Nursing, midwifery, and allied health professions research capacities and cultures: a survey of staff within a university and acute healthcare organisation.

BACKGROUND: There is an increasing focus on the development of research capacity and culture in Nursing, Midwifery and Allied Health Professions (NMAHP). However, better understanding of the existing research success and skills, motivators, barriers, and development needs of NMAHP professionals is required to inform this development. This study sought to identify such factors within a university and an acute healthcare organisation. METHODS: An online survey, incorporating the Research Capacity and Culture tool, was administered to NMAHP professionals and students at a university and an acute healthcare organisation in the United Kingdom. Ratings of success/skill levels of teams and individuals were compared between professional groups using Mann-Whitney U tests. Motivators, barriers, and development needs were reported using descriptive statistics. Descriptive thematic analysis was used for open-ended text responses. RESULTS: A total of 416 responses were received (N&M n = 223, AHP n = 133, Other n = 60). N&M respondents were more positive than their AHP counterparts about the success/skill levels of their teams. There were no significant differences between N&M and AHP in their ratings of individual successes/skills. Finding and critically reviewing relevant literature were identified as specific individual strengths; with weaknesses in securing research funding, submitting ethics applications, writing for publication, and advising less experienced researchers. The main motivators for research were to develop skills, increased job satisfaction, and career advancement; whilst barriers included lack of time for research and other work roles taking priority. Key support needs identified included mentorship (for teams and individuals) and in-service training. Open-ended questions generated main themes of 'Employment & staffing', 'Professional services support', 'Clinical & academic management', 'Training & development', 'Partnerships' and 'Operating principles'. Two cross-cutting themes described issues common to multiple main themes: 'Adequate working time for research' and 'Participating in research as an individual learning journey'. CONCLUSIONS: Rich information was generated to inform the development of strategies to enhance research capacity and culture in NMAHP. Much of this can be generic but some nuances may be required to address some specific differences between professional groups, particularly related to perceived team success/skills and priorities identified for support and development.

Physiotherapy management of joint hypermobility syndrome--a focus group study of patient and health professional perspectives.

OBJECTIVE: To develop an understanding of patient and health professional views and experiences of physiotherapy to manage joint hypermobility syndrome (JHS). DESIGN: An explorative qualitative design. Seven focus groups were convened, audio recorded, fully transcribed and analysed using a constant comparative method to inductively derive a thematic account of the data. SETTING: Four geographical areas of the U.K. PARTICIPANTS: 25 people with JHS and 16 health professionals (14 physiotherapists and two podiatrists). RESULTS: Both patients and health professionals recognised the chronic heterogeneous nature of JHS and reported a lack of awareness of the condition amongst health professionals, patients and wider society. Diagnosis and subsequent referral to physiotherapy services for JHS was often difficult and convoluted. Referral was often for acute single joint injury, failing to recognise the long-term multi-joint nature of the condition. Health professionals and patients felt that if left undiagnosed, JHS was more difficult to treat because of its chronic nature. When JHS was treated by health professionals with knowledge of the condition patients reported satisfactory outcomes. There was considerable agreement between health professionals and patients regarding an 'ideal' physiotherapy service. Education was reported as an overarching requirement for patients and health care professionals. CONCLUSIONS: Physiotherapy should be applied holistically to manage JHS as a long-term condition and should address injury prevention and symptom amelioration rather than cure. Education for health professionals and patients is needed to optimise physiotherapy provision. Further research is required to explore the specific therapeutic actions of physiotherapy for managing JHS.

The impact of cortical remapping interventions on pain and disability in chronic low back pain: a systematic review.

BACKGROUND: Cortical change, in the manner of cortical remapping is a common feature of and potential driver for chronic low back pain (CLBP). Novel interventions such as graded motor imagery (GMI) and mirror visual feedback (MVF) have been shown to facilitate correction of cortical changes and improve symptoms in other chronic pain states. However, little is known regarding the effectiveness of these treatment approaches in CLBP. OBJECTIVE: To identify and assess the current evidence regarding the effectiveness of interventions which target cortical remapping in the management of CLBP. DATA SOURCES: The electronic databases Medline, Embase, CINAHL, AMED, OVID, PEDro, BNI, PsycINFO, HMIC, and Cochrane library were systematically searched. STUDY SELECTION: Of 11 potential citations identified, 5 articles were identified for inclusion and critiqued. These comprised 3 randomised controlled trials (RCTs), 1 randomised cross-over study, and 1 multiple case study design. RESULTS: Visualisation of lumbar movement may significantly improve movement-related pain severity and duration. A combined sensorimotor retraining approach has been shown to produce short-term improvements in both pain and disability outcomes in CLBP. The relative effectiveness of individual interventions and their long-term efficacy have yet to be established. CONCLUSIONS: There is a paucity of robust literature which has examined the application and efficacy of these novel treatments in the management of CLBP. Results from the few CLBP studies which are available are encouraging. Further, robust research is needed to optimise treatment protocols and establish their long-term effectiveness in CLBP.

Cost-effectiveness of combining systematic identification and treatment of co-morbid major depression for people with chronic diseases: the example of cancer.

BACKGROUND: Co-morbid major depression occurs in approximately 10% of people suffering from a chronic medical condition such as cancer. Systematic integrated management that includes both identification and treatment has been advocated. However, we lack information on the cost-effectiveness of this combined approach, as published evaluations have focused solely on the systematic (collaborative care) treatment stage. We therefore aimed to use the best available evidence to estimate the cost-effectiveness of systematic integrated management (both identification and treatment) compared with usual practice, for patients attending specialist cancer clinics. METHOD: We conducted a cost-effectiveness analysis using a decision analytic model structured to reflect both the identification and treatment processes. Evidence was taken from reviews of relevant clinical trials and from observational studies, together with data from a large depression screening service. Sensitivity and scenario analyses were undertaken to determine the effects of variations in depression incidence rates, time horizons and patient characteristics. RESULTS: Systematic integrated depression management generated more costs than usual practice, but also more quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) was £11,765 per QALY. This finding was robust to tests of uncertainty and variation in key model parameters. CONCLUSIONS: Systematic integrated management of co-morbid major depression in cancer patients is likely to be cost-effective at widely accepted threshold values and may be a better way of generating QALYs for cancer patients than some existing medical and surgical treatments. It could usefully be applied to other chronic medical conditions.

Joint amplitude and connectivity compensatory mechanisms in Parkinson's disease.

Neuroimaging studies in Parkinson's disease (PD) have previously demonstrated several regions of hypo- and hyper-activation during voluntary movement. How these patterns of amplitude changes at multiple discrete foci relate to changes within functional networks recruited by a given task is unclear. Changes in both amplitude and connectivity have both been individually shown within the striato-thalamo-cortical (STC) loop in PD, as well as other regions, most consistently in the cerebellum and primary motor cortex. We have previously shown overactivation of the cerebellum and motor cortex in PD subjects off medication during a visuo-motor tracking task performed at three frequencies. Here, we show that this change in activation amplitude is also accompanied by significant changes in functional connectivity between regions of interest (ROIs), with enhanced connectivity within the cerebello-thalamo-cortical (CTC) loop as well as increased inter-hemispheric communication between several basal ganglia structures. Although changes in activation amplitude were influenced by the frequency of movement performed in the tracking task, functional connectivity changes were robustly present across all three task frequencies performed, suggesting that functional connectivity analysis in PD may be a more sensitive means of detecting plastic changes which are relatively invariant to the particulars of the experimental task. Additionally, we demonstrate amplitude and connectivity changes in structures that are typically active during the resting state, or "default-mode," in PD. Unlike in STC/CTC loops, where the direction of change was the same for amplitude and connectivity, default-mode regions showed increased amplitude but decreased connectivity. Our results further support that the CTC is recruited in PD to compensate for dysfunctional basal ganglia circuits, and that this recruitment involves both amplitude and connectivity changes. The differing relationship between amplitude and connectivity changes within individual loops highlights the importance of jointly examining them in order to fully elucidate functional changes in Parkinson's disease.

Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

OBJECTIVES: To determine the safety, clinical effectiveness and cost-effectiveness of radio frequency catheter ablation (RCFA) for the curative treatment of atrial fibrillation (AF) and typical atrial flutter. DATA SOURCES: For the systematic reviews of clinical studies 25 bibliographic databases and internet sources were searched in July 2006, with subsequent update searches for controlled trials conducted in April 2007. For the review of cost-effectiveness a broad range of studies was considered, including economic evaluations conducted alongside trials, modelling studies and analyses of administrative databases. REVIEW METHODS: Systematic reviews of clinical studies and economic evaluations of catheter ablation for AF and typical atrial flutter were conducted. The quality of the included studies was assessed using standard methods. A decision model was developed to evaluate a strategy of RFCA compared with long-term antiarrhythmic drug (AAD) treatment alone in adults with paroxysmal AF. This was used to estimate the cost-effectiveness of RFCA in terms of cost per quality-adjusted life-year (QALY) under a range of assumptions. Decision uncertainty associated with this analysis was presented and used to inform future research priorities using the value of information analysis. RESULTS: A total of 4858 studies were retrieved for the review of clinical effectiveness. Of these, eight controlled studies and 53 case series of AF were included. Two controlled studies and 23 case series of typical atrial flutter were included. For atrial fibrillation, freedom from arrhythmia at 12 months in case series ranged from 28% to 85.3% with a weighted mean of 76%. Three RCTs suggested that RFCA is more effective than long-term AAD therapy in patients with drug-refractory paroxysmal AF. Single RCTs also suggested superiority of RFCA over electrical cardioversion followed by long-term AAD therapy and of RFCA plus AAD therapy over AAD maintenance therapy alone in drug-refractory patients. The available RCTs provided insufficient evidence to determine the effectiveness of RFCA beyond 12 months or in patients with persistent or permanent AF. Adverse events and complications were generally rare. Mortality rates were low in both RCTs and case series. Cardiac tamponade and pulmonary vein stenosis were the most frequently recorded complications. For atrial flutter, freedom from arrhythmia at 12 months in case series ranged from 85% to 92% with a weighted mean of 88%. Neither of the atrial flutter RCTs reported freedom from arrhythmia at 12 months. One RCT found a statistically significant benefit favouring ablation over AADs in terms of freedom from arrhythmia at a mean follow-up of 22 months. A second RCT reported a more modest effect favouring ablation in terms of freedom from atrial flutter at follow-up in older patients (mean age 78 years) after their first episode of flutter. In the atrial flutter case series, mortality was rare and the most frequent complications were atrioventricular block and haematomas. Complications in the RCTs were similar, except for those events likely to have been caused by AAD therapy (e.g. thyroid dysfunction). The review of cost-effectiveness evidence found one relevant study, which from a UK NHS perspective had a number of important limitations. The base-case analysis in the decision model demonstrated that if the quality of life benefits of RFCA are maintained over the remaining lifetime of the patient then the cost-effectiveness of RFCA appears clear. These findings were robust over a wide range of alternative assumptions, being between 7763 and 7910 pounds per additional QALY with very little uncertainty. If the quality of life benefits of RFCA are assumed to be maintained for no more than 5 years, cost-effectiveness of RFCA is dependent on a number of factors. Estimates of cost-effectiveness that explored the influence of these factors ranged from 23,000 to 38,000 pounds per QALY. CONCLUSIONS: RFCA is a relatively safe and efficacious procedure for the therapeutic treatment of AF and typical atrial flutter. There is some randomised evidence to suggest that RFCA is superior to AADs in patients with drug-refractory paroxysmal AF in terms of freedom from arrhythmia at 12 months. RFCA appears to be cost-effective if the observed quality of life benefits are assumed to continue over a patient's lifetime. However, there remain uncertainties around longer-term effects of the intervention and the extent to which published effectiveness findings can be generalised to 'typical' UK practice. All catheter ablation procedures for the treatment of AF or atrial flutter undertaken in the UK should be recorded prospectively and centrally and measures to increase compliance in recording RFCA procedures may be needed. This would be of particular value in establishing the long-term benefits of RFCA and the true incidence and impact of any complications. Collection of appropriate quality of life data within any such registry would also be of value to future clinical and cost-effectiveness research in this area. Any planned multicentre RCTs comparing RFCA against best medical therapy for the treatment of AF and/or atrial flutter should be conducted among 'non-pioneering' centres using the techniques and equipment typically employed in UK practice and should measure relevant outcomes.

High-risk febrile neutropenia in Auckland 2003-2004: the influence of the microbiology laboratory on patient treatment and the use of pathogen-specific therapy.

BACKGROUND: International guidelines recommend routine microbiological assessment of patients with febrile neutropenia, but do not recommend a change from broad-spectrum antibiotic therapy to pathogen-specific therapy when a clinically relevant organism has been isolated. The aim of the study was to determine the aetiology of febrile neutropenia in adult haematology patients at Auckland City Hospital, to document the changes in treatment made following isolation of a clinically relevant organism and to assess adverse outcomes in any patient who received pathogen-specific therapy after a positive culture result. METHODS: The results of all microbiological tests together with antibiotic therapy were recorded from consecutive patients with fever and a neutrophil count <0.5 x 10(9)/L over 1 year beginning in May 2003. RESULTS: One thousand one hundred and ninety-six specimens were collected from 81 patients during 116 episodes of febrile neutropenia. A pathogen was isolated from blood cultures in 40 episodes: Gram-positive cocci accounted for 46% of isolates and Gram-negative bacilli for 35%. Isolation of a pathogen from blood cultures resulted in a change of treatment in 25 of 40 (62.5%, 95%CI 46-77%) episodes. In 12 of these episodes, antibiotic therapy was optimized to a single pathogen-specific agent. No adverse events or subsequent changes in antibiotic therapy occurred in any of these 12 patients. Isolation of a pathogen from specimens other than blood seldom led to a change in therapy. CONCLUSION: Isolation of a pathogen from blood cultures often allows antibiotic therapy to be simplified to a pathogen-specific regimen. Further study of this approach is warranted.

A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

OBJECTIVES: A systematic review was undertaken and an economic model constructed to evaluate the clinical effectiveness and cost-effectiveness of docetaxel (Taxotere, Sanofi-Aventis) in combination with prednisone/prednisolone for the treatment of metastatic hormone-refractory prostate cancer (mHRPC). The main comparators considered were other established chemotherapy regimens and best supportive care. DATA SOURCES: Twenty-one resources (including MEDLINE, EMBASE and the Cochrane Library) were searched to April 2005. REVIEW METHODS: Two reviewers independently assessed studies for inclusion. Data from included studies were extracted and quality assessed. Where appropriate, outcomes were synthesised using formal analytic approaches. A new economic model was developed in order to establish the cost-effectiveness of docetaxel compared with a range of potential comparators. A separate review was undertaken to identify sources of utility data required to estimate quality-adjusted life-years (QALYs). Sensitivity analyses were also undertaken to explore the robustness of the main analysis to alternative assumptions related to quality of life. Monte Carlo simulation was used to propagate uncertainty in input parameters through the model in such a way that the results of the analysis could be presented with their uncertainty. The impact of uncertainty surrounding the decision was established using value of information and implementation approaches. RESULTS: Seven randomised controlled trials were identified that met the inclusion criteria. A direct comparison of docetaxel plus prednisone versus mitoxantrone plus prednisone in an open-label randomised trial showed improved outcomes for docetaxel plus prednisone in terms of overall survival, quality of life, pain and prostate-specific antigen decline. Two other chemotherapy regimens that included docetaxel: docetaxel plus estramustine and docetaxel plus prednisone plus estramustine, also showed improved outcomes in comparison with mitoxantrone plus prednisone. Indirect comparison suggested that docetaxel plus prednisone seems to be superior to corticosteroids alone in terms of overall survival. Conclusions on cost-effectiveness were primarily informed by the results of the in-house model. This indicated that mitoxantrone plus a corticosteroid is probably cheaper and more effective than corticosteroid alone. Compared with mitoxantrone plus prednisone/prednisolone, the use of docetaxel plus prednisone/prednisolone (3-weekly) appears cost-effective only if the NHS is prepared to pay 33,000 pounds per QALY. The incremental cost-effectiveness ratio associated with docetaxel plus prednisone (3-weekly) remained fairly robust to these variations with estimates ranging from 28,000 pounds to 33,000 pounds per QALY. Value of information analysis revealed that further research is potentially valuable. Given a maximum acceptable ratio of 30,000 pounds per QALY, the expected value of information was estimated to be approximately 13 million pounds. CONCLUSIONS: This systematic review of the research suggests that docetaxel plus prednisone seems to be the most effective treatment for men with mHRPC. The economic model suggests that treatment with docetaxel plus prednisone/prednisolone is cost-effective in patients with mHRPC provided the NHS is prepared to pay 33,000 pounds per additional QALY. Future research should include the direct assessment of quality of life and utility gain associated with different treatments, including the effect of adverse events of treatment, using generic instruments, which are suitable for the purposes of cost-effectiveness analyses.

Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients.

BACKGROUND: Calcimimetic agents have recently been evaluated in the treatment of secondary hyperparathyroidism (SHPT) as add-on therapy to calcitriol and vitamin D analogues and dietary phosphate binders. OBJECTIVES: To evaluate the benefits and harms of calcimimetics for the prevention of secondary hyperparathyroid bone disease (including osteitis fibrosa cystica and adynamic bone disease) in dialysis patients with chronic kidney disease (CKD). SEARCH STRATEGY: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and conference proceedings were searched for randomised controlled trials (RCTs) evaluating any calcimimetic against placebo or another agent in pre-dialysis or dialysis patients with CKD. SELECTION CRITERIA: We included all RCTs of any calcimimetic agent, cinacalcet HCl (AMG-073, Sensipar), NPS R-467 or NPS R-568 administered to patients with CKD for the treatment of SHPT. DATA COLLECTION AND ANALYSIS: Data were extracted on all relevant patient-centred and surrogate outcomes. Analysis was by a random effects model and results expressed as relative risk (RR) or weighted mean difference (MD) with 95% confidence intervals. MAIN RESULTS: Eight studies (1429 patients) were identified, which compared a calcimimetic agent plus standard therapy to placebo plus standard therapy. The end of treatment values of parathyroid hormone (pg/mL) (MD -290.79, 95% CI -360.23 to -221.34), serum calcium (mg/dL) (MD -0.85, 95% CI -1.14 to -0.56), serum phosphorus (mg/dL) (MD -0.29, 95% CI -0.50 to -0.08) and the calcium by phosphorus product (mg(2)/dL(2))(MD -7.90, 95% CI -10.25 to -5.54) were significantly lower with calcimimetics compared to placebo. No significant effects on patient-based endpoints were demonstrated except for the risk of hypotension which was significantly reduced with calcimimetics compared to placebo (RR 0.53, 95%CI 0.36 to 0.79). AUTHORS' CONCLUSIONS: Calcimimetic treatment of SHPT leads to significant improvements in biochemical parameters that observational studies have shown to be associated with increased mortality, cardiovascular risk and osteitis fibrosa, but patient-based benefits have not yet been demonstrated in trials. For patients with SHPT, the benefits of calcimimetics over standard therapy remain uncertain until further RCTs become available.

The cost-effectiveness of screening for oral cancer in primary care.

OBJECTIVES: To use a decision-analytic model to determine the incremental costs and outcomes of alternative oral cancer screening programmes conducted in a primary care environment. DESIGN: The cost-effectiveness of oral cancer screening programmes in a number of primary care environments was simulated using a decision analysis model. Primary data on actual resource use and costs were collected by case note review in two hospitals. Additional data needed to inform the model were obtained from published costs, from systematic reviews and by expert opinion using the Trial Roulette approach. The value of future research was determined using expected value of perfect information (EVPI) for the decision to screen and for each of the model inputs. SETTING: Hypothetical screening programmes conducted in a number of primary care settings. Eight strategies were compared: (A) no screen; (B) invitational screen--general medical practice; (C) invitational screen--general dental practice; (D) opportunistic screen--general medical practice; (E) opportunistic screen--general dental practice; (F) opportunistic high-risk screen--general medical practice; (G) opportunistic high-risk screen--general dental practice; and (H) invitational screen--specialist. PARTICIPANTS: A hypothetical population over the age of 40 years was studied. MAIN OUTCOME MEASURES: The main measures were mean lifetime costs and quality-adjusted life-years (QALYs) of each alternative screening scenario and incremental cost-effectiveness ratios (ICERs) to determine the additional costs and benefits of each strategy over another. RESULTS: No screening (strategy A) was always the cheapest option. Strategies B, C, E and H were never cost-effective and were ruled out by dominance or extended dominance. Of the remaining strategies, the ICER for the whole population (age 49-79 years) ranged from pound 15,790 to pound 25,961 per QALY. Modelling a 20% reduction in disease progression always gave the lowest ICERs. Cost-effectiveness acceptability curves showed that there is considerable uncertainty in the optimal decision identified by the ICER, depending on both the maximum amount that the NHS may be prepared to pay and the impact that treatment has on the annual malignancy transformation rate. Overall, however, high-risk opportunistic screening by a general dental or medical practitioner (strategies F and G) may be cost-effective. EVPIs were high for all parameters with population values ranging from pound 8 million to pound 462 million. However, the values were significantly higher in males than females but also varied depending on malignant transformation rate, effects of treatment and willingness to pay. Partial EVPIs showed the highest values for malignant transformation rate, disease progression, self-referral and costs of cancer treatment. CONCLUSIONS: Opportunistic high-risk screening, particularly in general dental practice, may be cost-effective. This screening may more effectively be targeted to younger age groups, particularly 40-60 year olds. However, there is considerable uncertainty in the parameters used in the model, particularly malignant transformation rate, disease progression, patterns of self-referral and costs. Further study is needed on malignant transformation rates of oral potentially malignant lesions and to determine the outcome of treatment of oral potentially malignant lesions. Evidence has been published to suggest that intervention has no greater benefit than 'watch and wait'. Hence a properly planned randomised controlled trial may be justified. Research is also needed into the rates of progression of oral cancer and on referral pathways from primary to secondary care and their effects on delay and stage of presentation.

Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes: a systematic review and economic evaluation.

OBJECTIVES: To review systematically the clinical effectiveness and the cost-effectiveness of clopidogrel used in combination with standard therapy including aspirin, compared with standard therapy alone for the treatment of non-ST-segment elevation acute coronary syndromes (ACS). DATA SOURCES: Electronic databases. Manufacturers' submissions. REVIEW METHODS: Studies were selected using rigorous criteria. The quality of randomised controlled trials (RCTs) was assessed according to criteria based on NHS CRD Report No. 4, and the quality of systematic reviews was assessed according to the guidelines for the Database of Reviews of Effect (DARE) criteria. The quality of economic evaluations was assessed according to a specifically tailored checklist. The clinical effectiveness and cost-effectiveness of clopidogrel in combination with standard therapy compared with standard therapy alone were synthesised through a narrative review with full tabulation of the results of the included studies. In the economic evaluations, a cost-effectiveness model was constructed using the best available evidence to determine cost-effectiveness in a UK setting. RESULTS: One RCT (the CURE trial) was a randomised, double-blind, placebo-controlled trial of high quality and showed that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in patients with non-ST-segment elevation ACS for the composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or stroke over the 9-month treatment period. However, clopidogrel was associated with a significantly higher number of episodes of both major and minor bleeding. The results from the five systematic reviews that assessed the adverse events associated with long-term aspirin use showed that aspirin was associated with a significantly higher incidence of haemorrhagic stroke, extracranial haemorrhage and gastrointestinal haemorrhage compared with placebo. Of the cost-effectiveness evidence reviewed, only the manufacturer's submission was considered relevant from the perspective of the NHS. The review of this evidence highlighted potential limitations within the submission in its use of data and in the model structure used. These limitations led to the development of a new model with the aim of providing a more reliable estimate of the cost-effectiveness from the perspective of the UK NHS. This model indicated that clopidogrel appears cost-effective compared with standard care alone in patients with non-ST-elevation ACS as long as the NHS is willing to pay GBP6078 per quality of life year (QALY). The results were most sensitive to the inclusion of additional strategies that assessed alternative treatment durations with clopidogrel. Although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. CONCLUSIONS: The results of the CURE trial indicate that clopidogrel in combination with aspirin was significantly more effective than placebo combined with aspirin in a wide range of patients with ACS. This benefit was largely related to a reduction in Q-wave myocardial infarction. There was no statistically significant benefit in relation to mortality. The trial data suggested that a substantial part of the benefit derived from clopidogrel is achieved by 3 months, with a further small benefit over the remaining 9 months of chronic treatment. The results from the base-case model suggest that treatment with clopidogrel as an adjunct to standard therapy (including aspirin) for 12 months, compared with standard therapy alone, is cost-effective in non-ST elevation ACS patients as long as the health service is willing to pay GBP6078 per additional QALY. However, although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. To estimate the exact length of time that clopidogrel in addition to standard therapy should be prescribed for patients with non-ST-segment ACS would require a prospective trial that randomised patients to various durations of therapy. This would accurately assess whether a 'rebound' phenomenon occurs in patients if clopidogrel were stopped after 3 months of treatment.

Development and use of a population based injury surveillance system: the all Wales Injury Surveillance System (AWISS).

This report details the development and use of a population based emergency room surveillance system in the UK. Despite some difficulties in accessing high quality data the system has stimulated a considerable number of research and intervention projects. While surveillance systems with high quality data collection and coding parameters remain the gold standard, imperfect systems, particularly if population based, can play a substantial part in stimulating injury prevention initiatives.

Health-related quality of life and health care costs in severe, refractory irritable bowel syndrome.

BACKGROUND: The irritable bowel syndrome (IBS) may lead to considerable impairment of health-related quality of life and high health care costs. It is not clear whether these poor outcomes directly result from severe bowel symptoms or reflect a coexisting psychiatric disorder. OBJECTIVE: To determine whether bowel symptom severity and psychological symptoms directly influence health-related quality of life and health care costs. DESIGN: Cross-sectional survey. SETTING: Secondary and tertiary gastroenterology clinics. PATIENTS: 257 patients with severe IBS who did not respond to usual treatments and were recruited for a trial of psychological treatment. MEASUREMENTS: Predictors were abdominal pain, entries in a diary of 10 IBS symptoms, and measures of psychological symptoms. Outcomes were inability to work, health-related quality of life (measured by Medical Outcomes Survey 36-item short-form questionnaire [SF-36] physical component summary scores), and health care and productivity costs. Predictor and outcome measures were compared by using multiple regression and logistic regression analyses. RESULTS: Abdominal pain occurred on average 24 days per month and activities were restricted on 145 days of the previous 12 months. The mean (+/-SD) Hamilton depression score was 11.3 +/- 6.1. The SF-36 physical component summary score was low (37.7 +/- 10.6), and the patients had incurred high health care costs ($1743 +/- $2263) over the previous year. Global severity and somatization scores on the Symptom Checklist 90 Revised, abdominal pain, and Hamilton depression scores independently contributed to the physical component score of the SF-36 (adjusted R(2) = 35.2%), but only psychological scores were associated with disability due to ill health. These variables did not accurately predict health care or other costs (adjusted R(2) = 9.3%). History of sexual abuse was not an independent predictor of outcome. CONCLUSIONS: Both abdominal and psychological symptoms are independently associated with impaired health-related quality of life in patients with severe IBS. Optimal treatment is likely to require a holistic approach. Since health care and loss of productivity costs are not clearly associated with these symptoms, alleviation of them will not necessarily lead to reduced costs.

Laminar specific alterations of thalamocortical projections in organotypic cultures following layer 4 disruption in ferret somatosensory cortex.

The developing neocortex influences the growth of thalamocortical projections. Layer 4 in particular receives the majority of input from the thalamus and is important in instructing thalamic afferents to terminate. Previous in vivo experiments demonstrated that disruption of layer 4 during corticogenesis in ferret somatosensory cortex by application of methylazoxy methanol acetate (MAM) prevents proper termination of thalamic afferents in appropriate cortical regions. To further explore the role of layer 4 in thalamocortical development, we prepared organotypic cocultures consisting of normal gestational day 0 (P0) ferret thalamus paired with normal, embryonic day 33 (E33), or E38 MAM-treated cortex obtained from ferrets at either P0 or P7. Injection of MAM on E33 disrupts layer 4 formation, whereas similar injections on E38 interfere with layer 2 formation. The cocultures grew together for a number of days, then discrete injections of either fluorescent dextrans or 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) were made into the thalamic piece. The labeled thalamic afferents that grew into the cortical slice were analysed and the sites of their terminations quantified after 3, 5, or 7-10 days in culture (DIC). Our results varied somewhat with the amount of time in culture, but the preponderance of thalamic fibers in normal cortex terminated in layer 4, whereas their counterparts in E33 MAM-treated cortex grew beyond the cortical plate and many fibers terminated inappropriately within lower cortical layers or white matter. Terminal distribution of thalamic fibers in E38 MAM-treated cortex looked similar to normal. These results demonstrate that the cells of layer 4 provide thalamic afferents with important positional and termination cues.

Disruption of layers 3 and 4 during development results in altered thalamocortical projections in ferret somatosensory cortex.

The precision of projections from dorsal thalamus to neocortex are key toward understanding overall cortical organization and function. To identify the significance of layer 4 cells in receiving the bulk of thalamic projections in somatosensory cortex, we disrupted layer 4 genesis and studied the effect on thalamic terminations in ferrets. Second, we ascertained the result of layer 4 disruption on functional responses and topographic organization. Methylazoxy methanol (MAM) was injected into pregnant ferrets on embryonic day 33 (E33), when most layer 4 neurons of somatosensory cortex are generated. This treatment resulted in dramatic reduction in the thickness of targeted layer 4. E38 MAM treatment was used as a control, when layer 2-3 neurons are generated. The projections of ventrobasal thalamus into somatosensory cortex were studied using DiI injections. We found only subtle differences between groups (normal, E33, or E38 MAM-treated) in the thalamic afferent pattern on postnatal day 1 (P1) and P7. On P14, thalamic terminations distribute almost equally throughout the remaining cortical layers in the E33 MAM-treated group compared with normal and E38 MAM-treated animals, in which the ventrobasal thalamus projects primarily to central layers. Electrophysiological recordings conducted on mature ferrets treated with MAM on E33 demonstrated that somatotopic organization and receptive field size are normal. These findings emphasize the importance of layer 4 in determining the normal laminar pattern of thalamic termination and suggest that, although its absence is likely to impact on complex neocortical functional responses, topographic organization does not arise from the influence of layer 4.

The impact of lay pastoral telecare on the spiritual well-being of church attenders.

Examines the efficacy of Lay Pastoral Telecare (LPT) on the spiritual well-being and church satisfaction of churchgoers (N = 207). Compares an experimental and a control group and concludes that the use of telephone by lay pastoral caregivers can be a means of promoting interpersonal support and enhancement of spiritual well-being within a church congregations.

Use of complementary and alternative medicines by surgical patients.

This study examined the frequency of surgical patient use of complementary and alternative medicines prior to surgery. After conducting a literature review on the known effects of alternative medicines, we evaluated their potential interactions with anesthetics. At the University of Colorado Health Sciences Center, Denver, Colo, we surveyed 500 elective surgical outpatients about alternative medicines taken during the 2 weeks prior to surgery. Of the 500 patients surveyed, 51% preoperatively took herbs, vitamins, dietary supplements, or homeopathic medicines (range, 1-22 per patient). Substances from 2 or more categories of alternative medicines (herbs, vitamins, dietary supplements, or homeopathic medicines) were consumed by 24% of patients. Twenty-four percent of surveyed patients consumed 50 different herbs, 41% took 9 types of vitamins, 44% took 31 types of dietary supplements, and 1% of patients took the homeopathic arnica. Classification by potential adverse effects revealed that 27% of surgical patients consumed alternative medicines that may inhibit coagulation, affect blood pressure (12%), cause sedation (9%), have cardiac effects (5%), or alter electrolytes (4%). Greater communication, knowledge, and scientific research are needed to safely integrate complementary and alternative medicines in the future management of the surgical patient.

Construction of a high-resolution 2.5-Mb transcript map of the human 6p21.2-6p21.3 region immediately centromeric of the major histocompatibility complex.

We have constructed a 2.5-Mb physical and transcription map that spans the human 6p21.2-6p21.3 region and includes the centromeric end of the MHC, using a combination of techniques. In total 88 transcription units including exons, cDNAs, and cDNA contigs were characterized and 60 were confidently positioned on the physical map. These include a number of genes encoding nuclear and splicing factors (Ndr kinase, HSU09564, HSRP20); cell cycle, DNA packaging, and apoptosis related [p21, HMGI(Y), BAK]; immune response (CSBP, SAPK4); transcription activators and zinc finger-containing genes (TEF-5, ZNF76); embryogenesis related (Csa-19); cell signaling (DIPP); structural (HSET), and other genes (TULP1, HSPRARD, DEF-6, EO6811, cyclophilin), as well as a number of RP genes and pseudogenes (RPS10, RPS12-like, RPL12-like, RPL35-like). Furthermore, several novel genes (a Br140-like, a G2S-like, a FBN2-like, a ZNF-like, and B1/KIAA0229) have been identified, as well as cDNAs and cDNA contigs. The detailed map of the gene content of this chromosomal segment provides a number of candidate genes, which may be involved in several biological processes that have been associated with this region, such as spermatogenesis, development, embryogenesis, and neoplasia. The data provide useful tools for synteny studies between mice and humans, for genome structure analysis, gene density comparisons, and studies of nucleotide composition, of different isochores and Giemsa light and Giemsa dark bands.

Microbial desulfurization of alkylated dibenzothiophenes from a hydrodesulfurized middle distillate by Rhodococcus erythropolis I-19.

Rhodococcus erythropolis I-19, containing multiple copies of key dsz genes, was used to desulfurize alkylated dibenzothiophenes (Cx-DBTs) found in a hydrodesulfurized middle-distillate petroleum (MD 1850). Initial desulfurization rates of dibenzothiophene (DBT) and MD 1850 by I-19 were 5.0 and 2.5 micromol g dry cell weight(-1) min(-1), more than 25-fold higher than that for wild-type bacteria. According to sulfur K-edge X-ray absorption near-edge structure (XANES) analysis, thiophenic compounds accounted for >95% of the total sulfur found in MD 1850, predominantly Cx-DBTs and alkylated benzothiophenes. Extensive biodesulfurization resulted in a 67% reduction of total sulfur from 1,850 to 615 ppm S. XANES analysis of the 615-ppm material gave a sulfur distribution of 75% thiophenes, 11% sulfides, 2% sulfoxides, and 12% sulfones. I-19 preferentially desulfurized DBT and C1-DBTs, followed by the more highly alkylated Cx-DBTs. Shifting zero- to first-order (first-order) desulfurization rate kinetics were observed when MD 1850 was diluted with hexadecane. Apparent saturation rate constant (K(0)) and half-saturation rate constant (K(1)) values were calculated to be 2.8 micromol g dry cell weight(-1) min(-1) and 130 ppm, respectively. However, partial biocatalytic reduction of MD 1850 sulfur concentration followed by determination of initial rates with fresh biocatalyst led to a sigmoidal kinetic behavior. A competitive-substrate model suggested that the apparent K(1) values for each group of Cx-DBTs increased with increasing alkylation. Overall desulfurization rate kinetics with I-19 were affected by the concentration and distribution of Cx-DBTs according to the number and/or lengths of alkyl groups attached to the basic ring structure.