Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples

Objective Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasm...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:European journal of endocrinology 2020-01, Vol.182 (1), p.67-77
Hauptverfasser: Elfassy, Yaelle, Bongrani, Alice, Levy, Pierre, Foissac, Frantz, Fellahi, Soraya, Faure, Céline, McAvoy, Chloé, Capeau, Jacqueline, Dupont, Joëlle, Fève, Bruno, Levy, Rachel, Bastard, Jean-Philippe
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 77
container_issue 1
container_start_page 67
container_title European journal of endocrinology
container_volume 182
creator Elfassy, Yaelle
Bongrani, Alice
Levy, Pierre
Foissac, Frantz
Fellahi, Soraya
Faure, Céline
McAvoy, Chloé
Capeau, Jacqueline
Dupont, Joëlle
Fève, Bruno
Levy, Rachel
Bastard, Jean-Philippe
description Objective Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design Male partners of infertile couples referred to four medical French centers were enrolled in years 2013–2016. Methods Subjects (n = 160) aged 18–45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.
doi_str_mv 10.1530/EJE-19-0615
format Article
fullrecord <record><control><sourceid>proquest_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_03500744v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2332078299</sourcerecordid><originalsourceid>FETCH-LOGICAL-b430t-b59f9a2f0f90cce638009c98ef174d65c217a313c6a3d0ba82ab6bbd3cfac8773</originalsourceid><addsrcrecordid>eNp9kcGL1TAQh4Mo7tvVk3cJeFG0Omnapjkuy1tXeSCIgreQpBM2a9rUJl3xvzf1rXvw4GmG4eObSX6EPGPwlrUc3u0_7ismK-hY-4DsWCNk1fX820Oygx6aqukafkJOU7oBYKWHx-SEMwGtkGxH8mcMOvs4pWs_J2ow_0Sc6IhZmxi8pSnrvKY3NOHoJx2oHvwcv_sJy0xPA11wXuKw2uxvkbp1sn9k1G-OiboljqV3uGQfkNq4zgHTE_LI6ZDw6V09I18v918urqrDp_cfLs4PlSln5sq00kldO3ASrMWO9wDSyh4dE83QtbZmQnPGbaf5AEb3tTadMQO3TtteCH5GXh291zqoefGjXn6pqL26Oj-obQa8BRBNc8sK-_LIluf8WDFlNfpkMQQ9YVyTqssi3nZ9s2lf_IPexHUpn7NRvAbR11IW6vWRsktMaUF3fwEDtQWnSnCKSbUFV-jnd87VjDjcs3-TKgA7AsbHZD1O2Ttv9X-lvwEGSKRs</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2332078299</pqid></control><display><type>article</type><title>Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><creator>Elfassy, Yaelle ; Bongrani, Alice ; Levy, Pierre ; Foissac, Frantz ; Fellahi, Soraya ; Faure, Céline ; McAvoy, Chloé ; Capeau, Jacqueline ; Dupont, Joëlle ; Fève, Bruno ; Levy, Rachel ; Bastard, Jean-Philippe</creator><creatorcontrib>Elfassy, Yaelle ; Bongrani, Alice ; Levy, Pierre ; Foissac, Frantz ; Fellahi, Soraya ; Faure, Céline ; McAvoy, Chloé ; Capeau, Jacqueline ; Dupont, Joëlle ; Fève, Bruno ; Levy, Rachel ; Bastard, Jean-Philippe ; Metasperme group</creatorcontrib><description>Objective Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design Male partners of infertile couples referred to four medical French centers were enrolled in years 2013–2016. Methods Subjects (n = 160) aged 18–45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.</description><identifier>ISSN: 0804-4643</identifier><identifier>EISSN: 1479-683X</identifier><identifier>DOI: 10.1530/EJE-19-0615</identifier><identifier>PMID: 31705791</identifier><language>eng</language><publisher>England: Bioscientifica Ltd</publisher><subject>Adipokines - blood ; Adipokines - metabolism ; Adiponectin ; Adolescent ; Adult ; Chemokines - blood ; Chemokines - metabolism ; Clinical Study ; Couples ; Female ; Humans ; Infertility ; Infertility, Male - metabolism ; Infertility, Male - physiopathology ; Interleukin 6 ; Interleukin-6 - blood ; Interleukin-6 - metabolism ; Leptin ; Leptin - blood ; Leptin - metabolism ; Life Sciences ; Male ; Metabolic syndrome ; Metabolism ; Middle Aged ; Nicotinamide Phosphoribosyltransferase - blood ; Nicotinamide Phosphoribosyltransferase - metabolism ; Reproduction - physiology ; Reproductive Biology ; Semen ; Semen - metabolism ; Semen - physiology ; Sperm ; Sperm Count ; Sperm Motility - physiology ; Spermatozoa - metabolism ; Spermatozoa - physiology ; Young Adult</subject><ispartof>European journal of endocrinology, 2020-01, Vol.182 (1), p.67-77</ispartof><rights>2020 European Society of Endocrinology</rights><rights>Copyright BioScientifica Ltd. Jan 2020</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b430t-b59f9a2f0f90cce638009c98ef174d65c217a313c6a3d0ba82ab6bbd3cfac8773</citedby><orcidid>0000-0002-8046-7705 ; 0000-0002-1710-4186 ; 0000-0001-6577-9009 ; 0000-0003-0086-4821</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31705791$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.inrae.fr/hal-03500744$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Elfassy, Yaelle</creatorcontrib><creatorcontrib>Bongrani, Alice</creatorcontrib><creatorcontrib>Levy, Pierre</creatorcontrib><creatorcontrib>Foissac, Frantz</creatorcontrib><creatorcontrib>Fellahi, Soraya</creatorcontrib><creatorcontrib>Faure, Céline</creatorcontrib><creatorcontrib>McAvoy, Chloé</creatorcontrib><creatorcontrib>Capeau, Jacqueline</creatorcontrib><creatorcontrib>Dupont, Joëlle</creatorcontrib><creatorcontrib>Fève, Bruno</creatorcontrib><creatorcontrib>Levy, Rachel</creatorcontrib><creatorcontrib>Bastard, Jean-Philippe</creatorcontrib><creatorcontrib>Metasperme group</creatorcontrib><title>Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples</title><title>European journal of endocrinology</title><addtitle>Eur J Endocrinol</addtitle><description>Objective Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design Male partners of infertile couples referred to four medical French centers were enrolled in years 2013–2016. Methods Subjects (n = 160) aged 18–45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.</description><subject>Adipokines - blood</subject><subject>Adipokines - metabolism</subject><subject>Adiponectin</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Chemokines - blood</subject><subject>Chemokines - metabolism</subject><subject>Clinical Study</subject><subject>Couples</subject><subject>Female</subject><subject>Humans</subject><subject>Infertility</subject><subject>Infertility, Male - metabolism</subject><subject>Infertility, Male - physiopathology</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - blood</subject><subject>Interleukin-6 - metabolism</subject><subject>Leptin</subject><subject>Leptin - blood</subject><subject>Leptin - metabolism</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Metabolic syndrome</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Nicotinamide Phosphoribosyltransferase - blood</subject><subject>Nicotinamide Phosphoribosyltransferase - metabolism</subject><subject>Reproduction - physiology</subject><subject>Reproductive Biology</subject><subject>Semen</subject><subject>Semen - metabolism</subject><subject>Semen - physiology</subject><subject>Sperm</subject><subject>Sperm Count</subject><subject>Sperm Motility - physiology</subject><subject>Spermatozoa - metabolism</subject><subject>Spermatozoa - physiology</subject><subject>Young Adult</subject><issn>0804-4643</issn><issn>1479-683X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcGL1TAQh4Mo7tvVk3cJeFG0Omnapjkuy1tXeSCIgreQpBM2a9rUJl3xvzf1rXvw4GmG4eObSX6EPGPwlrUc3u0_7ismK-hY-4DsWCNk1fX820Oygx6aqukafkJOU7oBYKWHx-SEMwGtkGxH8mcMOvs4pWs_J2ow_0Sc6IhZmxi8pSnrvKY3NOHoJx2oHvwcv_sJy0xPA11wXuKw2uxvkbp1sn9k1G-OiboljqV3uGQfkNq4zgHTE_LI6ZDw6V09I18v918urqrDp_cfLs4PlSln5sq00kldO3ASrMWO9wDSyh4dE83QtbZmQnPGbaf5AEb3tTadMQO3TtteCH5GXh291zqoefGjXn6pqL26Oj-obQa8BRBNc8sK-_LIluf8WDFlNfpkMQQ9YVyTqssi3nZ9s2lf_IPexHUpn7NRvAbR11IW6vWRsktMaUF3fwEDtQWnSnCKSbUFV-jnd87VjDjcs3-TKgA7AsbHZD1O2Ttv9X-lvwEGSKRs</recordid><startdate>20200101</startdate><enddate>20200101</enddate><creator>Elfassy, Yaelle</creator><creator>Bongrani, Alice</creator><creator>Levy, Pierre</creator><creator>Foissac, Frantz</creator><creator>Fellahi, Soraya</creator><creator>Faure, Céline</creator><creator>McAvoy, Chloé</creator><creator>Capeau, Jacqueline</creator><creator>Dupont, Joëlle</creator><creator>Fève, Bruno</creator><creator>Levy, Rachel</creator><creator>Bastard, Jean-Philippe</creator><general>Bioscientifica Ltd</general><general>Oxford University Press</general><general>Oxford Univ. Press</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>7T5</scope><scope>H94</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-8046-7705</orcidid><orcidid>https://orcid.org/0000-0002-1710-4186</orcidid><orcidid>https://orcid.org/0000-0001-6577-9009</orcidid><orcidid>https://orcid.org/0000-0003-0086-4821</orcidid></search><sort><creationdate>20200101</creationdate><title>Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples</title><author>Elfassy, Yaelle ; Bongrani, Alice ; Levy, Pierre ; Foissac, Frantz ; Fellahi, Soraya ; Faure, Céline ; McAvoy, Chloé ; Capeau, Jacqueline ; Dupont, Joëlle ; Fève, Bruno ; Levy, Rachel ; Bastard, Jean-Philippe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b430t-b59f9a2f0f90cce638009c98ef174d65c217a313c6a3d0ba82ab6bbd3cfac8773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adipokines - blood</topic><topic>Adipokines - metabolism</topic><topic>Adiponectin</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Chemokines - blood</topic><topic>Chemokines - metabolism</topic><topic>Clinical Study</topic><topic>Couples</topic><topic>Female</topic><topic>Humans</topic><topic>Infertility</topic><topic>Infertility, Male - metabolism</topic><topic>Infertility, Male - physiopathology</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - blood</topic><topic>Interleukin-6 - metabolism</topic><topic>Leptin</topic><topic>Leptin - blood</topic><topic>Leptin - metabolism</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Metabolic syndrome</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Nicotinamide Phosphoribosyltransferase - blood</topic><topic>Nicotinamide Phosphoribosyltransferase - metabolism</topic><topic>Reproduction - physiology</topic><topic>Reproductive Biology</topic><topic>Semen</topic><topic>Semen - metabolism</topic><topic>Semen - physiology</topic><topic>Sperm</topic><topic>Sperm Count</topic><topic>Sperm Motility - physiology</topic><topic>Spermatozoa - metabolism</topic><topic>Spermatozoa - physiology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Elfassy, Yaelle</creatorcontrib><creatorcontrib>Bongrani, Alice</creatorcontrib><creatorcontrib>Levy, Pierre</creatorcontrib><creatorcontrib>Foissac, Frantz</creatorcontrib><creatorcontrib>Fellahi, Soraya</creatorcontrib><creatorcontrib>Faure, Céline</creatorcontrib><creatorcontrib>McAvoy, Chloé</creatorcontrib><creatorcontrib>Capeau, Jacqueline</creatorcontrib><creatorcontrib>Dupont, Joëlle</creatorcontrib><creatorcontrib>Fève, Bruno</creatorcontrib><creatorcontrib>Levy, Rachel</creatorcontrib><creatorcontrib>Bastard, Jean-Philippe</creatorcontrib><creatorcontrib>Metasperme group</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>European journal of endocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Elfassy, Yaelle</au><au>Bongrani, Alice</au><au>Levy, Pierre</au><au>Foissac, Frantz</au><au>Fellahi, Soraya</au><au>Faure, Céline</au><au>McAvoy, Chloé</au><au>Capeau, Jacqueline</au><au>Dupont, Joëlle</au><au>Fève, Bruno</au><au>Levy, Rachel</au><au>Bastard, Jean-Philippe</au><aucorp>Metasperme group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples</atitle><jtitle>European journal of endocrinology</jtitle><addtitle>Eur J Endocrinol</addtitle><date>2020-01-01</date><risdate>2020</risdate><volume>182</volume><issue>1</issue><spage>67</spage><epage>77</epage><pages>67-77</pages><issn>0804-4643</issn><eissn>1479-683X</eissn><abstract>Objective Adipokines could be a link between metabolic syndrome (MS) and infertility. While the association between circulating adipokines and fertility has been extensively studied in females, this relationship in males was less investigated, although some adipokines are detectable in seminal plasma (SP). The aim of this study was to determine adipokine levels in blood and SP and to assess the relationships between adipokines, MS and semen parameters in men from infertile couples. Design Male partners of infertile couples referred to four medical French centers were enrolled in years 2013–2016. Methods Subjects (n = 160) aged 18–45 years were assessed for anthropometric, biochemical, sperm, and circulating hormonal parameters. Leptin, adiponectin, resistin, chemerin, visfatin, and IL-6 were measured in serum and SP. Results Infertility duration was higher in men with than without MS. Adipokine concentrations were higher in blood than in SP, except for IL-6 and visfatin. The most striking result was the significant correlation observed between seminal IL-6 and spermatozoid concentration, progressive motility, and sperm vitality. Moreover, while men with MS exhibited an expected lower adiponectinemia, they displayed 2.1-fold higher adiponectin levels in SP than men without MS. Finally, logistic regression analysis showed that BMI, infertility duration, and adiponectin serum/SP ratio were independently associated with MS. Conclusions These results suggest an involvement of seminal adipokines to modulate fertility in men with MS and that seminal IL-6 could play a beneficial role on sperm functionality. Further mechanistic studies are necessary to investigate the precise roles of these adipokines in male reproduction.</abstract><cop>England</cop><pub>Bioscientifica Ltd</pub><pmid>31705791</pmid><doi>10.1530/EJE-19-0615</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-8046-7705</orcidid><orcidid>https://orcid.org/0000-0002-1710-4186</orcidid><orcidid>https://orcid.org/0000-0001-6577-9009</orcidid><orcidid>https://orcid.org/0000-0003-0086-4821</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0804-4643
ispartof European journal of endocrinology, 2020-01, Vol.182 (1), p.67-77
issn 0804-4643
1479-683X
language eng
recordid cdi_hal_primary_oai_HAL_hal_03500744v1
source Oxford University Press Journals All Titles (1996-Current); MEDLINE
subjects Adipokines - blood
Adipokines - metabolism
Adiponectin
Adolescent
Adult
Chemokines - blood
Chemokines - metabolism
Clinical Study
Couples
Female
Humans
Infertility
Infertility, Male - metabolism
Infertility, Male - physiopathology
Interleukin 6
Interleukin-6 - blood
Interleukin-6 - metabolism
Leptin
Leptin - blood
Leptin - metabolism
Life Sciences
Male
Metabolic syndrome
Metabolism
Middle Aged
Nicotinamide Phosphoribosyltransferase - blood
Nicotinamide Phosphoribosyltransferase - metabolism
Reproduction - physiology
Reproductive Biology
Semen
Semen - metabolism
Semen - physiology
Sperm
Sperm Count
Sperm Motility - physiology
Spermatozoa - metabolism
Spermatozoa - physiology
Young Adult
title Relationships between metabolic status, seminal adipokines, and reproductive functions in men from infertile couples
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T12%3A58%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Relationships%20between%20metabolic%20status,%20seminal%20adipokines,%20and%20reproductive%20functions%20in%20men%20from%20infertile%20couples&rft.jtitle=European%20journal%20of%20endocrinology&rft.au=Elfassy,%20Yaelle&rft.aucorp=Metasperme%20group&rft.date=2020-01-01&rft.volume=182&rft.issue=1&rft.spage=67&rft.epage=77&rft.pages=67-77&rft.issn=0804-4643&rft.eissn=1479-683X&rft_id=info:doi/10.1530/EJE-19-0615&rft_dat=%3Cproquest_hal_p%3E2332078299%3C/proquest_hal_p%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2332078299&rft_id=info:pmid/31705791&rfr_iscdi=true