High-contrast imager for Complex Aperture Telescopes (HiCAT): 1. Testbed design

Searching for nearby habitable worlds with direct imaging and spectroscopy will require a telescope large enough to provide angular resolution and sensitivity to planets around a significant sample of stars. Segmented telescopes are a compelling option to obtain such large apertures. However, these telescope designs have a complex geometry (central obstruction, support structures, segmentation) that makes high-contrast imaging more challenging. We are developing a new high-contrast imaging testbed at STScI to provide an integrated solution for wavefront control and starlight suppression on complex aperture geometries. We present our approach for the testbed optical design, which defines the surface requirements for each mirror to minimize the amplitude-induced errors from the propagation of out-of-pupil surfaces. Our approach guarantees that the testbed will not be limited by these Fresnel propagation effects, but only by the aperture geometry. This approach involves iterations between classical ray-tracing optical design optimization, and end-to-end Fresnel propagation with wavefront control (e.g. Electric Field Conjugation / Stroke Minimization). The construction of the testbed is planned to start in late Fall 2013.Comment: Proc. of the SPIE 8864, 10 pages, 3 figures, Techniques and Instrumentation for Detection of Exoplanets V

Correcting the z~8 Galaxy Luminosity Function for Gravitational Lensing Magnification Bias

We present a Bayesian framework to account for the magnification bias from both strong and weak gravitational lensing in estimates of high-redshift galaxy luminosity functions. We illustrate our method by estimating the $z\sim8$ UV luminosity function using a sample of 97 Y-band dropouts (Lyman break galaxies) found in the Brightest of Reionizing Galaxies (BoRG) survey and from the literature. We find the luminosity function is well described by a Schechter function with characteristic magnitude of $M^\star = -19.85^{+0.30}_{-0.35}$, faint-end slope of $\alpha = -1.72^{+0.30}_{-0.29}$, and number density of $\log_{10} \Psi^\star [\textrm{Mpc}^{-3}] = -3.00^{+0.23}_{-0.31}$. These parameters are consistent within the uncertainties with those inferred from the same sample without accounting for the magnification bias, demonstrating that the effect is small for current surveys at $z\sim8$, and cannot account for the apparent overdensity of bright galaxies compared to a Schechter function found recently by Bowler et al. (2014a,b) and Finkelstein et al. (2014). We estimate that the probability of finding a strongly lensed $z\sim8$ source in our sample is in the range $\sim 3-15 \%$ depending on limiting magnitude. We identify one strongly-lensed candidate and three cases of intermediate lensing in BoRG (estimated magnification $\mu>1.4$) in addition to the previously known candidate group-scale strong lens. Using a range of theoretical luminosity functions we conclude that magnification bias will dominate wide field surveys -- such as those planned for the Euclid and WFIRST missions -- especially at $z>10$. Magnification bias will need to be accounted for in order to derive accurate estimates of high-redshift luminosity functions in these surveys and to distinguish between galaxy formation models.Comment: Accepted for publication in ApJ. 20 pages, 13 figure

Does physical activity counselling enhance the effects of a pedometer-based intervention over the long-term : 12-month findings from the Walking for Wellbeing in the West study

Peer reviewedPublisher PD

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD

BACKGROUND: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD.METHODS: Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD.FINDINGS: Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency.INTERPRETATION: Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.</p

Neutrophil elastase activity is associated with exacerbations and lung function decline in Bronchiectasis

Rationale: Sputum neutrophil elastase and serum desmosine, a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis.Methods: This was a single-centre prospective cohort study using the TAYBRIDGE registry in Dundee, UK. 433 patients with HRCT-confirmed bronchiectasis provided blood samples for desmosine measurement and 381 provided sputum for baseline elastase activity measurements using an activity based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3-years.Results: Elastase activity in sputum was associated with the bronchiectasis severity index (r=0.49,p&lt;0.0001) and also correlated with MRC dyspnoea score (r=0.34,p&lt;0.0001), FEV1 % predicted (r=-0.33,p&lt;0.0001) and the radiological extent of bronchiectasis (r=0.29,p&lt;0.0001). During 3-years follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (p&lt;0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV1 decline (beta coefficient -0.139,p=0.001). Elastase showed good discrimination for severe exacerbations AUC 0.75 (0.72-0.79) and all-cause mortality AUC 0.70 (0.67-0.73) Sputum elastase activity increased at exacerbation (p=0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r=0.34,p&lt;0.0001), and was associated with risk of severe exacerbations HR 2.7 (1.42-5.29),p=0.003, but not lung function decline.Conclusions: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.</p

Educating and training a workforce for nutrition in a post-2015 world.

Nearly all countries in the world today are burdened with malnutrition, manifesting as undernutrition, micronutrient deficiencies, and/or overweight and obesity. Despite some progress, efforts to alleviate malnutrition are hampered by a shortage in number, skills, and geographic coverage, of a workforce for nutrition. Here, we report the findings of the Castel Gandolfo workshop, a convening of experts from diverse fields in March 2014 to consider how to develop the capacity of a global cadre of nutrition professionals for the post-2015 development era. Workshop participants identified several requirements for developing a workforce for nutrition, including an ability to work as part of a multisectoral team; communication, advocacy, and leadership skills to engage decision makers; and a set of technical skills to address future challenges for nutrition. Other opportunities were highlighted that could immediately contribute to capacity development, including the creation of a consortium to link global North and South universities, online training modules for middle managers, and practical, hands-on experiences for frontline nutrition workers. Institutional and organizational support is needed to enable workshop recommendations on education and training to be effectively implemented and sustained. The findings from the Castel Gandolfo workshop can contribute to the delivery of successful nutrition-relevant actions in the face of mounting external pressures and informing and attaining the forthcoming Sustainable Development Goals

Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease

BACKGROUND: Neutrophil extracellular traps (NETs) have been observed in the airway in COPD, but their clinical and pathophysiological implications have not been defined.OBJECTIVE: To determine if NETs are associated with disease severity in COPD, and how they are associated with microbiota composition and airway neutrophil function.METHODS: NET protein complexes (DNA-Elastase and Histone-Elastase complexes), cell free DNA and neutrophil biomarkers were quantified in soluble sputum and serum from COPD patients during periods of disease stability and during exacerbations, and compared to clinical measures of disease severity and sputum microbiome. Peripheral blood and airway neutrophil function was evaluated by flow cytometry ex vivo and experimentally following stimulation of NET formation.RESULTS: Sputum NET complexes were associated with the severity of COPD evaluated using the composite GOLD scale (p&lt;0.0001). This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by the COPD assessment test and higher levels of NET complexes in patients with frequent exacerbations (p=0.002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P=0.009) and dominance of Haemophilus spp operational taxonomic units. (P=0.01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with elevated sputum NET complexes. Consistent results were observed regardless of the method of quantifying sputum NETs. Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with COPD soluble sputum.CONCLUSION: NET formation is increased in severe COPD and is associated with more frequent exacerbations and a loss of microbiota diversity.</p

European Respiratory Society guidelines for the management of adult bronchiectasis

Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes

Folding-competent and folding-defective forms of Ricin A chain have different fates following retrotranslocation from the endoplasmic reticulum

We report that a toxic polypeptide retaining the potential to refold upon dislocation from the endoplasmic reticulum (ER) to the cytosol (ricin A chain; RTA) and a misfolded version that cannot (termed RTAΔ), follow ER-associated degradation (ERAD) pathways in Saccharomyces cerevisiae that substantially diverge in the cytosol. Both polypeptides are dislocated in a step mediated by the transmembrane Hrd1p ubiquitin ligase complex and subsequently degraded. Canonical polyubiquitylation is not a prerequisite for this interaction because a catalytically inactive Hrd1p E3 ubiquitin ligase retains the ability to retrotranslocate RTA, and variants lacking one or both endogenous lysyl residues also require the Hrd1p complex. In the case of native RTA, we established that dislocation also depends on other components of the classical ERAD-L pathway as well as an ongoing ER–Golgi transport. However, the dislocation pathways deviate strikingly upon entry into the cytosol. Here, the CDC48 complex is required only for RTAΔ, although the involvement of individual ATPases (Rpt proteins) in the 19S regulatory particle (RP) of the proteasome, and the 20S catalytic chamber itself, is very different for the two RTA variants. We conclude that cytosolic ERAD components, particularly the proteasome RP, can discriminate between structural features of the same substrate

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy