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Muala, Ala
Publications (10 of 13) Show all publications
Lepzien, R., Rankin, G., Pourazar, J., Muala, A., Eklund, A., Grunewald, J., . . . Smed-Sorensen, A. (2019). Mapping mononuclear phagocytes in blood, lungs, and lymph nodes of sarcoidosis patients. Journal of Leukocyte Biology, 105(4), 797-807
Open this publication in new window or tab >>Mapping mononuclear phagocytes in blood, lungs, and lymph nodes of sarcoidosis patients
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2019 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 105, no 4, p. 797-807Article in journal (Refereed) Published
Abstract [en]

Sarcoidosis is a T-cell driven inflammatory disease characterized by granuloma formation. Mononuclear phagocytes (MNPs)-macrophages, monocytes, and dendritic cells (DCs)-are likely critical in sarcoidosis as they initiate and maintain T cell activation and contribute to granuloma formation by cytokine production. Granulomas manifest primarily in lungs and lung-draining lymph nodes (LLNs) but these compartments are less studied compared to blood and bronchoalveolar lavage (BAL). Sarcoidosis can present with an acute onset (usually Lofgren's syndrome (LS)) or a gradual onset (non-LS). LS patients typically recover within 2 years while 60% of non-LS patients maintain granulomas for up to 5 years. Here, four LS and seven non-LS patients underwent bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). From each patient, blood, BAL, endobronchial biopsies (EBBs), and LLN samples obtained by EBUS-TBNA were collected and MNPs characterized using multicolor flow cytometry. Six MNP subsets were identified at varying frequencies in the anatomical compartments investigated. Importantly, monocytes and DCs were most mature with migratory potential in BAL and EBBs but not in the LLNs suggesting heterogeneity in MNPs in the compartments typically affected in sarcoidosis. Additionally, in LS patients, frequencies of DC subsets were lower or lacking in LLNs and EBBs, respectively, compared to non-LS patients that may be related to the disease outcome. Our work provides a foundation for future investigations of MNPs in sarcoidosis to identify immune profiles of patients at risk of developing severe disease with the aim to provide early treatment to slow down disease progression.

Place, publisher, year, edition, pages
Society for Leukocyte Biology, 2019
Keywords
dendritic cell, monocyte, sarcoidosis, lymph node, Lofgren's syndrome
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-158084 (URN)10.1002/JLB.5A0718-280RR (DOI)000462155000015 ()30742337 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research Council
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-04-15Bibliographically approved
Uski, O., Rankin, G., Lindgren, R., Lopez, N., Blomberg, A., Muala, A., . . . Sandström, T. (2018). In vitro toxicity of particulate matter derived from biomass cook stoves used in developing countries. Paper presented at International Conference of the American-Thoracic-Society, MAY 18-23, 2018, San Diego, CA. American Journal of Respiratory and Critical Care Medicine, 197
Open this publication in new window or tab >>In vitro toxicity of particulate matter derived from biomass cook stoves used in developing countries
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2018 (English)In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 197Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Thoraric Society, 2018
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-154090 (URN)000449978902089 ()
Conference
International Conference of the American-Thoracic-Society, MAY 18-23, 2018, San Diego, CA
Funder
Forte, Swedish Research Council for Health, Working Life and WelfareSwedish Heart Lung Foundation
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved
Lepzien, R., Rankin, G., Pourazar, J., Muala, A., Eklund, A., Grunewald, J., . . . Sörensen, A. S. (2018). Mononuclear phagocytes in lungs, lymph nodes and blood of sarcoidosis patients. Paper presented at 28th International Congress of the European-Respiratory-Society (ERS), SEP 15-19, 2018, Paris, FRANCE. European Respiratory Journal, 52
Open this publication in new window or tab >>Mononuclear phagocytes in lungs, lymph nodes and blood of sarcoidosis patients
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2018 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 52Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Sarcoidosis is characterized by granuloma formation primarily in the lung and lung-draining lymph nodes (LN). The disease can present with an acute onset (usually Löfgren’s syndrome (LS)) or a gradual onset (non-LS). Mononuclear phagocytes (MNPs) - macrophages, monocytes and dendritic cells (DC) - are likely critical in sarcoidosis as they initiate and maintain T cell activation and contribute to granuloma formation by production of cytokines. MNPs in lung tissue and LN are poorly studied in both, non-LS and LS sarcoidosis patients.

Aim: To characterise the distribution and phenotype of MNPs in BAL, endobronchial biopsies (EBB), LN sampled by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and blood from the same non-LS or LS sarcoidosis patients.

Results: We identified MNPs from all four anatomical compartments in non-LS (n=7) and LS (n=4) sarcoidosis patients. Blood, BAL and LN contained all MNP subsets while EBB only harboured one of three monocyte subsets. Frequencies, maturation and migratory status were different between the compartments as well as between non-LS and LS patients. Our results suggest heterogeneity in distribution and function of MNPs within organs typically affected in sarcoidosis and their potential involvement in the disease course.

Conclusions: We show that cells from BAL fluid do not necessarily reflect cells from EBB, a tissue primarily affected by granuloma formation. Our work provides a foundation for future investigations of MNPs in non-LS and LS sarcoidosis patients, allowing improved stratification to identify patients at risk of developing severe disease and provide early treatment to slow down disease progression.

Place, publisher, year, edition, pages
European Respiratory Society, 2018
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-156002 (URN)10.1183/13993003.congress-2018.PA5205 (DOI)000455567107030 ()
Conference
28th International Congress of the European-Respiratory-Society (ERS), SEP 15-19, 2018, Paris, FRANCE
Note

Supplement: 62

Meeting Abstract: PA5205

Available from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically approved
Pourazar, J., Rankin, G. D., Muala, A., Unosson, J., Sehlstedt, M., Behndig, A. F., . . . Sandstrom, T. (2016). Bronchoalveolar Eosinophilia In Human Subjects After Exposure To Biomass Smoke From Wood Pellet Combustion. In: : . Paper presented at International Conference of the American-Thoracic-Society (ATS), MAY 13-18, 2016, San Francisco, CA. , 193
Open this publication in new window or tab >>Bronchoalveolar Eosinophilia In Human Subjects After Exposure To Biomass Smoke From Wood Pellet Combustion
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2016 (English)Conference paper, Oral presentation with published abstract (Refereed)
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-131011 (URN)000390749607595 ()
Conference
International Conference of the American-Thoracic-Society (ATS), MAY 13-18, 2016, San Francisco, CA
Available from: 2017-02-09 Created: 2017-02-09 Last updated: 2018-06-09Bibliographically approved
Muala, A., Rankin, G., Sehlstedt, M., Unosson, J., Bosson, J. A., Behndig, A., . . . Sandström, T. (2015). Acute exposure to wood smoke from incomplete combustion - indications of cytotoxicity. Particle and Fibre Toxicology, 12, Article ID 33.
Open this publication in new window or tab >>Acute exposure to wood smoke from incomplete combustion - indications of cytotoxicity
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2015 (English)In: Particle and Fibre Toxicology, ISSN 1743-8977, E-ISSN 1743-8977, Vol. 12, article id 33Article in journal (Refereed) Published
Abstract [en]

Background: Smoke from combustion of biomass fuels is a major risk factor for respiratory disease, but the underlying mechanisms are poorly understood. The aim of this study was to determine whether exposure to wood smoke from incomplete combustion would elicit airway inflammation in humans. Methods: Fourteen healthy subjects underwent controlled exposures on two separate occasions to filtered air and wood smoke from incomplete combustion with PM1 concentration at 314 mu g/m(3) for 3 h in a chamber. Bronchoscopy with bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial mucosal biopsies was performed after 24 h. Differential cell counts and soluble components were analyzed, with biopsies stained for inflammatory markers using immunohistochemistry. In parallel experiments, the toxicity of the particulate matter (PM) generated during the chamber exposures was investigated in vitro using the RAW264.7 macrophage cell line. Results: Significant reductions in macrophage, neutrophil and lymphocyte numbers were observed in BW (p < 0.01, < 0.05, < 0.05, respectively) following the wood smoke exposure, with a reduction in lymphocytes numbers in BAL fluid (< 0.01. This unexpected cellular response was accompanied by decreased levels of sICAM-1, MPO and MMP-9 (p < 0.05, < 0.05 and < 0.01). In contrast, significant increases in submucosal and epithelial CD3+ cells, epithelial CD8+ cells and submucosal mast cells (p < 0.01, < 0.05, < 0.05 and < 0.05, respectively), were observed after wood smoke exposure. The in vitro data demonstrated that wood smoke particles generated under these incomplete combustion conditions induced cell death and DNA damage, with only minor inflammatory responses. Conclusions: Short-term exposure to sooty PAH rich wood smoke did not induce an acute neutrophilic inflammation, a classic hallmark of air pollution exposure in humans. While minor proinflammatory lymphocytic and mast cells effects were observed in the bronchial biopsies, significant reductions in BW and BAL cells and soluble components were noted. This unexpected observation, combined with the in vitro data, suggests that wood smoke particles from incomplete combustion could be potentially cytotoxic. Additional research is required to establish the mechanism of this dramatic reduction in airway leukocytes and to clarify how this acute response contributes to the adverse health effects attributed to wood smoke exposure.

Keywords
Air pollution, Biomass, Bronchoscopy, Cytotoxicity, Neutrophils, Lymphocytes, Mast cells
National Category
Environmental Sciences
Identifiers
urn:nbn:se:umu:diva-111761 (URN)10.1186/s12989-015-0111-7 (DOI)000363833500001 ()26511835 (PubMedID)2-s2.0-84945908415 (Scopus ID)
Available from: 2015-11-25 Created: 2015-11-23 Last updated: 2018-06-07Bibliographically approved
Pourazar, J., Behndig, A. F., Helleday, R., Muala, A., Rankin, G., Sehlstedt, M., . . . Bosson, J. A. (2015). Airway Inflammatory Response In Healthy Subjects Following Chamber Exposure To 100% Rme Biodiesel. Paper presented at International Conference of the American-Thoracic-Society (ATS), MAY 15-20, 2015, Denver, CO. American Journal of Respiratory and Critical Care Medicine, 191, Article ID A5252.
Open this publication in new window or tab >>Airway Inflammatory Response In Healthy Subjects Following Chamber Exposure To 100% Rme Biodiesel
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2015 (English)In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 191, article id A5252Article in journal, Meeting abstract (Other academic) Published
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-123483 (URN)000377582807072 ()
Conference
International Conference of the American-Thoracic-Society (ATS), MAY 15-20, 2015, Denver, CO
Available from: 2016-07-06 Created: 2016-07-04 Last updated: 2018-06-07Bibliographically approved
Muala, A., Nicklasson, H., Boman, C., Swietlicki, E., Nyström, R., Pettersson, E., . . . Löndahl, J. (2015). Respiratory Tract Deposition of Inhaled Wood Smoke Particles in Healthy Volunteers. Journal of Aerosol Medicine, 28(4), 237-246
Open this publication in new window or tab >>Respiratory Tract Deposition of Inhaled Wood Smoke Particles in Healthy Volunteers
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2015 (English)In: Journal of Aerosol Medicine, ISSN 1941-2711, E-ISSN 1941-2703, Vol. 28, no 4, p. 237-246Article in journal (Refereed) Published
Abstract [en]

Background: Respiratory tract deposition of air pollution particles is a key to their adverse health effects. This study was aimed to determine the size-resolved deposition fraction (DF) of sooty wood smoke particles in the lungs of healthy subjects. The type of wood smoke investigated is typical for household air pollution from solid fuels, which is among the largest environmental health problems globally.

Methods: Twelve healthy volunteers inhaled diluted wood smoke from incomplete soot-rich combustion in a common wood stove. The DF of smoke particles (10–500 nm) was measured during three 15-min exposures in each subject during spontaneous breathing. Lung function was measured using standard spirometry.

Results: The total DFs by particle number concentration were 0.34±0.08. This can be compared with DFs of 0.21–0.23 in healthy subjects during previous experiments with wood pellet combustion. For particle mass, the total DFs found in this study were 0.22±0.06. DF and breathing frequency were negatively correlated as expected from model calculations (p<0.01).

Conclusions: The DF of the investigated sooty wood smoke particles was higher than for previously investigated particles generated during more efficient combustion of biomass. Together with toxicological studies, which have indicated that incomplete biomass combustion particles rich in soot and polycyclic aromatic hydrocarbons (PAHs) are especially harmful, these data highlight the health risks of inadequate wood combustion.

Keywords
aerosol, biomass combustion, effective density, lung deposition, nanoparticles, toxicity
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-88608 (URN)10.1089/jamp.2014.1122 (DOI)000359795000001 ()
Note

Originally included in thesis in submitted form with the title "Respiratory tract deposition of inhaled wood smoke particles in healthy volunteers and subjects with COPD"

Available from: 2014-05-11 Created: 2014-05-11 Last updated: 2018-06-07Bibliographically approved
Muala, A., Sehlstedt, M., Bion, A., Österlund, C., Bosson, J. A., Behndig, A. F., . . . Sandström, T. (2014). Assessment of the capacity of vehicle cabin air inlet filters to reduce diesel exhaust-induced symptoms in human volunteers. Environmental health, 13(1), Article ID 16.
Open this publication in new window or tab >>Assessment of the capacity of vehicle cabin air inlet filters to reduce diesel exhaust-induced symptoms in human volunteers
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2014 (English)In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 13, no 1, article id 16Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Exposure to particulate matter (PM) air pollution especially derived from traffic is associated with increases in cardiorespiratory morbidity and mortality. In this study, we evaluated the ability of novel vehicle cabin air inlet filters to reduce diesel exhaust (DE)-induced symptoms and markers of inflammation in human subjects.

METHODS: Thirty healthy subjects participated in a randomized double-blind controlled crossover study where they were exposed to filtered air, unfiltered DE and DE filtered through two selected particle filters, one with and one without active charcoal. Exposures lasted for one hour. Symptoms were assessed before and during exposures and lung function was measured before and after each exposure, with inflammation assessed in peripheral blood five hours after exposures. In parallel, PM were collected from unfiltered and filtered DE and assessed for their capacity to drive damaging oxidation reactions in a cell-free model, or promote inflammation in A549 cells.

RESULTS: The standard particle filter employed in this study reduced PM10 mass concentrations within the exposure chamber by 46%, further reduced to 74% by the inclusion of an active charcoal component. In addition use of the active charcoal filter was associated by a 75% and 50% reduction in NO2 and hydrocarbon concentrations, respectively. As expected, subjects reported more subjective symptoms after exposure to unfiltered DE compared to filtered air, which was significantly reduced by the filter with an active charcoal component. There were no significant changes in lung function after exposures. Similarly diesel exhaust did not elicit significant increases in any of the inflammatory markers examined in the peripheral blood samples 5 hour post-exposure. Whilst the filters reduced chamber particle concentrations, the oxidative activity of the particles themselves, did not change following filtration with either filter. In contrast, diesel exhaust PM passed through the active charcoal combination filter appeared less inflammatory to A549 cells.

CONCLUSIONS: A cabin air inlet particle filter including an active charcoal component was highly effective in reducing both DE particulate and gaseous components, with reduced exhaust-induced symptoms in healthy volunteers. These data demonstrate the effectiveness of cabin filters to protect subjects travelling in vehicles from diesel exhaust emissions.

Place, publisher, year, edition, pages
BioMed Central, 2014
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-88557 (URN)10.1186/1476-069X-13-16 (DOI)000334547200001 ()24621126 (PubMedID)
Available from: 2014-05-08 Created: 2014-05-08 Last updated: 2018-06-07Bibliographically approved
Muala, A. (2014). Diesel exhaust and wood smoke: mechanisms, inflammation and intervention. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>Diesel exhaust and wood smoke: mechanisms, inflammation and intervention
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Particulate matter (PM) air pollution is associated with increased respiratory and cardiovascular morbidity and mortality. Diesel engine exhaust (DE) and wood combustion are major contributors to ambient air pollution and adverse health effects. The aim of this thesis was to investigate the fate of inhaled combustion-derived PM, the subsequent effects on pulmonary inflammation and symptomatology and to explore the potential for particle filters to improve public health. Additionally, it aimed at increasing the understanding of the pathophysiological mechanisms underlying the adverse vascular effects of PM inhalation in man.

Methods In study I, lung deposition of wood smoke-derived particulates from incomplete combustion was determined in healthy and COPD subjects. In study II, airway inflammation was assessed in healthy subjects exposed to wood smoke and filtered air. In study III, vehicle cabin air inlet filters were evaluated regarding filtering capacity for DE and whether they affected the toxicological potential of the filtered PM. Healthy subjects were then exposed to filtered air and unfiltered DE, as well as DE filtered through two selected filters. In study IV, healthy subjects were exposed to filtered air and DE. Nitric oxide bioavailability was assessed by plethysmography in the presence of an NO clamp (NO synthase inhibitor NG-monomethyl locally and systemically administered) with measurements of arterial stiffness, cardiac output and blood pressure (BP).

Results Study I: The total PM number deposition fraction of the wood smoke was 0.32 and 0.35 for healthy and COPD subjects respectively. Study II: Inhalation of wood smoke caused CD3+ and mast cell infiltration in the bronchial submucosa along with CD8+ cell recruitment to the epithelium. In bronchial wash, inflammatory cells, myeloperoxidase and matrix metalloproteinase 9 levels decreased. Study III: An efficient cabin air filter with an active charcoal component was most favourable in in-vitro tests and reduced symptoms in the human exposure study. Study IV: Local NO synthase inhibition caused similar vasoconstriction after exposure to DE and filtered air, along with an increase in plasma nitrate concentrations, suggesting an increase in the basal NO release due to oxidative stress. Systemic NO synthase inhibition increased arterial stiffness and blood pressure after DE exposure along with an increase in systemic vascular resistance and reduced cardiac output, implying that the increased basal NO release could not compensate for the reduced NO bioavailability in the conduit vessels.

Conclusion Wood smoke particles from incomplete combustion tend to have a greater airway deposition than particles from better combustion. The airway inflammatory responses to the former particles differ from what have been shown for other PM pollutants, which may be of importance for subsequent health effects. The vasomotor dysfunction shown after DE exposure may largely be explained by reduced NO bioavailability. A vehicle cabin air inlet particle filter with active charcoal was effective to reduce DE exposure and subsequent symptoms. This may conceptually be of benefit when it comes to decreasing engine exhaust-related adverse health effects.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. p. 85
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1641
Keywords
Air pollution, deposition, bronchoscopy, Immunohistochemstry, filter, NO bioavailability
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-88614 (URN)978-91-7601-028-0 (ISBN)
Public defence
2014-06-05, Hörsal Betula, byggnad 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2014-05-13 Created: 2014-05-11 Last updated: 2018-06-07Bibliographically approved
diva2:675439
Open this publication in new window or tab >>Altered nitric oxide bioavailability contributes to diesel exhaust inhalation-induced cardiovascular dysfunction in man
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2013 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 2, no 1, p. e004309-Article in journal (Refereed) Published
Abstract [en]

Background Diesel exhaust inhalation causes cardiovascular dysfunction including impaired vascular reactivity, increased blood pressure, and arterial stiffness. We investigated the role of nitric oxide (NO) bioavailability in mediating these effects.

Methods and Results In 2 randomized double-blind crossover studies, healthy nonsmokers were exposed to diesel exhaust or filtered air. Study 1: Bilateral forearm blood flow was measured during intrabrachial infusions of acetylcholine (ACh; 5 to 20 mu g/min) and sodium nitroprusside (SNP; 2 to 8 mu g/min) in the presence of the NO clamp (NO synthase inhibitor N-G-monomethyl-L-arginine (L-NMMA) 8 mu g/min coinfused with the NO donor SNP at 90 to 540 ng/min to restore basal blood flow). Study 2: Blood pressure, arterial stiffness, and cardiac output were measured during systemic NO synthase inhibition with intravenous L-NMMA (3 mg/kg). Following diesel exhaust inhalation, plasma nitrite concentrations were increased (68 +/- 48 versus 41 +/- 32 nmol/L; P=0.006) despite similar L-NMMA-induced reductions in basal blood flow (-20.6 +/- 14.7% versus -21.1 +/- 14.6%; P=0.559) compared to air. In the presence of the NO clamp, ACh and SNP caused dose-dependent vasodilatation that was not affected by diesel exhaust inhalation (P>0.05 for both). Following exposure to diesel exhaust, L-NMMA caused a greater increase in blood pressure (P=0.048) and central arterial stiffness (P=0.007), but reductions in cardiac output and increases in systemic vascular resistance (P>0.05 for both) were similar to those seen with filtered air.

Conclusions Diesel exhaust inhalation disturbs normal vascular homeostasis with enhanced NO generation unable to compensate for excess consumption. We suggest the adverse cardiovascular effects of air pollution are, in part, mediated through reduced NO bioavailability.

Place, publisher, year, edition, pages
American stroke association, 2013
Keywords
air pollution, endothelial function, nitric oxide, nitric oxide synthase, vascular biology
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-83653 (URN)10.1161/JAHA.112.004309 (DOI)000326336800023 ()
Funder
Swedish Heart Lung Foundation
Available from: 2013-12-03 Created: 2013-12-03 Last updated: 2018-06-08Bibliographically approved
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