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Kerry L Hancock,1 Sinthia Bosnic-Anticevich,2– 4 John D Blakey,5,6 Mark Hew,7,8 Li Ping Chung,9 Biljana Cvetkovski,3 Scott Claxton,10 Peter Del Fante,11 Eve Denton,7,8 Joe Doan,12 Kanchanamala Ranasinghe,13,14 Lucy Morgan,15– 17 Anita Sharma,18 Peter K Smith,19 Deb Stewart,20 Philip J Thompson,21– 23 Russell Wiseman,24 John W Upham,25 Kwok Y Yan,26 Victoria Carter,27 Kiranjeet Dhillon,28 Florian Heraud,28 Thao Le,27 Rebecca Vella,28 David Price27– 30 On behalf of the OPCA Improving Asthma outcomes in Australia Research Group1Chandlers Hill Surgery, Happy Valley, SA, 5159, Australia; 2Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; 3Woolcock Institute of Medical Research, Glebe, MSW, 2037, Australia; 4Sydney Local Health District, Camperdown, NSW, 2050, Australia; 5Respiratory Medicine, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, WA, 6009, Australia; 6Curtin University Medical School, Bentley, Western Australia, 6102, Australia; 7Allergy, Asthma & Clinical Immunology, Alfred Health, Melbourne, VIC, 3004, Australia; 8Public Health and Preventive Medicine, Monash University, Victoria, 3800, Australia; 9Fiona Stanley Hospital, 11 Robin Warren Dr, Murdoch, WA, 6150, Australia; 10Genesis Care Sleep and Respiratory, Joondalup, WA, 6027, Australia; 11Hutt Street General Practice, Adelaide, SA, 5000, Australia; 12HealthPlus Medical Centre, Kogarah, NSW, 2217, Australia; 13School of Medicine, Griffith University, Nathan, QLD, Australia; 14Cannon Hill Family Doctors, Cannon Hill, QLD, 4170, Australia; 15Sydney Medical School, University of Sydney, Sydney, NSW, Australia; 16Department of Thoracic Medicine, Concord Hospital, Sydney, NSW, Australia; 17Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia; 18Platinum Medical Centre, Chermside, QLD, 4032, Australia; 19Griffith University, Southport, QLD, Australia; 20Adjunct Lecturer, School of Medicine, University of Tasmania, Churchill Ave, Hobart, TAS, 7005, Australia; 21The Lung Health Clinic, Hollywood Medical Centre, Nedlands, 6009, Australia; 22The University of Western Australia, Perth, Western Australia, 6009, Australia; 23Curtin University, Bentley, Western Australia, 6102, Australia; 24Suncoast Medical Centre, Coolum Beach, QLD, 4573, Australia; 25Diamantina Institute & PA-Southside Clinical Unit, the University of Queensland, Woolloongabba, QLD, 4102, Australia; 26Department of Respiratory Medicine, W, Camperdown, NSW, 2050, Australia; 27Optimum Patient Care, Cambridgeshire, CB24 3BA, UK; 28Optimum Patient Care Australia, Brisbane, QLD, 4000, Australia; 29Observational and Pragmatic Research Institute, Midview City, 573969, Singapore; 30Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UKCorrespondence: David Price, Optimum Patient Care Australia, 320 Adelaide St, Brisbane, QLD, 4000, Australia, Tel +4 05 764 842, Email dprice@opri.sgIntroduction: Asthma poses a significant burden for the Australian population. Understanding severe exacerbation rates, and steroid-related burden for adults diagnosed with asthma stands to offer insights into how this could be reduced.Methods: Electronic medical records (EMR) and questionnaires from the Optimum Patient Care Research Database Australia (OPCRDA) were utilised retrospectively. OPCRDA is a real-world database with > 800,000 medical records from Australian primary care practices. Outcomes were severe asthma exacerbations in Australian adults, over a 12-month period, stratified by Global Initiative for Asthma (GINA) treatment intensity steps, and steroid associated comorbidities.Results: Of the 7868 adults treated for asthma, 19% experienced at least one severe exacerbation in the last 12-months. Severe exacerbation frequency increased with treatment intensity (≥ 1 severe exacerbation GINA 1 13%; GINA 4 23%; GINA 5a 33% and GINA 5b 28%). Questionnaire participants reported higher rates of severe exacerbations than suggested from their EMR (32% vs 23%) especially in steps 1, 4 and 5. Patients repeatedly exposed to steroids had an increased risk of osteoporosis (OR 1.95, 95% CI 1.43– 2.66) and sleep apnoea (OR 1.78, 95% CI 1.30– 2.46).Conclusion: The Australian population living with GINA 1, 4, 5a and 5b asthma have high severe exacerbation rates and steroid-related burden, especially when compared to other first world countries, with these patients needing alternative strategies or possibly specialist assessment to better manage their condition.Keywords: asthma, exacerbations, oral corticosteroids, adults, Australia

Chronic mucus hypersecretion (CMH) is a clinical phenotype of COPD. This exploratory post hoc analysis assessed relationship between CMH status and treatment response in IMPACT.Patients were randomized to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg, FF/VI 100/25 μg or UMEC/VI 62.5/25 μg and designated CMH+ if they scored 1/2 in St George's Respiratory Questionnaire (SGRQ) questions 1 and 2. Endpoints assessed by baseline CMH status included on-treatment exacerbation rates, change from baseline in trough forced expiratory volume in 1 second, SGRQ total score, COPD Assessment Test (CAT) score, proportion of SGRQ and CAT responders at Week 52 and safety.Of 10,355 patients in the intent-to-treat population, 10,250 reported baseline SGRQ data (CMH+: 62% [n = 6383]). FF/UMEC/VI significantly (p 0.001) reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in CMH+ (rate ratio: 0.87 and 0.72) and CMH- patients (0.82 and 0.80). FF/UMEC/VI significantly (p 0.05) reduced on-treatment severe exacerbation rates versus UMEC/VI in CMH+ (0.62) and CMH- (0.74) subgroups. Similar improvements in health status and lung function with FF/UMEC/VI were observed, regardless of CMH status. In CMH+ patients, FF/VI significantly (p 0.001) reduced on-treatment moderate/severe and severe exacerbation rates versus UMEC/VI (0.83 and 0.70).FF/UMEC/VI had a favourable benefit: risk profile versus dual therapies irrespective of CMH status. The presence of CMH did not influence treatment response or exacerbations, lung function and/or health status. However, CMH did generate differences when dual therapies were compared and the impact of CMH should be considered in future trial design.

The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5′-aza-2′-deoxycytidine’ treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by SOCS1 gene methylation or microRNA155 in these cells. In conclusion, we confirmed that IPF fibroblasts had lower levels of SOCS1 mRNA compared with control fibroblasts, but we were unable to determine the mechanism. Furthermore, although SOCS1 may be important in the fibrotic process, we were unable to find a significant role for SOCS1 in regulating fibroblast function.

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema. Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Background Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin-33 (IL-33) is a major contributor to type-2 inflammation in acute asthma. However, the link between IL-33 and type-2 inflammation has not been shown in naturally occurring asthma exacerbations. Objectives To determine if airway IL-33 is associated with type-2 inflammation measured by type-2 cytokines, FeNO and sputum eosinophils in patients presenting to the Emergency Department with an asthma exacerbations. Methods Adult patients hospitalized due to acute asthma were enrolled. Upper airways were sampled with nasal swabs and lower airways with induced sputum. Cytokines were measured at protein level using a Luminex® assay and mRNA expression level using droplet-digital-PCR. Airway sampling was repeated four weeks after exacerbation. Results At the time of exacerbation, upper airway IL-33 correlated with upper airway IL-5 and IL-13 (R = 0.84, p, Highlights • IL-33 correlates to type 2 cytokines in hospitalized patients with acute asthma. • Airway IL-13 and IL-33 positively correlate with fractional exhaled nitric oxide. • Airway IL-5 correlates to blood eosinophils in naturally occurring acute asthma.

Malignant mesothelioma is an aggressive and often fatal cancer associated with asbestos exposure. The disease originates in the mesothelial lining of the serosal cavities, most commonly affecting the pleura. Survival rates are low as diagnosis often occurs at an advanced stage and current treatments are limited. Identifying new diagnostic and therapeutic targets for mesothelioma remains a priority, particularly for the new wave of victims exposed to asbestos through do-it-yourself renovations and in countries where asbestos is still mined and used. Recent advances have demonstrated a biological role for the small but powerful gene regulators microRNA (miRNA) in mesothelioma. A number of potential therapeutic targets have been identified. MiRNA have also become popular as potential biomarkers for mesothelioma due to their stable expression in bodily fluid and tissues. In this review, we highlight the current challenges associated with the diagnosis and treatment of mesothelioma and discuss how targeting miRNA may improve diagnostic, prognostic and therapeutic approaches.

Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A1 -PI; 60 mg kg-1 week-1 ) therapy completed to date, demonstrated for the first time that A1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response.A disease progression model was constructed, utilizing observed A1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A1 -PI exposure and clinical response. Dose-exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A1 -PI exposure to lung density decline rate at varying exposure levels.A dose of 60 mg kg-1 week-1 achieved trough serum levels >11 μmol l-1 (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l-1 year-1 occurred more often in patients receiving A1 -PI: 63 vs. 12%.Weight-based A1 -PI dosing reliably raises serum levels above the 11 μmol l-1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.

Background: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. Objective: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. Methods: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both . cis- and . trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. Results: We tested the association between asthma and 17,190 genes that were found to have . cis- and/or . trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, . LIMS1, . TINF2, and . SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: . B4GALT3, . USMG5, . P2RY13, and . P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. Conclusion: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.

Introduction: Influenza is a highly contagious disease. Home Quarantine (HM) is a non-pharmaceutical intervention aimed at reducing viral transmission. To date, no studies have examined HM behaviours in adults with confirmed influenza who were hospitalised or attended the emergency Department (ED). Aim: To identify from a patient’s perspective, the essential HM information requirements, support needs and barriers to remaining at home. Methods: A qualitative descriptive study using semi-structured phone interviews of adults with proven influenza [polymerase chain reaction(PCR) assay], who had attended the ED or were hospitalised. Potential patients were contacted by letter informing them that they would be phoned in a particular week as per the approved protocol. Interview data were analysed using thematic analysis to describe participants’ report of HM actions, inflection control knowledge and barriers to being HM. Results: Fifty letters were sent to potential participants with positive PCR from the pathology database. Disconnected phone (7), invalid number (1), no phone (1), underage (1), deceased (2), request not to call (1), no answer on 2 occasions (17) and 11 refused to participate. Nine interviews were conducted and data saturation achieved. Patient’s mean age was 54.7 years, 6 were female, 6 of 9 had comorbid conditions, 5 of 9 were hospitalised (average length of stay 2.56 days). Four major themes identified (1)Knowledge-need to understand infectivity and selfcare (2)barriers-managing day to day running of family (3)support-education and need for a practical information booklet (4)post discharge care-role of GP. Conclusion: Adults with influenza had poor influenza knowledge. Accessible HM resources that addresses concerns identified as a patient need.

Complex lung diseases, such as asthma, are influenced by both genetic predisposition and environmental stimuli. The epigenetic landscape of such diseases is attracting increasing interest and research. Epigenetics broadly covers the transient and the inheritable changes to gene expression that are not directly due to changes in nucleotide sequences. Epigenetic mechanisms could have significant impact on asthma-related allergic, immune, and regulatory pathways, as well as on the generation of biomarkers and the heritable transmission of asthma phenotypes. Recent technological advances have allowed mapping of the epigenome and analysis of genome-wide epigenetic contributors to disease. As a result, ground-breaking observations regarding histone post-translational modifications in a number of immunological diseases have emerged. In this review, we look beyond the biological information coded by DNA and review the epigenetic modifications made to histones, with evidence suggesting a role for their modification in asthma.

Malignant pleural mesothelioma (MPM) is an incurable cancer of the pleura that can be difficult to diagnose. Biomarkers for an easier and/or earlier diagnosis are needed. Approximately 90% of MPM patients develop a pleural effusion (PE). PEs are ideal sources of biomarkers as the fluid would almost always require drainage for diagnostic and/or therapeutic reasons. However, differentiating MPM PE from PE caused by other diseases can be challenging. MicroRNAs are popular biomarkers given their stable expression in tissue and fluid. MicroRNAs have been analysed in PE cytology samples for the diagnosis of MPM but have not been measured in frozen/fresh PE. We hypothesise that microRNAs expressed in PE are biomarkers for MPM. TaqMan OpenArray was used to analyse over 700 microRNAs in PE cells and supernatants from 26 MPMs and 21 other PE-causing diseases. In PE cells, combining miR-143, miR-210, and miR-200c could differentiate MPM with an area under the curve (AUC) of 0.92. The three-microRNA signature could also discriminate MPM from a further 40 adenocarcinomas with an AUC of 0.9887. These results suggest that the expression of miR-143, miR-210, and miR-200c in PE cells might provide a signature for diagnosing MPM.

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis. An Author Correction to this article was published on 16 August 2018. https://www.nature.com/articles/s41588-018-0197-6

PURPOSE The 6-Minute Walk Test (6MWT) and Incremental Shuttle Walk Test (ISWT) are used to assess exercise capacity, but the reliability and responsiveness of these tests in individuals with non-cystic fibrosis (CF) bronchiectasis have not been determined. This study aimed to determine the reliability and responsiveness of both tests in adults with non-CF bronchiectasis. METHODS Eighty-five participants completed 2 6MWTs and 2 ISWTs in random order. Testing was repeated at the conclusion of an 8-week intervention period of exercise training. Reliability was assessed using intraclass correlation coefficients (ICC) and Bland-Altman analysis. Responsiveness was measured by effect size (ES) and standardized response mean (SRM). RESULTS At baseline, test-retest reliability was high for both tests (ICC ≥ 0.95). The mean (95% CI) increase in the 6MWT from test 1 to test 2 was 20 m (13-26 m): 3% (0-5%) change. The mean (95% CI) increase in the ISWT was 15 m (4-25m): 4% (2-6%) change. A significant learning effect persisted after 8 weeks for the 6MWT (P = .04), but not the ISWT (P = .61). The 6MWT ES was 0.32 and SRM was 0.68; for the ISWT, ES was 0.42 with SRM of 0.71. CONCLUSION The 6MWT and ISWT are reliable measures of exercise capacity in non-CF bronchiectasis and responsive to exercise training. The small learning effect in both measures at baseline suggests that 2 of each test are necessary to correctly assess exercise capacity. Completion of 2 6MWTs at followup may minimize the risk of underestimating a treatment effect.

In recent decades, sporotrichosis, caused by thermally dimorphic fungi Sporothrix schenckii complex, has become an emerging infection in many parts of the world. Pulmonary infection with S. schenckii still remains relatively uncommon, possibly due to underrecognition. Pulmonary sporotrichosis presents with distinct clinical and radiological patterns in both immunocompetent and immunocompromised hosts and can often result in significant morbidity and mortality despite treatment. Current understanding regarding S. schenckii biology, epidemiology, immunopathology, clinical diagnostics, and treatment options has been evolving in the recent years with increased availability of molecular sequencing techniques. However, this changing knowledge has not yet been fully translated into a better understanding of the clinical aspects of pulmonary sporotrichosis, as such current management guidelines remain unsupported by high-level clinical evidence. This article examines recent advances in the knowledge of sporotrichosis and its application to the difficult challenges of managing pulmonary sporotrichosis.

Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling. Implications: miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets. Mol Cancer Res; 13(7); 1106–18. ©2015 AACR.

During seasonal influenza epidemics and pandemics, virus transmission causes significant public health concern. Reduction of viral transmission by non-pharmaceutical interventions (NPI) has a significant appeal and is often recommended. However, the efficacy of such interventions is unclear. A systematic literature review was undertaken to identify and evaluate the published literature on NPI efficacy to prevent human transmission of influenza virus in adults. Reviewers assessed the quality of eligible studies utilizing the Critical Appraisal Skills Programme for bias and the Scottish Intercollegiate Guidelines Network for methodological quality. Studies were assessed for risk of bias domains of random sequence generation, allocation concealment, attribution bias, selective reporting and blinding. Relevant citations of 2247 were reduced to 100 for full-text evaluation. Only seven met all selection criteria and pooled analysis was not feasible. Of the seven studies, two were randomized controlled trials (RCT) and five were cluster RCT. The main NPI studied were disinfection and hygiene; barriers; and combined NPI. However, these seven RCT had significant design flaws. Only two studies used laboratory confirmed influenza and poor statistical power was a major problem. Positive significant interventions included professional oral hygiene intervention in the elderly and hand washing. Despite the potential for NPI in preventing influenza transmission, there is very limited data available. Hand washing and dental hygiene may be useful, but other interventions have not been fully assessed. Properly designed studies evaluating large populations including ‘at risk’ patients and in a variety of communities are needed.

Gli transcription factors of the Hedgehog (Hh) pathway have been reported to be drivers of malignant mesothelioma (MMe) cell survival. The Gli inhibitor GANT61 induces apoptosis in various cancer cell models, and has been associated directly with Gli inhibition. However various chemotherapeutics can induce cell death through generation of reactive oxygen species (ROS) but whether ROS mediates GANT61-induced apoptosis is unknown. In this study human MMe cells were treated with GANT61 and the mechanisms regulating cell death investigated. Exposure of MMe cells to GANT61 led to G1 phase arrest and apoptosis, which involved ROS but not its purported targets, GLI1 or GLI2. GANT61 triggered ROS generation and quenching of ROS protected MMe cells from GANT61-induced apoptosis. Furthermore, we demonstrated that mitochondria are important in mediating GANT61 effects: (1) ROS production and apoptosis were blocked by mitochondrial inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide, and were more resistant to apoptosis induced by GANT61 than wild-type cells. Our data demonstrate for the first time that GANT61 induces apoptosis by promoting mitochondrial superoxide generation independent of Gli inhibition, and highlights the therapeutic potential of mitochondrial ROS-mediated anticancer drugs in MMe.

Background: The chronic respiratory disease questionnaire (CRDQ) is designed to assess health-related quality of life (HRQOL) in chronic respiratory conditions, but its reliability, validity and responsiveness in individuals with mild to moderate non-cystic fibrosis (CF) bronchiectasis are unclear. Objectives: This study aimed to determine measurement properties of the CRDQ in non-CF bronchiectasis. Methods: Participants with non-CF bronchiectasis involved in a randomised controlled trial of exercise training were recruited. Internal consistency was assessed using Cronbach's α. Over 8 weeks, reliability was evaluated using intra-class correlation coefficients and Bland-Altman analysis for measures of agreement. Convergent and divergent validity was assessed by correlations with the other HRQOL questionnaires and the Hospital Anxiety and Depression Scale (HADS). The responsiveness to exercise training was assessed using effect sizes and standardised response means. Results: Eighty-five participants were included (mean age ± SD, 64 ± 13 years). Internal consistency was adequate (>0.7) for all CRDQ domains and the total score. Test-retest reliability ranged from 0.69 to 0.85 for each CRDQ domain and was 0.82 for the total score. Dyspnoea (CRDQ) was related to St George's respiratory questionnaire (SGRQ) symptoms only (r = 0.38), with no relationship to the Leicester cough questionnaire (LCQ) or HADS. Moderate correlations were found between the total score of the CRDQ, the SGRQ (rs = -0.49) and the LCQ score (rs = 0.51). Lower CRDQ scores were associated with higher anxiety and depression (rs = -0.46 to -0.56). The responsiveness of the CRDQ was small (effect size 0.1-0.24). Conclusions: The CRDQ is a valid and reliable measure of HRQOL in mild to moderate non-CF bronchiectasis, but responsiveness was limited.

Summary Background Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. Methods Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. Findings Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (−1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; −1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and −1·60 g/L per year [0·26] at FRC) than in the delayed-start group (−2·26 g/L per year [0·27] at TLC; −2·16 g/L per year [0·26] at TLC plus FRC, and −2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from −2·26 g/L per year to −1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (−1·51 g/L per year to −1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48. Interpretation RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment. Funding CSL Behring.

Summary Background The clinical benefit of inhaled antibiotics in non-cystic fibrosis bronchiectasis has not been established in randomised controlled trials. We aimed to assess safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with non-cystic fibrosis bronchiectasis and Gram-negative bacterial colonisation. Methods AIR-BX1 and AIR-BX2 were two double-blind, multicentre, randomised, placebo-controlled phase 3 trials, which included patients aged 18 years or older who had bronchiectasis and history of positive sputum or bronchoscopic culture for target Gram-negative organisms. Patients were randomly assigned to receive either AZLI or placebo (1:1). Randomisation was done without stratification and the code was generated by a Gilead designee. In both studies, two 4-week courses of AZLI 75 mg or placebo (three-times daily; eFlow nebulizer) were each followed by a 4-week off-treatment period. Primary endpoint was change from baseline Quality of Life-Bronchiectasis Respiratory Symptoms scores (QOL-B-RSS) at 4 weeks. These trials are registered with ClinicalTrials.gov, numbers are NCT01313624 for AIR-BX1 and NCT01314716 for AIR-BX2. Findings We recruited participants from 47 ambulatory clinics for AIR-BX1 and 65 ambulatory clinics for AIR-BX2; studies were done between April 25, 2011, and July 1, 2013. In AIR-BX1, of the 348 patients screened, 134 were randomly assigned to receive AZLI and 132 to receive placebo. In AIR-BX2, of the 404 patients screened, 136 were randomly assigned to receive AZLI and 138 to receive placebo. The difference between AZLI and placebo for adjusted mean change from baseline QOL-B-RSS was not significant at 4 weeks (0·8 [95% CI −3·1 to 4·7], p=0·68) in AIR-BX1, but was significant (4·6 [1·1 to 8·2], p=0·011) in AIR-BX2. The 4·6 point difference in QOL-B-RSS after 4 weeks in AIR-BX2 was not deemed clinically significant. In both studies, treatment-related adverse events were more common in the AZLI group than in the placebo group, as were discontinuations from adverse events. The most commonly reported treatment-emergent adverse events were dyspnea, cough, and increased sputum. Each was more common for AZLI-treated than for placebo-treated patients, but the incidences were more balanced in AIR-BX2. Interpretation AZLI treatment did not provide significant clinical benefit in non-cystic fibrosis bronchiectasis, as measured by QOL-B-RSS, suggesting a continued need for placebo-controlled studies to establish the clinical benefit of inhaled antibiotics in patients with this disorder. Funding Gilead Sciences.

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10 −9 ) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10 −8 ). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP . Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10 −7 ) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10 −6 ). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

BACKGROUND: Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. METHODS: In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment). Other outcomes included the rate of asthma exacerbations, asthma control, and safety. RESULTS: The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P=0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P=0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P=0.04) and a reduction of 0.52 points with respect to asthma symptoms (P=0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms. (Funded by GlaxoSmithKline; SIRIUS ClinicalTrials.gov number, NCT01691508.).

Pluripotent stem cells are cells that can differentiate into any tissue from all germ layers and include embryonic stem cells and induced pluripotent cells (iPS). Embryonic stem cells are derived from 8-day blastocysts obtained from unutilized embryos following in vitro fertilization, while iPS is obtained following transfection of dermal fibroblasts with pluripotent genes (sex determining region Y-binding, Kruppel-like factor 4, octamer-binding transcription factor 4 and c-Myc). The major challenge is to differentiate these cells into lung epithelium for therapeutic applications as well as to model lung diseases such as cystic fibrosis. In this review, the developmental pathways of the lung and how these pathways have been recapitulated in vitro to induce differentiation of pluripotent cells to lung epithelium were examined.

Background and objective The Asthma Insight and Management (AIM) survey was conducted in North America, Europe, the Asia-Pacific region and Latin America to characterize patients’ insights, attitudes and perceptions about their asthma and its treatment. We report findings from the Asia-Pacific survey. Methods Asthma patients (≥12 years) from Australia, China, Hong Kong, India, Malaysia, Singapore, South Korea, Taiwan and Thailand were surveyed. Patients answered 53 questions exploring general health, diagnosis/history, symptoms, exacerbations, patient burden, disease management, medications/treatments and patient's attitudes. The Global Initiative for Asthma guidelines were used to assess asthma control. The survey was conducted by random digit telephone dialling (Australia, China and Hong Kong) or by random face-to-face interviews (India, Malaysia, Singapore, South Korea, Taiwan and Thailand). Results There were 80 761 households screened. Data from 3630 patients were collected. Wide disparity existed between objective measures of control and patient perception. Reported exacerbations during the previous year ranged from 19% (Hong Kong) to 67% (India). Reported unscheduled urgent/emergency visits to a doctor's office/hospital/clinic in the previous year ranged from 15% (Hong Kong) to 46% (Taiwan). Patients who reported having controlled asthma in the previous month ranged from 27% (South Korea) to 84% (Taiwan). Substantial functional and emotional limitations due to asthma were identified by 13% (South Korea) to 78% (India) of patients. Conclusions Asthma has a profound impact on patients’ well-being despite the availability of effective treatments and evidence-based management guidelines. Substantial differences across the surveyed countries exist, suggesting unmet, country-specific cultural and educational needs. A large proportion of asthma patients overestimate their level of control.

Pulmonary infections by Sporothrix spp. manifest radiologically as cavitary or non-cavitary disease depending on whether the infection is primary pulmonary or multifocal sporotrichosis. Despite current guidelines, the optimal management for pulmonary sporotrichosis remains unclear. In order to clarify this, we present two cases of pulmonary sporotrichosis, as well as the results of a comprehensive literature review of treatment outcomes based on clinico-radiological presentation patterns of the disease. A literature search of all case reports in English language over the last 50 years (1960-2010) was conducted. Data on patient characteristics, risk factors, clinico-radiological patterns, treatment modalities and outcomes were collected and analyzed. A total of 86 cases were identified, i.e., 64 (74.4%) primary pulmonary and 22 (25.6%) multifocal sporotrichosis. Radiologically, primary pulmonary disease was commonly characterized by cavity formation which was lacking in multifocal infections (P = 0.0001). Immunosuppressant use was more common in multifocal sporotrichosis (P = 0.0001), while hemoptysis was more common in primary pulmonary form (P = 0.01). No other differences in patient characteristics or risk factors were noted. Extra-pulmonary multifocal sporotrichosis most commonly involved skin (81.8%) and joints (45.4%). For patients with cavitary primary pulmonary sporotrichosis, outcomes from medical therapy alone were inferior to surgical intervention (P = 0.02). However, for both primary pulmonary and multifocal sporotrichosis with non-cavitary disease, medical therapy alone provided good outcomes. Only 12 (16.7%) cases were treated with itraconazole. Treatment of pulmonary sporotrichosis should be guided by the clinico-radiological patterns of presentation. Medical therapy alone is likely sufficient for non-cavitary disease while early surgery should be considered for cavitary primary pulmonary sporotrichosis. The experience in treating cavitary disease with itraconazole alone is limited and further data are required.

Background The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery. Methods Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation—after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study. Results DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs −0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events. Conclusions Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.

Despite a better understanding of the pathophysiology of asthma, presence of reliable diagnostic tools, availability of a wide array of effective and affordable inhaled drugs and simplified national and international asthma management guidelines, asthma remains poorly managed in India.The Asia-Pacific Asthma Insight and Management (AP-AIM) study was aimed at understanding the characteristics of asthma, current management, level of asthma control and its impact on quality of life across Australia, China, Hong Kong, India, Malaysia, Singapore, South Korea, Taiwan and Thailand. This paper describes the results of asthma management issues in India in detail and provides a unique insight into asthma in India.The AP-AIM India study was conducted in eight urban cities in India, viz: Ajmer, Delhi, Kolkata, Rourkela, Chennai, Mangalore, Mumbai and Rajkot from February to July 2011. Face-to-face interviews were conducted in adult asthmatics and parents of asthmatic children between the ages of 12 and 17 years with a confirmed diagnosis or a treatment history of 1 year for asthma.Four hundred asthmatics (M:F::1:1.273), with a mean age of 50 ± 17.8 years, from across India were studied. 91% of the asthmatics in India perceived their asthma to be under control, however, none of the asthmatics had controlled asthma by objective measures. Asthmatics in India believed that their asthma was under control if they have up to 2 emergency doctor visits a year. The quality of life of these patients was significantly affected with 93% school/work absenteeism and a loss of 50% productivity. Seventy-five percent of the asthmatics have never had a lung function test. The common triggers for asthmatics in India were dust (49%) and air pollution (49%), while only 5% reported of pollen as triggers. Eighty-nine percent of Indian asthmatics reported an average use of oral steroids 10.5 times a year. Only 36% and 50% of Indian asthmatics used controller and rescue inhalers with a majority preferring the oral route of asthma medication.This study has clearly highlighted the fact that asthma management in India remains very poor, with a significant proportion of patients experiencing bothersome symptoms and worsened quality of life. There is a need for an urgent review of this situation and initiate active measures at local as well as national levels to improve asthma care in India.

INTRODUCTION: Pro-inflammatory signalling by the receptor for advanced glycation end products (RAGE), has been described in stable asthma, and a protective role of soluble RAGE (esRAGE) is well established, but the role of esRAGE and RAGE ligands (including enRAGE) is unknown in acute asthma. We aimed to determine whether RAGE signalling is involved in the increased inflammation seen during asthma exacerbations. METHODS: Adult asthmatics were recruited on presentation with acute asthma to Bispebjerg University Hospital during a one-year period. Spirometry and blood samples were collected within 24 hours of admission and repeated after 12 weeks. RESULTS: Patients (n=47) were 16-45 years old and 70% were females. Serum enRAGE was higher (78 ng/ml 95%CI 62-99, p = 0.001) at exacerbation than follow-up (41 ng/ml 95%CI 29-57), while serum esRAGE was lower (96 pg/ml 95%CI 79-115 vs. 158 pg/ml 95%CI 134-187, respectively, p Both enRAGE and the ratio of enRAGE to esRAGE correlated negatively with FEV 1 at exacerbation adjusting for age, gender, ICS usage, blood neutrophil count and detection of respiratory pathogens (p=0.012, R 2 =0.26 and p=0.014, R 2 =0.26, respectively). Patients with a severe or life threatening exacerbation, as defined by BTS guidelines (n=23), had higher enRAGE (83.9 95%CI 56.8-123.8, p=0.046) than patients with a mild to moderate exacerbation (52.1 95%CI 39.1-69.5). CONCLUSION: A systemic, pro-inflammatory response mediated by RAGE, is increased during acute asthma and correlates with the severity of symptoms.

The STAT inhibitor, SOCS1 is reduced in IPF lung fibroblasts, and has been linked to higher levels of type I collagen. Using IPF (n=6) and control (n=9) lung fibroblast cultures and control (n=4) and IPF (n=8) lung tissue, we investigated the mechanisms underlying SOCS1 down-regulation in IPF. We have demonstrated a significant reduction in basal SOCS1 mRNA in IPF fibroblasts and have observed a trend towards reduced SOCS3. Immunohistochemical analysis of lung tissue revealed an abundance of activated-STAT1 and -STAT3, target molecules of SOCS1 and SOCS3. There was no difference in collagen mRNA between IPF and control fibroblasts but high basal levels of collagen protein were detected in IPF cells. There was no difference in the ability of IPF fibroblasts to express pSTAT1, pSTAT3 or SOCS3 following IL-6 stimulation, although the magnitude of the response varied. Similarly, the kinetics of IFNγ-induced SOCS1 mRNA and pSTAT1 levels were not altered in IPF fibroblasts. SOCS1 has been identified as a target of miR155, so we investigated the capacity of miR155 to regulate SOCS1 in IPF. miR155 levels were significantly increased in IPF lung tissue, providing a possible explanation for reduced SOCS1. However, miR155 was reduced in IPF fibroblasts. Analysis of the methylation pattern at putative STAT1/3 binding sites within the SOCS1 promoter has revealed that these sites are unmethylated. In conclusion SOCS1 expression in human lung fibroblasts is not regulated by methylation at STAT1/3 transcription factor binding sites in the SOCS1 promoter or by miR155. Funding: NHMRC Project Grant# 458703 and Raine Medical Research Foundation Grant-in-aid

Background and objectives Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment. Methods In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p Results No genetic marker was significantly associated with the primary endpoint, clinically significant exacerbation rate. One genetic marker was associated with time to first clinically significant exacerbation, but this association was driven by the DREAM data and was not supported in additional sensitivity analyses by treatment regimen/dose. Conclusion No genetic effect on mepolizumab-treatment response was identified in this population on intensive asthma treatment, with history of frequent exacerbations and pre-selected for airway eosinophilia.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Background Functional variants in the interleukin-6 receptor gene (IL6R) are associated with asthma risk. We hypothesized that genes co-expressed with IL6R might also be regulated by genetic polymorphisms that are associated with asthma risk. The aim of this study was to identify such genes. Methods To identify genes whose expression was correlated with that of IL6R, we analyzed gene expression levels generated for 373 human lymphoblastoid cell lines by the Geuvadis consortium and for 38 hematopoietic cell types by the Differentiation Map Portal (DMAP) project. Genes correlated with IL6R were then screened for nearby single nucleotide polymorphisms (SNPs) that were significantly associated with both variation in gene expression levels (eSNPs) and asthma risk. Results We identified 90 genes with expression levels correlated with those of IL6R and that also had a nearby eSNP associated with disease risk in a published asthma GWAS (N = 20 776). For 16 (18%) genes, the association between the eSNP and asthma risk replicated with the same direction of effect in a further independent published asthma GWAS (N = 27 378). Among the top replicated associations (FDR < 0.05) were eSNPs for four known (IL18R1, IL18RAP, BCL6, and STAT6) and one putative novel asthma risk gene, stomatin-like protein 2 (STOML2). The expression of STOML2 was negatively correlated with IL6R, while eSNPs that increased the expression of STOML2 were associated with an increased asthma risk. Conclusion The expression of STOML2, a gene that plays a key role in mitochondrial function and T-cell activation, is associated with both IL-6 signaling and asthma risk.

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.

We aimed to estimate the effectiveness of H1N1/09 containing influenza vaccines against hospitalization from influenza in Australia. We performed a test-negative case control study in patients hospitalized in 15 sentinel Australian hospitals between March and November 2010, comparing influenza vaccination (H1N1/09 monovalent or 2010 seasonal trivalent) in hospitalized patients with PCR-confirmed influenza compared to PCR-negative controls. Between March and November 2010, 1169 hospitalized patients were tested for suspected influenza, of which influenza vaccine status was ascertained in 165/238 patients with H1N1/09 influenza, 40/64 with seasonal influenza and 558/867 test negative controls; 24% of H1N1/09 cases, 43% of seasonal influenza cases and 54% of controls were vaccinated. VE against hospitalisation with H1N1/09 influenza after adjusting for age, medical comorbidities and pregnancy status was estimated at 49% (95% CI: 13%, 70%). Influenza vaccination was associated with a reduction in hospitalisation caused by H1N1/09 influenza in the 2010 southern hemisphere winter season.

Serosal pathologies including malignant mesothelioma (MM) can show features of osseous and/or cartilaginous differentiation although the mechanism for its formation is unknown. Mesothelial cells have the capacity to differentiate into cells with myofibroblast, smooth muscle and endothelial cell characteristics. Whether they can differentiate into other cell types is unclear. This study tests the hypothesis that mesothelial cells can differentiate into cell lineages of the embryonic mesoderm including osteoblasts and adipocytes. To examine this, a functional assay of bone formation and an adipogenic assay were performed in vitro with primary rat and human mesothelial cells maintained in osteogenic or adipogenic medium (AM) for 0–26 days. Mesothelial cells expressed increasing levels of alkaline phosphatase, an early marker of the osteoblast phenotype, and formed mineralized bone-like nodules. Mesothelial cells also accumulated lipid indicative of a mature adipocyte phenotype when cultured in AM. All cells expressed several key osteoblast and adipocyte markers, including osteoblast-specific runt-related transcription factor 2, and demonstrated changes in mRNA expression consistent with epithelial-to-mesenchymal transition. In conclusion, these studies confirm that mesothelial cells have the capacity to differentiate into osteoblast- and adipocyte-like cells, providing definitive evidence of their multipotential nature. These data strongly support mesothelial cell differentiation as the potential source of different tissue types in MM tumours and other serosal pathologies, and add support for the use of mesothelial cells in regenerative therapies.