285 results found
Ritchie AI, Baker JR, Parekh TM, et al., 2021, Update in Chronic Obstructive Pulmonary Disease 2020, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 204, Pages: 14-22, ISSN: 1073-449X
Singh R, Belchamber K, Fenwick P, et al., 2021, Defective monocyte-derived macrophage phagocytosis is associated with exacerbation frequency in COPD, Respiratory Research, Vol: 22, Pages: 1-11, ISSN: 1465-9921
BackgroundLower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline. Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear. This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters.MethodsMonocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients. Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA. Sputum bacterial colonisation was measured by PCR.ResultsPhagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 103 RFU vs. 2.5 × 103 RFU, p < 0.01). There was no correlation for S. pneumoniae. There was no association between phagocytosis of either bacteria with age, lung function, smoking history or treatment with inhaled corticosteroids, or long-acting bronchodilators. Phagocytosis was not altered during an exacerbation, or in the 2 weeks post-exacerbation. In response to phagocytosis, MDM from exacerbating patients showed increased release of CXCL-8 (p < 0.001) and TNFα (p < 0.01) compared to stable state.ConclusionImpaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression. Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial.
Gregson FKA, Watson NA, Orton CM, et al., 2021, Comparing aerosol concentrations and particle size distributions generated by singing, speaking and breathing, Aerosol Science and Technology, Vol: 55, Pages: 681-691, ISSN: 0278-6826
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in an unprecedented shutdown in social and economic activity, with the cultural sector particularly severely affected. Restrictions on musical performances have arisen from a perception that there is a significantly higher risk of aerosol production from singing than speaking, based upon high-profile examples of clusters of COVID-19 following choral rehearsals. However, comparing aerosol generation from different types of vocalization, including singing, across a range of volumes is a rapidly evolving area of research. Here, we measured aerosols from singing, speaking and breathing from a large cohort of 25 professional singers in a range of musical genres in a zero-background environment, allowing unequivocal attribution of aerosol production to specific vocalizations. We do not assess the relative volumes at which people speak and sing. However, both showed steep increases in mass concentration with increase in loudness (spanning a factor of 20–30 across the dynamic range measured, p < 0.001). At the quietest volume (50 to 60 dBA), neither singing (p = 0.19) nor speaking (p = 0.20) were significantly different to breathing. At the loudest volume (90 to 100 dBA), a statistically significant difference (p < 0.001) was observed between singing and speaking, but with singing only generating a factor of between 1.5 and 3.4 more aerosol mass. Guidelines for musical performances should be based on the loudness and duration of the vocalization, the number of participants and the environment in which the activity occurs, rather than the type of vocalization. Mitigations such as the use of amplification and increased attention to ventilation should be employed where practicable.
Wang Z, Locantore N, Haldar K, et al., 2020, Inflammatory Endotype Associated Airway Microbiome in COPD Clinical Stability and Exacerbations - A Multi-Cohort Longitudinal Analysis., Am J Respir Crit Care Med
RATIONALE: Understanding the role of airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches. OBJECTIVES: To understand the association of airway microbiome with neutrophilic and eosinophilic COPD at stability and exacerbations. METHODS: An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 COPD patients recruited at four UK sites in BEAT-COPD, COPDMAP and AERIS cohorts. The microbiome was analyzed using COPDMAP and AERIS as discovery dataset and BEAT-COPD as validation dataset. RESULTS: The airway microbiome in neutrophilic COPD was heterogeneous with two primary community types differentiated by the predominance of Haemophilus. The Haemophilus-predominant subgroup had elevated sputum IL-1b and TNFa and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic-Haemophilus-predominant and eosinophilic states which were otherwise mutually exclusive. Time-series analysis on the microbiome showed the temporal trajectories of Campylobacter and Granulicatella were indicative of intra-patient switches from neutrophilic to eosinophilic inflammation, and in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns between neutrophilic-Haemophilus-predominant, neutrophilic-balanced-microbiome and eosinophilic subgroups. CONCLUSIONS: The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are inter-changeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status ov
Beech AS, Lea S, Kolsum U, et al., 2020, Bacteria and sputum inflammatory cell counts; a COPD cohort analysis, RESPIRATORY RESEARCH, Vol: 21
Wiseman DJ, Thwaites RS, Drysdale SB, et al., 2020, Immunological and inflammatory biomarkers of susceptibility and severity in adult respiratory syncytial virus infections, Journal of Infectious Diseases, Vol: 222, Pages: S584-S591, ISSN: 0022-1899
BACKGROUND: . Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults. METHODS: A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946-October 2016. Nine articles were identified plus 9 from other sources. RESULTS: From observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection. CONCLUSIONS: Factors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.
Nici L, Mammen MJ, Charbek E, et al., 2020, Pharmacologic Management of Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline (vol 201, pg e56, 2020), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 910-910, ISSN: 1073-449X
Ritchie AI, Brill SE, Vlies BH, et al., 2020, Targeted retreatment of incompletely recovered COPD exacerbations with ciprofloxacin: a double-blind, randomised, placebo-controlled, multicentre phase III trial, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 549-557, ISSN: 1073-449X
RATIONALE: COPD exacerbations are prone to non-recovery but there are no data about the effectiveness of retreatment on these prolonged events. We examined whether further therapy with ciprofloxacin for incompletely resolved COPD exacerbations prolonged the time until the next event. METHODS: This multi-centre randomised double-blind placebo-controlled trial studied retreatment with oral ciprofloxacin 500mg or matched placebo twice daily for 7 days in patients with GOLD stage II - IV COPD with persistent symptoms and/or serum C-reactive protein (CRP) ≥8mg/L initiated 14 (+/- 3) days after an index COPD exacerbation. The primary outcome was the time to the next exacerbation within a 90-day period. RESULTS: Of 826 patients screened at 4 centres, 144 eligible participants with incomplete recovery were randomised to receive ciprofloxacin (n=72) or placebo (n=72). 57% of patients in the ciprofloxacin group had experienced 1 or more exacerbations, compared to 53% in the placebo group. The median time to the next exacerbation was 32.5 days (IQR 13-50) in the placebo arm and 34 days (IQR 17-62) in the ciprofloxacin arm, which was not significantly different (adjusted hazard ratio = 1.07, 95% CI 0.68-1.68; p=0.76). No significant differences were seen in quality of life scores or lung function between treatment groups. CONCLUSION: In patients with persistent symptoms and/or raised CRP 14 days following a COPD exacerbation, an additional course of ciprofloxacin resulted in no additional benefit compared to placebo. This suggests that non-recovered exacerbations are not driven by ongoing bacterial infection and may potentially be targeted with anti-inflammatory therapy.
Haldar K, George L, Wang Z, et al., 2020, The sputum microbiome is distinct between COPD and health, independent of smoking history, Respiratory Research, Vol: 21, Pages: 1-12, ISSN: 1465-9921
BackgroundAirway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD.MethodsWe compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium.ResultsIn healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001).ConclusionThe healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.
Harhay MO, Donaldson GC, 2020, Guidance on statistical reporting to help improve your chances of a favorable statistical review, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1035-1038, ISSN: 1073-449X
Leisman DE, Harhay MO, Lederer DJ, et al., 2020, Development and reporting of prediction models: guidance for authors from editors of respiratory, sleep, and critical care journals, Critical Care Medicine, Vol: 48, Pages: 623-633, ISSN: 0090-3493
Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of “modifiable risk factors”, measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.
Nici L, Mammen MJ, Charbek E, et al., 2020, Pharmacologic management of COPD: an official American Thoracic Society clinical practice guideline., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1-14, ISSN: 1073-449X
BACKGROUND: This document provides clinical recommendations for the pharmacologic treatment of COPD. It represents a collaborative effort on the part of a panel of expert COPD clinicians and researchers along with a team of methodologists under the guidance of the ATS. METHODS: Comprehensive evidence syntheses were performed on all relevant studies which addressed the clinical questions and critical patient-centered outcomes agreed upon by the panel of experts. The evidence was appraised, rated, and graded, and recommendations were formulated using GRADE. RESULTS: After weighing the quality of evidence and balancing the desirable and undesirable effects, the guideline panel made six recommendations, listed in full in the document. CONCLUSIONS: The task force made recommendations on the pharmacologic treatment of COPD based on currently available evidence. Additional research in populations that are under-represented in clinical trials is needed, including studies in COPD patients 80 years of age and older, those with multiple chronic health conditions, and those with a co-diagnosis of COPD and asthma.
Hurst JR, Skolnik N, Hansen GJ, et al., 2020, Understanding the impact of chronic obstructive pulmonary disease exacerbations on patient health and quality of life, EUROPEAN JOURNAL OF INTERNAL MEDICINE, Vol: 73, Pages: 1-6, ISSN: 0953-6205
Long GH, Southworth T, Kolsum U, et al., 2020, The stability of blood Eosinophils in chronic obstructive pulmonary disease, Respiratory Research, Vol: 21, ISSN: 1465-9921
Blood eosinophils are a predictive biomarker of inhaled corticosteroid response in chronic obstructive pulmonary disease (COPD). We investigated blood eosinophil stability over 1 year using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 thresholds of < 100, 100- < 300 and ≥ 300 eosinophils/μL in 225 patients from the COPDMAP cohort. Blood eosinophils showed good stability (rho: 0.71, p < 0.001, ICC 0.84), and 69.3% of patients remained in the same eosinophil category at 1 year. 85.3% of patients with eosinophils < 100 cells/μL had stable counts. The majority of blood eosinophil counts remain stable over 1 year using the GOLD 2019 thresholds.
Vlies B, Allinson J, Brill SE, et al., 2020, A Randomised Controlled Trial Assessing the Effect of Daily Doxycycline on Exacerbation Rate in Patients with COPD, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Donaldson GC, Wiseman DJ, Ritchie AI, et al., 2020, Use of a Sample Tracking Log as a Measure of Chronic Bronchitis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Donaldson GC, Wiseman DJ, Ritchie AI, et al., 2020, Duration of Persistent Sputum Production Is Related to Lung Function Decline, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Beech AS, Lea S, Kolsum U, et al., 2020, Profiles of Airway Inflammation in Chronic Obstructive Pulmonary Disease Associated with Different Bacterial Species, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Ritchie A, Brill SE, Vlies BH, et al., 2019, Targeted Retreatment of Incompletely Resolved COPD Exacerbations With Ciprofloxacin, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Finney LJ, Belchamber KBR, Fenwick PS, et al., 2019, Human rhinovirus impairs the innate immune response to bacteria in alveolar macrophages in chronic obstructive pulmonary disease, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 1496-1507, ISSN: 1073-449X
Rationale Human rhinovirus (HRV) is a common cause of COPD exacerbations. Secondary bacterial infection is associated with more severe symptoms and delayed recovery. Alveolar macrophages clear bacteria from the lung and maintain lung homeostasis through cytokine secretion. These processes are defective in COPD. The effect of HRV on macrophage function is unknown. Objectives To investigate the effect of HRV on phagocytosis and cytokine response to bacteria by alveolar macrophages and monocyte derived macrophages (MDM) in COPD and healthy controls. Methods Alveolar macrophages were obtained by bronchoscopy and MDM by adherence. Macrophages were exposed to HRV 16 (multiplicity of infection 5), polyI:C 30μg/ml, interferon (IFN)-β 10μg/ml, IFN-γ 10μg/ml or medium control for 24 hours. Phagocytosis of fluorescently-labelled Haemophilus influenzae or Streptococcus pneumoniae was assessed by fluorimetry. CXCL8, TNF and IL-10 release was measured by ELISA. Main Results HRV significantly impaired phagocytosis of H. influenzae by 23% in MDM (n=37) and 18% in alveolar macrophages (n=20) in COPD. HRV also significantly reduced phagocytosis of S. pneumoniae by 33% in COPD MDM. There was no effect in healthy controls. Phagocytosis of H. influenzae was impaired by polyI:C but not IFN-β or IFN-γ. HRV significantly reduced cytokine responses to H. influenzae. The IL-10 response to H. influenzae was significantly impaired by polyI:C, IFN-β and IFN-γ. Conclusions HRV impairs phagocytosis of bacteria in COPD which may lead to an outgrowth of bacteria. HRV also impairs cytokine responses to bacteria via the TLR3/IFN pathway which may prevent resolution of inflammation leading to prolonged exacerbations in COPD.
Donaldson GC, Witt C, Näyhä S, 2019, Changes in cold-related mortalities between 1995 and 2016 in South East England, Public Health, Vol: 169, Pages: 36-40, ISSN: 0033-3506
OBJECTIVE: The aim of the study was to examine trends in cold-related mortalities between 1995 and 2016. STUDY DESIGN: This is a longitudinal mortality study. METHODS: For men and women aged 65-74 years or those older than 85 years in South East England, the relationship between daily mortality (deaths per million population) and outdoor temperatures below 18 °C, with allowance for influenza epidemics, was assessed by linear regression on an annual basis. The regression coefficients were expressed as a percentage of the mortality at 18 °C to adjust for changes in mortality through health care. Trends in 'specific' cold-related mortalities were then examined over two periods, 1977-1994 and 1995-2016. RESULTS: In contrast to the early period, annual trends in cold-related specific mortalities showed no decline between 1995 and 2016. 'Specific' cold-related mortality of women, but not men, in the age group older than 85 years showed a significant increase over the 1995-2016 period, which was different from the trend over the earlier period (P < 0.01). CONCLUSION: Despite state-funded benefits to help alleviate fuel poverty and public health advice, very elderly women appear to be at increasing risk of cold-related mortality-greater help may be necessary.
Pfeffer PE, Donaldson GC, Mackay AJ, et al., 2019, Increased COPD exacerbations of likely viral etiology follow elevated ambient nitrogen oxides, American Journal of Respiratory and Critical Care Medicine, Vol: 199, ISSN: 1073-449X
RATIONALE: Epidemiological research strongly supports an association between air pollution and COPD exacerbations. Numerous mechanisms may underlie any association as pollutants are toxic to pulmonary cells and may increase susceptibility to respiratory infections. The relationship between ambient pollution and exacerbation etiology has not been studied. OBJECTIVES: To evaluate the characteristics of pollution-associated exacerbations and whether the association is specific to exacerbations of infective or non-infective etiology. METHODS: We analyzed the effect of preceding ambient PM10, NOx and O3 on characterized COPD exacerbations in a regression model adjusted for temperature, seasonality and long-term trend. We specifically examined associations with exacerbations of suspected viral and/or bacterial, or non-infective etiology. For the associations identified we further examined the characteristics of pollution-associated exacerbations. MEASUREMENTS AND MAIN RESULTS: 4173 exacerbations occurred over the 20 year study period. Higher ambient NOx was consistently associated with increased viral-type exacerbations at 2-4 days lag (p=0.010). Recovery for viral-type exacerbations following higher ambient NOx was significantly prolonged. These findings were consistent in the subset of 2841 exacerbations treated with oral corticosteroids or antibiotics, with recovery 1.29 (95% CI 1-17-1.42; P<0.001) times longer with 'viral-type' exacerbations of onset 3 days after above versus below median ambient NOx. A likely bimodal association of PM10 with infective exacerbations was also evident, and supported by a daily time-series analysis. CONCLUSIONS: Higher levels of ambient NOx are associated with prolonged exacerbations of likely viral etiology, supporting toxicological effects of air pollution that increase susceptibility to, and severity of, infection.
Agusti A, Faner R, Donaldson G, et al., 2019, Chronic Airway Diseases Early Stratification (CADSET): a new ERS Clinical Research Collaboration, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
A recent editorial in the European Respiratory Journal highlighted the strategic importance of the Clinical Research Collaborations (CRCs) launched in 2013 by the European Respiratory Society (ERS) . These have the aim of 1) promoting the exchange of research ideas among clinicians and affiliated scientists in Europe and/or globally; 2) building an infrastructure for prospective clinical research; 3) securing additional funding through national and European Union funding streams; and 4) facilitating the planning, implementation, evaluation and publication of clinical and translational studies at pan-European level and beyond. So far, there are currently 17 ongoing CRCs that cover eight major respiratory disease domains (airway diseases, interstitial lung diseases, pulmonary vascular diseases, sleep and breathing disorders, respiratory critical care, paediatric respiratory diseases, respiratory infections and thoracic oncology), all of them linked to one or more ERS assemblies [2–12]. CADSET, an acronym that stands for “Chronic Airway Diseases Early Stratification”, is the latest addition to the list of ongoing CRCs (www.ersnet.org/research/clinical-research-collaborations). This editorial presents the rationale, goals and research strategy for CADSET.
Donaldson GC, Finney L, Wiseman D, et al., 2019, Comparison of Paper and Tablet Based App Diary Cards in COPD Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Ritchie AI, Donaldson GC, El-Emir E, et al., 2019, The British Lung Foundation Early COPD Consortium - Recruitment and Results from an Initial Pilot, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Finney L, Donaldson GC, Wiseman DJ, et al., 2019, Activity Monitoring in COPD: A Feasibility Study, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wiseman DJ, Kamal F, Finney L, et al., 2019, Respiratory Syncytial Virus (RSV) Detection Is Associated with an Increased Inflammatory Response in Stable (non-Exacerbating) Chronic Obstructive Pulmonary Disease (COPD) Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Finney L, Fenwick PS, Kemp S, et al., 2019, Interferon Response to Human Rhinovirus Is Impaired in Alveolar Macrophages but Not Bronchial Epithelial Cells in Chronic Obstructive Pulmonary Disease, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Donaldson GC, Cabrera C, Cappelletti C, et al., 2019, SABA Use Around COPD Symptom-Based Exacerbations in the London COPD Cohort, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Allinson JP, Hardy R, Donaldson GC, et al., 2018, Childhood exposures, asthma, smoking, interactions and the catch-up hypothesis, Annals of the American Thoracic Society, Vol: 15, Pages: 1241-1242, ISSN: 2329-6933
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