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Air quality degradation presents a significant public health challenge, particularly in rapidly urbanizing regions where changes in land use/land cover (LULC) can dramatically influence pollution levels. This study investigates the association between LULC changes and air pollution (AP) in the five fastest-growing cities of Bangladesh from 1998 to 2021. Leveraging satellite data from Landsat and Sentinel-5P, the analysis reveals a substantial increase in urban areas and sparse vegetation, with declines in dense vegetation and water bodies over this period. Urban expansion was most pronounced in Sylhet (22-254%), while Khulna experienced the largest increase in sparse vegetation (2-124%). Dense vegetation loss was highest in Dhaka (20-77%) and water bodies (9-59%) over this period. Concentrations of six major air pollutants (APTs) - aerosol index, CO, HCHO, NO 2 , O 3 , and SO 2 - were quantified, showing alarmingly high levels in densely populated industrial and commercial zones. Pearson's correlation indicates strong positive associations between APTs and urban land indices (R > 0.8), while negative correlations exist with vegetation indices. Geographically weighted regression modeling identifies city centers with dense urban built-up as pollution hotspots, where APTs exhibited stronger impacts on land cover changes (R 2  > 0.8) compared to other land classes. The highest daily emissions were observed for O 3 (1031 tons) and CO (356 tons) at Chittagong in 2021. In contrast, areas with substantial green cover displayed weaker pollutant-land cover associations. These findings underscore how unplanned urbanization drives AP by replacing natural land cover with emission sources, providing crucial insights to guide sustainable urban planning strategies integrating pollution mitigation and environmental resilience., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Urban noise pollution poses significant challenges to public health and environmental sustainability, particularly in rapidly developing tourist destinations. Noise pollution and associated annoyance level in five major intersections of Cox's Bazar City, Bangladesh, was assessed in this study during the peak tourist season. Noise measurements were conducted using various indices (L 10 , L eq , and TNI) across morning, midday, and afternoon time slots. TNI scores were compared with Mean Dissatisfaction Score (MDS) standards to assess traffic-induced noise annoyance levels. Additionally, a survey of 675 respondents was conducted to assess their perceptions of noise pollution. Statistical analyses included linear regression for noise indices, multinomial logistic regression for TNI-related dissatisfaction, and ordinal logistic regression for respondents' perceived annoyances. Results revealed significant noise pollution issues, with L eq scores consistently exceeding national guidelines across all intersections and time periods, particularly on weekends during afternoon timeslots. TNI values frequently surpassed standard dissatisfaction regulations, with 19 out of 105 time slots exhibiting extreme dissatisfaction levels. Link Road and Kolatoli Circle intersections consistently showed higher noise levels and dissatisfaction. Over 95% of survey respondents perceived increased noise pollution during peak tourist seasons, with 87.11% describing it as "extremely" or "very" noisy. Longer exposure duration and awareness of health risks were significantly associated with reported perceived annoyance levels. Respondents reported various health impacts, including annoyance (84.44%), headaches (62.37%), and cognitive impairment (44.44%). This comprehensive study provides valuable insights for policymakers, city planners, and environmentalists to develop sustainable urban strategies that balance the acoustic environment with the well-being of residents and tourists alike., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Formation of a pure Langmuir monolayer of lysozyme at the air-water interface and its investigation by means of a surface pressure ( π )-mean molecular area ( A ) isotherm has been accomplished under different subphase pH conditions. A normalized area-time curve confirms the stable nature of the lysozyme monolayer whose compressibility variation with an increased surface pressure at specific subphase pH has also been studied from π - A isotherms. The monolayers exhibit irreversible hysteresis behaviour irrespective of subphase pH conditions, as evidenced from successive compression-expansion π - A isotherm cycles. Comparison of surface thermodynamics under hysteresis with subphase pH variation confirms that the monolayer at subphase pH ≈ 4.0 involves a greater amount of energy to attain and retain the ordered and compact monolayer than the other two pH conditions (pH ≈ 7.0 and 9.5). In situ visualization of lysozyme monolayers by Brewster angle microscopy suggests the homogeneous and stripe-like pattern formation at lower and higher surface pressure respectively. Further investigations of lysozyme films at solid surfaces have been carried out with atomic force microscopy and X-ray reflectivity (XRR) analysis. Structural reversibility of lysozyme molecules under compression-expansion-compression of the monolayer is revealed from the comparison of height profiles of AFM images and electron density profiles as extracted from XRR analysis of the films deposited during both first and second compressions of the monolayer. The mechanism of the structural rearrangement of lysozyme molecules with surface pressure variation at different subphase pH is explored, correlating macroscopic and microscopic information., Competing Interests: The authors declare that there are no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Introduction: Previous studies have shown that the population attributable risk of low forced expiratory volume in one second (FEV 1 ) for coronary artery disease (CAD) is substantial. FEV 1 can be low either because of airflow obstruction or ventilatory restriction. It is not known if low FEV 1 arising from spirometric obstruction or restriction are differently associated with CAD., Methods: We analyzed high resolution computed tomography (CT) scans acquired at full inspiration in lifetime non-smoker adults with no lung disease (controls) and those with chronic obstructive pulmonary disease enrolled in the Genetic Epidemiology of COPD (COPDGene) study. We also analyzed CT scans of adults with idiopathic pulmonary fibrosis (IPF) from a cohort of patients attending a quaternary referral clinic. Participants with IPF were matched 1:1 by FEV 1 %predicted to adults with COPD and 1:1 by age to lifetime non-smokers. Coronary artery calcium (CAC), a surrogate for CAD, was measured by visual quantification on CT using the Weston score. Significant CAC was defined as Weston score ≥7. Multivariable regression models were used to test the association of the presence of COPD or IPF with CAC, with adjustment for age, sex, body-mass-index, smoking status, hypertension, diabetes mellitus, and hyperlipidemia., Results: We included 732 subjects in the study; 244 with IPF, 244 with COPD, and 244 lifetime non-smokers. The mean (SD) age was 72.6 (8.1), 62.6 (7.4), and 67.3 (6.6) years, and median (IQR) CAC was 6 (6), 2 (6), and 1 (4), in IPF, COPD, and non-smokers, respectively. On multivariable analyses, the presence of COPD was associated with higher CAC compared to non-smokers (adjusted regression coefficient, β = 1.10 ± SE0.51; P = 0.031). The presence of IPF was also associated with higher CAC compared to non-smokers (β = 03.43 ± SE0.41; P < 0.001). The adjusted odds ratio for having significant CAC was 1.3, 95% CI 0.6 to 2.8; P = 0.53 in COPD and 5.6, 95% CI 2.9 to 10.9; P < 0.001 in IPF, compared to non-smokers. In sex stratified analyses, these associations were mainly noted in women., Conclusion: Adults with IPF displayed higher coronary artery calcium than those with COPD after accounting for age and lung function impairment., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Antibacterial drug resistance, brought on by the overuse of antibiotics, is one of the biggest threats to human health. It is crucial to consider cutting-edge strategies, such as herbal remedies, to control multidrug-resistant (MDR) bacteria., Methods: This study evaluated the phytochemical, antioxidant and antibacterial properties of the various Tinospora cordifolia extracts. Functionalization of the isolated active compound was done using gold (Au) and silver (Ag) nanoparticles (NPs). Further, to understand the interaction of the isolated class, Cordifolisides, with its target, various in-silico methods were used., Results and Discussion: The plant was reported from the Charaideo district of Assam, whose methanolic stem extract showed the maximum activity towards the nosocomial pathogen Pseudomonas aeruginosa . Consequently, the active compound was isolated and characterized as belonging to the class Cordifoliside using NMR. The AuNPs and AgNPs functionalized isolates showed enhanced antimicrobial activity against P. aeruginosa compared to the unfunctionalized isolate. The most reactive compound, Cordifoliside C was determined using Density Functional Theory (DFT) analysis, whose interactions with the TolB protein were studied using molecular docking methods, which revealed good binding interactions of Cordifoliside C with the TolB protein., Conclusion: This study offers enormous potential for drug design and might be used as a pipeline to address the urgent problem of multidrug-resistance in bacteria. Graphical Abstract., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nath, Khataniar, Bania, Mukerjee, Al-Hussain, Zaki and Rajkhowa.)

Heavy metal-contaminated water can be effectively treated using adsorbents made from abundantly available biomass. The present investigation was carried out to adsorb Cd(II) from synthetic solution by banana pseudo-stem (BP) and Moringa oleifera stem bark (MB). Adsorption efficiencies of both adsorbents were studied in the batch reactor by conducting experiments to determine the consequences of changes of pH, adsorbent dosages, initial Cd(II) concentrations, incubation time, and temperature. The process parameters were tuned to attain the highest possible removal percentage. The characterization of the adsorbents was performed by utilizing Fourier-transform infrared spectroscopy (FTIR), field emission scanning electron microscopy (FESEM), and energy-dispersive X-ray (EDX) for the fresh and metal-loaded adsorbents. Atomic absorption spectroscopy (AAS) was employed to calculate the amount of Cd(II) in an aqueous solution. The experimental data were entirely consistent with the pseudo-second-order model for BP and MB. The findings of the study illustrated the better adsorption efficiency of BP-derived adsorbent (≈ 99%) at optimum conditions over the MB (≈ 97%), and the corresponding adsorption capacities were 11.98 and 7.04 mg/g, respectively. The 4 (four) well-known isotherm models were attempted both in linear and non-linear forms. BP (R 2 =0.995) and MB (R 2 =0.994) were found to be best described by the Freundlich isotherm, which was selected based on the highest R 2 value. In thermodynamic studies, ΔH and ΔS were calculated for both the adsorbents. Cd(II) adsorption on BP and MB was endothermic, as evidenced by the positive ΔH. Finally, the prediction of the removal percentage was made by the artificial neural network (ANN) modelling. The present work developed regionally derived waste materials which are helpful for small-scale industrial units for their waste management in an economical and sustainable way., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Observing the serological cross-reactivity between SARS-CoV-2 and dengue virus (DV), we aimed to elucidate its effect on dengue serodiagnosis and infectivity in a highly dengue-endemic city in India., Methods: A total of 52 COVID-19 (reverse transcription-polymerase chain reaction [RT-PCR] positive) serum samples were tested in rapid lateral flow immunoassays and DV immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) to detect DV or SARS-CoV-2 IgG/immunoglobulin M. The COVID-19 antibody (Ab) positive samples were subjected to a virus neutralization test (Huh7 cells) using DV type 1 (DV1) clinical isolate., Results: Most (93%) of the SARS-CoV-2 Ab-positive serum samples cross-reacted with DV in rapid or ELISA tests. All were DV RNA and nonstructural protein 1 (NS1) antigen-negative. COVID-19 serum samples that were DV cross-reactive neutralized DV1. Of these, 57% had no evidence of DV pre-exposure (DV NS1 Ab-negative). The computational study also supported potential interactions between SARS-CoV-2 Ab and DV1., Conclusion: DV serodiagnosis will be inconclusive in areas co-endemic for both viruses. The COVID-19 pandemic appears to impart a protective response against DV in DV-endemic populations., Competing Interests: Competing interests The authors have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Kala-azar/Visceral Leishmaniasis (VL) caused by Leishmania donovani (LD) is often associated with Leptomonas seymouri (LS) co-infection in India. Leptomonas seymouri narna-like virus 1 (Lepsey NLV1) has been reported in multi-passaged laboratory isolates of VL samples which showed LD-LS co-infection. A pertinent question was whether this virus of LS is detectable in direct clinical samples. DNA from the serum of twenty-eight LD diagnosed patients was subjected to LD-specific and LS-specific PCR to reconfirm the presence of LD parasites and to detect LD-LS co-infections. RNA extracted from same samples was subjected to RT-PCR, qRT-PCR and sequencing using virus-specific primers to detect/identify and quantify the virus. The presence of the virus was confirmed in thirteen of eighteen (72%) recently collected VL and PKDL samples. Cytokine profiling showed significantly elevated IL-18 in only LD infected patients compared to the virus-positive LD and control samples. IL-18 is crucial for Th1 and macrophage activation which eventually clears the parasite. The Lepsey NLV1 interaction with the immune system results in reduced IL-18 which favors LD survival and increased parasitic burden. The study emphasizes the need to revisit LD pathogenesis in the light of the association and persistence of a protozoan virus in kala-azar and PKDL patients., (© 2022. The Author(s).)

Dengue diagnosis primarily relies on NS1 ELISA and serological (IgG/IgM) tests. There are reports of low and variable sensitivity of the widely used NS1 ELISA tests. Poor sensitivity has been attributed to patient's infection status, prevalent serotypes, and the geographical origin of the samples. We investigated whether NS1 mutations directly have any impact on NS1 ELISA-based dengue virus (DENV) detection in clinical samples. Fifty-eight serum samples were collected from dengue-endemic area during 2015-2017 and tested with three commonly used NS1 ELISA kits. The samples were subjected to diagnostic RT-PCR and sequencing of structural gene(s). Sequencing of NS1 gene revealed amino acid changes which were transferred to respective wild type NS1 backbone to determine their effects on NS1 production and secretion in Huh-7, Vero, and A549 cells. Eighty-seven percent samples were virus RNA-positive but 65% of these were NS1 ELISA-positive. NS1-gene mutations like Val236➔Ala (DENV2) or Trp68➔stop codon in DENV3 were associated with decreased NS1 production and secretion. These mutations were originally identified in NS1 ELISA-negative clinical isolates. All DENV1 and > 80% DENV2 were NS1 ELISA-positive. The three NS1 ELISA could not detect recently circulating DENV3 single infections despite being RNA-positive. Among serotypes 1-3, wild-type NS1 production was highest for DENV1 and lowest for DENV3 in all cell lines tested. Mutations in circulating DENV directly correlated with NS1 production and secretion and, hence, ELISA-based NS1 detection. Further studies to define more NS1 mutations in clinical samples are needed to optimize ELISA kits for more sensitive dengue diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vascular calcification is most commonly due to atherosclerosis. It has been well documented that absence of coronary calcification on a chest CT (CCT) is associated with low cardiovascular events and good prognosis. High CT calcium scores often result in a higher incidence of cardiovascular events and worse survival. In asymptomatic patients with an intermediate risk for coronary artery disease, numerous studies have shown Coronary Calcium Scoring (CCS) has prognostic relevance and incremental prognostic value over conventional risk stratification. CT detected calcium score plays important role in patient management. This article will review various CT based coronary artery calcium scoring methods., (Copyright © 2021. Published by Elsevier Inc.)

Background: Anomalous coronary arteries (ACAs) may present increased risk for adverse cardiac events. We sought to evaluate the accuracy of conventional coronary angiography (CCA), as it is currently used in clinical practice, compared with expert interpretation and cardiac magnetic resonance imaging (CMR) in determining the site of origin and proximal course of ACAs., Methods: Fifty consecutive patients without concomitant congenital heart disease, who were referred for CMR to diagnose the course of an ACA, were retrospectively evaluated. Original CCA reports were reviewed. Angiography images were available in all patients and were interpreted by 2 experts blinded to the prior interpretation and CMR results. The accuracy of interpretation in each group was then compared to the current gold standard of CMR., Results: Identification of the site of origin (ie, aortic sinus) by referring angiographers was similar to that of expert angiographers (sensitivity, 89% vs 98%, respectively; P=.10). However, referring angiographers were less likely to correctly identify the proximal course as compared with expert angiographers (sensitivity, 27% vs 98%, respectively; P<.001)., Conclusions: As it is used in current practice, CCA does not provide sufficient diagnostic accuracy for identifying the proximal course of an ACA. Review by expert angiographers added sensitivity, improving the accuracy to nearly 100%. Expert consultation may be nearly as accurate as advanced imaging, and should be considered in cases of ACA in which there is diagnostic uncertainty.

Co-endemicity of SARS-CoV-2 and dengue virus (DV) infection is becoming a matter of serious concern as it has been already reported that antibodies (Ab) elicited by SARS-CoV-2 infection can produce false-positive results in dengue IgG and IgM rapid tests and vice versa . Here we communicate that five of thirteen DV antibody-positive serum samples from Kolkata, archived in 2017 (predating the COVID-19 outbreak), produced false-positive results in SARS-CoV-2 IgG/IgM lateral flow-based rapid tests. Our results emphasize the importance of implementing tests with higher specificity to conduct sero-surveillance for accurate estimation of SARS-CoV-2/DV prevalence in regions where both viruses now co-exist.

Objective: Pulmonary vascular resistance (PVR) is a measurement obtained with invasive right heart catheterization (RHC) that is commonly used for management of patients with pulmonary arterial hypertension (PAH). Computed tomography pulmonary angiography (CTPA) is also done as part of the workup for PAH in some cases. The aim of our study was to assess the correlation of contrast dynamic changes in the main pulmonary artery (MPA) on CTPA with PVR obtained with RHC., Methods: This is an IRB-approved retrospective study performed in two separate institutions (Medical College of Wisconsin and University of Alabama) between January 2010 and December 2013. During CTPA done as test bolus, serial images are acquired at the level of MPA after intravenous injection of contrast to determine timing of the CT acquisition. Since the PVR changes with the degree of PAH, we hypothesize that will be reflected in the contrast kinetics in MPA. A correlation of standard CT metrics (MPA diameter, right pulmonary artery [PA] diameter, left PA diameter, MPA/aorta ratio, and right ventricle/left ventricle [RV/LV] ratio) and dynamic (full width at half maximum) CTPA parameters in patients with known PAH was performed with PVR obtained from RHC done within 30 days. Statistical analysis was performed by Pearson correlation coefficient., Results: Among 221 patients in our database, 37 patients fulfilled the selection criteria. There was a strong correlation between full width half maximum (FWHM) and mean pulmonary artery pressure (mPAP) (r=0.69, p value<0.00001), PVR (r=0.8, p value<0.00001) and indexed PVR (PVRI) (r=0.75, p value<0.00001)., Conclusion: FWHM obtained from CTPA strongly correlates with RHC parameters and is potentially more helpful than static measurements for follow-up of patients with known PAH to assess response to treatment or progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Baruah et al.)

The world is going through the scourge of the COVID-19 pandemic since January 2020. However, the pandemic appears to be less severe in highly dengue endemic countries. In this connection, several studies reported that sero-diagnostic tests for dengue virus (DV) yielded considerable false-positive results for SARS-CoV-2 and vice versa in dengue endemic regions, thereby indicating towards potential cross-reactivity between these two viruses. We anticipated that SARS-CoV-2 and DV might share antigenic similarity and performed computational docking studies to test this hypothesis. Our results predicted with high confidence that human DV antibodies can indeed, bind to RBD of SARS-CoV-2 Spike protein. Some of these interactions can also potentially intercept human ACE2 receptor binding to RBM. Dengue serum samples predating the COVID-19, had been found to cross-react with SARS-CoV-2 Spike and this provides direct experimental validation of our predictions. Our analysis also showed that m396 and 80R antibodies (against SARS-CoV-1) did not dock with RBM of SARS-CoV-2, a fact already proven experimentally. This confirmed reliability and robustness of our approach. So, it is highly probable that immunological memory/antibodies to DV in endemic countries may reduce the severity and spread of COVID-19. It is not known whether SARS-CoV-2 antibodies will hinder DV infections by binding to DV particles and reduce dengue incidences in the future or, augment DV infection and severity by deploying antibody-dependent enhancement., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Two new coordination compounds involving hexanuclear Cu(ii), viz., [Cu6(phen)6(μ4-adpt)4(H2O)2](NO3)4·10H2O (1) and polymeric Co(ii), viz., {[(μ2-adpt)4Co(μ2-H2O)2Co(H2O)4]·4H2O}n (2) (phen = 1,10-phenanthroline; adpt = adipate) have been synthesized and characterized using elemental analysis, TGA, spectroscopic (IR, electronic and ESR), PXRD and single crystal X-ray diffraction techniques. Discrete nitrate-water clusters involving the [(H2O)3NO3]- core in 1 and linear (H2O)4 core in 2 provide stability to the layered network of the structures of the compounds. Interestingly, the water clusters in polymer 2 are encapsulated as guests in the voids of the host square grid that extends in 2D architecture. Theoretical studies have revealed the presence of interesting energetically significant cooperativity effects of π-stacking contacts that are responsible for the hexanuclear structure of compound 1. Both complexes significantly inhibit cell viability by inducing apoptotic cell death in the DL cancer cell line with negligible cytotoxicity in normal cells (PBMC). An assessment of ROS (reactive oxygen species) level study revealed a rapid increase of ROS in DL cells indicating cytotoxicity of the compounds against the DL cells. A decrease in MMP (mitochondrial membrane potential) is associated with an opening of the mitochondrial permeability transition pores which corroborates the apoptotic features of 1 and 2. The mode of action of the cytotoxic activities of the compounds has been explored with respect to their in silico docking ability and further inhibition of antiapoptotic proteins as evidenced by western blot analysis. SAR analyses based on pharmacophore modelling reveal that the molecular features of the structures of the compounds play important roles in biological activities.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene ® ), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality., Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene ® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV 1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined., Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene ® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics., Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop., Competing Interests: The COPDGene® study is funded by National Heart, Lung, and Blood Institute grants U01 HL089897 and U01 HL089856. The COPDGene® study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. While some individual authors of this manuscript were employed by one of the listed funders at the time the work of this study was conducted, these employment relationships did not constitute undue influence by funders. These funders have had no official role in the collection, management, analysis and interpretation of the data or design and conduct of the study. All authors have completed a Conflict of Interest form, disclosing any real or apparent financial relationships including receiving royalties, honoraria or fees for consulting, lectures, speakers’ bureaus, continuing education, medical advisory boards or expert testimony; receipt of grants; travel reimbursement; direct employment compensation. These disclosure forms have been filed with the Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation Editorial Office and are available for review, upon request, at COPDC@njhealth.org., (JCOPDF © 2019.)

Background: COPD is associated with cardiovascular disease (CVD), and coronary artery calcification (CAC) provides additional prognostic information. With increasing use of nongated CT scans in clinical practice, this study hypothesized that the visual Weston CAC score would perform as well as the Agatston score in predicting prevalent and incident coronary artery disease (CAD) and CVD in COPD., Methods: CAC was measured by using Agatston and Weston scores on baseline CT scans in 1,875 current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study. Baseline cardiovascular disease and incident cardiac events on longitudinal follow-up were recorded. Accuracy of the CAC scores was measured by using receiver-operating characteristic analysis, and Cox proportional hazards analyses were used to estimate the risk of incident cardiac events., Results: CAD was reported by 133 (7.1%) subjects at baseline. A total of 413 (22.0%) and 241 (12.9%) patients had significant CAC according to the Weston (≥ 7) and Agatston (≥ 400) scores, respectively; the two methods were significantly correlated (r = 0.84; P < .001). Over 5 years of follow-up, 127 patients (6.8%) developed incident CVD. For predicting prevalent CAD, c-indices for the Weston and Agatston scores were 0.78 and 0.74 and for predicting incident CVD, they were 0.62 and 0.61. After adjustment for age, race, sex, smoking pack-years, FEV 1 , percent emphysema, and CT scanner type, a Weston score ≥ 7 was associated with time to first acute coronary event (hazard ratio, 2.16 [95% CI, 1.32 to 3.53]; P = .002), but a Agatston score ≥ 400 was not (hazard ratio, 1.75 [95% CI, 0.99-3.09]; P = .053)., Conclusions: A simple visual score for CAC performed well in predicting incident CAD in smokers with and without COPD., Trial Registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Expiratory central airway collapse is associated with respiratory morbidity independent of underlying lung disease. However, not all smokers develop expiratory central airway collapse, and the etiology of expiratory central airway collapse in adult smokers is unclear. Paraseptal emphysema in the paratracheal location, by untethering airway walls, may predispose smokers to developing expiratory central airway collapse., Objectives: To evaluate whether paratracheal paraseptal emphysema is associated with expiratory central airway collapse., Methods: We analyzed paired inspiratory and expiratory computed tomography scans from participants enrolled in a multicenter study (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) of smokers aged 45 to 80 years. Expiratory central airway collapse was defined as greater than or equal to 50% reduction in cross-sectional area of the trachea during expiration. In a nested case-control design, participants with and without expiratory central airway collapse were included in a 1:2 fashion, and inspiratory scans were further analyzed using the Fleischner Society criteria for presence of centrilobular emphysema, paraseptal emphysema, airway wall thickening, and paratracheal paraseptal emphysema (maximal diameter ≥ 0.5 cm)., Results: A total of 1,320 patients were included, 440 with and 880 without expiratory central airway collapse. Those with expiratory central airway collapse were older, had higher body mass index, and were less likely to be men or current smokers. Paratracheal paraseptal emphysema was more frequent in those with expiratory central airway collapse than control subjects (16.6 vs. 11.8%; P = 0.016), and after adjustment for age, race, sex, body mass index, smoking pack-years, and forced expiratory volume in 1 second, paratracheal paraseptal emphysema was independently associated with expiratory central airway collapse (adjusted odds ratio, 1.53; 95% confidence interval, 1.18-1.98; P = 0.001). Furthermore, increasing size of paratracheal paraseptal emphysema (maximal diameter of at least 1 cm and 1.5 cm) was associated with greater odds of expiratory central airway collapse (adjusted odds ratio, 1.63; 95% confidence interval, 1.18-2.25; P = 0.003 and 1.77; 95% confidence interval, 1.19-2.64; P = 0.005, respectively)., Conclusions: Paraseptal emphysema adjacent to the trachea is associated with expiratory central airway collapse. The identification of this risk factor on inspiratory scans should prompt further evaluation for expiratory central airway collapse. Clinical trial registered with ClinicalTrials.gov (NCT 00608764).

Purpose: The National Lung Screening Trial (NLST) demonstrated a reduction in lung cancer and all-cause mortality with low-dose CT (LDCT) screening. The aim of our study was to examine the time to diagnosis (TTD) of lung cancer in the LDCT arm of the NLST and assess its relationship with cancer characteristics and survival., Methods: The subjects (N = 462) with a positive baseline screen and subsequent lung cancer diagnosis within 3 years were evaluated by data and image review to confirm the baseline abnormality. The cases were analysed for the relationship between TTD and imaging features, cancer type, stage and survival for 7 years from baseline screen., Results: Cancer was judged to be present at baseline in 397/462 cases. The factors that showed significant association (p value trend less than 0.05) with longer TTD included smaller nodule size, pure ground glass nodules (GGNs), smooth/lobulated margins, stages I/II, adenocarcinoma, and decreasing lung cancer mortality. The logistic regression model for lung cancer death showed significant inverse relationships with size less than 20 mm (OR = 0.32), pure GGNs (OR = 0.24), adenocarcinoma (OR = 0.57) and direct relationship with age (OR = 1.4)., Conclusion: TTD after a positive LDCT screen in the NLST showed a strong association with imaging features, stage and mortality., Key Points: • NLST observed variable time to lung cancer diagnosis from positive baseline screen. • Time to diagnosis was associated with imaging features, cancer type and stage. • In univariate but not multivariate analysis, longer TTD correlated with decreased mortality.

Rationale: A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known., Objectives: To identify subthreshold structural disease in normal-appearing lung regions in smokers., Methods: We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity., Measurements and Main Results: The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV 1 (adjusted β = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted β = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted β = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted β = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV 1 change at follow-up (adjusted β = -3.013; 95% CI, -4.478 to -1.548; P = 0.001)., Conclusions: Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Objectives: This study retrospectively analyses the screening CT examinations and outcomes of the National Lung Screening Trial (NLST) participants who had interval lung cancer diagnosed within 1 year after a negative CT screen and before the next annual screen., Methods: The screening CTs of all 44 participants diagnosed with interval lung cancer (cases) were matched with negative CT screens of participants who did not develop lung cancer (controls). A majority consensus process was used to classify each CT screen as positive or negative according to the NLST criteria and to estimate the likelihood that any abnormalities detected retrospectively were due to lung cancer., Results: By retrospective review, 40/44 cases (91%) and 17/44 controls (39%) met the NLST criteria for a positive screen (P < 0.001). Cases had higher estimated likelihood of lung cancer (P < 0.001). Abnormalities included pulmonary nodules ≥4 mm (n = 16), mediastinal (n = 8) and hilar (n = 6) masses, and bronchial lesions (n = 6). Cancers were stage III or IV at diagnosis in 32/44 cases (73%); 37/44 patients (84%) died of lung cancer, compared to 225/649 (35%) for all screen-detected cancers (P < 0.0001)., Conclusion: Most cases met the NLST criteria for a positive screen. Awareness of missed abnormalities and interpretation errors may aid lung cancer identification in CT screening., Key Points: • Lung cancer within a year of a negative CT screen was rare. • Abnormalities likely due to lung cancer were identified retrospectively in most patients. • Awareness of error types may help identify lung cancer sooner.

Tauopathies are neurodegenerative disorders characterized by abnormal intracellular aggregates of tau protein, and include Alzheimer's disease, corticobasal degeneration, frontotemporal dementia, and traumatic brain injury. Glutamate metabolism is altered in neurodegenerative disorders manifesting in higher or lower concentrations of glutamate, its transporters or receptors. Previously, glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) demonstrated that glutamate levels are reduced in regions of synapse loss in the hippocampus of a mouse model of late-stage tauopathy. We performed a longitudinal GluCEST imaging experiment paired with a cross-sectional study of histologic markers of tauopathy to determine whether (1) early GluCEST changes are associated with synapse loss before volume loss occurs in the hippocampus, and whether (2) subhippocampal dynamics in GluCEST are associated with histopathologic events related to glutamate alterations in tauopathy. Live imaging of the hippocampus in three serial slices was performed without exogenous contrast agents, and subregions were segmented based on a k-means cluster model. Subregions of the hippocampus were analyzed (cornu ammonis CA1, CA3, dentate gyrus DG, and ventricle) in order to associate local MRI-observable changes in glutamate with histological measures of glial cell proliferation (GFAP), synapse density (synaptophysin, VGlut1) and glutamate receptor (NMDA-NR1) levels. Early differences in GluCEST between healthy and tauopathy mice were measured in the CA1 and DG subregions (30% reduction, P ≤ 0.001). Synapse density was also significantly reduced in every subregion of the hippocampus in tauopathy mice by 6 months. Volume was not significantly reduced in any subregion until 13 months. Further, a gradient in glutamate levels was observed in vivo along hippocampal axes that became polarized as tauopathy progressed. Dynamics in hippocampal glutamate levels throughout lifetime were most closely correlated with combined changes in synaptophysin and GFAP, indicating that GluCEST imaging may be a surrogate marker of glutamate concentration in glial cells and at the synaptic level. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown., Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up., Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events., Measurements and Main Results: In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline., Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Background: Relative pulmonary arterial enlargement, defined by a pulmonary artery to aorta (PA/A) ratio > 1 on CT scanning, predicts hospitalization for acute exacerbations of COPD (AECOPD). However, it is unclear how AECOPD affect the PA/A ratio. We hypothesized that the PA/A ratio would increase at the time of AECOPD and that a ratio > 1 would be associated with worse clinical outcomes., Methods: Patients discharged with an International Classification of Diseases, Ninth Revision, diagnosis of AECOPD from a single center over a 5-year period were identified. Patients were included who had a CT scan performed during the stable period prior to the index AECOPD episode as well as a CT scan at the time of hospitalization. A subset of patients also underwent postexacerbation CT scans. The pulmonary arterial diameter, ascending aortic diameter, and the PA/A ratio were measured on CT scans. Demographic data, comorbidities, troponin level, and hospital outcome data were analyzed., Results: A total of 134 patients were included in the study. They had a mean age of 65 ± 10 years, 47% were male, and 69% were white; overall, patients had a mean FEV1 of 47% ± 19%. The PA/A ratio increased from baseline at the time of exacerbation (0.97 ± 0.15 from 0.91 ± 0.17; P < .001). Younger age and known pulmonary hypertension were independently associated with an exacerbation PA/A ratio > 1. Patients with PA/A ratio > 1 had higher troponin values. Those with a PA/A ratio > 1 and troponin levels > 0.01 ng/mL had increased acute respiratory failure, ICU admission, or inpatient mortality compared with those without both factors (P = .0028). The PA/A ratio returned to baseline values following AECOPD., Conclusions: The PA/A ratio increased at the time of severe AECOPD and a ratio > 1 predicted cardiac injury and a more severe hospital course., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Aim: The present study was conducted to explore the effect of supplemental heat on mortality rate, growth performance, and blood biochemical profiles of indigenous Ghungroo piglets in sub-tropical cold and humid climatic conditions of Tripura, a state of the north eastern hill (NEH) region of India., Materials and Methods: The experiment was conducted on 38 indigenous Ghungroo piglets from birth up to 60 days of age. Among the 38 piglets, 19 piglets were provided with supplemental heat ranging between 17.0°C and 21.1°C for the period of the first 30 days and thereafter between 24.1°C and 29.9°C for the next 30 days. The other 19 piglets were exposed to natural environmental minimum temperatures ranging between 7.2°C and 15.0°C during the first 30 days and then between 18.5°C and 25.5°C for the next 30 days., Results: The supplemental heat resulted in 10.6% reduction of piglet mortality from the 2(nd) till the 7(th) day of age. These beneficial effects could be related with the lower (p<0.05) plasma glutamate pyruvate transaminase (GPT) and cortisol levels and higher (p<0.05) plasma alkaline phosphatase (AP) concentrations in heat supplemented group compared to control group. Plasma AP, GPT, glucose, triiodothyronine, and luteinizing hormone concentrations decreased (p<0.05) gradually with the advancement of age in both control and supplemental heat treated piglets., Conclusion: Supplemental heat could be beneficial since it is related to a reduction of piglet mortality during the first week of life under farm management system in the sub-tropical climate of NEH region of India.

Importance: Central airway collapse greater than 50% of luminal area during exhalation (expiratory central airway collapse [ECAC]) is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, its prevalence and clinical significance are unknown., Objective: To determine whether ECAC is associated with respiratory morbidity in smokers independent of underlying lung disease., Design, Setting, and Participants: Analysis of paired inspiratory-expiratory computed tomography images from a large multicenter study (COPDGene) of current and former smokers from 21 clinical centers across the United States. Participants were enrolled from January 2008 to June 2011 and followed up longitudinally until October 2014. Images were initially screened using a quantitative method to detect at least a 30% reduction in minor axis tracheal diameter from inspiration to end-expiration. From this sample of screen-positive scans, cross-sectional area of the trachea was measured manually at 3 predetermined levels (aortic arch, carina, and bronchus intermedius) to confirm ECAC (>50% reduction in cross-sectional area)., Exposures: Expiratory central airway collapse., Main Outcomes and Measures: The primary outcome was baseline respiratory quality of life (St George's Respiratory Questionnaire [SGRQ] scale 0 to 100; 100 represents worst health status; minimum clinically important difference [MCID], 4 units). Secondary outcomes were baseline measures of dyspnea (modified Medical Research Council [mMRC] scale 0 to 4; 4 represents worse dyspnea; MCID, 0.7 units), baseline 6-minute walk distance (MCID, 30 m), and exacerbation frequency (events per 100 person-years) on longitudinal follow-up., Results: The study included 8820 participants with and without COPD (mean age, 59.7 [SD, 6.9] years; 4667 [56.7%] men; 4559 [51.7%] active smokers). The prevalence of ECAC was 5% (443 cases). Patients with ECAC compared with those without ECAC had worse SGRQ scores (30.9 vs 26.5 units; P < .001; absolute difference, 4.4 [95% CI, 2.2-6.6]) and mMRC scale scores (median, 2 [interquartile range [IQR], 0-3]) vs 1 [IQR, 0-3]; P < .001]), but no significant difference in 6-minute walk distance (399 vs 417 m; absolute difference, 18 m [95% CI, 6-30]; P = .30), after adjustment for age, sex, race, body mass index, forced expiratory volume in the first second, pack-years of smoking, and emphysema. On follow-up (median, 4.3 [IQR, 3.2-4.9] years), participants with ECAC had increased frequency of total exacerbations (58 vs 35 events per 100 person-years; incidence rate ratio [IRR], 1.49 [95% CI, 1.29-1.72]; P < .001) and severe exacerbations requiring hospitalization (17 vs 10 events per 100 person-years; IRR, 1.83 [95% CI, 1.51-2.21]; P < .001)., Conclusions and Relevance: In a cross-sectional analysis of current and former smokers, the presence of ECAC was associated with worse respiratory quality of life. Further studies are needed to assess long-term associations with clinical outcomes., Competing Interests: Dr. Terry, Dr. Nath and Mr. Zach have no conflicts of interest. Dr. Tschirren is an employee and shareholder at VIDA Diagnostics. Dr. Bolding, Mr. Stinson, Ms. Wilson, Dr. Everett, Dr. Putcha and Dr. Soler have no conflicts of interest.

The ACR recognizes that low-dose CT for lung cancer screening has the potential to significantly reduce mortality from lung cancer in the appropriate high-risk population. The ACR supports the recommendations of the US Preventive Services Task Force and the National Comprehensive Cancer Network for screening patients. To be effective, lung cancer screening should be performed at sites providing high-quality low-dose CT examinations overseen and interpreted by qualified physicians using a structured reporting and management system. The ACR has developed a set of tools necessary for radiologists to take the lead on the front lines of lung cancer screening. The ACR Lung Cancer Screening Center designation is built upon the ACR CT accreditation program and requires use of Lung-RADS or a similar structured reporting and management system. This designation provides patients and referring providers with the assurance that they will receive high-quality screening with appropriate follow-up care., (Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: While some retrospective studies have suggested that β-blocker use in patients with COPD is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen may be harmful., Methods: Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicentre observational cohort of current and former smokers were recruited. Total and severe exacerbation rates were compared between groups categorised by β-blocker use on longitudinal follow-up using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on CT, respiratory medications, presence of coronary artery disease, congestive heart failure and coronary artery calcification, and after adjustment for propensity to prescribe β-blockers., Results: 3464 subjects were included. During a median of 2.1 years of follow-up, β-blocker use was associated with a significantly lower rate of total (incidence risk ratio (IRR) 0.73, 95% CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67, 95% CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.33, 95% CI 0.19 to 0.58; p<0.001) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76; p=0.008). Exacerbation reduction was greatest in GOLD stage B. There was no difference in all-cause mortality with β-blocker use., Conclusions: β-Blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction. The findings of this study should be tested in a randomised, placebo-controlled trial., Trial Registration Number: (ClinicalTrials.gov NCT00608764)., Competing Interests: SPB has grant support from the American Heart Association. He has no conflicts of interest relevant to this manuscript. JMW’s institution has contracts with GSK and Forest. Dr. Wells has no conflicts of interest relevant to this manuscript. JEH receives grant support from the National Health Lung and Blood Institute and from the American Diabetes Association. Dr. Hokanson has no conflicts of interest relevant to this manuscript. In the past three years, EKS received honoraria and consulting fees from Merck and grant support and consulting fees from GSK. GRW reports receiving consulting fees from Merck and GSK. His spouse works for Merck. WCB has received personal fees from DLA Piper. MTD has served as a consultant for GSK, BI, Boston Scientific and Ikaria. His institution has received research grant support from AHA, NHLBI, GSK and Forest and has received contracted support for enrolment in clinical trials from Aeris, AstraZeneca, BI, Boston Scientific, Centocor, GSK, Forest, Otsuka, Pearl, Pfizer, PneumRx, and Pulmonx. GLK, YK, JC and HN have no conflicts of interest to declare., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Rationale: Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification., Objectives: To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes., Methods: We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival., Measurements and Main Results: A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P < 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases., Conclusions: CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas.

Small animal models of lung fibrosis are essential for unraveling the molecular mechanisms underlying human fibrotic lung diseases; additionally, they are useful for preclinical testing of candidate antifibrotic agents. The current end-point measures of experimental lung fibrosis involve labor-intensive histological and biochemical analyses. These measures fail to account for dynamic changes in the disease process in individual animals and are limited by the need for large numbers of animals for longitudinal studies. The emergence of noninvasive imaging technologies provides exciting opportunities to image lung fibrosis in live animals as often as needed and to longitudinally track the efficacy of novel antifibrotic compounds. Data obtained by noninvasive imaging provide complementary information to histological and biochemical measurements. In addition, the use of noninvasive imaging in animal studies reduces animal usage, thus satisfying animal welfare concerns. In this article, we review these new imaging modalities with the potential for evaluation of lung fibrosis in small animal models. Such techniques include micro-computed tomography (micro-CT), magnetic resonance imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and multimodal imaging systems including PET/CT and SPECT/CT. It is anticipated that noninvasive imaging will be increasingly used in animal models of fibrosis to gain insights into disease pathogenesis and as preclinical tools to assess drug efficacy.

Background: Lung cancer screening with low-dose computed tomography (LDCT) has been recommended, based primarily on the results of the NLST (National Lung Screening Trial). The American College of Radiology recently released Lung-RADS, a classification system for LDCT lung cancer screening., Objective: To retrospectively apply the Lung-RADS criteria to the NLST., Design: Secondary analysis of a group from a randomized trial., Setting: 33 U.S. screening centers., Patients: Participants were randomly assigned to the LDCT group of the NLST, were aged 55 to 74 years, had at least a 30-pack-year history of smoking, and were current smokers or had quit within the past 15 years., Intervention: 3 annual LDCT lung cancer screenings., Measurements: Lung-RADS classifications for LDCT screenings. Lung-RADS categories 1 to 2 constitute negative screening results, and categories 3 to 4 constitute positive results., Results: Of 26 722 LDCT group participants, 26 455 received a baseline screening; 48 671 screenings were done after baseline. At baseline, the false-positive result rate (1 minus the specificity rate) for Lung-RADS was 12.8% (95% CI, 12.4% to 13.2%) versus 26.6% (CI, 26.1% to 27.1%) for the NLST; after baseline, the false-positive result rate was 5.3% (CI, 5.1% to 5.5%) for Lung-RADS versus 21.8% (CI, 21.4% to 22.2%) for the NLST. Baseline sensitivity was 84.9% (CI, 80.8% to 89.0%) for Lung-RADS versus 93.5% (CI, 90.7% to 96.3%) for the NLST, and sensitivity after baseline was 78.6% (CI, 74.6% to 82.6%) for Lung-RADS versus 93.8% (CI, 91.4% to 96.1%) for the NLST., Limitation: Lung-RADS criteria were applied retrospectively., Conclusion: Lung-RADS may substantially reduce the false-positive result rate; however, sensitivity is also decreased. The effect of using Lung-RADS criteria in clinical practice must be carefully studied., Primary Funding Source: National Institutes of Health.

Background: Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography-detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function., Methods and Results: A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm(2). Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance., Conclusions: The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764., (© 2015 American Heart Association, Inc.)

Objective: Current and former smokers are at an increased risk for lung cancer and cardiovascular disease (CVD). We investigated two methods of visual scoring of coronary artery calcium on lung cancer screening computed tomography (CT) to predict cardiovascular and all-cause mortality., Participants and Methods: Cases were 1000 participants, age 55-74 years, enrolled in the National Lung Screening Trial CT arm who died during the study. An equal number of participants alive at the end of the study (controls) were matched in terms of sex, CT scanner vendor, and model, and 5-year age and smoking pack-years group. Coronary calcium was measured visually by three readers using two semiquantitative scoring schemes. Conditional logistic regression was used to analyze the association between the presence and the extent of coronary calcium and all-cause and cardiovascular mortality, stratified on matching criteria., Results: Cases and controls were well matched for age (64±6 vs. 64±5, P=0.95) and mean pack-years smoking (61±24 vs. 62±24, P=1.0). Cases were significantly more likely to have coronary calcium than controls (85 vs. 77%, P<0.001). Having any calcium was associated with an increased risk for CVD mortality using either visual scoring method (odds ratio 3.4, 95% confidence interval 2.0-5.6, P<0.001, and odds ratio 3.3, 95% confidence interval 2.0-5.6, P<0.001)., Conclusion: Visual scoring of coronary calcium predicts all-cause and CVD mortality in National Lung Screening Trial participants, independent of current versus former smoking status. Visual coronary calcium scoring in low-dose CT scans helps identify individuals at high risk for mortality who may benefit from further CVD prevention.

The ACR recognizes that low-dose CT for lung cancer screening has the potential to significantly reduce mortality from lung cancer in the appropriate high-risk population. The ACR supports the recommendations of the US Preventive Services Task Force and the National Comprehensive Cancer Network for screening patients. To be effective, lung cancer screening should be performed at sites providing high-quality low-dose CT examinations overseen and interpreted by qualified physicians using a structured reporting and management system. The ACR has developed a set of tools necessary for radiologists to take the lead on the front lines of lung cancer screening. The ACR Lung Cancer Screening Center designation is built upon the ACR CT accreditation program and requires use of Lung-RADS or a similar structured reporting and management system. This designation provides patients and referring providers with the assurance that they will receive high-quality screening with appropriate follow-up care., (Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: Bronchodilator response has been noted in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response to β₂ agonists resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely to be far more common than is symptomatic bronchoconstriction with β₂ agonists, but no systematic studies have been done. We assessed the prevalence of paradoxical response in current and former smokers with and without COPD, and its radiological correlates and clinical implications., Methods: Non-Hispanic white and African-American patients (aged 45-80 years) from a large multicentre study COPDGene were classified into two groups on the basis of a paradoxical response, defined as at least a 12% and 200 mL reduction in forced expiratory volume in 1 sec (FEV₁) or forced vital capacity (FVC), or both, after administration of a shortacting β₂ agonist (180 μg salbutamol)., Findings: Patients were recruited from January, 2008, to June, 2011. 9986 (96%) of 10,364 patients enrolled in the COPDGene study were included in the analysis population (mean age 59·6 years [SD 9·0]). Paradoxical response was noted in 453 (5%) of 9986 patients and the frequency was similar in patients with COPD (198 [4%] of 4439) and smokers without airflow obstruction (255 [5%] of 5547). Compared with white patients, a paradoxical response was twice as common in African-American patients (227 [7%] of 3282 vs 226 [3%] of 6704; p<0·0001). In the multivariate analyses, African-American ethnic origin (adjusted odds ratio 1·89, 95% CI 1·50-2·39; p<0·0001), less emphysema (0·96, 0·92-0·99; p=0·023), and increased wall-area percentage of the segmental airways (1·04, 1·01-1·08; p=0·023) were independently associated with a paradoxical response. A paradoxical response was independently associated with worse dyspnoea (adjusted β for Modified Medical Research Council Dyspnoea Scale 0·12 [95% CI 0·00 to 0·24]; p=0·05), lower 6 min walk distance (-45·8 [-78·5 to -13·2]; p=0·006), higher Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index (0·31 [0·19 to 0·43]; p<0·0001), and a greater frequency of severe exacerbations (increased by a factor of 1·35, 1·00-1·81; p=0·048)., Interpretation: Paradoxical response to β₂ agonists is associated with respiratory morbidity and is more common in African-Americans. These findings might have implications for the use of β2agonists in some patients., Funding: National Institutes of Health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Computed tomography (CT) screening for lung cancer has been associated with a high frequency of false positive results because of the high prevalence of indeterminate but usually benign small pulmonary nodules. The acceptability of reducing false-positive rates and diagnostic evaluations by increasing the nodule size threshold for a positive screen depends on the projected balance between benefits and risks., Methods: We examined data from the National Lung Screening Trial (NLST) to estimate screening CT performance and outcomes for scans with nodules above the 4mm NLST threshold used to classify a CT screen as positive. Outcomes assessed included screening results, subsequent diagnostic tests performed, lung cancer histology and stage distribution, and lung cancer mortality. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the different nodule size thresholds. All statistical tests were two-sided., Results: In 64% of positive screens (11598/18141), the largest nodule was 7 mm or less in greatest transverse diameter. By increasing the threshold, the percentages of lung cancer diagnoses that would have been missed or delayed and false positives that would have been avoided progressively increased, for example from 1.0% and 15.8% at a 5 mm threshold to 10.5% and 65.8% at an 8 mm threshold, respectively. The projected reductions in postscreening follow-up CT scans and invasive procedures also increased as the threshold was raised. Differences across nodules sizes for lung cancer histology and stage distribution were small but statistically significant. There were no differences across nodule sizes in survival or mortality., Conclusion: Raising the nodule size threshold for a positive screen would substantially reduce false-positive CT screenings and medical resource utilization with a variable impact on screening outcomes., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Cardiovascular morbidity and mortality is high in patients with chronic obstructive pulmonary disease (COPD) and arterial stiffness is a potentially modifiable risk factor with added predictive value beyond that obtained from traditional risk factors. Arterial stiffness has been the target of pharmacologic and exercise interventions in patients with COPD, but the effects appear limited to those patients with more significant elevations in arterial stiffness. We aimed to identify predictors of increased arterial stiffness in a cohort with moderate to severe COPD., Methods: Aortic pulse wave velocity (aPWV) was measured in subjects with moderate to severe COPD enrolled in a multicenter randomized controlled trial. Subjects were categorized into quartiles based on aPWV values and factors affecting high arterial stiffness were assessed. Multivariate models were created to identify independent predictors of high aPWV, and cardiovascular disease (CVD)., Results: 153 patients were included. Mean age was 63.2 (SD 8.2) years and mean FEV1 was 55.4 (SD 15.2) % predicted. Compared to the quartile with the lowest aPWV, subjects in the highest quartile were older, had higher systolic blood pressure (SBP), were more likely to be current smokers, and had greater burden of thoracic aortic calcification. On multivariate analyses, age (adjusted OR 1.14, 95%CI 1.05 to 1.25, p = 0.003) and SBP (adjusted OR 1.06, 95% CI 1.02 to 1.09, p = 0.001) were independent predictors of elevated aPWV. Body mass index, therapy with cholesterol lowering medications and coronary calcification were independent predictors of CVD., Conclusions: Elevated arterial stiffness in patients with COPD can be predicted using age, blood pressure and thoracic aortic calcification. This will help identify subjects for enrollment in clinical trials using aPWV for assessing the impact of COPD therapies on CV outcomes.

The National Lung Screening Trial (NLST) reported a 20% reduction in lung cancer specific mortality using low-dose chest CT (LDCT) compared with chest radiograph (CXR) screening. The high number of false positive screens with LDCT (around 25%) raises concerns. NLST radiologists reported LDCT screens as either positive or not positive, based primarily on the presence of a 4+ mm non-calcified lung nodule (NCN). They did not explicitly record a propensity score for lung cancer. However, by using maximum NCN size, or alternatively, radiologists' recommendations for diagnostic follow-up categorized hierarchically, surrogate propensity scores (PSSZ and PSFR) were created. These scores were then used to compute ROC curves, which determine possible operating points of sensitivity versus false positive rate (1-Specificity). The area under the ROC curve (AUC) was 0.934 and 0.928 for PSFR and PSSZ, respectively; the former was significantly greater than the latter. With the NLST definition of a positive screen, sensitivity and specificity of LDCT was 93.1% and 76.5%, respectively. With cutoffs based on PSFR, a specificity of 92.4% could be achieved while only lowering sensitivity to 86.9%. Radiologists using LDCT have good predictive ability; the optimal operating point for sensitivity and specificity remains to be determined.

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations., Methods: We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation., Results: Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations., Conclusions: Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.).

Purpose: To measure reader variability related to the evaluation of screening chest radiographs (CXRs) for findings of primary lung cancer., Materials and Methods: From the National Lung Screening Trial (NLST), 100 cases were randomly selected from baseline CXR examinations for retrospective interpretation by 9 NLST radiologists; images with noncalcified lung nodules (NCNs) or other abnormalities suspicious for lung cancer as determined by the original NLST reader were oversampled. Agreement on the presence of pulmonary nodules and abnormalities suspicious for cancer and recommendations for follow-up were assessed by the multirater κ statistic., Results: The multirater κ statistic for interreader agreement on the presence of at least 1 NCN was 0.38. Rates at which readers reported the presence of at least 1 NCN ranged from 32% to 63% (mean, 41%); among 16 subjects with NCN and a cancer diagnosis within 1 year of the CXR examination, an average of 87% (range, 81% to 94%) of cases were classified as suspicious for cancer across all readers. The multirater κ for agreement on follow-up recommendations was 0.34; pairwise κ values ranged from 0.15 to 0.64 (mean, 0.36). For all subjects, readers recommended a follow-up procedure classified as high level (computed tomography, fluorodeoxyglucose-positron emission tomography, or biopsy) 42% of the time on average (range, 30% to 67%); this increased to 84% (range, 52% to 100%) when readers reported an NCN and 88% (range, 82% to 94%) for subjects with cancer., Conclusion: Reader agreement for screening CXR interpretation and follow-up recommendations is fair overall but is high for malignant lesions.

Unlabelled: The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring., Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9-11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements., Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively., Conclusions: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.

Nepal faces the challenge of high levels of poverty, difficult access to health facilities and poor, though improving, health indicators. In response, in the past 5 years it has been experimenting with a range of approaches to removing user fees. Access to health care is now enshrined as a constitutional right for all. This article examines the latest policy, which was introduced in January 2009: free delivery care across the country. The study objective was to understand the effects of the policy on health facilities. Study methods included structured forms to retrieve financial and activity data from national, district and facility records (comparing 10 months before implementation with 10 months after). These were supplemented by semi-structured interviews with key informants at different levels of the health system. Findings include that utilization of services (at the facilities visited) continues to rise, with caesareans proportionate to the general growth in deliveries. Funds for the free delivery policy ('Aama') are found to be adequate to cover the main costs of services, with some surplus which can be invested in staff and in improving services. The system for reimbursing facilities is operating without undue delay and there is satisfaction with the flexibility of use of resources which it allows and the additional incentives for staff. The main concerns relate to wider systemic issues-in particular, understaffing in some key posts and areas, and dwindling general revenues for the facilities, especially through loss of wider user fee revenues. This may explain the ongoing charges for patients, which both facilities and patients report. It will be challenging to build on the gains of the past few years and sustain them, at the same time as merging the separate free care funding streams.

Objective: Coronary artery calcification (CAC) and thoracic aortic calcification, (TAC) are frequently detected on ungated multidetector computed tomography (MDCT) performed for lung evaluations. We sought to evaluate concordance of CAC and TAC scores on ungated (thoracic) and electrocardiogaphically (ECG)-gated (cardiac) MDCT scans., Methods: Fifty patients, enrolled in the Genetic Epidemiology of COPD study (COPDGene), were recruited to undergo gated CAC scans with 64-detector row CT, in addition to the ungated thoracic studies already being obtained as part of their study evaluation. Coronary and thoracic calcium were measured similarly (Agatston score, requiring 3 contiguous voxels of >130 Hounsfield units) with low-dose ungated studies and ECG-gated MDCT performed at the same scanning session. Intertechnique scoring variability and concordance were calculated., Results: Correlations between gated and ungated CAC and TAC were excellent (r = 0.96). The relative differences (median variability) measured by ECG-gated versus ungated MDCT were relatively high for CAC (44%) but not for TAC (8%). Prevalence of depicted CAC (n = 33; 66%) and TAC (n = 21; 42%) were coincident between ECG-gated and ungated MDCT, respectively (intertechnique concordance, 100%). Bland-Altman plots for CAC showed mean differences of 354 (confidence interval, 169-538) and 16.1 (confidence interval, -89 to 121)., Conclusion: Low-dose ungated MDCT is reliable for prediction of the presence of CAC and assessment of Agatston score. Concordance between methods and between TAC and CAC is high. This technique should allow for atherosclerotic disease risk stratification among patients undergoing ungated lung CT evaluation without requiring additional scanning. Measurement of TAC is almost as accurate from gated CT, and CAC scores are highly concordant., (Copyright © 2011 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

COPD patients are at increased risk for cardiovascular morbidity and mortality independent of smoking habits. Recent studies suggest CT emphysema is an independent predictor of cardiovascular risk as evidenced by its association with arterial stiffness and impaired endothelial function. We examined the relationship between demographics, lung function, CT emphysema and airway wall thickness and thoracic aortic calcification, another marker of cardiovascular risk, in the National Lung Screening Trial. We hypothesized that CT emphysema would be independently associated with thoracic aortic calcification. Two hundred forty current and former smokers were enrolled. After CT examination, we recorded subjects' demographics and they performed spirometry. Subjects were classified into COPD and non-COPD subgroups. CT emphysema was quantified as a percentage of lung volume and measurements of the right upper lobe airway were performed using standard methods and expressed as wall area (%). Total calcification scores for the thoracic aorta were computed using TeraRecon image analysis. Univariate and multivariate analyses were performed to determine the associations between calcium score and subject characteristics. Subjects with COPD were older, more often male, heavier smokers and had more CT emphysema and greater aortic calcification than those without COPD. Calcium score was associated with age, pack-years, CT emphysema, wall area%, and lung function on univariate testing but only with age and CT emphysema on multivariate analysis. We conclude that CT emphysema is independently associated with thoracic calcification and thus may be used to assess cardiovascular risk in smokers with and without COPD.