Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis.

PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low µM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.

Frontal sinus stenting in endoscopic sinus surgery: the 10-year Oxford experience.

BACKGROUND: Frontal sinus stents have been introduced to reduce frontal sinus re-stenosis after surgery and to improve outcomes. METHOD: This study was a retrospective analysis of 19 patients who had endoscopic sinus surgery with approach to the frontal sinus and insertion of a soft sinus stent. RESULTS: The frontal recess was patent in 78.9 per cent and stenosed in 21.1 per cent of patients; no completely closed recesses were observed. Mean follow up was 20.7 months, and time period of stenting was 9.8 months on average; complications were observed in 47.4 per cent of the patients, with post-operative sinonasal infection being the most common. CONCLUSION: In the authors' experience, indications for frontal sinus stenting include recalcitrant chronic rhinosinusitis after multiple functional endoscopic sinus surgeries (especially in chronic rhinosinusitis with nasal polyps), patients with history of important craniofacial surgery or trauma, and recurrent mucoceles. The stent was overall well tolerated as only minor complications were observed. Close clinical follow up is mandatory.

Evaluation of a training programme for critical incident debrief facilitators.

BACKGROUND: Critical incident debriefs are a commonly used occupational health tool for supporting staff after traumatic work incidents. However, there is a dearth of literature evaluating training programmes for debrief facilitators. AIMS: To evaluate a 5-day training programme to equip healthcare, social care and voluntary, community and social enterprise sector staff to act as post-incident peer supporters and debrief facilitators. METHODS: A mixed-methods, single-arm, before-and-after study. Data were collected at baseline and post-training. The quantitative outcome measure was 'Confidence'; the sum of two items measuring confidence in (i) supporting peers after critical incidents and (ii) facilitating post-incident structured team discussions. At post-training, quantitative and qualitative feedback regarding experiences and perceptions of the training was also gathered. RESULTS: We recruited 45 participants between October 2021 and January 2022. Confidence in supporting peers following incidents and facilitating post-incident structured team discussions increased significantly following the training, t(35) = -6.77, P < 0.001. A majority of participants reported they would do things differently because of the training and that they found the training relevant, useful and engaging. Summative content analysis of qualitative feedback indicated that participants (i) believed the role plays were an important learning tool and (ii) thought it was important that the trainer was engaging. Some participants would have preferred in-person delivery. CONCLUSIONS: Participants valued training in post-incident peer support and debriefing skills. Organizations implementing post-incident support pathways could usefully include this training and ensure optimal uptake and engagement by (i) providing in-person and online delivery options and (ii) including role play as a learning technique.

Desmoid tumour of the external ear and mastoid following middle-ear surgery.

BACKGROUND: Desmoid tumours (aggressive fibromatosis) are rare, locally invasive, benign tumours. The following case represented a diagnostic challenge, because of the uncommon nature of the lesion. CASE REPORT: A 26-year-old woman, who had previously undergone middle-ear surgery for cholesteatoma, presented with a painful swelling involving the post-auricular area and the conchal bowl. Initially, it was believed to be an infective process related to the surgery or an unusual cholesteatoma recurrence. Following investigations, which involved imaging and histology, the swelling was diagnosed as a desmoid tumour, and the patient received chemotherapy. CONCLUSION: Two incidences of paediatric desmoid tumours affecting the ear have been described in the literature, but there is no previous report of a desmoid tumour related to ear surgery. Desmoid tumours have, however, been reported following trauma, including surgery.

Design and preparation of N-linked hydroxypyridine-based APJ agonists.

Agonism of the apelin receptor (APJ) has demonstrated beneficial effects in models of heart failure. We have previously disclosed compounds such as 4, which showed good APJ agonist activity but were metabolized to the mono-demethylated, non-interconverting atropisomer metabolites. Herein, we detail the design and optimization of a novel series of N-linked APJ agonists with good potency, metabolic stability, and rat pharmacokinetic profile, which are unable to undergo the same metabolic mono-demethylation cleavage.

Outcomes of Patients with a pH<7.0 Presenting to the Emergency Department (OPpHED Study).

Objectives The aim of this study was to assess the mortality and predictive factors in patients presenting with a pH<7.0 to the emergency department (ED). Methods A retrospective study of patients presenting to the ED of University Hospital Galway with a pH<7.0 from January 2014 to December 2017 was performed. A pH<7.0 on arrival to the ED from either an arterial or venous sample as measured by the blood gas analyser machine were assessed for inclusion. Results A total of 130 patients presented to ED over a 4-year period, with a mean age of 58 ±20 years. Eighty-one (63%) patients of the total cohort were male. In terms of aetiology of presentation, 66 (51%) cases were from cardiac arrest (CA), while the remaining 64 (49%) cases were non-cardiac arrest (NCA) related. Twenty-eight-day mortality was 69.5% overall, with significant mortality in the CA group (89%) compared to the NCA group (48%) (p<0.00). A modified early warning score (MEWS) (odds ratio [OR] 1.37, 95% CI: 1.18-1.59) and PCO2 ([OR] 1.35, 95% CI: 1.08-1.68.) were predictive of mortality. Conclusion In patients presenting to the ED with a pH of <7.0 the overall mortality was 69.5%, with survival more likely in NCA aetiologies. Mortality was associated with higher pCO2 and MEWS.

The use of modified Montgomery T-tubes as frontal sinus stents: how I do it.

BACKGROUND: Frontal sinus surgery is challenging as the frontal recess is prone to re-stenosis and there is subsequent occlusion of the frontal sinus outflow tract. In an attempt to maintain the frontal recess calibre and reduce frontal sinus re-stenosis, frontal sinus stents have been used with different materials and varying results. OBJECTIVE: This paper presents the technique of using a modified Montgomery T-tube as a frontal sinus stent. RESULTS AND CONCLUSION: The use of a soft, self-retaining and non-absorbable stent that can be used for stenting of the frontal sinus is described. Our technique is safe, effective, inexpensive and well tolerated.

Direct drive with the argon fluoride laser as a path to high fusion gain with sub-megajoule laser energy.

Argon fluoride (ArF) is currently the shortest wavelength laser that can credibly scale to the energy and power required for high gain inertial fusion. ArF's deep ultraviolet light and capability to provide much wider bandwidth than other contemporary inertial confinement fusion (ICF) laser drivers would drastically improve the laser target coupling efficiency and enable substantially higher pressures to drive an implosion. Our radiation hydrodynamics simulations indicate gains greater than 100 are feasible with a sub-megajoule ArF driver. Our laser kinetics simulations indicate that the electron beam-pumped ArF laser can have intrinsic efficiencies of more than 16%, versus about 12% for the next most efficient krypton fluoride excimer laser. We expect at least 10% 'wall plug' efficiency for delivering ArF light to target should be achievable using solid-state pulsed power and efficient electron beam transport to the laser gas that was demonstrated with the U.S. Naval Research Laboratory's Electra facility. These advantages could enable the development of modest size and lower cost fusion power plant modules. This would drastically change the present view on inertial fusion energy as being too expensive and the power plant size too large. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 1)'.

Salmonella source attribution in a subtropical state of Australia: capturing environmental reservoirs of infection.

Salmonellosis is a leading cause of hospitalisation due to gastroenteritis in Australia. A previous source attribution analysis for a temperate state in Australia attributed most infections to chicken meat or eggs. Queensland is in northern Australia and includes subtropical and tropical climate zones. We analysed Queensland notifications for salmonellosis and conducted source attribution to compare reservoir sources with those in southern Australia. In contrast to temperate Australia, most infections were due to non-Typhimurium serotypes, with particularly high incidence in children under 5 years and strong seasonality, peaking in summer. We attributed 65.3% (95% credible interval (CrI) 60.6-73.2) of cases to either chicken meat or eggs and 15.5% (95% CrI 7.0-19.5) to nuts. The subtypes with the strongest associations with nuts were Salmonella Aberdeen, S. Birkenhead, S. Hvittingfoss, S. Potsdam and S. Waycross. All five subtypes had high rates of illness in children under 5 years (ranging from 4/100 000 to 23/100 000), suggesting that nuts may be serving as a proxy for environmental transmission in the model. Australia's climatic range allows us to conduct source attribution in different climate zones with similar food consumption patterns. This attribution provides evidence for environment-mediated transmission of salmonellosis in sub-tropical regions.

Mitigation of cross-beam energy transfer in inertial-confinement-fusion plasmas with enhanced laser bandwidth.

Cross-beam energy transfer (CBET) is a significant energy-loss mechanism in directly driven inertial-confinement-fusion (ICF) targets. One strategy for mitigating CBET is to increase the bandwidth of the laser light, thereby disrupting the resonant three-wave interactions that underlie this nonlinear scattering process. Here, we report on numerical simulations performed with the wave-based code lpse that show a significant reduction in CBET for bandwidths of 2-5 THz (corresponding to a normalized bandwidth of 0.2%-0.6% at a laser wavelength of 351nm) under realistic plasma conditions. Such bandwidths are beyond those available with current high-energy lasers used for ICF, but could be achieved using stimulated rotation Raman scattering in diatomic gases like nitrogen.

Increasing likelihood of advanced pulmonary tuberculosis at initial diagnosis in a low-incidence US state.

SETTING: Arkansas, USA. OBJECTIVE: To investigate the relationship between an increase in the proportion of cases with advanced disease at first diagnosis and the recently observed slowing of the decline in tuberculosis (TB) incidence in low-incidence US states. DESIGN: We conducted descriptive statistical analyses of de-identified surveillance data of 1246 culture-confirmed TB patients reported in Arkansas during 1996-2013. We then fitted stepwise, multivariate logistic regression models to identify predictors for advanced disease at diagnosis, defined as having either smear-positive sputum or lung cavitation. RESULTS: From 1996 to 2013, the proportion of new cases with positive sputum smear and cases with lung cavitation increased from 51.6% to 75% and from 37.7% to 50%, respectively. Patients diagnosed during 2006-2013 were more likely to have positive sputum smears (adjusted odds ratio [aOR] 2.55, 95%CI 1.95-3.35) or lung cavitation (aOR 1.49, 95%CI 1.14-1.95) than those diagnosed during 1996-2005. During 1996-2013, age 15-64 years and excessive alcohol use were predictive of positive sputum smear or lung cavitation. CONCLUSION: Measures to reduce the proportion of cases with advanced disease at first diagnosis may be helpful to achieve further decline in TB incidence in low-incidence settings.

Variation in water disappearance, daily dose, and synovial fluid concentrations of tylvalosin and 3-O-acetyltylosin in commerical pigs during five day water medication with tylvalosin under field conditions.

Tylvalosin (TVN) is a water soluble macrolide used in swine production to treat enteric, respiratory, and arthritic pathogens. There is limited data on its distribution to synovial fluid beyond gavage studies, which do not represent field conditions. This study measured water disappearance, TVN concentration in the medicated water, daily dose, and concentrations of TVN and 3-O-acetyltylosin (3AT) in the synovial fluid and plasma of treated pigs over the administration period. The study emphasized understanding variation in tissue TVN concentrations within the context of a field setting. Sixty finisher pigs were housed individually with individual waterers. Six pigs were randomly allocated to the following time points for sample collection: 0, 48, 60, 72, 84, 96, 102, 108, 114, and 120 hr on medication. TVN was administered daily in the water for 5 days. Water disappearance and medicated water concentration were measured daily. At each time point, six pigs were euthanized and plasma and synovial fluid were collected for analysis. Median TVN synovial fluid concentrations ranged between <1 ng/ml (hour 0) to 3.6 ng/ml (hour 84). There was substantial variation between individual pigs for water disappearance (mean 4.36L and range 0-7.84). Median TVN water concentration was 59 ppm (range 38-75 ppm).

Origins and Scaling of Hot-Electron Preheat in Ignition-Scale Direct-Drive Inertial Confinement Fusion Experiments.

Planar laser-plasma interaction (LPI) experiments at the National Ignition Facility (NIF) have allowed access for the first time to regimes of electron density scale length (∼500 to 700 µm), electron temperature (∼3 to 5 keV), and laser intensity (6 to 16×10^{14} W/cm^{2}) that are relevant to direct-drive inertial confinement fusion ignition. Unlike in shorter-scale-length plasmas on OMEGA, scattered-light data on the NIF show that the near-quarter-critical LPI physics is dominated by stimulated Raman scattering (SRS) rather than by two-plasmon decay (TPD). This difference in regime is explained based on absolute SRS and TPD threshold considerations. SRS sidescatter tangential to density contours and other SRS mechanisms are observed. The fraction of laser energy converted to hot electrons is ∼0.7% to 2.9%, consistent with observed levels of SRS. The intensity threshold for hot-electron production is assessed, and the use of a Si ablator slightly increases this threshold from ∼4×10^{14} to ∼6×10^{14} W/cm^{2}. These results have significant implications for mitigation of LPI hot-electron preheat in direct-drive ignition designs.

Graduate Medical Education-Accelerated Change.

Graduate medical education (GME) is a critical link in the educational chain for physicians. Graduating from a strict apprenticeship model, GME has become a highly structured educational system whose peer-review organization provides an intentional and direct approach to ensuring that GME not only addresses the public's expectations of the profession but also positions itself to be a foundational structure in the outcomes-focused healthcare environment of the nation. GME is currently in a state of accelerated change-grounded in both educational and patient outcomes. This article provides an update on the significant changes that have occurred in GME over the past 10 years, a review of current initiatives and the perspectives related to educating physicians-in-training. Additionally, an analysis is provided on the future of GME, including areas of continued focus and uncertainty.

Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors.

Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.

Pulling together and pulling apart: influences of convergence and divergence on distributed healthcare teams.

Effective healthcare requires both competent individuals and competent teams. With this recognition, health professions education is grappling with how to factor team competence into training and assessment strategies. These efforts are impeded, however, by the absence of a sophisticated understanding of the the relationship between competent individuals and competent teams . Using data from a constructivist grounded theory study of team-based healthcare for patients with advanced heart failure, this paper explores the relationship between individual team members' perceived goals, understandings, values and routines and the collective competence of the team. Individual interviews with index patients and their healthcare team members formed Team Sampling Units (TSUs). Thirty-seven TSUs consisting of 183 interviews were iteratively analysed for patterns of convergence and divergence in an inductive process informed by complex adaptive systems theory. Convergence and divergence were identifiable on all teams, regularly co-occurred on the same team, and involved recurring themes. Convergence and divergence had nonlinear relationships to the team's collective functioning. Convergence could foster either shared action or collective paralysis; divergence could foster problematic incoherence or productive disruption. These findings advance our understanding of the complex relationship between the individual and the collective on a healthcare team, and they challenge conventional narratives of healthcare teamwork which derive largely from acute care settings and emphasize the importance of common goals and shared mental models. Complex adaptive systems theory helps us to understand the implications of these insights for healthcare teams' delivery of care for the complex, chronically ill.

'Multi-cropping', Intercropping and Adaptation to Variable Environments in Indus South Asia.

Past human populations are known to have managed crops in a range of ways. Various methods can be used, singly or in conjunction, to reconstruct these strategies, a process which lends itself to the exploration of socio-economic and political themes. This paper endeavours to unpack the concept of 'multi-cropping' by considering diversity and variation in the cropping practices of the populations of South Asia's Indus Civilisation. It argues that nuanced interpretations of the evidence provided by the combinations of crop seeds and weeds present in specific contexts and phases of occupation can reveal much about Indus cropping strategies, which in turn enables consideration of issues related to adaptation, intensification and resilience in the face of changing social, political, economic and environmental climates.

Approaching rice domestication in South Asia: New evidence from Indus settlements in northern India.

The nature and timing of rice domestication and the development of rice cultivation in South Asia is much debated. In northern South Asia there is presently a significant gap (c.4200 years) between earliest evidence for the exploitation of wild rice (Lahuradewa c.6000 BCE) and earliest dated evidence for the utilisation of fully domesticated rice (Mahagara c.1800 BCE). The Indus Civilisation (c.3000-1500 BCE) developed and declined during the intervening period, and there has been debate about whether rice was adopted and exploited by Indus populations during this 'gap'. This paper presents new analysis of spikelet bases and weeds collected from three Indus Civilisation settlements in north-west India, which provide insight into the way that rice was exploited. This analysis suggests that starting in the period before the Indus urban phase (Early Harappan) and continuing through the urban (Mature Harappan/Harappan), post-urban (Late Harappan) and on into the post-Indus Painted Grey Ware (PGW) period, there was a progressive increase in the proportion of domesticated-type spikelet bases and a decrease in wild-types. This pattern fits with a model of the slow development of rice exploitation from wild foraging to agriculture involving full cultivation. Importantly, the accompanying weeds show no increased proportions of wetland species during this period. Instead a mix of wetland and dryland species was identified, and although these data are preliminary, they suggest that the development of an independent rice tradition may have been intertwined with the practices of the eastern most Indus peoples. These data also suggest that when fully domesticated Oryza sativa ssp. japonica was introduced around 2000 BCE, it arrived in an area that was already familiar with domesticated rice cultivation and a range of cultivation techniques.