Cross-talk between IL-6 trans-signaling and AIM2 inflammasome/IL-1ß axes bridge innate immunity and epithelial apoptosis to promote emphysema.

Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema. In the lungs of emphysematous patients, as well as spontaneous gp130F/F and cigarette smoke (CS)-induced mouse models of emphysema, the expression (messenger RNA and protein) and activation of ASC, Caspase-1, and the inflammasome-associated PRR and DNA sensor AIM2 were up-regulated. AIM2 up-regulation in emphysema coincided with the biased production of the mature downstream inflammasome effector cytokine IL-1ß but not IL-18. These observations were supported by the genetic blockade of ASC, AIM2, and the IL-1 receptor and therapy with AIM2 antagonistic suppressor oligonucleotides, which ameliorated emphysema in gp130F/F mice by preventing elevated alveolar cell apoptosis. The functional requirement for AIM2 in driving apoptosis in the lung epithelium was independent of its expression in hematopoietic-derived immune cells and the recruitment of infiltrating immune cells in the lung. Genetic and inhibitor-based blockade of AIM2 also protected CS-exposed mice from pulmonary alveolar cell apoptosis. Intriguingly, IL-6 trans-signaling via the soluble IL-6 receptor, facilitated by elevated levels of IL-6, acted upstream of the AIM2 inflammasome to augment AIM2 expression in emphysema. Collectively, we reveal cross-talk between the AIM2 inflammasome/IL-1ß and IL-6 trans-signaling axes for potential exploitation as a therapeutic strategy for emphysema.

Granulocyte Colony-Stimulating Factor is a Determinant of Severe Bronchopulmonary Dysplasia and Coincident Retinopathy.

Bronchopulmonary dysplasia (BPD), also called chronic lung disease of immaturity, afflicts approximately one third of all extremely premature infants, causing lifelong lung damage. There is no effective treatment other than supportive care. Retinopathy of prematurity (ROP), which impairs vision irreversibly, is common in BPD, suggesting a related pathogenesis. However, specific mechanisms of BPD and ROP are not known. Herein, a neonatal mouse hyperoxic model of coincident BPD and retinopathy was used to screen for candidate mediators, which revealed that granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3, was up-regulated significantly in mouse lung lavage fluid and plasma at postnatal day 14 in response to hyperoxia. Preterm infants with more severe BPD had increased plasma G-CSF. G-CSF-deficient neonatal pups showed significantly reduced alveolar simplification, normalized alveolar and airway resistance, and normalized weight gain compared with wild-type pups after hyperoxic lung injury. This was associated with a marked reduction in the intensity, and activation state, of neutrophilic and monocytic inflammation and its attendant oxidative stress response, and protection of lung endothelial cells. G-CSF deficiency also provided partial protection against ROP. The findings in this study implicate G-CSF as a pathogenic mediator of BPD and ROP, and suggest the therapeutic utility of targeting G-CSF biology to treat these conditions.

The Inverted Case Study Technique: changing the traditional case-study approach to prioritize physiological mechanisms over correct diagnosis and treatment.

The traditional case study has been used as a learning tool for the past 100 years, and in our program, graduate physiology students are presented with a real-world scenario and must determine the diagnosis and treatment of the patient. We found that students defaulted to memorization of disease with treatment and bypassed gaining an understanding of the mechanistic physiology behind disease and treatment. To adjust our student's approach, we developed a novel way to enhance student learning. To accomplish this shift from memorization to physiological mastery, we created the Inverted Case Study. This approach diverges from the traditional model in that students are given the diagnosis and treatment beforehand and are tasked with explaining the actual physiology of the case. In this way, students can no longer rely on the memorization of symptoms-disease-treatment but rather gain a solid understanding of the physiological mechanisms of the disease since that is the focus of the Inverted Case Study Technique. The Inverted Case Study approach is an effective approach to apply and hone critical thinking skills.NEW & NOTEWORTHY This article presents a novel approach to century-old learning techniques that enhances students' self-reported learning and also their attitudes toward learning mechanistic physiology and increases their perception of preparedness for professional school.

Elarekibep (PRS-060/AZD1402), a new class of inhaled Anticalin medicine targeting IL-4Ra for type 2 endotype asthma.

BACKGROUND: Type 2 endotype asthma is driven by IL-4 and IL-13 signaling via IL-4Ra, which is highly expressed on airway epithelium, airway smooth muscle, and immunocytes in the respiratory mucosa, suggesting potential advantages of an inhalable antagonist. Lipocalin 1 (Lcn1), a 16 kDa protein abundant in human periciliary fluid, has a robust drug-like structure well suited to protein engineering, but it has never been used to make an inhaled Anticalin protein therapeutic. OBJECTIVES: We sought to reengineer Lcn1 into an inhalable IL-4Ra antagonist and assess its pharmacodynamic/kinetic profile. METHODS: Lcn1 was systematically modified by directed protein mutagenesis yielding a high-affinity, slowly dissociating, long-acting full antagonist of IL-4Ra designated PRS-060 with properties analogous to dupilumab, competitively antagonizing IL-4Ra-dependent cell proliferation, mucus induction, and eotaxin expression in vitro. Because PRS-060 displayed exquisite specificity for human IL-4Ra, with no cross-reactivity to rodents or higher primates, we created a new triple-humanized mouse model substituting human IL-4Ra, IL-4, and IL-13 at their correct syntenic murine loci to model clinical dosing. RESULTS: Inhaled PRS-060 strongly suppressed acute allergic inflammation indexes in triple-humanized mice with a duration of action longer than its bulk clearance, suggesting that it may act locally in the lung. CONCLUSION: Lcn1 can be reengineered into the Anticalin antagonist PRS-060 (elarekibep), exemplifying a new class of inhaled topical, long-acting therapeutic drugs with the potential to treat type 2 endotype asthma.

Enhanced Lyn Activity Causes Severe, Progressive Emphysema and Lung Cancer.

The epidemiological patterns of incident chronic obstructive pulmonary disease (COPD) and lung adenocarcinoma are changing, with an increasing fraction of disease occurring in patients who are never-smokers or were not exposed to traditional risk factors. However, causative mechanism(s) are obscure. Overactivity of Src family kinases (SFKs) and myeloid cell-dependent inflammatory lung epithelial and endothelial damage are independent candidate mechanisms, but their pathogenic convergence has not been demonstrated. Here we present a novel preclinical model in which an activating mutation in Lyn, a nonreceptor SFK that is expressed in immune cells, epithelium, and endothelium-all strongly implicated in the pathogenesis of COPD-causes spontaneous inflammation, early-onset progressive emphysema, and lung adenocarcinoma. Surprisingly, even though activated macrophages, elastolytic enzymes, and proinflammatory cytokines were prominent, bone marrow chimeras formally demonstrated that myeloid cells were not disease initiators. Rather, lung disease arose from aberrant epithelial cell proliferation and differentiation, microvascular lesions within an activated endothelial microcirculation, and amplified EGFR (epidermal growth factor receptor) expression. In human bioinformatics analyses, LYN expression was increased in patients with COPD and was correlated with increased EGFR expression, a known lung oncogenic pathway, and LYN was linked to COPD. Our study shows that a singular molecular defect causes a spontaneous COPD-like immunopathology and lung adenocarcinoma. Furthermore, we identify Lyn and, by implication, its associated signaling pathways as new therapeutic targets for COPD and cancer. Moreover, our work may inform the development of molecular risk screening and intervention methods for disease susceptibility, progression, and prevention of these increasingly prevalent conditions.

Cigarette smoke depletes alveolar macrophages and delays clearance of Legionella pneumophila.

Legionella pneumophila is the main etiological agent of Legionnaires' disease, a severe bacterial pneumonia. L. pneumophila is initially engulfed by alveolar macrophages (AMs) and subvert normal cellular functions to establish a replicative vacuole. Cigarette smokers are particularly susceptible to developing Legionnaires' disease and other pulmonary infections; however, little is known about the cellular mechanisms underlying this susceptibility. To investigate this, we used a mouse model of acute cigarette smoke exposure to examine the immune response to cigarette smoke and subsequent L. pneumophila infection. Contrary to previous reports, we show that cigarette smoke exposure alone causes a significant depletion of AMs using enzymatic digestion to extract cells, or via imaging intact lung lobes by light-sheet microscopy. Furthermore, treatment of mice deficient in specific types of cell death with smoke suggests that NLRP3-driven pyroptosis is a contributor to smoke-induced death of AMs. After infection, smoke-exposed mice displayed increased pulmonary L. pneumophila loads and developed more severe disease compared with air-exposed controls. We tested if depletion of AMs was related to this phenotype by directly depleting them with clodronate liposomes and found that this also resulted in increased L. pneumophila loads. In summary, our results showed that cigarette smoke depleted AMs from the lung and that this likely contributed to more severe Legionnaires' disease. Furthermore, the role of AMs in L. pneumophila infection is more nuanced than simply providing a replicative niche, and our studies suggest they play a major role in bacterial clearance.

Particle generation and dispersion from high-speed dental drilling.

OBJECTIVE: To investigate the characteristics of particle generation and dispersion during dental procedure using digital inline holography (DIH) METHODS: Particles at two locations, near-field and far-field, which represent the field closer to the procedure location and within 0.5 m from the procedure location respectively, are studied using two different DIH systems. The effect of three parameters namely rotational speed, coolant flow rate, and bur angle on particle generation and dispersion are evaluated by using 10 different operating conditions. The particle characteristics at different operating conditions are estimated from the holograms using machine learning-based analysis. RESULTS: The particle concentration decreased by at least two orders of magnitude between the near-field and far-field locations across the 10 different operating conditions, indicating significant dispersion of the particles. High rotational speed is found to produce a larger number of smaller particles, while lower rotational speeds generate larger particles. Coolant flow rate is found to have a greater impact on particle transport to the far-field location. Irregular shape dental particles account for 29% of total particles at far-field location, with the majority of these irregular shape particles having diameters ranging from 12 to 18 µm. CONCLUSIONS: All three parameters have significant effects on particle generation and dispersion, with rotational speed having a more significant influence on particle generation at near-field and coolant flow rate playing a more important role on particle transport to the far-field. CLINICAL RELEVANCE: This study provides valuable insights on particle characteristics during high-speed drilling. It can help dental professionals minimize exposure risks for themselves and patients by optimizing clinical operating conditions.

CCL17 in Inflammation and Pain.

It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from Ccl17E/+ reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4+ non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.

Cultivation of Scenedesmus dimorphus with air contaminants from a pig confinement building.

The continual consolidation and concentration of animal feeding operations (AFOs) raises various environmental challenges, including air pollutant emission. Cost-effective mitigation technologies are pursued to protect the health and wellbeing of animals and farmers as well as the environment. Previous lab studies utilized ammonia (NH3) and carbon dioxide (CO2), two major air pollutants in AFOs, for microalgal cultivation. However, the field performance of this algae-based mitigation approach has yet to be investigated. In this study, two photobioreactors (PBRs) were tested in a nursery pig barn to mitigate NH3 and CO2 while growing Scenedesmus dimorphus (S. dimorphus). Pit air was fed into the PBRs where the two pollutants were adsorbed by S. dimorphus as nutrients to produce algal biomass and oxygen gas (O2). The cleaned air then recirculated back to the room space. S. dimorphus reached its maximum cell count on the 17th day of the experiment when NH3 and CO2 concentrations in the pit air were 25.6 ppm and 3150 ppm, respectively. The maximum biomass concentration occurred on the 11th day when the NH3 and CO2 concentrations were 14.6 and 2250 ppm, respectively. The average mitigation efficiency was 31-50% for NH3 and 1-1.7% for CO2. The costs for removing 1 g NH3 and CO2 were estimated to be $3.77 and $0.20, respectively. This study shows that an integrated PBR system is technically feasible for reducing pig barn air pollutant emission while producing microalgae as a valuable product.

Heterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort.

BACKGROUND: Studies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice. We investigated heterogeneity and overlap by diagnosis and severity in this cohort. METHODS: Patients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, and stratified by diagnosis and severity. Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity. Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis. RESULTS: Of 11 243 patients, 5940 (52.8%) had physician-assigned asthma, 1396 (12.4%) had asthma+COPD and 3907 (34.8%) had COPD; almost half were from primary care. Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD, with 23%, 62% and 64% of patients, respectively, having a ratio of post-bronchodilator forced expiratory volume in 1 s to forced vital capacity below the lower limit of normal. Symptoms and exacerbations increased with greater physician-assessed severity and were higher in asthma+COPD. However, 24.3% with mild asthma and 20.4% with mild COPD had experienced ≥1 exacerbation in the past 12 months. Medication records suggested both under-treatment and over-treatment relative to severity. Blood eosinophil counts varied little across diagnosis and severity groups, but blood neutrophil counts increased with severity across all diagnoses. CONCLUSION: This analysis demonstrates marked heterogeneity within, and overlap between, physician-assigned diagnosis and severity groups in patients with asthma and/or COPD. Current diagnostic and severity classifications in clinical practice poorly differentiate between clinical phenotypes that may have specific risks and treatment implications.

Single-Cell-Based Digital PCR Detection and Association of Shiga Toxin-Producing Escherichia coli Serogroups and Major Virulence Genes.

Escherichia coli serogroups O157, O26, O45, O103, O111, O121, and O145, when carrying major virulence genes, the Shiga toxin genes stx1 and stx2 and the intimin gene eae, are important foodborne pathogens. They are referred to as the "top 7" Shiga toxin-producing E. coli (STEC) serogroups and were declared by the USDA as adulterants to human health. Since top 7 serogroup-positive cattle feces and ground beef can also contain nonadulterant E. coli strains, regular PCR cannot confirm whether the virulence genes are carried by adulterant or nonadulterant E. coli serogroups. Thus, traditional gold-standard STEC detection requires bacterial isolation and characterization, which are not compatible with high-throughput settings and often take a week to obtain a definitive result. In this study, we demonstrated that the partition-based multichannel digital PCR (dPCR) system can be used to detect and associate the E. coli serogroup-specific gene with major virulence genes and developed a single-cell-based dPCR approach for rapid (within 1 day) and accurate detection and confirmation of major STEC serogroups in high-throughput settings. Major virulence genes carried by each of the top 7 STEC serogroups were detected by dPCR with appropriately diluted intact bacterial cells from pure cultures, culture-spiked cattle feces, and culture-spiked ground beef. Furthermore, from 100 randomly collected, naturally shed cattle fecal samples, 3 O103 strains carrying eae and 2 O45 strains carrying stx1 were identified by this dPCR assay and verified by the traditional isolation method. This novel and rapid dPCR assay is a culture-independent, high-throughput, accurate, and sensitive method for STEC detection and confirmation.

Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties.

A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg.

Data standards for interoperability of care team information to support care coordination of complex pediatric patients.

OBJECTIVE: Seamless access to information about the individuals and organizations involved in the care of a specific patient ("care teams") is crucial to effective and efficient care coordination. This is especially true for vulnerable and complex patient populations such as pediatric patients with special needs. Despite wide adoption of electronic health records (EHR), current EHR systems do not adequately support the visualization and management of care teams within and across health care organizations. Electronic health information exchange has the potential to address this issue. In the present study, we assessed the adequacy of available health information exchange data standards to support the information needs related to care coordination of complex pediatric patients. METHODS: We derived data elements from the information needs of clinicians and parents to support patient care teams; and mapped them to data elements in the Health Level Seven (HL7) Consolidated Clinical Document Architecture (C-CDA) standard and in the HL7 Fast Healthcare Interoperability Resources (FHIR) standard. We also identified additional C-CDA data elements and FHIR resources that include patients' care team members. RESULTS: Information about care team members involved in patient care is generally well-represented in the C-CDA and FHIR specifications. However, there are gaps related to patients' non-clinical events and care team actions. In addition, there is no single place to find information about care team members; rather, information about practitioners and organizations may be available in several different types of C-CDA data elements and FHIR resources. CONCLUSION: Through standards-based electronic health information exchange, it appears to be feasible to build patient care team representations irrespective of the location of patient care. In order to gather care team information across disparate systems, exchange of multiple C-CDA documents and/or execution of multiple FHIR queries will be necessary. This approach has the potential to enable comprehensive patient care team views that may help improve care coordination.

Body condition, rather than size, predicts risk-taking and resource holding potential in hatchery reared juvenile lake sturgeon Acipenser fulvescens.

To test how body size might influence lake sturgeon Acipenser fulvescens anti-predator behaviour, asymmetrically body-size-matched individuals were exposed to conspecific chemical alarm cues with the presence or absence of food. Additionally, to test resource holding potential (RHP), hatchery-reared juvenile A. fulvescens were asymmetrically (c. 60% mass difference) and symmetrically (c. 3% mass difference) size matched in individual tanks. Results suggest that A. fulvescens of higher body condition, rather than body length or mass, may take greater risks when presented with foraging opportunities and realize a higher RHP. As hatcheries are likely to select individuals of higher body condition, more research is necessary to understand the role body condition may have on behavioural responses and ensuing fitness post-release.

Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment.

Matrix metalloproteinase-9 (MMP-9) is increased in a number of pathological lung conditions, where the proteinase contributes to deleterious remodelling of the airways. While both lung cancer and COPD are associated with increased MMP-9 expression, the cellular and molecular drivers of MMP-9 remain unresolved. In this study, MMP-9 transcript measured within the tumour region from patients with non-small-cell lung cancer (NSCLC) and coexisting COPD was found to be uniformly increased relative to adjacent tumour-free tissue. MMP-9 gene expression and immunohistochemistry identified tumour-associated neutrophils, but not macrophages, as a predominant source of this proteinase. In addition, PTEN gene expression was significantly reduced in tumour and there was evidence of epithelial MMP-9 expression. To explore whether PTEN can regulate epithelial MMP-9 expression, a small interfering (si)RNA knockdown strategy was used in Beas-2B bronchial epithelial cells. PTEN knockdown by siRNA selectively increased MMP-9 expression in response to lipopolysaccharide in a corticosteroid-insensitive manner. In summary, tumour-associated neutrophils represent an important source of MMP-9 in NSCLC, and loss of epithelial PTEN may further augment steroid-insensitive expression.

Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System.

M-CSF (or CSF-1) and GM-CSF can regulate the development and function of the mononuclear phagocyte system (MPS). To address some of the outstanding and sometimes conflicting issues surrounding this biology, we undertook a comparative analysis of the effects of neutralizing mAbs to these CSFs on murine MPS populations in the steady-state and during acute inflammatory reactions. CSF-1 neutralization, but not of GM-CSF, in normal mice rapidly reduced the numbers of more mature Ly6C(-) monocytes in blood and bone marrow, without any effect on proliferating precursors, and also the numbers of the resident peritoneal macrophages, observations consistent with CSF-1 signaling being essential only at a relatively late state in steady-state MPS development; in contrast, GM-CSF neutralization had no effect on the numbers of these particular populations. In Ag-induced peritonitis (AIP), thioglycolate-induced peritonitis, and LPS-induced lung inflammation, CSF-1 neutralization lowered inflammatory macrophage number; in the AIP model, this reduced number was not due to suppressed proliferation. More detailed studies with the convenient AIP model indicated that CSF-1 neutralization led to a relatively uniform reduction in all inflammatory cell populations; GM-CSF neutralization, in contrast, was more selective, resulting in the preferential loss among the MPS populations of a cycling, monocyte-derived inflammatory dendritic cell population. Some mechanistic options for the specific CSF-dependent biologies enumerated are discussed.

Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.

RATIONALE: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. OBJECTIVES: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. METHODS: We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. MEASUREMENTS AND MAIN RESULTS: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. CONCLUSIONS: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

Identifying NIST Impacts on Patenting: A Novel Data Set and Potential Uses.

The National Institute of Standards and Technology's (NIST's) mission is to "promote U.S. innovation and industrial competitiveness." To meet this mission, NIST scientists produce a great variety of scientific and technical outputs. This paper presents results from a novel effort to measure usage and impact of a more complete set of outputs, including patents, publications, research data, software, reference materials, and a variety of additional formal and informal scientific outputs. This effort captures a significantly broader set of scientific outputs than traditional citation analysis which typically examines patent-to-patent citations or more recently patent-to-(peer-reviewed) paper citations. This may be of significant importance to NIST as NIST scientists produce a wide variety of scientific and technical outputs beyond patents and papers. Our results indicate that metrics that solely rely on patents issued to NIST inventors understate NIST's true impact on invention and do not capture usage of much of NIST's scientific output by other inventors. Thus, identifying the magnitude and varied usage of different types of NIST outputs represents a significant improvement in NIST impact metrics. The results clearly indicate that different companies, industries and technologies rely on different types of NIST outputs. Therefore, reliance on a limited set of technology transfer tools by either researchers or policy makers creates a risk that NIST knowledge and capabilities will not be transferred to and adopted by businesses and other organizations. Finally, the data developed here suggest a number of new technology transfer metrics that promote shared technology transfer responsibilities and may focus attention on activities that increase the impact of current research without fundamentally altering the infrastructural character of this research.

Balance and Falls in Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Prospective Study.

Individuals with chronic obstructive pulmonary disease (COPD) have demonstrated balance impairment and a higher fall incidence. However, these have not been investigated in acute exacerbations of the disease (ECOPD). This study evaluates balance in patients during an ECOPD compared to stable COPD and healthy controls, and examines the fall incidence rate after hospitalisation due to ECOPD compared to individuals with stable COPD. Balance performance of 26 hospitalised patients with ECOPD was compared to 26 community-dwelling participants with stable COPD and 25 matched healthy controls. Balance was evaluated using computerised posturography and the Berg Balance Scale (BBS). Prospective falls were monitored by monthly calendars for 12 months in both COPD groups. Compared to controls, greater balance impairment was observed during ECOPD for most posturography variables across standing conditions (p ≤ 0.05). Both COPD groups had worse BBS scores (p ≤ 0.05) compared to controls. Increased dyspnoea and reduced quadriceps' strength were associated with impaired balance performance. A higher fall incidence (1.76 falls/person/year) was observed following hospitalisation in patients with ECOPD compared to stable COPD (0.53 falls/person/year) at 12 months. Patients with ECOPD demonstrate balance impairments which are associated with increased dyspnoea and reduced muscle strength. Balance impairment during ECOPD may contribute to a high incidence of falls following hospitalisation.

Highly diverse posaviruses in swine faeces are aquatic in origin.

Posaviruses are a group of highly divergent viruses identified in swine faeces that are distantly related to other members of the order Picornavirales. Eighteen posavirus genomes were assembled from 10 out of 25 (40 %) faecal-swab pools collected from healthy adult swine. Phylogenetic analysis of the conserved RNA-dependent RNA polymerase (Pol) domain found that posaviruses form a large, highly diverse, monophyletic clade, which includes similar viruses identified in human (husavirus) and fish (fisavirus) faeces or intestinal contents, respectively. Quantitative reverse transcription PCR analysis of water samples collected from commercial swine barns identified four out of 19 (21 %) samples were positive using a 5'-nuclease assay targeting the Pol region of posavirus 1. ICPD (immunoprecipitation coupled to PCR detection) assays to explore serological evidence of posavirus infection found only a single positive sample, suggesting posaviruses do not commonly infect swine, and together these results suggests a likely aquatic host.