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Effects of Centralizing Acute Stroke Services on Stroke Care Provision in Two Large Metropolitan Areas in England
No full textBackground and Purpose-In 2010, Greater Manchester and London centralized acute stroke care into hyperacute units (Greater Manchester=3, London=8), with additional units providing ongoing specialist stroke care nearer patients' homes. Greater Manchester patients presenting within 4 hours of symptom onset were eligible for hyperacute unit admission; all London patients were eligible. Research indicates that postcentralization, only London's stroke mortality fell significantly more than elsewhere in England. This article attempts to explain this difference by analyzing how centralization affects provision of evidence-based clinical interventions. Methods-Controlled before and after analysis was conducted, using national audit data covering Greater Manchester, London, and a noncentralized urban comparator (38 623 adult stroke patients, April 2008 to December 2012). Likelihood of receiving all interventions measured reliably in pre- and postcentralization audits (brain scan; stroke unit admission; receiving antiplatelet; physiotherapist, nutrition, and swallow assessments) was calculated, adjusting for age, sex, stroke-type, consciousness, and whether stroke occurred in-hospital. Results-Postcentralization, likelihood of receiving interventions increased in all areas. London patients were overall significantly more likely to receive interventions, for example, brain scan within 3 hours: Greater Manchester=65.2% (95% confidence interval=64.3-66.2); London=72.1% (71.4-72.8); comparator=55.5% (54.8-56.3). Hyperacute units were significantly more likely to provide interventions, but fewer Greater Manchester patients were admitted to these (Greater Manchester=39%; London=93%). Differences resulted from contrasting hyperacute unit referral criteria and how reliably they were followed. Conclusions-Centralized systems admitting all stroke patients to hyperacute units, as in London, are significantly more likely to provide evidence-based clinical interventions. This may help explain previous research showing better outcomes associated with fully centralized models
The Reliability and Reproducibility of Corneal Confocal Microscopy in Children
No full textPURPOSE: To assess the image and patient level interrater agreement and repeatability within 1 month for corneal nerve fiber length (CNFL) measured using in vivo corneal confocal microscopy (IVCCM) in children.METHODS: Seventy-one subjects (mean [SD] age 14.3 [2.6] years, range 8-18 years; 44 with type 1 diabetes and 27 controls; 36 males and 35 females) were included. 547 images (∼6 images per subject) were analyzed manually by two independent and masked observers. One-month repeat visit images were analyzed by a single masked observer in 21 patients. Automated image analysis was then performed using a specialized computerized software (ACCMetrics).RESULTS: For CNFL, the ICC (95% CI) were 0.94 (0.93-0.95) for image-level, 0.86 (0.78-0.91) for patient-level, and 0.88 (0.72-0.95) for the 1-month repeat assessment, and the Bland-Altman plots showed minimal bias between observers. Although there was excellent agreement between manual and automated analysis according to an ICC 0.89 (0.82-0.93), the Bland-Altman plot showed a consistent bias with manual measurements providing higher readings.CONCLUSIONS: In vivo corneal confocal microscopy image analysis shows good reproducibility with excellent intraindividual and interindividual variability in pediatric subjects. Since the image-level reproducibility is stronger than the patient-level reproducibility, refinement of the method for image selection will likely further increase the robustness of this novel, rapid, and noninvasive approach to detect early neuropathy in children with diabetes. Further studies on the use of IVCCM to identify early subclinical neuropathy in children are indicated.</p
Carers' experiences of involvement in care planning: a qualitative exploration of the facilitators and barriers to engagement with mental health services.
No full textBACKGROUND: Formal recognition and involvement of carers in mental health services has been the focus of recent policy and practice initiatives as well as being supported by carers themselves. However, carers still report feeling marginalised and distanced from services. A prominent theme is that that they are not listened to and their concerns are not taken seriously. Compared to service user views, the reasons underpinning carers' dissatisfaction with care-planning procedures have been relatively neglected in the research literature, despite the substantial and significant contribution that they make to mental health services. The aim of the study was to explore carers' experiences of the care planning process for people with severe mental illness. METHODS: Qualitative interviews and focus groups were undertaken with carers. Data were combined and analysed using framework analysis. RESULTS: Whilst identifying a shared desire for involvement and confirming a potential role for carers within services, our data highlighted that many carers perceive a lack of involvement in care planning and a lack of recognition and appreciation of their role from health professionals. Barriers to involvement included structural barriers, such as the timing and location of meetings, cultural barriers relating to power imbalances within the system and specific barriers relating to confidentiality. CONCLUSIONS: This qualitative study led by a researcher who was a carer herself has developed the understanding of the potential role of carers within the care planning process within mental health services, along with the facilitators and barriers to achieving optimal involvement
Study protocol for the randomised controlled trial: Ketamine augmentation of ECT to improve outcomes in depression (Ketamine-ECT study)
No full textBACKGROUND: There is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT. METHODS/DESIGN: The ketamine ECT study is a multi-site randomised, placebo-controlled, double blind trial. It was originally planned to recruit 160 moderately to severely depressed patients who had been clinically prescribed ECT. This recruitment target was subsequently revised to 100 patients due to recruitment difficulties. Patients will be randomly allocated on a 1:1 basis to receive either adjunctive ketamine or saline in addition to standard anaesthesia for ECT. The primary neuropsychological outcome measure is anterograde verbal memory (Hopkins Verbal Learning Test-Revised delayed recall task) after 4 ECT treatments. Secondary cognitive outcomes include verbal fluency, autobiographical memory, visuospatial memory and digit span. Efficacy is assessed using observer and self-report efficacy measures of depressive symptomatology. The effects of ECT and ketamine on cortical activity during cognitive tasks will be studied in a sub-sample using functional near-infrared spectroscopy (fNIRS). DISCUSSION: The ketamine-ECT study aims to establish whether or not adjunctive ketamine used together with standard anaesthesia for ECT will significantly reduce the adverse cognitive effects observed after ECT. Potential efficacy benefits of increased speed of symptom improvement and a reduction in the number of ECT treatments required will also be assessed, as will safety and tolerability of adjunctive ketamine. This study will provide important evidence as to whether adjunctive ketamine is routinely indicated for ECT given for depression in routine NHS clinical practice. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN14689382 (assigned 30/07/2012); EudraCT Number: 2011-005476-41
Influence of Extreme Weather and Climate Change on the Resilience of Power Systems: Impacts and Possible Mitigation Strategies
No full textA key driver for developing more sustainable energy systems is to decrease the effects of climate change, which could include an increase in the frequency, intensity and duration of severe weather events. Amongst others, extreme weather has a significant impact on critical infrastructures, and is considered one of the main causes of wide-area electrical disturbances worldwide. In fact, weather-related power interruptions often tend to be of high impact and sustained duration, ranging from hours to days, because of the large damage on transmission and distribution facilities. Hence, enhancing the grid resilience to such events is becoming of increasing interest. In this outlook, this paper first discusses the influence of weather and climate change on the reliability and operation of power system components. Since modeling the impact of weather is a difficult task because of its stochastic and unpredicted nature, a review of existing methodologies is provided in order to get an understanding of the key modeling approaches, challenges and requirements for assessing the effect of extreme weather on the frequency and duration of power system blackouts. Then, the emerging concept of resilience is discussed in the context of power systems as critical infrastructure, including several defense plans for boosting the resilience of power systems to extreme weather events. A comprehensive research framework is finally outlined, which can help understand and model the impact of extreme weather on power systems and how this can be prevented or mitigated in the future
High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: Different implications for vaccine prevention and prognosis
No full textBackground Characterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS). Method Dual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models. Results HPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p <0.0001) and OS (63% versus 13%; p <0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS (p <0.0001) and OS (p = 0.002). Conclusion In ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC
The Role of Protein-Ligand Contacts in Allosteric Regulation of the Escherichia coli Catabolite Activator Protein
No full textAllostery is a fundamental process by which ligand binding to a protein alters its activity at a distant site. Both experimental and theoretical evidence demonstrate that allostery can be communicated through altered slow relaxation protein dynamics without conformational change. The catabolite activator protein (CAP) of Escherichia coli is an exemplar for the analysis of such entropically driven allostery. Negative allostery in CAP occurs between identical cAMP binding sites. Changes to the cAMP-binding pocket can therefore impact the allosteric properties of CAP. Here we demonstrate, through a combination of coarse-grained modeling, isothermal calorimetry, and structural analysis, that decreasing the affinity of CAP for cAMP enhances negative cooperativity through an entropic penalty for ligand binding. The use of variant cAMP ligands indicates the data are not explained by structural heterogeneity between protein mutants. We observe computationally that altered interaction strength between CAP and cAMP variously modifies the change in allosteric cooperativity due to second site CAP mutations. As the degree of correlated motion between the cAMP-contacting site and a second site on CAP increases, there is a tendency for computed double mutations at these sites to drive CAP toward noncooperativity. Naturally occurring pairs of covarying residues in CAP do not display this tendency, suggesting a selection pressure to fine tune allostery on changes to the CAP ligand-binding pocket without a drive to a noncooperative state. In general, we hypothesize an evolutionary selection pressure to retain slow relaxation dynamics-induced allostery in proteins in which evolution of the ligand-binding site is occurring
Transnational capital and the political settlement of Ghana's oil economy
No full textGhana’s recent status as an oil producer focuses attention on the relationshipbetween domestic politics and transnational actors. While the political settlementsliterature is useful for focusing on how elite coalitions shape the governance ofnatural resources it is not explicit about the role of transnational factors in shapingand enabling these coalitions. As such there is a tendency to downplay thesignificance of transnational-national interactions and national-local dynamics. Thispaper analyses the changing nature of the political settlement in Ghana pre- andpost-oil and the role that transnational actors play in reshaping the coalitions whichunderpin and reproduce the overall settlement. We find that the discovery of oil hasnot radically altered the nature of Ghana’s political settlement, which remains of acompetitive clientelist form within which institutional functioning and policy actors are heavily influenced by the need of political elites to secure success in increasingly tightly-fought elections. These tendencies and the ongoing structural inequalities between transnational capital and the sovereign state have resulted in oil licences being negotiated on terms favouring external actors. Through primary data collected from key informant interviews and case studies we show that power lies with the external actors albeit through the elite brokerage of contracts. Within these bargaining processes we see parts of the Ghanaian state acting strongly andeffectively to serve both the interests of domestic elites and transnational capital. The combined effect of competitive clientelism and new sources of foreign capital is that structural issues and longer term planning decisions are largely deprioritised infavour of shorter-term gains
Drug Metabolism by Cytochrome P450 Enzymes: What Distinguishes the Pathways Leading to Substrate Hydroxylation Over Desaturation?
No full textCytochrome P450 enzymes are highly versatile biological catalysts in our body that react with a broad range of substrates. Key functions in the liver include the metabolism of drugs and xenobiotics. One particular metabolic pathway that is poorly understood relates to the P450 activation of aliphatic groups leading to either hydroxylation or desaturation pathways. A DFT and QM/MM study has been carried out on the factors that determine the regioselectivity of aliphatic hydroxylation over desaturation of compounds by P450 isozymes. The calculations establish multistate reactivity patterns, whereby the product distributions differ on each of the spin-state surfaces; hence spin-selective product formation was found. The electronic and thermochemical factors that determine the bifurcation pathways were analysed and a model that predicts the regioselectivity of aliphatic hydroxylation over desaturation pathways was established from valence bond and molecular orbital theories. Thus, the difference in energy of the O[BOND]H versus the O[BOND]C bond formed and the π-conjugation energy determines the degree of desaturation products. In addition, environmental effects of the substrate binding pocket that affect the regioselectivities were identified. These studies imply that bioengineering P450 isozymes for desaturation reactions will have to include modifications in the substrate binding pocket to restrict the hydroxylation rebound reaction