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Biomedical subjects

M Eccles

Publications and source records attributed to M Eccles.

At least 19 recordsLinked to original sources

PAX2 inactivation enhances cisplatin-induced apoptosis in renal carcinoma cells.

Renal cell carcinoma (RCC) is the most common kidney malignancy and has a poor prognosis owing to its resistance to chemotherapy. RCC cells overexpress the transcription factor, PAX2, normally expressed in fetal kidney but downregulated at birth. Since Pax2 suppresses apoptosis during renal development, we reasoned that PAX2 may confer resistance to cisplatin-induced apoptosis in RCC. Here, we show that PAX2 confers resistance to cisplatin-induced apoptosis in normal kidney cells and fetal kidney explants. Human embryonic kidney 293 cells transfected with a PAX2 expression vector and exposed to cisplatin (40 microM) exhibited 45 +/- 15% as much caspase-3 cleavage compared to control cells. Conversely, murine collecting duct cells stably transfected with PAX2 antisense cDNA had twofold increase in cisplatin-induced apoptosis. Murine fetal (embryonic day 15) kidney explants from PAX2(1Neu)+/- mice exposed to cisplatin (25 microM x 24 h) had 50% increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining). We then show that RCC cells (CAKI-1 (human, Caucasian, kidney, carcinoma) and ACHN (human, Caucasian, kidney, adenocarcinoma)) express PAX2 protein. PAX2-small interfering RNA (100 nM) reduces endogenous PAX2 protein (10% of baseline) and induces apoptosis (Annexin-V staining). Pax2 knockdown sensitized RCC cells to cisplatin-induced apoptosis, killing 50-60% of cisplatin-resistant ACHN and CAKI-1 cells. These findings suggest that PAX2 confers resistance to cisplatin-induced apoptosis in non-transformed kidney cells and fetal kidney explants. Similarly, Pax2 overexpression in RCC cells contributes to cisplatin resistance. Conceivably, a therapeutic strategy that inactivates Pax2 in vivo might enhance the efficacy of conventional cytotoxic drugs against RCC.

Adenocarcinoma↗

Leptospirosis in febrile men ingesting Agouti paca in South America.

To explore the relationship between the ingestion of Agouti paca (AP) and human leptospirosis in Guyana, 19 febrile men who said they had hunted and eaten A. paca were screened for malaria, using bloodsmears, and for leptospirosis, using an enzyme immuno-assay that detects Leptospira -specific IgM. Those found positive for anti-Leptospira IgM were then evaluated further, with a microscopical agglutination test based on a limited panel of serovars from three pathogenic species of Leptospira. Although six of the 18 patients who provided suitable samples for the serology were found seropositive for acute leptospirosis, only three of the 19 patients were found smear-positive for malaria. A clinical-decision model, based on medical histories, the results of physical examinations, and the use of routine urine dipsticks, and enabling prediction of the serological results, was developed. This model, which had 83% sensitivity and 100% specificity for leptospirosis, indicated that, in the absence of serology, most febrile patients reporting AP ingestion could be correctly treated if each was checked for malaria using traditional bloodsmears. The smear-positives should be treated with antimalarial drugs whereas the smear-negatives should be treated for leptospirosis if they had any of the following: a skin rash; lymphadenopathy; abnormal urine sediment (proteinuria or haematuria); and/or no previous history of malaria. In the present study, the relative risk of leptospirosis among the patients who were smear-negative for malaria and fulfilled at least one of these four criteria was 13 (P = 0.0007). In Guyana at least, leptospirosis appears to be common among men who hunt, prepare and ingest AP. Vaccines may be the best, practical form of protection among such men.

Adult↗

Assessing the long-term effect of educational reminder messages on primary care radiology referrals.

AIM: To investigate whether the effect of educational reminder messages for knee and lumbar spine radiographs varied over a 12 month period. MATERIALS AND METHODS: In a previous randomized, controlled trial, educational reminder messages attached to x-ray reports were shown to be effective in reducing the number of radiograph requests by general practitioners for knee and lumbar spine radiographs. In this study, all radiology departments from the previous trial were asked for monthly referral records for the 12 month intervention period for knee and lumbar spine radiographs for each general practice. Poisson regression was used to test for a change over time in the number of referrals between control and intervention practices. RESULTS: Data were obtained for 66% of the general practices in the main trial. The number of referrals for both knee and lumbar spine radiographs remained consistently and statistically significantly lower in the educational reminder messages group compared with the control group (relative risk=0.65 and 0.64, respectively). There was no evidence that this difference increased or decreased throughout the 12 month period. CONCLUSIONS: The effect of educational reminder messages was produced as soon as the intervention was delivered and maintained throughout the intervention period. There was no evidence of the effect of the intervention wearing off.

Family Practice↗

Research designs for studies evaluating the effectiveness of change and improvement strategies.

The methods of evaluating change and improvement strategies are not well described. The design and conduct of a range of experimental and non-experimental quantitative designs are considered. Such study designs should usually be used in a context where they build on appropriate theoretical, qualitative and modelling work, particularly in the development of appropriate interventions. A range of experimental designs are discussed including single and multiple arm randomised controlled trials and the use of more complex factorial and block designs. The impact of randomisation at both group and individual levels and three non-experimental designs (uncontrolled before and after, controlled before and after, and time series analysis) are also considered. The design chosen will reflect both the needs (and resources) in any particular circumstances and also the purpose of the evaluation. The general principle underlying the choice of evaluative design is, however, simple-those conducting such evaluations should use the most robust design possible to minimise bias and maximise generalisability.

Cluster Analysis↗

When is it cost-effective to change the behavior of health professionals?

Because of the workings of health care systems, new, important, and cost-effective treatments sometimes do not become routine care while well-marketed products of equivocal value achieve widespread adoption. Should policymakers attempt to influence clinical behavior and correct for these inefficiencies? Implementation methods achieve a certain level of behavioral change but cost money to enact. These factors can be combined with the cost-effectiveness of treatments to estimate an overall policy cost-effectiveness. In general, policy cost-effectiveness is always less attractive than treatment cost-effectiveness. Consequently trying to improve the uptake of underused cost-effective care or reduce the overuse of new and expensive treatments may not always make economic sense. In this article, we present a method for calculating policy cost-effectiveness and illustrate it with examples from a recent trial, conducted during 1997 and 1998, of educational outreach by community pharmacists to influence physician prescribing in England.

Cost-Benefit Analysis↗

Decision analysis in patient care.

To help patients to fully participate in shared decision making is becoming an important goal in clinical practice and one which is receiving increasing attention in terms of the requisite skills and technological development. We discuss the potential application of decision analysis-a specific technology that has been introduced into clinical practice but to date only within research contexts-and examine the usefulness and feasibility of the technique for patients, particularly in settings where clinical presentations are diverse and characterised by uncertainty.

Decision Support Techniques↗

Characterization of the murine Lbx2 promoter, identification of the human homologue, and evaluation as a candidate for Alström syndrome.

The murine Lbx2 gene is a member of the ladybird family of homeobox genes, which is expressed in the developing urogenital system, eye, and brain. Using transgenic mice, we demonstrate that 9 kb of the 5' flanking region of mouse Lbx2 is able to direct expression of a reporter gene in a tissue-specific manner recapitulating the endogenous expression pattern. This regulatory region provides a novel reagent allowing for transgenic expression in the developing urogenital ridge. In addition, we describe the identification of the human homologue, LBX2. Comparison of the human LBX2 and mouse Lbx2 sequences upstream of the coding regions reveals sequence conservation suggesting conserved regulatory regions. Both the human LBX2 and the mouse Lbx2 genes have similar genomic structures and are composed of two exons separated by an intron. We mapped the mouse Lbx2 gene to 35 cM on chromosome 6 and the human LBX2 gene to a homologous region of chromosome 2p13. This is a candidate region for several inherited disorders, including Alström syndrome, a disorder that includes ocular, urogenital, and renal abnormalities. Given the expression pattern of Lbx2, the chromosomal location in humans, and the potential function of mammalian ladybird genes, we have begun to analyze patients with ocular disorders and those with Alström syndrome for mutations in LBX2. Although polymorphisms were identified, our results indicate that mutations in the coding region of LBX2 do not account for Alström syndrome in the six kindreds analyzed.

Amino Acid Sequence↗

Effect of audit and feedback, and reminder messages on primary-care radiology referrals: a randomised trial.

BACKGROUND: Radiological tests are often used by general practitioners (GPs). These tests can be overused and contribute little to clinical management. We aimed to assess two methods of reducing GP requests for radiological tests in accordance with the UK Royal College of Radiologists' guidelines on lumbar spine and knee radiographs. METHODS: We assessed audit and feedback, and educational reminder messages in six radiology departments and 244 general practices that they served. The study was a before-and-after, pragmatic, cluster randomised controlled trial with a 232 factorial design. A random subset of GP patients' records were examined for concordance with the guidelines. The main outcome measure was number of radiograph requests per 1000 patients per year. Analysis was by intention to treat. FINDINGS: The effect of educational reminder messages (ie, the change in request rate after intervention) was an absolute change of -1.53 (95% CI -2.5 to -0.57) for lumbar spine and of -1.61 (-2.6 to -0.62) for knee radiographs, both relative reductions of about 20%. The effect of audit and feedback was an absolute change of -0.07 (-1.3 to 0.9) for lumbar spine of 0.04 (-0.95 to 1.03) for knee radiograph requests, both relative reductions of about 1%. Concordance between groups did not differ significantly. INTERPRETATION: 6-monthly feedback of audit data is ineffective but the routine attachment of educational reminder messages to radiographs is effective and does not affect quality of referrals. Any department of radiology that handles referrals from primary care could deliver this intervention to good effect.

Adult↗

The potential influence of small group processes on guideline development.

The authors discuss the important and often neglected role of psychosocial factors in guideline development. Such factors can influence the process by which guideline development groups interact, make decisions and achieve consensus, which may have important implications for the validity and reliability of the recommendations they produce. Particular attention is paid to the role of social influence within multidisciplinary groups and the importance of good chairmanship. Recommendations for participants, chairmen and guideline development bodies are given.

Decision Making↗

Evidence-based guideline for the primary care management of stable angina.

This is an updated version of the first North of England Stable Angina Guideline (1,2) and summarizes the full guideline. (3) This paper presents all the recommendations within the guideline; and where these are new or substantially altered from the original version, it also presents a summary of the supporting evidence. The aims and methods of development (summarized in Box 1) of this guideline are unchanged from the original version, to which readers are directed for more detail. The research questions raised during the development of this guideline are shown in Box 2.

Angina Pectoris↗

Evidence-based guideline on the primary care management of asthma.

This is an updated version of the first North of England Asthma Guideline (1,2) and summarizes the full guideline. (3) This paper presents all the recommendations within the guideline and, where these are new or substantially altered from the original version, it also presents a summary of the supporting evidence. The aims and methods of development (summarized in Box 1) of this guideline are unchanged from the original version, to which readers are directed for more detail. The research questions raised during the development of this guideline are shown in Box 2.

Asthma↗

Is untargeted outreach visiting in primary care effective? A pragmatic randomized controlled trial.

BACKGROUND: There is increasing evidence that clinical guidelines can lead to improvements in clinical care. However, they are not self-implementing. Outreach visits may improve prescribing behaviour. METHODS: Within a before-and-after pragmatic randomized controlled trial, involving all general practices in one health district, routine methods were used to distribute guidelines for management of Helicobacter pylori eradication. Intervention practices were offered a visit and the conduct of an audit by a pharmacist trained in the techniques of outreach visiting. The intervention was evaluated using level three Prescribing Analysis and Cost (PACT) data for metronidazole and omeprazole for the two 12 month periods around the introduction of the guidelines. RESULTS: Of the 38 intervention practices 19 accepted an outreach visit and three accepted the offer of an audit. There was a significant increase in omeprazole use during the study of 0.24 [95 per cent confidence interval (CI) +0.19 to +0.29] dose units per year but no effect from the offer [-0.02 (95 per cent CI -0.12 to +0.08) dose units] or acceptance of a visit [-0.03 (95 per cent CI -0.15 to +0.08) dose units]. The results for metronidazole were similar, with an increase in use of 0.028 (95 per cent CI +0.018 to +0.038) dose units per year. The effect of the intervention was a non-significant change in prescribing of -0.005 (95 per cent CI -0.025 to +0.015) dose units. Accepting a visit had little effect on prescribing: a change of 0.003 (95 per cent CI -0.021 to +0.027) dose units. CONCLUSIONS: The routine use of untargeted outreach visiting is probably not a worthwhile strategy.

Amoxicillin↗

Involvement of consumers in the development of evidence based clinical guidelines: practical experiences from the North of England evidence based guideline development programme.

BACKGROUND: Consumer involvement in clinical guidelines has long been advocated although there are few empirical accounts of attempts to do so. It is therefore not surprising that there is a lack of clarity about how and when to involve consumers and what to expect from them within the process of guideline development. METHODS: The North of England evidence based guideline development programme has used four different methods of consumer involvement. RESULTS: When individual patients were included in a guideline development group they contributed infrequently and had problems with the use of technical language. Although they contributed most in discussions of patient education, their contributions were not subsequently acted on. In a "one off" meeting with a group of patients there were again reported problems with medical terminology and the group were most interested in sections on patient education and self management. However, their understanding of the use of scientific evidence in order to contribute to a more cost effective health care remained unclear. In a workshop it was possible to explain the technical elements of guideline development to patients who could then engage with such a process and make relevant suggestions as a consequence. However, this was relatively resource intensive. A patient advocate within a guideline development group felt confidence to speak, was used to having discussions with health professionals, and was familiar with the medical terminology. CONCLUSIONS: Consumers should be involved in all stages of guideline development. While this is possible, it is not straightforward. There is no one right way to accomplish this and there is a clear need for further work on how best to achieve it.

Decision Making, Organizational↗

How patients with atrial fibrillation value different health outcomes: a standard gamble study.

BACKGROUND AND PURPOSE: The assessment of any health care intervention should consider both risks and benefits and take patients' preferences about these into account. The study reported in this paper aimed to elicit patient valuations of health states relevant to assessment of the prevention of stroke by warfarin anticoagulation therapy for patients with atrial fibrillation. METHODS: A sample of patients over the age of 60 years with atrial fibrillation from three family practices in North-East England was interviewed. Their health state values were elicited using the standard gamble method for general practitioner (GP)-managed warfarin treatment, hospital-managed warfarin treatment, major bleed, mild stroke and severe stroke. RESULTS: Of 180 patients, 69 (38%) agreed to participate, of whom 57 (83%) completed interviews. Median (mean) utility values were for GP-managed warfarin treatment 0.986 (0.948), hospital-managed warfarin treatment 0.984 (0.941), major bleed 0.880 (0.841), mild stroke 0.675 (0.641) and severe stroke 0 (0.189). There was wide variation in values between patients and the distributions were highly skewed. CONCLUSIONS: The results are of value in applying decision analysis to groups of patients. They should be used with caution in reaching decisions about appropriate treatment for individual patients, but may provide a starting point for necessary further exploration of those patients' individual preferences.

Anticoagulants↗

How to develop cost-conscious guidelines.

BACKGROUND: Clinical guidelines, defined as 'systematically developed statements to assist both practitioner and patient decisions in specific circumstances', have become an increasingly familiar part of clinical care. Guidelines are viewed as useful tools for making care more consistent and efficient and for closing the gap between what clinicians do and what scientific evidence supports. Interest in clinical guidelines is international and has its origin in issues faced by most healthcare systems: rising healthcare costs; variations in service delivery with the presumption that at least some of this variation stems from inappropriate care; the intrinsic desire of healthcare professionals to offer, and patients to receive, the best care possible. Within the UK, there is ongoing interest in the development of guidelines and a fast-developing clinical-effectiveness agenda within which guidelines figure prominently. Over the last decade, the methods of developing guidelines have steadily improved, moving from solely consensus methods to methods that take explicit account of relevant evidence. However, UK guidelines have tended to focus on issues of effectiveness and have not explicitly considered broader issues, particularly cost. This report describes the methods developed to handle benefit, harm and cost concepts in clinical guidelines. It reports a series of case studies, each describing the development of a clinical guideline; each case study illustrates different issues in incorporating these different types of evidence. HEALTH ECONOMICS AND CLINICAL GUIDELINES: There has been no widely accepted successful way of incorporating economic considerations into guidelines. Unlike other areas of guideline development, there is little practical or theoretical experience to direct the incorporation of cost issues within clinical guidelines. However, the reasons for considering costs are clearly stated: "health interventions are not free, people are not infinitely rich, and the budgets of [health care] programmes are limited. For every dollar's worth of health care that is consumed, a dollar will be paid. While these payments can be laundered, disguised or hidden, they will not go away" (Eddy DM. A manual for assessing health practices and designing practice policies: the explicit approach. Philadelphia: American College of Physicians; 1992). Such opportunity costs are a universal phenomenon. In the USA it has been recommended that every set of clinical guidelines should include information on the cost implications of the alternative preventive, diagnostic, and management strategies for each clinical situation. The stated rationale was that this information would help potential users to evaluate better the potential consequences of different practices. However, it was acknowledged that "the reality is that this recommendation poses major methodological and practical challenges" (Institute of Medicine. Guidelines for clinical practice: from development to use. Washington: National Academy Press; 1992). METHODS OF DEVELOPING CLINICAL GUIDELINES: A guideline development process summarises the technical information about the value of treatments in a manner that makes them accessible and ready for use in clinical practice, alongside information on contextual issues. The requirement is that the presentation of costs and benefits of treatments is methodologically sound, robust and accessible. This report includes a summary of the current best practice in evidence-based guideline development, including recent methodological advances. The manner in which cost and cost-effectiveness concepts have been successfully incorporated into the guideline process is introduced. GUIDELINE DEVELOPMENT CASE STUDIES: The 'cost-effectiveness' sections of 11 guidelines are reported to illustrate both the range of methods used and the nature of the recommendations reached by the guideline development groups when considering the profile of consequences of treatments including costs. These guidelines are broadly grouped as: (1) those using qualitative evidence summary methods; (2) those using quantitative evidence summary methods and addressing relatively narrow clinical questions; (3) those using quantitative evidence summary methods and addressing a broad clinical area; (4) a guideline based upon a decision analysis model. CONCLUSIONS: The focus of this project was to explore the methods of incorporating cost issues within clinical guidelines. However, the process of reviewing evidence in guideline development groups is becoming increasingly sophisticated, not only in considerations of cost but also in review techniques and group process. At the outset of the project it was unclear how narrowly or broadly the concept of 'cost' could be considered. (ABSTRACT TRUNCATED)

Arthritis↗