A New Diagnostic Algorithm for Antibody‐Mediated Microcirculation Inflammation in Kidney Transplants

We studied the significance of microcirculation inflammation in kidney transplants, including 329 indication biopsies from 251 renal allograft recipients, who were mostly nonpresensitized (crossmatch negative). Glomerulitis (g) and peritubular capillaritis (ptc) were often associated with antibody‐m...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:American journal of transplantation 2012-05, Vol.12 (5), p.1168-1179
Hauptverfasser: Sis, B., Jhangri, G. S., Riopel, J., Chang, J., de Freitas, D. G., Hidalgo, L., Mengel, M., Matas, A., Halloran, P. F.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1179
container_issue 5
container_start_page 1168
container_title American journal of transplantation
container_volume 12
creator Sis, B.
Jhangri, G. S.
Riopel, J.
Chang, J.
de Freitas, D. G.
Hidalgo, L.
Mengel, M.
Matas, A.
Halloran, P. F.
description We studied the significance of microcirculation inflammation in kidney transplants, including 329 indication biopsies from 251 renal allograft recipients, who were mostly nonpresensitized (crossmatch negative). Glomerulitis (g) and peritubular capillaritis (ptc) were often associated with antibody‐mediated rejection (65% and 75%, respectively), but were also found in other diseases in the absence of donor‐specific antibody (DSA): T‐cell‐mediated rejection (ptc, g), glomerulonephritis (g) and acute tubular necrosis (ptc). To develop rules for reducing the nonspecificity of microcirculation inflammation and defining the best grading thresholds associated with DSA, we built and validated a decision tree to predict DSA. The decision tree revealed that g + ptc sum (addition of g‐score plus ptc‐score) was the best predictor of DSA, followed by time posttransplant, then C4d, which had a small role. Late biopsies with g + ptc > 0 showed higher frequency of DSA compared to early biopsies with g + ptc > 0 (79% vs. 27%). Microcirculation inflammation in early biopsies was often false positive (antibody‐independent). The decision tree predicted DSA with higher sensitivity and accuracy than C4d staining. Microcirculation inflammation sum score predicted graft failure independently of time, C4d and transplant glomerulopathy. Thus any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicates presence of DSA and predicts progression to graft failure. This study proposes a new diagnostic algorithm to distinguish antibody‐mediated microcirculation inflammation from antibody‐independent etiologies in conventional nonhighly presensitized kidney transplants, and defines a grading threshold for microcirculation inflammation with a high specificity for antibody‐mediated rejection.
doi_str_mv 10.1111/j.1600-6143.2011.03931.x
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1257725339</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1257725339</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5481-596b051110eae6175cffd9d13866373c1647c9a705d14f7abae1723a1d3cefbb3</originalsourceid><addsrcrecordid>eNqNkctOGzEUhi0EKre-AvIGiU0GHzv2TBZdjLgXaDdhbXl8oY7mEuyJIDsegWfkSfCQNF0Wb3wsf8c-__8jhIFkkNbpLANByEjAmGWUAGSETRhkL1tob3OxvakZ30X7Mc4IgZwW9BvapZQRIgjsIVfiX_YZn3v12Hax9xqX9WMXfP-nwa4LuGx7X3Vm-f76dm-NV701-N7r0Gkf9KJWve9afNO6WjXN6uBbfOtNa5d4GlQb57Vq-3iIdpyqo_2-3g_Qw-XF9Ox6dPf76uasvBtpPi5gxCeiIjwpJFZZATnXzpmJAVYIwXKmQYxzPVE54QbGLleVskkSU2CYtq6q2AE6Wb07D93TwsZeNj5qW6chbLeIEijPc8pZsuu_KAFCGaWFSGixQpPuGIN1ch58o8IyQXIIRM7k4LUcfJdDIPIzEPmSWo_WvyyqxppN498EEnC8BlTUqnbJM-3jPy5ZwoAP4_5Ycc--tssvDyDLn9OhYh9r9acS</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1010232286</pqid></control><display><type>article</type><title>A New Diagnostic Algorithm for Antibody‐Mediated Microcirculation Inflammation in Kidney Transplants</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Sis, B. ; Jhangri, G. S. ; Riopel, J. ; Chang, J. ; de Freitas, D. G. ; Hidalgo, L. ; Mengel, M. ; Matas, A. ; Halloran, P. F.</creator><creatorcontrib>Sis, B. ; Jhangri, G. S. ; Riopel, J. ; Chang, J. ; de Freitas, D. G. ; Hidalgo, L. ; Mengel, M. ; Matas, A. ; Halloran, P. F.</creatorcontrib><description>We studied the significance of microcirculation inflammation in kidney transplants, including 329 indication biopsies from 251 renal allograft recipients, who were mostly nonpresensitized (crossmatch negative). Glomerulitis (g) and peritubular capillaritis (ptc) were often associated with antibody‐mediated rejection (65% and 75%, respectively), but were also found in other diseases in the absence of donor‐specific antibody (DSA): T‐cell‐mediated rejection (ptc, g), glomerulonephritis (g) and acute tubular necrosis (ptc). To develop rules for reducing the nonspecificity of microcirculation inflammation and defining the best grading thresholds associated with DSA, we built and validated a decision tree to predict DSA. The decision tree revealed that g + ptc sum (addition of g‐score plus ptc‐score) was the best predictor of DSA, followed by time posttransplant, then C4d, which had a small role. Late biopsies with g + ptc &gt; 0 showed higher frequency of DSA compared to early biopsies with g + ptc &gt; 0 (79% vs. 27%). Microcirculation inflammation in early biopsies was often false positive (antibody‐independent). The decision tree predicted DSA with higher sensitivity and accuracy than C4d staining. Microcirculation inflammation sum score predicted graft failure independently of time, C4d and transplant glomerulopathy. Thus any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicates presence of DSA and predicts progression to graft failure. This study proposes a new diagnostic algorithm to distinguish antibody‐mediated microcirculation inflammation from antibody‐independent etiologies in conventional nonhighly presensitized kidney transplants, and defines a grading threshold for microcirculation inflammation with a high specificity for antibody‐mediated rejection.</description><identifier>ISSN: 1600-6135</identifier><identifier>EISSN: 1600-6143</identifier><identifier>DOI: 10.1111/j.1600-6143.2011.03931.x</identifier><identifier>PMID: 22300601</identifier><language>eng</language><publisher>Malden, USA: Blackwell Publishing Inc</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Algorithms ; Antigens, CD - metabolism ; Banff ; Biological and medical sciences ; Child ; Child, Preschool ; Decision Trees ; diagnosis ; Female ; Follow-Up Studies ; Glomerulonephritis - immunology ; Glomerulonephritis - pathology ; Graft Rejection - blood ; Graft Rejection - diagnosis ; Graft Rejection - immunology ; Graft Survival - immunology ; Humans ; Immunoenzyme Techniques ; Inflammation - immunology ; Isoantibodies - blood ; Isoantibodies - immunology ; kidney ; Kidney Transplantation - immunology ; Male ; Medical sciences ; Microcirculation - immunology ; Middle Aged ; pathology ; Prognosis ; rejection ; Renal Circulation - immunology ; Risk Factors ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; survival ; Survival Rate ; transplantation ; Young Adult</subject><ispartof>American journal of transplantation, 2012-05, Vol.12 (5), p.1168-1179</ispartof><rights>Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5481-596b051110eae6175cffd9d13866373c1647c9a705d14f7abae1723a1d3cefbb3</citedby><cites>FETCH-LOGICAL-c5481-596b051110eae6175cffd9d13866373c1647c9a705d14f7abae1723a1d3cefbb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1600-6143.2011.03931.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1600-6143.2011.03931.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=25963159$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22300601$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sis, B.</creatorcontrib><creatorcontrib>Jhangri, G. S.</creatorcontrib><creatorcontrib>Riopel, J.</creatorcontrib><creatorcontrib>Chang, J.</creatorcontrib><creatorcontrib>de Freitas, D. G.</creatorcontrib><creatorcontrib>Hidalgo, L.</creatorcontrib><creatorcontrib>Mengel, M.</creatorcontrib><creatorcontrib>Matas, A.</creatorcontrib><creatorcontrib>Halloran, P. F.</creatorcontrib><title>A New Diagnostic Algorithm for Antibody‐Mediated Microcirculation Inflammation in Kidney Transplants</title><title>American journal of transplantation</title><addtitle>Am J Transplant</addtitle><description>We studied the significance of microcirculation inflammation in kidney transplants, including 329 indication biopsies from 251 renal allograft recipients, who were mostly nonpresensitized (crossmatch negative). Glomerulitis (g) and peritubular capillaritis (ptc) were often associated with antibody‐mediated rejection (65% and 75%, respectively), but were also found in other diseases in the absence of donor‐specific antibody (DSA): T‐cell‐mediated rejection (ptc, g), glomerulonephritis (g) and acute tubular necrosis (ptc). To develop rules for reducing the nonspecificity of microcirculation inflammation and defining the best grading thresholds associated with DSA, we built and validated a decision tree to predict DSA. The decision tree revealed that g + ptc sum (addition of g‐score plus ptc‐score) was the best predictor of DSA, followed by time posttransplant, then C4d, which had a small role. Late biopsies with g + ptc &gt; 0 showed higher frequency of DSA compared to early biopsies with g + ptc &gt; 0 (79% vs. 27%). Microcirculation inflammation in early biopsies was often false positive (antibody‐independent). The decision tree predicted DSA with higher sensitivity and accuracy than C4d staining. Microcirculation inflammation sum score predicted graft failure independently of time, C4d and transplant glomerulopathy. Thus any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicates presence of DSA and predicts progression to graft failure. This study proposes a new diagnostic algorithm to distinguish antibody‐mediated microcirculation inflammation from antibody‐independent etiologies in conventional nonhighly presensitized kidney transplants, and defines a grading threshold for microcirculation inflammation with a high specificity for antibody‐mediated rejection.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Algorithms</subject><subject>Antigens, CD - metabolism</subject><subject>Banff</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Decision Trees</subject><subject>diagnosis</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Glomerulonephritis - immunology</subject><subject>Glomerulonephritis - pathology</subject><subject>Graft Rejection - blood</subject><subject>Graft Rejection - diagnosis</subject><subject>Graft Rejection - immunology</subject><subject>Graft Survival - immunology</subject><subject>Humans</subject><subject>Immunoenzyme Techniques</subject><subject>Inflammation - immunology</subject><subject>Isoantibodies - blood</subject><subject>Isoantibodies - immunology</subject><subject>kidney</subject><subject>Kidney Transplantation - immunology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microcirculation - immunology</subject><subject>Middle Aged</subject><subject>pathology</subject><subject>Prognosis</subject><subject>rejection</subject><subject>Renal Circulation - immunology</subject><subject>Risk Factors</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</subject><subject>survival</subject><subject>Survival Rate</subject><subject>transplantation</subject><subject>Young Adult</subject><issn>1600-6135</issn><issn>1600-6143</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkctOGzEUhi0EKre-AvIGiU0GHzv2TBZdjLgXaDdhbXl8oY7mEuyJIDsegWfkSfCQNF0Wb3wsf8c-__8jhIFkkNbpLANByEjAmGWUAGSETRhkL1tob3OxvakZ30X7Mc4IgZwW9BvapZQRIgjsIVfiX_YZn3v12Hax9xqX9WMXfP-nwa4LuGx7X3Vm-f76dm-NV701-N7r0Gkf9KJWve9afNO6WjXN6uBbfOtNa5d4GlQb57Vq-3iIdpyqo_2-3g_Qw-XF9Ox6dPf76uasvBtpPi5gxCeiIjwpJFZZATnXzpmJAVYIwXKmQYxzPVE54QbGLleVskkSU2CYtq6q2AE6Wb07D93TwsZeNj5qW6chbLeIEijPc8pZsuu_KAFCGaWFSGixQpPuGIN1ch58o8IyQXIIRM7k4LUcfJdDIPIzEPmSWo_WvyyqxppN498EEnC8BlTUqnbJM-3jPy5ZwoAP4_5Ycc--tssvDyDLn9OhYh9r9acS</recordid><startdate>201205</startdate><enddate>201205</enddate><creator>Sis, B.</creator><creator>Jhangri, G. S.</creator><creator>Riopel, J.</creator><creator>Chang, J.</creator><creator>de Freitas, D. G.</creator><creator>Hidalgo, L.</creator><creator>Mengel, M.</creator><creator>Matas, A.</creator><creator>Halloran, P. F.</creator><general>Blackwell Publishing Inc</general><general>Wiley</general><scope>IQODW</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>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>201205</creationdate><title>A New Diagnostic Algorithm for Antibody‐Mediated Microcirculation Inflammation in Kidney Transplants</title><author>Sis, B. ; Jhangri, G. S. ; Riopel, J. ; Chang, J. ; de Freitas, D. G. ; Hidalgo, L. ; Mengel, M. ; Matas, A. ; Halloran, P. F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5481-596b051110eae6175cffd9d13866373c1647c9a705d14f7abae1723a1d3cefbb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Algorithms</topic><topic>Antigens, CD - metabolism</topic><topic>Banff</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Decision Trees</topic><topic>diagnosis</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Glomerulonephritis - immunology</topic><topic>Glomerulonephritis - pathology</topic><topic>Graft Rejection - blood</topic><topic>Graft Rejection - diagnosis</topic><topic>Graft Rejection - immunology</topic><topic>Graft Survival - immunology</topic><topic>Humans</topic><topic>Immunoenzyme Techniques</topic><topic>Inflammation - immunology</topic><topic>Isoantibodies - blood</topic><topic>Isoantibodies - immunology</topic><topic>kidney</topic><topic>Kidney Transplantation - immunology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microcirculation - immunology</topic><topic>Middle Aged</topic><topic>pathology</topic><topic>Prognosis</topic><topic>rejection</topic><topic>Renal Circulation - immunology</topic><topic>Risk Factors</topic><topic>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</topic><topic>survival</topic><topic>Survival Rate</topic><topic>transplantation</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sis, B.</creatorcontrib><creatorcontrib>Jhangri, G. S.</creatorcontrib><creatorcontrib>Riopel, J.</creatorcontrib><creatorcontrib>Chang, J.</creatorcontrib><creatorcontrib>de Freitas, D. G.</creatorcontrib><creatorcontrib>Hidalgo, L.</creatorcontrib><creatorcontrib>Mengel, M.</creatorcontrib><creatorcontrib>Matas, A.</creatorcontrib><creatorcontrib>Halloran, P. F.</creatorcontrib><collection>Pascal-Francis</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>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>American journal of transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sis, B.</au><au>Jhangri, G. S.</au><au>Riopel, J.</au><au>Chang, J.</au><au>de Freitas, D. G.</au><au>Hidalgo, L.</au><au>Mengel, M.</au><au>Matas, A.</au><au>Halloran, P. F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A New Diagnostic Algorithm for Antibody‐Mediated Microcirculation Inflammation in Kidney Transplants</atitle><jtitle>American journal of transplantation</jtitle><addtitle>Am J Transplant</addtitle><date>2012-05</date><risdate>2012</risdate><volume>12</volume><issue>5</issue><spage>1168</spage><epage>1179</epage><pages>1168-1179</pages><issn>1600-6135</issn><eissn>1600-6143</eissn><abstract>We studied the significance of microcirculation inflammation in kidney transplants, including 329 indication biopsies from 251 renal allograft recipients, who were mostly nonpresensitized (crossmatch negative). Glomerulitis (g) and peritubular capillaritis (ptc) were often associated with antibody‐mediated rejection (65% and 75%, respectively), but were also found in other diseases in the absence of donor‐specific antibody (DSA): T‐cell‐mediated rejection (ptc, g), glomerulonephritis (g) and acute tubular necrosis (ptc). To develop rules for reducing the nonspecificity of microcirculation inflammation and defining the best grading thresholds associated with DSA, we built and validated a decision tree to predict DSA. The decision tree revealed that g + ptc sum (addition of g‐score plus ptc‐score) was the best predictor of DSA, followed by time posttransplant, then C4d, which had a small role. Late biopsies with g + ptc &gt; 0 showed higher frequency of DSA compared to early biopsies with g + ptc &gt; 0 (79% vs. 27%). Microcirculation inflammation in early biopsies was often false positive (antibody‐independent). The decision tree predicted DSA with higher sensitivity and accuracy than C4d staining. Microcirculation inflammation sum score predicted graft failure independently of time, C4d and transplant glomerulopathy. Thus any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicates presence of DSA and predicts progression to graft failure. This study proposes a new diagnostic algorithm to distinguish antibody‐mediated microcirculation inflammation from antibody‐independent etiologies in conventional nonhighly presensitized kidney transplants, and defines a grading threshold for microcirculation inflammation with a high specificity for antibody‐mediated rejection.</abstract><cop>Malden, USA</cop><pub>Blackwell Publishing Inc</pub><pmid>22300601</pmid><doi>10.1111/j.1600-6143.2011.03931.x</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1600-6135
ispartof American journal of transplantation, 2012-05, Vol.12 (5), p.1168-1179
issn 1600-6135
1600-6143
language eng
recordid cdi_proquest_miscellaneous_1257725339
source MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Adolescent
Adult
Aged
Aged, 80 and over
Algorithms
Antigens, CD - metabolism
Banff
Biological and medical sciences
Child
Child, Preschool
Decision Trees
diagnosis
Female
Follow-Up Studies
Glomerulonephritis - immunology
Glomerulonephritis - pathology
Graft Rejection - blood
Graft Rejection - diagnosis
Graft Rejection - immunology
Graft Survival - immunology
Humans
Immunoenzyme Techniques
Inflammation - immunology
Isoantibodies - blood
Isoantibodies - immunology
kidney
Kidney Transplantation - immunology
Male
Medical sciences
Microcirculation - immunology
Middle Aged
pathology
Prognosis
rejection
Renal Circulation - immunology
Risk Factors
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
survival
Survival Rate
transplantation
Young Adult
title A New Diagnostic Algorithm for Antibody‐Mediated Microcirculation Inflammation in Kidney Transplants
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T01%3A45%3A00IST&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=A%20New%20Diagnostic%20Algorithm%20for%20Antibody%E2%80%90Mediated%20Microcirculation%20Inflammation%20in%20Kidney%20Transplants&rft.jtitle=American%20journal%20of%20transplantation&rft.au=Sis,%20B.&rft.date=2012-05&rft.volume=12&rft.issue=5&rft.spage=1168&rft.epage=1179&rft.pages=1168-1179&rft.issn=1600-6135&rft.eissn=1600-6143&rft_id=info:doi/10.1111/j.1600-6143.2011.03931.x&rft_dat=%3Cproquest_cross%3E1257725339%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=1010232286&rft_id=info:pmid/22300601&rfr_iscdi=true