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

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

Lessons from the evaluation of the UK's NHS R&D Implementation Methods Programme

Background: Concern about the effective use of research was a major factor behind the creation of the NHS R&D Programme in 1991. In 1994, an advisory group was established to identify research priorities in research implementation. The Implementation Methods Programme (IMP) flowed from this, and its commissioning group funded 36 projects. In 2000 responsibility for the programme passed to the National Co-ordinating Centre for NHS Service Delivery and Organisation R&D, which asked the Health Economics Research Group (HERG), Brunel University, to conduct an evaluation in 2002. By then most projects had been completed. This evaluation was intended to cover: the quality of outputs, lessons to be learnt about the communication strategy and the commissioning process, and the benefits from the projects. Methods: We adopted a wide range of quantitative and qualitative methods. They included: documentary analysis, interviews with key actors, questionnaires to the funded lead researchers, questionnaires to potential users, and desk analysis. Results: Quantitative assessment of outputs and dissemination revealed that the IMP funded useful research projects, some of which had considerable impact against the various categories in the HERG payback model, such as publications, further research, research training, impact on health policy, and clinical practice. Qualitative findings from interviews with advisory and commissioning group members indicated that when the IMP was established, implementation research was a relatively unexplored field. This was reflected in the understanding brought to their roles by members of the advisory and commissioning groups, in the way priorities for research were chosen and developed, and in how the research projects were commissioned. The ideological and methodological debates associated with these decisions have continued among those working in this field. The need for an effective communication strategy for the programme as a whole was particularly important. However, such a strategy was never developed, making it difficult to establish the general influence of the IMP as a programme. Conclusion: Our findings about the impact of the work funded, and the difficulties faced by those developing the IMP, have implications for the development of strategic programmes of research in general, as well as for the development of more effective research in this field

Perceived Social Standing, Medication Nonadherence, and Systolic Blood Pressure in the Rural South

Purpose: Little is known about how perceived social standing versus traditional socioeconomic characteristics influence medication adherence and blood pressure (BP) among African American and white patients with hypertension in the rural southeastern United States. Methods: Perceived social standing, socioeconomic characteristics, self-reported antihypertensive medication adherence, and BP were measured at baseline in a cohort of rural African American and white patients (n = 495) with uncontrolled hypertension attending primary care practices. Multivariate models examined the relationship of perceived social standing and socioeconomic indicators with medication adherence and systolic BP. Findings: Medication nonadherence was reported by 40% of patients. Younger age [β = 0.20; P = .001], African American race [β = -0.30; P = .03], and lower perceived social standing [β = 0.08; P = .002] but not sex or traditional socioeconomic characteristics including education and household income, were significantly associated with lower medication adherence. Race-specific analyses revealed that this pattern was limited to African Americans and not observed in whites. In stepwise modeling, older age [β = 0.57, P = .001], African American race [β = 4.4; P = .03], and lower medication adherence [β = -1.7, P = .01] but not gender, education, or household income, were significantly associated with higher systolic BP. Conclusions: Lower perceived social standing and age, but not traditional socioeconomic characteristics, were significantly associated with lower medication adherence in African Americans. Lower medication adherence was associated with higher systolic BP. These findings suggest the need for tailored, culturally relevant medication adherence interventions in rural communities

Facilitators of Transforming Primary Care: A Look Under the Hood at Practice Leadership

This study examined how characteristics of practice leadership affect the change process in a statewide initiative to improve the quality of diabetes and asthma care

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

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)

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