Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion
Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery f...
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| Veröffentlicht in: | Basic research in cardiology 2018-11, Vol.113 (6), p.47-16, Article 47 |
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| creator | Edwards, Kristin S. Ashraf, Sadia Lomax, Tyler M. Wiseman, Jessica M. Hall, Michael E. Gava, Fabio N. Hall, John E. Hosler, Jonathan P. Harmancey, Romain |
| description | Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R). After confirming that myocardial UCP3 levels were systematically decreased by 20–49% in animal models of insulin resistance and type 2 diabetes, we genetically engineered Sprague–Dawley rats with partial loss of UCP3 (ucp3
+/−
). Wild-type littermates (ucp3
+/+
) were used as controls. Isolated working hearts from ucp3
+/−
rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3
+/−
hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3
+/−
cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion. |
| doi_str_mv | 10.1007/s00395-018-0707-9 |
| format | Article |
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+/−
). Wild-type littermates (ucp3
+/+
) were used as controls. Isolated working hearts from ucp3
+/−
rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3
+/−
hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3
+/−
cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion.</description><identifier>ISSN: 0300-8428</identifier><identifier>EISSN: 1435-1803</identifier><identifier>DOI: 10.1007/s00395-018-0707-9</identifier><identifier>PMID: 30374710</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animal models ; Cardiology ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Electron transport ; Electron transport chain ; Fatty acids ; Genetic engineering ; Heart ; Insulin ; Insulin resistance ; Ischemia ; Medicine ; Medicine & Public Health ; Mitochondria ; Muscle contraction ; Myocardial infarction ; Original Contribution ; Oxidation ; Oxidation resistance ; Patients ; Protein deficiency ; Proteins ; Rats ; Reactive oxygen species ; Recovery ; Reperfusion ; Supplements</subject><ispartof>Basic research in cardiology, 2018-11, Vol.113 (6), p.47-16, Article 47</ispartof><rights>The Author(s) 2018</rights><rights>Basic Research in Cardiology is a copyright of Springer, (2018). All Rights Reserved. © 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-afe7251451206f1e4bef5cdafa8d2b05f116a0812fac303d414a940274f7f75a3</citedby><cites>FETCH-LOGICAL-c470t-afe7251451206f1e4bef5cdafa8d2b05f116a0812fac303d414a940274f7f75a3</cites><orcidid>0000-0002-5040-4500</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00395-018-0707-9$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00395-018-0707-9$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30374710$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Edwards, Kristin S.</creatorcontrib><creatorcontrib>Ashraf, Sadia</creatorcontrib><creatorcontrib>Lomax, Tyler M.</creatorcontrib><creatorcontrib>Wiseman, Jessica M.</creatorcontrib><creatorcontrib>Hall, Michael E.</creatorcontrib><creatorcontrib>Gava, Fabio N.</creatorcontrib><creatorcontrib>Hall, John E.</creatorcontrib><creatorcontrib>Hosler, Jonathan P.</creatorcontrib><creatorcontrib>Harmancey, Romain</creatorcontrib><title>Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion</title><title>Basic research in cardiology</title><addtitle>Basic Res Cardiol</addtitle><addtitle>Basic Res Cardiol</addtitle><description>Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R). After confirming that myocardial UCP3 levels were systematically decreased by 20–49% in animal models of insulin resistance and type 2 diabetes, we genetically engineered Sprague–Dawley rats with partial loss of UCP3 (ucp3
+/−
). Wild-type littermates (ucp3
+/+
) were used as controls. Isolated working hearts from ucp3
+/−
rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3
+/−
hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3
+/−
cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion.</description><subject>Animal models</subject><subject>Cardiology</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Electron transport</subject><subject>Electron transport chain</subject><subject>Fatty acids</subject><subject>Genetic engineering</subject><subject>Heart</subject><subject>Insulin</subject><subject>Insulin resistance</subject><subject>Ischemia</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mitochondria</subject><subject>Muscle contraction</subject><subject>Myocardial infarction</subject><subject>Original Contribution</subject><subject>Oxidation</subject><subject>Oxidation resistance</subject><subject>Patients</subject><subject>Protein deficiency</subject><subject>Proteins</subject><subject>Rats</subject><subject>Reactive oxygen species</subject><subject>Recovery</subject><subject>Reperfusion</subject><subject>Supplements</subject><issn>0300-8428</issn><issn>1435-1803</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kUtv1TAQhSMEopfCD2CDLLHpJnTsOHGyQUIVL6kSG7q25jrjW1eJHeykkBV_vY5uKQ-J1SzmO2fm6BTFSw5vOIA6TwBVV5fA2xIUqLJ7VOy4rOqSt1A9LnZQAZStFO1J8SylGwAum4Y_LU4qqJRUHHbFzytvwjINzh_YFMNMzrOK9WSdceTNytw4oYuJjWswGHuHA7M4zytD43oWfrgeZxc8Q98zE_wc0cxuIBbJhFuKK7NhGML3zd8lc02jw_NIE0W7pKx7XjyxOCR6cT9Pi6sP779efCovv3z8fPHusjRSwVyiJSVqLmsuoLGc5J5sbXq02PZiD7XlvEFoubBocrhecomdBKGkVVbVWJ0Wb4--07IfqTe0fTroKboR46oDOv33xrtrfQi3uhHQNm2TDc7uDWL4tlCa9Zjz0DCgp7AkLbhQAngtZUZf_4PehCX6HG-jGtV0XcczxY-UiSGlSPbhGQ56q1cf69W5Xr3Vq7usefVnigfFrz4zII5Ayit_oPj79P9d7wB5GLPz</recordid><startdate>20181101</startdate><enddate>20181101</enddate><creator>Edwards, Kristin S.</creator><creator>Ashraf, Sadia</creator><creator>Lomax, Tyler M.</creator><creator>Wiseman, Jessica M.</creator><creator>Hall, Michael E.</creator><creator>Gava, Fabio N.</creator><creator>Hall, John E.</creator><creator>Hosler, Jonathan P.</creator><creator>Harmancey, Romain</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7Z</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5040-4500</orcidid></search><sort><creationdate>20181101</creationdate><title>Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion</title><author>Edwards, Kristin S. ; Ashraf, Sadia ; Lomax, Tyler M. ; Wiseman, Jessica M. ; Hall, Michael E. ; Gava, Fabio N. ; Hall, John E. ; Hosler, Jonathan P. ; Harmancey, Romain</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-afe7251451206f1e4bef5cdafa8d2b05f116a0812fac303d414a940274f7f75a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animal models</topic><topic>Cardiology</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Electron transport</topic><topic>Electron transport chain</topic><topic>Fatty acids</topic><topic>Genetic engineering</topic><topic>Heart</topic><topic>Insulin</topic><topic>Insulin resistance</topic><topic>Ischemia</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mitochondria</topic><topic>Muscle contraction</topic><topic>Myocardial infarction</topic><topic>Original Contribution</topic><topic>Oxidation</topic><topic>Oxidation resistance</topic><topic>Patients</topic><topic>Protein deficiency</topic><topic>Proteins</topic><topic>Rats</topic><topic>Reactive oxygen species</topic><topic>Recovery</topic><topic>Reperfusion</topic><topic>Supplements</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Edwards, Kristin S.</creatorcontrib><creatorcontrib>Ashraf, Sadia</creatorcontrib><creatorcontrib>Lomax, Tyler M.</creatorcontrib><creatorcontrib>Wiseman, Jessica M.</creatorcontrib><creatorcontrib>Hall, Michael E.</creatorcontrib><creatorcontrib>Gava, Fabio N.</creatorcontrib><creatorcontrib>Hall, John E.</creatorcontrib><creatorcontrib>Hosler, Jonathan P.</creatorcontrib><creatorcontrib>Harmancey, Romain</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Basic research in cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Edwards, Kristin S.</au><au>Ashraf, Sadia</au><au>Lomax, Tyler M.</au><au>Wiseman, Jessica M.</au><au>Hall, Michael E.</au><au>Gava, Fabio N.</au><au>Hall, John E.</au><au>Hosler, Jonathan P.</au><au>Harmancey, Romain</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion</atitle><jtitle>Basic research in cardiology</jtitle><stitle>Basic Res Cardiol</stitle><addtitle>Basic Res Cardiol</addtitle><date>2018-11-01</date><risdate>2018</risdate><volume>113</volume><issue>6</issue><spage>47</spage><epage>16</epage><pages>47-16</pages><artnum>47</artnum><issn>0300-8428</issn><eissn>1435-1803</eissn><abstract>Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R). After confirming that myocardial UCP3 levels were systematically decreased by 20–49% in animal models of insulin resistance and type 2 diabetes, we genetically engineered Sprague–Dawley rats with partial loss of UCP3 (ucp3
+/−
). Wild-type littermates (ucp3
+/+
) were used as controls. Isolated working hearts from ucp3
+/−
rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3
+/−
hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3
+/−
cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>30374710</pmid><doi>10.1007/s00395-018-0707-9</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-5040-4500</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Basic research in cardiology, 2018-11, Vol.113 (6), p.47-16, Article 47 |
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| source | SpringerLink Journals |
| subjects | Animal models Cardiology Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Electron transport Electron transport chain Fatty acids Genetic engineering Heart Insulin Insulin resistance Ischemia Medicine Medicine & Public Health Mitochondria Muscle contraction Myocardial infarction Original Contribution Oxidation Oxidation resistance Patients Protein deficiency Proteins Rats Reactive oxygen species Recovery Reperfusion Supplements |
| title | Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion |
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