Factors Affecting Prognosis and Prediction of Outcome in Cystic Fibrosis Lung Disease

Cystic fibrosis (CF) is a multisystem disorder with a significantly shortened life expectancy with the major cause of mortality related to lung disease. Inflammation is seen in the CF airways from a very early age and contributes significantly to symptoms and disease progression. As the condition worsens over time, lung function declines, usually measured by Forced Expiratory Volume in 1 second (FEV1)% predicted, and extra-pulmonary complications often manifest. While the life expectancy in CF is still short, the median age of death and predicted survival age are continually increasing. Therapeutic interventions for CF have improved significantly in the last 20 years and now there are targeted therapies towards specific elements in CF that may impact upon exacerbation frequency, symptoms, and eventually mortality due to lung disease

Pleural Fluid Analysis: Standstill or a Work in Progress?

Pleural fluid analysis yields important diagnostic information in pleural effusions in combination with clinical history, examination, and radiology. For more than 30 years, the initial and most pragmatic step in this process is to determine whether the fluid is a transudate or an exudate. Light's criteria remain the most robust in separating the transudate-exudate classification which dictates further investigations or management. Recent studies have led to the evaluation and implementation of a number of additional fluid analyses that may improve the diagnostic utility of this method. This paper discusses the current practice and future direction of pleural fluid analysis in determining the aetiology of a pleural effusion. While this has been performed for a few decades, a number of other pleural characteristics are becoming available suggesting that this diagnostic tool is indeed a work in progress

Geelong region survey of business trends 2014

The Deakin Business School and the Geelong Chamber of Commerce undertook a survey of business confidence and industry activity in the Geelong region in 2014. The main objectives of the research were to measure current and future business confidence, activity, and profitability and to provide information relevant to the needs of businesses and industry for planning and other purposes. Information wascollected by an on-line survey of 1,571 businesses with 194 usable responses representing a 12.3% response rate. The findings are relevant to responses frombusinesses registered with the Geelong Chamber of Commerce and the Geelong Central Marketing group. The report contains information about business activity, perceptions about the future of business in Geelong and the barriers that have to be addressed to ensure success

Inhaled hypertonic saline for cystic fibrosis: reviewing the potential evidence for modulation of neutrophil signalling and function.

Cystic fibrosis (CF) is a multisystem disorder with significantly shortened life expectancy. The major cause of mortality and morbidity is lung disease with increasing pulmonary exacerbations and decline in lung function predicting significantly poorer outcomes. The pathogenesis of lung disease in CF is characterised in part by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. This leads to accumulation of viscous mucus in the CF airway, providing an ideal environment for bacterial pathogens to grow and colonise, propagating airway inflammation in CF. The use of nebulised hypertonic saline (HTS) treatments has been shown to improve mucus clearance in CF and impact positively upon exacerbations, quality of life, and lung function. Several mechanisms of HTS likely improve outcome, resulting in clinically relevant enhancement in disease parameters related to increase in mucociliary clearance. There is increasing evidence to suggest that HTS is also beneficial through its anti-inflammatory properties and its ability to reduce bacterial activity and biofilm formation. This review will first describe the use of HTS in treatment of CF focusing on its efficacy and tolerability. The emphasis will then change to the potential benefits of aerosolized HTS for the attenuation of receptor mediated neutrophil functions, including down-regulation of oxidative burst activity, adhesion molecule expression, and the suppression of neutrophil degranulation of proteolytic enzymes

Pleural Fluid Analysis: Standstill or a Work in Progress?

Pleural fluid analysis yields important diagnostic information in pleural effusions in combination with clinical history, examination, and radiology. For more than 30 years, the initial and most pragmatic step in this process is to determine whether the fluid is a transudate or an exudate. Light's criteria remain the most robust in separating the transudate-exudate classification which dictates further investigations or management. Recent studies have led to the evaluation and implementation of a number of additional fluid analyses that may improve the diagnostic utility of this method. This paper discusses the current practice and future direction of pleural fluid analysis in determining the aetiology of a pleural effusion. While this has been performed for a few decades, a number of other pleural characteristics are becoming available suggesting that this diagnostic tool is indeed a work in progress

5 Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%-2.5% of the target level from years 1-5 in these same patients without any additional recombinant adeno-associated virus serotype-1 alpha-1 antitrypsin vector administration. In addition, we observed partial correction of disease-associated neutrophil defects, including neutrophil elastase inhibition, markers of degranulation, and membrane-bound anti-neutrophil antibodies. There was also evidence of an active T regulatory cell response (similar to the 1 year data) and an exhausted cytotoxic T cell response to adeno-associated virus serotype-1 capsid. These findings suggest that muscle-based alpha-1 antitrypsin gene replacement is tolerogenic and that stable levels of M-AAT may exert beneficial neutrophil effects at lower concentrations than previously anticipated

Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: A multisite study

Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1–69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a 5% prevalence across centres. Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher total anaerobe/ total aerobe CFU ratio was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared with a Pseudomonas-dominated group with similar proportions of subjects that were homozygous for F508del. In summary, anaerobic bacteria occurred at an early age. In sputum-producing subjects anaerobic bacteria were associated with milder disease, suggesting that targeted eradication of anaerobes may not be warranted in sputum-producing CF subjects

Trappin-2/Elafin Modulate Innate Immune Responses of Human Endometrial Epithelial Cells to PolyI∶C

BACKGROUND: Upon viral recognition, innate and adaptive antiviral immune responses are initiated by genital epithelial cells (ECs) to eradicate or contain viral infection. Such responses, however, are often accompanied by inflammation that contributes to acquisition and progression of sexually transmitted infections (STIs). Hence, interventions/factors enhancing antiviral protection while reducing inflammation may prove beneficial in controlling the spread of STIs. Serine antiprotease trappin-2 (Tr) and its cleaved form, elafin (E), are alarm antimicrobials secreted by multiple cells, including genital epithelia. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated whether and how each Tr and E (Tr/E) contribute to antiviral defenses against a synthetic mimic of viral dsRNA, polyinosine-polycytidylic acid (polyI:C) and vesicular stomatitis virus. We show that delivery of a replication-deficient adenovector expressing Tr gene (Ad/Tr) to human endometrial epithelial cells, HEC-1A, resulted in secretion of functional Tr, whereas both Tr/E were detected in response to polyI:C. Moreover, Tr/E were found to significantly reduce viral replication by either acting directly on virus or through enhancing polyI:C-driven antiviral protection. The latter was associated with reduced levels of pro-inflammatory factors IL-8, IL-6, TNFα, lowered expression of RIG-I, MDA5 and attenuated NF-κB activation. Interestingly, enhanced polyI:C-driven antiviral protection of HEC-Ad/Tr cells was partially mediated through IRF3 activation, but not associated with higher induction of IFNβ, suggesting multiple antiviral mechanisms of Tr/E and the involvement of alternative factors or pathways. CONCLUSIONS AND SIGNIFICANCE: This is the first evidence of both Tr/E altering viral binding/entry, innate recognition and mounting of antiviral and inflammatory responses in genital ECs that could have significant implications for homeostasis of the female genital tract

Circulating polymers in α1-antitrypsin deficiency.

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Updated guidance on the management of COVID-19:from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020)

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. METHODS: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. RESULTS: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. CONCLUSIONS: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.status: Published onlin