One-year timeline kinetics of cytokine-mediated cellular immunity in dogs vaccinated against visceral leishmaniasis
BACKGROUND: The main control strategy for visceral leishmaniasis in Brazil has been based on the elimination of seropositive dogs, although this is not widely accepted. In this context, the use of a long-lasting protective vaccine against canine visceral leishmaniasis (CVL) has been highly expected....
Gespeichert in:
Veröffentlicht in: | BMC veterinary research 2015-04, Vol.11 (1), p.92-92, Article 92 |
---|---|
Hauptverfasser: | , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 92 |
---|---|
container_issue | 1 |
container_start_page | 92 |
container_title | BMC veterinary research |
container_volume | 11 |
creator | Costa-Pereira, Christiane Moreira, Marcela L Soares, Rodrigo P Marteleto, Bruno H Ribeiro, Vitor M França-Dias, Michelle H Cardoso, Ludmila M Viana, Kelvinson F Giunchetti, Rodolfo C Martins-Filho, Olindo A Araújo, Márcio S S |
description | BACKGROUND: The main control strategy for visceral leishmaniasis in Brazil has been based on the elimination of seropositive dogs, although this is not widely accepted. In this context, the use of a long-lasting protective vaccine against canine visceral leishmaniasis (CVL) has been highly expected. The aim of this work was to determine the timeline kinetics of the cytokine microenvironment derived from circulating leukocytes as supportive immunological biomarkers triggered by Leishmune® vaccine. Cross-sectional kinetic analysis of cellular immunity cytokines was carried out at three times (1, 6 and 12 months) after primovaccination with Leishmune®. In vitro short-term whole blood cultures were stimulated with Leishmania infantum soluble antigen (SLAg). The secreted cytokine signatures and their major sources were determined. RESULTS: At six months after vaccination, Leishmune® induced an increase in IL-8, IFN-γ, IL-17a and TNF-α levels and a decrease in IL-10. Cytokine signature analysis revealed a shift in the microenvironment towards a pro-inflammatory profile mediated by IL-8 and IFN-γ. Both, CD4⁺(↑TNF-α⁺and ↑IFN-γ⁺) and CD8⁺(↑IL-17a and ↓IL-4) T-cells contributed to the acquired immune responses observed after stimulation with SLAg. CONCLUSIONS: The changes observed in the cytokine profile suggested that Leishmune® was able to induce an effective response at six months after primovaccination. After one year, it returned to baseline suggesting the need of additional boosting. |
doi_str_mv | 10.1186/s12917-015-0397-6 |
format | Article |
fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4405846</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A541462348</galeid><sourcerecordid>A541462348</sourcerecordid><originalsourceid>FETCH-LOGICAL-c523t-adeba39c6a5bc8bde11cef17389a0a47da6f2c9da63f3718e5174d848a1454473</originalsourceid><addsrcrecordid>eNqNkstu1TAQhiMEoqXwAGwgUjdsUjzxNRukquImVeoCurbmOJPUkNglTo503h6HlKqVWCBLHl---T1j_UXxGtgZgFHvE9QN6IqBrBhvdKWeFMeghaoUCPP0wfqoeJHSD8aEaLR6XhzV0himhDou0lWg6kA4lbMfafCByp95mr1LZexKd5jjuq9Gaj3O1JaOhmEZMu_HcQl-PpQ-lG3sU7lH53z4A2GPPqS53PvkaMKhHMinmxGDx-TTy-JZh0OiV3fxpLj-9PH7xZfq8urz14vzy8rJms8VtrRD3jiFcufMriUARx1obhpkKHSLqqtdkwPvuAZDMvfbGmEQhBRC85Piw6Z7u-xy_Y7CnGuxt5MfcTrYiN4-vgn-xvZxb4Vg0giVBd7dCUzx10JptuPa0DBgoLgkC8ooDcAa-R-olkZDbZqMnm5ojwNZH7qYH3crbs-lAKFqLkymzv5B5dHS6F0M1Pl8_igBtgQ3xZQm6u4bBWZXu9jNLjbbxa52sWuDbx7-0H3GX39k4O0GdBgt9pNP9vpbnRUYA9Uwxflvw67GZg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1675871289</pqid></control><display><type>article</type><title>One-year timeline kinetics of cytokine-mediated cellular immunity in dogs vaccinated against visceral leishmaniasis</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>SpringerLink Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><source>Springer Nature OA Free Journals</source><creator>Costa-Pereira, Christiane ; Moreira, Marcela L ; Soares, Rodrigo P ; Marteleto, Bruno H ; Ribeiro, Vitor M ; França-Dias, Michelle H ; Cardoso, Ludmila M ; Viana, Kelvinson F ; Giunchetti, Rodolfo C ; Martins-Filho, Olindo A ; Araújo, Márcio S S</creator><creatorcontrib>Costa-Pereira, Christiane ; Moreira, Marcela L ; Soares, Rodrigo P ; Marteleto, Bruno H ; Ribeiro, Vitor M ; França-Dias, Michelle H ; Cardoso, Ludmila M ; Viana, Kelvinson F ; Giunchetti, Rodolfo C ; Martins-Filho, Olindo A ; Araújo, Márcio S S</creatorcontrib><description>BACKGROUND: The main control strategy for visceral leishmaniasis in Brazil has been based on the elimination of seropositive dogs, although this is not widely accepted. In this context, the use of a long-lasting protective vaccine against canine visceral leishmaniasis (CVL) has been highly expected. The aim of this work was to determine the timeline kinetics of the cytokine microenvironment derived from circulating leukocytes as supportive immunological biomarkers triggered by Leishmune® vaccine. Cross-sectional kinetic analysis of cellular immunity cytokines was carried out at three times (1, 6 and 12 months) after primovaccination with Leishmune®. In vitro short-term whole blood cultures were stimulated with Leishmania infantum soluble antigen (SLAg). The secreted cytokine signatures and their major sources were determined. RESULTS: At six months after vaccination, Leishmune® induced an increase in IL-8, IFN-γ, IL-17a and TNF-α levels and a decrease in IL-10. Cytokine signature analysis revealed a shift in the microenvironment towards a pro-inflammatory profile mediated by IL-8 and IFN-γ. Both, CD4⁺(↑TNF-α⁺and ↑IFN-γ⁺) and CD8⁺(↑IL-17a and ↓IL-4) T-cells contributed to the acquired immune responses observed after stimulation with SLAg. CONCLUSIONS: The changes observed in the cytokine profile suggested that Leishmune® was able to induce an effective response at six months after primovaccination. After one year, it returned to baseline suggesting the need of additional boosting.</description><identifier>ISSN: 1746-6148</identifier><identifier>EISSN: 1746-6148</identifier><identifier>DOI: 10.1186/s12917-015-0397-6</identifier><identifier>PMID: 25880646</identifier><language>eng</language><publisher>England: Springer-Verlag</publisher><subject>Analysis ; Animals ; Antigens ; Biomarkers ; Brazil ; Brazil - epidemiology ; cell-mediated immunity ; Cross-Sectional Studies ; Cytokines - genetics ; Cytokines - metabolism ; Dog Diseases - prevention & control ; Dogs ; Female ; Gene Expression Regulation ; Health aspects ; Immunity, Cellular - physiology ; interferon-gamma ; interleukin-10 ; interleukin-17 ; interleukin-8 ; Leishmania infantum ; Leishmaniasis, Visceral - epidemiology ; Leishmaniasis, Visceral - prevention & control ; Leishmaniasis, Visceral - veterinary ; Leukocytes - physiology ; Male ; Protozoan Vaccines - immunology ; seroprevalence ; T-lymphocytes ; Time Factors ; tumor necrosis factor-alpha ; vaccination ; vaccines ; visceral leishmaniasis</subject><ispartof>BMC veterinary research, 2015-04, Vol.11 (1), p.92-92, Article 92</ispartof><rights>COPYRIGHT 2015 BioMed Central Ltd.</rights><rights>Costa-Pereira et al.; licensee BioMed Central. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-adeba39c6a5bc8bde11cef17389a0a47da6f2c9da63f3718e5174d848a1454473</citedby><cites>FETCH-LOGICAL-c523t-adeba39c6a5bc8bde11cef17389a0a47da6f2c9da63f3718e5174d848a1454473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405846/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405846/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25880646$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Costa-Pereira, Christiane</creatorcontrib><creatorcontrib>Moreira, Marcela L</creatorcontrib><creatorcontrib>Soares, Rodrigo P</creatorcontrib><creatorcontrib>Marteleto, Bruno H</creatorcontrib><creatorcontrib>Ribeiro, Vitor M</creatorcontrib><creatorcontrib>França-Dias, Michelle H</creatorcontrib><creatorcontrib>Cardoso, Ludmila M</creatorcontrib><creatorcontrib>Viana, Kelvinson F</creatorcontrib><creatorcontrib>Giunchetti, Rodolfo C</creatorcontrib><creatorcontrib>Martins-Filho, Olindo A</creatorcontrib><creatorcontrib>Araújo, Márcio S S</creatorcontrib><title>One-year timeline kinetics of cytokine-mediated cellular immunity in dogs vaccinated against visceral leishmaniasis</title><title>BMC veterinary research</title><addtitle>BMC Vet Res</addtitle><description>BACKGROUND: The main control strategy for visceral leishmaniasis in Brazil has been based on the elimination of seropositive dogs, although this is not widely accepted. In this context, the use of a long-lasting protective vaccine against canine visceral leishmaniasis (CVL) has been highly expected. The aim of this work was to determine the timeline kinetics of the cytokine microenvironment derived from circulating leukocytes as supportive immunological biomarkers triggered by Leishmune® vaccine. Cross-sectional kinetic analysis of cellular immunity cytokines was carried out at three times (1, 6 and 12 months) after primovaccination with Leishmune®. In vitro short-term whole blood cultures were stimulated with Leishmania infantum soluble antigen (SLAg). The secreted cytokine signatures and their major sources were determined. RESULTS: At six months after vaccination, Leishmune® induced an increase in IL-8, IFN-γ, IL-17a and TNF-α levels and a decrease in IL-10. Cytokine signature analysis revealed a shift in the microenvironment towards a pro-inflammatory profile mediated by IL-8 and IFN-γ. Both, CD4⁺(↑TNF-α⁺and ↑IFN-γ⁺) and CD8⁺(↑IL-17a and ↓IL-4) T-cells contributed to the acquired immune responses observed after stimulation with SLAg. CONCLUSIONS: The changes observed in the cytokine profile suggested that Leishmune® was able to induce an effective response at six months after primovaccination. After one year, it returned to baseline suggesting the need of additional boosting.</description><subject>Analysis</subject><subject>Animals</subject><subject>Antigens</subject><subject>Biomarkers</subject><subject>Brazil</subject><subject>Brazil - epidemiology</subject><subject>cell-mediated immunity</subject><subject>Cross-Sectional Studies</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>Dog Diseases - prevention & control</subject><subject>Dogs</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Health aspects</subject><subject>Immunity, Cellular - physiology</subject><subject>interferon-gamma</subject><subject>interleukin-10</subject><subject>interleukin-17</subject><subject>interleukin-8</subject><subject>Leishmania infantum</subject><subject>Leishmaniasis, Visceral - epidemiology</subject><subject>Leishmaniasis, Visceral - prevention & control</subject><subject>Leishmaniasis, Visceral - veterinary</subject><subject>Leukocytes - physiology</subject><subject>Male</subject><subject>Protozoan Vaccines - immunology</subject><subject>seroprevalence</subject><subject>T-lymphocytes</subject><subject>Time Factors</subject><subject>tumor necrosis factor-alpha</subject><subject>vaccination</subject><subject>vaccines</subject><subject>visceral leishmaniasis</subject><issn>1746-6148</issn><issn>1746-6148</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkstu1TAQhiMEoqXwAGwgUjdsUjzxNRukquImVeoCurbmOJPUkNglTo503h6HlKqVWCBLHl---T1j_UXxGtgZgFHvE9QN6IqBrBhvdKWeFMeghaoUCPP0wfqoeJHSD8aEaLR6XhzV0himhDou0lWg6kA4lbMfafCByp95mr1LZexKd5jjuq9Gaj3O1JaOhmEZMu_HcQl-PpQ-lG3sU7lH53z4A2GPPqS53PvkaMKhHMinmxGDx-TTy-JZh0OiV3fxpLj-9PH7xZfq8urz14vzy8rJms8VtrRD3jiFcufMriUARx1obhpkKHSLqqtdkwPvuAZDMvfbGmEQhBRC85Piw6Z7u-xy_Y7CnGuxt5MfcTrYiN4-vgn-xvZxb4Vg0giVBd7dCUzx10JptuPa0DBgoLgkC8ooDcAa-R-olkZDbZqMnm5ojwNZH7qYH3crbs-lAKFqLkymzv5B5dHS6F0M1Pl8_igBtgQ3xZQm6u4bBWZXu9jNLjbbxa52sWuDbx7-0H3GX39k4O0GdBgt9pNP9vpbnRUYA9Uwxflvw67GZg</recordid><startdate>20150411</startdate><enddate>20150411</enddate><creator>Costa-Pereira, Christiane</creator><creator>Moreira, Marcela L</creator><creator>Soares, Rodrigo P</creator><creator>Marteleto, Bruno H</creator><creator>Ribeiro, Vitor M</creator><creator>França-Dias, Michelle H</creator><creator>Cardoso, Ludmila M</creator><creator>Viana, Kelvinson F</creator><creator>Giunchetti, Rodolfo C</creator><creator>Martins-Filho, Olindo A</creator><creator>Araújo, Márcio S S</creator><general>Springer-Verlag</general><general>BioMed Central Ltd</general><general>BioMed Central</general><scope>FBQ</scope><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>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20150411</creationdate><title>One-year timeline kinetics of cytokine-mediated cellular immunity in dogs vaccinated against visceral leishmaniasis</title><author>Costa-Pereira, Christiane ; Moreira, Marcela L ; Soares, Rodrigo P ; Marteleto, Bruno H ; Ribeiro, Vitor M ; França-Dias, Michelle H ; Cardoso, Ludmila M ; Viana, Kelvinson F ; Giunchetti, Rodolfo C ; Martins-Filho, Olindo A ; Araújo, Márcio S S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-adeba39c6a5bc8bde11cef17389a0a47da6f2c9da63f3718e5174d848a1454473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Antigens</topic><topic>Biomarkers</topic><topic>Brazil</topic><topic>Brazil - epidemiology</topic><topic>cell-mediated immunity</topic><topic>Cross-Sectional Studies</topic><topic>Cytokines - genetics</topic><topic>Cytokines - metabolism</topic><topic>Dog Diseases - prevention & control</topic><topic>Dogs</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>Health aspects</topic><topic>Immunity, Cellular - physiology</topic><topic>interferon-gamma</topic><topic>interleukin-10</topic><topic>interleukin-17</topic><topic>interleukin-8</topic><topic>Leishmania infantum</topic><topic>Leishmaniasis, Visceral - epidemiology</topic><topic>Leishmaniasis, Visceral - prevention & control</topic><topic>Leishmaniasis, Visceral - veterinary</topic><topic>Leukocytes - physiology</topic><topic>Male</topic><topic>Protozoan Vaccines - immunology</topic><topic>seroprevalence</topic><topic>T-lymphocytes</topic><topic>Time Factors</topic><topic>tumor necrosis factor-alpha</topic><topic>vaccination</topic><topic>vaccines</topic><topic>visceral leishmaniasis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Costa-Pereira, Christiane</creatorcontrib><creatorcontrib>Moreira, Marcela L</creatorcontrib><creatorcontrib>Soares, Rodrigo P</creatorcontrib><creatorcontrib>Marteleto, Bruno H</creatorcontrib><creatorcontrib>Ribeiro, Vitor M</creatorcontrib><creatorcontrib>França-Dias, Michelle H</creatorcontrib><creatorcontrib>Cardoso, Ludmila M</creatorcontrib><creatorcontrib>Viana, Kelvinson F</creatorcontrib><creatorcontrib>Giunchetti, Rodolfo C</creatorcontrib><creatorcontrib>Martins-Filho, Olindo A</creatorcontrib><creatorcontrib>Araújo, Márcio S S</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BMC veterinary research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Costa-Pereira, Christiane</au><au>Moreira, Marcela L</au><au>Soares, Rodrigo P</au><au>Marteleto, Bruno H</au><au>Ribeiro, Vitor M</au><au>França-Dias, Michelle H</au><au>Cardoso, Ludmila M</au><au>Viana, Kelvinson F</au><au>Giunchetti, Rodolfo C</au><au>Martins-Filho, Olindo A</au><au>Araújo, Márcio S S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>One-year timeline kinetics of cytokine-mediated cellular immunity in dogs vaccinated against visceral leishmaniasis</atitle><jtitle>BMC veterinary research</jtitle><addtitle>BMC Vet Res</addtitle><date>2015-04-11</date><risdate>2015</risdate><volume>11</volume><issue>1</issue><spage>92</spage><epage>92</epage><pages>92-92</pages><artnum>92</artnum><issn>1746-6148</issn><eissn>1746-6148</eissn><abstract>BACKGROUND: The main control strategy for visceral leishmaniasis in Brazil has been based on the elimination of seropositive dogs, although this is not widely accepted. In this context, the use of a long-lasting protective vaccine against canine visceral leishmaniasis (CVL) has been highly expected. The aim of this work was to determine the timeline kinetics of the cytokine microenvironment derived from circulating leukocytes as supportive immunological biomarkers triggered by Leishmune® vaccine. Cross-sectional kinetic analysis of cellular immunity cytokines was carried out at three times (1, 6 and 12 months) after primovaccination with Leishmune®. In vitro short-term whole blood cultures were stimulated with Leishmania infantum soluble antigen (SLAg). The secreted cytokine signatures and their major sources were determined. RESULTS: At six months after vaccination, Leishmune® induced an increase in IL-8, IFN-γ, IL-17a and TNF-α levels and a decrease in IL-10. Cytokine signature analysis revealed a shift in the microenvironment towards a pro-inflammatory profile mediated by IL-8 and IFN-γ. Both, CD4⁺(↑TNF-α⁺and ↑IFN-γ⁺) and CD8⁺(↑IL-17a and ↓IL-4) T-cells contributed to the acquired immune responses observed after stimulation with SLAg. CONCLUSIONS: The changes observed in the cytokine profile suggested that Leishmune® was able to induce an effective response at six months after primovaccination. After one year, it returned to baseline suggesting the need of additional boosting.</abstract><cop>England</cop><pub>Springer-Verlag</pub><pmid>25880646</pmid><doi>10.1186/s12917-015-0397-6</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1746-6148 |
ispartof | BMC veterinary research, 2015-04, Vol.11 (1), p.92-92, Article 92 |
issn | 1746-6148 1746-6148 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4405846 |
source | MEDLINE; DOAJ Directory of Open Access Journals; SpringerLink Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; PubMed Central Open Access; Springer Nature OA Free Journals |
subjects | Analysis Animals Antigens Biomarkers Brazil Brazil - epidemiology cell-mediated immunity Cross-Sectional Studies Cytokines - genetics Cytokines - metabolism Dog Diseases - prevention & control Dogs Female Gene Expression Regulation Health aspects Immunity, Cellular - physiology interferon-gamma interleukin-10 interleukin-17 interleukin-8 Leishmania infantum Leishmaniasis, Visceral - epidemiology Leishmaniasis, Visceral - prevention & control Leishmaniasis, Visceral - veterinary Leukocytes - physiology Male Protozoan Vaccines - immunology seroprevalence T-lymphocytes Time Factors tumor necrosis factor-alpha vaccination vaccines visceral leishmaniasis |
title | One-year timeline kinetics of cytokine-mediated cellular immunity in dogs vaccinated against visceral leishmaniasis |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T03%3A02%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=One-year%20timeline%20kinetics%20of%20cytokine-mediated%20cellular%20immunity%20in%20dogs%20vaccinated%20against%20visceral%20leishmaniasis&rft.jtitle=BMC%20veterinary%20research&rft.au=Costa-Pereira,%20Christiane&rft.date=2015-04-11&rft.volume=11&rft.issue=1&rft.spage=92&rft.epage=92&rft.pages=92-92&rft.artnum=92&rft.issn=1746-6148&rft.eissn=1746-6148&rft_id=info:doi/10.1186/s12917-015-0397-6&rft_dat=%3Cgale_pubme%3EA541462348%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1675871289&rft_id=info:pmid/25880646&rft_galeid=A541462348&rfr_iscdi=true |