Loading…

Rifaximin use favoured micafungin-resistant Candida spp. infections in recipients of allogeneic hematopoietic cell transplantation

Damage to gut mucosa following conditioning regimens may favour bacterial infections that can trigger graft versus host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Rifaximin, an oral and non-absorbable antibiotic, has been recently proposed as eff...

Full description

Saved in:
Bibliographic Details
Published in:Annals of hematology 2021-09, Vol.100 (9), p.2375-2380
Main Authors: Marzuttini, Francesca, Mancusi, Antonella, Bonato, Samanta, Griselli, Mario, Tricarico, Sara, Casarola, Genni, Paradiso, Matteo, Ruggeri, Loredana, Terenzi, Adelmo, Merluzzi, Mara, Prigitano, Anna, Tortorano, Anna Maria, Pitzurra, Lucia, Falini, Brunangelo, Carotti, Alessandra, Velardi, Andrea, Pierini, Antonio
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-c451t-9ba24bd9a6d94b05606edc27be4fdfa70a9835212e5bb8c0d8fdfd8f14cf63d3
cites cdi_FETCH-LOGICAL-c451t-9ba24bd9a6d94b05606edc27be4fdfa70a9835212e5bb8c0d8fdfd8f14cf63d3
container_end_page 2380
container_issue 9
container_start_page 2375
container_title Annals of hematology
container_volume 100
creator Marzuttini, Francesca
Mancusi, Antonella
Bonato, Samanta
Griselli, Mario
Tricarico, Sara
Casarola, Genni
Paradiso, Matteo
Ruggeri, Loredana
Terenzi, Adelmo
Merluzzi, Mara
Prigitano, Anna
Tortorano, Anna Maria
Pitzurra, Lucia
Falini, Brunangelo
Carotti, Alessandra
Velardi, Andrea
Pierini, Antonio
description Damage to gut mucosa following conditioning regimens may favour bacterial infections that can trigger graft versus host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Rifaximin, an oral and non-absorbable antibiotic, has been recently proposed as effective prophylaxis to reduce bacterial infections in the gut and consequently acute GvHD in this setting. The present study evaluated safety and outcomes of HSCT patients that were treated with rifaximin prophylaxis at Perugia University Hospital. Rifaximin prophylaxis was introduced as standard of care in HSCT patients in May 2018. We retrieved data from 118 consecutive transplants, and we compared the outcomes of rifaximin-treated patients with historical controls that did not receive antibiotic prophylaxis. While incidences of neutropenic fever, documented bacterial infections, and aGvHD were similar in the two groups, we found an increased frequency of invasive candidiasis and clinically relevant Candida spp. infections in rifaximin-treated patients (5 patients vs 1 patient, 25% [± 0.99%] vs 1% [± 0.01%], p 
doi_str_mv 10.1007/s00277-021-04569-x
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8357665</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2560161784</sourcerecordid><originalsourceid>FETCH-LOGICAL-c451t-9ba24bd9a6d94b05606edc27be4fdfa70a9835212e5bb8c0d8fdfd8f14cf63d3</originalsourceid><addsrcrecordid>eNp9kU1rHSEUhqU0NLdJ_kBXQtem6jhfm0K59AsChZK9OHq8MczoVJ1wu-0v70luaOmmLvSo7_N68CXkjeDXgvP-XeFc9j3jUjCu2m5kxxdkJ1QjGW8H9ZLs-NiMrMVxTl6Xcs-5kIOSr8h5o8SAcLMjv74Hb45hCZFuBag3D2nL4OgSrPFbPITIMpRQqomV7k10wRla1vWahujB1pBiwZJmsGENEGuhyVMzz-kAEYKld7CYmtYUoOLOwjzTmk0s64yO5pG_JGfezAWuntcLcvvp4-3-C7v59vnr_sMNs6oVlY2TkWpyo-ncqCbedrwDZ2U_gfLOm56bcWhaKSS00zRY7gY8xkko67vGNRfk_cl23aYFSew1m1mvOSwm_9TJBP3vTQx3-pAeNLr2Xdeiwdtng5x-bFCqvse_itiyltiN6EQ_KFTJk8rmVEoG_-cFwfVjbPoUm8bY9FNs-ohQc4IKiuMB8l_r_1C_AYt5n7E</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2560161784</pqid></control><display><type>article</type><title>Rifaximin use favoured micafungin-resistant Candida spp. infections in recipients of allogeneic hematopoietic cell transplantation</title><source>Springer Nature</source><creator>Marzuttini, Francesca ; Mancusi, Antonella ; Bonato, Samanta ; Griselli, Mario ; Tricarico, Sara ; Casarola, Genni ; Paradiso, Matteo ; Ruggeri, Loredana ; Terenzi, Adelmo ; Merluzzi, Mara ; Prigitano, Anna ; Tortorano, Anna Maria ; Pitzurra, Lucia ; Falini, Brunangelo ; Carotti, Alessandra ; Velardi, Andrea ; Pierini, Antonio</creator><creatorcontrib>Marzuttini, Francesca ; Mancusi, Antonella ; Bonato, Samanta ; Griselli, Mario ; Tricarico, Sara ; Casarola, Genni ; Paradiso, Matteo ; Ruggeri, Loredana ; Terenzi, Adelmo ; Merluzzi, Mara ; Prigitano, Anna ; Tortorano, Anna Maria ; Pitzurra, Lucia ; Falini, Brunangelo ; Carotti, Alessandra ; Velardi, Andrea ; Pierini, Antonio</creatorcontrib><description>Damage to gut mucosa following conditioning regimens may favour bacterial infections that can trigger graft versus host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Rifaximin, an oral and non-absorbable antibiotic, has been recently proposed as effective prophylaxis to reduce bacterial infections in the gut and consequently acute GvHD in this setting. The present study evaluated safety and outcomes of HSCT patients that were treated with rifaximin prophylaxis at Perugia University Hospital. Rifaximin prophylaxis was introduced as standard of care in HSCT patients in May 2018. We retrieved data from 118 consecutive transplants, and we compared the outcomes of rifaximin-treated patients with historical controls that did not receive antibiotic prophylaxis. While incidences of neutropenic fever, documented bacterial infections, and aGvHD were similar in the two groups, we found an increased frequency of invasive candidiasis and clinically relevant Candida spp. infections in rifaximin-treated patients (5 patients vs 1 patient, 25% [± 0.99%] vs 1% [± 0.01%], p &lt; .0001). Three rifaximin-treated patients experienced life-threating candidemia (2 C. krusei , 1 C. orthopsilosis ). Rifaximin was the only factor that increased the risk of Candida spp. infections. Rifaximin could have contributed to microbiome disruption which favoured an outbreak of life-threatening Candida infections. This important complication forced us to halt its use. Larger, prospective studies are needed to assess the impact of rifaximin prophylaxis on incidence of bacterial infections, aGvHD, and survival of HSCT patients.</description><identifier>ISSN: 0939-5555</identifier><identifier>EISSN: 1432-0584</identifier><identifier>DOI: 10.1007/s00277-021-04569-x</identifier><identifier>PMID: 34180023</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Antibiotics ; Antifungal agents ; Bacterial infections ; Disease prevention ; Graft versus host disease ; Hematology ; Infections ; Medicine ; Medicine &amp; Public Health ; Oncology ; Original ; Original Article ; Stem cell transplantation ; Transplants &amp; implants</subject><ispartof>Annals of hematology, 2021-09, Vol.100 (9), p.2375-2380</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021. This work 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-c451t-9ba24bd9a6d94b05606edc27be4fdfa70a9835212e5bb8c0d8fdfd8f14cf63d3</citedby><cites>FETCH-LOGICAL-c451t-9ba24bd9a6d94b05606edc27be4fdfa70a9835212e5bb8c0d8fdfd8f14cf63d3</cites><orcidid>0000-0003-3518-0665</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></links><search><creatorcontrib>Marzuttini, Francesca</creatorcontrib><creatorcontrib>Mancusi, Antonella</creatorcontrib><creatorcontrib>Bonato, Samanta</creatorcontrib><creatorcontrib>Griselli, Mario</creatorcontrib><creatorcontrib>Tricarico, Sara</creatorcontrib><creatorcontrib>Casarola, Genni</creatorcontrib><creatorcontrib>Paradiso, Matteo</creatorcontrib><creatorcontrib>Ruggeri, Loredana</creatorcontrib><creatorcontrib>Terenzi, Adelmo</creatorcontrib><creatorcontrib>Merluzzi, Mara</creatorcontrib><creatorcontrib>Prigitano, Anna</creatorcontrib><creatorcontrib>Tortorano, Anna Maria</creatorcontrib><creatorcontrib>Pitzurra, Lucia</creatorcontrib><creatorcontrib>Falini, Brunangelo</creatorcontrib><creatorcontrib>Carotti, Alessandra</creatorcontrib><creatorcontrib>Velardi, Andrea</creatorcontrib><creatorcontrib>Pierini, Antonio</creatorcontrib><title>Rifaximin use favoured micafungin-resistant Candida spp. infections in recipients of allogeneic hematopoietic cell transplantation</title><title>Annals of hematology</title><addtitle>Ann Hematol</addtitle><description>Damage to gut mucosa following conditioning regimens may favour bacterial infections that can trigger graft versus host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Rifaximin, an oral and non-absorbable antibiotic, has been recently proposed as effective prophylaxis to reduce bacterial infections in the gut and consequently acute GvHD in this setting. The present study evaluated safety and outcomes of HSCT patients that were treated with rifaximin prophylaxis at Perugia University Hospital. Rifaximin prophylaxis was introduced as standard of care in HSCT patients in May 2018. We retrieved data from 118 consecutive transplants, and we compared the outcomes of rifaximin-treated patients with historical controls that did not receive antibiotic prophylaxis. While incidences of neutropenic fever, documented bacterial infections, and aGvHD were similar in the two groups, we found an increased frequency of invasive candidiasis and clinically relevant Candida spp. infections in rifaximin-treated patients (5 patients vs 1 patient, 25% [± 0.99%] vs 1% [± 0.01%], p &lt; .0001). Three rifaximin-treated patients experienced life-threating candidemia (2 C. krusei , 1 C. orthopsilosis ). Rifaximin was the only factor that increased the risk of Candida spp. infections. Rifaximin could have contributed to microbiome disruption which favoured an outbreak of life-threatening Candida infections. This important complication forced us to halt its use. Larger, prospective studies are needed to assess the impact of rifaximin prophylaxis on incidence of bacterial infections, aGvHD, and survival of HSCT patients.</description><subject>Antibiotics</subject><subject>Antifungal agents</subject><subject>Bacterial infections</subject><subject>Disease prevention</subject><subject>Graft versus host disease</subject><subject>Hematology</subject><subject>Infections</subject><subject>Medicine</subject><subject>Medicine &amp; Public Health</subject><subject>Oncology</subject><subject>Original</subject><subject>Original Article</subject><subject>Stem cell transplantation</subject><subject>Transplants &amp; implants</subject><issn>0939-5555</issn><issn>1432-0584</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kU1rHSEUhqU0NLdJ_kBXQtem6jhfm0K59AsChZK9OHq8MczoVJ1wu-0v70luaOmmLvSo7_N68CXkjeDXgvP-XeFc9j3jUjCu2m5kxxdkJ1QjGW8H9ZLs-NiMrMVxTl6Xcs-5kIOSr8h5o8SAcLMjv74Hb45hCZFuBag3D2nL4OgSrPFbPITIMpRQqomV7k10wRla1vWahujB1pBiwZJmsGENEGuhyVMzz-kAEYKld7CYmtYUoOLOwjzTmk0s64yO5pG_JGfezAWuntcLcvvp4-3-C7v59vnr_sMNs6oVlY2TkWpyo-ncqCbedrwDZ2U_gfLOm56bcWhaKSS00zRY7gY8xkko67vGNRfk_cl23aYFSew1m1mvOSwm_9TJBP3vTQx3-pAeNLr2Xdeiwdtng5x-bFCqvse_itiyltiN6EQ_KFTJk8rmVEoG_-cFwfVjbPoUm8bY9FNs-ohQc4IKiuMB8l_r_1C_AYt5n7E</recordid><startdate>20210901</startdate><enddate>20210901</enddate><creator>Marzuttini, Francesca</creator><creator>Mancusi, Antonella</creator><creator>Bonato, Samanta</creator><creator>Griselli, Mario</creator><creator>Tricarico, Sara</creator><creator>Casarola, Genni</creator><creator>Paradiso, Matteo</creator><creator>Ruggeri, Loredana</creator><creator>Terenzi, Adelmo</creator><creator>Merluzzi, Mara</creator><creator>Prigitano, Anna</creator><creator>Tortorano, Anna Maria</creator><creator>Pitzurra, Lucia</creator><creator>Falini, Brunangelo</creator><creator>Carotti, Alessandra</creator><creator>Velardi, Andrea</creator><creator>Pierini, Antonio</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3518-0665</orcidid></search><sort><creationdate>20210901</creationdate><title>Rifaximin use favoured micafungin-resistant Candida spp. infections in recipients of allogeneic hematopoietic cell transplantation</title><author>Marzuttini, Francesca ; Mancusi, Antonella ; Bonato, Samanta ; Griselli, Mario ; Tricarico, Sara ; Casarola, Genni ; Paradiso, Matteo ; Ruggeri, Loredana ; Terenzi, Adelmo ; Merluzzi, Mara ; Prigitano, Anna ; Tortorano, Anna Maria ; Pitzurra, Lucia ; Falini, Brunangelo ; Carotti, Alessandra ; Velardi, Andrea ; Pierini, Antonio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-9ba24bd9a6d94b05606edc27be4fdfa70a9835212e5bb8c0d8fdfd8f14cf63d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antibiotics</topic><topic>Antifungal agents</topic><topic>Bacterial infections</topic><topic>Disease prevention</topic><topic>Graft versus host disease</topic><topic>Hematology</topic><topic>Infections</topic><topic>Medicine</topic><topic>Medicine &amp; Public Health</topic><topic>Oncology</topic><topic>Original</topic><topic>Original Article</topic><topic>Stem cell transplantation</topic><topic>Transplants &amp; implants</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marzuttini, Francesca</creatorcontrib><creatorcontrib>Mancusi, Antonella</creatorcontrib><creatorcontrib>Bonato, Samanta</creatorcontrib><creatorcontrib>Griselli, Mario</creatorcontrib><creatorcontrib>Tricarico, Sara</creatorcontrib><creatorcontrib>Casarola, Genni</creatorcontrib><creatorcontrib>Paradiso, Matteo</creatorcontrib><creatorcontrib>Ruggeri, Loredana</creatorcontrib><creatorcontrib>Terenzi, Adelmo</creatorcontrib><creatorcontrib>Merluzzi, Mara</creatorcontrib><creatorcontrib>Prigitano, Anna</creatorcontrib><creatorcontrib>Tortorano, Anna Maria</creatorcontrib><creatorcontrib>Pitzurra, Lucia</creatorcontrib><creatorcontrib>Falini, Brunangelo</creatorcontrib><creatorcontrib>Carotti, Alessandra</creatorcontrib><creatorcontrib>Velardi, Andrea</creatorcontrib><creatorcontrib>Pierini, Antonio</creatorcontrib><collection>SpringerOpen</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing &amp; Allied Health Database</collection><collection>ProQuest Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Annals of hematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marzuttini, Francesca</au><au>Mancusi, Antonella</au><au>Bonato, Samanta</au><au>Griselli, Mario</au><au>Tricarico, Sara</au><au>Casarola, Genni</au><au>Paradiso, Matteo</au><au>Ruggeri, Loredana</au><au>Terenzi, Adelmo</au><au>Merluzzi, Mara</au><au>Prigitano, Anna</au><au>Tortorano, Anna Maria</au><au>Pitzurra, Lucia</au><au>Falini, Brunangelo</au><au>Carotti, Alessandra</au><au>Velardi, Andrea</au><au>Pierini, Antonio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rifaximin use favoured micafungin-resistant Candida spp. infections in recipients of allogeneic hematopoietic cell transplantation</atitle><jtitle>Annals of hematology</jtitle><stitle>Ann Hematol</stitle><date>2021-09-01</date><risdate>2021</risdate><volume>100</volume><issue>9</issue><spage>2375</spage><epage>2380</epage><pages>2375-2380</pages><issn>0939-5555</issn><eissn>1432-0584</eissn><abstract>Damage to gut mucosa following conditioning regimens may favour bacterial infections that can trigger graft versus host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Rifaximin, an oral and non-absorbable antibiotic, has been recently proposed as effective prophylaxis to reduce bacterial infections in the gut and consequently acute GvHD in this setting. The present study evaluated safety and outcomes of HSCT patients that were treated with rifaximin prophylaxis at Perugia University Hospital. Rifaximin prophylaxis was introduced as standard of care in HSCT patients in May 2018. We retrieved data from 118 consecutive transplants, and we compared the outcomes of rifaximin-treated patients with historical controls that did not receive antibiotic prophylaxis. While incidences of neutropenic fever, documented bacterial infections, and aGvHD were similar in the two groups, we found an increased frequency of invasive candidiasis and clinically relevant Candida spp. infections in rifaximin-treated patients (5 patients vs 1 patient, 25% [± 0.99%] vs 1% [± 0.01%], p &lt; .0001). Three rifaximin-treated patients experienced life-threating candidemia (2 C. krusei , 1 C. orthopsilosis ). Rifaximin was the only factor that increased the risk of Candida spp. infections. Rifaximin could have contributed to microbiome disruption which favoured an outbreak of life-threatening Candida infections. This important complication forced us to halt its use. Larger, prospective studies are needed to assess the impact of rifaximin prophylaxis on incidence of bacterial infections, aGvHD, and survival of HSCT patients.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>34180023</pmid><doi>10.1007/s00277-021-04569-x</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-3518-0665</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0939-5555
ispartof Annals of hematology, 2021-09, Vol.100 (9), p.2375-2380
issn 0939-5555
1432-0584
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8357665
source Springer Nature
subjects Antibiotics
Antifungal agents
Bacterial infections
Disease prevention
Graft versus host disease
Hematology
Infections
Medicine
Medicine & Public Health
Oncology
Original
Original Article
Stem cell transplantation
Transplants & implants
title Rifaximin use favoured micafungin-resistant Candida spp. infections in recipients of allogeneic hematopoietic cell transplantation
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T01%3A44%3A11IST&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=Rifaximin%20use%20favoured%20micafungin-resistant%20Candida%20spp.%20infections%20in%20recipients%20of%20allogeneic%20hematopoietic%20cell%20transplantation&rft.jtitle=Annals%20of%20hematology&rft.au=Marzuttini,%20Francesca&rft.date=2021-09-01&rft.volume=100&rft.issue=9&rft.spage=2375&rft.epage=2380&rft.pages=2375-2380&rft.issn=0939-5555&rft.eissn=1432-0584&rft_id=info:doi/10.1007/s00277-021-04569-x&rft_dat=%3Cproquest_pubme%3E2560161784%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c451t-9ba24bd9a6d94b05606edc27be4fdfa70a9835212e5bb8c0d8fdfd8f14cf63d3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2560161784&rft_id=info:pmid/34180023&rfr_iscdi=true