Safe medicine recommendation via star interactive enhanced-based transformer model

With the rapid development of electronic medical records (EMRs), most existing medicine recommendation systems based on EMRs explore knowledge from the diagnosis history to help doctors prescribe medication correctly. However, due to the limitations of the EMRs’ content, recommendation systems canno...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Computers in biology and medicine 2022-02, Vol.141, p.105159-105159, Article 105159
Hauptverfasser: Wang, Nanxin, Cai, Xiaoyan, Yang, Libin, Mei, Xin
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 105159
container_issue
container_start_page 105159
container_title Computers in biology and medicine
container_volume 141
creator Wang, Nanxin
Cai, Xiaoyan
Yang, Libin
Mei, Xin
description With the rapid development of electronic medical records (EMRs), most existing medicine recommendation systems based on EMRs explore knowledge from the diagnosis history to help doctors prescribe medication correctly. However, due to the limitations of the EMRs’ content, recommendation systems cannot explicitly reflect relevant medical data, such as drug interactions. In recent years, medicine recommendation approaches based on medical knowledge graphs and graph neural networks have been proposed, and the methods based on the Transformer model have been widely used in medicine recommendation systems. Transformer-based medicine recommendation approaches are readily applicable to inductive problems. Unfortunately, traditional Transformer-based medicine recommendation approaches require complex computing power and suffer information loss among the multi-heads in Transformer model, which causes poor performance. At the same time, these approaches have rarely considered the side effects of drug interaction in traditional medical recommendation approaches. To overcome the drawbacks of the current medicine recommendation approaches, we propose a Star Interactive Enhanced-based Transformer (SIET) model. It first constructs a high-quality heterogeneous graph by bridging EMR (MIMIC-III) and a medical knowledge graph (ICD-9 ontology and DrugBank). Then, based on the constructed heterogeneous graph, it extracts a disease homogeneous graph, a medicine homogeneous graph, and a negative factors homogeneous graph to get auxiliary information of disease or drug (named enhanced neighbors). These are fed into the SIET model in conjunction with the relevant information in the EMRs to obtain representations of diseases and drugs. It finally generates the recommended drug list by calculating the cosine similarity between disease combination representations and drug combination representations. Extensive experiments on the MIMIC-III, DrugBank, and ICD-9 ontology datasets demonstrate the outstanding performance of our proposed model. Meanwhile, we show that our SIET model outperforms strong baselines on an inductive medicine recommendation task. •A novel neural model, called SIET, is proposed for medicine recommendation.•An inductive learning-based method is developed to learn entity (disease, medicine) embedding.•SIET achieves state-of-art performance in MIMIC-III, DrugBank and ICD-9 ontology datasets.
doi_str_mv 10.1016/j.compbiomed.2021.105159
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2615922049</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0010482521009537</els_id><sourcerecordid>2623597693</sourcerecordid><originalsourceid>FETCH-LOGICAL-c402t-fa91f71d02b88dce9414d02f4e1fb52298ecbd5d5386b5cc4897b6808dde92ab3</originalsourceid><addsrcrecordid>eNqFkE1rGzEQhkVpaZy0f6EIcullnZFW2pWOTUiaQCCQtmehj1kq45VcaW3ov6-MEwq99CRG88w7w0MIZbBmwIarzdrneedinjGsOXDWviWT-g1ZMTXqDmQv3pIVAINOKC7PyHmtGwAQ0MN7ctYLPTKt2Io8f7MT0hYTfUxIC7bgGVOwS8yJHqKldbGFxrRgsX6JB6SYftrkMXTOVgx0KTbVKZcZC51zwO0H8m6y24ofX94L8uPu9vvNfff49PXh5stj5wXwpZusZtPIAnCnVPCoBROtmASyyUnOtULvggyyV4OT3gulRzcoUCGg5tb1F-TzKXdX8q891sXMsXrcbm3CvK-GD80I5yB0Qy__QTd5X1K7rlG8l3ocdN8odaJ8ybUWnMyuxNmW34aBOXo3G_PXuzl6NyfvbfTTy4K9O_ZeB19FN-D6BGAzcohYTPURjxpjc76YkOP_t_wB9R6ZgA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2623597693</pqid></control><display><type>article</type><title>Safe medicine recommendation via star interactive enhanced-based transformer model</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Wang, Nanxin ; Cai, Xiaoyan ; Yang, Libin ; Mei, Xin</creator><creatorcontrib>Wang, Nanxin ; Cai, Xiaoyan ; Yang, Libin ; Mei, Xin</creatorcontrib><description>With the rapid development of electronic medical records (EMRs), most existing medicine recommendation systems based on EMRs explore knowledge from the diagnosis history to help doctors prescribe medication correctly. However, due to the limitations of the EMRs’ content, recommendation systems cannot explicitly reflect relevant medical data, such as drug interactions. In recent years, medicine recommendation approaches based on medical knowledge graphs and graph neural networks have been proposed, and the methods based on the Transformer model have been widely used in medicine recommendation systems. Transformer-based medicine recommendation approaches are readily applicable to inductive problems. Unfortunately, traditional Transformer-based medicine recommendation approaches require complex computing power and suffer information loss among the multi-heads in Transformer model, which causes poor performance. At the same time, these approaches have rarely considered the side effects of drug interaction in traditional medical recommendation approaches. To overcome the drawbacks of the current medicine recommendation approaches, we propose a Star Interactive Enhanced-based Transformer (SIET) model. It first constructs a high-quality heterogeneous graph by bridging EMR (MIMIC-III) and a medical knowledge graph (ICD-9 ontology and DrugBank). Then, based on the constructed heterogeneous graph, it extracts a disease homogeneous graph, a medicine homogeneous graph, and a negative factors homogeneous graph to get auxiliary information of disease or drug (named enhanced neighbors). These are fed into the SIET model in conjunction with the relevant information in the EMRs to obtain representations of diseases and drugs. It finally generates the recommended drug list by calculating the cosine similarity between disease combination representations and drug combination representations. Extensive experiments on the MIMIC-III, DrugBank, and ICD-9 ontology datasets demonstrate the outstanding performance of our proposed model. Meanwhile, we show that our SIET model outperforms strong baselines on an inductive medicine recommendation task. •A novel neural model, called SIET, is proposed for medicine recommendation.•An inductive learning-based method is developed to learn entity (disease, medicine) embedding.•SIET achieves state-of-art performance in MIMIC-III, DrugBank and ICD-9 ontology datasets.</description><identifier>ISSN: 0010-4825</identifier><identifier>EISSN: 1879-0534</identifier><identifier>DOI: 10.1016/j.compbiomed.2021.105159</identifier><identifier>PMID: 34971981</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Deep learning ; Disease ; Drug interaction ; Drug interactions ; Electronic Health Records ; Electronic medical records ; Graph embedding ; Graph neural networks ; Knowledge representation ; Medical research ; Medicine ; Medicine recommendation ; Neural networks ; Neural Networks, Computer ; Ontology ; Patients ; Performance evaluation ; Physicians ; Prescription drugs ; Recommender systems ; Side effects ; Star interactive enhanced-based transformer ; Transformers</subject><ispartof>Computers in biology and medicine, 2022-02, Vol.141, p.105159-105159, Article 105159</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><rights>2021. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-fa91f71d02b88dce9414d02f4e1fb52298ecbd5d5386b5cc4897b6808dde92ab3</citedby><cites>FETCH-LOGICAL-c402t-fa91f71d02b88dce9414d02f4e1fb52298ecbd5d5386b5cc4897b6808dde92ab3</cites><orcidid>0000-0001-5316-7689</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0010482521009537$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34971981$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Nanxin</creatorcontrib><creatorcontrib>Cai, Xiaoyan</creatorcontrib><creatorcontrib>Yang, Libin</creatorcontrib><creatorcontrib>Mei, Xin</creatorcontrib><title>Safe medicine recommendation via star interactive enhanced-based transformer model</title><title>Computers in biology and medicine</title><addtitle>Comput Biol Med</addtitle><description>With the rapid development of electronic medical records (EMRs), most existing medicine recommendation systems based on EMRs explore knowledge from the diagnosis history to help doctors prescribe medication correctly. However, due to the limitations of the EMRs’ content, recommendation systems cannot explicitly reflect relevant medical data, such as drug interactions. In recent years, medicine recommendation approaches based on medical knowledge graphs and graph neural networks have been proposed, and the methods based on the Transformer model have been widely used in medicine recommendation systems. Transformer-based medicine recommendation approaches are readily applicable to inductive problems. Unfortunately, traditional Transformer-based medicine recommendation approaches require complex computing power and suffer information loss among the multi-heads in Transformer model, which causes poor performance. At the same time, these approaches have rarely considered the side effects of drug interaction in traditional medical recommendation approaches. To overcome the drawbacks of the current medicine recommendation approaches, we propose a Star Interactive Enhanced-based Transformer (SIET) model. It first constructs a high-quality heterogeneous graph by bridging EMR (MIMIC-III) and a medical knowledge graph (ICD-9 ontology and DrugBank). Then, based on the constructed heterogeneous graph, it extracts a disease homogeneous graph, a medicine homogeneous graph, and a negative factors homogeneous graph to get auxiliary information of disease or drug (named enhanced neighbors). These are fed into the SIET model in conjunction with the relevant information in the EMRs to obtain representations of diseases and drugs. It finally generates the recommended drug list by calculating the cosine similarity between disease combination representations and drug combination representations. Extensive experiments on the MIMIC-III, DrugBank, and ICD-9 ontology datasets demonstrate the outstanding performance of our proposed model. Meanwhile, we show that our SIET model outperforms strong baselines on an inductive medicine recommendation task. •A novel neural model, called SIET, is proposed for medicine recommendation.•An inductive learning-based method is developed to learn entity (disease, medicine) embedding.•SIET achieves state-of-art performance in MIMIC-III, DrugBank and ICD-9 ontology datasets.</description><subject>Deep learning</subject><subject>Disease</subject><subject>Drug interaction</subject><subject>Drug interactions</subject><subject>Electronic Health Records</subject><subject>Electronic medical records</subject><subject>Graph embedding</subject><subject>Graph neural networks</subject><subject>Knowledge representation</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine recommendation</subject><subject>Neural networks</subject><subject>Neural Networks, Computer</subject><subject>Ontology</subject><subject>Patients</subject><subject>Performance evaluation</subject><subject>Physicians</subject><subject>Prescription drugs</subject><subject>Recommender systems</subject><subject>Side effects</subject><subject>Star interactive enhanced-based transformer</subject><subject>Transformers</subject><issn>0010-4825</issn><issn>1879-0534</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkE1rGzEQhkVpaZy0f6EIcullnZFW2pWOTUiaQCCQtmehj1kq45VcaW3ov6-MEwq99CRG88w7w0MIZbBmwIarzdrneedinjGsOXDWviWT-g1ZMTXqDmQv3pIVAINOKC7PyHmtGwAQ0MN7ctYLPTKt2Io8f7MT0hYTfUxIC7bgGVOwS8yJHqKldbGFxrRgsX6JB6SYftrkMXTOVgx0KTbVKZcZC51zwO0H8m6y24ofX94L8uPu9vvNfff49PXh5stj5wXwpZusZtPIAnCnVPCoBROtmASyyUnOtULvggyyV4OT3gulRzcoUCGg5tb1F-TzKXdX8q891sXMsXrcbm3CvK-GD80I5yB0Qy__QTd5X1K7rlG8l3ocdN8odaJ8ybUWnMyuxNmW34aBOXo3G_PXuzl6NyfvbfTTy4K9O_ZeB19FN-D6BGAzcohYTPURjxpjc76YkOP_t_wB9R6ZgA</recordid><startdate>202202</startdate><enddate>202202</enddate><creator>Wang, Nanxin</creator><creator>Cai, Xiaoyan</creator><creator>Yang, Libin</creator><creator>Mei, Xin</creator><general>Elsevier Ltd</general><general>Elsevier Limited</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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AL</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>JQ2</scope><scope>K7-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0N</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>M7Z</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5316-7689</orcidid></search><sort><creationdate>202202</creationdate><title>Safe medicine recommendation via star interactive enhanced-based transformer model</title><author>Wang, Nanxin ; Cai, Xiaoyan ; Yang, Libin ; Mei, Xin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-fa91f71d02b88dce9414d02f4e1fb52298ecbd5d5386b5cc4897b6808dde92ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Deep learning</topic><topic>Disease</topic><topic>Drug interaction</topic><topic>Drug interactions</topic><topic>Electronic Health Records</topic><topic>Electronic medical records</topic><topic>Graph embedding</topic><topic>Graph neural networks</topic><topic>Knowledge representation</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine recommendation</topic><topic>Neural networks</topic><topic>Neural Networks, Computer</topic><topic>Ontology</topic><topic>Patients</topic><topic>Performance evaluation</topic><topic>Physicians</topic><topic>Prescription drugs</topic><topic>Recommender systems</topic><topic>Side effects</topic><topic>Star interactive enhanced-based transformer</topic><topic>Transformers</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Nanxin</creatorcontrib><creatorcontrib>Cai, Xiaoyan</creatorcontrib><creatorcontrib>Yang, Libin</creatorcontrib><creatorcontrib>Mei, Xin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Computing Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Computer Science Collection</collection><collection>Computer Science Database</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Computing Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Research Library (Corporate)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Computers in biology and medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Nanxin</au><au>Cai, Xiaoyan</au><au>Yang, Libin</au><au>Mei, Xin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Safe medicine recommendation via star interactive enhanced-based transformer model</atitle><jtitle>Computers in biology and medicine</jtitle><addtitle>Comput Biol Med</addtitle><date>2022-02</date><risdate>2022</risdate><volume>141</volume><spage>105159</spage><epage>105159</epage><pages>105159-105159</pages><artnum>105159</artnum><issn>0010-4825</issn><eissn>1879-0534</eissn><abstract>With the rapid development of electronic medical records (EMRs), most existing medicine recommendation systems based on EMRs explore knowledge from the diagnosis history to help doctors prescribe medication correctly. However, due to the limitations of the EMRs’ content, recommendation systems cannot explicitly reflect relevant medical data, such as drug interactions. In recent years, medicine recommendation approaches based on medical knowledge graphs and graph neural networks have been proposed, and the methods based on the Transformer model have been widely used in medicine recommendation systems. Transformer-based medicine recommendation approaches are readily applicable to inductive problems. Unfortunately, traditional Transformer-based medicine recommendation approaches require complex computing power and suffer information loss among the multi-heads in Transformer model, which causes poor performance. At the same time, these approaches have rarely considered the side effects of drug interaction in traditional medical recommendation approaches. To overcome the drawbacks of the current medicine recommendation approaches, we propose a Star Interactive Enhanced-based Transformer (SIET) model. It first constructs a high-quality heterogeneous graph by bridging EMR (MIMIC-III) and a medical knowledge graph (ICD-9 ontology and DrugBank). Then, based on the constructed heterogeneous graph, it extracts a disease homogeneous graph, a medicine homogeneous graph, and a negative factors homogeneous graph to get auxiliary information of disease or drug (named enhanced neighbors). These are fed into the SIET model in conjunction with the relevant information in the EMRs to obtain representations of diseases and drugs. It finally generates the recommended drug list by calculating the cosine similarity between disease combination representations and drug combination representations. Extensive experiments on the MIMIC-III, DrugBank, and ICD-9 ontology datasets demonstrate the outstanding performance of our proposed model. Meanwhile, we show that our SIET model outperforms strong baselines on an inductive medicine recommendation task. •A novel neural model, called SIET, is proposed for medicine recommendation.•An inductive learning-based method is developed to learn entity (disease, medicine) embedding.•SIET achieves state-of-art performance in MIMIC-III, DrugBank and ICD-9 ontology datasets.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>34971981</pmid><doi>10.1016/j.compbiomed.2021.105159</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-5316-7689</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 0010-4825
ispartof Computers in biology and medicine, 2022-02, Vol.141, p.105159-105159, Article 105159
issn 0010-4825
1879-0534
language eng
recordid cdi_proquest_miscellaneous_2615922049
source MEDLINE; Elsevier ScienceDirect Journals
subjects Deep learning
Disease
Drug interaction
Drug interactions
Electronic Health Records
Electronic medical records
Graph embedding
Graph neural networks
Knowledge representation
Medical research
Medicine
Medicine recommendation
Neural networks
Neural Networks, Computer
Ontology
Patients
Performance evaluation
Physicians
Prescription drugs
Recommender systems
Side effects
Star interactive enhanced-based transformer
Transformers
title Safe medicine recommendation via star interactive enhanced-based transformer model
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T11%3A49%3A51IST&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=Safe%20medicine%20recommendation%20via%20star%20interactive%20enhanced-based%20transformer%20model&rft.jtitle=Computers%20in%20biology%20and%20medicine&rft.au=Wang,%20Nanxin&rft.date=2022-02&rft.volume=141&rft.spage=105159&rft.epage=105159&rft.pages=105159-105159&rft.artnum=105159&rft.issn=0010-4825&rft.eissn=1879-0534&rft_id=info:doi/10.1016/j.compbiomed.2021.105159&rft_dat=%3Cproquest_cross%3E2623597693%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=2623597693&rft_id=info:pmid/34971981&rft_els_id=S0010482521009537&rfr_iscdi=true