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  1. Article ; Online: Anti-acid Therapies in Idiopathic Pulmonary Fibrosis: Premature to Dismiss?

    Crowley, Louise E / Wilson, Andrew / Thickett, David R

    American journal of respiratory and critical care medicine

    2022  Volume 206, Issue 10, Page(s) 1297

    MeSH term(s) Female ; Humans ; Idiopathic Pulmonary Fibrosis/drug therapy ; Premature Birth
    Language English
    Publishing date 2022-08-03
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.202207-1420LE
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Predicting the pulmonary effects of long-term e-cigarette use: are the clouds clearing?

    Davis, Lauren C / Sapey, Elizabeth / Thickett, David R / Scott, Aaron

    European respiratory review : an official journal of the European Respiratory Society

    2022  Volume 31, Issue 163

    Abstract: Commercially available since 2007, e-cigarettes are a popular electronic delivery device of ever-growing complexity. Given their increasing use by ex-smokers, smokers and never-smokers, it is important to evaluate evidence of their potential pulmonary ... ...

    Abstract Commercially available since 2007, e-cigarettes are a popular electronic delivery device of ever-growing complexity. Given their increasing use by ex-smokers, smokers and never-smokers, it is important to evaluate evidence of their potential pulmonary effects and predict effects of long-term use, since there has been insufficient time to study a chronic user cohort. It is crucial to evaluate indicators of harm seen in cigarette use, and those potentially unique to e-cigarette exposure. Evaluation must also account for the vast variation in e-cigarette devices (now including at least five generations of devices) and exposure methods used
    MeSH term(s) Electronic Nicotine Delivery Systems ; Humans ; Longitudinal Studies ; Smokers ; Vaping/adverse effects
    Language English
    Publishing date 2022-01-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1077620-5
    ISSN 1600-0617 ; 0905-9180
    ISSN (online) 1600-0617
    ISSN 0905-9180
    DOI 10.1183/16000617.0121-2021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Observational cohort study protocol: neutrophil function and energetics in adults with pneumonia and sepsis - Pneumonia Metabolism in Ageing (PUMA).

    Grudzinska, Frances S / Faniyi, Aduragbemi A / Scott, Aaron / Sapey, Elizabeth / Thickett, David R

    BMJ open respiratory research

    2023  Volume 10, Issue 1

    Abstract: Introduction: Community-acquired pneumonia has high mortality and is associated with significant healthcare costs. In older adults with community-acquired pneumonia neutrophil dysfunction has been identified and is associated with poor outcomes for ... ...

    Abstract Introduction: Community-acquired pneumonia has high mortality and is associated with significant healthcare costs. In older adults with community-acquired pneumonia neutrophil dysfunction has been identified and is associated with poor outcomes for patients. Immunometabolism is a rapidly developing field which links immune cell function to metabolism. This study aims to explore neutrophil metabolism in community-acquired pneumonia.
    Methods and analysis: Pneumonia Metabolism in Ageing study is a prospective observational study recruiting older adults hospitalised with community-acquired pneumonia to examine neutrophil function and metabolic status. Controls will be older adults with no acute illness. The primary endpoint is neutrophil chemotaxis.
    Ethics and dissemination: The study has ethical approval from the Research Ethics Committee Wales, reference 19/WA/0299. This study involves participants who may lack the capacity to consent to research involvement, in this situation, personal or professional assent will be sought. The results from this study will be submitted for publication in peer-reviewed journals and disseminated at local and international conferences.
    MeSH term(s) Humans ; Aged ; Neutrophils/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Pneumonia/metabolism ; Cohort Studies ; Aging ; Sepsis ; Community-Acquired Infections ; Observational Studies as Topic
    Chemical Substances Apoptosis Regulatory Proteins
    Language English
    Publishing date 2023-10-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2736454-9
    ISSN 2052-4439 ; 2052-4439
    ISSN (online) 2052-4439
    ISSN 2052-4439
    DOI 10.1136/bmjresp-2023-001806
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Understanding potential mechanisms of harm: the drivers of electronic cigarette-induced changes in alveolar macrophages, neutrophils, and lung epithelial cells.

    Jasper, Alice E / Sapey, Elizabeth / Thickett, David R / Scott, Aaron

    American journal of physiology. Lung cellular and molecular physiology

    2021  Volume 321, Issue 2, Page(s) L336–L348

    Abstract: Electronic (e-) cigarettes are growing in popularity despite uncertainties regarding their long-term health implications. The link between cigarette smoking and initiation of chronic lung disease took decades to unpick so in vitro studies mimicking e- ... ...

    Abstract Electronic (e-) cigarettes are growing in popularity despite uncertainties regarding their long-term health implications. The link between cigarette smoking and initiation of chronic lung disease took decades to unpick so in vitro studies mimicking e-cigarette exposure aim to detect early indicators of harm. In response to e-cigarette exposure, alveolar macrophages adopt a proinflammatory phenotype of increased secretion of proinflammatory cytokines, reduction in phagocytosis, and efferocytosis and reactive oxygen species generation. These effects are largely driven by free radical exposure, changes in PI3K/Akt signaling pathways, nicotine-induced reduction in phagocytosis receptors, and impaired lipid homeostasis leading to a foam-like lipid-laden phenotype. Neutrophils exhibit disrupted chemotaxis and transmigration to chemokines, reduced phagocytosis and bacterial killing, and an increase in protease secretion without corresponding antiproteases in response to e-cigarette exposure. This is driven by an altered ability to respond and to polarize toward chemoattractants, an activation of the p38 MAPK signaling pathway and inability to assemble NADPH oxidase. E-cigarettes induce lung epithelial cells to display decreased ciliary beat frequency and ion channel conductance as well as changes in chemokine secretion and surface protein expression. Changes in gene expression, mitochondrial function, and signaling pathways have been demonstrated in lung epithelial cells to explain these changes. Many functional outputs of alveolar macrophages, neutrophils, and lung epithelial cells have not been fully explored in the context of e-cigarette exposure and the underlying driving mechanisms are poorly understood. This review discusses current evidence surrounding the effects of e-cigarettes on alveolar macrophages, neutrophils, and lung epithelial cells with particular focus on the cellular mechanisms of change.
    Language English
    Publishing date 2021-05-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00081.2021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Real-time assessment of neutrophil metabolism and oxidative burst using extracellular flux analysis.

    Grudzinska, Frances S / Jasper, Alice / Sapey, Elizabeth / Thickett, David R / Mauro, Claudio / Scott, Aaron / Barlow, Jonathan

    Frontiers in immunology

    2023  Volume 14, Page(s) 1083072

    Abstract: Neutrophil responses are critical during inflammatory and infective events, and neutrophil dysregulation has been associated with poor patient outcomes. Immunometabolism is a rapidly growing field that has provided insights into cellular functions in ... ...

    Abstract Neutrophil responses are critical during inflammatory and infective events, and neutrophil dysregulation has been associated with poor patient outcomes. Immunometabolism is a rapidly growing field that has provided insights into cellular functions in health and disease. Neutrophils are highly glycolytic when activated, with inhibition of glycolysis associated with functional deficits. There is currently very limited data available assessing metabolism in neutrophils. Extracellular flux (XF) analysis assesses real time oxygen consumption and the rate of proton efflux in cells. This technology allows for the automated addition of inhibitors and stimulants to visualise the effect on metabolism. We describe optimised protocols for an XFe96 XF Analyser to (i) probe glycolysis in neutrophils under basal and stimulated conditions, (ii) probe phorbol 12-myristate 13-acetate induced oxidative burst, and (iii) highlight challenges of using XF technology to examine mitochondrial function in neutrophils. We provide an overview of how to analyze XF data and identify pitfalls of probing neutrophil metabolism with XF analysis. In summary we describe robust methods for assessing glycolysis and oxidative burst in human neutrophils and discuss the challenges around using this technique to assess mitochondrial respiration. XF technology is a powerful platform with a user-friendly interface and data analysis templates, however we suggest caution when assessing neutrophil mitochondrial respiration.
    MeSH term(s) Humans ; Respiratory Burst ; Neutrophils/metabolism ; Oxygen Consumption ; Mitochondria/metabolism
    Language English
    Publishing date 2023-04-25
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1083072
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D

    Thein, Onn Shaun / Ali, Naeman Akbar / Mahida, Rahul Y. / Dancer, Rachel C. A. / Ostermann, Marlies / Amrein, Karin / Martucci, Gennaro / Scott, Aaron / Thickett, David R. / Parekh, Dhruv

    Biology (Basel). 2023 Feb. 14, v. 12, no. 2

    2023  

    Abstract: Background: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) ... ...

    Abstract Background: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) patients. We aimed to determine if there was a similar relationship between FGF23 levels and mortality in critically ill patients. Methods: Plasma FGF23 levels were measured by ELISA in two separate cohorts of patients receiving vitamin D supplementation: critical illness patients (VITdAL-ICU trial, n = 475) and elective oesophagectomy patients (VINDALOO trial, n = 76). Mortality data were recorded at 30 and 180 days or at two years, respectively. FGF23 levels in a healthy control cohort were also measured (n = 27). Results: Elevated FGF23 (quartile 4 vs. quartiles 1–3) was associated with increased short-term (30 and 180 day) mortality in critical illness patients (p < 0.001) and long-term (two-year) mortality in oesophagectomy patients (p = 0.0149). Patients who died had significantly higher FGF23 levels than those who survived: In the critical illness cohort, those who died had 1194.6 pg/mL (range 0–14,000), while those who survived had 120.4 pg/mL (range = 15–14,000) (p = 0.0462). In the oesophagectomy cohort, those who died had 1304 pg/mL (range = 154–77,800), while those who survived had 644 pg/mL (range = 179–54,894) (p < 0.001). This was found to be independent of vitamin D or CKD status (critical illness p = 0.3507; oesophagectomy p = 0.3800). FGF23 levels in healthy controls were similar to those seen in oesophagectomy patients (p = 0.4802). Conclusions: Elevated baseline serum FGF23 is correlated with increased mortality in both the post-oesophagectomy cohort and the cohort of patients with critical illness requiring intensive care admission. This was independent of vitamin D status, supplementation, or CKD status, which suggests the presence of vitamin D-independent mechanisms of FGF23 action during the acute and convalescent stages of critical illness, warranting further investigation.
    Keywords blood serum ; calcium ; fibroblast growth factors ; homeostasis ; kidney diseases ; mortality ; phosphates ; risk factors ; vitamin D
    Language English
    Dates of publication 2023-0214
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article ; Online
    ZDB-ID 2661517-4
    ISSN 2079-7737
    ISSN 2079-7737
    DOI 10.3390/biology12020309
    Database NAL-Catalogue (AGRICOLA)

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  7. Article ; Online: A scalable federated learning solution for secondary care using low-cost microcomputing: privacy-preserving development and evaluation of a COVID-19 screening test in UK hospitals.

    Soltan, Andrew A S / Thakur, Anshul / Yang, Jenny / Chauhan, Anoop / D'Cruz, Leon G / Dickson, Phillip / Soltan, Marina A / Thickett, David R / Eyre, David W / Zhu, Tingting / Clifton, David A

    The Lancet. Digital health

    2024  Volume 6, Issue 2, Page(s) e93–e104

    Abstract: Background: Multicentre training could reduce biases in medical artificial intelligence (AI); however, ethical, legal, and technical considerations can constrain the ability of hospitals to share data. Federated learning enables institutions to ... ...

    Abstract Background: Multicentre training could reduce biases in medical artificial intelligence (AI); however, ethical, legal, and technical considerations can constrain the ability of hospitals to share data. Federated learning enables institutions to participate in algorithm development while retaining custody of their data but uptake in hospitals has been limited, possibly as deployment requires specialist software and technical expertise at each site. We previously developed an artificial intelligence-driven screening test for COVID-19 in emergency departments, known as CURIAL-Lab, which uses vital signs and blood tests that are routinely available within 1 h of a patient's arrival. Here we aimed to federate our COVID-19 screening test by developing an easy-to-use embedded system-which we introduce as full-stack federated learning-to train and evaluate machine learning models across four UK hospital groups without centralising patient data.
    Methods: We supplied a Raspberry Pi 4 Model B preloaded with our federated learning software pipeline to four National Health Service (NHS) hospital groups in the UK: Oxford University Hospitals NHS Foundation Trust (OUH; through the locally linked research University, University of Oxford), University Hospitals Birmingham NHS Foundation Trust (UHB), Bedfordshire Hospitals NHS Foundation Trust (BH), and Portsmouth Hospitals University NHS Trust (PUH). OUH, PUH, and UHB participated in federated training, training a deep neural network and logistic regressor over 150 rounds to form and calibrate a global model to predict COVID-19 status, using clinical data from patients admitted before the pandemic (COVID-19-negative) and testing positive for COVID-19 during the first wave of the pandemic. We conducted a federated evaluation of the global model for admissions during the second wave of the pandemic at OUH, PUH, and externally at BH. For OUH and PUH, we additionally performed local fine-tuning of the global model using the sites' individual training data, forming a site-tuned model, and evaluated the resultant model for admissions during the second wave of the pandemic. This study included data collected between Dec 1, 2018, and March 1, 2021; the exact date ranges used varied by site. The primary outcome was overall model performance, measured as the area under the receiver operating characteristic curve (AUROC). Removable micro secure digital (microSD) storage was destroyed on study completion.
    Findings: Clinical data from 130 941 patients (1772 COVID-19-positive), routinely collected across three hospital groups (OUH, PUH, and UHB), were included in federated training. The evaluation step included data from 32 986 patients (3549 COVID-19-positive) attending OUH, PUH, or BH during the second wave of the pandemic. Federated training of a global deep neural network classifier improved upon performance of models trained locally in terms of AUROC by a mean of 27·6% (SD 2·2): AUROC increased from 0·574 (95% CI 0·560-0·589) at OUH and 0·622 (0·608-0·637) at PUH using the locally trained models to 0·872 (0·862-0·882) at OUH and 0·876 (0·865-0·886) at PUH using the federated global model. Performance improvement was smaller for a logistic regression model, with a mean increase in AUROC of 13·9% (0·5%). During federated external evaluation at BH, AUROC for the global deep neural network model was 0·917 (0·893-0·942), with 89·7% sensitivity (83·6-93·6) and 76·6% specificity (73·9-79·1). Site-specific tuning of the global model did not significantly improve performance (change in AUROC <0·01).
    Interpretation: We developed an embedded system for federated learning, using microcomputing to optimise for ease of deployment. We deployed full-stack federated learning across four UK hospital groups to develop a COVID-19 screening test without centralising patient data. Federation improved model performance, and the resultant global models were generalisable. Full-stack federated learning could enable hospitals to contribute to AI development at low cost and without specialist technical expertise at each site.
    Funding: The Wellcome Trust, University of Oxford Medical and Life Sciences Translational Fund.
    MeSH term(s) Humans ; Secondary Care ; Artificial Intelligence ; Privacy ; State Medicine ; COVID-19/diagnosis ; Hospitals ; United Kingdom
    Language English
    Publishing date 2024-01-26
    Publishing country England
    Document type Journal Article
    ISSN 2589-7500
    ISSN (online) 2589-7500
    DOI 10.1016/S2589-7500(23)00226-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease.

    Lugg, Sebastian T / Scott, Aaron / Parekh, Dhruv / Naidu, Babu / Thickett, David R

    Thorax

    2021  Volume 77, Issue 1, Page(s) 94–101

    Abstract: Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the ... ...

    Abstract Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the interface between the airway lumen and the alveolar spaces. These are the most abundant immune cells and are the first line of defence against inhaled particulates and pathogens. Recently, there has been a better understanding about the ontogeny, phenotype and function of alveolar macrophages and their role, not only in phagocytosis, but also in initiating and resolving immune response. Many of the functions of the alveolar macrophage have been shown to be dysregulated following exposure to cigarette smoke. While the mechanisms for these changes remain poorly understood, they are important in the understanding of cigarette smoking-induced lung disease. We review the mechanisms by which smoking influences alveolar macrophage: (1) recruitment, (2) phenotype, (3) immune function (bacterial killing, phagocytosis, proteinase/anti-proteinase release and reactive oxygen species production) and (4) homeostasis (surfactant/lipid processing, iron homeostasis and efferocytosis). Further understanding of the mechanisms of cigarette smoking on alveolar macrophages and other lung monocyte/macrophage populations may allow novel ways of restoring cellular function in those patients who have stopped smoking in order to reduce the risk of subsequent infection or further lung injury.
    MeSH term(s) Humans ; Lung ; Macrophages, Alveolar ; Phagocytosis ; Pneumonia ; Smoke ; Smoking/adverse effects
    Chemical Substances Smoke
    Language English
    Publishing date 2021-05-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 204353-1
    ISSN 1468-3296 ; 0040-6376
    ISSN (online) 1468-3296
    ISSN 0040-6376
    DOI 10.1136/thoraxjnl-2020-216296
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: CD14-positive extracellular vesicles in bronchoalveolar lavage fluid as a new biomarker of acute respiratory distress syndrome.

    Mahida, Rahul Y / Price, Joshua / Lugg, Sebastian T / Li, Hui / Parekh, Dhruv / Scott, Aaron / Harrison, Paul / Matthay, Michael A / Thickett, David R

    American journal of physiology. Lung cellular and molecular physiology

    2022  Volume 322, Issue 4, Page(s) L617–L624

    Abstract: Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary ... ...

    Abstract Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within bronchoalveolar lavage (BAL) fluid of patients with ARDS, and to determine whether BAL EV could be used as a potential biomarker in ARDS. BAL was collected from patients with sepsis with and without ARDS, and from esophagectomy patients postoperatively (of whom a subset later developed ARDS during hospital admission). BAL EVs were characterized with regard to size, number, and cell of origin. Patients with sepsis-related ARDS had significantly higher numbers of CD14
    MeSH term(s) Biomarkers ; Bronchoalveolar Lavage Fluid ; Extracellular Vesicles ; Humans ; Respiratory Distress Syndrome ; Sepsis/diagnosis
    Chemical Substances Biomarkers
    Language English
    Publishing date 2022-03-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00052.2022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Mepolizumab rescue therapy for acute pneumonitis secondary to DRESS.

    Thein, Onn Shaun / Sutton, Benjamin / Thickett, David R / Parekh, Dhruv

    BMJ case reports

    2019  Volume 12, Issue 10

    Abstract: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe adverse drug reaction driven by eosinophilia. Treatment is focused on withdrawal of medication, supportive care and immunosuppression such as high-dose ... ...

    Abstract Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe adverse drug reaction driven by eosinophilia. Treatment is focused on withdrawal of medication, supportive care and immunosuppression such as high-dose corticosteroid therapy. Here we report a 56-year-old male patient who initially presented with breathlessness and eosinophilia, subsequent development of respiratory failure and admission to ITU for non-invasive ventilation. The patient continued to deteriorate despite high-dose prednisolone and methylprednisolone. Other causes of hypereosinophilia were normal. He was diagnosed with DRESS syndrome secondary to pregabalin and was treated with subcutaneous mepolizumab. We observed the rapid resolution of eosinophilia and clinical improvement; the patient was discharged home within a month of administration. This represents the successful use of mepolizumab in the acute setting of pulmonary failure secondary to DRESS. A similar approach could be adopted in other acute conditions with refractory eosinophilic inflammation where standard steroid therapy has failed.
    MeSH term(s) Antibodies, Monoclonal, Humanized/therapeutic use ; Diagnosis, Differential ; Drug Hypersensitivity Syndrome/complications ; Eosinophilia/complications ; Eosinophilia/drug therapy ; Humans ; Male ; Middle Aged ; Pneumonia/drug therapy ; Pneumonia/etiology ; Pregabalin/adverse effects
    Chemical Substances Antibodies, Monoclonal, Humanized ; Pregabalin (55JG375S6M) ; mepolizumab (90Z2UF0E52)
    Language English
    Publishing date 2019-10-10
    Publishing country England
    Document type Case Reports ; Journal Article
    ISSN 1757-790X
    ISSN (online) 1757-790X
    DOI 10.1136/bcr-2019-231355
    Database MEDical Literature Analysis and Retrieval System OnLINE

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