Nitric oxide donation lowers blood pressure in adrenocorticotrophic hormone-induced hypertensive rats.

Adrenocorticotrophic hormone (ACTH) elevates systolic blood pressure (SBP) and lowers plasma reactive nitrogen intermediates in rats. We assessed the ability of NO donation from isosorbide dinitrate (ISDN) to prevent or reverse the hypertension caused by ACTH. In the prevention study, male Sprague Dawley rats were treated with ACTH (0.2 mg/kg/day) or saline control for 8 days, with either concurrent ISDN (100 mg/kg/day) via the drinking water or water alone. Animals receiving ISDN via the drinking water were provided with nitrate-free water for 8 hours every day. In the reversal study ISDN (100 mg/kg) or vehicle was given as a single oral dose on day 8. SBP was measured daily by the indirect tail-cuff method in conscious, restrained rats. ACTH caused a significant increase in SBP compared with saline (P < 0.0015). In the prevention study, chronic administration of ISDN (100 mg/kg/day) did not affect the SBP in either group. In the reversal study, ISDN significantly lowered SBP in ACTH-treated rats at 1 and 2.5 hours (132 +/- 3 mmHg (1 h) and 131 +/- 2 mmHg (2.5 h) versus 143 +/- 3 mmHg (0 h), P < 0.002), but not to control levels. It had no effect in control (saline treated) rats. In conclusion, the lowering of SBP by NO donation is consistent with the notion that ACTH-induced hypertension involves an impaired bioavailability or action of NO in vivo

Plugging a hole and lightening the burden: A process evaluation of a practice education team

Aim: To investigate the perceptions of clinical and senior managers about the role of Practice Educators employed in one acute hospital in the UK. Background: Producing nurses who are fit for practice, purpose and academic award is a key issue for nurse education partnership providers in the UK. Various new models for practice learning support structures and new roles within health care institutions have been established. To sustain funding and policy support for these models, there is a need for evaluation research. Design: A process evaluation methodology was employed to determine the current value of a practice education team and to provide information to guide future direction. Methods: Data were collected through semi-structured telephone interviews using a previously designed schedule. All senior nurse managers (N=5) and a purposive sample of clinical managers (n=13) who had personal experience of and perceptions about the role of practice educators provided the data. Interview notes were transcribed, coded and a thematic framework devised to present the results. Results: A number of key themes emerged including: qualities needed for being a successful practice educator; visibility and presence of practice educators; providing a link with the university; ‘plugging a hole’ in supporting learning needs; providing relief to practitioners in dealing with ‘the burden of students’; alleviating the ‘plight of students’; and effects on student attrition. Conclusions: Findings provided evidence for the continued funding of the practice educator role with improvements to be made in dealing with stakeholder expectations and outcomes. Relevance to clinical practice: In the UK, there still remain concerns about the fitness for practice of newly registered nurses, prompting a recent national consultation by the professional regulating body. Despite fiscal pressures, recommendations for further strengthening of all systems that will support the quality of practice learning may continue to sustain practice learning support roles

Preindustrial control simulations with HadGEM3-GC3.1 for CMIP6

Pre‐industrial control simulations with the HadGEM3‐GC3.1 climate model are presented at two resolutions. These are N216ORCA025, which has a horizontal resolution of 60km in the atmosphere and 0.25° in the ocean, and N96ORCA1, which has a horizontal resolution of 130km in the atmosphere and 1° in the ocean. The aim of this study is to document the climate variability in these simulations, make comparisons against present‐day observations (albeit under different forcing), and discuss differences arising due to resolution. In terms of interannual variability in the leading modes of climate variability the two resolutions behave generally very similarly. Notable differences are in the westward extent of El‐Niño and the pattern of Atlantic multidecadal variability, in which N216ORCA025 compares more favourably to observations, and in the Antarctic Circumpolar Current, which is far too weak in N216ORCA025. In the North Atlantic region, N216ORCA025 has a stronger and deeper AMOC, which compares well against observations, and reduced biases in temperature and salinity in the North Atlantic subpolar gyre (NA SPG). These simulations are being provided to the sixth Coupled Model Intercomparison Project (CMIP6) and provide a baseline against which further forced experiments may be assessed

Exploring Alternative Terrain in the Rehabilitation and Treatment of Offenders: Findings from a Prison-based Music Project

The arts in prison settings have provided an alternative or complimentary component to rehabilitation. Despite increased interest, studies capturing the voice of offenders participating in projects and the long-term impact are limited. Data from semistructured interviews with 18 men who had taken part in a music-based project while incarcerated, including one group of five participants who were tracked for 18 months with supplemented data from correctional staff and official documentation, is presented. Participants of the art-based projects comment on changes they believe to have derived from participating in the project, particularly relating to emotions, self-esteem, self-confidence, communication and social skills. An exoffender sample of participants reported that participation in art projects provide experiences that promote beneficial skills that have been useful for post prison life

Spelling-to-sound correspondences affect acronym recognition processes

A large body of research has examined the factors which affect the speed with which words are recognised in lexical decision tasks. Nothing has yet been reported concerning the important factors in differentiating acronyms (e.g. BBC, HIV, NASA) from non-words. It appears that this task poses little problem for skilled readers, in spite of the fact that acronyms have uncommon, even illegal, spellings in English. We used regression techniques to examine the role of a number of lexical and non-lexical variables known to be important in word processing in relation to lexical decision for acronym targets. Findings indicated that acronym recognition is affected by age of acquisition and imageability. In a departure from findings in word recognition,acronym recognition was not affected by frequency. Lexical decision responses for acronyms were also affected by the relationship between spelling and sound - a pattern not usually observed in word recognition. We argue that the complexity of acronym recognition means that the process draws phonological information in addition to semantics

Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure

Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a “MITF‐high” phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance “AXL‐high” phenotype. > 50% of melanomas progress with enriched “AXL‐high” populations, and because AXL is linked to de‐differentiation and invasiveness avoiding an “AXL‐high relapse” is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF‐induced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK re‐activation in a paracrine manner. Most importantly, EDN1 not only supports MITF‐high populations through the endothelin receptor B (EDNRB), but also AXL‐high populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXL‐high‐expressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXL‐high cells

Modelling UK house prices with structural breaks and conditional variance analysis

This paper differs from previous research by examining the existence of structural breaks in the UK regional house prices as well as in the prices of the different property types (flats, terraced, detached and semi-detached houses) in the UK as a whole, motivated by the uncertainty in the UK housing market and various financial events that may lead to structural changes within the housing market. Our paper enhances the conventional unit root tests by allowing for structural breaks, while including structural break tests strengthens our analysis. Our empirical results support the existence of structural breaks in the mean equation in seven out of thirteen regions of the UK as well as in three out of four property types, and in the variance equation in six regions and three property types. In addition, using a multivariate GARCH approach we examine both the behaviour of variances and covariances of the house price returns over time. Our results have significant implications for appropriate economic policy selection and investment management

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (\u3e4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies

Exploring PERMA in spectator sport: Applying positive psychology to examine the individual-level benefits of sport consumption

Sport spectating provides numerous benefits for sport organisations and individuals. In this paper we use a positive psychology approach to examine the individual-level benefits of sport consumption in order to investigate the activation of five domains of well-being: positive emotions, engagement, relationships, meaning, and accomplishment (PERMA). Using a two-study panel research design, we collected qualitative data from a sample of Australian Rules Football consumers. In the first study, we explored how the PERMA domains were activated during the season. Study two included a follow-up interview with eight initial respondents in the off-season. We found evidence of four PERMA domains that were activated in the sport spectator context by a variety of consumer experiences. The emergence of these domains in both studies suggests sport marketers would benefit from actions including: creating more social spaces within their stadiums, hosting regular off-season events, and creating social-media based competitions which promote fan engagement and interactions throughout the calendar year