The synthetic synergistic cinnamon oil CIN-102 is active against Madurella mycetomatis, the most common causative agent of mycetoma

Mycetoma is a devastating neglected tropical infection of the subcutaneous tissue and most commonly caused by the fungus Madurella mycetomatis. Treatment of mycetoma consists of a combination of a long term antifungal treatment with itraconazole and surgery. However, treatment is associated with low...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:PLoS neglected tropical diseases 2021-06, Vol.15 (6), p.e0009488-e0009488
Hauptverfasser: Konings, Mickey, Eadie, Kimberly, Lim, Wilson, Fahal, Ahmed H, Mouton, Johan, Tesse, Nicolas, van de Sande, Wendy W. J
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page e0009488
container_issue 6
container_start_page e0009488
container_title PLoS neglected tropical diseases
container_volume 15
creator Konings, Mickey
Eadie, Kimberly
Lim, Wilson
Fahal, Ahmed H
Mouton, Johan
Tesse, Nicolas
van de Sande, Wendy W. J
description Mycetoma is a devastating neglected tropical infection of the subcutaneous tissue and most commonly caused by the fungus Madurella mycetomatis. Treatment of mycetoma consists of a combination of a long term antifungal treatment with itraconazole and surgery. However, treatment is associated with low success rates. Therefore, there is a need to identify novel treatments for mycetoma. CIN-102 is a synthetic partial copy of cinnamon oils with activity against many pathogenic bacteria and fungi. In this study we determined the in vitro activity of CIN-102 against 21 M. mycetomatis isolates and its in vivo efficacy in a M. mycetomatis infected Galleria mellonella larval model. In vitro, CIN-102 was active against M. mycetomatis with MICs ranging from 32 [mu]g/mL to 512 [mu]g/mL. 128 [mu]g/mL was needed to inhibit the growth in 50% of tested isolates. In vivo, concentrations below the MIC of 40 mg/kg and 80 mg/kg CIN-102 prolonged larval survival, but higher concentrations of CIN-102 did not.
doi_str_mv 10.1371/journal.pntd.0009488
format Article
fullrecord <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_2552289311</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A668346727</galeid><doaj_id>oai_doaj_org_article_658b6137611949a88170eb4e82f1935b</doaj_id><sourcerecordid>A668346727</sourcerecordid><originalsourceid>FETCH-LOGICAL-c601t-d0dc0c0ab2907ab2e5ca43530e5667167a1ed8b5c5d0b82bd67a0796b5587da43</originalsourceid><addsrcrecordid>eNptkt-L1DAQx4so3rn6HwgGBPHBXZOmSdMX4Vj8sXDqy_kcpkm6m6VN1iQ92Gf_cdPbetzKEUiGyWe-k5lMUbwmeEVoTT7u_Rgc9KuDS3qFMW4qIZ4Ul6ShbFnWlD19YF8UL2LcY8waJsjz4oJWBPOG0sviz83OoHh0aWeSVZNlwtbGyVbWORi8Q972aL35sSS4RDYiUMneGgRbsC4m9B30GEzfAxqOyiQ_QLLxA8qCaPD5XvlhElEwRpgDjUvId_f8y-JZB300r-ZzUfz68vlm_W15_fPrZn11vVQck7TUWCusMLRlg-u8G6agooxiwzivCa-BGC1appjGrShbnT24bnjLmKh1RhfFm5PuofdRzv2LsmSsLEVDCcnE5kRoD3t5CHaAcJQerLxz-LCVEHJveiM5Ey3PH8EJaaoGhCA1Nm1lRNlNbW-z1qc529gORqtcdID-TPT8xtmd3PpbKUrCWf61RfF-Fgj-92hikoONauq0M36c3k0bIQSmOKNv_0Mfr26mtpALsK7zOa-aROUV54JWvL5Lu3qEykubwSrvTGez_yzg3YOAnYE-7aLvx2S9i-dgdQJV8DEG0903g2A5zfS_V8tppuU80_QvMvTpjA</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2552289311</pqid></control><display><type>article</type><title>The synthetic synergistic cinnamon oil CIN-102 is active against Madurella mycetomatis, the most common causative agent of mycetoma</title><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central Open Access</source><source>Public Library of Science (PLoS) Journals Open Access</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Konings, Mickey ; Eadie, Kimberly ; Lim, Wilson ; Fahal, Ahmed H ; Mouton, Johan ; Tesse, Nicolas ; van de Sande, Wendy W. J</creator><contributor>Salgado, Claudio Guedes</contributor><creatorcontrib>Konings, Mickey ; Eadie, Kimberly ; Lim, Wilson ; Fahal, Ahmed H ; Mouton, Johan ; Tesse, Nicolas ; van de Sande, Wendy W. J ; Salgado, Claudio Guedes</creatorcontrib><description>Mycetoma is a devastating neglected tropical infection of the subcutaneous tissue and most commonly caused by the fungus Madurella mycetomatis. Treatment of mycetoma consists of a combination of a long term antifungal treatment with itraconazole and surgery. However, treatment is associated with low success rates. Therefore, there is a need to identify novel treatments for mycetoma. CIN-102 is a synthetic partial copy of cinnamon oils with activity against many pathogenic bacteria and fungi. In this study we determined the in vitro activity of CIN-102 against 21 M. mycetomatis isolates and its in vivo efficacy in a M. mycetomatis infected Galleria mellonella larval model. In vitro, CIN-102 was active against M. mycetomatis with MICs ranging from 32 [mu]g/mL to 512 [mu]g/mL. 128 [mu]g/mL was needed to inhibit the growth in 50% of tested isolates. In vivo, concentrations below the MIC of 40 mg/kg and 80 mg/kg CIN-102 prolonged larval survival, but higher concentrations of CIN-102 did not.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0009488</identifier><identifier>PMID: 34106933</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Antifungal agents ; Biology and Life Sciences ; Care and treatment ; Cinnamon ; Drug dosages ; Essences and essential oils ; Fungal diseases ; Fungi ; Fungicides ; Genomes ; Health aspects ; Infections ; Itraconazole ; Larvae ; Madurella mycetomatis ; Medicine and Health Sciences ; Minimum inhibitory concentration ; Mycetoma ; Oils &amp; fats ; Pathogenic bacteria ; Pathogens ; People and Places ; Pharmacology, Experimental ; Physical Sciences ; Solvents ; Surgery ; Survival ; Tropical climate ; Tropical diseases</subject><ispartof>PLoS neglected tropical diseases, 2021-06, Vol.15 (6), p.e0009488-e0009488</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Konings et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Konings et al 2021 Konings et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c601t-d0dc0c0ab2907ab2e5ca43530e5667167a1ed8b5c5d0b82bd67a0796b5587da43</citedby><cites>FETCH-LOGICAL-c601t-d0dc0c0ab2907ab2e5ca43530e5667167a1ed8b5c5d0b82bd67a0796b5587da43</cites><orcidid>0000-0002-8652-8783 ; 0000-0002-7263-7268</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/PMC8216527/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216527/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23868,27926,27927,53793,53795</link.rule.ids></links><search><contributor>Salgado, Claudio Guedes</contributor><creatorcontrib>Konings, Mickey</creatorcontrib><creatorcontrib>Eadie, Kimberly</creatorcontrib><creatorcontrib>Lim, Wilson</creatorcontrib><creatorcontrib>Fahal, Ahmed H</creatorcontrib><creatorcontrib>Mouton, Johan</creatorcontrib><creatorcontrib>Tesse, Nicolas</creatorcontrib><creatorcontrib>van de Sande, Wendy W. J</creatorcontrib><title>The synthetic synergistic cinnamon oil CIN-102 is active against Madurella mycetomatis, the most common causative agent of mycetoma</title><title>PLoS neglected tropical diseases</title><description>Mycetoma is a devastating neglected tropical infection of the subcutaneous tissue and most commonly caused by the fungus Madurella mycetomatis. Treatment of mycetoma consists of a combination of a long term antifungal treatment with itraconazole and surgery. However, treatment is associated with low success rates. Therefore, there is a need to identify novel treatments for mycetoma. CIN-102 is a synthetic partial copy of cinnamon oils with activity against many pathogenic bacteria and fungi. In this study we determined the in vitro activity of CIN-102 against 21 M. mycetomatis isolates and its in vivo efficacy in a M. mycetomatis infected Galleria mellonella larval model. In vitro, CIN-102 was active against M. mycetomatis with MICs ranging from 32 [mu]g/mL to 512 [mu]g/mL. 128 [mu]g/mL was needed to inhibit the growth in 50% of tested isolates. In vivo, concentrations below the MIC of 40 mg/kg and 80 mg/kg CIN-102 prolonged larval survival, but higher concentrations of CIN-102 did not.</description><subject>Antifungal agents</subject><subject>Biology and Life Sciences</subject><subject>Care and treatment</subject><subject>Cinnamon</subject><subject>Drug dosages</subject><subject>Essences and essential oils</subject><subject>Fungal diseases</subject><subject>Fungi</subject><subject>Fungicides</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>Infections</subject><subject>Itraconazole</subject><subject>Larvae</subject><subject>Madurella mycetomatis</subject><subject>Medicine and Health Sciences</subject><subject>Minimum inhibitory concentration</subject><subject>Mycetoma</subject><subject>Oils &amp; fats</subject><subject>Pathogenic bacteria</subject><subject>Pathogens</subject><subject>People and Places</subject><subject>Pharmacology, Experimental</subject><subject>Physical Sciences</subject><subject>Solvents</subject><subject>Surgery</subject><subject>Survival</subject><subject>Tropical climate</subject><subject>Tropical diseases</subject><issn>1935-2735</issn><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNptkt-L1DAQx4so3rn6HwgGBPHBXZOmSdMX4Vj8sXDqy_kcpkm6m6VN1iQ92Gf_cdPbetzKEUiGyWe-k5lMUbwmeEVoTT7u_Rgc9KuDS3qFMW4qIZ4Ul6ShbFnWlD19YF8UL2LcY8waJsjz4oJWBPOG0sviz83OoHh0aWeSVZNlwtbGyVbWORi8Q972aL35sSS4RDYiUMneGgRbsC4m9B30GEzfAxqOyiQ_QLLxA8qCaPD5XvlhElEwRpgDjUvId_f8y-JZB300r-ZzUfz68vlm_W15_fPrZn11vVQck7TUWCusMLRlg-u8G6agooxiwzivCa-BGC1appjGrShbnT24bnjLmKh1RhfFm5PuofdRzv2LsmSsLEVDCcnE5kRoD3t5CHaAcJQerLxz-LCVEHJveiM5Ey3PH8EJaaoGhCA1Nm1lRNlNbW-z1qc529gORqtcdID-TPT8xtmd3PpbKUrCWf61RfF-Fgj-92hikoONauq0M36c3k0bIQSmOKNv_0Mfr26mtpALsK7zOa-aROUV54JWvL5Lu3qEykubwSrvTGez_yzg3YOAnYE-7aLvx2S9i-dgdQJV8DEG0903g2A5zfS_V8tppuU80_QvMvTpjA</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Konings, Mickey</creator><creator>Eadie, Kimberly</creator><creator>Lim, Wilson</creator><creator>Fahal, Ahmed H</creator><creator>Mouton, Johan</creator><creator>Tesse, Nicolas</creator><creator>van de Sande, Wendy W. J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7SS</scope><scope>7T2</scope><scope>7T7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>F1W</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>H95</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8652-8783</orcidid><orcidid>https://orcid.org/0000-0002-7263-7268</orcidid></search><sort><creationdate>20210601</creationdate><title>The synthetic synergistic cinnamon oil CIN-102 is active against Madurella mycetomatis, the most common causative agent of mycetoma</title><author>Konings, Mickey ; Eadie, Kimberly ; Lim, Wilson ; Fahal, Ahmed H ; Mouton, Johan ; Tesse, Nicolas ; van de Sande, Wendy W. J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c601t-d0dc0c0ab2907ab2e5ca43530e5667167a1ed8b5c5d0b82bd67a0796b5587da43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antifungal agents</topic><topic>Biology and Life Sciences</topic><topic>Care and treatment</topic><topic>Cinnamon</topic><topic>Drug dosages</topic><topic>Essences and essential oils</topic><topic>Fungal diseases</topic><topic>Fungi</topic><topic>Fungicides</topic><topic>Genomes</topic><topic>Health aspects</topic><topic>Infections</topic><topic>Itraconazole</topic><topic>Larvae</topic><topic>Madurella mycetomatis</topic><topic>Medicine and Health Sciences</topic><topic>Minimum inhibitory concentration</topic><topic>Mycetoma</topic><topic>Oils &amp; fats</topic><topic>Pathogenic bacteria</topic><topic>Pathogens</topic><topic>People and Places</topic><topic>Pharmacology, Experimental</topic><topic>Physical Sciences</topic><topic>Solvents</topic><topic>Surgery</topic><topic>Survival</topic><topic>Tropical climate</topic><topic>Tropical diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Konings, Mickey</creatorcontrib><creatorcontrib>Eadie, Kimberly</creatorcontrib><creatorcontrib>Lim, Wilson</creatorcontrib><creatorcontrib>Fahal, Ahmed H</creatorcontrib><creatorcontrib>Mouton, Johan</creatorcontrib><creatorcontrib>Tesse, Nicolas</creatorcontrib><creatorcontrib>van de Sande, Wendy W. J</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Public Health Database</collection><collection>Technology Research Database</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 UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) 1: Biological Sciences &amp; Living Resources</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) 3: Aquatic Pollution &amp; Environmental Quality</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) Professional</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS neglected tropical diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Konings, Mickey</au><au>Eadie, Kimberly</au><au>Lim, Wilson</au><au>Fahal, Ahmed H</au><au>Mouton, Johan</au><au>Tesse, Nicolas</au><au>van de Sande, Wendy W. J</au><au>Salgado, Claudio Guedes</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The synthetic synergistic cinnamon oil CIN-102 is active against Madurella mycetomatis, the most common causative agent of mycetoma</atitle><jtitle>PLoS neglected tropical diseases</jtitle><date>2021-06-01</date><risdate>2021</risdate><volume>15</volume><issue>6</issue><spage>e0009488</spage><epage>e0009488</epage><pages>e0009488-e0009488</pages><issn>1935-2735</issn><issn>1935-2727</issn><eissn>1935-2735</eissn><abstract>Mycetoma is a devastating neglected tropical infection of the subcutaneous tissue and most commonly caused by the fungus Madurella mycetomatis. Treatment of mycetoma consists of a combination of a long term antifungal treatment with itraconazole and surgery. However, treatment is associated with low success rates. Therefore, there is a need to identify novel treatments for mycetoma. CIN-102 is a synthetic partial copy of cinnamon oils with activity against many pathogenic bacteria and fungi. In this study we determined the in vitro activity of CIN-102 against 21 M. mycetomatis isolates and its in vivo efficacy in a M. mycetomatis infected Galleria mellonella larval model. In vitro, CIN-102 was active against M. mycetomatis with MICs ranging from 32 [mu]g/mL to 512 [mu]g/mL. 128 [mu]g/mL was needed to inhibit the growth in 50% of tested isolates. In vivo, concentrations below the MIC of 40 mg/kg and 80 mg/kg CIN-102 prolonged larval survival, but higher concentrations of CIN-102 did not.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>34106933</pmid><doi>10.1371/journal.pntd.0009488</doi><orcidid>https://orcid.org/0000-0002-8652-8783</orcidid><orcidid>https://orcid.org/0000-0002-7263-7268</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1935-2735
ispartof PLoS neglected tropical diseases, 2021-06, Vol.15 (6), p.e0009488-e0009488
issn 1935-2735
1935-2727
1935-2735
language eng
recordid cdi_plos_journals_2552289311
source DOAJ Directory of Open Access Journals; PubMed Central Open Access; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Antifungal agents
Biology and Life Sciences
Care and treatment
Cinnamon
Drug dosages
Essences and essential oils
Fungal diseases
Fungi
Fungicides
Genomes
Health aspects
Infections
Itraconazole
Larvae
Madurella mycetomatis
Medicine and Health Sciences
Minimum inhibitory concentration
Mycetoma
Oils & fats
Pathogenic bacteria
Pathogens
People and Places
Pharmacology, Experimental
Physical Sciences
Solvents
Surgery
Survival
Tropical climate
Tropical diseases
title The synthetic synergistic cinnamon oil CIN-102 is active against Madurella mycetomatis, the most common causative agent of mycetoma
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T03%3A59%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20synthetic%20synergistic%20cinnamon%20oil%20CIN-102%20is%20active%20against%20Madurella%20mycetomatis,%20the%20most%20common%20causative%20agent%20of%20mycetoma&rft.jtitle=PLoS%20neglected%20tropical%20diseases&rft.au=Konings,%20Mickey&rft.date=2021-06-01&rft.volume=15&rft.issue=6&rft.spage=e0009488&rft.epage=e0009488&rft.pages=e0009488-e0009488&rft.issn=1935-2735&rft.eissn=1935-2735&rft_id=info:doi/10.1371/journal.pntd.0009488&rft_dat=%3Cgale_plos_%3EA668346727%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2552289311&rft_id=info:pmid/34106933&rft_galeid=A668346727&rft_doaj_id=oai_doaj_org_article_658b6137611949a88170eb4e82f1935b&rfr_iscdi=true