Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?
The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can su...
Gespeichert in:
| Veröffentlicht in: | Advances in biological regulation 2021-08, Vol.81, p.100820-100820, Article 100820 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 100820 |
|---|---|
| container_issue | |
| container_start_page | 100820 |
| container_title | Advances in biological regulation |
| container_volume | 81 |
| creator | Montanari, Mariele Canonico, Barbara Nordi, Evelyn Vandini, Daniela Barocci, Simone Benedetti, Serena Carlotti, Eugenio Zamai, Loris |
| description | The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1–7 and Ang 1–9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome. |
| doi_str_mv | 10.1016/j.jbior.2021.100820 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8359569</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S2212492621000361</els_id><sourcerecordid>2581869402</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4020-101841f781dbecf25f1ca4d36c74ce963e59e4afe923007e7d3853e239747ef53</originalsourceid><addsrcrecordid>eNp9kUtv1DAUhS1ERavSX4CELLFhQaZ-J14AQsOjlSp1w0NiY3mcm4lDxi520mr-PR6mjAoLvPGV_d1zfXwQekbJghKqzofFsPIxLRhhtJyQhpFH6IQxyiqhuXh8qJk6Rmc5D6QsVTqFfIKOuRBU1zU_Qd-_9d71OAbIr_BdDwHb0JZii3Mf57HFCYIPlQ1rHycI2Qect3mCDfah9ys_xZTxXUw_sF1bH_KEl9dfL99XVL99io46O2Y4u99P0ZePHz4vL6qr60-Xy3dXlROEkarYaQTt6oa2K3Adkx11VrRcuVo40IqD1CBsB5pxQmqoW95IDozrWtTQSX6K3ux1b-bVBloHYUp2NDfJb2zammi9-fsm-N6s461puNRS6SLw8l4gxZ8z5MlsfHYwjjZAnLNhUnGllWS7WS_-QYc4p1DsFaqhjdLFU6H4nnIp5pygOzyGErOLzwzmd3xmF5_Zx1e6nj_0cej5E1YBXu8BKL956yGZ7DwEB61P4CbTRv_fAb8AiiKrpA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2581869402</pqid></control><display><type>article</type><title>Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Montanari, Mariele ; Canonico, Barbara ; Nordi, Evelyn ; Vandini, Daniela ; Barocci, Simone ; Benedetti, Serena ; Carlotti, Eugenio ; Zamai, Loris</creator><creatorcontrib>Montanari, Mariele ; Canonico, Barbara ; Nordi, Evelyn ; Vandini, Daniela ; Barocci, Simone ; Benedetti, Serena ; Carlotti, Eugenio ; Zamai, Loris</creatorcontrib><description>The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1–7 and Ang 1–9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.</description><identifier>ISSN: 2212-4926</identifier><identifier>EISSN: 2212-4934</identifier><identifier>DOI: 10.1016/j.jbior.2021.100820</identifier><identifier>PMID: 34419773</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>ACE2 ; ADAM17 ; ADAM17 Protein - antagonists & inhibitors ; ADAM17 Protein - biosynthesis ; Angiotensin ; Angiotensin I - metabolism ; Angiotensin-converting enzyme 2 ; Angiotensin-Converting Enzyme 2 - antagonists & inhibitors ; Angiotensin-Converting Enzyme 2 - biosynthesis ; Coronaviruses ; COVID-19 ; COVID-19 - metabolism ; COVID-19 Drug Treatment ; Endocrine system ; Enzymes ; Gene Expression Regulation, Enzymologic ; Humans ; Hyperactivity ; Hypertension ; Hypotheses ; Inflammation ; Peptide Fragments - metabolism ; Peptides ; Positive feedback ; RAS inhibitors ; Renin ; Renin-Angiotensin System ; SARS-CoV-2 - metabolism ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Spike Glycoprotein, Coronavirus - antagonists & inhibitors ; Spike Glycoprotein, Coronavirus - metabolism ; Spike N-Terminal domain ; Thromboembolism ; Thrombosis ; Up-Regulation ; Vaccines ; Viral diseases ; Zinc-chelating agents ; Zinc-metalloproteases</subject><ispartof>Advances in biological regulation, 2021-08, Vol.81, p.100820-100820, Article 100820</ispartof><rights>2021</rights><rights>Copyright © 2021. Published by Elsevier Ltd.</rights><rights>Copyright Elsevier BV 2021</rights><rights>2021 Published by Elsevier Ltd. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4020-101841f781dbecf25f1ca4d36c74ce963e59e4afe923007e7d3853e239747ef53</citedby><cites>FETCH-LOGICAL-c4020-101841f781dbecf25f1ca4d36c74ce963e59e4afe923007e7d3853e239747ef53</cites><orcidid>0000-0002-4361-1026 ; 0000-0003-3383-715X ; 0000-0001-9999-1526 ; 0000-0003-4848-3390 ; 0000-0002-9320-2028</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34419773$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Montanari, Mariele</creatorcontrib><creatorcontrib>Canonico, Barbara</creatorcontrib><creatorcontrib>Nordi, Evelyn</creatorcontrib><creatorcontrib>Vandini, Daniela</creatorcontrib><creatorcontrib>Barocci, Simone</creatorcontrib><creatorcontrib>Benedetti, Serena</creatorcontrib><creatorcontrib>Carlotti, Eugenio</creatorcontrib><creatorcontrib>Zamai, Loris</creatorcontrib><title>Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?</title><title>Advances in biological regulation</title><addtitle>Adv Biol Regul</addtitle><description>The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1–7 and Ang 1–9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.</description><subject>ACE2</subject><subject>ADAM17</subject><subject>ADAM17 Protein - antagonists & inhibitors</subject><subject>ADAM17 Protein - biosynthesis</subject><subject>Angiotensin</subject><subject>Angiotensin I - metabolism</subject><subject>Angiotensin-converting enzyme 2</subject><subject>Angiotensin-Converting Enzyme 2 - antagonists & inhibitors</subject><subject>Angiotensin-Converting Enzyme 2 - biosynthesis</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>COVID-19 - metabolism</subject><subject>COVID-19 Drug Treatment</subject><subject>Endocrine system</subject><subject>Enzymes</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Humans</subject><subject>Hyperactivity</subject><subject>Hypertension</subject><subject>Hypotheses</subject><subject>Inflammation</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptides</subject><subject>Positive feedback</subject><subject>RAS inhibitors</subject><subject>Renin</subject><subject>Renin-Angiotensin System</subject><subject>SARS-CoV-2 - metabolism</subject><subject>Severe acute respiratory syndrome</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Spike Glycoprotein, Coronavirus - antagonists & inhibitors</subject><subject>Spike Glycoprotein, Coronavirus - metabolism</subject><subject>Spike N-Terminal domain</subject><subject>Thromboembolism</subject><subject>Thrombosis</subject><subject>Up-Regulation</subject><subject>Vaccines</subject><subject>Viral diseases</subject><subject>Zinc-chelating agents</subject><subject>Zinc-metalloproteases</subject><issn>2212-4926</issn><issn>2212-4934</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtv1DAUhS1ERavSX4CELLFhQaZ-J14AQsOjlSp1w0NiY3mcm4lDxi520mr-PR6mjAoLvPGV_d1zfXwQekbJghKqzofFsPIxLRhhtJyQhpFH6IQxyiqhuXh8qJk6Rmc5D6QsVTqFfIKOuRBU1zU_Qd-_9d71OAbIr_BdDwHb0JZii3Mf57HFCYIPlQ1rHycI2Qect3mCDfah9ys_xZTxXUw_sF1bH_KEl9dfL99XVL99io46O2Y4u99P0ZePHz4vL6qr60-Xy3dXlROEkarYaQTt6oa2K3Adkx11VrRcuVo40IqD1CBsB5pxQmqoW95IDozrWtTQSX6K3ux1b-bVBloHYUp2NDfJb2zammi9-fsm-N6s461puNRS6SLw8l4gxZ8z5MlsfHYwjjZAnLNhUnGllWS7WS_-QYc4p1DsFaqhjdLFU6H4nnIp5pygOzyGErOLzwzmd3xmF5_Zx1e6nj_0cej5E1YBXu8BKL956yGZ7DwEB61P4CbTRv_fAb8AiiKrpA</recordid><startdate>20210801</startdate><enddate>20210801</enddate><creator>Montanari, Mariele</creator><creator>Canonico, Barbara</creator><creator>Nordi, Evelyn</creator><creator>Vandini, Daniela</creator><creator>Barocci, Simone</creator><creator>Benedetti, Serena</creator><creator>Carlotti, Eugenio</creator><creator>Zamai, Loris</creator><general>Elsevier Ltd</general><general>Elsevier BV</general><general>Published by Elsevier Ltd</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>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4361-1026</orcidid><orcidid>https://orcid.org/0000-0003-3383-715X</orcidid><orcidid>https://orcid.org/0000-0001-9999-1526</orcidid><orcidid>https://orcid.org/0000-0003-4848-3390</orcidid><orcidid>https://orcid.org/0000-0002-9320-2028</orcidid></search><sort><creationdate>20210801</creationdate><title>Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?</title><author>Montanari, Mariele ; Canonico, Barbara ; Nordi, Evelyn ; Vandini, Daniela ; Barocci, Simone ; Benedetti, Serena ; Carlotti, Eugenio ; Zamai, Loris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4020-101841f781dbecf25f1ca4d36c74ce963e59e4afe923007e7d3853e239747ef53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>ACE2</topic><topic>ADAM17</topic><topic>ADAM17 Protein - antagonists & inhibitors</topic><topic>ADAM17 Protein - biosynthesis</topic><topic>Angiotensin</topic><topic>Angiotensin I - metabolism</topic><topic>Angiotensin-converting enzyme 2</topic><topic>Angiotensin-Converting Enzyme 2 - antagonists & inhibitors</topic><topic>Angiotensin-Converting Enzyme 2 - biosynthesis</topic><topic>Coronaviruses</topic><topic>COVID-19</topic><topic>COVID-19 - metabolism</topic><topic>COVID-19 Drug Treatment</topic><topic>Endocrine system</topic><topic>Enzymes</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Humans</topic><topic>Hyperactivity</topic><topic>Hypertension</topic><topic>Hypotheses</topic><topic>Inflammation</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptides</topic><topic>Positive feedback</topic><topic>RAS inhibitors</topic><topic>Renin</topic><topic>Renin-Angiotensin System</topic><topic>SARS-CoV-2 - metabolism</topic><topic>Severe acute respiratory syndrome</topic><topic>Severe acute respiratory syndrome coronavirus 2</topic><topic>Spike Glycoprotein, Coronavirus - antagonists & inhibitors</topic><topic>Spike Glycoprotein, Coronavirus - metabolism</topic><topic>Spike N-Terminal domain</topic><topic>Thromboembolism</topic><topic>Thrombosis</topic><topic>Up-Regulation</topic><topic>Vaccines</topic><topic>Viral diseases</topic><topic>Zinc-chelating agents</topic><topic>Zinc-metalloproteases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Montanari, Mariele</creatorcontrib><creatorcontrib>Canonico, Barbara</creatorcontrib><creatorcontrib>Nordi, Evelyn</creatorcontrib><creatorcontrib>Vandini, Daniela</creatorcontrib><creatorcontrib>Barocci, Simone</creatorcontrib><creatorcontrib>Benedetti, Serena</creatorcontrib><creatorcontrib>Carlotti, Eugenio</creatorcontrib><creatorcontrib>Zamai, Loris</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Advances in biological regulation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Montanari, Mariele</au><au>Canonico, Barbara</au><au>Nordi, Evelyn</au><au>Vandini, Daniela</au><au>Barocci, Simone</au><au>Benedetti, Serena</au><au>Carlotti, Eugenio</au><au>Zamai, Loris</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?</atitle><jtitle>Advances in biological regulation</jtitle><addtitle>Adv Biol Regul</addtitle><date>2021-08-01</date><risdate>2021</risdate><volume>81</volume><spage>100820</spage><epage>100820</epage><pages>100820-100820</pages><artnum>100820</artnum><issn>2212-4926</issn><eissn>2212-4934</eissn><abstract>The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1–7 and Ang 1–9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34419773</pmid><doi>10.1016/j.jbior.2021.100820</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-4361-1026</orcidid><orcidid>https://orcid.org/0000-0003-3383-715X</orcidid><orcidid>https://orcid.org/0000-0001-9999-1526</orcidid><orcidid>https://orcid.org/0000-0003-4848-3390</orcidid><orcidid>https://orcid.org/0000-0002-9320-2028</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2212-4926 |
| ispartof | Advances in biological regulation, 2021-08, Vol.81, p.100820-100820, Article 100820 |
| issn | 2212-4926 2212-4934 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8359569 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | ACE2 ADAM17 ADAM17 Protein - antagonists & inhibitors ADAM17 Protein - biosynthesis Angiotensin Angiotensin I - metabolism Angiotensin-converting enzyme 2 Angiotensin-Converting Enzyme 2 - antagonists & inhibitors Angiotensin-Converting Enzyme 2 - biosynthesis Coronaviruses COVID-19 COVID-19 - metabolism COVID-19 Drug Treatment Endocrine system Enzymes Gene Expression Regulation, Enzymologic Humans Hyperactivity Hypertension Hypotheses Inflammation Peptide Fragments - metabolism Peptides Positive feedback RAS inhibitors Renin Renin-Angiotensin System SARS-CoV-2 - metabolism Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus - antagonists & inhibitors Spike Glycoprotein, Coronavirus - metabolism Spike N-Terminal domain Thromboembolism Thrombosis Up-Regulation Vaccines Viral diseases Zinc-chelating agents Zinc-metalloproteases |
| title | Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19? |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-10T12%3A50%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Which%20ones,%20when%20and%20why%20should%20renin-angiotensin%20system%20inhibitors%20work%20against%20COVID-19?&rft.jtitle=Advances%20in%20biological%20regulation&rft.au=Montanari,%20Mariele&rft.date=2021-08-01&rft.volume=81&rft.spage=100820&rft.epage=100820&rft.pages=100820-100820&rft.artnum=100820&rft.issn=2212-4926&rft.eissn=2212-4934&rft_id=info:doi/10.1016/j.jbior.2021.100820&rft_dat=%3Cproquest_pubme%3E2581869402%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2581869402&rft_id=info:pmid/34419773&rft_els_id=S2212492621000361&rfr_iscdi=true |