Loading…

Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support

The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with cases of refractory acute respiratory distress syndrome (ARDS) sometimes requiring support with extracorporeal membrane oxygenation (ECMO). Bivalirudin can be used for anticoagulation in patients on ECMO support, but its effic...

Full description

Saved in:
Bibliographic Details
Published in:Journal of cardiothoracic and vascular anesthesia 2022-02, Vol.36 (2), p.414-418
Main Authors: Trigonis, Russell, Smith, Nikki, Porter, Shelley, Anderson, Eve, Jennings, Mckenna, Kapoor, Rajat, Hage, Chadi, Moiz, Salwa, Garcia, Jose, Rahman, Omar
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c455t-833640628bc85c0fbbcea438a323d392dc264da9ab7c2093cca43c79ea86439f3
cites cdi_FETCH-LOGICAL-c455t-833640628bc85c0fbbcea438a323d392dc264da9ab7c2093cca43c79ea86439f3
container_end_page 418
container_issue 2
container_start_page 414
container_title Journal of cardiothoracic and vascular anesthesia
container_volume 36
creator Trigonis, Russell
Smith, Nikki
Porter, Shelley
Anderson, Eve
Jennings, Mckenna
Kapoor, Rajat
Hage, Chadi
Moiz, Salwa
Garcia, Jose
Rahman, Omar
description The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with cases of refractory acute respiratory distress syndrome (ARDS) sometimes requiring support with extracorporeal membrane oxygenation (ECMO). Bivalirudin can be used for anticoagulation in patients on ECMO support, but its efficacy and safety in patients with COVID-19 is unknown. The authors set out to compare the pharmacologic characteristics and dosing requirements of bivalirudin in patients requiring ECMO support for ARDS due to COVID-19 versus ARDS from other etiologies. This retrospective case-control study was performed at Indiana University Health Methodist Hospital in Indianapolis, Indiana. Patients were included if they were on venovenous ECMO support between June 2019 and June 2020, and divided into two groups: ARDS secondary to COVID-19 and those with ARDS from another etiology (Non-COVID). Patient demographics, such as age, sex, weight, chronic comorbid conditions, baseline antiplatelet and anticoagulant use, antiplatelet use during ECMO, and need for renal replacement therapy were collected, and compared between groups. Time to activated partial thromboplastin time (aPTT) goal, percentage of time at aPTT goal, bivalirudin rates, total bivalirudin requirements, total duration on bivalirudin, total duration on ECMO, mortality, and complications associated with ECMO were collected and compared between groups. A total of 42 patients met inclusion criteria (n = 19 COVID-19, n = 23 non-COVID). However, percentages of aPTTs at goal were maintained more consistently in patients with COVID-19 versus non-COVID (86% v 74%: p < 0.01). Higher median (IQR) daily rates (3.1 μg/kg/min [2.3-5.2] v 2.4 μg/kg/min [1.7-3.3]: p = 0.05) and higher median (IQR) maximum rates of bivalirudin (5 μg/kg/min [3.7-7.5] v 3.8 μg/kg/min [2.5-5]: p = 0.03) were required in the COVID-19 group versus the non-COVID group. Time to goal aPTT was similar between groups. There were no differences in complications associated with anticoagulation, as demonstrated by similar rates of bleeding and thrombosis between both groups. Patients on ECMO with ARDS from COVID-19 require more bivalirudin overall and higher rates of bivalirudin to maintain goal aPTTs compared with patients without COVID-19. However, COVID-19 patients more consistently maintain goal aPTT. Future randomized trials are needed to support efficacy and safety of bivalirudin for anticoagulation of COVID-19 patients on ECMO.
doi_str_mv 10.1053/j.jvca.2021.10.026
format article
fullrecord <record><control><sourceid>elsevier_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8526440</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1053077021009435</els_id><sourcerecordid>S1053077021009435</sourcerecordid><originalsourceid>FETCH-LOGICAL-c455t-833640628bc85c0fbbcea438a323d392dc264da9ab7c2093cca43c79ea86439f3</originalsourceid><addsrcrecordid>eNp9kN9KwzAYxYMobk5fwAvJC3SmSfoPRJhz6mAy0eltSL-mW0rX1LQd7O3NmA698SYJ5zvnJPkhdOmToU8Cdl0Miw3IISXUd8KQ0PAI9f2AUS_mlB67s3N5JIpID501TUGI7wdBdIp6jEcxpYz3EUzyXIOELTY5vtMbWWrbZbrCubF4sVJW1qprNeBR5VYjl10pW20q7Czj-cf03vMT_OIkVbUNflWfnba6WuLJ-HmO37q6NrY9Rye5LBt18b0P0PvDZDF-8mbzx-l4NPOAB0HrxYyFnIQ0TiEOgORpCkpyFktGWcYSmgENeSYTmUZAScIA3BSiRMk45CzJ2QDd7nvrLl2rDNyTrCxFbfVa2q0wUou_k0qvxNJsRBy4Zk5cAd0XgDVNY1V-yPpE7GCKQuyQix3yneaQu9DV71sPkR_GznCzNyj3941WVjTgcIHKtFXQiszo__q_AK5qlAk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support</title><source>ScienceDirect Journals</source><creator>Trigonis, Russell ; Smith, Nikki ; Porter, Shelley ; Anderson, Eve ; Jennings, Mckenna ; Kapoor, Rajat ; Hage, Chadi ; Moiz, Salwa ; Garcia, Jose ; Rahman, Omar</creator><creatorcontrib>Trigonis, Russell ; Smith, Nikki ; Porter, Shelley ; Anderson, Eve ; Jennings, Mckenna ; Kapoor, Rajat ; Hage, Chadi ; Moiz, Salwa ; Garcia, Jose ; Rahman, Omar</creatorcontrib><description>The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with cases of refractory acute respiratory distress syndrome (ARDS) sometimes requiring support with extracorporeal membrane oxygenation (ECMO). Bivalirudin can be used for anticoagulation in patients on ECMO support, but its efficacy and safety in patients with COVID-19 is unknown. The authors set out to compare the pharmacologic characteristics and dosing requirements of bivalirudin in patients requiring ECMO support for ARDS due to COVID-19 versus ARDS from other etiologies. This retrospective case-control study was performed at Indiana University Health Methodist Hospital in Indianapolis, Indiana. Patients were included if they were on venovenous ECMO support between June 2019 and June 2020, and divided into two groups: ARDS secondary to COVID-19 and those with ARDS from another etiology (Non-COVID). Patient demographics, such as age, sex, weight, chronic comorbid conditions, baseline antiplatelet and anticoagulant use, antiplatelet use during ECMO, and need for renal replacement therapy were collected, and compared between groups. Time to activated partial thromboplastin time (aPTT) goal, percentage of time at aPTT goal, bivalirudin rates, total bivalirudin requirements, total duration on bivalirudin, total duration on ECMO, mortality, and complications associated with ECMO were collected and compared between groups. A total of 42 patients met inclusion criteria (n = 19 COVID-19, n = 23 non-COVID). However, percentages of aPTTs at goal were maintained more consistently in patients with COVID-19 versus non-COVID (86% v 74%: p &lt; 0.01). Higher median (IQR) daily rates (3.1 μg/kg/min [2.3-5.2] v 2.4 μg/kg/min [1.7-3.3]: p = 0.05) and higher median (IQR) maximum rates of bivalirudin (5 μg/kg/min [3.7-7.5] v 3.8 μg/kg/min [2.5-5]: p = 0.03) were required in the COVID-19 group versus the non-COVID group. Time to goal aPTT was similar between groups. There were no differences in complications associated with anticoagulation, as demonstrated by similar rates of bleeding and thrombosis between both groups. Patients on ECMO with ARDS from COVID-19 require more bivalirudin overall and higher rates of bivalirudin to maintain goal aPTTs compared with patients without COVID-19. However, COVID-19 patients more consistently maintain goal aPTT. Future randomized trials are needed to support efficacy and safety of bivalirudin for anticoagulation of COVID-19 patients on ECMO.</description><identifier>ISSN: 1053-0770</identifier><identifier>EISSN: 1532-8422</identifier><identifier>DOI: 10.1053/j.jvca.2021.10.026</identifier><identifier>PMID: 34782234</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Anticoagulants - adverse effects ; anticoagulation ; Bivalirudin ; Case-Control Studies ; COVID-19 ; ECMO ; Extracorporeal Membrane Oxygenation ; Hirudins ; Humans ; Original ; Peptide Fragments ; Recombinant Proteins ; Respiratory Failure ; Retrospective Studies ; SARS-CoV-2 ; thrombosis</subject><ispartof>Journal of cardiothoracic and vascular anesthesia, 2022-02, Vol.36 (2), p.414-418</ispartof><rights>2021 Elsevier Inc.</rights><rights>Copyright © 2021 Elsevier Inc. All rights reserved.</rights><rights>2021 Elsevier Inc. All rights reserved. 2021 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-833640628bc85c0fbbcea438a323d392dc264da9ab7c2093cca43c79ea86439f3</citedby><cites>FETCH-LOGICAL-c455t-833640628bc85c0fbbcea438a323d392dc264da9ab7c2093cca43c79ea86439f3</cites><orcidid>0000-0002-4277-5280 ; 0000-0002-9700-6796 ; 0000-0003-0109-6350</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34782234$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Trigonis, Russell</creatorcontrib><creatorcontrib>Smith, Nikki</creatorcontrib><creatorcontrib>Porter, Shelley</creatorcontrib><creatorcontrib>Anderson, Eve</creatorcontrib><creatorcontrib>Jennings, Mckenna</creatorcontrib><creatorcontrib>Kapoor, Rajat</creatorcontrib><creatorcontrib>Hage, Chadi</creatorcontrib><creatorcontrib>Moiz, Salwa</creatorcontrib><creatorcontrib>Garcia, Jose</creatorcontrib><creatorcontrib>Rahman, Omar</creatorcontrib><title>Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support</title><title>Journal of cardiothoracic and vascular anesthesia</title><addtitle>J Cardiothorac Vasc Anesth</addtitle><description>The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with cases of refractory acute respiratory distress syndrome (ARDS) sometimes requiring support with extracorporeal membrane oxygenation (ECMO). Bivalirudin can be used for anticoagulation in patients on ECMO support, but its efficacy and safety in patients with COVID-19 is unknown. The authors set out to compare the pharmacologic characteristics and dosing requirements of bivalirudin in patients requiring ECMO support for ARDS due to COVID-19 versus ARDS from other etiologies. This retrospective case-control study was performed at Indiana University Health Methodist Hospital in Indianapolis, Indiana. Patients were included if they were on venovenous ECMO support between June 2019 and June 2020, and divided into two groups: ARDS secondary to COVID-19 and those with ARDS from another etiology (Non-COVID). Patient demographics, such as age, sex, weight, chronic comorbid conditions, baseline antiplatelet and anticoagulant use, antiplatelet use during ECMO, and need for renal replacement therapy were collected, and compared between groups. Time to activated partial thromboplastin time (aPTT) goal, percentage of time at aPTT goal, bivalirudin rates, total bivalirudin requirements, total duration on bivalirudin, total duration on ECMO, mortality, and complications associated with ECMO were collected and compared between groups. A total of 42 patients met inclusion criteria (n = 19 COVID-19, n = 23 non-COVID). However, percentages of aPTTs at goal were maintained more consistently in patients with COVID-19 versus non-COVID (86% v 74%: p &lt; 0.01). Higher median (IQR) daily rates (3.1 μg/kg/min [2.3-5.2] v 2.4 μg/kg/min [1.7-3.3]: p = 0.05) and higher median (IQR) maximum rates of bivalirudin (5 μg/kg/min [3.7-7.5] v 3.8 μg/kg/min [2.5-5]: p = 0.03) were required in the COVID-19 group versus the non-COVID group. Time to goal aPTT was similar between groups. There were no differences in complications associated with anticoagulation, as demonstrated by similar rates of bleeding and thrombosis between both groups. Patients on ECMO with ARDS from COVID-19 require more bivalirudin overall and higher rates of bivalirudin to maintain goal aPTTs compared with patients without COVID-19. However, COVID-19 patients more consistently maintain goal aPTT. Future randomized trials are needed to support efficacy and safety of bivalirudin for anticoagulation of COVID-19 patients on ECMO.</description><subject>Anticoagulants - adverse effects</subject><subject>anticoagulation</subject><subject>Bivalirudin</subject><subject>Case-Control Studies</subject><subject>COVID-19</subject><subject>ECMO</subject><subject>Extracorporeal Membrane Oxygenation</subject><subject>Hirudins</subject><subject>Humans</subject><subject>Original</subject><subject>Peptide Fragments</subject><subject>Recombinant Proteins</subject><subject>Respiratory Failure</subject><subject>Retrospective Studies</subject><subject>SARS-CoV-2</subject><subject>thrombosis</subject><issn>1053-0770</issn><issn>1532-8422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kN9KwzAYxYMobk5fwAvJC3SmSfoPRJhz6mAy0eltSL-mW0rX1LQd7O3NmA698SYJ5zvnJPkhdOmToU8Cdl0Miw3IISXUd8KQ0PAI9f2AUS_mlB67s3N5JIpID501TUGI7wdBdIp6jEcxpYz3EUzyXIOELTY5vtMbWWrbZbrCubF4sVJW1qprNeBR5VYjl10pW20q7Czj-cf03vMT_OIkVbUNflWfnba6WuLJ-HmO37q6NrY9Rye5LBt18b0P0PvDZDF-8mbzx-l4NPOAB0HrxYyFnIQ0TiEOgORpCkpyFktGWcYSmgENeSYTmUZAScIA3BSiRMk45CzJ2QDd7nvrLl2rDNyTrCxFbfVa2q0wUou_k0qvxNJsRBy4Zk5cAd0XgDVNY1V-yPpE7GCKQuyQix3yneaQu9DV71sPkR_GznCzNyj3941WVjTgcIHKtFXQiszo__q_AK5qlAk</recordid><startdate>20220201</startdate><enddate>20220201</enddate><creator>Trigonis, Russell</creator><creator>Smith, Nikki</creator><creator>Porter, Shelley</creator><creator>Anderson, Eve</creator><creator>Jennings, Mckenna</creator><creator>Kapoor, Rajat</creator><creator>Hage, Chadi</creator><creator>Moiz, Salwa</creator><creator>Garcia, Jose</creator><creator>Rahman, Omar</creator><general>Elsevier 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>5PM</scope><orcidid>https://orcid.org/0000-0002-4277-5280</orcidid><orcidid>https://orcid.org/0000-0002-9700-6796</orcidid><orcidid>https://orcid.org/0000-0003-0109-6350</orcidid></search><sort><creationdate>20220201</creationdate><title>Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support</title><author>Trigonis, Russell ; Smith, Nikki ; Porter, Shelley ; Anderson, Eve ; Jennings, Mckenna ; Kapoor, Rajat ; Hage, Chadi ; Moiz, Salwa ; Garcia, Jose ; Rahman, Omar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-833640628bc85c0fbbcea438a323d392dc264da9ab7c2093cca43c79ea86439f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Anticoagulants - adverse effects</topic><topic>anticoagulation</topic><topic>Bivalirudin</topic><topic>Case-Control Studies</topic><topic>COVID-19</topic><topic>ECMO</topic><topic>Extracorporeal Membrane Oxygenation</topic><topic>Hirudins</topic><topic>Humans</topic><topic>Original</topic><topic>Peptide Fragments</topic><topic>Recombinant Proteins</topic><topic>Respiratory Failure</topic><topic>Retrospective Studies</topic><topic>SARS-CoV-2</topic><topic>thrombosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Trigonis, Russell</creatorcontrib><creatorcontrib>Smith, Nikki</creatorcontrib><creatorcontrib>Porter, Shelley</creatorcontrib><creatorcontrib>Anderson, Eve</creatorcontrib><creatorcontrib>Jennings, Mckenna</creatorcontrib><creatorcontrib>Kapoor, Rajat</creatorcontrib><creatorcontrib>Hage, Chadi</creatorcontrib><creatorcontrib>Moiz, Salwa</creatorcontrib><creatorcontrib>Garcia, Jose</creatorcontrib><creatorcontrib>Rahman, Omar</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cardiothoracic and vascular anesthesia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Trigonis, Russell</au><au>Smith, Nikki</au><au>Porter, Shelley</au><au>Anderson, Eve</au><au>Jennings, Mckenna</au><au>Kapoor, Rajat</au><au>Hage, Chadi</au><au>Moiz, Salwa</au><au>Garcia, Jose</au><au>Rahman, Omar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support</atitle><jtitle>Journal of cardiothoracic and vascular anesthesia</jtitle><addtitle>J Cardiothorac Vasc Anesth</addtitle><date>2022-02-01</date><risdate>2022</risdate><volume>36</volume><issue>2</issue><spage>414</spage><epage>418</epage><pages>414-418</pages><issn>1053-0770</issn><eissn>1532-8422</eissn><abstract>The Coronavirus Disease 2019 (COVID-19) pandemic has been associated with cases of refractory acute respiratory distress syndrome (ARDS) sometimes requiring support with extracorporeal membrane oxygenation (ECMO). Bivalirudin can be used for anticoagulation in patients on ECMO support, but its efficacy and safety in patients with COVID-19 is unknown. The authors set out to compare the pharmacologic characteristics and dosing requirements of bivalirudin in patients requiring ECMO support for ARDS due to COVID-19 versus ARDS from other etiologies. This retrospective case-control study was performed at Indiana University Health Methodist Hospital in Indianapolis, Indiana. Patients were included if they were on venovenous ECMO support between June 2019 and June 2020, and divided into two groups: ARDS secondary to COVID-19 and those with ARDS from another etiology (Non-COVID). Patient demographics, such as age, sex, weight, chronic comorbid conditions, baseline antiplatelet and anticoagulant use, antiplatelet use during ECMO, and need for renal replacement therapy were collected, and compared between groups. Time to activated partial thromboplastin time (aPTT) goal, percentage of time at aPTT goal, bivalirudin rates, total bivalirudin requirements, total duration on bivalirudin, total duration on ECMO, mortality, and complications associated with ECMO were collected and compared between groups. A total of 42 patients met inclusion criteria (n = 19 COVID-19, n = 23 non-COVID). However, percentages of aPTTs at goal were maintained more consistently in patients with COVID-19 versus non-COVID (86% v 74%: p &lt; 0.01). Higher median (IQR) daily rates (3.1 μg/kg/min [2.3-5.2] v 2.4 μg/kg/min [1.7-3.3]: p = 0.05) and higher median (IQR) maximum rates of bivalirudin (5 μg/kg/min [3.7-7.5] v 3.8 μg/kg/min [2.5-5]: p = 0.03) were required in the COVID-19 group versus the non-COVID group. Time to goal aPTT was similar between groups. There were no differences in complications associated with anticoagulation, as demonstrated by similar rates of bleeding and thrombosis between both groups. Patients on ECMO with ARDS from COVID-19 require more bivalirudin overall and higher rates of bivalirudin to maintain goal aPTTs compared with patients without COVID-19. However, COVID-19 patients more consistently maintain goal aPTT. Future randomized trials are needed to support efficacy and safety of bivalirudin for anticoagulation of COVID-19 patients on ECMO.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>34782234</pmid><doi>10.1053/j.jvca.2021.10.026</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0002-4277-5280</orcidid><orcidid>https://orcid.org/0000-0002-9700-6796</orcidid><orcidid>https://orcid.org/0000-0003-0109-6350</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1053-0770
ispartof Journal of cardiothoracic and vascular anesthesia, 2022-02, Vol.36 (2), p.414-418
issn 1053-0770
1532-8422
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8526440
source ScienceDirect Journals
subjects Anticoagulants - adverse effects
anticoagulation
Bivalirudin
Case-Control Studies
COVID-19
ECMO
Extracorporeal Membrane Oxygenation
Hirudins
Humans
Original
Peptide Fragments
Recombinant Proteins
Respiratory Failure
Retrospective Studies
SARS-CoV-2
thrombosis
title Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T21%3A09%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-elsevier_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Efficacy%20of%20Bivalirudin%20for%20Therapeutic%20Anticoagulation%20in%20COVID-19%20Patients%20Requiring%20ECMO%20Support&rft.jtitle=Journal%20of%20cardiothoracic%20and%20vascular%20anesthesia&rft.au=Trigonis,%20Russell&rft.date=2022-02-01&rft.volume=36&rft.issue=2&rft.spage=414&rft.epage=418&rft.pages=414-418&rft.issn=1053-0770&rft.eissn=1532-8422&rft_id=info:doi/10.1053/j.jvca.2021.10.026&rft_dat=%3Celsevier_pubme%3ES1053077021009435%3C/elsevier_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c455t-833640628bc85c0fbbcea438a323d392dc264da9ab7c2093cca43c79ea86439f3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/34782234&rfr_iscdi=true