Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilms

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Objectives: PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO)-donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against non-typeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. Methods: The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free LC/MS proteomic analyses were performed to identify differentially expressed proteins following NO treatment. Results: PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log-fold reduction in viability (p<0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log reduction was observed (p<0.01). Label-free proteomics showed that NO increased expression of sixteen proteins involved in metabolic and transcriptional/translational functions. Conclusions: NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm associated antibiotic tolerance

The added value of using convective-permitting regional climate model simulations to represent cloud band events over South America

Climate science has long explored whether higher resolution regional climate models (RCMs) provide improved simulation of regional climates over global climate models (GCMs). The advent of convective-permitting RCMs (CPRCMs), where sufficiently fine-scale grids allow explicitly resolving rather than parametrising convection, has created a clear distinction between RCM and GCM formulations. This study investigates the simulation of tropical-extratropical (TE) cloud bands in a suite of pan-South America convective-permitting Met Office Unified Model (UM) and Weather Research and Forecasting (WRF) climate simulations. All simulations produce annual cycles in TE cloud band frequency within 10–30% of observed climatology. However, too few cloud band days are simulated during the early summer (Nov–Dec) and too many during the core summer (Jan–Feb). Compared with their parent forcing, CPRCMs simulate more dry days but systematically higher daily rainfall rates, keeping the total rain biases low. During cloud band systems, the CPRCMs correctly reproduced the observed changes in tropical rain rates and their importance to climatology. Circulation analysis suggests that simulated lower subtropical rain rates during cloud bands systems, in contrast to the higher rates in the tropics, are associated with weaker northwesterly moisture flux from the Amazon towards southeast South America, more evident in the CPRCMs. Taken together, the results suggest that CPRCMs tend to be more effective at producing heavy daily rainfall rates than parametrised simulations for a given level of near-surface moist energy. The extent to which this improves or degrades biases present in the parent simulations is strongly region-dependent

Recent progress in understanding climate thresholds: ice sheets, the Atlantic meridional overturning circulation, tropical forests and responses to ocean acidification

This article reviews recent scientific progress, relating to four major systems that could exhibit threshold behaviour: ice sheets, the Atlantic meridional overturning circulation (AMOC), tropical forests and ecosystem responses to ocean acidification. The focus is on advances since the Intergovernmental Panel on Climate Change Fifth Assessment Report (IPCC AR5). The most significant developments in each component are identified by synthesizing input from multiple experts from each field. For ice sheets, some degree of irreversible loss (timescales of millennia) of part of the West Antarctic Ice Sheet (WAIS) may have already begun, but the rate and eventual magnitude of this irreversible loss is uncertain. The observed AMOC overturning has decreased from 2004–2014, but it is unclear at this stage whether this is forced or is internal variability. New evidence from experimental and natural droughts has given greater confidence that tropical forests are adversely affected by drought. The ecological and socio-economic impacts of ocean acidification are expected to greatly increase over the range from today’s annual value of around 400, up to 650 ppm CO2 in the atmosphere (reached around 2070 under RCP8.5), with the rapid development of aragonite undersaturation at high latitudes affecting calcifying organisms. Tropical coral reefs are vulnerable to the interaction of ocean acidification and temperature rise, and the rapidity of those changes, with severe losses and risks to survival at 2 °C warming above pre-industrial levels. Across the four systems studied, however, quantitative evidence for a difference in risk between 1.5 and 2 °C warming above pre-industrial levels is limited

Sun, Moon, Stars, Rain, Vol. 1 No. 1

The first issue of Sun, Moon, Stars, Rain a literary magazine published by Sigma Tau Delta

Sun, Moon, Stars, Rain, Vol. 1 No. 1

The first issue of Sun, Moon, Stars, Rain a literary magazine published by Sigma Tau Delta.https://scholarworks.sfasu.edu/smsr/1001/thumbnail.jp

Integrating a health-related-quality-of-life module within electronic health records: a comparative case study assessing value added

<p>Abstract</p> <p>Background</p> <p>Health information technology (HIT) applications that incorporate point-of-care use of health-related quality of life (HRQL) assessments are believed to promote patient-centered interactions between seriously ill patients and physicians. However, it is unclear how willing primary care providers are to use such HRQL HIT applications. The specific aim of this study was to explore factors that providers consider when assessing the value added of an HRQL application for their geriatric patients.</p> <p>Methods</p> <p>Three case studies were developed using the following data sources: baseline surveys with providers and staff, observations of staff and patients, audio recordings of patient-provider interactions, and semi-structured interviews with providers and staff.</p> <p>Results</p> <p>The primary factors providers considered when assessing value added were whether the HRQL information from the module was (1) duplicative of information gathered via other means during the encounter; (2) specific enough to be useful and/or acted upon, and; (3) useful for enough patients to warrant time spent reviewing it for all geriatric patients. Secondary considerations included level of integration of the HRQL and EHR, impact on nursing workflow, and patient reluctance to provide HRQL information.</p> <p>Conclusions</p> <p>Health-related quality of life modules within electronic health record systems offer the potential benefit of improving patient centeredness and quality of care. However, the modules must provide benefits that are substantial and prominent in order for physicians to decide that they are worthwhile and sustainable. Implications of this study for future research include the identification of perceived "costs" as well as a foundation for operationalizing the concept of "usefulness" in the context of such modules. Finally, developers of these modules may need to make their products customizable for practices to account for variation in EHR capabilities and practice workflows.</p

Bricoleurs Extraordinaire: Sports Coaches in Inter War Britain

In Inter War Britain, individuals exploited their athletic skills by pursuing professional careers, or adopting amateur roles, as instructors, trainers and coaches, invariably drawing from, and elaborating on, existing practices. The coach was the master of a body of specialist craft knowledge, the tacit nature of which was transmitted through ‘stealing with the eyes’ as the apprentice watched the master in action (Gamble, 2001). Professional coaches saw themselves as practical men whose experiential knowledge concerning diet, physiological and psychological preparation, stimulants, massaging, medical treatments, talent identification, and so on provided critical components in their coaching ‘toolbox’ (Nelson, 1924, 25-26). Craft knowledge was never static. Coaching expertise is a fluid, cyclical process with practitioners continuously redeveloping their competencies (Turner, Nelson and Potrac, 2012, 323), and part of traditional craft expertise was the ability to react positively to shifting circumstances. Coaches were constantly stimulated to experiment by competitors, commercialisation, and emerging technologies (Clegg, 1977, 244), and they exemplified the notion of the ‘Bricoleur’ in constantly trialling emerging knowledge, intuitively accepting or rejecting appropriate material. This paper explores the ways in which practitioners developed their coaching ‘toolbox’ in Inter War Britain by drawing on examples from newspaper reports, personal and public archives, and instructional texts (eg. Tilden, 1920; Gent, 1922; Nelson, 1924; Mussabini, 1926; Lowe and Porritt, 1929; Abrahams and Abrahams, 1936). The author highlights the range of knowledge that coaches had at their command, well before the emergence of sports science and coaching certification programmes, and questions assumptions that coaches can no longer rely solely on ‘learning the trade’ through experience (Evans and Light, 2007). As Winchester et al. (2013) have emphasised, knowledge, skills, attitudes, and insights are developed from daily experiences in sport, work and at home, as well as through exposure to the coaching environment, and contemporary coaches still employ a largely implicit form of knowledge, closely connected to past experiences, which shares similarities with Inter War craft knowledge (Smith and Cushion, 2006, 363; Jones, Armour and Potrac, 2003), while identifying experimentation and experience as key reference points (Irwin, Hanton and Kerwin, 2004, 436, 439; Potrac, Jones and Cushion, 2007)

Who needs what from a national health research system: Lessons from reforms to the English Department of Health's R&D system

This article has been made available through the Brunel Open Access Publishing Fund.Health research systems consist of diverse groups who have some role in health research, but the boundaries around such a system are not clear-cut. To explore what various stakeholders need we reviewed the literature including that on the history of English health R&D reforms, and we also applied some relevant conceptual frameworks. We first describe the needs and capabilities of the main groups of stakeholders in health research systems, and explain key features of policymaking systems within which these stakeholders operate in the UK. The five groups are policymakers (and health care managers), health professionals, patients and the general public, industry, and researchers. As individuals and as organisations they have a range of needs from the health research system, but should also develop specific capabilities in order to contribute effectively to the system and benefit from it. Second, we discuss key phases of reform in the development of the English health research system over four decades - especially that of the English Department of Health's R&D system - and identify how far legitimate demands of key stakeholder interests were addressed. Third, in drawing lessons we highlight points emerging from contemporary reports, but also attempt to identify issues through application of relevant conceptual frameworks. The main lessons are: the importance of comprehensively addressing the diverse needs of various interacting institutions and stakeholders; the desirability of developing facilitating mechanisms at interfaces between the health research system and its various stakeholders; and the importance of additional money in being able to expand the scope of the health research system whilst maintaining support for basic science. We conclude that the latest health R&D strategy in England builds on recent progress and tackles acknowledged weaknesses. The strategy goes a considerable way to identifying and more effectively meeting the needs of key groups such as medical academics, patients and industry, and has been remarkably successful in increasing the funding for health research. There are still areas that might benefit from further recognition and resourcing, but the lessons identified, and progress made by the reforms are relevant for the design and coordination of national health research systems beyond England.This article is available through the Brunel Open Access Publishing Fund

Community advisory boards guiding engaged research efforts within a clinical translational sciences award: Key contextual factors explored

Background: Engaging stakeholders in research carries the promise of enhancing the research relevance, transparency, and speed of getting findings into practice. By describing the context and functional aspects of stakeholder groups, like those working as community advisory boards (CABs), others can learn from these experiences and operationalize their own CABs. Our objective is to describe our experiences with diverse CABs affiliated with our community engagement group within our institution’s Clinical Translational Sciences Award (CTSA). We identify key contextual elements that are important to administering CABs. Methods: A group of investigators, staff, and community members engaged in a 6-month collaboration to describe their experiences of working with six research CABs. We identified the key contextual domains that illustrate how CABS are developed and sustained. Two lead authors, with experience with CABs and identifying contextual domains in other work, led a team of 13 through the process. Additionally, we devised a list of key tips to consider when devising CABs. Results: The final domains include (1) aligned missions among stakeholders (2) resources/support, (3) defined operational processes/shared power, (4) well-described member roles, and (5) understanding and mitigating challenges. The tips are a set of actions that support the domains. Conclusions: Identifying key contextual domains was relatively easy, despite differences in the respective CAB’s condition of focus, overall mission, or patient demographics represented. By contextualizing these five domains, other research and community partners can take an informed approach to move forward with CAB planning and engaged research