62.8%). The majority of respondents were most comfortable with pharmacists detecting and preventing prescription errors (76.4%; 95% confidence interval (CI) 69.5–81.2%) and patient education (57.9%; CI 51.2–63.4%) but they were not comfortable with pharmacists suggesting the use of prescription medications to patients (56.7%; CI 49.8–62.4%). Most physicians (62.4%; CI 56.8–69.1%) expected the pharmacist to educate their patients about the safe and appropriate use of their medication. However, approximately one-third (31.7%; CI 26.0–39.6%) did not expect pharmacists to be available for consultation during rounds. Physicians' experiences with pharmacists were less favourable; whereas 77% (CI 70.2–81.5%) of the physicians agreed that pharmacists were always a reliable source of information, only 11.5% (CI 6.2–16.4%) agreed that pharmacists appeared to be willing to take responsibility for solving any drug-related problems. Conclusion -The present study showed that hospital physicians are more likely to accept traditional pharmacy services than newer clinical services for hospital-based pharmacists in the West Bank, Palestine. Pharmacists should therefore interact more positively and more frequently with physicians. This will close the gap between the physicians' commonly held perceptions of what they expect pharmacists to do and what pharmacists can actually do, and gain support for an extended role of hospital-based pharmacists in future patient therapy management.

Microarray-formatted clinical biomarker assay development using peptide aptamers to anterior gradient-2

Anterior gradient-2 protein was identified using proteomic technologies as a p53 inhibitor which is overexpressed in human cancers, and this protein presents a novel pro-oncogenic target with which to develop diagnostic assays for biomarker detection in clinical tissue. Combinatorial phage-peptide libraries were used to select 12 amino acid polypeptide aptamers toward anterior gradient-2 to determine whether methods can be developed to affinity purify the protein from clinical biopsies. Selecting phage aptamers through four rounds of screening on recombinant human anterior gradient-2 protein identified two classes of peptide ligand that bind to distinct epitopes on anterior gradient-2 protein in an immunoblot. Synthetic biotinylated peptide aptamers bound in an ELISA format to anterior gradient-2, and substitution mutagenesis further minimized one polypeptide aptamer to a hexapeptide core. Aptamers containing this latter consensus sequence could be used to affinity purify to homogeneity human anterior gradient-2 protein from a single clinical biopsy. The spotting of a panel of peptide aptamers onto a protein microarray matrix could be used to quantify anterior gradient-2 protein from crude clinical biopsy lysates, providing a format for quantitative screening. These data highlight the utility of peptide combinatorial libraries to acquire rapidly a high-affinity ligand that can selectively bind a target protein from a clinical biopsy and provide a technological approach for clinical biomarker assay development in an aptamer microarray format.

Construction project control in the UK:current practice, existing problems and recommendations for future improvement

The aim of this study is to address the main deficiencies with the prevailing project cost and time control practices for construction projects in the UK. A questionnaire survey was carried out with 250 top companies followed by in-depth interviews with 15 experienced practitioners from these companies in order to gain further insights of the identified problems, and their experience of good practice on how these problems can be tackled. On the basis of these interviews and syntheses with literature, a list of 65 good practice recommendations have been developed for the key project control tasks: planning, monitoring, reporting and analysing. The Delphi method was then used, with the participation of a panel of 8 practitioner experts, to evaluate these improvement recommendations and to establish their degree of relevance. After two rounds of Delphi, these recommendations are put forward as "critical", "important", or "helpful" measures for improving project control practice.

Departmental elections and the changing landscape of French politics

The departmental elections of March 2015 redrew the French political landscape, setting the new terms of electoral competition in advance of the regional elections of December 2015 and, more critically, the presidential election of April–May 2017. These elections saw the far-right National Front (FN) come top in both rounds only to be outmanoeuvred by the mainstream parties and prevented from winning a single department. As a case study in vote–seat distortion, the elections highlighted a voting system effective in keeping the FN out of executive power but deficient in terms of democratic representation and inadequate as a response to the new tripartite realities of France's changing political landscape.

Recreational Foodservice management: A Delphi study of needed competencies

The purpose of this study was to identify the needed competencies of a Recreational Foodservice manager. A three round Delphi method of iteration was used. Delphi is a research method that utilizes iterating rounds to elicit the opinion of a panel of experts regarding a specific subject.^ A nominating committee of 22 industry leaders was consulted to establish a panel of 40 management experts, of which 35 (87.5%) completed all three rounds of the Delphi study.^ Round One of the study identified 17 specific job functions of a Recreational Foodservice manager. The researcher prepared an instrument detailing 60 competencies derived from an analysis of Round One results and distributed it as a Round Two instrument requesting the panel opinion regarding the relative importance of each listed competency on a five point Likert scale.^ The results of Round Two were tabulated and analyzed to ascertain areas of consensus. A Round Three instrument was prepared advising panelists of all areas of consensus, their dissenting opinions, if any, and a request for a revised opinion.^ A final report was prepared listing the 60 competencies and the panel opinion that eight were of highest priority, 29 of above average priority, and 23 of average priority. No item received two other available ratings, below average priority and lowest priority.^ The implications of these findings suggest necessary areas of curriculum development and industry management development to implement professionalism for Recreational Foodservice managers. ^