The Maresin 1-LGR6 axis decreases respiratory syncytial virus-induced lung inflammation.

The resolution of infection is an active process with specific molecular and cellular mechanisms that temper inflammation and enhance pathogen clearance. Here, the specialized pro-resolving mediator (SPM) Maresin 1 (MaR1) inhibited respiratory syncytial virus (RSV)-induced inflammation. inlerleukin-13 production from type 2 innate lymphoid cells (ILC) and CD4 T helper type 2 cells was decreased by exogenous MaR1. In addition, MaR1 increased amphiregulin production and decreased RSV viral transcripts to promote resolution. MaR1 also promoted interferon-ß production in mouse lung tissues and also in pediatric lung slices. MaR1 significantly inhibited the RSV-triggered aberrant inflammatory phenotype in FoxP3-expressing Tregs. The receptor for MaR1, leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), was constitutively expressed on Tregs. Following RSV infection, mice lacking Lgr6 had exacerbated type 2 immune responses with an increased viral burden and blunted responses to MaR1. Together, these findings have uncovered a multi-pronged protective signaling axis for MaR1-Lgr6, improving Tregs's suppressive function and upregulating host antiviral genes resulting in decreased viral burden and pathogen-mediated inflammation, ultimately promoting restoration of airway mucosal homeostasis.

Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases.

Airborne pathogens and environmental stimuli evoke immune responses in the lung. It is critical to health that these responses be controlled to prevent tissue damage and the compromise of organ function. Resolution of inflammation is a dynamic process that is coordinated by biochemical and cellular mechanisms. Recently, specialized proresolving mediators (SPMs) have been identified in resolution exudates. These molecules orchestrate anti-inflammatory and proresolving actions that are cell type specific. In this review, we highlight SPM biosynthesis, the influence of SPMs on the innate and adaptive immune responses in the lung, as well as recent insights from SPMs on inflammatory disease pathophysiology. Uncovering these mediators and cellular mechanisms for resolution is providing new windows into physiology and disease pathogenesis.

Slow oscillation-spindle cross-frequency coupling predicts overnight declarative memory consolidation in older adults.

Cross-frequency coupling (CFC) between brain oscillations during non-rapid-eye-movement (NREM) sleep (e.g. slow oscillations [SO] and spindles) may be a neural mechanism of overnight memory consolidation. Declines in CFC across the lifespan might accompany coinciding memory problems with ageing. However, there are few reports of CFC changes during sleep after learning in older adults, controlling for baseline effects. Our objective was to examine NREM CFC in healthy older adults, with an emphasis on spindle activity and SOs from frontal electroencephalogram (EEG), during a learning night after a declarative learning task, as compared to a baseline night without learning. Twenty-five older adults (M [SD] age = 69.12 [5.53] years; 64% female) completed a two-night study, with a pre- and post-sleep word-pair associates task completed on the second night. SO-spindle coupling strength and a measure of coupling phase distance from the SO up-state were both examined for between-night differences and associations with memory consolidation. Coupling strength and phase distance from the up-state peak were both stable between nights. Change in coupling strength between nights was not associated with memory consolidation, but a shift in coupling phase towards (vs. away from) the up-state peak after learning predicted better memory consolidation. Also, an exploratory interaction model suggested that associations between coupling phase closer to the up-state peak and memory consolidation may be moderated by higher (vs. lower) coupling strength. This study supports a role for NREM CFC in sleep-related memory consolidation in older adults.

Human NK Cell Cytoskeletal Dynamics and Cytotoxicity Are Regulated by LIM Kinase.

NK cells provide immune surveillance and host protection against viruses and tumors through their cytotoxic effector function. Cytoskeletal rearrangement is necessary for NK cell lytic granule trafficking and immune synapse formation to trigger apoptosis of targeted cells. LIM kinase (LIMK) regulates F-actin remodeling by phosphorylating cofilin to inhibit actin severing and depolymerization. In this study, in human NK cells, the glucocorticoid dexamethasone downregulated LIMK expression, F-actin accumulation at the immune synapse, lytic granule trafficking, and cytotoxicity. In contrast, the specialized proresolving mediator lipoxin A4 promoted NK cell LIMK expression, lytic granule polarization to the immune synapse and cytotoxicity. Using a LIMK inhibitor, we show that LIMK activity is necessary for NK cell cytotoxicity, including lipoxin A4's proresolving actions. Together, our findings identify LIMK as an important control mechanism for NK cell cytoskeletal rearrangement that is differentially regulated by glucocorticoids and specialized proresolving mediators to influence NK cell cytotoxicity.

Spontaneous generation of hydrogen peroxide from aqueous microdroplets.

We show H2O2 is spontaneously produced from pure water by atomizing bulk water into microdroplets (1 µm to 20 µm in diameter). Production of H2O2, as assayed by H2O2-sensitve fluorescence dye peroxyfluor-1, increased with decreasing microdroplet size. Cleavage of 4-carboxyphenylboronic acid and conversion of phenylboronic acid to phenols in microdroplets further confirmed the generation of H2O2 The generated H2O2 concentration was ∼30 µM (∼1 part per million) as determined by titration with potassium titanium oxalate. Changing the spray gas to O2 or bubbling O2 decreased the yield of H2O2 in microdroplets, indicating that pure water microdroplets directly generate H2O2 without help from O2 either in air surrounding the droplet or dissolved in water. We consider various possible mechanisms for H2O2 formation and report a number of different experiments exploring this issue. We suggest that hydroxyl radical (OH) recombination is the most likely source, in which OH is generated by loss of an electron from OH- at or near the surface of the water microdroplet. This catalyst-free and voltage-free H2O2 production method provides innovative opportunities for green production of hydrogen peroxide.

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-κB Regulators in Bacterial Pneumonia.

Specialized proresolving mediators (SPMs) decrease NF-κB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-κB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A4 (15-epi-LXA4), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-κB regulators A20 and single Ig IL-1R-related molecule (SIGIRR). Of interest, 15-epi-LXA4 induced A20 and SIGIRR in an lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) receptor-dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-κB-induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA4 also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-κB activity and to establish mechanisms for NF-κB regulation by SPMs for pneumonia resolution.

Harnessing Pseudomonas protegens to Control Bacterial Panicle Blight of Rice.

Bacterial panicle blight of rice is a seedborne disease caused by the bacterium Burkholderia glumae. This disease has affected rice production worldwide and its effects are likely to become more devastating with the continuous increase in global temperatures, especially during the growing season. The bacterium can cause disease symptoms in different tissues and at different developmental stages. In reproductive stages, the bacterium interferes with grain development in the panicles and, as a result, directly affects rice yield. Currently, there are no methods to control the disease because chemical control is not effective and completely resistant cultivars are not available. Thus, a promising approach is the use of antagonistic microorganisms. In this work, we identified one strain of Pseudomonas protegens and one strain of B. cepacia with antimicrobial activity against B. glumae in vitro and in planta. We further characterized the antimicrobial activity of P. protegens and found that this activity is associated with bacterial secretions. Cell-free secretions from P. protegens inhibited the growth of B. glumae in vitro and also prevented B. glumae from causing disease in rice. Although the specific molecules associated with these activities have not been identified, these findings suggest that the secreted fractions from P. protegens could be harnessed as biopesticides to control bacterial panicle blight of rice.

Mechanistic Study of Ruthenium-Catalyzed C-H Hydroxylation Reveals an Unexpected Pathway for Catalyst Arrest.

We have recently disclosed [(dtbpy)2RuCl2] as an effective precatalyst for chemoselective C-H hydroxylation of C(sp3)-H bonds and have noted a marked disparity in reaction performance between 4,4'-di- tert-butyl-2,2'-bipyridine (dtbpy)- and 2,2'-bipyridine (bpy)-derived complexes. A desire to understand the origin of this difference and to further advance this catalytic method has motivated the comprehensive mechanistic investigation described herein. Details of this reaction have been unveiled through evaluation of ligand structure-activity relationships, electrochemical and kinetic studies, and pressurized sample infusion high-resolution mass spectrometry (PSI-MS). Salient findings from this investigation include the identification of more than one active oxidant and three disparate mechanisms for catalyst decomposition/arrest. Catalyst efficiency, as measured by turnover number, has a strong inverse correlation with the rate and extent of ligand dissociation, which is dependent on the identity of bipyridyl 4,4'-substituent groups. Dissociated bipyridyl ligand is oxidized to mono- and bis- N-oxide species under the reaction conditions, the former of which is found to act as a potent catalyst poison, yielding a catalytically inactive tris-ligated [Ru(dtbpy)2(dtbpy N-oxide)]2+ complex. Insights gained through this work highlight the power of PSI-MS for studies of complex reaction processes and are guiding ongoing efforts to develop high-performance, next-generation catalyst systems for C-H hydroxylation.

Medical perspectives regarding goals-of-care consultations in Emergency Departments.

Goals-of-care discussions aim to establish patient values for shared medical decision-making. These discussions are relevant towards end-of-life as patients may receive non-beneficial treatments if they have never discussed preferences for care. End-of-life care is provided in Emergency Departments (EDs) but little is known regarding ED-led goals-of-care discussions. We aimed to explore practitioner perspectives on goals-of-care discussions for adult ED patients nearing end-of-life. We report the qualitative component of a mixed methods study regarding a 'Goals-of-Care' form in an Australian ED. Eighteen out of 34 doctors who completed the form were interviewed. We characterised ED-led goals-of-care consultations for the first time. Emergency doctors perceive goals-of-care discussions to be relevant to their practice and occurring frequently. They aim to ensure appropriate care is provided prior to review by the admitting team, focusing on limitations of treatment and clarity in the care process. ED doctors felt they could recognise end-of-life and that ED visits often prompt consideration of end-of-life care planning. They wanted long-term practitioners to initiate discussions prior to patient deterioration. There were numerous interpretations of palliative care concepts. Standardisation of language, education, collaboration and further research is required to ensure Emergency practitioners are equipped to facilitate these challenging conversations.

Human Trafficking Victim Identification, Assessment, and Intervention Strategies in South Texas Emergency Departments.

INTRODUCTION: Human-trafficking victims seek assistance for health issues in emergency departments. This point of contact provides an opportunity for screening and identification of the victim's situation, enabling intervention. METHODS: This descriptive research study was designed to identify whether a standard protocol is currently used to identify, assess, and intervene for human-trafficking victims in 47 south Texas counties. ED leaders were surveyed using a sequential set of strategies including online, e-mail, and/or phone surveys to identify the methods used in emergency departments screening for adult and child human-trafficking victims. RESULTS: Researchers surveyed 99 emergency departments in south Texas, which includes 21 counties bordering Mexico. Twenty-seven ED leaders responded (27.3%). Despite being located in an area with high rates of human trafficking, these leaders stated that few trafficking victims were identified in 2017. Eleven (40.7%) of the responding emergency departments specifically screened adults for human trafficking, and 10 (37.0%) specifically screened children for human trafficking. A variety of methods were used by each of these emergency departments to identify human-trafficking victims. DISCUSSION: The failure to recognize human-trafficking victims prevents assessment of the victim's status and further delays referral to appropriate resources. Barriers to screening for human trafficking included lack of awareness of the human-trafficking experience, need for clinical education related to evidence-based protocols, and need for validated screening instruments and standardization of processes that promote action and provide victim assistance.

Ligand-Induced Reductive Elimination of Ethane from Azopyridine Palladium Dimethyl Complexes.

Reductive elimination (RE) is a critical step in many catalytic processes. The reductive elimination of unsaturated groups (aryl, vinyl and ethynyl) from Pd(II) species is considerably faster than RE of saturated alkyl groups. Pd(II) dimethyl complexes ligated by chelating diimine ligands are stable toward RE unless subjected to a thermal or redox stimulus. Herein, we report the spontaneous RE of ethane from (azpy)PdMe2 complexes and the unique role of the redox-active azopyridine (azpy) ligands in facilitating this reaction. The (azpy)PdMe2 complexes are air- and moisture-stable in the solid form, but they readily produce ethane upon dissolution in polar solvents at temperatures from 10 °C to room temperature without the need for an external oxidant or elevated temperatures. Experimental and computational studies indicate that a bimolecular methyl transfer precedes the reductive elimination step, where both steps are facilitated by the redox-active azopyridine ligand.

Emergency consultants value medical scribes and most prefer to work with them, a few would rather not: a qualitative Australian study.

OBJECTIVE: The utilisation of medical scribes in the USA has enabled productivity gains for emergency consultants, though their personal experiences have not been widely documented. We aimed to evaluate the consultant experience of working with scribes in an Australian ED. METHODS: Emergency consultants working with scribes and those who declined to work with scribes were invited to participate in individual interviews (structured and semistructured questions) about scribes, scribe work and the scribe program in October 2016. RESULTS: Of 16 consultants, 13 participated in interviews, that is, 11 worked with scribes and 2 did not and 3 left Cabrini prior to the interviews. Consultants working with scribes found them most useful for capturing initial patient encounters, for finding information and completing discharge tasks. Scribes captured more details than consultants usually did. Editing was required for omissions, misunderstandings and rearranging information order, but this improved with increasing scribe experience. Consultants described changing their style to give more information to the patient in the room. Consultants felt more productive and able to meet demands. They also described enjoyment, less stress, less cognitive loading, improved ability to multitask, see complex patients and less fatigue.In interviews with the two consultants declining scribes, theme saturation was not achieved. Consultants declining scribes preferred to work independently. They did not like templated notes and felt that consultation nuances were lost. They valued their notes write-up time as time for cognitive processing of the presentation. They thought the scribe and computer impacted negatively on communication with the patient. CONCLUSION: Medical scribes were seen to improve physician productivity, enjoyment at work, ability to multitask and to lower stress levels. Those who declined scribes were concerned about losing important nuances and cognitive processing time for the case.

Feasibility evaluation of a pilot scribe-training program in an Australian emergency department.

Objective Medical scribes have an emerging and expanding role in health, particularly in Emergency Medicine in the US. Scribes assist physicians with documentation and clerical tasks at the bedside while the physician consults with his or her patient. Scribes increase medical productivity. The aim of the present study was to examine the feasibility of a pilot hospital-administered scribe-training program in Australia and to evaluate the ability of an American training course (Medical Scribe Training Systems) to prepare trainee scribes for clinical training in an emergency department in Australia. Methods The present study was a pilot, prospective, observational cohort study from September 2015 to February 2016 at Cabrini Emergency Department, Melbourne. Scribe trainees were enrolled in the pre-work course and then trained clinically. Feasibility of training scribes and limited efficacy testing of the course was undertaken. Results The course was acceptable to users and demand for training exists. There were many implementation tasks and issues experienced and resources were required to prepare the site for scribe implementation. Ten trainees were enrolled for preclinical training. Six candidates undertook clinical training, five achieved competency (required seven to 16 clinical shifts after the preclinical course). The training course was helpful and provided a good introduction to the scribe role. The course required adaptation to a non-US setting and the specific hospital setting. In addition, it needed more detail in some common emergency department topics. Conclusion Training scribes at a hospital in Australia is feasible. The US training course used can assist with preclinical training. Course modification is required. What is known about the topic? Scribes increase emergency physician productivity in Australia. There is no previous work on how to train scribes in Australia. What does this paper add? We show that implementing a scribe-training program is feasible and that a training package can be purchased from the US to train scribes in Australia and that it is useful. We also show the adaptation that the course may require to meet Australian emergency department needs. What are the implications for practitioners? Scribes could become an additional member of the emergency department team in Australia and can be trained locally.

Mechanism of Catalytic Oxidation of Styrenes with Hydrogen Peroxide in the Presence of Cationic Palladium(II) Complexes.

Kinetic studies, isotope labeling, and in situ high-resolution mass spectrometry are used to elucidate the mechanism for the catalytic oxidation of styrenes using aqueous hydrogen peroxide (H2O2) and the cationic palladium(II) compound, [(PBO)Pd(NCMe)2][OTf]2 (PBO = 2-(pyridin-2-yl)benzoxazole). Previous studies have shown that this reaction yields acetophenones with high selectivity. We find that H2O2 binds to Pd(II) followed by styrene binding to generate a Pd-alkylperoxide that liberates acetophenone by at least two competitive processes, one of which involves a palladium enolate intermediate that has not been previously observed in olefin oxidation reactions. We suggest that acetophenone is formed from the palladium enolate intermediate by protonation from H2O2. We replaced hydrogen peroxide with t-butyl hydroperoxide and found that, although the palladium enolate intermediate was observed, it was not on the major product-generating pathway, indicating that the form of the oxidant plays a key role in the reaction mechanism.

Catalytic Carbonylative Spirolactonization of Hydroxycyclopropanols.

A palladium-catalyzed cascade carbonylative spirolactonization of hydroxycyclopropanols has been developed to efficiently synthesize oxaspirolactones common to many complex natural products of important therapeutic value. The mild reaction conditions, high atom economy, broad substrate scope, and scalability of this new method were highlighted in expedient total syntheses of the Turkish tobacco natural products α-levantanolide and α-levantenolide in two and four steps, respectively. The hydroxycyclopropanol substrates are readily available in one step via a Kulinkovich reaction of the corresponding lactones. Mechanistic studies utilizing high-resolution electrospray ionization mass spectrometry (ESI-MS) identified several key intermediates in the catalytic cycle, as well as those related to catalyst decomposition and competitive pathways.

Characterizing the Long-Term PM2.5 Concentration-Response Function: Comparing the Strengths and Weaknesses of Research Synthesis Approaches.

The magnitude, shape, and degree of certainty in the association between long-term population exposure to ambient fine particulate matter (PM2.5 ) and the risk of premature death is one of the most intensely studied issues in environmental health. For regulatory risk analysis, this relationship is described quantitatively by a concentration-response (C-R) function that relates exposure to ambient concentrations with the risk of premature mortality. Four data synthesis techniques develop the basis for, and derive, this function: systematic review, expert judgment elicitation, quantitative meta-analysis, and integrated exposure-response (IER) assessment. As part of an academic workshop aiming to guide the use of research synthesis approaches, we developed criteria with which to evaluate and select among the approaches for their ability to inform policy choices. These criteria include the quality and extent of scientific support for the method, its transparency and verifiability, its suitability to the policy problem, and the time and resources required for its application. We find that these research methods are both complementary and interdependent. A systematic review of the multidisciplinary evidence is a starting point for all methods, providing the broad conceptual basis for the nature, plausibility, and strength of the associations between PM exposure and adverse health effects. Further, for a data-rich application like PM2.5 and premature mortality, all three quantitative approaches can produce estimates that are suitable for regulatory and benefit analysis. However, when fewer data are available, more resource-intensive approaches such as expert elicitation may be more important for understanding what scientists know, where they agree or disagree, and what they believe to be the most important areas of uncertainty. Whether implicitly or explicitly, all require considerable judgment by scientists. Finding ways for all these methods to acknowledge, appropriately elicit, and examine the implications of that judgment would be an important step forward for research synthesis.

An economic evaluation of the costs of training a medical scribe to work in Emergency Medicine.

OBJECTIVE: To undertake a cost analysis of training medical scribes in an ED. METHODS: This was a pilot, observational, single-centre study at Cabrini ED, Melbourne, Australia, studying the costs of initiating a scribe programme from the perspective of the hospital and Australian Health sector. Recruitment and training occurred between August 2015 and February 2016 and comprised of a prework course (1 month), prework training sessions and clinical training shifts for scribe trainees (2-4 months, one shift per week) who were trained by emergency physicians. Costs of start-up, recruitment, administration, preclinical training, clinical training shifts and productivity changes for trainers were calculated. RESULTS: 10 trainees were recruited to the prework course, 9 finished, 6 were offered clinical training after simulation assessment, 5 achieved competency. Scribes required clinical training ranging from 68 to 118 hours to become competent after initial classroom training. Medical students (2) required 7 shifts to become competent, premedical students (3) 8-16 shifts, while a trainee from an alternative background did not achieve competency. Based on a scribe salary of US$15.91/hour (including 25% on-costs) plus shift loadings, costs were: recruitment and start-up US$3111, education US$1257, administration US$866 and clinical shift costs US$1137 (overall cost US$6317 per competent scribe). Physicians who trained the clinical trainee scribes during shifts did not lose productivity. CONCLUSIONS: Training scribes outside the USA is feasible using an on-line training course and local physicians. It makes economic sense to hire individuals who can work over a long period of time to recoup training costs. TRIAL REGISTRATION NUMBER: ACTRN12615000607572.