Yorkshire Lung Screening Trial (YLST): protocol for a randomised controlled trial to evaluate invitation to community-based low-dose CT screening for lung cancer versus usual care in a targeted population at risk

Introduction: Lung cancer is the world’s leading cause of cancer death. Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the US National Lung Screening Trial. Here, we present the Yorkshire Lung Screening Trial (YLST), which will address key questions of relevance for screening implementation. / Methods and analysis: Using a single-consent Zelen’s design, ever-smokers aged 55–80 years registered with a general practice in Leeds will be randomised (1:1) to invitation to a telephone-based risk-assessment for a Lung Health Check or to usual care. The anticipated number randomised by household is 62 980 individuals. Responders at high risk will be invited for LDCT scanning for lung cancer on a mobile van in the community. There will be two rounds of screening at an interval of 2 years. Primary objectives are (1) measure participation rates, (2) compare the performance of PLCOM2012 (threshold ≥1.51%), Liverpool Lung Project (V.2) (threshold ≥5%) and US Preventive Services Task Force eligibility criteria for screening population selection and (3) assess lung cancer outcomes in the intervention and usual care arms. Secondary evaluations include health economics, quality of life, smoking rates according to intervention arm, screening programme performance with ancillary biomarker and smoking cessation studies. / Ethics and dissemination: The study has been approved by the Greater Manchester West research ethics committee (18-NW-0012) and the Health Research Authority following review by the Confidentiality Advisory Group. The results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and on the YLST website. / Trial registration numbers: ISRCTN42704678 and NCT03750110

First-principles design and subsequent synthesis of a material to search for the permanent electric dipole moment of the electron

We describe the first-principles design and subsequent synthesis of a new material with the specific functionalities required for a solid-state-based search for the permanent electric dipole moment of the electron. We show computationally that perovskite-structure europium barium titanate should exhibit the required large and pressure-dependent ferroelectric polarization, local magnetic moments, and absence of magnetic ordering even at liquid helium temperature. Subsequent synthesis and characterization of Eu$_{0.5}$Ba$_{0.5}$TiO$_3$ ceramics confirm the predicted desirable properties.Comment: Nature Materials, in pres

Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype

BACKGROUND: MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells. The occurrence of tumors is accelerated in experiments that activate FGF proto-oncogenes or remove the tumor suppressor genes Pten or P53, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma. It is not known, however, which oncogenic pathways contribute to Wnt1-induced tumorigenesis – further experimental manipulation of these mice is needed. Secondary events also appear to be required for mammary tumorigenesis in MMTV-Neu transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase. METHODS: cDNA or DNA from the mammary glands and mammary tumors from MMTV-Wnt1, MMTV-Wnt1/p53(-/-), MMTV-Neu transgenic mice, and newly generated MMTV-Wnt1/MMTV-Neu bitransgenic mice, was sequenced to seek activating mutations in H-Ras, K-Ras, and N-Ras genes, or in the MMTV-Neu transgene. In addition, tumors from bitransgenic animals were examined to determine the cellular phenotype. RESULTS: We found activating mutations at codons 12, 13, and 61 of H-Ras in just over half of the mammary tumors in MMTV-Wnt1 transgenic mice, and we confirmed the high frequency of activating mutations of Neu in tumors in MMTV-Neu transgenic mice. Tumors appeared earlier in bitransgenic MMTV-Wnt1/MMTV-Neu mice, but no Ras or MMTV-Neu mutations were found in these tumors, which were phenotypically similar to those arising in MMTV-Wnt1 mice. In addition, no Ras mutations were found in the mammary tumors that arise in MMTV-Wnt1 transgenic mice lacking an intact P53 gene. CONCLUSIONS: Tumorigenic properties of cells undergoing functionally significant secondary mutations in H-Ras or the MMTV-Neu transgene allow selection of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype

Chapter 12: Systematic Review of Prognostic Tests

A number of new biological markers are being studied as predictors of disease or adverse medical events among those who already have a disease. Systematic reviews of this growing literature can help determine whether the available evidence supports use of a new biomarker as a prognostic test that can more accurately place patients into different prognostic groups to improve treatment decisions and the accuracy of outcome predictions. Exemplary reviews of prognostic tests are not widely available, and the methods used to review diagnostic tests do not necessarily address the most important questions about prognostic tests that are used to predict the time-dependent likelihood of future patient outcomes. We provide suggestions for those interested in conducting systematic reviews of a prognostic test. The proposed use of the prognostic test should serve as the framework for a systematic review and to help define the key questions. The outcome probabilities or level of risk and other characteristics of prognostic groups are the most salient statistics for review and perhaps meta-analysis. Reclassification tables can help determine how a prognostic test affects the classification of patients into different prognostic groups, hence their treatment. Review of studies of the association between a potential prognostic test and patient outcomes would have little impact other than to determine whether further development as a prognostic test might be warranted

Ambient biomass smoke and cardio-respiratory hospital admissions in Darwin, Australia

<p>Abstract</p> <p>Background</p> <p>Increasing severe vegetation fires worldwide has been attributed to both global environmental change and land management practices. However there is little evidence concerning the population health effects of outdoor air pollution derived from biomass fires. Frequent seasonal bushfires near Darwin, Australia provide an opportunity to examine this issue. We examined the relationship between atmospheric particle loadings <10 microns in diameter (PM₁₀), and emergency hospital admissions for cardio-respiratory conditions over the three fire seasons of 2000, 2004 and 2005. In addition we examined the differential impacts on Indigenous Australians, a high risk population subgroup.</p> <p>Methods</p> <p>We conducted a case-crossover analysis of emergency hospital admissions with principal ICD10 diagnosis codes J00–J99 and I00–I99. Conditional logistic regression models were used to calculate odds ratios for admission with 10 μg/m³rises in PM₁₀. These were adjusted for weekly influenza rates, same day mean temperature and humidity, the mean temperature and humidity of the previous three days, days with rainfall > 5 mm, public holidays and holiday periods.</p> <p>Results</p> <p>PM₁₀ranged from 6.4 – 70.0 μg/m³(mean 19.1). 2466 admissions were examined of which 23% were for Indigenous people. There was a positive relationship between PM₁₀and admissions for all respiratory conditions (OR 1.08 95%CI 0.98–1.18) with a larger magnitude in the Indigenous subpopulation (OR1.17 95% CI 0.98–1.40). While there was no relationship between PM₁₀and cardiovascular admissions overall, there was a positive association with ischaemic heart disease in Indigenous people, greatest at a lag of 3 days (OR 1.71 95%CI 1.14–2.55).</p> <p>Conclusion</p> <p>PM10 derived from vegetation fires was predominantly associated with respiratory rather than cardiovascular admissions. This outcome is consistent with the few available studies of ambient biomass smoke pollution. Indigenous people appear to be at higher risk of cardio-respiratory hospital admissions associated with exposure to PM10.</p

Anthrax Toxins Inhibit Neutrophil Signaling Pathways in Brain Endothelium and Contribute to the Pathogenesis of Meningitis

Anthrax meningitis is the main neurological complication of systemic infection with Bacillus anthracis approaching 100% mortality. The presence of bacilli in brain autopsies indicates that vegetative bacteria are able to breach the blood-brain barrier (BBB). The BBB represents not only a physical barrier but has been shown to play an active role in initiating a specific innate immune response that recruits neutrophils to the site of infection. Currently, the basic pathogenic mechanisms by which B. anthracis penetrates the BBB and causes anthrax meningitis are poorly understood.Using an in vitro BBB model, we show for the first time that B. anthracis efficiently invades human brain microvascular endothelial cells (hBMEC), the single cell layer that comprises the BBB. Furthermore, transcriptional profiling of hBMEC during infection with B. anthracis revealed downregulation of 270 (87%) genes, specifically key neutrophil chemoattractants IL-8, CXCL1 (Gro alpha) and CXCL2 (Gro beta), thereby strongly contrasting hBMEC responses observed with other meningeal pathogens. Further studies using specific anthrax toxin-mutants, quantitative RT-PCR, ELISA and in vivo assays indicated that anthrax toxins actively suppress chemokine production and neutrophil recruitment during infection, allowing unrestricted proliferation and dissemination of the bacteria. Finally, mice challenged with B. anthracis Sterne, but not the toxin-deficient strain, developed meningitis.These results suggest a significant role for anthrax toxins in thwarting the BBB innate defense response promoting penetration of bacteria into the central nervous system. Furthermore, establishment of a mouse model for anthrax meningitis will aid in our understanding of disease pathogenesis and development of more effective treatment strategies

Segregation of Fluorescent Membrane Lipids into Distinct Micrometric Domains: Evidence for Phase Compartmentation of Natural Lipids?

Background: We recently reported that sphingomyelin (SM) analogs substituted on the alkyl chain by various fluorophores (e.g. BODIPY) readily inserted at trace levels into the plasma membrane of living erythrocytes or CHO cells and spontaneously concentrated into micrometric domains. Despite sharing the same fluorescent ceramide backbone, BODIPY-SM domains segregated from similar domains labelled by BODIPY-D-e-lactosylceramide (D-e-LacCer) and depended on endogenous SM. Methodology/Principal Findings. We show here that BODIPY-SM further differed from BODIPY-D-e-LacCer or -glucosylceramide (GlcCer) domains in temperature dependence, propensity to excimer formation, association with a glycosylphosphatidylinositol (GPI)-anchored fluorescent protein reporter, and lateral diffusion by FRAP, thus demonstrating different lipid phases and boundaries. Whereas BODIPY-D-e-LacCer behaved like BODIPY-GlcCer, its artificial stereoisomer, BODIPY-L-t-LacCer, behaved like BODIPY- and NBD-phosphatidylcholine (PC). Surprisingly, these two PC analogs also formed micrometric patches yet preferably at low temperature, did not show excimer, never associated with the GPI reporter and showed major restriction to lateral diffusion when photobleached in large fields. This functional comparison supported a three-phase micrometric compartmentation, of decreasing order: BODIPY-GSLs > -SM > -PC (or artificial L-t-LacCer). Co-existence of three segregated compartments was further supported by double labelling experiments and was confirmed by additive occupancy, up to ~70% cell surface coverage. Specific alterations of BODIPY-analogs domains by manipulation of corresponding endogenous sphingolipids suggested that distinct fluorescent lipid partition might reflect differential intrinsic propensity of endogenous membrane lipids to form large assemblies. Conclusions/Significance. We conclude that fluorescent membrane lipids spontaneously concentrate into distinct micrometric assemblies. We hypothesize that these might reflect preexisting compartmentation of endogenous PM lipids into non-overlapping domains of differential order: GSLs > SM > PC, resulting into differential self-adhesion of the two former, with exclusion of the latter

Urban air pollution and emergency room admissions for respiratory symptoms: a case-crossover study in Palermo, Italy

<p>Abstract</p> <p>Background</p> <p>Air pollution from vehicular traffic has been associated with respiratory diseases. In Palermo, the largest metropolitan area in Sicily, urban air pollution is mainly addressed to traffic-related pollution because of lack of industrial settlements, and the presence of a temperate climate that contribute to the limited use of domestic heating plants. This study aimed to investigate the association between traffic-related air pollution and emergency room admissions for acute respiratory symptoms.</p> <p>Methods</p> <p>From January 2004 through December 2007, air pollutant concentrations and emergency room visits were collected for a case-crossover study conducted in Palermo, Sicily. Risk estimates of short-term exposures to particulate matter and gaseous ambient pollutants including carbon monoxide, nitrogen dioxide, and sulfur dioxide were calculated by using a conditional logistic regression analysis.</p> <p>Results</p> <p>Emergency departments provided data on 48,519 visits for respiratory symptoms. Adjusted case-crossover analyses revealed stronger effects in the warm season for the most part of the pollutants considered, with a positive association for PM₁₀(odds ratio = 1.039, 95% confidence interval: 1.020 - 1.059), SO₂(OR = 1.068, 95% CI: 1.014 - 1.126), nitrogen dioxide (NO₂: OR = 1.043, 95% CI: 1.021 - 1.065), and CO (OR = 1.128, 95% CI: 1.074 - 1.184), especially among females (according to an increase of 10 μg/m³in PM₁₀, NO₂, SO₂, and 1 mg/m³in CO exposure). A positive association was observed either in warm or in cold season only for PM₁₀.</p> <p>Conclusions</p> <p>Our findings suggest that, in our setting, exposure to ambient levels of air pollution is an important determinant of emergency room (ER) visits for acute respiratory symptoms, particularly during the warm season. ER admittance may be considered a good proxy to evaluate the adverse effects of air pollution on respiratory health.</p

Standardized and reproducible methodology for the comprehensive and systematic assessment of surgical resection margins during breast-conserving surgery for invasive breast cancer

<p>Abstract</p> <p>Background</p> <p>The primary goal of breast-conserving surgery (BCS) is to completely excise the tumor and achieve "adequate" or "negative" surgical resection margins while maintaining an acceptable level of postoperative cosmetic outcome. Nevertheless, precise determination of the adequacy of BCS has long been debated. In this regard, the aim of the current paper was to describe a standardized and reproducible methodology for comprehensive and systematic assessment of surgical resection margins during BCS.</p> <p>Methods</p> <p>Retrospective analysis of 204 BCS procedures performed for invasive breast cancer from August 2003 to June 2007, in which patients underwent a standard BCS resection and systematic sampling of nine standardized re-resection margins (superior, superior-medial, superior-lateral, medial, lateral, inferior, inferior-medial, inferior-lateral, and deep-posterior). Multiple variables (including patient, tumor, specimen, and follow-up variables) were evaluated.</p> <p>Results</p> <p>6.4% (13/204) of patients had positive BCS specimen margins (defined as tumor at inked edge of BCS specimen) and 4.4% (9/204) of patients had close margins (defined as tumor within 1 mm or less of inked edge but not at inked edge of BCS specimen). 11.8% (24/204) of patients had at least one re-resection margin containing additional disease, independent of the status of the BCS specimen margins. 7.1% (13/182) of patients with negative BCS specimen margins (defined as no tumor cells seen within 1 mm or less of inked edge of BCS specimen) had at least one re-resection margin containing additional disease. Thus, 54.2% (13/24) of patients with additional disease in a re-resection margin would not have been recognized by a standard BCS procedure alone (P < 0.001). The nine standardized resection margins represented only 26.8% of the volume of the BCS specimen and 32.6% of the surface area of the BCS specimen.</p> <p>Conclusion</p> <p>Our methodology accurately assesses the adequacy of surgical resection margins for determination of which individuals may need further resection to the affected breast in order to minimize the potential risk of local recurrence while attempting to limit the volume of additional breast tissue excised, as well as to determine which individuals are not realistically amendable to BCS and instead need a completion mastectomy to successfully remove multifocal disease.</p

Salivary gland branching morphogenesis: a quantitative systems analysis of the Eda/Edar/NFκB paradigm

<p>Abstract</p> <p>Background</p> <p>Ectodysplasin-A appears to be a critical component of branching morphogenesis. Mutations in mouse <it>Eda </it>or human <it>EDA </it>are associated with absent or hypoplastic sweat glands, sebaceous glands, lacrimal glands, salivary glands (SMGs), mammary glands and/or nipples, and mucous glands of the bronchial, esophageal and colonic mucosa. In this study, we utilized <it>Eda</it>^{<it>Ta </it>}(Tabby) mutant mice to investigate how a marked reduction in functional Eda propagates with time through a defined genetic subcircuit and to test the proposition that canonical NFκB signaling is sufficient to account for the differential expression of developmentally regulated genes in the context of <it>Eda </it>polymorphism.</p> <p>Results</p> <p>The quantitative systems analyses do not support the stated hypothesis. For most NFκB-regulated genes, the observed time course of gene expression is nearly unchanged in Tabby (<it>Eda</it>^<it>Ta</it>) as compared to wildtype mice, as is NFκB itself. Importantly, a subset of genes is dramatically differentially expressed in Tabby (<it>Edar</it>, <it>Fgf8</it>, <it>Shh</it>, <it>Egf</it>, <it>Tgfa</it>, <it>Egfr</it>), strongly suggesting the existence of an alternative Eda-mediated transcriptional pathway pivotal for SMG ontogeny. Experimental and <it>in silico </it>investigations have identified C/EBPα as a promising candidate.</p> <p>Conclusion</p> <p>In Tabby SMGs, upregulation of the Egf/Tgfα/Egfr pathway appears to mitigate the potentially severe abnormal phenotype predicted by the downregulation of Fgf8 and Shh. Others have suggested that the buffering of the phenotypic outcome that is coincident with variant Eda signaling could be a common mechanism that permits viable and diverse phenotypes, normal and abnormal. Our results support this proposition. Further, if branching epithelia use variations of a canonical developmental program, our results are likely applicable to understanding the phenotypes of other branching organs affected by <it>Eda </it>(<it>EDA</it>) mutation.</p