76 research outputs found
Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis
No full textAccumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 201
"Test me and treat me" - attitudes to vitamin D deficiency and supplementation: a qualitative study
No full text© 2015 BMJ Open, "Test me and treat me"-attitudes to vitamin D deficiency and supplementation: a qualitative study. This manuscript version is made available under the Creative Commons Attribution Licens
Maintaining contact with people with severe mental illness: 5-year follow-up of assertive outreach.
No full textBACKGROUND: Assertive outreach is a central strand of Government mental health policy in England. Are different long-term models of mental health care which include assertive outreach associated with different service user outcomes and cost? METHOD: We conducted a multi-site 5-year follow-up study of people with severe mental illness. From 0 to 18 months all three sites had Intensive Case Management (ICM) teams practising assertive outreach. From 18 to 60 months one team sustained ICM, one team merged and another was disbanded. All 131 original ICM team clients were the study participants. Outcome was measured in terms of sustained engagement with statutory mental health services, psychiatric symptoms, social functioning, resource use and cost. RESULTS: All 120 live participants were traced. Only four people had no service contact; when contacted by a researcher they appeared to be coping well. No incidents of serious violence were discovered. No differences existed between teams in the mean total symptom or total social functioning change scores at follow-up, after controlling for baseline differences. No differences existed in mean cost between teams during the first 18 months. Mean (standard deviation) annualised costs varied considerably in the 18-60 month period: sustained team Pound Sterling13,734 (10,820); integrated team Pound Sterling11,037 (13,603); disbanded team Pound Sterling5,742 (7,007) (F=4.4, 105 df, p=0.015). CONCLUSION: Continued specialist assertive outreach service models have higher costs than non-specialist services for no apparent benefit. In the long term new assertive outreach services should have procedures in place to transfer people to lower intensity and lower cost care
Green space management & residents’ benefits
No full textManagement of green spaces in rental multi-family housing areas is discussed in a Swedish context and the benefits of maintenance for residents examined in this thesis. In Sweden, these green spaces are an important part of the urban green structure and the housing companies who manage these spaces are important green space providers. However, the management and maintenance of such green spaces and its benefits for residents seldom receive attention in research. The residents’ perspective is the main interest here, since they are to benefit from maintenance. The perspective of the providers (housing staff) is also included, because of their influence through provision on residents’ experiences. Taking an ex-plorative and mainly qualitative approach, two empirical studies were conducted using interviews as the main method of collecting data. In a case study of three rental and multi-family housing areas, 27 residents and 13 housing staff were interviewed regarding their experience of the maintenance of green space and their views on maintenance provision respectively. In a telephone survey of 30 municipal housing companies, housing staff were asked how they organised maintenance of green spaces and what motivated that choice. The case study identified several benefits of green space maintenance for residents and three were further explored: (1) green space being ‘well-kept’ (2) the housing area being safe and (3) a just distribution of maintenance. The results showed that several elements of maintenance and the social context, such as views of maintenance staff and of other residents, contribute to residents’ experience of these bene-fits. Views of well-kept green space were for example not simply about technical quality but e.g. the image of maintenance staff and their efforts was also considered. There is consequently a need to widen the technical discussion about how to manage and maintain green spaces
Author Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
No full textauthor correctio
The safety and effectiveness of different methods of ear wax removal: a systematic review and economic evaluation
No full textEar wax (cerumen) is a natural secretion produced to protect the inner ear from dirt and other fragments by moving these particles towards the outer ear. If this process does not happen properly, wax may build up causing blockage in the ear canal and the possibility of impaction. People with a build up of ear wax may suffer from hearing loss, discomfort and, on occasions, infection. It may present problems in assessing hearing, blocking the view of the ear drum during medical examination and interfering with the fitting or function of hearing aids. Although it is thought to affect between 2% and 6% of the population in the England and Wales, some groups may be at a higher risk, such as those using hearing aids or with small ear canals and/or skin conditions. Recurrence is thought to be high among some of these groups. The consequences of the build up of ear wax in the ear canal are thought to be a common reason for consultation and cost in general practice with over 2 million consultations per year in the NHS.Methods of removal of ear wax include drops, flushing with water in general practice, and removal with suction or probes in specialist clinics. The relative safety and benefits of these different methods of removal remains uncertain. This research will systematically review published and unpublished evidence on the clinical and cost effectiveness of different methods for the removal of ear wax. Where appropriate, it will develop an economic model using data from this systematic review and other relevant sources to estimate the relative costs and benefits of different methods. In addition, the project will provide recommendations for future research to try to help answer any remaining areas of uncertainty
The clinical effectiveness and cost-effectiveness of topotecan for small cell lung cancer: a systematic review and economic evaluation
No full textObjectives: To assess the clinical effectiveness and cost-effectiveness of topotecan as second-line treatment for small cell lung cancer (SCLC).Data sources: Bibliographic databases were searched from 1990 to February 2009, including the Cochrane library, MEDLINE (Ovid), EMBASE (Ovid), PREMEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were assessed and experts were contacted to identify additional references and the manufacturer’s submission to NICE was also searched.Review methods: Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text of retrieved papers using a standard form. For the clinical effectiveness review, the studies were randomised controlled trials (RCTs), which included adult participants with relapsed SCLC who responded to first-line treatment and for whom re-treatment with first-line therapy was inappropriate. The treatment was topotecan (oral or intravenous, i.v.) compared with one another, best supportive care (BSC) or other chemotherapy regimens. Outcomes included measures of response or disease progression and measures of survival. For the cost-effectiveness review studies were eligible for inclusion if they reported cost-effectiveness, cost–utility, cost–benefit or cost–consequence analyses. Data extraction and quality assessment of included studies was undertaken by one reviewer and checked by a second. Studies were synthesised through a narrative review with full tabulation of results. An independent economic model estimated the cost-effectiveness of topotecan (oral or i.v.) compared with BSC. The model used survival analysis methods to derive estimates of mean survival for patients treated with topotecan or receiving BSC alone. These were combined with quality of life (QoL) weights to derive estimates of mean quality-adjusted life expectancy for patients receiving BSC alone or topotecan plus BSC. Categories of costs included in the model included drug use, chemotherapy administration and on-treatment monitoring, management of adverse events, monitoring for disease progression and palliative care.Results: A total of 434 references were identified of which five were included in the clinical effectiveness review. In these trials topotecan was compared with BSC, CAV [cyclophosphamide, Adriamycin (doxorubicin) and vincristine] or amrubicin, or oral topotecan was compared with i.v. topotecan. No economic evaluations were identified. There were no statistically significant differences between groups when i.v. topotecan was compared with either CAV or oral topotecan for overall response rate (ORR). Response rate was significantly better in participants receiving i.v. amrubicin than in those receiving a low dose of i.v. topotecan (38% versus 13%, respectively, p = 0.039). There was a statistically significant benefit in favour of oral topotecan compared with BSC (HR 0.61, 95% CI 0.43 to 0.87, p = 0.01). Drug acquisition costs for four cycles of treatment were estimated at £2550 for oral topotecan and £5979 for i.v. topotecan. Non-drug treatment costs accounted for an additional £1097 for oral topotecan and £4289 for i.v. topotecan. Total costs for the modelled time horizon of 5 years were £4854 for BSC, £11,048 for oral topotecan and between £16,914 and £17,369 for i.v. topotecan (depending on assumptions regarding time progression). Life expectancy was 0.4735, 0.7984 and 0.7784 years for BSC, oral topotecan and i.v. topotecan respectively. Total quality-adjusted life-years (QALYs) were 0.2247 and 0.4077, for BSC and oral topotecan respectively, resulting in an incremental cost-effectiveness ratio (ICER) of £33,851 per QALY gained. Total QALYs for i.v. topotecan were between 0.3875 and 0.4157 (depending on assumptions regarding time progression) resulting in an ICER between £74,074 and £65,507 per QALY gained.Conclusions: Topotecan appeared to be better than BSC alone in terms of improved survival, and was as effective as CAV and less favourable than i.v. amrubicin in terms of response. Oral topotecan and i.v. topotecan were similar in efficacy. Topotecan offers additional benefit over BSC, but at increased cost. ICERs for i.v. topotecan, compared with BSC, were high and suggest that it is unlikely to be a cost-effective option. The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective. Further research into the QoL of patients with relapsed SCLC could identify the impacts of disease progression and treatment response.<br/
Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients
No full textObjectives: To assess the effectiveness and costeffectiveness of oesophageal Doppler monitoring (ODM) compared with conventional clinical assessment and other methods of monitoring cardiovascular function. Data sources: Electronic databases and relevant websites from 1990 to May 2007 were searched. Review methods: This review was based on a systematic review conducted by the US Agency for Healthcare Research and Quality (AHRQ), supplemented by evidence from any additional studies identified. Comparator interventions for effectiveness were standard care, pulmonary artery catheters (PACs), pulse contour analysis monitoring and lithium or thermodilution cardiac monitoring. Data were extracted on mortality, length of stay overall and in critical care, complications and quality of life. The economic assessment evaluated strategies involving ODM compared with standard care, PACs, pulse contour analysis monitoring and lithium or thermodilution cardiac monitoring. Results: The AHRQ report contained eight RCTs and was judged to be of high quality overall. Four comparisons were reported: ODM plus central venous pressure (CVP) monitoring plus conventional assessment vs CVP monitoring plus conventional assessment
during surgery; ODM plus conventional assessment vs CVP monitoring plus conventional assessment during surgery; ODM plus conventional assessment vs conventional assessment during surgery; and ODM plus CVP monitoring plus conventional assessment vs CVP monitoring plus conventional assessment postoperatively. Five studies compared ODM plus CVP monitoring plus conventional assessment with CVP monitoring plus conventional assessment during surgery. There were fewer deaths [Peto odds ratio (OR) 0.13, 95% CI 0.02–0.96], fewer major complications (Peto OR 0.12, 95% CI 0.04–0.31), fewer total complications (fixed-effects OR 0.43, 95% CI 0.26–0.71) and shorter length of stay (pooled estimate not presented, 95% CI –2.21 to –0.57) in the ODM group. The results of the meta analysis of mortality should be treated with caution owing to the low number of events and low overall number of patients in the combined totals. Three studies compared ODM plus conventional assessment with conventional assessment during surgery. There was no evidence of a difference in mortality (fixed-effects OR 0.81, 95% CI 0.23–2.77). Length of hospital stay was shorter in all three studies in the ODM group. Two studies compared ODM plus CVP monitoring plus conventional assessment vs CVP monitoring plus conventional assessment in critically ill patients. The patient groups were quite different (cardiac surgery and major trauma) and neither study, nor a meta-analysis, showed a statistically significant difference in mortality (fixed-effects OR 0.84, 95% CI 0.41–1.70). Fewer patients in the ODM group experienced complications (OR 0.49, 95% CI 0.30–0.81) and both studies reported a statistically significant shorter median length of hospital stay in that group. No economic evaluations that met the inclusion criteria were identified from the existing literature so a series of balance sheets was constructed. The results show that ODM strategies are likely to be cost-effective. Conclusions: More formal economic evaluation would allow better use of the available data. All identified studies were conducted in unconscious patients. However, further research is needed to evaluate new ODM probes that may be tolerated by awake patients. Given the paucity of the existing economic evidence base, any further primary research should include an economic evaluation or should provide data suitable for use in an economic model.The Health Services Research Unit and the Health Economics Research Unit are both core funded by the Chief Scientist Office of the Scottish Government Health Directorate.Peer reviewedPublisher PD
The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis.
No full textObjectives: To review the evidence for an association of white matter hyperintensities with risk of stroke, cognitive decline, dementia, and death.
Design: Systematic review and meta-analysis.
Data sources: PubMed from 1966 to 23 November 2009.
Study selection: Prospective longitudinal studies that used magnetic resonance imaging and assessed the impact of white matter hyperintensities on risk of incident stroke, cognitive decline, dementia, and death, and, for the meta-analysis, studies that provided risk estimates for a categorical measure of white matter hyperintensities, assessing the impact of these lesions on risk of stroke, dementia, and death.
Data extraction: Population studied, duration of follow-up, method used to measure white matter hyperintensities, definition of the outcome, and measure of the association of white matter hyperintensities with the outcome.
Data synthesis: 46 longitudinal studies evaluated the association of white matter hyperintensities with risk of stroke (n=12), cognitive decline (n=19), dementia (n=17), and death (n=10). 22 studies could be included in a meta-analysis (nine of stroke, nine of dementia, eight of death). White matter hyperintensities were associated with an increased risk of stroke (hazard ratio 3.3, 95% confidence interval 2.6 to 4.4), dementia (1.9, 1.3 to 2.8), and death (2.0, 1.6 to 2.7). An association of white matter hyperintensities with a faster decline in global cognitive performance, executive function, and processing speed was also suggested.
Conclusion: White matter hyperintensities predict an increased risk of stroke, dementia, and death. Therefore white matter hyperintensities indicate an increased risk of cerebrovascular events when identified as part of diagnostic investigations, and support their use as an intermediate marker in a research setting. Their discovery should prompt detailed screening for risk factors of stroke and dementia
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