Brain network integration dynamics are associated with loss and recovery of consciousness induced by sevoflurane

The dynamic interplay of integration and segregation in the brain is at the core of leading theoretical accounts of consciousness. The human brain dynamically alternates between a sub‐state where integration predominates, and a predominantly segregated sub‐state, with different roles in supporting c...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Human brain mapping 2021-06, Vol.42 (9), p.2802-2822
Hauptverfasser: Luppi, Andrea I., Golkowski, Daniel, Ranft, Andreas, Ilg, Rüdiger, Jordan, Denis, Menon, David K., Stamatakis, Emmanuel A.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 2822
container_issue 9
container_start_page 2802
container_title Human brain mapping
container_volume 42
creator Luppi, Andrea I.
Golkowski, Daniel
Ranft, Andreas
Ilg, Rüdiger
Jordan, Denis
Menon, David K.
Stamatakis, Emmanuel A.
description The dynamic interplay of integration and segregation in the brain is at the core of leading theoretical accounts of consciousness. The human brain dynamically alternates between a sub‐state where integration predominates, and a predominantly segregated sub‐state, with different roles in supporting cognition and behaviour. Here, we combine graph theory and dynamic functional connectivity to compare resting‐state functional MRI data from healthy volunteers before, during, and after loss of responsiveness induced with different concentrations of the inhalational anaesthetic, sevoflurane. We show that dynamic states characterised by high brain integration are especially vulnerable to general anaesthesia, exhibiting attenuated complexity and diminished small‐world character. Crucially, these effects are reversed upon recovery, demonstrating their association with consciousness. Higher doses of sevoflurane (3% vol and burst‐suppression) also compromise the temporal balance of integration and segregation in the human brain. Additionally, we demonstrate that reduced anticorrelations between the brain's default mode and executive control networks dynamically reconfigure depending on the brain's state of integration or segregation. Taken together, our results demonstrate that the integrated sub‐state of brain connectivity is especially vulnerable to anaesthesia, in terms of both its complexity and information capacity, whose breakdown represents a generalisable biomarker of loss of consciousness and its recovery. We use functional MRI to study the effects of sevoflurane anaesthesia on the dynamics of integration and segregation in the human brain. We show that brain states characterised by high integration are especially vulnerable to general anaesthesia, in terms of both complexity and information capacity. Higher doses of sevoflurane also compromise the temporal balance of integration and segregation in the human brain.
doi_str_mv 10.1002/hbm.25405
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8127159</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2503436195</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4435-851905f47dd4c164145dd0256be8e2f9850357f4a22e9594eb26e8aadfd253503</originalsourceid><addsrcrecordid>eNp1kc1O3DAURi1ExW8XfYHKEpuyCNiOncQbJEAFKlF1Q9eWY98wpok9tZMZ5e3xdAC1SF3Z0nd0fK8_hD5RckYJYeeLdjhjghOxgw4okXVBqCx3N_dKFJLXdB8dpvRECKWC0D20X5Z12TRSHqDlVdTOYw_jOsRf2PkRHqMeXfDYzl4PziSsI2CdUjBOj2Dx2o0L3IeUA29xBBNWEGccOmyCT8aFKXnIqfN2MplvZ5xgFbp-itrDMfrQ6T7Bx5fzCP28-fpwfVfc_7j9dn15XxjOS1E0gkoiOl5byw2tOOXCWsJE1UIDrJONIKWoO64ZAykkh5ZV0GhtO8tEmcMjdLH1Lqd2AGvAj1H3ahndoOOsgnbq38S7hXoMK9VQVlMhs-DLiyCG3xOkUQ0uGej7vEReUbH8CC8rKkVGT96hT2GKPq-XKdaQqqJ8IzzdUibmz4vQvQ1Didr0qHKP6k-Pmf389_Rv5GtxGTjfAmvXw_x_k7q7-r5VPgMFDalU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2528066149</pqid></control><display><type>article</type><title>Brain network integration dynamics are associated with loss and recovery of consciousness induced by sevoflurane</title><source>Wiley-Blackwell Journals</source><source>MEDLINE</source><source>NCBI_PubMed Central(免费)</source><source>DOAJ Directory of Open Access Journals</source><source>Wiley_OA刊</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Luppi, Andrea I. ; Golkowski, Daniel ; Ranft, Andreas ; Ilg, Rüdiger ; Jordan, Denis ; Menon, David K. ; Stamatakis, Emmanuel A.</creator><creatorcontrib>Luppi, Andrea I. ; Golkowski, Daniel ; Ranft, Andreas ; Ilg, Rüdiger ; Jordan, Denis ; Menon, David K. ; Stamatakis, Emmanuel A.</creatorcontrib><description>The dynamic interplay of integration and segregation in the brain is at the core of leading theoretical accounts of consciousness. The human brain dynamically alternates between a sub‐state where integration predominates, and a predominantly segregated sub‐state, with different roles in supporting cognition and behaviour. Here, we combine graph theory and dynamic functional connectivity to compare resting‐state functional MRI data from healthy volunteers before, during, and after loss of responsiveness induced with different concentrations of the inhalational anaesthetic, sevoflurane. We show that dynamic states characterised by high brain integration are especially vulnerable to general anaesthesia, exhibiting attenuated complexity and diminished small‐world character. Crucially, these effects are reversed upon recovery, demonstrating their association with consciousness. Higher doses of sevoflurane (3% vol and burst‐suppression) also compromise the temporal balance of integration and segregation in the human brain. Additionally, we demonstrate that reduced anticorrelations between the brain's default mode and executive control networks dynamically reconfigure depending on the brain's state of integration or segregation. Taken together, our results demonstrate that the integrated sub‐state of brain connectivity is especially vulnerable to anaesthesia, in terms of both its complexity and information capacity, whose breakdown represents a generalisable biomarker of loss of consciousness and its recovery. We use functional MRI to study the effects of sevoflurane anaesthesia on the dynamics of integration and segregation in the human brain. We show that brain states characterised by high integration are especially vulnerable to general anaesthesia, in terms of both complexity and information capacity. Higher doses of sevoflurane also compromise the temporal balance of integration and segregation in the human brain.</description><identifier>ISSN: 1065-9471</identifier><identifier>ISSN: 1097-0193</identifier><identifier>EISSN: 1097-0193</identifier><identifier>DOI: 10.1002/hbm.25405</identifier><identifier>PMID: 33738899</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley &amp; Sons, Inc</publisher><subject>Adult ; anaesthesia ; Anesthesia ; Anesthetics, Inhalation - pharmacology ; Biomarkers ; Brain ; Brain - diagnostic imaging ; Brain - drug effects ; Brain - physiology ; Cognition ; Complexity ; Connectome ; Consciousness ; Consciousness - drug effects ; Consciousness - physiology ; Default Mode Network - diagnostic imaging ; Default Mode Network - drug effects ; Default Mode Network - physiology ; dynamic functional connectivity ; Executive function ; Functional magnetic resonance imaging ; Graph theory ; Humans ; Integration ; integration‐segregation ; Magnetic Resonance Imaging ; Male ; Nerve Net - diagnostic imaging ; Nerve Net - drug effects ; Nerve Net - physiology ; Neural networks ; Recovery ; Sevoflurane ; Sevoflurane - pharmacology ; small‐world network ; Young Adult</subject><ispartof>Human brain mapping, 2021-06, Vol.42 (9), p.2802-2822</ispartof><rights>2021 The Authors. published by Wiley Periodicals LLC.</rights><rights>2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4435-851905f47dd4c164145dd0256be8e2f9850357f4a22e9594eb26e8aadfd253503</citedby><cites>FETCH-LOGICAL-c4435-851905f47dd4c164145dd0256be8e2f9850357f4a22e9594eb26e8aadfd253503</cites><orcidid>0000-0002-7569-7936 ; 0000-0002-3228-9692 ; 0000-0002-3461-6431 ; 0000-0001-6955-9601</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/PMC8127159/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127159/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33738899$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luppi, Andrea I.</creatorcontrib><creatorcontrib>Golkowski, Daniel</creatorcontrib><creatorcontrib>Ranft, Andreas</creatorcontrib><creatorcontrib>Ilg, Rüdiger</creatorcontrib><creatorcontrib>Jordan, Denis</creatorcontrib><creatorcontrib>Menon, David K.</creatorcontrib><creatorcontrib>Stamatakis, Emmanuel A.</creatorcontrib><title>Brain network integration dynamics are associated with loss and recovery of consciousness induced by sevoflurane</title><title>Human brain mapping</title><addtitle>Hum Brain Mapp</addtitle><description>The dynamic interplay of integration and segregation in the brain is at the core of leading theoretical accounts of consciousness. The human brain dynamically alternates between a sub‐state where integration predominates, and a predominantly segregated sub‐state, with different roles in supporting cognition and behaviour. Here, we combine graph theory and dynamic functional connectivity to compare resting‐state functional MRI data from healthy volunteers before, during, and after loss of responsiveness induced with different concentrations of the inhalational anaesthetic, sevoflurane. We show that dynamic states characterised by high brain integration are especially vulnerable to general anaesthesia, exhibiting attenuated complexity and diminished small‐world character. Crucially, these effects are reversed upon recovery, demonstrating their association with consciousness. Higher doses of sevoflurane (3% vol and burst‐suppression) also compromise the temporal balance of integration and segregation in the human brain. Additionally, we demonstrate that reduced anticorrelations between the brain's default mode and executive control networks dynamically reconfigure depending on the brain's state of integration or segregation. Taken together, our results demonstrate that the integrated sub‐state of brain connectivity is especially vulnerable to anaesthesia, in terms of both its complexity and information capacity, whose breakdown represents a generalisable biomarker of loss of consciousness and its recovery. We use functional MRI to study the effects of sevoflurane anaesthesia on the dynamics of integration and segregation in the human brain. We show that brain states characterised by high integration are especially vulnerable to general anaesthesia, in terms of both complexity and information capacity. Higher doses of sevoflurane also compromise the temporal balance of integration and segregation in the human brain.</description><subject>Adult</subject><subject>anaesthesia</subject><subject>Anesthesia</subject><subject>Anesthetics, Inhalation - pharmacology</subject><subject>Biomarkers</subject><subject>Brain</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - drug effects</subject><subject>Brain - physiology</subject><subject>Cognition</subject><subject>Complexity</subject><subject>Connectome</subject><subject>Consciousness</subject><subject>Consciousness - drug effects</subject><subject>Consciousness - physiology</subject><subject>Default Mode Network - diagnostic imaging</subject><subject>Default Mode Network - drug effects</subject><subject>Default Mode Network - physiology</subject><subject>dynamic functional connectivity</subject><subject>Executive function</subject><subject>Functional magnetic resonance imaging</subject><subject>Graph theory</subject><subject>Humans</subject><subject>Integration</subject><subject>integration‐segregation</subject><subject>Magnetic Resonance Imaging</subject><subject>Male</subject><subject>Nerve Net - diagnostic imaging</subject><subject>Nerve Net - drug effects</subject><subject>Nerve Net - physiology</subject><subject>Neural networks</subject><subject>Recovery</subject><subject>Sevoflurane</subject><subject>Sevoflurane - pharmacology</subject><subject>small‐world network</subject><subject>Young Adult</subject><issn>1065-9471</issn><issn>1097-0193</issn><issn>1097-0193</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc1O3DAURi1ExW8XfYHKEpuyCNiOncQbJEAFKlF1Q9eWY98wpok9tZMZ5e3xdAC1SF3Z0nd0fK8_hD5RckYJYeeLdjhjghOxgw4okXVBqCx3N_dKFJLXdB8dpvRECKWC0D20X5Z12TRSHqDlVdTOYw_jOsRf2PkRHqMeXfDYzl4PziSsI2CdUjBOj2Dx2o0L3IeUA29xBBNWEGccOmyCT8aFKXnIqfN2MplvZ5xgFbp-itrDMfrQ6T7Bx5fzCP28-fpwfVfc_7j9dn15XxjOS1E0gkoiOl5byw2tOOXCWsJE1UIDrJONIKWoO64ZAykkh5ZV0GhtO8tEmcMjdLH1Lqd2AGvAj1H3ahndoOOsgnbq38S7hXoMK9VQVlMhs-DLiyCG3xOkUQ0uGej7vEReUbH8CC8rKkVGT96hT2GKPq-XKdaQqqJ8IzzdUibmz4vQvQ1Didr0qHKP6k-Pmf389_Rv5GtxGTjfAmvXw_x_k7q7-r5VPgMFDalU</recordid><startdate>20210615</startdate><enddate>20210615</enddate><creator>Luppi, Andrea I.</creator><creator>Golkowski, Daniel</creator><creator>Ranft, Andreas</creator><creator>Ilg, Rüdiger</creator><creator>Jordan, Denis</creator><creator>Menon, David K.</creator><creator>Stamatakis, Emmanuel A.</creator><general>John Wiley &amp; Sons, Inc</general><scope>24P</scope><scope>WIN</scope><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>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7569-7936</orcidid><orcidid>https://orcid.org/0000-0002-3228-9692</orcidid><orcidid>https://orcid.org/0000-0002-3461-6431</orcidid><orcidid>https://orcid.org/0000-0001-6955-9601</orcidid></search><sort><creationdate>20210615</creationdate><title>Brain network integration dynamics are associated with loss and recovery of consciousness induced by sevoflurane</title><author>Luppi, Andrea I. ; Golkowski, Daniel ; Ranft, Andreas ; Ilg, Rüdiger ; Jordan, Denis ; Menon, David K. ; Stamatakis, Emmanuel A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4435-851905f47dd4c164145dd0256be8e2f9850357f4a22e9594eb26e8aadfd253503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adult</topic><topic>anaesthesia</topic><topic>Anesthesia</topic><topic>Anesthetics, Inhalation - pharmacology</topic><topic>Biomarkers</topic><topic>Brain</topic><topic>Brain - diagnostic imaging</topic><topic>Brain - drug effects</topic><topic>Brain - physiology</topic><topic>Cognition</topic><topic>Complexity</topic><topic>Connectome</topic><topic>Consciousness</topic><topic>Consciousness - drug effects</topic><topic>Consciousness - physiology</topic><topic>Default Mode Network - diagnostic imaging</topic><topic>Default Mode Network - drug effects</topic><topic>Default Mode Network - physiology</topic><topic>dynamic functional connectivity</topic><topic>Executive function</topic><topic>Functional magnetic resonance imaging</topic><topic>Graph theory</topic><topic>Humans</topic><topic>Integration</topic><topic>integration‐segregation</topic><topic>Magnetic Resonance Imaging</topic><topic>Male</topic><topic>Nerve Net - diagnostic imaging</topic><topic>Nerve Net - drug effects</topic><topic>Nerve Net - physiology</topic><topic>Neural networks</topic><topic>Recovery</topic><topic>Sevoflurane</topic><topic>Sevoflurane - pharmacology</topic><topic>small‐world network</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Luppi, Andrea I.</creatorcontrib><creatorcontrib>Golkowski, Daniel</creatorcontrib><creatorcontrib>Ranft, Andreas</creatorcontrib><creatorcontrib>Ilg, Rüdiger</creatorcontrib><creatorcontrib>Jordan, Denis</creatorcontrib><creatorcontrib>Menon, David K.</creatorcontrib><creatorcontrib>Stamatakis, Emmanuel A.</creatorcontrib><collection>Wiley_OA刊</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human brain mapping</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Luppi, Andrea I.</au><au>Golkowski, Daniel</au><au>Ranft, Andreas</au><au>Ilg, Rüdiger</au><au>Jordan, Denis</au><au>Menon, David K.</au><au>Stamatakis, Emmanuel A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Brain network integration dynamics are associated with loss and recovery of consciousness induced by sevoflurane</atitle><jtitle>Human brain mapping</jtitle><addtitle>Hum Brain Mapp</addtitle><date>2021-06-15</date><risdate>2021</risdate><volume>42</volume><issue>9</issue><spage>2802</spage><epage>2822</epage><pages>2802-2822</pages><issn>1065-9471</issn><issn>1097-0193</issn><eissn>1097-0193</eissn><abstract>The dynamic interplay of integration and segregation in the brain is at the core of leading theoretical accounts of consciousness. The human brain dynamically alternates between a sub‐state where integration predominates, and a predominantly segregated sub‐state, with different roles in supporting cognition and behaviour. Here, we combine graph theory and dynamic functional connectivity to compare resting‐state functional MRI data from healthy volunteers before, during, and after loss of responsiveness induced with different concentrations of the inhalational anaesthetic, sevoflurane. We show that dynamic states characterised by high brain integration are especially vulnerable to general anaesthesia, exhibiting attenuated complexity and diminished small‐world character. Crucially, these effects are reversed upon recovery, demonstrating their association with consciousness. Higher doses of sevoflurane (3% vol and burst‐suppression) also compromise the temporal balance of integration and segregation in the human brain. Additionally, we demonstrate that reduced anticorrelations between the brain's default mode and executive control networks dynamically reconfigure depending on the brain's state of integration or segregation. Taken together, our results demonstrate that the integrated sub‐state of brain connectivity is especially vulnerable to anaesthesia, in terms of both its complexity and information capacity, whose breakdown represents a generalisable biomarker of loss of consciousness and its recovery. We use functional MRI to study the effects of sevoflurane anaesthesia on the dynamics of integration and segregation in the human brain. We show that brain states characterised by high integration are especially vulnerable to general anaesthesia, in terms of both complexity and information capacity. Higher doses of sevoflurane also compromise the temporal balance of integration and segregation in the human brain.</abstract><cop>Hoboken, USA</cop><pub>John Wiley &amp; Sons, Inc</pub><pmid>33738899</pmid><doi>10.1002/hbm.25405</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0002-7569-7936</orcidid><orcidid>https://orcid.org/0000-0002-3228-9692</orcidid><orcidid>https://orcid.org/0000-0002-3461-6431</orcidid><orcidid>https://orcid.org/0000-0001-6955-9601</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1065-9471
ispartof Human brain mapping, 2021-06, Vol.42 (9), p.2802-2822
issn 1065-9471
1097-0193
1097-0193
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8127159
source Wiley-Blackwell Journals; MEDLINE; NCBI_PubMed Central(免费); DOAJ Directory of Open Access Journals; Wiley_OA刊; EZB-FREE-00999 freely available EZB journals
subjects Adult
anaesthesia
Anesthesia
Anesthetics, Inhalation - pharmacology
Biomarkers
Brain
Brain - diagnostic imaging
Brain - drug effects
Brain - physiology
Cognition
Complexity
Connectome
Consciousness
Consciousness - drug effects
Consciousness - physiology
Default Mode Network - diagnostic imaging
Default Mode Network - drug effects
Default Mode Network - physiology
dynamic functional connectivity
Executive function
Functional magnetic resonance imaging
Graph theory
Humans
Integration
integration‐segregation
Magnetic Resonance Imaging
Male
Nerve Net - diagnostic imaging
Nerve Net - drug effects
Nerve Net - physiology
Neural networks
Recovery
Sevoflurane
Sevoflurane - pharmacology
small‐world network
Young Adult
title Brain network integration dynamics are associated with loss and recovery of consciousness induced by sevoflurane
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T07%3A13%3A32IST&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=Brain%20network%20integration%20dynamics%20are%20associated%20with%20loss%20and%20recovery%20of%20consciousness%20induced%20by%20sevoflurane&rft.jtitle=Human%20brain%20mapping&rft.au=Luppi,%20Andrea%20I.&rft.date=2021-06-15&rft.volume=42&rft.issue=9&rft.spage=2802&rft.epage=2822&rft.pages=2802-2822&rft.issn=1065-9471&rft.eissn=1097-0193&rft_id=info:doi/10.1002/hbm.25405&rft_dat=%3Cproquest_pubme%3E2503436195%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=2528066149&rft_id=info:pmid/33738899&rfr_iscdi=true