Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis
Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extr...
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| Veröffentlicht in: | The Journal of clinical investigation 2020-11, Vol.130 (11), p.6151-6157 |
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| creator | Skendros, Panagiotis Mitsios, Alexandros Chrysanthopoulou, Akrivi Mastellos, Dimitrios C Metallidis, Simeon Rafailidis, Petros Ntinopoulou, Maria Sertaridou, Eleni Tsironidou, Victoria Tsigalou, Christina Tektonidou, Maria Konstantinidis, Theocharis Papagoras, Charalampos Mitroulis, Ioannis Germanidis, Georgios Lambris, John D Ritis, Konstantinos |
| description | Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition. |
| doi_str_mv | 10.1172/JCI141374 |
| format | Article |
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Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI141374</identifier><identifier>PMID: 32759504</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Aged ; Aorta ; Autophagy ; Betacoronavirus - immunology ; Betacoronavirus - metabolism ; Biomedical research ; Complement activation ; Complement Activation - drug effects ; Complement component C3 ; Complement Membrane Attack Complex - immunology ; Complement Membrane Attack Complex - metabolism ; Complement system ; Complications and side effects ; Concise Communication ; Coronaviridae ; Coronavirus Infections - blood ; Coronavirus Infections - immunology ; Coronaviruses ; COVID-19 ; Development and progression ; Endothelial cells ; Extracellular Traps - immunology ; Extracellular Traps - metabolism ; Female ; Health aspects ; Humans ; Immune response ; Investigations ; Leukocytes (neutrophilic) ; Male ; Middle Aged ; Mortality ; Neutrophils ; Neutrophils - immunology ; Neutrophils - metabolism ; Pandemics ; Patients ; Peptides, Cyclic - pharmacology ; Plasma ; Plasma levels ; Platelets ; Pneumonia, Viral - blood ; Pneumonia, Viral - immunology ; Receptor, Anaphylatoxin C5a - antagonists & inhibitors ; Receptor, Anaphylatoxin C5a - blood ; Receptor, Anaphylatoxin C5a - immunology ; Respiratory Distress Syndrome - blood ; Respiratory Distress Syndrome - immunology ; Respiratory Distress Syndrome - virology ; Risk factors ; SARS-CoV-2 ; Severe acute respiratory syndrome coronavirus 2 ; Thrombin ; Thrombin - immunology ; Thrombin - metabolism ; Thromboplastin - immunology ; Thromboplastin - metabolism ; Thrombosis ; Thrombosis - blood ; Thrombosis - immunology ; Thrombosis - virology ; Thrombotic microangiopathy ; Tissue factor</subject><ispartof>The Journal of clinical investigation, 2020-11, Vol.130 (11), p.6151-6157</ispartof><rights>COPYRIGHT 2020 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Nov 2020</rights><rights>2020 American Society for Clinical Investigation 2020 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c647t-1a34a56aa11a8c78e00bc52e34fc7e5e91b216d0538d9bb38bbf0de87a2f236e3</citedby><cites>FETCH-LOGICAL-c647t-1a34a56aa11a8c78e00bc52e34fc7e5e91b216d0538d9bb38bbf0de87a2f236e3</cites><orcidid>0000-0003-0456-7015 ; 0000-0002-9370-5776</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598040/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598040/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32759504$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Skendros, Panagiotis</creatorcontrib><creatorcontrib>Mitsios, Alexandros</creatorcontrib><creatorcontrib>Chrysanthopoulou, Akrivi</creatorcontrib><creatorcontrib>Mastellos, Dimitrios C</creatorcontrib><creatorcontrib>Metallidis, Simeon</creatorcontrib><creatorcontrib>Rafailidis, Petros</creatorcontrib><creatorcontrib>Ntinopoulou, Maria</creatorcontrib><creatorcontrib>Sertaridou, Eleni</creatorcontrib><creatorcontrib>Tsironidou, Victoria</creatorcontrib><creatorcontrib>Tsigalou, Christina</creatorcontrib><creatorcontrib>Tektonidou, Maria</creatorcontrib><creatorcontrib>Konstantinidis, Theocharis</creatorcontrib><creatorcontrib>Papagoras, Charalampos</creatorcontrib><creatorcontrib>Mitroulis, Ioannis</creatorcontrib><creatorcontrib>Germanidis, Georgios</creatorcontrib><creatorcontrib>Lambris, John D</creatorcontrib><creatorcontrib>Ritis, Konstantinos</creatorcontrib><title>Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.</description><subject>Aged</subject><subject>Aorta</subject><subject>Autophagy</subject><subject>Betacoronavirus - immunology</subject><subject>Betacoronavirus - metabolism</subject><subject>Biomedical research</subject><subject>Complement activation</subject><subject>Complement Activation - drug effects</subject><subject>Complement component C3</subject><subject>Complement Membrane Attack Complex - immunology</subject><subject>Complement Membrane Attack Complex - metabolism</subject><subject>Complement system</subject><subject>Complications and side effects</subject><subject>Concise Communication</subject><subject>Coronaviridae</subject><subject>Coronavirus Infections - blood</subject><subject>Coronavirus Infections - immunology</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>Development and progression</subject><subject>Endothelial cells</subject><subject>Extracellular Traps - immunology</subject><subject>Extracellular Traps - metabolism</subject><subject>Female</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immune response</subject><subject>Investigations</subject><subject>Leukocytes (neutrophilic)</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Neutrophils</subject><subject>Neutrophils - immunology</subject><subject>Neutrophils - metabolism</subject><subject>Pandemics</subject><subject>Patients</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Plasma</subject><subject>Plasma levels</subject><subject>Platelets</subject><subject>Pneumonia, Viral - blood</subject><subject>Pneumonia, Viral - immunology</subject><subject>Receptor, Anaphylatoxin C5a - antagonists & inhibitors</subject><subject>Receptor, Anaphylatoxin C5a - blood</subject><subject>Receptor, Anaphylatoxin C5a - immunology</subject><subject>Respiratory Distress Syndrome - blood</subject><subject>Respiratory Distress Syndrome - immunology</subject><subject>Respiratory Distress Syndrome - virology</subject><subject>Risk factors</subject><subject>SARS-CoV-2</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Thrombin</subject><subject>Thrombin - immunology</subject><subject>Thrombin - metabolism</subject><subject>Thromboplastin - immunology</subject><subject>Thromboplastin - metabolism</subject><subject>Thrombosis</subject><subject>Thrombosis - blood</subject><subject>Thrombosis - immunology</subject><subject>Thrombosis - virology</subject><subject>Thrombotic microangiopathy</subject><subject>Tissue factor</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkk1v1DAQhiMEokvhwB9AlpAQHFLs2I6dS6UqFFhUaSU-erWcZLJxSeyt7VTtv8crytJFe0A-2LKfeccz72TZS4JPCBHF-y_1kjBCBXuULQjnMpcFlY-zBcYFyStB5VH2LIQrjAljnD3NjmgheMUxW2TXtZs2I0xgI9K2Q9GEMAPqdRudz8F60w7QIQtz9G4zmBHBbfS6hXGcR-1ROm8C0h7QT7hDnTc34AMyFtWry-WHnFTITNNsXRy8mxoXTHiePen1GODF_X6c_fh4_r3-nF-sPi3rs4u8LZmIOdGUaV5qTYiWrZCAcdPyAijrWwEcKtIUpOwwp7KrmobKpulxB1Looi9oCfQ4O_2tu5mbCbo2Vej1qDbeTNrfKaeN2n-xZlBrd6NSayRmOAm8vRfw7nqGENVkwrZwbcHNQRWMEomrilYJff0PeuVmb1N5ieJSCMlK-Zda6xGUsb3bdnIrqs5KRjAXJd-mzQ9Qa7CQPuks9CZd7_EnB_i0OphMezDg3V5AYmIyda3nENTy29f_Z1eX--ybB-wAeoxDcOMcjbPhoGjrXQge-p0pBKvtQKvdQCf21UMXd-SfCaa_AHnd7ag</recordid><startdate>20201101</startdate><enddate>20201101</enddate><creator>Skendros, Panagiotis</creator><creator>Mitsios, Alexandros</creator><creator>Chrysanthopoulou, Akrivi</creator><creator>Mastellos, Dimitrios C</creator><creator>Metallidis, Simeon</creator><creator>Rafailidis, Petros</creator><creator>Ntinopoulou, Maria</creator><creator>Sertaridou, Eleni</creator><creator>Tsironidou, Victoria</creator><creator>Tsigalou, Christina</creator><creator>Tektonidou, Maria</creator><creator>Konstantinidis, Theocharis</creator><creator>Papagoras, Charalampos</creator><creator>Mitroulis, Ioannis</creator><creator>Germanidis, Georgios</creator><creator>Lambris, John D</creator><creator>Ritis, Konstantinos</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0456-7015</orcidid><orcidid>https://orcid.org/0000-0002-9370-5776</orcidid></search><sort><creationdate>20201101</creationdate><title>Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis</title><author>Skendros, Panagiotis ; Mitsios, Alexandros ; Chrysanthopoulou, Akrivi ; Mastellos, Dimitrios C ; Metallidis, Simeon ; Rafailidis, Petros ; Ntinopoulou, Maria ; Sertaridou, Eleni ; Tsironidou, Victoria ; Tsigalou, Christina ; Tektonidou, Maria ; Konstantinidis, Theocharis ; Papagoras, Charalampos ; Mitroulis, Ioannis ; Germanidis, Georgios ; Lambris, John D ; Ritis, Konstantinos</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c647t-1a34a56aa11a8c78e00bc52e34fc7e5e91b216d0538d9bb38bbf0de87a2f236e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Aorta</topic><topic>Autophagy</topic><topic>Betacoronavirus - immunology</topic><topic>Betacoronavirus - metabolism</topic><topic>Biomedical research</topic><topic>Complement activation</topic><topic>Complement Activation - drug effects</topic><topic>Complement component C3</topic><topic>Complement Membrane Attack Complex - immunology</topic><topic>Complement Membrane Attack Complex - metabolism</topic><topic>Complement system</topic><topic>Complications and side effects</topic><topic>Concise Communication</topic><topic>Coronaviridae</topic><topic>Coronavirus Infections - blood</topic><topic>Coronavirus Infections - immunology</topic><topic>Coronaviruses</topic><topic>COVID-19</topic><topic>Development and progression</topic><topic>Endothelial cells</topic><topic>Extracellular Traps - immunology</topic><topic>Extracellular Traps - metabolism</topic><topic>Female</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Immune response</topic><topic>Investigations</topic><topic>Leukocytes (neutrophilic)</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Neutrophils</topic><topic>Neutrophils - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Skendros, Panagiotis</au><au>Mitsios, Alexandros</au><au>Chrysanthopoulou, Akrivi</au><au>Mastellos, Dimitrios C</au><au>Metallidis, Simeon</au><au>Rafailidis, Petros</au><au>Ntinopoulou, Maria</au><au>Sertaridou, Eleni</au><au>Tsironidou, Victoria</au><au>Tsigalou, Christina</au><au>Tektonidou, Maria</au><au>Konstantinidis, Theocharis</au><au>Papagoras, Charalampos</au><au>Mitroulis, Ioannis</au><au>Germanidis, Georgios</au><au>Lambris, John D</au><au>Ritis, Konstantinos</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2020-11-01</date><risdate>2020</risdate><volume>130</volume><issue>11</issue><spage>6151</spage><epage>6157</epage><pages>6151-6157</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>32759504</pmid><doi>10.1172/JCI141374</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-0456-7015</orcidid><orcidid>https://orcid.org/0000-0002-9370-5776</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2020-11, Vol.130 (11), p.6151-6157 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7598040 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Aged Aorta Autophagy Betacoronavirus - immunology Betacoronavirus - metabolism Biomedical research Complement activation Complement Activation - drug effects Complement component C3 Complement Membrane Attack Complex - immunology Complement Membrane Attack Complex - metabolism Complement system Complications and side effects Concise Communication Coronaviridae Coronavirus Infections - blood Coronavirus Infections - immunology Coronaviruses COVID-19 Development and progression Endothelial cells Extracellular Traps - immunology Extracellular Traps - metabolism Female Health aspects Humans Immune response Investigations Leukocytes (neutrophilic) Male Middle Aged Mortality Neutrophils Neutrophils - immunology Neutrophils - metabolism Pandemics Patients Peptides, Cyclic - pharmacology Plasma Plasma levels Platelets Pneumonia, Viral - blood Pneumonia, Viral - immunology Receptor, Anaphylatoxin C5a - antagonists & inhibitors Receptor, Anaphylatoxin C5a - blood Receptor, Anaphylatoxin C5a - immunology Respiratory Distress Syndrome - blood Respiratory Distress Syndrome - immunology Respiratory Distress Syndrome - virology Risk factors SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 Thrombin Thrombin - immunology Thrombin - metabolism Thromboplastin - immunology Thromboplastin - metabolism Thrombosis Thrombosis - blood Thrombosis - immunology Thrombosis - virology Thrombotic microangiopathy Tissue factor |
| title | Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-29T08%3A21%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Complement%20and%20tissue%20factor-enriched%20neutrophil%20extracellular%20traps%20are%20key%20drivers%20in%20COVID-19%20immunothrombosis&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Skendros,%20Panagiotis&rft.date=2020-11-01&rft.volume=130&rft.issue=11&rft.spage=6151&rft.epage=6157&rft.pages=6151-6157&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI141374&rft_dat=%3Cgale_pubme%3EA641057650%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2458778468&rft_id=info:pmid/32759504&rft_galeid=A641057650&rfr_iscdi=true |