Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial
The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy‐confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (...
Gespeichert in:
Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2011-11, Vol.54 (5), p.1610-1619 |
---|---|
Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 1619 |
---|---|
container_issue | 5 |
container_start_page | 1610 |
container_title | Hepatology (Baltimore, Md.) |
container_volume | 54 |
creator | Zein, Claudia O. Yerian, Lisa M. Gogate, Prema Lopez, Rocio Kirwan, John P. Feldstein, Ariel E. McCullough, Arthur J. |
description | The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy‐confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention‐to‐treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, versus −0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score −0.9 versus −0.04 with placebo, P < 0.001) and lobular inflammation (median change −1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161). (HEPATOLOGY 2011) |
doi_str_mv | 10.1002/hep.24544 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3205292</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3958146801</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5054-18848c511ca08242082354847564fb36964d592f18e44f1488a6419c90bd47e13</originalsourceid><addsrcrecordid>eNp1kd9qFDEYxYMo7Vp70ReQARHai2mTzJd_XgilVCsU7IVeSshmMm5KZjIms7XrlY_gM_okzbprrYI3-SD5cc6XcxA6IPiYYExPFm48psAAHqEZYVTUTcPwYzTDVOBakUbtoqc5X2OMFVC5g3YpESAFZzP06coNU7z13SoEP7jK92OKNy5XQxxMsHERg7dVnpyZYrExk598flWdVskMbez9N9dWYzDWzePP7z9sHKYUQyiXU_ImPENPOhOy29_OPfTxzfmHs4v68v3bd2enl7VlmEFNpARpGSHWYEmBlqNhIEEwDt284YpDyxTtiHQAHQEpDQeirMLzFoQjzR56vdEdl_Petbb8KZmgx-R7k1Y6Gq__fhn8Qn-ON7qhmFFFi8DhViDFL0uXJ937bF0IZnBxmTURgnOOcbNGX_yDXsdlKmGtKc4lZWUU6mhD2RRzTq67X4ZgvS5NlzT1r9IK-_zh9vfk75YK8HILmGxN6Er21uc_HAhQJa3CnWy4rz641f8d9cX51cb6Dg77ryc</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1766825176</pqid></control><display><type>article</type><title>Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Zein, Claudia O. ; Yerian, Lisa M. ; Gogate, Prema ; Lopez, Rocio ; Kirwan, John P. ; Feldstein, Ariel E. ; McCullough, Arthur J.</creator><creatorcontrib>Zein, Claudia O. ; Yerian, Lisa M. ; Gogate, Prema ; Lopez, Rocio ; Kirwan, John P. ; Feldstein, Ariel E. ; McCullough, Arthur J.</creatorcontrib><description>The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy‐confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention‐to‐treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, versus −0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score −0.9 versus −0.04 with placebo, P < 0.001) and lobular inflammation (median change −1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161). (HEPATOLOGY 2011)</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.24544</identifier><identifier>PMID: 21748765</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adiponectin - blood ; Adult ; Alanine Transaminase - metabolism ; Apoptosis - drug effects ; Aspartate Aminotransferases - metabolism ; Biological and medical sciences ; Biopsy ; Fatty Liver - drug therapy ; Fatty Liver - pathology ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Hepatology ; Humans ; Insulin Resistance ; Liver - pathology ; Liver cirrhosis ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Middle Aged ; Non-alcoholic Fatty Liver Disease ; Pentoxifylline - administration & dosage ; Pentoxifylline - adverse effects ; Placebos ; Platelet Aggregation Inhibitors - administration & dosage ; Platelet Aggregation Inhibitors - adverse effects ; Treatment Outcome ; Tumor Necrosis Factor-alpha - blood</subject><ispartof>Hepatology (Baltimore, Md.), 2011-11, Vol.54 (5), p.1610-1619</ispartof><rights>Copyright © 2011 American Association for the Study of Liver Diseases</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5054-18848c511ca08242082354847564fb36964d592f18e44f1488a6419c90bd47e13</citedby><cites>FETCH-LOGICAL-c5054-18848c511ca08242082354847564fb36964d592f18e44f1488a6419c90bd47e13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.24544$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.24544$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24749847$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21748765$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zein, Claudia O.</creatorcontrib><creatorcontrib>Yerian, Lisa M.</creatorcontrib><creatorcontrib>Gogate, Prema</creatorcontrib><creatorcontrib>Lopez, Rocio</creatorcontrib><creatorcontrib>Kirwan, John P.</creatorcontrib><creatorcontrib>Feldstein, Ariel E.</creatorcontrib><creatorcontrib>McCullough, Arthur J.</creatorcontrib><title>Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy‐confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention‐to‐treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, versus −0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score −0.9 versus −0.04 with placebo, P < 0.001) and lobular inflammation (median change −1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161). (HEPATOLOGY 2011)</description><subject>Adiponectin - blood</subject><subject>Adult</subject><subject>Alanine Transaminase - metabolism</subject><subject>Apoptosis - drug effects</subject><subject>Aspartate Aminotransferases - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biopsy</subject><subject>Fatty Liver - drug therapy</subject><subject>Fatty Liver - pathology</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Insulin Resistance</subject><subject>Liver - pathology</subject><subject>Liver cirrhosis</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Non-alcoholic Fatty Liver Disease</subject><subject>Pentoxifylline - administration & dosage</subject><subject>Pentoxifylline - adverse effects</subject><subject>Placebos</subject><subject>Platelet Aggregation Inhibitors - administration & dosage</subject><subject>Platelet Aggregation Inhibitors - adverse effects</subject><subject>Treatment Outcome</subject><subject>Tumor Necrosis Factor-alpha - blood</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kd9qFDEYxYMo7Vp70ReQARHai2mTzJd_XgilVCsU7IVeSshmMm5KZjIms7XrlY_gM_okzbprrYI3-SD5cc6XcxA6IPiYYExPFm48psAAHqEZYVTUTcPwYzTDVOBakUbtoqc5X2OMFVC5g3YpESAFZzP06coNU7z13SoEP7jK92OKNy5XQxxMsHERg7dVnpyZYrExk598flWdVskMbez9N9dWYzDWzePP7z9sHKYUQyiXU_ImPENPOhOy29_OPfTxzfmHs4v68v3bd2enl7VlmEFNpARpGSHWYEmBlqNhIEEwDt284YpDyxTtiHQAHQEpDQeirMLzFoQjzR56vdEdl_Petbb8KZmgx-R7k1Y6Gq__fhn8Qn-ON7qhmFFFi8DhViDFL0uXJ937bF0IZnBxmTURgnOOcbNGX_yDXsdlKmGtKc4lZWUU6mhD2RRzTq67X4ZgvS5NlzT1r9IK-_zh9vfk75YK8HILmGxN6Er21uc_HAhQJa3CnWy4rz641f8d9cX51cb6Dg77ryc</recordid><startdate>201111</startdate><enddate>201111</enddate><creator>Zein, Claudia O.</creator><creator>Yerian, Lisa M.</creator><creator>Gogate, Prema</creator><creator>Lopez, Rocio</creator><creator>Kirwan, John P.</creator><creator>Feldstein, Ariel E.</creator><creator>McCullough, Arthur J.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>Wiley Subscription Services, Inc</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>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>5PM</scope></search><sort><creationdate>201111</creationdate><title>Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial</title><author>Zein, Claudia O. ; Yerian, Lisa M. ; Gogate, Prema ; Lopez, Rocio ; Kirwan, John P. ; Feldstein, Ariel E. ; McCullough, Arthur J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5054-18848c511ca08242082354847564fb36964d592f18e44f1488a6419c90bd47e13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adiponectin - blood</topic><topic>Adult</topic><topic>Alanine Transaminase - metabolism</topic><topic>Apoptosis - drug effects</topic><topic>Aspartate Aminotransferases - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biopsy</topic><topic>Fatty Liver - drug therapy</topic><topic>Fatty Liver - pathology</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Insulin Resistance</topic><topic>Liver - pathology</topic><topic>Liver cirrhosis</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Non-alcoholic Fatty Liver Disease</topic><topic>Pentoxifylline - administration & dosage</topic><topic>Pentoxifylline - adverse effects</topic><topic>Placebos</topic><topic>Platelet Aggregation Inhibitors - administration & dosage</topic><topic>Platelet Aggregation Inhibitors - adverse effects</topic><topic>Treatment Outcome</topic><topic>Tumor Necrosis Factor-alpha - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zein, Claudia O.</creatorcontrib><creatorcontrib>Yerian, Lisa M.</creatorcontrib><creatorcontrib>Gogate, Prema</creatorcontrib><creatorcontrib>Lopez, Rocio</creatorcontrib><creatorcontrib>Kirwan, John P.</creatorcontrib><creatorcontrib>Feldstein, Ariel E.</creatorcontrib><creatorcontrib>McCullough, Arthur J.</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>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zein, Claudia O.</au><au>Yerian, Lisa M.</au><au>Gogate, Prema</au><au>Lopez, Rocio</au><au>Kirwan, John P.</au><au>Feldstein, Ariel E.</au><au>McCullough, Arthur J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2011-11</date><risdate>2011</risdate><volume>54</volume><issue>5</issue><spage>1610</spage><epage>1619</epage><pages>1610-1619</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of nonalcoholic steatohepatitis (NASH). In all, 55 adults with biopsy‐confirmed NASH were randomized to receive PTX at a dose of 400 mg three times a day (n = 26) or placebo (n = 29) over 1 year. The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥2 points in the nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 1 year, intention‐to‐treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on PTX versus 13.8% of those on placebo (P = 0.036). Per protocol analysis, a decrease of ≥2 points in the NAS from baseline was observed in 50% of the patients on PTX versus 15.4% of those on placebo (P = 0.01). The mean change in NAS score from baseline was −1.6 in the PTX group, versus −0.1 in the placebo group (P < 0.001). PTX significantly improved steatosis (mean change in score −0.9 versus −0.04 with placebo, P < 0.001) and lobular inflammation (median change −1 versus 0 with placebo, P = 0.02). No significant effects in hepatocellular ballooning were observed. PTX also improved liver fibrosis (mean change in fibrosis score was −0.2 among those on PTX versus +0.4 among those on placebo, P = 0.038). Although not statistically significant (P = 0.17), improvement in fibrosis was observed in a greater proportion (35%) of patients in the PTX group compared to placebo (15%). Adverse effects were similar in both groups. Conclusion: PTX improved histological features of NASH compared to placebo. PTX was well tolerated in patients with NASH (ClinicalTrials.gov number NCT00590161). (HEPATOLOGY 2011)</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>21748765</pmid><doi>10.1002/hep.24544</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0270-9139 |
ispartof | Hepatology (Baltimore, Md.), 2011-11, Vol.54 (5), p.1610-1619 |
issn | 0270-9139 1527-3350 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3205292 |
source | MEDLINE; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals |
subjects | Adiponectin - blood Adult Alanine Transaminase - metabolism Apoptosis - drug effects Aspartate Aminotransferases - metabolism Biological and medical sciences Biopsy Fatty Liver - drug therapy Fatty Liver - pathology Female Gastroenterology. Liver. Pancreas. Abdomen Hepatology Humans Insulin Resistance Liver - pathology Liver cirrhosis Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Middle Aged Non-alcoholic Fatty Liver Disease Pentoxifylline - administration & dosage Pentoxifylline - adverse effects Placebos Platelet Aggregation Inhibitors - administration & dosage Platelet Aggregation Inhibitors - adverse effects Treatment Outcome Tumor Necrosis Factor-alpha - blood |
title | Pentoxifylline improves nonalcoholic steatohepatitis: A randomized placebo‐controlled trial |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T02%3A43%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pentoxifylline%20improves%20nonalcoholic%20steatohepatitis:%20A%20randomized%20placebo%E2%80%90controlled%20trial&rft.jtitle=Hepatology%20(Baltimore,%20Md.)&rft.au=Zein,%20Claudia%20O.&rft.date=2011-11&rft.volume=54&rft.issue=5&rft.spage=1610&rft.epage=1619&rft.pages=1610-1619&rft.issn=0270-9139&rft.eissn=1527-3350&rft.coden=HPTLD9&rft_id=info:doi/10.1002/hep.24544&rft_dat=%3Cproquest_pubme%3E3958146801%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1766825176&rft_id=info:pmid/21748765&rfr_iscdi=true |