Publications
121 results found
Almond M, Farne HA, Jackson MM, et al., 2023, Obesity dysregulates the pulmonary antiviral immune response., Nat Commun, Vol: 14
Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.
Antunes KH, Singanayagam A, Williams L, et al., 2023, Airway-delivered short-chain fatty acid acetate boosts antiviral immunity during rhinovirus infection, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 151, Pages: 447-+, ISSN: 0091-6749
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- Citations: 5
de Souza APD, Singanayagam A, Porto BN, 2023, Editorial: Role of lung and gut microbiota in the immune response against respiratory viral infections, FRONTIERS IN IMMUNOLOGY, Vol: 13, ISSN: 1664-3224
Mekov E, Miravitlles M, Topalovic M, et al., 2023, Stepping Up the Personalized Approach in COPD with Machine Learning, CURRENT RESPIRATORY MEDICINE REVIEWS, Vol: 19, Pages: 165-169, ISSN: 1573-398X
George PM, Reed A, Desai SR, et al., 2022, A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae., Science Translational Medicine, Vol: 14, Pages: 1-16, ISSN: 1946-6234
Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.
Farne H, Glanville N, Johnson N, et al., 2022, Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomized controlled trial, Thorax, Vol: 77, Pages: 950-959, ISSN: 0040-6376
Background and aimsThe CRTH2 antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesized that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomized to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 three weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post-infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant- and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0-14 (difference 3.0 (95% CI -29.0 to 17.0), P=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo- but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events, or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.
Farne H, Lin L, Jackson D, et al., 2022, In vivo bronchial epithelial interferon responses are augmented in asthma on day 4 following experimental rhinovirus infection, Thorax, Vol: 77, Pages: 929-932, ISSN: 0040-6376
Despite good evidence of impaired innate antiviral responses in asthma, trials of inhaled interferon-β given during exacerbations showed only modest benefits in moderate/severe asthma. Using human experimental rhinovirus infection, we observe robust in vivo induction of bronchial epithelial interferon response genes four days after virus inoculation in 25 subjects with asthma but not 11 control subjects. This signature correlated with virus loads and lower respiratory symptoms. Our data indicate that the in vivo innate antiviral response is dysregulated in asthma and open up the potential that prophylactic rather than therapeutic interferon therapy may have greater clinical benefit.
Faiez TS, Singanayagam A, 2022, Down to a T: The Functional Importance of Lymphopenia in Severe COVID-19, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 1370-1372, ISSN: 1073-449X
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- Citations: 1
Gerovasili V, Shah A, Singanayagam A, et al., 2022, Impaired humoral and cellular responses to COVID-19 vaccine in heart and lung transplant recipients, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1476-1479, ISSN: 1073-449X
Morton R, Singanayagam A, 2022, The respiratory tract microbiome: moving from correlation to causation, EUROPEAN RESPIRATORY JOURNAL, Vol: 59, ISSN: 0903-1936
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- Citations: 3
Pinto AL, Rai RK, Brown JC, et al., 2022, Ultrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium, Nature Communications, Vol: 13, Pages: 1-14, ISSN: 2041-1723
Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.
Singanayagam A, Footitt J, Marczynski M, et al., 2022, Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease., Journal of Clinical Investigation, Vol: 132, Pages: 1-16, ISSN: 0021-9738
The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway MUC5AC and MUC5B concentrations during spontaneous and experimentally-induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with virus load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation as Muc5ac-deficient (Muc5ac-/-) mice had attenuated rhinovirus (RV)-induced airway inflammation and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of rhinovirus-induced inflammation in mice. Therapeutic suppression of mucin production using an epidermal growth factor receptor (EGFR) antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identifies a pro-inflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.
Mincham KT, Bruno N, Singanayagam A, et al., 2021, Our evolving view of neutrophils in defining the pathology of chronic lung disease, IMMUNOLOGY, Vol: 164, Pages: 701-721, ISSN: 0019-2805
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- Citations: 14
Prendecki M, Clarke C, Edwards H, et al., 2021, Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression., Annals of the Rheumatic Diseases, Vol: 80, Pages: 1322-1329, ISSN: 0003-4967
OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.
Kamal F, Kumar S, Edwards MR, et al., 2021, Virus-induced volatile organic compounds are detectable in exhaled breath during pulmonary infection., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 1075-1085, ISSN: 1073-449X
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation trigger is important to guide appropriate therapy but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection aetiology. METHODS: We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC production during acute respiratory viral infection. Highly sensitive gas-chromatography mass spectrometry (GC-MS) techniques were used to measure VOC production from infected airway epithelial cell cultures and in exhaled breath samples of healthy subjects experimentally challenged with rhinovirus A16 and COPD subjects with naturally-occurring exacerbations. RESULTS: We identified a novel VOC signature comprising of decane and other related long chain alkane compounds that is induced during rhinovirus infection of cultured airway epithelial cells and is also increased in the exhaled breath of healthy subjects experimentally challenged with rhinovirus and of COPD patients during naturally-occurring viral exacerbations. These compounds correlated with magnitude of anti-viral immune responses, virus burden and exacerbation severity but were not induced by bacterial infection, suggesting they represent a specific virus-inducible signature. CONCLUSION: Our study highlights the potential for measurement of exhaled breath VOCs as rapid, non-invasive biomarkers of viral infection. Further studies are needed to determine whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.
Farne H, Singanayagam A, 2021, Gateway to the lungs: Viral entry receptors and susceptibility to COVID-19, RESPIROLOGY, Vol: 26, Pages: 404-405, ISSN: 1323-7799
Padayachee Y, Faiez TS, Singanayagam A, et al., 2021, Asthma and viruses: A focus on rhinoviruses and SARS-CoV-2, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 147, Pages: 1648-1651, ISSN: 0091-6749
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- Citations: 4
Farne H, Singanayagam A, 2021, Inhaled corticosteroids and angiotensin-converting enzyme-2 in COPD Reply, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 147, Pages: 1117-1118, ISSN: 0091-6749
Brown JC, Goldhill DH, Zhou J, et al., 2021, Increased transmission of SARS-CoV-2 lineage B.1.1.7 (VOC 2020212/01) is not accounted for by a replicative advantage in primary airway cells or antibody escape
<jats:title>Abstract</jats:title><jats:p>Lineage B.1.1.7 (Variant of Concern 202012/01) is a new SARS-CoV-2 variant which was first sequenced in the UK in September 2020 before becoming the majority strain in the UK and spreading worldwide. The rapid spread of the B.1.1.7 variant results from increased transmissibility but the virological characteristics which underpin this advantage over other circulating strains remain unknown. Here, we demonstrate that there is no difference in viral replication between B.1.1.7 and other contemporaneous SARS-CoV-2 strains in primary human airway epithelial (HAE) cells. However, B.1.1.7 replication is disadvantaged in Vero cells potentially due to increased furin-mediated cleavage of its spike protein as a result of a P681H mutation directly adjacent to the S1/S2 cleavage site. In addition, we show that B.1.1.7 does not escape neutralisation by convalescent or post-vaccination sera. Thus, increased transmission of B.1.1.7 is not caused by increased replication, as measured on HAE cells, or escape from serological immunity.</jats:p>
Finney L, Glanville N, Farne H, et al., 2021, Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 510-519.e5, ISSN: 0091-6749
Background: The mechanisms underlying altered susceptibility and propensity to severe Coronavirus disease 2019 (COVID-19) disease in at-risk groups such as patients with chronic obstructive pulmonary disease (COPD) are poorly understood. Inhaled corticosteroids (ICS) are widely used in COPD but the extent to which these therapies protect or expose patients to risk of severe COVID-19 is unknown. Objective: The aim of this study was to evaluate the effect of ICS upon pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme (ACE)-2.Methods: We evaluated the effect of ICS administration upon pulmonary ACE2 expression in vitro in human airway epithelial cell cultures and in vivo in mouse models of ICS administration. Mice deficient in the type I interferon-α/β receptor (Ifnar1−/−) and exogenous interferon-β administration experiments were used to study the functional role of type-I IFN signalling in ACE2 expression. We compared sputum ACE2 expression in patients with COPD stratified according to use or non-use of ICS.ResultsICS administration attenuated ACE2 expression in mice, an effect that was reversed by exogenous interferon-β administration and Ifnar1−/− mice had reduced ACE2 expression, indicating that type I interferon contributes mechanistically to this effect. ICS administration attenuated expression of ACE2 in COPD airway epithelial cell cultures and in mice with elastase-induced COPD-like changes. COPD patients taking ICS also had reduced sputum expression of ACE2 compared to non-ICS users.Conclusion: ICS therapies in COPD reduce expression of the SARS-CoV-2 entry receptor ACE2. This effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD.
Williams TC, Jackson DJ, Maltby S, et al., 2020, Rhinovirus-induced CCL17 and CCL22 in asthma exacerbations and differential regulation by STAT6., American Journal of Respiratory Cell and Molecular Biology, Vol: 64, Pages: 344-356, ISSN: 1044-1549
The interplay of type-2 inflammation and anti-viral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma, however mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild-to-moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then employed to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface (ALI) differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression: increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6 which was required for CCL17, but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-kB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, findings suggest therapeutic targeting of type-2-STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.
Farne H, Singanayagam A, 2020, Why asthma might surprisingly protect against poor outcomes in COVID-19, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936
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- Citations: 26
Singanayagam A, Johnston SL, 2020, Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 146, Pages: 1292-1294, ISSN: 0091-6749
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- Citations: 14
Farne H, Kumar K, Ritchie AI, et al., 2020, Repurposing existing drugs for the treatment of COVID-19, Annals of the American Thoracic Society, Vol: 17, Pages: 1186-1194, ISSN: 1546-3222
The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by SARS-CoV-2 viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist, thus development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and anti-inflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date only dexamethasone and remedesivir have been shown to be effective, but several other promising candidates are in trials.
Kamal F, Glanville N, Xia W, et al., 2020, Beclomethasone has lesser suppressive effects on inflammation and anti-bacterial immunity than Fluticasone or Budesonide in experimental infection models., Chest, Vol: 158, Pages: 947-951, ISSN: 0012-3692
Ritchie AI, Singanayagam A, 2020, Metagenomic Characterization of the Respiratory Microbiome A Piece de Resistance, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 321-322, ISSN: 1073-449X
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- Citations: 3
Kumar K, Losa F, Kebadze T, et al., 2020, Differences in induction of asthma-relevant pro-inflammatory mediators by β2-agonists and muscarinic antagonists in human bronchial epithelial cells, European-Academy-of-Allergology-and-Clinical-Immunology Digital Congress (EAACI), Publisher: WILEY, Pages: 163-164, ISSN: 0105-4538
Finney LJ, Glanville N, Farne H, et al., 2020, Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon
<jats:title>Abstract</jats:title><jats:p>Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a new rapidly spreading infectious disease. Early reports of hospitalised COVID-19 cases have shown relatively low frequency of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) but increased risk of adverse outcome. The mechanisms of altered susceptibility to viral acquisition and/or severe disease in at-risk groups are poorly understood. Inhaled corticosteroids (ICS) are widely used in the treatment of COPD but the extent to which these therapies protect or expose patients with a COPD to risk of increased COVID-19 severity is unknown. Here, using a combination of human and animal<jats:italic>in vitro</jats:italic>and<jats:italic>in vivo</jats:italic>disease models, we show that ICS administration attenuates pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme (ACE)-2. This effect was mechanistically driven by suppression of type I interferon as exogenous interferon-β reversed ACE2 downregulation by ICS. Mice deficient in the type I interferon-α/β receptor (<jats:italic>Ifnar1</jats:italic><jats:sup>−/−</jats:sup>) also had reduced expression of ACE2. Collectively, these data suggest that use of ICS therapies in COPD reduces expression of the SARS-CoV-2 entry receptor ACE2 and this effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD.</jats:p>
Kumar K, Hinks TSC, Singanayagam A, 2020, Treatment of COVID-19-exacerbated asthma: should systemic corticosteroids be used?, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 318, Pages: L1244-L1247, ISSN: 1040-0605
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- Citations: 22
Mathioudakis AG, Janssens W, Sivapalan P, et al., 2020, Acute exacerbations of chronic obstructive pulmonary disease: in search of diagnostic biomarkers and treatable traits, THORAX, Vol: 75, Pages: 520-527, ISSN: 0040-6376
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- Citations: 82
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