Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma
Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactiva...
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| Veröffentlicht in: | PloS one 2015-04, Vol.10 (3), p.e0122041-e0122041 |
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| creator | Jang, Jeong Won Kim, Young Woon Lee, Sung Won Kwon, Jung Hyun Nam, Soon Woo Bae, Si Hyun Choi, Jong Young Yoon, Seung Kew Chung, Kyu Won |
| description | Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactivation in HBsAg-negative patients undergoing transarterial chemoembolization (TACE).
A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2-3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46).
During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216-116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation.
TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation. |
| doi_str_mv | 10.1371/journal.pone.0122041 |
| format | Article |
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A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2-3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46).
During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216-116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation.
TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0122041</identifier><identifier>PMID: 25894607</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Aged ; Analysis ; Antigens ; Antineoplastic Agents - therapeutic use ; Antiviral agents ; Antiviral drugs ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - therapy ; Carcinoma, Hepatocellular - virology ; Care and treatment ; Chemoembolization ; Chemoembolization, Therapeutic ; Chemotherapy ; Chronic infection ; Cirrhosis ; Deoxyribonucleic acid ; Development and progression ; Disease prevention ; DNA ; Drugs ; Female ; Hepatitis ; Hepatitis B ; Hepatitis B surface antigen ; Hepatitis B Surface Antigens - metabolism ; Hepatitis B virus ; Hepatitis B virus - physiology ; Hepatocellular carcinoma ; Hepatology ; Hospitals ; Humans ; Incidence ; Infections ; Interferon ; Internal medicine ; Liver cancer ; Liver cirrhosis ; Liver Neoplasms - metabolism ; Liver Neoplasms - therapy ; Liver Neoplasms - virology ; Lymphoma ; Male ; Medicine ; Metastasis ; Middle Aged ; Multivariate analysis ; Patients ; Prophylaxis ; Radiation therapy ; Radiotherapy ; Retrospective Studies ; Reversion ; Risk analysis ; Risk Factors ; Treatment Outcome ; Tumors ; Virus Activation ; Viruses</subject><ispartof>PloS one, 2015-04, Vol.10 (3), p.e0122041-e0122041</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Jang 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>2015 Jang et al 2015 Jang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-7f1d69e90ba8b1b88a4f78c4e778752ee6041c0b324f147e0cc89b7e783d01a23</citedby><cites>FETCH-LOGICAL-c692t-7f1d69e90ba8b1b88a4f78c4e778752ee6041c0b324f147e0cc89b7e783d01a23</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/PMC4403914/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403914/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23870,27928,27929,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25894607$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chemin, Isabelle A</contributor><creatorcontrib>Jang, Jeong Won</creatorcontrib><creatorcontrib>Kim, Young Woon</creatorcontrib><creatorcontrib>Lee, Sung Won</creatorcontrib><creatorcontrib>Kwon, Jung Hyun</creatorcontrib><creatorcontrib>Nam, Soon Woo</creatorcontrib><creatorcontrib>Bae, Si Hyun</creatorcontrib><creatorcontrib>Choi, Jong Young</creatorcontrib><creatorcontrib>Yoon, Seung Kew</creatorcontrib><creatorcontrib>Chung, Kyu Won</creatorcontrib><title>Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactivation in HBsAg-negative patients undergoing transarterial chemoembolization (TACE).
A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2-3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46).
During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216-116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation.
TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation.</description><subject>Activation</subject><subject>Aged</subject><subject>Analysis</subject><subject>Antigens</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antiviral agents</subject><subject>Antiviral drugs</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - therapy</subject><subject>Carcinoma, Hepatocellular - virology</subject><subject>Care and treatment</subject><subject>Chemoembolization</subject><subject>Chemoembolization, Therapeutic</subject><subject>Chemotherapy</subject><subject>Chronic infection</subject><subject>Cirrhosis</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>Disease prevention</subject><subject>DNA</subject><subject>Drugs</subject><subject>Female</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B surface antigen</subject><subject>Hepatitis B Surface Antigens - metabolism</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B virus - physiology</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Incidence</subject><subject>Infections</subject><subject>Interferon</subject><subject>Internal medicine</subject><subject>Liver cancer</subject><subject>Liver cirrhosis</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - therapy</subject><subject>Liver Neoplasms - virology</subject><subject>Lymphoma</subject><subject>Male</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Multivariate analysis</subject><subject>Patients</subject><subject>Prophylaxis</subject><subject>Radiation therapy</subject><subject>Radiotherapy</subject><subject>Retrospective Studies</subject><subject>Reversion</subject><subject>Risk analysis</subject><subject>Risk Factors</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>Virus Activation</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</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>eNqNk01v1DAQhiMEoqXwDxBEQkJw2MVfiZ0L0rYCulKlSuXjwMVynEnWq2y82M4C_x6HpNUG9YByiGU_7zue8UySPMdoiSnH77a2d51ql3vbwRJhQhDDD5JTXFCyyAmiD4_WJ8kT77cIZVTk-ePkhGSiYDnip8n3G1A6mIMKxnaprdMN7OM6GJ-epwfjep-aLr0896tm0UETjw6QDgR0wac_TdiMCquhbftWuVQrp01nd-pp8qhWrYdn0_8s-frxw5eLy8XV9af1xepqofOChAWvcZUXUKBSiRKXQihWc6EZcC54RgDymJhGJSWsxowD0loUJQcuaIWwIvQseTn67lvr5VQWL3HOGcuwoDgS65GorNrKvTM75X5Lq4z8u2FdI5ULRrcgQfCqKoQiBAgjnAokMoTLTHOBc10O0d5P0fpyB5WOdXCqnZnOTzqzkY09SMYQLTCLBm8mA2d_9OCD3Bk_VE91YPvx3kV8G0oj-uof9P7sJqpRMQHT1TbG1YOpXDFCRSY4QpFa3kPFr4Kd0bGHahP3Z4K3M0FkAvwKjeq9l-vPN__PXn-bs6-P2A2oNmy8bfuhAf0cZCOonfXeQX1XZIzkMAK31ZDDCMhpBKLsxfED3Ylue57-AQ9YACE</recordid><startdate>20150420</startdate><enddate>20150420</enddate><creator>Jang, Jeong Won</creator><creator>Kim, Young Woon</creator><creator>Lee, Sung Won</creator><creator>Kwon, Jung Hyun</creator><creator>Nam, Soon Woo</creator><creator>Bae, Si Hyun</creator><creator>Choi, Jong Young</creator><creator>Yoon, Seung Kew</creator><creator>Chung, Kyu Won</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150420</creationdate><title>Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma</title><author>Jang, Jeong Won ; Kim, Young Woon ; Lee, Sung Won ; Kwon, Jung Hyun ; Nam, Soon Woo ; Bae, Si Hyun ; Choi, Jong Young ; Yoon, Seung Kew ; Chung, Kyu Won</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-7f1d69e90ba8b1b88a4f78c4e778752ee6041c0b324f147e0cc89b7e783d01a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Activation</topic><topic>Aged</topic><topic>Analysis</topic><topic>Antigens</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Antiviral agents</topic><topic>Antiviral drugs</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - therapy</topic><topic>Carcinoma, Hepatocellular - virology</topic><topic>Care and treatment</topic><topic>Chemoembolization</topic><topic>Chemoembolization, Therapeutic</topic><topic>Chemotherapy</topic><topic>Chronic infection</topic><topic>Cirrhosis</topic><topic>Deoxyribonucleic acid</topic><topic>Development and progression</topic><topic>Disease prevention</topic><topic>DNA</topic><topic>Drugs</topic><topic>Female</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatitis B surface antigen</topic><topic>Hepatitis B Surface Antigens - metabolism</topic><topic>Hepatitis B virus</topic><topic>Hepatitis B virus - physiology</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatology</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Incidence</topic><topic>Infections</topic><topic>Interferon</topic><topic>Internal medicine</topic><topic>Liver cancer</topic><topic>Liver cirrhosis</topic><topic>Liver Neoplasms - 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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>Jang, Jeong Won</au><au>Kim, Young Woon</au><au>Lee, Sung Won</au><au>Kwon, Jung Hyun</au><au>Nam, Soon Woo</au><au>Bae, Si Hyun</au><au>Choi, Jong Young</au><au>Yoon, Seung Kew</au><au>Chung, Kyu Won</au><au>Chemin, Isabelle A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-20</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0122041</spage><epage>e0122041</epage><pages>e0122041-e0122041</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Despite increasing attention to hepatitis B virus (HBV) reactivation in hematologic settings, information on reactivation in hepatitis B surface (HBsAg)-negative patients with hepatocellular carcinoma (HCC) remains unknown. This study aimed to determine the incidence and risk factors of HBV reactivation in HBsAg-negative patients undergoing transarterial chemoembolization (TACE).
A total of 109 HBsAg-negative patients with HCC were consecutively recruited for this study and treated with either mono- (n = 75), combination-drug TACE (n = 20), or combination-drug TACE plus radiotherapy (n = 14). With serial monitoring of virological markers every 2-3 months, patients were observed for HBV reactivation (defined as the reappearance of HBV DNA or sero-reversion of HBsAg) in comparison with control subjects with HBsAg-negative cirrhosis (n = 16) or HBsAg loss (n = 46).
During the study period, HBV reactivation occurred in 12 (11.0%) and 1 (1.6%) patients in the TACE and control groups, respectively. The median level of HBV DNA at reactivation was 5,174 copies/ml (range: 216-116,058). Of the 12 patients with HBV reactivation, four (33.3%) developed clinical hepatitis, including one patient who suffered from decompensation. All antiviral-treated patients achieved undetectable HBV DNA or HBsAg loss after commencement of antiviral drugs. TACE was significantly correlated with a high incidence of HBV reactivation, with increasing risk of reactivation with intensive treatment. On multivariate analysis, treatment intensity and a prior history of chronic hepatitis B remained independently predictive of reactivation.
TACE can reactivate HBV replication in HBsAg-negative patients, with a dose-risk relationship between treatment intensity and reactivation. Patients with prior chronic HBV infection who are to undergo intensive TACE should be closely monitored, with an alternative approach of antiviral prophylaxis against HBV reactivation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25894607</pmid><doi>10.1371/journal.pone.0122041</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-04, Vol.10 (3), p.e0122041-e0122041 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1674451831 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Aged Analysis Antigens Antineoplastic Agents - therapeutic use Antiviral agents Antiviral drugs Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - therapy Carcinoma, Hepatocellular - virology Care and treatment Chemoembolization Chemoembolization, Therapeutic Chemotherapy Chronic infection Cirrhosis Deoxyribonucleic acid Development and progression Disease prevention DNA Drugs Female Hepatitis Hepatitis B Hepatitis B surface antigen Hepatitis B Surface Antigens - metabolism Hepatitis B virus Hepatitis B virus - physiology Hepatocellular carcinoma Hepatology Hospitals Humans Incidence Infections Interferon Internal medicine Liver cancer Liver cirrhosis Liver Neoplasms - metabolism Liver Neoplasms - therapy Liver Neoplasms - virology Lymphoma Male Medicine Metastasis Middle Aged Multivariate analysis Patients Prophylaxis Radiation therapy Radiotherapy Retrospective Studies Reversion Risk analysis Risk Factors Treatment Outcome Tumors Virus Activation Viruses |
| title | Reactivation of hepatitis B virus in HBsAg-negative patients with hepatocellular carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-17T00%3A34%3A29IST&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=Reactivation%20of%20hepatitis%20B%20virus%20in%20HBsAg-negative%20patients%20with%20hepatocellular%20carcinoma&rft.jtitle=PloS%20one&rft.au=Jang,%20Jeong%20Won&rft.date=2015-04-20&rft.volume=10&rft.issue=3&rft.spage=e0122041&rft.epage=e0122041&rft.pages=e0122041-e0122041&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0122041&rft_dat=%3Cgale_plos_%3EA423858700%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=1674451831&rft_id=info:pmid/25894607&rft_galeid=A423858700&rft_doaj_id=oai_doaj_org_article_e87dd98a22e24273808501b5c7816cb2&rfr_iscdi=true |