Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition

Objective Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood idiopathic localization‐related epilepsy syndrome. BECTS presents normal routine magnetic resonance imaging (MRI); however, quantitative analytic techniques have captured subtle cortical and subcortical magneti...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Epilepsia (Copenhagen) 2019-09, Vol.60 (9), p.1838-1848
Hauptverfasser: Garcia‐Ramos, Camille, Dabbs, Kevin, Lin, Jack J., Jones, Jana E., Stafstrom, Carl E., Hsu, David A., Meyerand, Mary Elizabeth, Prabhakaran, Vivek, Hermann, Bruce P.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1848
container_issue 9
container_start_page 1838
container_title Epilepsia (Copenhagen)
container_volume 60
creator Garcia‐Ramos, Camille
Dabbs, Kevin
Lin, Jack J.
Jones, Jana E.
Stafstrom, Carl E.
Hsu, David A.
Meyerand, Mary Elizabeth
Prabhakaran, Vivek
Hermann, Bruce P.
description Objective Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood idiopathic localization‐related epilepsy syndrome. BECTS presents normal routine magnetic resonance imaging (MRI); however, quantitative analytic techniques have captured subtle cortical and subcortical magnetic resonance anomalies. Network science, including graph theory (GT) analyses, facilitates understanding of brain covariance patterns, potentially informing in important ways how this common self‐limiting epilepsy syndrome may impact normal patterns of brain and cognitive development. Methods GT analyses examined the developmental covariance among cortical and subcortical regions in children with new/recent onset BECTS (n = 19) and typically developing healthy controls (n = 22) who underwent high‐resolution MRI and cognitive assessment at baseline and 2 years later. Global (transitivity, global efficiency, and modularity index [Q]) and regional measures (local efficiency and hubs) were investigated to characterize network development in each group. Associations between baseline‐based GT measures and cognition at both time points addressed the implications of GT analyses for cognition and prospective cognitive development. Furthermore, an individual contribution measure was investigated, reflecting how important for cognition it is for BECTS to resemble the correlation matrices of controls. Results Groups exhibited similar Q and overall network configuration, with BECTS presenting significantly higher transitivity and both global and local efficiency. Furthermore, both groups presented a similar number of hubs, with BECTS showing a higher number in temporal lobe regions compared to controls. The investigated measures were negatively associated with 2‐year cognitive outcomes in BECTS. Significance Children with BECTS present a higher‐than‐normal global developmental configuration compared to controls, along with divergence from normality in terms of regional configuration. Baseline GT measures demonstrate potential as a cognitive biomarker to predict cognitive outcome in BECTS 2 years after diagnosis. Similarities and differences in developmental network configurations and their implications for cognition and behavior across common epilepsy syndromes are of theoretical interest and clinical relevance.
doi_str_mv 10.1111/epi.16290
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2265746584</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2285799600</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3880-8997f1bd1afd940001063780e32eb77883490165adb3420cb70964020b3075d83</originalsourceid><addsrcrecordid>eNp1kc1u1TAQhS0EoreFBS-ALLFpF2nHcfyTJaoKVKqABawjJ5m0bpPY2E6v8g48NL6ksEDCi7Fm9OnYcw4hbxics3wu0NtzJssanpEdE6UuGJPqOdkBMF7UQsMROY7xHgCUVPwlOeKMV4oJsSM_P2Pau_BAzWzGNdpI3UB9cNFjl-wj0jYYO9MeH3F0fsI50dyubkl3dG9zaXG2tzPNXxjRx3UbdpkLLuHkXTAjjd4-YMxP9NSmSAOOJlk3xzvraXK0c7ezPQxekReDGSO-frpPyPcPV98uPxU3Xz5eX76_KTquNRS6rtXA2p6Zoa-rvBUDyZUG5CW2SmnNqxqYFKZveVVC1yqoZQUltByU6DU_Iaebbl70x4IxNZONHY6jmdEtsSlLKVQlha4y-u4f9N4tIXt1oLRQdS0BMnW2UV12LgYcGh_sZMLaMGgOETXZn-Z3RJl9-6S4tBP2f8k_mWTgYgP22dL1_0rN1dfrTfIXqcGcLQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2285799600</pqid></control><display><type>article</type><title>Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Garcia‐Ramos, Camille ; Dabbs, Kevin ; Lin, Jack J. ; Jones, Jana E. ; Stafstrom, Carl E. ; Hsu, David A. ; Meyerand, Mary Elizabeth ; Prabhakaran, Vivek ; Hermann, Bruce P.</creator><creatorcontrib>Garcia‐Ramos, Camille ; Dabbs, Kevin ; Lin, Jack J. ; Jones, Jana E. ; Stafstrom, Carl E. ; Hsu, David A. ; Meyerand, Mary Elizabeth ; Prabhakaran, Vivek ; Hermann, Bruce P.</creatorcontrib><description>Objective Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood idiopathic localization‐related epilepsy syndrome. BECTS presents normal routine magnetic resonance imaging (MRI); however, quantitative analytic techniques have captured subtle cortical and subcortical magnetic resonance anomalies. Network science, including graph theory (GT) analyses, facilitates understanding of brain covariance patterns, potentially informing in important ways how this common self‐limiting epilepsy syndrome may impact normal patterns of brain and cognitive development. Methods GT analyses examined the developmental covariance among cortical and subcortical regions in children with new/recent onset BECTS (n = 19) and typically developing healthy controls (n = 22) who underwent high‐resolution MRI and cognitive assessment at baseline and 2 years later. Global (transitivity, global efficiency, and modularity index [Q]) and regional measures (local efficiency and hubs) were investigated to characterize network development in each group. Associations between baseline‐based GT measures and cognition at both time points addressed the implications of GT analyses for cognition and prospective cognitive development. Furthermore, an individual contribution measure was investigated, reflecting how important for cognition it is for BECTS to resemble the correlation matrices of controls. Results Groups exhibited similar Q and overall network configuration, with BECTS presenting significantly higher transitivity and both global and local efficiency. Furthermore, both groups presented a similar number of hubs, with BECTS showing a higher number in temporal lobe regions compared to controls. The investigated measures were negatively associated with 2‐year cognitive outcomes in BECTS. Significance Children with BECTS present a higher‐than‐normal global developmental configuration compared to controls, along with divergence from normality in terms of regional configuration. Baseline GT measures demonstrate potential as a cognitive biomarker to predict cognitive outcome in BECTS 2 years after diagnosis. Similarities and differences in developmental network configurations and their implications for cognition and behavior across common epilepsy syndromes are of theoretical interest and clinical relevance.</description><identifier>ISSN: 0013-9580</identifier><identifier>EISSN: 1528-1167</identifier><identifier>DOI: 10.1111/epi.16290</identifier><identifier>PMID: 31347155</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Adolescent ; Algorithms ; Benign ; benign epilepsy with centrotemporal spikes ; Brain - diagnostic imaging ; brain volume development ; Child ; Children ; cognition ; Cognition &amp; reasoning ; Cognition - physiology ; Cognitive ability ; Cognitive development ; Cortex ; Efficiency ; Epilepsy ; Epilepsy, Rolandic - diagnostic imaging ; Epilepsy, Rolandic - psychology ; Female ; graph theory ; Humans ; Localization ; Magnetic Resonance Imaging ; Male ; Nerve Net - diagnostic imaging ; Neuroimaging ; Neuropsychological Tests ; NMR ; Nuclear magnetic resonance ; Rolandic epilepsy ; Temporal lobe</subject><ispartof>Epilepsia (Copenhagen), 2019-09, Vol.60 (9), p.1838-1848</ispartof><rights>Wiley Periodicals, Inc. © 2019 International League Against Epilepsy</rights><rights>Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.</rights><rights>Copyright © 2019 International League Against Epilepsy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3880-8997f1bd1afd940001063780e32eb77883490165adb3420cb70964020b3075d83</citedby><cites>FETCH-LOGICAL-c3880-8997f1bd1afd940001063780e32eb77883490165adb3420cb70964020b3075d83</cites><orcidid>0000-0003-4365-9895</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fepi.16290$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fepi.16290$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31347155$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Garcia‐Ramos, Camille</creatorcontrib><creatorcontrib>Dabbs, Kevin</creatorcontrib><creatorcontrib>Lin, Jack J.</creatorcontrib><creatorcontrib>Jones, Jana E.</creatorcontrib><creatorcontrib>Stafstrom, Carl E.</creatorcontrib><creatorcontrib>Hsu, David A.</creatorcontrib><creatorcontrib>Meyerand, Mary Elizabeth</creatorcontrib><creatorcontrib>Prabhakaran, Vivek</creatorcontrib><creatorcontrib>Hermann, Bruce P.</creatorcontrib><title>Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition</title><title>Epilepsia (Copenhagen)</title><addtitle>Epilepsia</addtitle><description>Objective Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood idiopathic localization‐related epilepsy syndrome. BECTS presents normal routine magnetic resonance imaging (MRI); however, quantitative analytic techniques have captured subtle cortical and subcortical magnetic resonance anomalies. Network science, including graph theory (GT) analyses, facilitates understanding of brain covariance patterns, potentially informing in important ways how this common self‐limiting epilepsy syndrome may impact normal patterns of brain and cognitive development. Methods GT analyses examined the developmental covariance among cortical and subcortical regions in children with new/recent onset BECTS (n = 19) and typically developing healthy controls (n = 22) who underwent high‐resolution MRI and cognitive assessment at baseline and 2 years later. Global (transitivity, global efficiency, and modularity index [Q]) and regional measures (local efficiency and hubs) were investigated to characterize network development in each group. Associations between baseline‐based GT measures and cognition at both time points addressed the implications of GT analyses for cognition and prospective cognitive development. Furthermore, an individual contribution measure was investigated, reflecting how important for cognition it is for BECTS to resemble the correlation matrices of controls. Results Groups exhibited similar Q and overall network configuration, with BECTS presenting significantly higher transitivity and both global and local efficiency. Furthermore, both groups presented a similar number of hubs, with BECTS showing a higher number in temporal lobe regions compared to controls. The investigated measures were negatively associated with 2‐year cognitive outcomes in BECTS. Significance Children with BECTS present a higher‐than‐normal global developmental configuration compared to controls, along with divergence from normality in terms of regional configuration. Baseline GT measures demonstrate potential as a cognitive biomarker to predict cognitive outcome in BECTS 2 years after diagnosis. Similarities and differences in developmental network configurations and their implications for cognition and behavior across common epilepsy syndromes are of theoretical interest and clinical relevance.</description><subject>Adolescent</subject><subject>Algorithms</subject><subject>Benign</subject><subject>benign epilepsy with centrotemporal spikes</subject><subject>Brain - diagnostic imaging</subject><subject>brain volume development</subject><subject>Child</subject><subject>Children</subject><subject>cognition</subject><subject>Cognition &amp; reasoning</subject><subject>Cognition - physiology</subject><subject>Cognitive ability</subject><subject>Cognitive development</subject><subject>Cortex</subject><subject>Efficiency</subject><subject>Epilepsy</subject><subject>Epilepsy, Rolandic - diagnostic imaging</subject><subject>Epilepsy, Rolandic - psychology</subject><subject>Female</subject><subject>graph theory</subject><subject>Humans</subject><subject>Localization</subject><subject>Magnetic Resonance Imaging</subject><subject>Male</subject><subject>Nerve Net - diagnostic imaging</subject><subject>Neuroimaging</subject><subject>Neuropsychological Tests</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Rolandic epilepsy</subject><subject>Temporal lobe</subject><issn>0013-9580</issn><issn>1528-1167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1u1TAQhS0EoreFBS-ALLFpF2nHcfyTJaoKVKqABawjJ5m0bpPY2E6v8g48NL6ksEDCi7Fm9OnYcw4hbxics3wu0NtzJssanpEdE6UuGJPqOdkBMF7UQsMROY7xHgCUVPwlOeKMV4oJsSM_P2Pau_BAzWzGNdpI3UB9cNFjl-wj0jYYO9MeH3F0fsI50dyubkl3dG9zaXG2tzPNXxjRx3UbdpkLLuHkXTAjjd4-YMxP9NSmSAOOJlk3xzvraXK0c7ezPQxekReDGSO-frpPyPcPV98uPxU3Xz5eX76_KTquNRS6rtXA2p6Zoa-rvBUDyZUG5CW2SmnNqxqYFKZveVVC1yqoZQUltByU6DU_Iaebbl70x4IxNZONHY6jmdEtsSlLKVQlha4y-u4f9N4tIXt1oLRQdS0BMnW2UV12LgYcGh_sZMLaMGgOETXZn-Z3RJl9-6S4tBP2f8k_mWTgYgP22dL1_0rN1dfrTfIXqcGcLQ</recordid><startdate>201909</startdate><enddate>201909</enddate><creator>Garcia‐Ramos, Camille</creator><creator>Dabbs, Kevin</creator><creator>Lin, Jack J.</creator><creator>Jones, Jana E.</creator><creator>Stafstrom, Carl E.</creator><creator>Hsu, David A.</creator><creator>Meyerand, Mary Elizabeth</creator><creator>Prabhakaran, Vivek</creator><creator>Hermann, Bruce P.</creator><general>Wiley Subscription Services, Inc</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>7TK</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4365-9895</orcidid></search><sort><creationdate>201909</creationdate><title>Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition</title><author>Garcia‐Ramos, Camille ; Dabbs, Kevin ; Lin, Jack J. ; Jones, Jana E. ; Stafstrom, Carl E. ; Hsu, David A. ; Meyerand, Mary Elizabeth ; Prabhakaran, Vivek ; Hermann, Bruce P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3880-8997f1bd1afd940001063780e32eb77883490165adb3420cb70964020b3075d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adolescent</topic><topic>Algorithms</topic><topic>Benign</topic><topic>benign epilepsy with centrotemporal spikes</topic><topic>Brain - diagnostic imaging</topic><topic>brain volume development</topic><topic>Child</topic><topic>Children</topic><topic>cognition</topic><topic>Cognition &amp; reasoning</topic><topic>Cognition - physiology</topic><topic>Cognitive ability</topic><topic>Cognitive development</topic><topic>Cortex</topic><topic>Efficiency</topic><topic>Epilepsy</topic><topic>Epilepsy, Rolandic - diagnostic imaging</topic><topic>Epilepsy, Rolandic - psychology</topic><topic>Female</topic><topic>graph theory</topic><topic>Humans</topic><topic>Localization</topic><topic>Magnetic Resonance Imaging</topic><topic>Male</topic><topic>Nerve Net - diagnostic imaging</topic><topic>Neuroimaging</topic><topic>Neuropsychological Tests</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Rolandic epilepsy</topic><topic>Temporal lobe</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Garcia‐Ramos, Camille</creatorcontrib><creatorcontrib>Dabbs, Kevin</creatorcontrib><creatorcontrib>Lin, Jack J.</creatorcontrib><creatorcontrib>Jones, Jana E.</creatorcontrib><creatorcontrib>Stafstrom, Carl E.</creatorcontrib><creatorcontrib>Hsu, David A.</creatorcontrib><creatorcontrib>Meyerand, Mary Elizabeth</creatorcontrib><creatorcontrib>Prabhakaran, Vivek</creatorcontrib><creatorcontrib>Hermann, Bruce P.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Epilepsia (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Garcia‐Ramos, Camille</au><au>Dabbs, Kevin</au><au>Lin, Jack J.</au><au>Jones, Jana E.</au><au>Stafstrom, Carl E.</au><au>Hsu, David A.</au><au>Meyerand, Mary Elizabeth</au><au>Prabhakaran, Vivek</au><au>Hermann, Bruce P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition</atitle><jtitle>Epilepsia (Copenhagen)</jtitle><addtitle>Epilepsia</addtitle><date>2019-09</date><risdate>2019</risdate><volume>60</volume><issue>9</issue><spage>1838</spage><epage>1848</epage><pages>1838-1848</pages><issn>0013-9580</issn><eissn>1528-1167</eissn><abstract>Objective Benign epilepsy with centrotemporal spikes (BECTS) is the most common childhood idiopathic localization‐related epilepsy syndrome. BECTS presents normal routine magnetic resonance imaging (MRI); however, quantitative analytic techniques have captured subtle cortical and subcortical magnetic resonance anomalies. Network science, including graph theory (GT) analyses, facilitates understanding of brain covariance patterns, potentially informing in important ways how this common self‐limiting epilepsy syndrome may impact normal patterns of brain and cognitive development. Methods GT analyses examined the developmental covariance among cortical and subcortical regions in children with new/recent onset BECTS (n = 19) and typically developing healthy controls (n = 22) who underwent high‐resolution MRI and cognitive assessment at baseline and 2 years later. Global (transitivity, global efficiency, and modularity index [Q]) and regional measures (local efficiency and hubs) were investigated to characterize network development in each group. Associations between baseline‐based GT measures and cognition at both time points addressed the implications of GT analyses for cognition and prospective cognitive development. Furthermore, an individual contribution measure was investigated, reflecting how important for cognition it is for BECTS to resemble the correlation matrices of controls. Results Groups exhibited similar Q and overall network configuration, with BECTS presenting significantly higher transitivity and both global and local efficiency. Furthermore, both groups presented a similar number of hubs, with BECTS showing a higher number in temporal lobe regions compared to controls. The investigated measures were negatively associated with 2‐year cognitive outcomes in BECTS. Significance Children with BECTS present a higher‐than‐normal global developmental configuration compared to controls, along with divergence from normality in terms of regional configuration. Baseline GT measures demonstrate potential as a cognitive biomarker to predict cognitive outcome in BECTS 2 years after diagnosis. Similarities and differences in developmental network configurations and their implications for cognition and behavior across common epilepsy syndromes are of theoretical interest and clinical relevance.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>31347155</pmid><doi>10.1111/epi.16290</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-4365-9895</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0013-9580
ispartof Epilepsia (Copenhagen), 2019-09, Vol.60 (9), p.1838-1848
issn 0013-9580
1528-1167
language eng
recordid cdi_proquest_miscellaneous_2265746584
source Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Adolescent
Algorithms
Benign
benign epilepsy with centrotemporal spikes
Brain - diagnostic imaging
brain volume development
Child
Children
cognition
Cognition & reasoning
Cognition - physiology
Cognitive ability
Cognitive development
Cortex
Efficiency
Epilepsy
Epilepsy, Rolandic - diagnostic imaging
Epilepsy, Rolandic - psychology
Female
graph theory
Humans
Localization
Magnetic Resonance Imaging
Male
Nerve Net - diagnostic imaging
Neuroimaging
Neuropsychological Tests
NMR
Nuclear magnetic resonance
Rolandic epilepsy
Temporal lobe
title Network analysis of prospective brain development in youth with benign epilepsy with centrotemporal spikes and its relationship to cognition
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T06%3A15%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Network%20analysis%20of%20prospective%20brain%20development%20in%20youth%20with%20benign%20epilepsy%20with%20centrotemporal%20spikes%20and%20its%20relationship%20to%20cognition&rft.jtitle=Epilepsia%20(Copenhagen)&rft.au=Garcia%E2%80%90Ramos,%20Camille&rft.date=2019-09&rft.volume=60&rft.issue=9&rft.spage=1838&rft.epage=1848&rft.pages=1838-1848&rft.issn=0013-9580&rft.eissn=1528-1167&rft_id=info:doi/10.1111/epi.16290&rft_dat=%3Cproquest_cross%3E2285799600%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2285799600&rft_id=info:pmid/31347155&rfr_iscdi=true