Bronchoscopy is frequently nondiagnostic in patients with pulmonary lesions suspected to be lung cancer. This often results in additional invasive testing, although many lesions are benign. We sought ...to validate a bronchial-airway gene-expression classifier that could improve the diagnostic performance of bronchoscopy.
Current or former smokers undergoing bronchoscopy for suspected lung cancer were enrolled at 28 centers in two multicenter prospective studies (AEGIS-1 and AEGIS-2). A gene-expression classifier was measured in epithelial cells collected from the normal-appearing mainstem bronchus to assess the probability of lung cancer.
A total of 639 patients in AEGIS-1 (298 patients) and AEGIS-2 (341 patients) met the criteria for inclusion. A total of 43% of bronchoscopic examinations were nondiagnostic for lung cancer, and invasive procedures were performed after bronchoscopy in 35% of patients with benign lesions. In AEGIS-1, the classifier had an area under the receiver-operating-characteristic curve (AUC) of 0.78 (95% confidence interval CI, 0.73 to 0.83), a sensitivity of 88% (95% CI, 83 to 92), and a specificity of 47% (95% CI, 37 to 58). In AEGIS-2, the classifier had an AUC of 0.74 (95% CI, 0.68 to 0.80), a sensitivity of 89% (95% CI, 84 to 92), and a specificity of 47% (95% CI, 36 to 59). The combination of the classifier plus bronchoscopy had a sensitivity of 96% (95% CI, 93 to 98) in AEGIS-1 and 98% (95% CI, 96 to 99) in AEGIS-2, independent of lesion size and location. In 101 patients with an intermediate pretest probability of cancer, the negative predictive value of the classifier was 91% (95% CI, 75 to 98) among patients with a nondiagnostic bronchoscopic examination.
The gene-expression classifier improved the diagnostic performance of bronchoscopy for the detection of lung cancer. In intermediate-risk patients with a nondiagnostic bronchoscopic examination, a negative classifier score provides support for a more conservative diagnostic approach. (Funded by Allegro Diagnostics and others; AEGIS-1 and AEGIS-2 ClinicalTrials.gov numbers, NCT01309087 and NCT00746759.).
The twenty-first century has seen LGBTQ+ rights emerge at the forefront of public discourse and national politics in ways that would once have been hard to imagine. Focusing on the small screens of ...Europe and North America, "Lesbians on Television" maps the contemporary shifts in lesbian visibility within popular media and, from this, extracts a figure of the new 'lesbian normal' that both helps and hinders those it represents. This book offers a unique and layered account of the complex dynamics in the modern moment of social change, drawing together critical social and cultural theory as well empirical research, which includes interviews and multi-platform media analyses. Structured around five central case studies of popular British and American television shows featuring lesbian, bisexual and queer women characters – "The L Word", "Skins", "Glee", "Coronation Street" and "The Fosters".
Honeybees and their products are useful biomonitors of metal distribution in urban centres. This study investigates particulate sources that foraging honeybees encounter in Metro Vancouver. Metal ...concentrations and lead (Pb) isotope compositions were measured in topsoil (top 2 cm, n = 14) colocated with existing research hives and in particulate matter ≤10 μm (PM10, n = 27) collected throughout Metro Vancouver (British Columbia, Canada) during honeybee foraging hours over the course of one year (2018–2019). Topsoil served as a proxy for resuspended/coarse PM and, together with PM10, covered the size range of particulates collected by foraging bees both actively (pollen) and passively (dusts). Particulate matter ≤ 2.5 μm (PM2.5, n = 7) was collected on Whistler Mountain during two transpacific events (in spring 2014) to estimate the possible effect of transpacific particulate input on the Pb isotope composition of Western Canada aerosols. Metal concentrations and Pb isotopes in topsoil and PM from this study and bees and hive products from previous studies (collected in 2014–2019) reveal similar spatial trends: there were elevated amounts of some metals associated with anthropogenic activity (e.g., Pb, Zn, Sb) and less radiogenic Pb isotope compositions in most samples collected nearer to the city centre in comparison to samples collected in more suburban or rural areas. Bees and hive products have a smoothing effect on the spatiotemporal variability of the data; metal concentrations and Pb isotope compositions vary less in hive products than in PM, presumably because bees interact with multiple environmental domains while foraging. Wildfire smoke and transpacific input are phenomena that cause measurable shifts in Pb isotope compositions of PM, but not in hive matrices. The findings highlight important considerations to make (i.e., the smoothing effect) when linking public health data and decisions with environmental data from hive products in urban centres.
Display omitted
•Apis mellifera samples PM from multiple environmental domains while foraging.•Pb isotope compositions of PM10, topsoil, and colocated hive products overlap.•Wildfires can shift metal concentrations and Pb isotope compositions of local PM10.•Seasonal events do not shift metal concentrations or Pb isotopes in hive products.•Hive products have a smoothing effect, offering an aggregate environmental lens.
The algorithm selection problem Rice 1976 seeks to answer the question: Which algorithm is likely to perform best for my problem? Recognizing the problem as a learning task in the early 1990's, the ...machine learning community has developed the field of meta-learning, focused on learning about learning algorithm performance on classification problems. But there has been only limited generalization of these ideas beyond classification, and many related attempts have been made in other disciplines (such as AI and operations research) to tackle the algorithm selection problem in different ways, introducing different terminology, and overlooking the similarities of approaches. In this sense, there is much to be gained from a greater awareness of developments in meta-learning, and how these ideas can be generalized to learn about the behaviors of other (nonlearning) algorithms. In this article we present a unified framework for considering the algorithm selection problem as a learning problem, and use this framework to tie together the crossdisciplinary developments in tackling the algorithm selection problem. We discuss the generalization of meta-learning concepts to algorithms focused on tasks including sorting, forecasting, constraint satisfaction, and optimization, and the extension of these ideas to bioinformatics, cryptography, and other fields.
Summary
During pregnancy, the maternal host must adapt in order to enable growth of the fetus. These changes affect all organ systems and are designed both to protect the fetus and to minimize risk ...to the mother. One of the most prominent adaptations involves the immune system. The semi‐allogenic fetoplacental unit has non‐self components and must be protected against attack from the host. This requires both attenuation of adaptive immunity and protection from innate immune defense mechanisms. One of the key innate immune players is complement, and it is important that the fetoplacental unit is not identified as non‐self and subjected to complement attack. Adaptation of the complement response must, however, be managed in such a way that maternal protection against infection is not compromised. As the complement system also plays a significant facilitating role in many of the stages of a normal pregnancy, it is also important that any necessary adaptation to accommodate the semi‐allogenic aspects of the fetoplacental unit does not compromise this. In this review, both the physiological role of the alternative pathway of complement in facilitating a normal pregnancy, and its detrimental participation in pregnancy‐specific disorders, are discussed.
Relations between Australia and Japan have undergone both testing and celebrated times since 1952, when Australia's ambassadorial representation in Tokyo commenced. Over the years, interactions have ...deepened beyond mutual trade objectives to encompass economic, defence and strategic interests within the Indo-Pacific region and beyond. This 'special relationship’ has been characterised by the high volume of people moving between Australia and Japan for education, tourism, business, science and research. Cultural ties, from artists-in-residence to sister-city agreements, have flourished. Australia has supported Japan in times of need, including the aftermath of the 2011 Tohoku earthquake. This book shows how the Australian embassy in Tokyo, through its programs and people, has been central to these developments. The embassy’s buildings, its gardens and grounds, and, above all, its occupants—from senior Australian diplomats to locally engaged staff—are the focus of this multidimensional study by former diplomats and expert observers of Australia’s engagement with Japan. Drawing on oral histories, memoirs, and archives, this volume sheds new light on the complexity of Australia’s diplomatic work in Japan, and the role of the embassy in driving high-level negotiations as well as fostering soft‑power influences. ‘With a similar vision for the Indo-Pacific region and a like-minded approach to the challenges facing us, Australia and Japan have become more intimate and more strategic as partners. I am very pleased to see this slice of Australian diplomatic history so well accounted for in this book.’ — Jan Adams AO PSM, Secretary, Australian Department of Foreign Affairs and Trade; Australia’s Ambassador to Japan, November 2020–June 2022
The transition to parenthood is one of the most joyful, yet stressful life events, however, there is little evidence to support paternity coaching as an intervention. This action research study draws ...on gender studies and maternity and transition coaching literature to inform the research. A cohort of four fathers participated in the research, each receiving three coaching sessions, followed by an interview. Themes emerging were responsibility, self-care and adapting to the new role. Practitioners and academics will find the research helps in understanding the themes supporting transition coaching for fathers, and in identifying further gaps for future research.
Crop residue incorporation is a common practice to increase or restore organic matter stocks in agricultural soils. However, this practice often increases emissions of the powerful greenhouse gas ...nitrous oxide (N2O). Previous meta-analyses have linked various biochemical properties of crop residues to N2O emissions, but the relationships between these properties have been overlooked, hampering our ability to predict N2O emissions from specific residues. Here we combine comprehensive databases for N2O emissions from crop residues and crop residue biochemical characteristics with a random-meta-forest approach, to develop a predictive framework of crop residue effects on N2O emissions. On average, crop residue incorporation increased soil N2O emissions by 43% compared to residue removal, however crop residues led to both increases and reductions in N2O emissions. Crop residue effects on N2O emissions were best predicted by easily degradable fractions (i.e. water soluble carbon, soluble Van Soest fraction (NDS)), structural fractions and N returned with crop residues. The relationship between these biochemical properties and N2O emissions differed widely in terms of form and direction. However, due to the strong correlations among these properties, we were able to develop a simplified classification for crop residues based on the stage of physiological maturity of the plant at which the residue was generated. This maturity criteria provided the most robust and yet simple approach to categorize crop residues according to their potential to regulate N2O emissions. Immature residues (high water soluble carbon, soluble NDS and total N concentration, low relative cellulose, hemicellulose, lignin fractions, and low C:N ratio) strongly stimulated N2O emissions, whereas mature residues with opposite characteristics had marginal effects on N2O. The most important crop types belonging to the immature residue group – cover crops, grasslands and vegetables – are important for the delivery of multiple ecosystem services. Thus, these residues should be managed properly to avoid their potentially high N2O emissions.
Display omitted
•Meta-analysis to identify best predictors of crop residue N2O emissions•Nitrogen returned with residues and residue characteristics were good predictors.•The predictive power of individual residue characteristics was limited.•Using correlations between chemical characteristics, we developed a maturity class.•Immature residues stimulate N2O emissions, mature residues have marginal effects.
Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, only 15%–20% of ovarian cancers harbor BRCA mutations, therefore ...additional therapies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are sensitive to a poly(ADP-ribose) glycohydrolase (PARG) inhibitor. Sensitivity is due to underlying DNA replication vulnerabilities that cause persistent fork stalling and replication catastrophe. PARG inhibition is synthetic lethal with inhibition of DNA replication factors, allowing additional models to be sensitized by CHK1 inhibitors. Because PARG and PARP inhibitor sensitivity are mutually exclusive, our observations demonstrate that PARG inhibitors have therapeutic potential to complement PARP inhibitor strategies in the treatment of ovarian cancer.
Display omitted
•Ovarian cancer cells show differential sensitivity to PARP and PARG inhibitors•PARG inhibitor sensitivity is due to an underlying DNA replication vulnerability•PARG inhibition blocks fork restart leading to persistent replication stress•PARG inhibition sensitizes cells to drugs targeting the CHK1 kinase
Pillay et al. show that ovarian cancer cells respond to inhibition of poly(ADP-ribose) (PAR) polymerase and inhibition of PAR glycohydrolase (PARG) differently; sensitivity to the latter is due to persistent fork stalling and replication catastrophe. Inhibiting CHK1 sensitizes tumor cells to PARG inhibition.
CX‐ASAP is a new open‐source software project designed to greatly reduce the time required to analyse crystallographic data collected under varying conditions. Scripted in Python3, CX‐ASAP can ...automatically refine, finalize and analyse data collections with wide‐ranging temperatures, pressures etc. This is achieved using a reference structure, allowing for quick identification of problems, phase changes and even model comparison. The modular design means that new features and customized scripts can be easily added, tailoring the capabilities to the specific needs of the user. It is envisioned that CX‐ASAP will help to close the growing gap between fast collection times and slow data finalization.
CX‐ASAP is a new open‐source software project designed to greatly reduce the time required to analyse crystallographic data collected under varying conditions. This software will allow the rapid refinement and finalization of dynamic crystallographic experiments.
PDF
