399 results on '"Christopher B, Cooper"'
Search Results
2. A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD
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Katarina M. DiLillo, Katy C. Norman, Christine M. Freeman, Stephanie A. Christenson, Neil E. Alexis, Wayne H. Anderson, Igor Z. Barjaktarevic, R. Graham Barr, Alejandro P. Comellas, Eugene R. Bleecker, Richard C. Boucher, David J. Couper, Gerard J. Criner, Claire M. Doerschuk, J. Michael Wells, MeiLan K. Han, Eric A. Hoffman, Nadia N. Hansel, Annette T. Hastie, Robert J. Kaner, Jerry A. Krishnan, Wassim W. Labaki, Fernando J. Martinez, Deborah A. Meyers, Wanda K. O’Neal, Victor E. Ortega, Robert Paine, Stephen P. Peters, Prescott G. Woodruff, Christopher B. Cooper, Russell P. Bowler, Jeffrey L. Curtis, Kelly B. Arnold, and SPIROMICS investigators
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Medicine ,Science - Abstract
Abstract Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV1) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD.
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- 2023
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3. Single Volume Lung Biomechanics from Chest Computed Tomography Using a Mode Preserving Generative Adversarial Network.
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Muhammad F. A. Chaudhary, Sarah E. Gerard, Di Wang, Gary E. Christensen, Christopher B. Cooper, Joyce D. Schroeder, Eric A. Hoffman, and Joseph M. Reinhardt
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- 2022
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4. Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial
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Anna J. Podolanczuk, John S. Kim, Christopher B. Cooper, Joseph A. Lasky, Susan Murray, Justin M. Oldham, Ganesh Raghu, Kevin R. Flaherty, Cathie Spino, Imre Noth, Fernando J. Martinez, and for the PRECISIONS Study Team
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IPF ,Clinical trial ,Protocol ,N-acetylcysteine ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial. Methods The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC. Discussion The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920
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- 2022
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5. Black carbon content in airway macrophages is associated with increased severe exacerbations and worse COPD morbidity in SPIROMICS
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Vickram Tejwani, Han Woo, Chen Liu, Anna K. Tillery, Amanda J. Gassett, Richard E. Kanner, Eric A. Hoffman, Fernando J. Martinez, Prescott G. Woodruff, R. Graham Barr, Ashraf Fawzy, Kirsten Koehler, Jeffrey L. Curtis, Christine M. Freeman, Christopher B. Cooper, Alejandro P. Comellas, Cheryl Pirozzi, Robert Paine, Donald Tashkin, Jerry A. Krishnan, Coralynn Sack, Nirupama Putcha, Laura M. Paulin, Marina Zusman, Joel D. Kaufman, Neil E. Alexis, and Nadia N. Hansel
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Macrophage ,Black carbon ,COPD ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Airway macrophages (AM), crucial for the immune response in chronic obstructive pulmonary disease (COPD), are exposed to environmental particulate matter (PM), which they retain in their cytoplasm as black carbon (BC). However, whether AM BC accurately reflects environmental PM2.5 exposure, and can serve as a biomarker of COPD outcomes, is unknown. Methods We analyzed induced sputum from participants at 7 of 12 sites SPIROMICS sites for AM BC content, which we related to exposures and to lung function and respiratory outcomes. Models were adjusted for batch (first vs. second), age, race (white vs. non-white), income (
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- 2022
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6. A case study of a unique advanced clinical skills elective at the David Geffen School of Medicine at UCLA [version 1; peer review: 2 approved]
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Michael E. Lazarus, Daniel G. Kahn, Estebes A. Hernandez, Christopher B. Cooper, and Stacey Vigallon
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Clinical skills ,visual intelligence ,pattern recognition ,clinical reasoning ,birding ,burnout mitigation ,eng ,Special aspects of education ,LC8-6691 ,Medicine - Abstract
Proficiency in clinical examination skills upon graduation from medical school is a core competency. Over the last few decades, the ability and confidence in this fundamental and crucial skill set has declined. The motivation and interest in meticulous physical examination by recently graduated residents has also eroded. In this case study, we describe a comprehensive, innovative, and immersive advanced clinical skills elective taken during the second half of the final year of medical school for students at the David Geffen School of Medicine. The course utilizes novel approaches to inspire, refresh and consolidate essential bedside observation skills and examination techniques. This approach gives senior students the confidence and fundamental understanding of how dedication to the patient exam can improve the doctor-patient relationship, core clinical reasoning and the practice of cost-effective and evidence-based care through their careers. We describe how the integration of fine art appreciation and introductory biding techniques are used to help students hone their visual diagnostic skills. We show how this is solidified through a longitudinal series of clinical image review sessions with diagnostic reasoning principles to formulate a clear differential. Point of care ultrasound, EKG analysis, advanced cardiac auscultation and diagnostic imaging skills are integrated in a comprehensive and memorable fashion. We present this case study to inspire clinical skills teachers everywhere to replicate our methods in resurrecting the importance of physical exams for their learners. Opening their trainees’ eyes to new methods of honing their visual intelligence and developing healthy habits for stress and burnout reduction will aid the rest of their professional careers.
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- 2023
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7. A molecular design approach towards elastic and multifunctional polymer electronics
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Yu Zheng, Zhiao Yu, Song Zhang, Xian Kong, Wesley Michaels, Weichen Wang, Gan Chen, Deyu Liu, Jian-Cheng Lai, Nathaniel Prine, Weimin Zhang, Shayla Nikzad, Christopher B. Cooper, Donglai Zhong, Jaewan Mun, Zhitao Zhang, Jiheong Kang, Jeffrey B.-H. Tok, Iain McCulloch, Jian Qin, Xiaodan Gu, and Zhenan Bao
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Science - Abstract
Next-generation skin-inspired electronics require enhanced mechanical robustness and device complexity including elasticity, solvent resistance, and facile patternability. Here, the authors show a molecular design concept that simultaneously achieves all these requirements by covalently linking an in-situ formed rubber matrix with polymer electronic materials.
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- 2021
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8. High Energy Density Shape Memory Polymers Using Strain-Induced Supramolecular Nanostructures
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Christopher B. Cooper, Shayla Nikzad, Hongping Yan, Yuto Ochiai, Jian-Cheng Lai, Zhiao Yu, Gan Chen, Jiheong Kang, and Zhenan Bao
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Chemistry ,QD1-999 - Published
- 2021
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9. Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium
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Silva Kasela, Victor E. Ortega, Molly Martorella, Suresh Garudadri, Jenna Nguyen, Elizabeth Ampleford, Anu Pasanen, Srilaxmi Nerella, Kristina L. Buschur, Igor Z. Barjaktarevic, R. Graham Barr, Eugene R. Bleecker, Russell P. Bowler, Alejandro P. Comellas, Christopher B. Cooper, David J. Couper, Gerard J. Criner, Jeffrey L. Curtis, MeiLan K. Han, Nadia N. Hansel, Eric A. Hoffman, Robert J. Kaner, Jerry A. Krishnan, Fernando J. Martinez, Merry-Lynn N. McDonald, Deborah A. Meyers, Robert Paine, Stephen P. Peters, Mario Castro, Loren C. Denlinger, Serpil C. Erzurum, John V. Fahy, Elliot Israel, Nizar N. Jarjour, Bruce D. Levy, Xingnan Li, Wendy C. Moore, Sally E. Wenzel, Joe Zein, NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Charles Langelier, Prescott G. Woodruff, Tuuli Lappalainen, and Stephanie A. Christenson
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COVID-19 ,SARS-CoV-2 ,ACE2 ,eQTL ,Bronchial epithelium ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. Methods We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. Results We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. Conclusions These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.
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- 2021
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10. Computational Approaches to Model X-ray Photon Correlation Spectroscopy from Molecular Dynamics.
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Shaswat Mohanty, Christopher B. Cooper, Hui Wang, Mengning Liang, and Wei Cai 0004
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- 2022
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11. Latent traits of lung tissue patterns in former smokers derived by dual channel deep learning in computed tomography images
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Frank Li, Jiwoong Choi, Chunrui Zou, John D. Newell, Alejandro P. Comellas, Chang Hyun Lee, Hongseok Ko, R. Graham Barr, Eugene R. Bleecker, Christopher B. Cooper, Fereidoun Abtin, Igor Barjaktarevic, David Couper, MeiLan Han, Nadia N. Hansel, Richard E. Kanner, Robert Paine, Ella A. Kazerooni, Fernando J. Martinez, Wanda O’Neal, Stephen I. Rennard, Benjamin M. Smith, Prescott G. Woodruff, Eric A. Hoffman, and Ching-Long Lin
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Medicine ,Science - Abstract
Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.
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- 2021
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12. Lung microbiota associations with clinical features of COPD in the SPIROMICS cohort
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Kristopher Opron, Lesa A. Begley, John R. Erb-Downward, Christine Freeman, Siddharth Madapoosi, Neil E. Alexis, Igor Barjaktarevic, R. Graham Barr, Eugene R. Bleecker, Russell P. Bowler, Stephanie A. Christenson, Alejandro P. Comellas, Christopher B. Cooper, David J. Couper, Claire M. Doerschuk, Mark T. Dransfield, MeiLan K. Han, Nadia N. Hansel, Annette T. Hastie, Eric A. Hoffman, Robert J. Kaner, Jerry Krishnan, Wanda K. O’Neal, Victor E. Ortega, Robert Paine, Stephen P. Peters, J. Michael Wells, Prescott G. Woodruff, Fernando J. Martinez, Jeffrey L. Curtis, Gary B. Huffnagle, and Yvonne J. Huang
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Microbial ecology ,QR100-130 - Abstract
Abstract Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25–75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.
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- 2021
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13. Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease: Highly Effective but Often Overlooked
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Michael T. Arnold, Brett A. Dolezal, and Christopher B. Cooper
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pulmonary disease, chronic obstructive ,pulmonary rehabilitation ,exercise limitation ,exercise prescription ,Diseases of the respiratory system ,RC705-779 - Abstract
Patients with chronic obstructive pulmonary disease receive a range of treatments including but not limited to inhaled bronchodilators, inhaled and systemic corticosteroids, supplemental oxygen, and pulmonary rehabilitation. Pulmonary rehabilitation is a multidisciplinary intervention that seeks to combine patient education, exercise, and lifestyle changes into a comprehensive program. Programs 6 to 8 weeks in length have been shown to improve health, reduce dyspnea, increase exercise capacity, improve psychological well-being, and reduce healthcare utilization and hospitalization. Although the use of pulmonary rehabilitation is widely supported by the literature, controversy still exists regarding what should be included in the programs. The goal of this review was to summarize the evidence for pulmonary rehabilitation and identify the areas that hold promise in improving its utilization and effectiveness.
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- 2020
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14. Preserving nanoscale features in polymers during laser induced graphene formation using sequential infiltration synthesis
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David S. Bergsman, Bezawit A. Getachew, Christopher B. Cooper, and Jeffrey C. Grossman
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Science - Abstract
High temperatures induced during lasing can deform the substrate polymer used for fabrication of electrically conductive membranes. Here, the authors show that sequential infiltration synthesis of alumina stabilizes polyethersulfone (PES) membranes against deformation above the polymers’ glass transition temperature.
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- 2020
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15. Correlation between Hand Grip Strength and Peak Inspiratory Flow Rate in Patients with Stable Chronic Obstructive Pulmonary Disease
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Apisara Suriyakul, Narongkorn Saiphoklang, Igor Barjaktarevic, and Christopher B. Cooper
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Accuhaler ,dry powder inhalers ,hand grip strength ,peak inspiratory flow rate ,Turbuhaler ,Medicine (General) ,R5-920 - Abstract
Optimal peak inspiratory flow rate (PIFR) is required for effective drug delivery to distal airways when using dry powder inhalers (DPIs). This study aimed to examine the association between PIFR and hand grip strength (HGS) in stable COPD patients. A cross-sectional study was conducted. PIFR was measured using the In-check DIAL to assess for Accuhaler and Turbuhaler DPIs. HGS was measured using a handheld dynamometer. A PIFR of 1 was 65.3 ± 23.7%. The prevalence of suboptimal PIFR was 38% and 59% for Accuhaler and Turbuhaler, respectively. HGS in the suboptimal PIFR group was lower than in the optimal PIFR group for Accuhaler (22.8 ± 4.7 vs. 33.2 ± 6.9 kg, p < 0.001) and for Turbuhaler (25.3 ± 6.4 vs. 35.1 ± 6.3 kg, p < 0.001). The equation for predicted Accuhaler PIFR (L/min) was −30.340 + (0.274 × hand grip strength) − (0.206 × age) + (0.219 × height) + (1.019 × FVC). The equation for predicted Turbuhaler PIFR (L/min) was 56.196 + (0.321 × hand grip strength) − (0.196 × female) − (0.224 × age) + (0.304 × FVC). The best cutoff values of HGS for predicting optimal PIFR in Accuhaler and Turbuhaler were 26.8 kg (with 82% sensitivity and 84% specificity) and 31.9 kg (with 79% sensitivity and 90% specificity), respectively. In conclusion, HGS correlated with PIFR in patients with clinically stable COPD, especially in the group with pronounced symptoms without frequent exacerbations. HGS threshold values associated with suboptimal PIFR were identified. HGS may be used as an alternative tool to assess an optimal inspiratory force for DPIs.
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- 2022
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16. Synthesis and Structure–Activity Relationships for the Anti-Mycobacterial Activity of 3-Phenyl-N-(Pyridin-2-ylmethyl)Pyrazolo[1,5-a]Pyrimidin-7-Amines
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Hamish S. Sutherland, Peter J. Choi, Guo-Liang Lu, Anna C. Giddens, Amy S. T. Tong, Scott G. Franzblau, Christopher B. Cooper, Brian D. Palmer, and William A. Denny
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pyrazolopyrimidines ,structure–activity relationships ,synthesis ,tuberculosis ,ATP synthase ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Pyrazolo[1,5-a]pyrimidines have been reported as potent inhibitors of mycobacterial ATP synthase for the treatment of Mycobacterium tuberculosis (M.tb). In this work, we report the design and synthesis of approximately 70 novel 3,5-diphenyl-N-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amines and their comprehensive structure–activity relationship studies. The most effective pyrazolo[1,5-a]pyrimidin-7-amine analogues contained a 3-(4-fluoro)phenyl group, together with a variety of 5-alkyl, 5-aryl and 5-heteroaryl substituents. A range of substituted 7-(2-pyridylmethylamine) derivatives were also active. Some of these compounds exhibited potent in vitro M.tb growth inhibition, low hERG liability and good mouse/human liver microsomal stabilities, highlighting their potential as inhibitors of M.tb.
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- 2022
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17. Single volume lung biomechanics from chest computed tomography using a mode preserving generative adversarial network.
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Muhammad F. A. Chaudhary, Sarah E. Gerard, Di Wang, Gary E. Christensen, Christopher B. Cooper, Joyce D. Schroeder, Eric A. Hoffman, and Joseph M. Reinhardt
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- 2021
18. Imaging-based clusters in former smokers of the COPD cohort associate with clinical characteristics: the SubPopulations and intermediate outcome measures in COPD study (SPIROMICS)
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Babak Haghighi, Sanghun Choi, Jiwoong Choi, Eric A. Hoffman, Alejandro P. Comellas, John D. Newell, Chang Hyun Lee, R. Graham Barr, Eugene Bleecker, Christopher B. Cooper, David Couper, Mei Lan Han, Nadia N. Hansel, Richard E. Kanner, Ella A. Kazerooni, Eric A. C. Kleerup, Fernando J. Martinez, Wanda O’Neal, Robert Paine, Stephen I. Rennard, Benjamin M. Smith, Prescott G. Woodruff, and Ching-Long Lin
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COPD ,Emphysema ,Functional small airway disease ,Former smokers ,Imaging-based cluster analysis ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. Methods An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. Results We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. Conclusions QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes.
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- 2019
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19. Patient characteristics and outcomes of a home mechanical ventilation program in a developing country
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Narongkorn Saiphoklang, Apichart Kanitsap, Pitchayapa Ruchiwit, Pattarin Pirompanich, Thiti Sricharoenchai, and Christopher B Cooper
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Chronic obstructive pulmonary disease ,complication ,developing country ,mechanical ventilation ,ventilator-associated pneumonia ,Diseases of the respiratory system ,RC705-779 - Abstract
Background: There are limited data on home mechanical ventilation (HMV) in developing countries. This study aimed to describe the patient characteristics, feasibility, and outcomes of an HMV program at a university hospital in Thailand. Materials and Methods: Data were collected on all patients who were discharged with HMV between October 2014 and August 2015 at Thammasat University Hospital. Results: Twelve patients (eight men and four women) underwent HMV. They were aged 71.5 ± 17.6 years; mean ± standard deviation. Indications for HMV were 6 neurologic diseases (4 amyotrophic lateral sclerosis, 1 multiple system atrophy, and 1 stroke), 2 chronic obstructive pulmonary disease (COPD), 1 tracheomalacia, and 3 combined neurologic diseases and respiratory diseases (2 stroke and COPD, 1 stroke and tracheomalacia). The duration of follow-up was 799.5 ± 780.5 days. The ratio of family income to cost of HMV usage was 77.2:1 ± 5.5:1. All patients had tracheostomies. Modes of HMV were biphasic positive airway pressure (66.7%), pressure-controlled ventilation (16.7%), pressure-support ventilation (8.3%), and volume-controlled ventilation (8.3%). Complications occurred in ten patients (83.3%), including tracheobronchitis (20 events) and ventilator-associated pneumonia (12 events). Overall mortality was 41.7% (5/12 patients), including two patients who died due to ventilator-associated pneumonia. There were no instances of ventilator malfunction. Conclusions: HMV is feasible for patients with neurological diseases and COPD in a developing country. The relatively high rate of complications indicates the need for more comprehensive clinical services for chronic ventilator-dependent patients in this setting.
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- 2019
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20. Heterogeneous burden of lung disease in smokers with borderline airflow obstruction
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Cheryl S. Pirozzi, Tian Gu, Pedro M. Quibrera, Elizabeth E. Carretta, MeiLan K. Han, Susan Murray, Christopher B. Cooper, Donald P. Tashkin, Eric C. Kleerup, Igor Barjaktarevic, Eric A. Hoffman, Carlos H. Martinez, Stephanie A. Christenson, Nadia N. Hansel, R. Graham Barr, Eugene R. Bleecker, Victor E. Ortega, Fernando J. Martinez, Richard E. Kanner, Robert Paine, and for the NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)
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Chronic obstructive pulmonary disease ,Pulmonary function tests ,Spirometry ,Airway obstruction ,Emphysema ,Forced expiratory volume ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background The identification of smoking-related lung disease in current and former smokers with normal FEV1 is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV1/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group. Methods We compared spirometry, chest CT characteristics, and symptoms between 161 ever-smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV1 and FEV1/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV1/FVC criteria thresholds. Results The discordant group had more CT defined emphysema and non-emphysematous gas trapping, lower post-bronchodilator FEV1 and FEF25–75, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non-emphysematous gas trapping; an FEV1/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality. Conclusions Ever-smokers with normal FEV1 and FEV1/FVC LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone.
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- 2018
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21. Bronchodilator Responsiveness in Tobacco-Exposed People With or Without COPD
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Spyridon Fortis, Pedro M. Quibrera, Alejandro P. Comellas, Surya P. Bhatt, Donald P. Tashkin, Eric A. Hoffman, Gerard J. Criner, MeiLan K. Han, R. Graham Barr, Mehrdad Arjomandi, Mark B. Dransfield, Stephen P. Peters, Brett A. Dolezal, Victor Kim, Nirupama Putcha, Stephen I. Rennard, Robert Paine, Richard E. Kanner, Jeffrey L. Curtis, Russell P. Bowler, Fernando J. Martinez, Nadia N. Hansel, Jerry A. Krishnan, Prescott G. Woodruff, Igor Z. Barjaktarevic, David Couper, Wayne H. Anderson, Christopher B. Cooper, Neil E. Alexis, Igor Barjaktarevic, Patricia Basta, Lori A. Bateman, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, David J. Couper, Ronald G. Crystal, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, Annette T. Hastie, Yvonne Huang, Robert J. Kaner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Cheryl Pirozzi, Elizabeth C. Oelsner, Wanda K. O’Neal, Victor E. Ortega, Sanjeev Raman, J. Michael Wells, and Robert A. Wise
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Pulmonary and Respiratory Medicine ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine - Abstract
Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features.Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEVBoth consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEVDemonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.
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- 2023
22. Prolonged, physiologically relevant nicotine concentrations in the airways of smokers
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Charles R, Esther, Wanda K, O'Neal, Neil E, Alexis, Abigail L, Koch, Christopher B, Cooper, Igor, Barjaktarevic, Laura M, Raffield, Russel P, Bowler, Alejandro P, Comellas, Stephen P, Peters, Annette T, Hastie, Jeffrey L, Curtis, Bonnie, Ronish, Victor E, Ortega, J Michael, Wells, Eitan, Halper-Stromberg, Stephen I, Rennard, and Richard C, Boucher
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Pulmonary and Respiratory Medicine ,Nicotine ,Pulmonary Disease, Chronic Obstructive ,Smokers ,Physiology ,Physiology (medical) ,Respiratory System ,Humans ,Cell Biology ,Cotinine ,Biomarkers - Abstract
Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8–10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70–850 ng/mL (∼0.5–5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.
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- 2023
23. Use of a Wearable Biosensor to Study Heart Rate Variability in Chronic Obstructive Pulmonary Disease and Its Relationship to Disease Severity.
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Seon-Cheol Park, Narongkorn Saiphoklang, Donghyun Jung, David Gomez, Jonathan E. Phillips, Brett A. Dolezal, Donald P. Tashkin, Igor Barjaktarevic, and Christopher B. Cooper
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- 2022
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24. The influence of social support on COPD outcomes mediated by depression.
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Leonard Turnier, Michelle Eakin, Han Woo, Mark Dransfield, Trisha Parekh, Jerry A Krishnan, Richard Kanner, Christopher B Cooper, Prescott G Woodruff, Robert Wise, MeiLan K Han, Karina Romero, Laura M Paulin, Stephen Peters, Brad Drummond, Eugene R Bleecker, Russell Bowler, Alejandro P Comellas, David Couper, Robert Paine, Fernando Martinez, Graham Barr, Nirupama Putcha, and Nadia N Hansel
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Medicine ,Science - Abstract
BackgroundThe purpose of this study was to explore the association between perceived social support and COPD outcomes and to determine whether the associations are mediated by depressive symptoms.MethodsSubjects with COPD who were enrolled as part of SPIROMICS were included in this analysis. Questionnaires relating to quality of life, symptom burden, and functional status were administered at annual clinic visits for over a 3 year period. In both cross-sectional and longitudinal analyses, we examined the association of social support as measured by the FACIT-F with COPD outcomes. Cross sectional analyses used multivariable linear or logistic regression, adjusting for covariates. For longitudinal analyses, generalized linear mixed models with random intercepts were used. Models were adjusted with and without depressive symptoms and mediation analyses performed.ResultsOf the 1831 subjects with COPD, 1779 completed the FACIT- F questionnaire. In adjusted cross-sectional analysis without depressive symptoms, higher perceived social support was associated with better quality of life, well-being, 6 minute walk distance, and less dyspnea. When also adjusting for depressive symptoms, all associations between social support and COPD outcomes were attenuated and no longer statistically significant. Mediation analysis suggested that depressive symptoms explained the majority (> = 85%) of the association between social support and measured COPD outcomes. Results of the longitudinal analysis were consistent with the cross-sectional analyses. There was no association between social support and odds of exacerbations.ConclusionHigher social support was associated with better COPD outcomes across several measures of morbidity including quality of life, respiratory symptoms, and functional status. In addition, these associations were largely attenuated when accounting for depressive symptoms suggesting that the beneficial association of social support with COPD outcomes may be largely mediated by the association between social support and depression.Trial registrationSPIROMICS was approved by Institutional Review Boards at each center and all participants provided written informed consent (clinicaltrials.gov: NCT01969344).
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- 2021
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25. A novel geometric method for determining the time constant for oxygen uptake kinetics
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Christopher B. Cooper and Alan Garfinkel
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Oxygen ,Kinetics ,Oxygen Consumption ,Physiology ,Physiology (medical) ,Exercise Test ,Humans ,Exercise - Abstract
The kinetic response of oxygen uptake (V̇osub2/sub) to transitions of exercise intensity is one of the important parameters of aerobic function. The typical kinetic response between two steady states can be reasonably well fitted with a mono-exponential function that has a time constant τV̇osub2/sub. However, due to the variability of breath-by-breath measures of V̇osub2/subdetermination of τV̇osub2/subhas usually required superimposition of repeated exercise protocols. We developed a novel geometric method of determining τV̇osub2/subfrom the analysis of slopes and intercepts of a plot of cumulative oxygen uptake (cumV̇osub2/sub) versus time for single exercise protocols. We used mathematical modeling to generate 3,600 series of breath-by-breath V̇osub2/submeasures versus time for various exercise protocols. To test whether our geometric method was robust to the presence of real-life variability, we applied random (Gaussian) variation to both the interval between breaths and to the measured values of V̇osub2/sub. Our method derived values for τV̇osub2/subthat were accurate to within 1.5-3.5 s for both on- and off-transits and for models that represented healthy normal subjects as well as persons with cardiovascular disease. The coefficient of variation for multiple iterations of the method waslt;10% as long as the signal-to-noise ratio wasgt;20:1. We present a novel geometric method for deriving the τV̇osub2/subof oxygen uptake kinetics. This method uses analysis of the slopes and intercepts of a plot of cumulative V̇osub2/subversus time and does not require multiple repetitions of the exercise protocol but still gives accurate estimates of τV̇osub2/sub.bNEWamp; NOTEWORTHY/bWe present a novel geometric method for deriving the τV̇osub2/subof oxygen uptake kinetics. This method uses analysis of the slopes and intercepts of a plot of cumulative V̇osub2/subversus time and does not require multiple repetitions of the exercise protocol but still gives accurate estimates of τV̇osub2/sub.
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- 2022
26. Realizing Intrinsically Stretchable Semiconducting Polymer Films by Nontoxic Additives
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Hao-Wen Cheng, Song Zhang, Lukas Michalek, Xiaozhou Ji, Shaochuan Luo, Christopher B. Cooper, Huaxin Gong, Shayla Nikzad, Jerika A. Chiong, Yilei Wu, Yu Zheng, Qianhe Liu, Donglai Zhong, Yusheng Lei, Yoko Tomo, Kung-Hwa Wei, Dongshan Zhou, Jeffrey B.-H. Tok, and Zhenan Bao
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General Chemical Engineering ,Biomedical Engineering ,General Materials Science - Published
- 2022
27. Imaging-based clusters in current smokers of the COPD cohort associate with clinical characteristics: the SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)
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Babak Haghighi, Sanghun Choi, Jiwoong Choi, Eric A. Hoffman, Alejandro P. Comellas, John D. Newell, R. Graham Barr, Eugene Bleecker, Christopher B. Cooper, David Couper, Mei Lan Han, Nadia N. Hansel, Richard E. Kanner, Ella A. Kazerooni, Eric A. C. Kleerup, Fernando J. Martinez, Wanda O’Neal, Stephen I. Rennard, Prescott G. Woodruff, and Ching-Long Lin
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COPD ,Current smokers ,Emphysema ,Functional small airway disease ,Imaging-based cluster analysis ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD. Methods Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering. Results Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters. Conclusions Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.
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- 2018
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28. Genome-wide association study of lung function and clinical implication in heavy smokers
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Xingnan Li, Victor E. Ortega, Elizabeth J. Ampleford, R. Graham Barr, Stephanie A. Christenson, Christopher B. Cooper, David Couper, Mark T. Dransfield, Mei Lan K. Han, Nadia N. Hansel, Eric A. Hoffman, Richard E. Kanner, Eric C. Kleerup, Fernando J. Martinez, Robert Paine, Prescott G. Woodruff, Gregory A. Hawkins, Eugene R. Bleecker, Deborah A. Meyers, and for the SPIROMICS Research Group
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COPD ,GWAS ,Lung function ,rs28929474 ,SERPINA1 ,SPIROMICS ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background The aim of this study is to identify genetic loci associated with post-bronchodilator FEV1/FVC and FEV1, and develop a multi-gene predictive model for lung function in COPD. Methods Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers. Results A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV1/FVC (p = 1.2 × 10− 8) and FEV1 (p = 2.1 × 10− 9). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10− 4) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV1/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P
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- 2018
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29. Effect of altering breathing frequency on maximum voluntary ventilation in healthy adults
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Eric V. Neufeld, Brett A. Dolezal, William Speier, and Christopher B. Cooper
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Pulmonary function test ,Standardization ,Breathing frequency ,Exercise testing ,Ventilatory reserve ,Maximal exercise ventilation ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Compared to other pulmonary function tests, there is a lack of standardization regarding how a maximum voluntary ventilation (MVV) maneuver is performed. Specifically, little is known about the variation in breathing frequency (f R) and its potential impact on the accuracy of test results. This study examines the effect of several preselected values for f R and one self-selected f R (f Rself) on MVV. Methods Ten participants performed MVV maneuvers at various f R values, ranging from 50 to 130 breaths·min− 1 in 10 breaths·min− 1 intervals and at one f Rself. Three identical trials with 2-min rest periods were conducted at each f R, and the sequence in which f R was tested was randomized. Ventilation and related parameters were measured directly by gas exchange analysis via a metabolic measurement system. Results A third-order polynomial regression analysis showed that MVV = − 0.0001(f R)3 + 0.0258(f R)2–1.38(f R) + 96.9 at preselected f R and increased up to approximately 100 breaths·min− 1 (r2 = 0.982, P
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- 2018
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30. Embedding Azobenzene-Functionalized Carbon Nanotubes into a Polymer Matrix for Stretchable, Composite Solar Thermal Devices
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Thomas W. Colburn, Alea C. Delmastro, Michael Figueroa, Francisco Lopez, and Christopher B. Cooper
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General Energy ,Physical and Theoretical Chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials - Published
- 2022
31. Reversible Airflow Obstruction Predicts Future Chronic Obstructive Pulmonary Disease Development in the SPIROMICS Cohort: An Observational Cohort Study
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Russell G. Buhr, Igor Z. Barjaktarevic, P. Miguel Quibrera, Lori A. Bateman, Eugene R. Bleecker, David J. Couper, Jeffrey L. Curtis, Brett A. Dolezal, MeiLan K. Han, Nadia N. Hansel, Jerry A. Krishnan, Fernando J. Martinez, William McKleroy, Robert Paine, Stephen I. Rennard, Donald P. Tashkin, Prescott G. Woodruff, Richard E. Kanner, Christopher B. Cooper, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, R. Graham Barr, Surya P. Bhatt, Richard C. Boucher, Russell P. Bowler, Stephanie A. Christenson, Alejandro P. Comellas, Gerard J. Criner, Ronald G. Crystal, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, Annette T. Hastie, Eric A. Hoffman, Yvonne Huang, Robert J. Kaner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Stephen P. Peters, Cheryl Pirozzi, Nirupama Putcha, Elizabeth C. Oelsner, Wanda K. O’Neal, Victor E. Ortega, Sanjeev Raman, J. Michael Wells, and Robert A. Wise
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Airway Obstruction ,Cohort Studies ,Pulmonary and Respiratory Medicine ,Pulmonary Disease, Chronic Obstructive ,Spirometry ,Forced Expiratory Volume ,Vital Capacity ,Humans ,Critical Care and Intensive Care Medicine ,Asthma ,Bronchodilator Agents - Published
- 2022
32. Lung Microbiota and Metabolites Collectively Associate with Clinical Outcomes in Milder Stage Chronic Obstructive Pulmonary Disease
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Siddharth S. Madapoosi, Charmion Cruickshank-Quinn, Kristopher Opron, John R. Erb-Downward, Lesa A. Begley, Gen Li, Igor Barjaktarevic, R. Graham Barr, Alejandro P. Comellas, David J. Couper, Christopher B. Cooper, Christine M. Freeman, MeiLan K. Han, Robert J. Kaner, Wassim Labaki, Fernando J. Martinez, Victor E. Ortega, Stephen P. Peters, Robert Paine, Prescott Woodruff, Jeffrey L. Curtis, Gary B. Huffnagle, Kathleen A. Stringer, Russell P. Bowler, Charles R. Esther, Nichole Reisdorph, Yvonne J. Huang, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, Gerard J. Criner, Ronald G. Crystal, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Craig Galban, Nadia N. Hansel, Annette T. Hastie, Eric A. Hoffman, Richard E. Kanner, Eric C. Kleerup, Jerry A. Krishnan, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Cheryl Pirozzi, Nirupama Putcha, Elizabeth C. Oelsner, Wanda K. O’Neal, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, J. Michael Wells, and Robert A. Wise
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Pulmonary and Respiratory Medicine ,Critical Care and Intensive Care Medicine - Published
- 2022
33. Tunable, reusable, and recyclable perfluoropolyether periodic dynamic polymers with high underwater adhesion strength
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Tomoko Nogusa, Christopher B. Cooper, Zhiao Yu, Yu Zheng, Yuran Shi, and Zhenan Bao
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General Materials Science - Published
- 2023
34. Identification of Sputum Biomarkers Predictive of Pulmonary Exacerbations in COPD
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Charles R. Esther, Wanda K. O’Neal, Wayne H. Anderson, Mehmet Kesimer, Agathe Ceppe, Claire M. Doerschuk, Neil E. Alexis, Annette T. Hastie, R. Graham Barr, Russell P. Bowler, J. Michael Wells, Elizabeth C. Oelsner, Alejandro P. Comellas, Yohannes Tesfaigzi, Victor Kim, Laura M. Paulin, Christopher B. Cooper, MeiLan K. Han, Yvonne J. Huang, Wassim W. Labaki, Jeffrey L. Curtis, Richard C. Boucher, Mehrdad Arjomandi, Igor Barjaktarevic, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Stephanie A. Christenson, David J. Couper, Gerard J. Criner, Ronald G. Crystal, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, Nadia N. Hansel, Eric A. Hoffman, Yvonne Huang, Robert J. Kaner, Richard E. Kanner, Eric C. Kleerup, Jerry A. Krishnan, Lisa M. LaVange, Stephen C. Lazarus, Fernando J. Martinez, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Robert Paine, Laura Paulin, Stephen P. Peters, Cheryl Pirozzi, Nirupama Putcha, Victor E. Ortega, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, Robert A. Wise, and Prescott G. Woodruff
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Pulmonary and Respiratory Medicine ,Spirometry ,Subpopulations and Intermediate Outcome Measures in COPD Study ,Chronic Obstructive ,Exacerbation ,Chronic Obstructive Pulmonary Disease ,Clinical Sciences ,Respiratory System ,Critical Care and Intensive Care Medicine ,Cystic fibrosis ,COPD: Original Research ,Pulmonary Disease ,Pulmonary Disease, Chronic Obstructive ,mucus ,Clinical Research ,medicine ,Humans ,glutathione ,Lung ,COPD ,medicine.diagnostic_test ,business.industry ,methionine salvage ,Sputum ,Area under the curve ,medicine.disease ,metabolomics ,N-Acetylneuraminic Acid ,Pathophysiology ,respiratory tract diseases ,Good Health and Well Being ,adenosine ,inflammation ,Hypoxanthines ,Immunology ,Respiratory ,Biomarker (medicine) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov
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- 2022
35. Significance of FEV3/FEV6 in Recognition of Early Airway Disease in Smokers at Risk of Development of COPD
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Russell G. Buhr, Mehrdad Arjomandi, David Couper, Russell P. Bowler, Jeffrey L. Curtis, MeiLan K. Han, Victor E. Ortega, Christopher B. Cooper, Robert Paine, Spyridon Fortis, Eric A. Hoffman, Daniela Markovic, Fernando J. Martinez, Igor Barjaktarevic, Nathan Yee, Wayne Anderson, Prescott G. Woodruff, M. Bradley Drummond, Donald P. Tashkin, James M. Wells, R. Graham Barr, and Victor Kim
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Pulmonary and Respiratory Medicine ,Spirometry ,medicine.medical_specialty ,Vital capacity ,COPD ,medicine.diagnostic_test ,business.industry ,Critical Care and Intensive Care Medicine ,medicine.disease ,respiratory tract diseases ,FEV1/FVC ratio ,Quality of life ,DLCO ,Internal medicine ,Cohort ,medicine ,Lung volumes ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Small airways are known to be affected early in the course of chronic obstructive pulmonary disease (COPD); however, traditional spirometric indices may not accurately identify small airways disease. Research Question Can FEV3/FEV6 identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD? Study Design and Methods We included eight hundred thirty-two current and former smokers with post-bronchodilator FEV1/FVC ≥0.7 from the SPIROMICS cohort. Participants were classified as having a reduced pre-bronchodilator FEV3/FEV6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV3 and FEV6. Regression modeling was used to evaluate the relationship between baseline FEV3/FEV6 and outcome measures including functional small airways disease on thoracic imaging and respiratory exacerbations. Interval censored analysis was used to assess progression to COPD. Results FEV3/FEV6 Interpretation FEV3/FEV6 is a routinely available and repeatable spirometric index which can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV3/FEV6 can identify those at risk for future development of COPD and respiratory exacerbations.
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- 2022
36. Association of occupational exposures and chronic obstructive pulmonary disease morbidity
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Jennifer S. Rous, Peter S. J. Lees, Kirsten Koehler, Jessie P. Buckley, Lesliam Quirós-Alcalá, MeiLan K. Han, Eric A. Hoffman, Wassim Labaki, R. Graham Barr, Stephen P. Peters, Robert Paine, Cheryl Pirozzi, Christopher B. Cooper, Mark T. Dransfield, Alejandro P. Comellas, Richard E. Kanner, M. Bradley Drummond, Nirupama Putcha, Nadia N. Hansel, and Laura M. Paulin
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Public Health, Environmental and Occupational Health - Published
- 2023
37. Medicinal Chemistry for Neglected Diseases – Malaria, Tuberculosis, Sleeping Sickness, Leishmaniasis and River Blindness
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Jeremy N. Burrows, Christopher B. Cooper, Charles Mowbray, and Peter Sjö
- Abstract
Not every life-threatening or debilitating disease has a sufficient armoury of therapies available nor a pipeline of future products to combat the remaining unmet areas of medical need. This is particularly so in the areas of infectious diseases affecting, disproportionately, those in low- and middle-income countries where market forces, namely the inability to recoup research and development costs through sales, disincentivises new discovery and product innovation. This is further exacerbated by the inevitable challenges of resistance to anti-infectious agents and thus their controlled and careful use only in cases of need. The Medicines for Malaria Venture (MMV), the Global Alliance for TB Drug Development (GATB) and Drugs for Neglected Diseases initiative (DNDi) are Product Development Partnerships that were created to address this market failure as donor-funded organisations seeking to deliver the medicines of the future for malaria, tuberculosis and many neglected tropical diseases. The science of drug discovery, despite the resource constraints, remains unchanged from commercial therapeutic areas and MMV, GATB and DNDi work with partners globally applying state-of-the-art medicinal chemistry and thinking to diseases that affect over 250 million symptomatic disease episodes each year. The discovery strategies in each disease will be illustrated with case studies that have progressed into clinical development.
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- 2023
38. Comparative Impact of Depressive Symptoms and FEV
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Jacqueline, O'Toole, Han, Woo, Nirupama, Putcha, Christopher B, Cooper, Prescott, Woodruff, Richard E, Kanner, Robert, Paine, Russell P, Bowler, Alejandro, Comellas, Karin F, Hoth, Jerry A, Krishnan, Meilan, Han, Mark, Dransfield, Anand S, Iyer, David, Couper, Stephen P, Peters, Gerard, Criner, Victor, Kim, R Graham, Barr, Fernando J, Martinez, Nadia N, Hansel, Michelle N, Eakin, and Prescott G, Woodruff
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Pulmonary Disease, Chronic Obstructive ,Depression ,Forced Expiratory Volume ,Surveys and Questionnaires ,Smoking ,Quality of Life ,Humans ,Female ,Respiratory Function Tests ,Original Research - Abstract
RATIONALE: Individuals with chronic obstructive pulmonary disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. OBJECTIVES: Examine the impact of depressive symptoms compared with FEV(1)% on COPD morbidity. METHODS: Using longitudinal data from individuals with COPD in the Subpopulations and Intermediate Outcome Measures in COPD Study, longitudinal growth analysis was performed to assess COPD morbidity by assessing differences in baseline 6-minute walk distance and patient reported outcomes (PROs) and their rate of change over time explained by depressive symptoms or lung function, as measured by Hospital Anxiety and Depression Scale or FEV(1)% respectively. PROs consisted of in-person completion of St. George's Respiratory Questionnaire, COPD Assessment Test, Functional Assessment of Chronic Illness Therapy Fatigue, and Modified Medical Research Council Dyspnea Scale measures. RESULTS: Of the individuals analyzed (n = 1,830), 43% were female, 81% Caucasian with mean ± SD age of 65.1 ± 8.1, and 52.7 ± 27.5 pack-years smoking. Mean ± SD FEV(1)% was 60.9 ± 23.0% and 20% had clinically significant depressive symptoms. Adjusted models showed higher Hospital Anxiety and Depression Scale scores and lower FEV(1)% each were associated with worse PROs at baseline (P ⩽ 0.001). Depression accounted for more baseline variance in St. George's Respiratory Questionnaire, COPD Assessment Test, and Functional Assessment of Chronic Illness Therapy Fatigue than FEV(1)%, explaining 30–67% of heterogeneity. FEV(1)% accounted for more baseline variance in Modified Medical Research Council Dyspnea Scale and 6-minute walk distance than depression, explaining 16–32% of heterogeneity. Depressive symptoms accounted for 3–17% variance in change over time in PROs. In contrast, FEV(1)% accounted for 1–4% variance over time in PROs. CONCLUSIONS: Depression is more strongly associated with many PROs at baseline and their change over time compared with FEV(1)%. Recognizing and incorporating the impact of depressive symptoms into individualized care may improve COPD outcomes.
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- 2023
39. Ambient Air Pollution Exposure and Sleep Quality in COPD
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Mudiaga O. Sowho, Abigail L. Koch, Nirupama Putcha, Han Woo, Amanda Gassett, Laura M. Paulin, Kirsten Koehler, R. Graham Barr, Alejandro P. Comellas, Christopher B. Cooper, Igor Barjaktarevic, Michelle R. Zeidler, Martha E. Billings, Russell P. Bowler, MeiLan K. Han, Victor Kim, Robert Paine III, Trisha M. Parekh, Jerry A. Krishnan, Stephen P. Peters, Prescott G. Woodruff, Aaron M. Baugh, Joel D. Kaufman, David Couper, and Nadia N. Hansel
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Pulmonary and Respiratory Medicine ,Origianl Research - Abstract
Rationale: Ambient air pollution exposure is associated with respiratory morbidity among individuals with chronic obstructive pulmonary disease (COPD), particularly among those with concomitant obesity. Although people with COPD report high incidence of poor sleep quality, no studies have evaluated the association between air pollution exposure, obesity, and sleep disturbances in COPD. Methods: We analyzed data collected from current and former smokers with COPD enrolled in the Subpopulations and Intermediate Outcome Measures in COPD -Air Pollution ancillary study (SPIROMICS AIR). Socio-demographics and anthropometric measurements were collected, and 1-year mean historical ambient particulate matter (PM(2.5)) and ozone concentrations at participants’ residences were estimated by cohort-specific spatiotemporal modeling. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI), and regression models were constructed to determine the association of 1-year PM(2.5 )(1Yr-PM(2.5)) and 1-year ozone (1Yr-ozone) with the PSQI score, and whether obesity modified the association. Results: In 1308 participants (age: 65.8±7.8 years, 42% women), results of regression analyses suggest that each 10µg/m(3) increase in 1Yr-PM(2.5 )was associated with a 2.1-point increase in PSQI (P=0.03). Obesity modified the association between 1Yr-PM(2.5) and PSQI (P=0.03). In obese and overweight participants, a 10µg/m(3) increase in 1Yr-PM(2.5) was associated with a higher PSQI (4.0 points, P
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- 2023
40. Impact of Marijuana Smoking on COPD Progression in a Cohort of Middle-Aged and Older Persons
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Igor Barjaktarevic, Christopher B. Cooper, Tracie Shing, Russell G. Buhr, Eric A. Hoffman, Prescott G. Woodruff, M. Bradley Drummond, Richard E. Kanner, MeiLan K. Han, Nadia N. Hansel, Russell P. Bowler, Gregory L. Kinney, Sean Jacobson, Madeline A. Morris, Fernando J. Martinez, Jill Ohar, David Couper, and Donald P. Tashkin
- Subjects
Pulmonary and Respiratory Medicine - Published
- 2023
41. Changes in Lung Volumes with Spirometric Disease Progression in COPD
- Author
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Mehrdad Arjomandi, Siyang Zeng, Jianhong Chen, Surya P. Bhatt, Fereidoun Abtin, Igor Barjaktarevic, R. Graham Barr, Eugene R. Bleecker, Russell G. Buhr, Gerard J. Criner, Alejandro P. Comellas, David J. Couper, Jeffrey L. Curtis, Mark T. Dransfield, Spyridon Fortis, MeiLan K. Han, Nadia N. Hansel, Eric A. Hoffman, John E. Hokanson, Robert J. Kaner, Richard E. Kanner, Jerry A. Krishnan, Wassim Labaki, David A. Lynch, Victor E. Ortega, Stephen P. Peters, Prescott G. Woodruff, Christopher B. Cooper, Russell P. Bowler, Robert Paine, III, Stephen I. Rennard, and Donald P. Tashkin
- Subjects
Pulmonary and Respiratory Medicine - Published
- 2023
42. Impact of Bronchiectasis on COPD Severity and Alpha-1 Antitrypsin Deficiency as a Risk Factor in Individuals with a Heavy Smoking History
- Author
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Manuel Izquierdo, Chad R. Marion, Frank Genese, John D. Newell, Wanda K. O'Neal, Xingnan Li, Gregory A. Hawkins, Igor Barjaktarevic, R. Graham Barr, Stephanie Christenson, Christopher B. Cooper, David Couper, Jeffrey Curtis, Meilan K. Han, Nadia N. Hansel, Richard E. Kanner, Fernando J. Martinez, Robert Paine, III, Vickram Tejwani, Prescott G. Woodruff, Joe G. Zein, Eric A. Hoffman, Stephen P. Peters, Deborah A. Meyers, Eugene R. Bleecker, and Victor E. Ortega
- Subjects
Pulmonary and Respiratory Medicine - Published
- 2023
43. Comparative Impact of Depressive Symptoms and FEV1% on Chronic Obstructive Pulmonary Disease
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Jacqueline O’Toole, Han Woo, Nirupama Putcha, Christopher B. Cooper, Prescott Woodruff, Richard E. Kanner, Robert Paine, Russell P. Bowler, Alejandro Comellas, Karin F. Hoth, Jerry A. Krishnan, Meilan Han, Mark Dransfield, Anand S. Iyer, David Couper, Stephen P. Peters, Gerard Criner, Victor Kim, R. Graham Barr, Fernando J. Martinez, Nadia N. Hansel, Michelle N. Eakin, Neil E. Alexis, Wayne H. Anderson, Mehrdad Arjomandi, Igor Barjaktarevic, Lori A. Bateman, Surya P. Bhatt, Eugene R. Bleecker, Richard C. Boucher, Stephanie A. Christenson, Alejandro P. Comellas, David J. Couper, Gerard J. Criner, Ronald G. Crystal, Jeffrey L. Curtis, Claire M. Doerschuk, Mark T. Dransfield, Brad Drummond, Christine M. Freeman, Craig Galban, MeiLan K. Han, Annette T. Hastie, Eric A. Hoffman, Yvonne Huang, Robert J. Kaner, Eric C. Kleerup, Lisa M. LaVange, Stephen C. Lazarus, Deborah A. Meyers, Wendy C. Moore, John D. Newell, Laura Paulin, Cheryl Pirozzi, Elizabeth C. Oelsner, Wanda K. O’Neal, Victor E. Ortega, Sanjeev Raman, Stephen I. Rennard, Donald P. Tashkin, J Michael Wells, Robert A. Wise, and Prescott G. Woodruff
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,COPD ,business.industry ,Internal medicine ,medicine ,Pulmonary disease ,medicine.disease ,business ,Depressive symptoms ,Depression (differential diagnoses) ,respiratory tract diseases - Abstract
Rationale: Individuals with Chronic Obstructive Pulmonary Disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. Objectives:...
- Published
- 2022
44. Clinically Significant and Comorbid Anxiety and Depression Symptoms Predict Severe Respiratory Exacerbations in Smokers: A Post Hoc Analysis of the COPDGene and SPIROMICS Cohorts
- Author
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Anand S. Iyer, Trisha M. Parekh, Jacqueline O’Toole, Surya P. Bhatt, Michelle N. Eakin, Jerry A. Krishnan, Abebaw M. Yohannes, Prescott G. Woodruff, Christopher B. Cooper, Richard E. Kanner, Nicola A. Hanania, Mark T. Dransfield, Elizabeth A. Regan, Karin F. Hoth, Victor Kim, James D. Crapo, Edwin K. Silverman, Barry J. Make, Terri Beaty, Ferdouse Begum, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Huries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San José Estépar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Kendra A. Young, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Los Angeles, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Comorbid anxiety ,business.industry ,Internal medicine ,Post-hoc analysis ,Medicine ,Respiratory system ,business ,Depressive symptoms - Published
- 2022
45. Defining Resilience to Smoking-related Lung Disease: A Modified Delphi Approach from SPIROMICS
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Anita L. Oh, Richard A. Mularski, Igor Barjaktarevic, R. Graham Barr, Russell P. Bowler, Alejandro P. Comellas, Christopher B. Cooper, Gerard J. Criner, MeiLan K. Han, Nadia N. Hansel, Eric A. Hoffman, Richard E. Kanner, Jerry A. Krishnan, Robert Paine, Trisha M. Parekh, Stephen P. Peters, Stephanie A. Christenson, Prescott G. Woodruff, Wayne H. Anderson, Mehrdad Arjomandi, Nirav Bhakta, Surya P. Bhatt, Russell Buhr, Jeffrey L. Curtis, M. Bradley Drummond, Victor Kim, Wassim Labaki, Allison Lambert, Stephen C. Lazarus, Alex Mackay, Wendy Moore, Sarah L. O'Beirne, Laura Paulin, Benjamin M. Smith, Donald P. Tashkin, and James Michael Wells
- Subjects
Pulmonary and Respiratory Medicine ,Spirometry ,medicine.medical_specialty ,media_common.quotation_subject ,Modified delphi ,Pulmonary disease ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Forced Expiratory Volume ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Lung ,media_common ,COPD ,medicine.diagnostic_test ,business.industry ,Smoking ,Editorials ,medicine.disease ,respiratory tract diseases ,030228 respiratory system ,Lung disease ,Psychological resilience ,Consensus development ,business - Abstract
Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory di...
- Published
- 2021
46. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort
- Author
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Eugene R. Bleecker, Richard C. Boucher, Prescott G. Woodruff, Annette T. Hastie, MeiLan K. Han, Neil E. Alexis, R. Graham Barr, Wanda K. O'Neal, Eric A. Hoffman, Agathe Ceppe, Giorgia Radicioni, Amina A. Ford, Nadia N. Hansel, Esin Ozkan, Fernando J. Martinez, Christopher B. Cooper, Stephanie A. Christenson, Robert Paine, Mehmet Kesimer, and Richard E. Kanner
- Subjects
Adult ,Pulmonary and Respiratory Medicine ,Vital capacity ,medicine.medical_specialty ,Exacerbation ,Mucin 5AC ,Article ,Pulmonary function testing ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,FEV1/FVC ratio ,0302 clinical medicine ,Forced Expiratory Volume ,Internal medicine ,medicine ,Humans ,Lung volumes ,Prospective Studies ,030212 general & internal medicine ,Lung ,Aged ,Aged, 80 and over ,COPD ,business.industry ,Odds ratio ,Middle Aged ,respiratory system ,medicine.disease ,Mucin-5B ,respiratory tract diseases ,Cross-Sectional Studies ,medicine.anatomical_structure ,030228 respiratory system ,Disease Progression ,business - Abstract
Summary Background We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD. Methods SPIROMICS was a multicentre, observational study in patients aged 40–80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV1, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF25–75%). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344). Findings This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV1 and FEF25–75%, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04–1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV1, FEV1/FVC, FEF25–75%, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years. Interpretation These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents. Funding National Institutes of Health; National Heart, Lung, and Blood Institute.
- Published
- 2021
47. Synergistic Activity of Nitroimidazole-Oxazolidinone Conjugates against Anaerobic Bacteria
- Author
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Zhijun Zhuang, Dawei Wan, Jun Ding, Shijie He, Qian Zhang, Xiaomei Wang, Ying Yuan, Yu Lu, Charles Z. Ding, Anthony Simon Lynch, Anna M. Upton, Christopher B. Cooper, William A. Denny, and Zhenkun Ma
- Subjects
drug conjugates ,anaerobic bacterium ,synergy ,nitroimidazole and oxazolidinone ,Organic chemistry ,QD241-441 - Abstract
The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections.
- Published
- 2020
- Full Text
- View/download PDF
48. Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline
- Author
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Peter J. Choi, Daniel Conole, Hamish S. Sutherland, Adrian Blaser, Amy S.T. Tong, Christopher B. Cooper, Anna M. Upton, Brian D. Palmer, and William A. Denny
- Subjects
bedaquiline ,tmc207 ,sirturo ,bedaquiline analogues ,tbaj-876 ,mycobacterium tuberculosis ,tuberculosis ,drug development ,Organic chemistry ,QD241-441 - Abstract
Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.
- Published
- 2020
- Full Text
- View/download PDF
49. PHASER: Physiological Health Assessment System for emergency responders.
- Author
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Maxim A. Batalin, Eric Yuen, Brett A. Dolezal, Denise Smith, Christopher B. Cooper, and Jalal Mapar
- Published
- 2013
- Full Text
- View/download PDF
50. Racial Segregation and Respiratory Outcomes among Urban Black Residents with and at Risk of Chronic Obstructive Pulmonary Disease
- Author
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Jerry A. Krishnan, Miranda R. Jones, Richard E. Kanner, Russell P. Bowler, Eric A. Hoffman, Nirupama Putcha, Nadia N. Hansel, Laura M. Paulin, Han Woo, Trisha M. Parekh, Victor E. Ortega, Panagis Galiatsatos, Gabriela R. Oates, MeiLan K. Han, Amanda J. Gassett, R. Graham Barr, Christopher B. Cooper, Joel D. Kaufman, Stephanie A. Christenson, Sarath Raju, Kassandra Allbright, D. Belz, Emily P. Brigham, Alejandro P. Comellas, C.O. Ejike, Fernando J. Martinez, and Gerard J. Criner
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Urban Population ,Pulmonary disease ,Critical Care and Intensive Care Medicine ,Health outcomes ,Pulmonary Disease, Chronic Obstructive ,Residence Characteristics ,Surveys and Questionnaires ,Humans ,Medicine ,Respiratory system ,Intensive care medicine ,Aged ,Aged, 80 and over ,COPD ,Social Segregation ,business.industry ,Editorials ,Health Status Disparities ,Middle Aged ,medicine.disease ,United States ,Health equity ,Black or African American ,Social Class ,Female ,business - Abstract
Rationale: Racial residential segregation has been associated with worse health outcomes, but the link with chronic obstructive pulmonary disease (COPD) morbidity has not been established.Objective...
- Published
- 2021
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