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

Positive Predictive Value of Mammography: Comparison of Interpretations of Screening and Diagnostic Images by the Same Radiologist and by Different Radiologists

The purpose of this study was to evaluate whether the positive predictive value (PPV) after a recommendation for biopsy differs when one as opposed to more than one radiologist performs the workup after abnormal findings are discovered at screening mammography

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

Impact of Extrinsic Incubation Temperature on Natural Selection During Zika Virus Infection of Aedes Aegypti and Aedes Albopictus

Arthropod-borne viruses (arboviruses) require replication across a wide range of temperatures to perpetuate. While vertebrate hosts tend to maintain temperatures of approximately 37°C-40°C, arthropods are subject to ambient temperatures which can have a daily fluctuation of \u3e 10°C. Temperatures impact vector competence, extrinsic incubation period, and mosquito survival unimodally, with optimal conditions occurring at some intermediate temperature. In addition, the mean and range of daily temperature fluctuations influence arbovirus perpetuation and vector competence. The impact of temperature on arbovirus genetic diversity during systemic mosquito infection, however, is poorly understood. Therefore, we determined how constant extrinsic incubation temperatures of 25°C, 28°C, 32°C, and 35°C control Zika virus (ZIKV) vector competence and population dynamics within Aedes aegypti and Aedes albopictus mosquitoes. We also examined fluctuating temperatures which better mimic field conditions in the tropics. We found that vector competence varied in a unimodal manner for constant temperatures peaking between 28°C and 32°C for both Aedes species. Transmission peaked at 10 days post-infection for Aedes aegypti and 14 days for Aedes albopictus. Conversely, fluctuating temperature decreased vector competence. Using RNA-seq to characterize ZIKV population structure, we identified that temperature alters the selective environment in unexpected ways. During mosquito infection, constant temperatures more often elicited positive selection whereas fluctuating temperatures led to strong purifying selection in both Aedes species. These findings demonstrate that temperature has multiple impacts on ZIKV biology, including major effects on the selective environment within mosquitoes

Cost to Primary Care Practices of Responding to Payer Requests for Quality and Performance Data

PURPOSE We wanted to determine how much it costs primary care practices to participate in programs that require them to gather and report data on care quality indicators

Identification of a novel gene regulating amygdala-mediated fear extinction.

Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal nets, which are developmentally implicated in extinction. Next, by profiling extinction-driven BLA expression of QTL-linked genes, we nominated Ppid (peptidylprolyl isomerase D, a member of the tetratricopeptide repeat (TPR) protein family) as an extinction-related candidate gene. We then showed that Ppid was enriched in excitatory and inhibitory BLA neuronal populations, but at lower levels in the extinction-impaired mouse strain. Using a virus-based approach to directly regulate Ppid function, we demonstrated that downregulating BLA-Ppid impaired extinction, while upregulating BLA-Ppid facilitated extinction and altered in vivo neuronal extinction encoding. Next, we showed that Ppid colocalized with the glucocorticoid receptor (GR) in BLA neurons and found that the extinction-facilitating effects of Ppid upregulation were blocked by a GR antagonist. Collectively, our results identify Ppid as a novel gene involved in regulating extinction via functional actions in the BLA, with possible implications for understanding genetic and pathophysiological mechanisms underlying risk for trauma-related disorders

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

Lessons learned from implementing health coaching in the heart healthy lenoir hypertension study

Background: Health coaching is increasingly important in patient-centered medical homes. Objectives: Describe formative evaluation results and lessons learned from implementing health coaching to improve hypertension self-management in rural primary care. Methods: A hypertension collaborative was formed consisting of six primary care sites. Twelve monthly health coaching phone calls were attempted for 487 participants with hypertension. Lessons Learned: Participant engagement was challenging; 58% remained engaged, missing fewer than three consecutive calls. Multivariate analyses revealed that older age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01–1.05), African American race (O,R 1.73; 95% CI, 1.15–2.60), greater number of comorbidities (OR, 1.17; 95% CI, 1.05–1.30) and receiving coaching closer to enrollment (OR, 5.03; 95% CI, 2.53–9.99) were correlated independently with engagement. Participants reported the coaching valuable; 96% would recommend health coaching to others. Conclusions: Health coaching in hypertension care can be successful strategy for engaging more vulnerable groups. A more tailored approach may improve engagement with counseling