Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution
The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-ove...
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| creator | Aachmann-Andersen, Niels Jacob Just Christensen, Søren Lisbjerg, Kristian Oturai, Peter Meinild-Lundby, Anne-Kristine Holstein-Rathlou, Niels-Henrik Lundby, Carsten Vidiendal Olsen, Niels |
| description | The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2)% (p |
| doi_str_mv | 10.1371/journal.pone.0110903 |
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We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2)% (p<0.00001) and 45.2 (7.3)% (p<0.00001). Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8)% (p<0.00001) and 46.1 (10.4)% (p<0.00001). In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4)% (p=0.029); low-dose Epoetin beta: 73.1 (17.8)% (p=0.039)). In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0110903</identifier><identifier>PMID: 25335123</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Biology and Life Sciences ; Blood pressure ; Body mass index ; Change detection ; Chromatography ; Cross-Over Studies ; Erythropoietin ; Erythropoietin - administration & dosage ; Erythropoietin - blood ; Erythropoietin - genetics ; Glucosamine ; Glycoproteins ; Glycosylation ; Humans ; Immunoassay ; Isoforms ; Lectins ; Male ; Medicine and Health Sciences ; Methods ; Neurosciences ; Pharmacology ; Physiology ; Protein Isoforms - blood ; Protein Isoforms - genetics ; Recombinant erythropoietin ; Recombinant Proteins - administration & dosage ; Recombinant Proteins - blood ; Recombinant Proteins - genetics ; Studies</subject><ispartof>PloS one, 2014-10, Vol.9 (10), p.e110903-e110903</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Aachmann-Andersen 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>2014 Aachmann-Andersen et al 2014 Aachmann-Andersen et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-82062efce649c065228ca83378ae7e87638bcc1b7910c962a93dfb006bb6a8e93</citedby><cites>FETCH-LOGICAL-c692t-82062efce649c065228ca83378ae7e87638bcc1b7910c962a93dfb006bb6a8e93</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/PMC4204994/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204994/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25335123$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Freson, Kathleen</contributor><creatorcontrib>Aachmann-Andersen, Niels Jacob</creatorcontrib><creatorcontrib>Just Christensen, Søren</creatorcontrib><creatorcontrib>Lisbjerg, Kristian</creatorcontrib><creatorcontrib>Oturai, Peter</creatorcontrib><creatorcontrib>Meinild-Lundby, Anne-Kristine</creatorcontrib><creatorcontrib>Holstein-Rathlou, Niels-Henrik</creatorcontrib><creatorcontrib>Lundby, Carsten</creatorcontrib><creatorcontrib>Vidiendal Olsen, Niels</creatorcontrib><title>Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2)% (p<0.00001) and 45.2 (7.3)% (p<0.00001). Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8)% (p<0.00001) and 46.1 (10.4)% (p<0.00001). In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4)% (p=0.029); low-dose Epoetin beta: 73.1 (17.8)% (p=0.039)). In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.</description><subject>Adult</subject><subject>Biology and Life Sciences</subject><subject>Blood pressure</subject><subject>Body mass index</subject><subject>Change detection</subject><subject>Chromatography</subject><subject>Cross-Over Studies</subject><subject>Erythropoietin</subject><subject>Erythropoietin - administration & dosage</subject><subject>Erythropoietin - blood</subject><subject>Erythropoietin - genetics</subject><subject>Glucosamine</subject><subject>Glycoproteins</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>Immunoassay</subject><subject>Isoforms</subject><subject>Lectins</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Methods</subject><subject>Neurosciences</subject><subject>Pharmacology</subject><subject>Physiology</subject><subject>Protein Isoforms - blood</subject><subject>Protein Isoforms - genetics</subject><subject>Recombinant erythropoietin</subject><subject>Recombinant Proteins - administration & dosage</subject><subject>Recombinant Proteins - blood</subject><subject>Recombinant Proteins - genetics</subject><subject>Studies</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6D0QLgujFjPlo0-RGWBY_BhYW1o_bkKannQxtMpuk4v57MzPdZap7IQkkJM_7nuQkJ8teYrTEtMIfNm70VvXLrbOwRBgjgeij7BQLShaMIPr4aH6SPQthg1BJOWNPsxNSUlpiQk8zew3aDbWxysYc_G1ce7d1BqKxeerrcVA25GsVcpVvveud7aDJoW1Bx9zZXBuvx14lvPtHHlzr_JA3JkRv6jEaZ59nT1rVB3gxjWfZj8-fvl98XVxefVldnF8uNBMkLjhBjECrgRVCI1YSwrXilFZcQQW8YpTXWuO6EhhpwYgStGlrhFhdM8VB0LPs9cF327sgp1QFiRkuKyY42xGrA9E4tZFbbwblb6VTRu4XnO-k8tHoHiRpC66EQATVvChqUFWheFuWgjJOqoInr49TtLEeoNFgo1f9zHS-Y81adu6XLAgqhCiSwbvJwLubEUKUgwka-l5ZcOP-3KyoUlZ2sd78hT58u4nqVLqAsa1LcfXOVJ4XmGNSpcCJWj5ApdbAYHT6V61J6zPB-5kgMRF-x06NIcjVt-v_Z69-ztm3R-waVB_XwfX7LxPmYHEAtXcheGjvk4yR3JXFXTbkrizkVBZJ9ur4ge5Fd3VA_wCi0gj_</recordid><startdate>20141021</startdate><enddate>20141021</enddate><creator>Aachmann-Andersen, Niels Jacob</creator><creator>Just Christensen, Søren</creator><creator>Lisbjerg, Kristian</creator><creator>Oturai, Peter</creator><creator>Meinild-Lundby, Anne-Kristine</creator><creator>Holstein-Rathlou, Niels-Henrik</creator><creator>Lundby, Carsten</creator><creator>Vidiendal Olsen, Niels</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141021</creationdate><title>Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution</title><author>Aachmann-Andersen, Niels Jacob ; Just Christensen, Søren ; Lisbjerg, Kristian ; Oturai, Peter ; Meinild-Lundby, Anne-Kristine ; Holstein-Rathlou, Niels-Henrik ; Lundby, Carsten ; Vidiendal Olsen, Niels</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-82062efce649c065228ca83378ae7e87638bcc1b7910c962a93dfb006bb6a8e93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Biology and Life Sciences</topic><topic>Blood pressure</topic><topic>Body mass index</topic><topic>Change detection</topic><topic>Chromatography</topic><topic>Cross-Over Studies</topic><topic>Erythropoietin</topic><topic>Erythropoietin - administration & dosage</topic><topic>Erythropoietin - blood</topic><topic>Erythropoietin - genetics</topic><topic>Glucosamine</topic><topic>Glycoproteins</topic><topic>Glycosylation</topic><topic>Humans</topic><topic>Immunoassay</topic><topic>Isoforms</topic><topic>Lectins</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Methods</topic><topic>Neurosciences</topic><topic>Pharmacology</topic><topic>Physiology</topic><topic>Protein Isoforms - blood</topic><topic>Protein Isoforms - genetics</topic><topic>Recombinant erythropoietin</topic><topic>Recombinant Proteins - administration & dosage</topic><topic>Recombinant Proteins - blood</topic><topic>Recombinant Proteins - genetics</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aachmann-Andersen, Niels Jacob</creatorcontrib><creatorcontrib>Just Christensen, Søren</creatorcontrib><creatorcontrib>Lisbjerg, Kristian</creatorcontrib><creatorcontrib>Oturai, Peter</creatorcontrib><creatorcontrib>Meinild-Lundby, Anne-Kristine</creatorcontrib><creatorcontrib>Holstein-Rathlou, Niels-Henrik</creatorcontrib><creatorcontrib>Lundby, Carsten</creatorcontrib><creatorcontrib>Vidiendal Olsen, Niels</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science 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>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</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>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aachmann-Andersen, Niels Jacob</au><au>Just Christensen, Søren</au><au>Lisbjerg, Kristian</au><au>Oturai, Peter</au><au>Meinild-Lundby, Anne-Kristine</au><au>Holstein-Rathlou, Niels-Henrik</au><au>Lundby, Carsten</au><au>Vidiendal Olsen, Niels</au><au>Freson, Kathleen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-10-21</date><risdate>2014</risdate><volume>9</volume><issue>10</issue><spage>e110903</spage><epage>e110903</epage><pages>e110903-e110903</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2)% (p<0.00001) and 45.2 (7.3)% (p<0.00001). Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8)% (p<0.00001) and 46.1 (10.4)% (p<0.00001). In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4)% (p=0.029); low-dose Epoetin beta: 73.1 (17.8)% (p=0.039)). In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25335123</pmid><doi>10.1371/journal.pone.0110903</doi><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Biology and Life Sciences Blood pressure Body mass index Change detection Chromatography Cross-Over Studies Erythropoietin Erythropoietin - administration & dosage Erythropoietin - blood Erythropoietin - genetics Glucosamine Glycoproteins Glycosylation Humans Immunoassay Isoforms Lectins Male Medicine and Health Sciences Methods Neurosciences Pharmacology Physiology Protein Isoforms - blood Protein Isoforms - genetics Recombinant erythropoietin Recombinant Proteins - administration & dosage Recombinant Proteins - blood Recombinant Proteins - genetics Studies |
| title | Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-01T05%3A35%3A23IST&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=Recombinant%20erythropoietin%20in%20humans%20has%20a%20prolonged%20effect%20on%20circulating%20erythropoietin%20isoform%20distribution&rft.jtitle=PloS%20one&rft.au=Aachmann-Andersen,%20Niels%20Jacob&rft.date=2014-10-21&rft.volume=9&rft.issue=10&rft.spage=e110903&rft.epage=e110903&rft.pages=e110903-e110903&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0110903&rft_dat=%3Cgale_plos_%3EA418127049%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=1615769869&rft_id=info:pmid/25335123&rft_galeid=A418127049&rft_doaj_id=oai_doaj_org_article_2f48a99020b844bea74a8f5593682748&rfr_iscdi=true |