Improving the precision of search strategies for guideline surveillance.

INTRODUCTION AND AIM: NICE guideline surveillance determines whether previously published guidelines need updating. The surveillance process must balance time constraints with methodological rigor. It includes a rapid review to identify new evidence to contradict, reinforce or clarify guideline recommendations. Despite this approach, the screening burden can still be high. Applying additional search techniques may increase the precision of the database searches. METHODS: A retrospective analysis was conducted on five surveillance reviews with less than 2% of the studies included after screening. Modified searches were run in MEDLINE, Embase and PsycINFO (where appropriate) to test the impact of additional search techniques: focused subject headings, subheadings, frequency operators and title only searches. Modified searches were compared to original search results to determine: the retrieval of included studies, the precision of the search and the number needed to read. Studies not retrieved by the modified search were checked to determine if the surveillance decision would have been affected. RESULTS: The additional search techniques tested indicated that a combination of focused subject headings and frequency operators could improve the precision of surveillance searches. The modified search retrieved all the original studies included in the surveillance review for three of the reviews tested. Some of the original included studies were not retrieved for two reviews but the missing studies would not have affected the surveillance decision. CONCLUSIONS: Combining focused subject headings and frequency operators is a viable option for improving the precision of surveillance searches without compromising recall and without impacting the surveillance decision.

NICE update NICE public health guidance update.

This article covers recently published National Institute for Health and Care Excellence (NICE) guidance relevant to public health and a review of evidence published since we released the NICE guidance on unintentional injury prevention in under 15 year olds. The article features some of this evidence that was found to reinforce published recommendations on safety in the home and on the roads, indicating the guidance remains up to date and relevant. In addition, it importantly highlights that there is great opportunity to prevent future unintentional injury through integrated and coordinated, evidence and intelligence-informed approaches.

Looking beyond satisfaction: evaluating the value and impact of information skills training.

In this feature guest writers Michael Raynor and Jenny Craven from the National Institute for Health and Care Excellence (NICE) present an overview of their evaluative research study on the value and impact of the information skills training courses they provide at NICE. In particular, this small study used a combination of qualitative and quantitative data to look beyond satisfaction and confidence levels and identify whether learning had actually taken place as a result of attending the sessions, and how new skills were used by the attendees in their day-to-day work. H.S.

Developing information literacy skills in pre-registration nurses: an experimental study of teaching methods.

AIM: To compare the effectiveness of an online information literacy tutorial with a face-to-face session for teaching information literacy skills to nurses. DESIGN: Randomised control trial. PARTICIPANTS: Seventy-seven first year undergraduate pre-registration diploma nursing students. INTERVENTION: Online in-house information literacy tutorial COMPARISON: One hour face-to-face session, covering the same material as the intervention, delivered by the nursing subject librarian. METHODS: Search histories were scored using a validated checklist covering keyword selection, boolean operators, truncation and synonyms. Skills retention was measured at 1 month using the same checklist. Inferential statistics were used to compare search skills within and between groups pre and post-session. RESULTS: The searching skills of first year pre-registration nursing students improve following information literacy sessions (p<0.001), and remain unchanged 1 month later, regardless of teaching method. The two methods produce a comparable improvement (p=0.263). There is no improvement or degradation of skills 1 month post-session for either method (p=0.216). CONCLUSION: Nurses Information literacy skills improve after both face-to-face and online instruction. There is no skills degradation at 1 month post-intervention for either method.

Methylation profiling of normal individuals reveals mosaic promoter methylation of cancer-associated genes.

Epigenetic silencing by promoter methylation of genes associated with cancer initiation and progression is a hallmark of tumour cells. As a consequence, testing for DNA methylation biomarkers in plasma or other body fluids shows great promise for detection of malignancies at early stages and/or for monitoring response to treatment. However, DNA from normal leukocytes may contribute to the DNA in plasma and will affect biomarker specificity if there is any methylation in the leukocytes. DNA from 48 samples of normal peripheral blood mononuclear cells was evaluated for the presence of methylation of a panel of DNA methylation biomarkers that have been implicated in cancer. SMART-MSP, a methylation specific PCR (MSP) methodology based on real time PCR amplification, high-resolution melting and strategic primer design, enabled quantitative detection of low levels of methylated DNA. Methylation was observed in all tested mononuclear cell DNA samples for the CDH1 and HIC1 promoters and in majority of DNA samples for the TWIST1 and DAPK1 promoters. APC and RARB promoter methylation, at a lower average level, was also detected in a substantial proportion of DNA samples. We found no BRCA1, CDKN2A, GSTP1 and RASSF1A promoter methylation in this sample set. Several individuals had higher levels of methylation at several loci suggestive of a methylator phenotype. In conclusion, methylation of many potential DNA methylation biomarkers can be detected in normal peripheral blood mononuclear cells, and is likely to affect their specificity for detecting low level disease. However, we found no evidence of promoter methylation for other genes indicating that panels of analytically sensitive and specific methylation biomarkers in body fluids can be obtained.

Identification of circulating tumour cells in early stage breast cancer patients using multi marker immunobead RT-PCR.

INTRODUCTION: The ability to screen blood of early stage operable breast cancer patients for circulating tumour cells is of potential importance for identifying patients at risk of developing distant relapse. We present the results of a study of the efficacy of the immunobead RT-PCR method in identifying patients with circulating tumour cells. RESULTS: Immunomagnetic enrichment of circulating tumour cells followed by RT-PCR (immunobead RT-PCR) with a panel of five epithelial specific markers (ELF3, EPHB4, EGFR, MGB1 and TACSTD1) was used to screen for circulating tumour cells in the peripheral blood of 56 breast cancer patients. Twenty patients were positive for two or more RT-PCR markers, including seven patients who were node negative by conventional techniques. Significant increases in the frequency of marker positivity was seen in lymph node positive patients, in patients with high grade tumours and in patients with lymphovascular invasion. A strong trend towards improved disease free survival was seen for marker negative patients although it did not reach significance (p = 0.08). CONCLUSION: Multi-marker immunobead RT-PCR analysis of peripheral blood is a robust assay that is capable of detecting circulating tumour cells in early stage breast cancer patients.

Online anatomy and physiology: piloting the use of an anatomy and physiology e-book-VLE hybrid in pre-registration and post-qualifying nursing programmes at the University of Salford.

BACKGROUND: Anatomy and physiology (A&P) teaching and learning in nursing curricula poses problems for educators because of the often varying levels of students' background knowledge. This study reports on a pilot project that attempted to normalize these differentials by delivering A&P teaching using an online interactive e-book-virtual learning environment (VLE) hybrid. OBJECTIVES: Evaluate the effectiveness of using an online interactive resource to deliver A&P teaching. METHODS: Data were collected from pre-registration and post-qualifying students by questionnaire and observation, and from lecturers by structured interviews. Scale-up issues were identified and documented as part of support for the ongoing pilot. RESULTS: The pre-registration group encountered problems accessing the resource and yielded evidence to suggest that inexperienced learners require a high level of direction to use the resource effectively. The post-qualifying group benefited from the resource's interactive elements and 24/7 availability. There was clear evidence that the group were able to relate knowledge gained from the resource to practice. CONCLUSIONS: This hybrid has great potential to add value to A&P learning on nursing programmes at post-qualifying level. The resource could replace its printed equivalent; however, negotiations need to take place between institutions and publishers in order to resolve scale-up issues.

Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma.

BACKGROUND: The EphB4 receptor tyrosine kinase has been reported as increased in tumours originating from several different tissues and its expression in a prostate cancer xenograft model has been reported. METHODS: RT-PCR, western blotting and immunohistochemical techniques were used to examine EphB4 expression and protein levels in human prostate cancer cell lines LNCaP, DU145 and PC3. Immunohistochemistry was also used to examine localisation of EphB4 in tissue samples from 15 patients with prostate carcinomas. RESULTS: All three prostate cancer cell lines expressed the EphB4 gene and protein. EphB4 immunoreactivity in vivo was significantly greater in human prostate cancers as compared with matched normal prostate epithelium and there appeared to be a trend towards increased expression with higher grade disease. CONCLUSION: EphB4 is expressed in prostate cancer cell lines with increased expression in human prostate cancers when compared with matched normal tissue. EphB4 may therefore be a useful anti-prostate cancer target.

Structural and functional consequences of glutamine tract variation in the androgen receptor.

The androgen receptor (AR) gene contains a polymorphic trinucleotide repeat region, (CAG)(n), in its N-terminal transactivation domain (NTD) that encodes a polyglutamine (polyQ) tract in the receptor protein. Whereas the length of the CAG repeat ranges from 6 to 39 in healthy individuals, the variations in repeat length both within and outside the normal range are associated with disease, including impaired spermatogenesis and Kennedy's disease, and with the risk of developing breast and prostate cancer. Whereas it has been proposed that the inverse relationship between polyQ tract length within the normal range and AR transactivation potential may be responsible for altered risk of disease, the molecular mechanisms underlying polyQ length modulation of AR function have not been elucidated. In this study, we provide detailed characterization of a somatic AR gene mutation detected in a human prostate tumor that results in interruption of the polyQ tract by two non-consecutive leucine residues (AR-polyQ2L). Compared with wtAR, AR-polyQ2L exhibits disrupted inter-domain communication (N/C interaction) and a lower protein level, but paradoxically has markedly increased transactivation activity. Molecular modeling and the response to cofactors indicate that the increased activity of AR-polyQ2L results from the presentation of a more stable platform for the recruitment of accessory proteins than wild-type AR. Analysis of the relationship between polyQ tract length and AR function revealed a critical size (Q16-Q29) for maintenance of N/C interaction. That between 91 and 99% of AR alleles in different racial-ethnic groups encode a polyQ tract in the range of Q16-Q29 suggests that N/C interaction has been preserved as an essential component of androgen-induced AR signaling.

Why hard-nosed executives should care about management theory.

Theory often gets a bum rap among managers because it's associated with the word "theoretical," which connotes "impractical." But it shouldn't. Because experience is solely about the past, solid theories are the only way managers can plan future actions with any degree of confidence. The key word here is "solid." Gravity is a solid theory. As such, it lets us predict that if we step off a cliff we will fall, without actually having to do so. But business literature is replete with theories that don't seem to work in practice or actually contradict each other. How can a manager tell a good business theory from a bad one? The first step is understanding how good theories are built. They develop in three stages: gathering data, organizing it into categories highlighting significant differences, then making generalizations explaining what causes what, under which circumstances. For instance, professor Ananth Raman and his colleagues collected data showing that bar code-scanning systems generated notoriously inaccurate inventory records. These observations led them to classify the types of errors the scanning systems produced and the types of shops in which those errors most often occurred. Recently, some of Raman's doctoral students have worked as clerks to see exactly what kinds of behavior cause the errors. From this foundation, a solid theory predicting under which circumstances bar code systems work, and don't work, is beginning to emerge. Once we forgo one-size-fits-all explanations and insist that a theory describes the circumstances under which it does and doesn't work, we can bring predictable success to the world of management.

Optimisation of the RT-PCR detection of immunomagnetically enriched carcinoma cells.

BACKGROUND: Immunomagnetic enrichment followed by RT-PCR (immunobead RT-PCR) is an efficient methodology to identify disseminated carcinoma cells in the blood and bone marrow. The RT-PCR assays must be both specific for the tumor cells and sufficiently sensitive to enable detection of single tumor cells. We have developed a method to test RT-PCR assays for any cancer. This has been investigated using a panel of RT-PCR markers suitable for the detection of breast cancer cells. METHODS: In the assay, a single cell line-derived tumor cell is added to 100 peripheral blood mononuclear cells (PBMNCs) after which mRNA is isolated and reverse transcribed for RT-PCR analysis. PBMNCs without added tumor cells are used as specificity controls. The previously studied markers epidermal growth factor receptor (EGFR), mammaglobin 1 (MGB1), epithelial cell adhesion molecule (EpCAM/TACSTD1), mucin 1 (MUC1), carcinoembryonic antigen (CEA) were tested. Two new epithelial-specific markers ELF3 and EphB4 were also tested. RESULTS: MUC1 was unsuitable as strong amplification was detected in 100 cell PBMNC controls. Expression of ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 was found to be both specific for the tumor cell, as demonstrated by the absence of a signal in most 100 cell PBMNC controls, and sensitive enough to detect a single tumor cell in 100 PBMNCs using a single round of RT-PCR. CONCLUSIONS: ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 are appropriate RT-PCR markers for use in a marker panel to detect disseminated breast cancer cells after immunomagnetic enrichment.