Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years

Abstract Background The persistence of HIV residual replication in patients with an undetectable plasma viral load (pVL) may limit immune recovery and facilitate inflammation-induced comorbidities. Objective The objective was to evaluate any correlation between immune restoration and intracellular [...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of clinical virology 2013-08, Vol.57 (4), p.351-355
Hauptverfasser: Poizot-Martin, Isabelle, Faucher, Olivia, Obry-Roguet, Véronique, Nicolino-Brunet, Corinne, Ronot-Bregigeon, Sylvie, Dignat-George, Françoise, Tamalet, Catherine
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 355
container_issue 4
container_start_page 351
container_title Journal of clinical virology
container_volume 57
creator Poizot-Martin, Isabelle
Faucher, Olivia
Obry-Roguet, Véronique
Nicolino-Brunet, Corinne
Ronot-Bregigeon, Sylvie
Dignat-George, Françoise
Tamalet, Catherine
description Abstract Background The persistence of HIV residual replication in patients with an undetectable plasma viral load (pVL) may limit immune recovery and facilitate inflammation-induced comorbidities. Objective The objective was to evaluate any correlation between immune restoration and intracellular [IC] HIV-DNA in cART-treated patients with a sustained undetectable pVL. Study design This retrospective cross sectional study included 62 patients with a median duration of undetectable pVL of 10.3 years. IC HIV DNA in peripheral mononuclear blood cells (PBMCs) and T cell subsets were measured at the last visit. pVL, CD4+ and CD8+ T cell counts were retrospectively collected from the onset of long-term inhibition by antiretroviral treatment. The patients were separated into two groups: 27 non-blippers (sustained pVL < threshold value during all the visits) and 35 blippers (≥1 episodes of pVL > threshold but
doi_str_mv 10.1016/j.jcv.2013.04.007
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1371270314</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>1_s2_0_S1386653213001285</els_id><sourcerecordid>1371270314</sourcerecordid><originalsourceid>FETCH-LOGICAL-c408t-cc3864da521ddb9fde12bd229123b44eaf3aa53ff0295c8d55bed0e6ff241ff3</originalsourceid><addsrcrecordid>eNp9ks1u1TAQhSMEoqXwAGyQl2wS_JO_KySkqgVa6QoWVGwtxx6rTh37YjupLk_G4-E0hQULVrbsb85ozpmieE1wRTBp343VKJeKYsIqXFcYd0-KU9J3rGx2bfc031nflm3D6EnxIsYRY9KwuntenFDWtnVHm9Pi117IO-Q1kj4EsCIZ79AA6R7AoXQLKJqfsP5fXX9Hh-AXE4RFl1_OUYAIYfEmIOHUA2phAbuyZppmB0jIZJZN0bhVoDROg0yg0CE_g0sR3Zt0iwSKc0zCuPwzOwUpQ2Kw8NB062i9UEj7gAhGRxAhviyeaWEjvHo8z4qbTx9vLq7K_dfP1xfn-1LWuE-llNmDWomGEqWGnVZA6KAo3RHKhroGoZkQDdMa010je9U0AygMrda0Jlqzs-LtJptn_zFDTHwyUYK1woGfIyesI7TDjNQZJRsqg48xgOaHYCYRjpxgvubFR57z4mteHNc855Vr3jzKz8ME6m_Fn4Ay8H4DIM-4GAg8yuycBGVCdokrb_4r_-GfammNM1LYOzhCHP0cXDaPEx4px_zbujDrvhCWd4X2DfsNnqC9wg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1371270314</pqid></control><display><type>article</type><title>Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Poizot-Martin, Isabelle ; Faucher, Olivia ; Obry-Roguet, Véronique ; Nicolino-Brunet, Corinne ; Ronot-Bregigeon, Sylvie ; Dignat-George, Françoise ; Tamalet, Catherine</creator><creatorcontrib>Poizot-Martin, Isabelle ; Faucher, Olivia ; Obry-Roguet, Véronique ; Nicolino-Brunet, Corinne ; Ronot-Bregigeon, Sylvie ; Dignat-George, Françoise ; Tamalet, Catherine</creatorcontrib><description>Abstract Background The persistence of HIV residual replication in patients with an undetectable plasma viral load (pVL) may limit immune recovery and facilitate inflammation-induced comorbidities. Objective The objective was to evaluate any correlation between immune restoration and intracellular [IC] HIV-DNA in cART-treated patients with a sustained undetectable pVL. Study design This retrospective cross sectional study included 62 patients with a median duration of undetectable pVL of 10.3 years. IC HIV DNA in peripheral mononuclear blood cells (PBMCs) and T cell subsets were measured at the last visit. pVL, CD4+ and CD8+ T cell counts were retrospectively collected from the onset of long-term inhibition by antiretroviral treatment. The patients were separated into two groups: 27 non-blippers (sustained pVL &lt; threshold value during all the visits) and 35 blippers (≥1 episodes of pVL &gt; threshold but &lt;1000 copies/ml). The median pVL in blippers was 115 copies/ml. Results The median IC HIV DNA rate was 34 copies/106 PBMCs (71% ≥20 copies/106 PBMCs) with no significant difference between the groups. The proportion of CD8+ CD38+ and CD8+ DR+ T cells was higher in blipper patients, but the difference was only significant for the CD8+ DR+ marker ( p = 0.036). No correlation was found between markers of immune activation on CD4+ and CD8+ T cells and the IC HIV-DNA level. Conclusion No relation was found between the size of HIV reservoirs and immune activation in patients with sustained undetectable pVL. Mechanisms of immune activation have to be better understood in order to define specific therapeutic interventions.</description><identifier>ISSN: 1386-6532</identifier><identifier>EISSN: 1873-5967</identifier><identifier>DOI: 10.1016/j.jcv.2013.04.007</identifier><identifier>PMID: 23664725</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Adult ; Allergy and Immunology ; Anti-HIV Agents - immunology ; Anti-HIV Agents - therapeutic use ; Antiretroviral Therapy, Highly Active - methods ; CD4-Positive T-Lymphocytes - drug effects ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - virology ; CD8-Positive T-Lymphocytes - drug effects ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - virology ; Cross-Sectional Studies ; DNA, Viral - genetics ; DNA, Viral - immunology ; Female ; HIV - genetics ; HIV - immunology ; HIV DNA-proviral ; HIV Infections - blood ; HIV Infections - drug therapy ; HIV Infections - immunology ; HIV Infections - virology ; HIV reservoir ; HIV-1 ; Humans ; Immune activation markers ; Infectious Disease ; Leukocytes, Mononuclear - immunology ; Leukocytes, Mononuclear - virology ; Lymphocyte Activation - immunology ; Male ; Middle Aged ; Retrospective Studies ; RNA, Viral - blood ; RNA, Viral - immunology ; T-Lymphocyte Subsets - drug effects ; T-Lymphocyte Subsets - immunology ; T-Lymphocyte Subsets - virology ; Viral Load - immunology</subject><ispartof>Journal of clinical virology, 2013-08, Vol.57 (4), p.351-355</ispartof><rights>Elsevier B.V.</rights><rights>2013 Elsevier B.V.</rights><rights>Copyright © 2013 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-cc3864da521ddb9fde12bd229123b44eaf3aa53ff0295c8d55bed0e6ff241ff3</citedby><cites>FETCH-LOGICAL-c408t-cc3864da521ddb9fde12bd229123b44eaf3aa53ff0295c8d55bed0e6ff241ff3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1386653213001285$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23664725$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Poizot-Martin, Isabelle</creatorcontrib><creatorcontrib>Faucher, Olivia</creatorcontrib><creatorcontrib>Obry-Roguet, Véronique</creatorcontrib><creatorcontrib>Nicolino-Brunet, Corinne</creatorcontrib><creatorcontrib>Ronot-Bregigeon, Sylvie</creatorcontrib><creatorcontrib>Dignat-George, Françoise</creatorcontrib><creatorcontrib>Tamalet, Catherine</creatorcontrib><title>Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years</title><title>Journal of clinical virology</title><addtitle>J Clin Virol</addtitle><description>Abstract Background The persistence of HIV residual replication in patients with an undetectable plasma viral load (pVL) may limit immune recovery and facilitate inflammation-induced comorbidities. Objective The objective was to evaluate any correlation between immune restoration and intracellular [IC] HIV-DNA in cART-treated patients with a sustained undetectable pVL. Study design This retrospective cross sectional study included 62 patients with a median duration of undetectable pVL of 10.3 years. IC HIV DNA in peripheral mononuclear blood cells (PBMCs) and T cell subsets were measured at the last visit. pVL, CD4+ and CD8+ T cell counts were retrospectively collected from the onset of long-term inhibition by antiretroviral treatment. The patients were separated into two groups: 27 non-blippers (sustained pVL &lt; threshold value during all the visits) and 35 blippers (≥1 episodes of pVL &gt; threshold but &lt;1000 copies/ml). The median pVL in blippers was 115 copies/ml. Results The median IC HIV DNA rate was 34 copies/106 PBMCs (71% ≥20 copies/106 PBMCs) with no significant difference between the groups. The proportion of CD8+ CD38+ and CD8+ DR+ T cells was higher in blipper patients, but the difference was only significant for the CD8+ DR+ marker ( p = 0.036). No correlation was found between markers of immune activation on CD4+ and CD8+ T cells and the IC HIV-DNA level. Conclusion No relation was found between the size of HIV reservoirs and immune activation in patients with sustained undetectable pVL. Mechanisms of immune activation have to be better understood in order to define specific therapeutic interventions.</description><subject>Adult</subject><subject>Allergy and Immunology</subject><subject>Anti-HIV Agents - immunology</subject><subject>Anti-HIV Agents - therapeutic use</subject><subject>Antiretroviral Therapy, Highly Active - methods</subject><subject>CD4-Positive T-Lymphocytes - drug effects</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD4-Positive T-Lymphocytes - virology</subject><subject>CD8-Positive T-Lymphocytes - drug effects</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - virology</subject><subject>Cross-Sectional Studies</subject><subject>DNA, Viral - genetics</subject><subject>DNA, Viral - immunology</subject><subject>Female</subject><subject>HIV - genetics</subject><subject>HIV - immunology</subject><subject>HIV DNA-proviral</subject><subject>HIV Infections - blood</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Infections - immunology</subject><subject>HIV Infections - virology</subject><subject>HIV reservoir</subject><subject>HIV-1</subject><subject>Humans</subject><subject>Immune activation markers</subject><subject>Infectious Disease</subject><subject>Leukocytes, Mononuclear - immunology</subject><subject>Leukocytes, Mononuclear - virology</subject><subject>Lymphocyte Activation - immunology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Retrospective Studies</subject><subject>RNA, Viral - blood</subject><subject>RNA, Viral - immunology</subject><subject>T-Lymphocyte Subsets - drug effects</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocyte Subsets - virology</subject><subject>Viral Load - immunology</subject><issn>1386-6532</issn><issn>1873-5967</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9ks1u1TAQhSMEoqXwAGyQl2wS_JO_KySkqgVa6QoWVGwtxx6rTh37YjupLk_G4-E0hQULVrbsb85ozpmieE1wRTBp343VKJeKYsIqXFcYd0-KU9J3rGx2bfc031nflm3D6EnxIsYRY9KwuntenFDWtnVHm9Pi117IO-Q1kj4EsCIZ79AA6R7AoXQLKJqfsP5fXX9Hh-AXE4RFl1_OUYAIYfEmIOHUA2phAbuyZppmB0jIZJZN0bhVoDROg0yg0CE_g0sR3Zt0iwSKc0zCuPwzOwUpQ2Kw8NB062i9UEj7gAhGRxAhviyeaWEjvHo8z4qbTx9vLq7K_dfP1xfn-1LWuE-llNmDWomGEqWGnVZA6KAo3RHKhroGoZkQDdMa010je9U0AygMrda0Jlqzs-LtJptn_zFDTHwyUYK1woGfIyesI7TDjNQZJRsqg48xgOaHYCYRjpxgvubFR57z4mteHNc855Vr3jzKz8ME6m_Fn4Ay8H4DIM-4GAg8yuycBGVCdokrb_4r_-GfammNM1LYOzhCHP0cXDaPEx4px_zbujDrvhCWd4X2DfsNnqC9wg</recordid><startdate>20130801</startdate><enddate>20130801</enddate><creator>Poizot-Martin, Isabelle</creator><creator>Faucher, Olivia</creator><creator>Obry-Roguet, Véronique</creator><creator>Nicolino-Brunet, Corinne</creator><creator>Ronot-Bregigeon, Sylvie</creator><creator>Dignat-George, Françoise</creator><creator>Tamalet, Catherine</creator><general>Elsevier B.V</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>7X8</scope></search><sort><creationdate>20130801</creationdate><title>Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years</title><author>Poizot-Martin, Isabelle ; Faucher, Olivia ; Obry-Roguet, Véronique ; Nicolino-Brunet, Corinne ; Ronot-Bregigeon, Sylvie ; Dignat-George, Françoise ; Tamalet, Catherine</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-cc3864da521ddb9fde12bd229123b44eaf3aa53ff0295c8d55bed0e6ff241ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Allergy and Immunology</topic><topic>Anti-HIV Agents - immunology</topic><topic>Anti-HIV Agents - therapeutic use</topic><topic>Antiretroviral Therapy, Highly Active - methods</topic><topic>CD4-Positive T-Lymphocytes - drug effects</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD4-Positive T-Lymphocytes - virology</topic><topic>CD8-Positive T-Lymphocytes - drug effects</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>CD8-Positive T-Lymphocytes - virology</topic><topic>Cross-Sectional Studies</topic><topic>DNA, Viral - genetics</topic><topic>DNA, Viral - immunology</topic><topic>Female</topic><topic>HIV - genetics</topic><topic>HIV - immunology</topic><topic>HIV DNA-proviral</topic><topic>HIV Infections - blood</topic><topic>HIV Infections - drug therapy</topic><topic>HIV Infections - immunology</topic><topic>HIV Infections - virology</topic><topic>HIV reservoir</topic><topic>HIV-1</topic><topic>Humans</topic><topic>Immune activation markers</topic><topic>Infectious Disease</topic><topic>Leukocytes, Mononuclear - immunology</topic><topic>Leukocytes, Mononuclear - virology</topic><topic>Lymphocyte Activation - immunology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Retrospective Studies</topic><topic>RNA, Viral - blood</topic><topic>RNA, Viral - immunology</topic><topic>T-Lymphocyte Subsets - drug effects</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocyte Subsets - virology</topic><topic>Viral Load - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Poizot-Martin, Isabelle</creatorcontrib><creatorcontrib>Faucher, Olivia</creatorcontrib><creatorcontrib>Obry-Roguet, Véronique</creatorcontrib><creatorcontrib>Nicolino-Brunet, Corinne</creatorcontrib><creatorcontrib>Ronot-Bregigeon, Sylvie</creatorcontrib><creatorcontrib>Dignat-George, Françoise</creatorcontrib><creatorcontrib>Tamalet, Catherine</creatorcontrib><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><jtitle>Journal of clinical virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Poizot-Martin, Isabelle</au><au>Faucher, Olivia</au><au>Obry-Roguet, Véronique</au><au>Nicolino-Brunet, Corinne</au><au>Ronot-Bregigeon, Sylvie</au><au>Dignat-George, Françoise</au><au>Tamalet, Catherine</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years</atitle><jtitle>Journal of clinical virology</jtitle><addtitle>J Clin Virol</addtitle><date>2013-08-01</date><risdate>2013</risdate><volume>57</volume><issue>4</issue><spage>351</spage><epage>355</epage><pages>351-355</pages><issn>1386-6532</issn><eissn>1873-5967</eissn><abstract>Abstract Background The persistence of HIV residual replication in patients with an undetectable plasma viral load (pVL) may limit immune recovery and facilitate inflammation-induced comorbidities. Objective The objective was to evaluate any correlation between immune restoration and intracellular [IC] HIV-DNA in cART-treated patients with a sustained undetectable pVL. Study design This retrospective cross sectional study included 62 patients with a median duration of undetectable pVL of 10.3 years. IC HIV DNA in peripheral mononuclear blood cells (PBMCs) and T cell subsets were measured at the last visit. pVL, CD4+ and CD8+ T cell counts were retrospectively collected from the onset of long-term inhibition by antiretroviral treatment. The patients were separated into two groups: 27 non-blippers (sustained pVL &lt; threshold value during all the visits) and 35 blippers (≥1 episodes of pVL &gt; threshold but &lt;1000 copies/ml). The median pVL in blippers was 115 copies/ml. Results The median IC HIV DNA rate was 34 copies/106 PBMCs (71% ≥20 copies/106 PBMCs) with no significant difference between the groups. The proportion of CD8+ CD38+ and CD8+ DR+ T cells was higher in blipper patients, but the difference was only significant for the CD8+ DR+ marker ( p = 0.036). No correlation was found between markers of immune activation on CD4+ and CD8+ T cells and the IC HIV-DNA level. Conclusion No relation was found between the size of HIV reservoirs and immune activation in patients with sustained undetectable pVL. Mechanisms of immune activation have to be better understood in order to define specific therapeutic interventions.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>23664725</pmid><doi>10.1016/j.jcv.2013.04.007</doi><tpages>5</tpages></addata></record>
fulltext fulltext
identifier ISSN: 1386-6532
ispartof Journal of clinical virology, 2013-08, Vol.57 (4), p.351-355
issn 1386-6532
1873-5967
language eng
recordid cdi_proquest_miscellaneous_1371270314
source MEDLINE; Elsevier ScienceDirect Journals
subjects Adult
Allergy and Immunology
Anti-HIV Agents - immunology
Anti-HIV Agents - therapeutic use
Antiretroviral Therapy, Highly Active - methods
CD4-Positive T-Lymphocytes - drug effects
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - virology
CD8-Positive T-Lymphocytes - drug effects
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - virology
Cross-Sectional Studies
DNA, Viral - genetics
DNA, Viral - immunology
Female
HIV - genetics
HIV - immunology
HIV DNA-proviral
HIV Infections - blood
HIV Infections - drug therapy
HIV Infections - immunology
HIV Infections - virology
HIV reservoir
HIV-1
Humans
Immune activation markers
Infectious Disease
Leukocytes, Mononuclear - immunology
Leukocytes, Mononuclear - virology
Lymphocyte Activation - immunology
Male
Middle Aged
Retrospective Studies
RNA, Viral - blood
RNA, Viral - immunology
T-Lymphocyte Subsets - drug effects
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - virology
Viral Load - immunology
title Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-06T01%3A03%3A18IST&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=Lack%20of%20correlation%20between%20the%20size%20of%20HIV%20proviral%20DNA%20reservoir%20and%20the%20level%20of%20immune%20activation%20in%20HIV-infected%20patients%20with%20a%20sustained%20undetectable%20HIV%20viral%20load%20for%2010%20years&rft.jtitle=Journal%20of%20clinical%20virology&rft.au=Poizot-Martin,%20Isabelle&rft.date=2013-08-01&rft.volume=57&rft.issue=4&rft.spage=351&rft.epage=355&rft.pages=351-355&rft.issn=1386-6532&rft.eissn=1873-5967&rft_id=info:doi/10.1016/j.jcv.2013.04.007&rft_dat=%3Cproquest_cross%3E1371270314%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=1371270314&rft_id=info:pmid/23664725&rft_els_id=1_s2_0_S1386653213001285&rfr_iscdi=true