HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study

Purpose Currently available local anesthetics have not demonstrated sufficient analgesia beyond 12–24 h postoperatively. The purpose of the study was to assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer ® polymer technology), a long-acting investigational anestheti...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Hernia : the journal of hernias and abdominal wall surgery 2019-12, Vol.23 (6), p.1071-1080
Hauptverfasser: Viscusi, E., Minkowitz, H., Winkle, P., Ramamoorthy, S., Hu, J., Singla, N.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1080
container_issue 6
container_start_page 1071
container_title Hernia : the journal of hernias and abdominal wall surgery
container_volume 23
creator Viscusi, E.
Minkowitz, H.
Winkle, P.
Ramamoorthy, S.
Hu, J.
Singla, N.
description Purpose Currently available local anesthetics have not demonstrated sufficient analgesia beyond 12–24 h postoperatively. The purpose of the study was to assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer ® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl). Methods A phase 3, randomized, double-blind, active-controlled multi-center study (EPOCH 2; NCT03237481) in subjects undergoing unilateral open inguinal herniorrhaphy with mesh placement was performed. Subjects randomly received a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl, or saline placebo prior to closure. Results The study evaluated 418 subjects, and the primary and all key secondary efficacy endpoints were in favor of HTX-011. HTX-011 reduced mean pain intensity by 23% versus placebo (primary endpoint; p  
doi_str_mv 10.1007/s10029-019-02023-6
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6938470</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2275700831</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-f0f30978406df36a139fbcbfeecd763dcc946e2290c772839bb6a68340949bf63</originalsourceid><addsrcrecordid>eNp9kcuKFDEUhgtRnHH0BVxIwI2b0twmVXEhSDPawsC4GMFdSCUnUxmqkjKpNPQD-N6m7XG8LFzkAuf_v3MOf9M8J_g1wbh7k-tNZYtJPRRT1ooHzSmhvG8lxfzh4S_OWy6xOGme5HyLMe656B83J4xwKqvjtPm-vf5aCQQlsMWARYv2AfmwQsh-3SMdLIqLj94iE0Mu87L6GNAOUi4ZDWXxO22qBdB2M1UfGiEFH1Ma9TLu31ZsLtOakUtxRusIaBl1BsTQxeerzRZRlNdi90-bR05PGZ7dvWfNlw8X15tte3n18dPm_WVreMfX1mHHsOx6joV1TGjCpBvM4ACM7QSzxkgugNbVTNfRnslhEFr0jGPJ5eAEO2veHblLGWawBsKa9KSW5Ged9ipqr_6uBD-qm7hTQrKed7gCXt0BUvxWIK9q9tnANOkAsWRFGaV1Kk4OvV7-I72NJYW6nqK0O-9qGIxUFT2qTIo5J3D3wxCsDimrY8qqpqx-pqwO6Bd_rnFv-RVrFbCjINdSuIH0u_d_sD8AsBKzcA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2275700831</pqid></control><display><type>article</type><title>HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study</title><source>MEDLINE</source><source>SpringerNature Complete Journals</source><creator>Viscusi, E. ; Minkowitz, H. ; Winkle, P. ; Ramamoorthy, S. ; Hu, J. ; Singla, N.</creator><creatorcontrib>Viscusi, E. ; Minkowitz, H. ; Winkle, P. ; Ramamoorthy, S. ; Hu, J. ; Singla, N.</creatorcontrib><description>Purpose Currently available local anesthetics have not demonstrated sufficient analgesia beyond 12–24 h postoperatively. The purpose of the study was to assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer ® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl). Methods A phase 3, randomized, double-blind, active-controlled multi-center study (EPOCH 2; NCT03237481) in subjects undergoing unilateral open inguinal herniorrhaphy with mesh placement was performed. Subjects randomly received a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl, or saline placebo prior to closure. Results The study evaluated 418 subjects, and the primary and all key secondary efficacy endpoints were in favor of HTX-011. HTX-011 reduced mean pain intensity by 23% versus placebo (primary endpoint; p  &lt; 0.001) and by 21% versus bupivacaine HCl ( p  &lt; 0.001) with significant reductions in the number of patients experiencing severe pain. Opioid consumption over 72 h was reduced by 38% versus placebo ( p  &lt; 0.001) and 25% versus bupivacaine HCl ( p  = 0.024). Overall, 51% of HTX-011 subjects were opioid-free through 72 h (versus 22% for placebo [ p  &lt; 0.001] and 40% for bupivacaine HCl [ p  = 0.049]). HTX-011 was generally well-tolerated with fewer opioid-related adverse events reported compared to the bupivacaine HCl and placebo and no evidence of local anesthetic systemic toxicity. Conclusions HTX-011 demonstrated significant improvement in postoperative pain control and a clinically meaningful reduction in opioid consumption when compared to the most widely used local anesthetic, bupivacaine HCl.</description><identifier>ISSN: 1265-4906</identifier><identifier>EISSN: 1248-9204</identifier><identifier>DOI: 10.1007/s10029-019-02023-6</identifier><identifier>PMID: 31429023</identifier><language>eng</language><publisher>Paris: Springer Paris</publisher><subject><![CDATA[Abdominal Surgery ; Adult ; Analgesia ; Analgesics, Opioid - administration & dosage ; Anesthetics ; Anesthetics, Local - administration & dosage ; Bupivacaine ; Bupivacaine - administration & dosage ; Chronic Pain ; Double-Blind Method ; Female ; Hernia, Inguinal - surgery ; Herniorrhaphy ; Humans ; Local anesthetics ; Male ; Medicine ; Medicine & Public Health ; Meloxicam ; Meloxicam - administration & dosage ; Middle Aged ; Narcotics ; Opioids ; Original ; Original Article ; Pain ; Pain Management ; Pain Measurement ; Pain perception ; Pain, Postoperative - diagnosis ; Pain, Postoperative - etiology ; Pain, Postoperative - prevention & control ; Toxicity]]></subject><ispartof>Hernia : the journal of hernias and abdominal wall surgery, 2019-12, Vol.23 (6), p.1071-1080</ispartof><rights>The Author(s) 2019</rights><rights>Hernia is a copyright of Springer, (2019). All Rights Reserved. © 2019. 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-c474t-f0f30978406df36a139fbcbfeecd763dcc946e2290c772839bb6a68340949bf63</citedby><cites>FETCH-LOGICAL-c474t-f0f30978406df36a139fbcbfeecd763dcc946e2290c772839bb6a68340949bf63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10029-019-02023-6$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10029-019-02023-6$$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/31429023$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Viscusi, E.</creatorcontrib><creatorcontrib>Minkowitz, H.</creatorcontrib><creatorcontrib>Winkle, P.</creatorcontrib><creatorcontrib>Ramamoorthy, S.</creatorcontrib><creatorcontrib>Hu, J.</creatorcontrib><creatorcontrib>Singla, N.</creatorcontrib><title>HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study</title><title>Hernia : the journal of hernias and abdominal wall surgery</title><addtitle>Hernia</addtitle><addtitle>Hernia</addtitle><description>Purpose Currently available local anesthetics have not demonstrated sufficient analgesia beyond 12–24 h postoperatively. The purpose of the study was to assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer ® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl). Methods A phase 3, randomized, double-blind, active-controlled multi-center study (EPOCH 2; NCT03237481) in subjects undergoing unilateral open inguinal herniorrhaphy with mesh placement was performed. Subjects randomly received a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl, or saline placebo prior to closure. Results The study evaluated 418 subjects, and the primary and all key secondary efficacy endpoints were in favor of HTX-011. HTX-011 reduced mean pain intensity by 23% versus placebo (primary endpoint; p  &lt; 0.001) and by 21% versus bupivacaine HCl ( p  &lt; 0.001) with significant reductions in the number of patients experiencing severe pain. Opioid consumption over 72 h was reduced by 38% versus placebo ( p  &lt; 0.001) and 25% versus bupivacaine HCl ( p  = 0.024). Overall, 51% of HTX-011 subjects were opioid-free through 72 h (versus 22% for placebo [ p  &lt; 0.001] and 40% for bupivacaine HCl [ p  = 0.049]). HTX-011 was generally well-tolerated with fewer opioid-related adverse events reported compared to the bupivacaine HCl and placebo and no evidence of local anesthetic systemic toxicity. Conclusions HTX-011 demonstrated significant improvement in postoperative pain control and a clinically meaningful reduction in opioid consumption when compared to the most widely used local anesthetic, bupivacaine HCl.</description><subject>Abdominal Surgery</subject><subject>Adult</subject><subject>Analgesia</subject><subject>Analgesics, Opioid - administration &amp; dosage</subject><subject>Anesthetics</subject><subject>Anesthetics, Local - administration &amp; dosage</subject><subject>Bupivacaine</subject><subject>Bupivacaine - administration &amp; dosage</subject><subject>Chronic Pain</subject><subject>Double-Blind Method</subject><subject>Female</subject><subject>Hernia, Inguinal - surgery</subject><subject>Herniorrhaphy</subject><subject>Humans</subject><subject>Local anesthetics</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine &amp; Public Health</subject><subject>Meloxicam</subject><subject>Meloxicam - administration &amp; dosage</subject><subject>Middle Aged</subject><subject>Narcotics</subject><subject>Opioids</subject><subject>Original</subject><subject>Original Article</subject><subject>Pain</subject><subject>Pain Management</subject><subject>Pain Measurement</subject><subject>Pain perception</subject><subject>Pain, Postoperative - diagnosis</subject><subject>Pain, Postoperative - etiology</subject><subject>Pain, Postoperative - prevention &amp; control</subject><subject>Toxicity</subject><issn>1265-4906</issn><issn>1248-9204</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kcuKFDEUhgtRnHH0BVxIwI2b0twmVXEhSDPawsC4GMFdSCUnUxmqkjKpNPQD-N6m7XG8LFzkAuf_v3MOf9M8J_g1wbh7k-tNZYtJPRRT1ooHzSmhvG8lxfzh4S_OWy6xOGme5HyLMe656B83J4xwKqvjtPm-vf5aCQQlsMWARYv2AfmwQsh-3SMdLIqLj94iE0Mu87L6GNAOUi4ZDWXxO22qBdB2M1UfGiEFH1Ma9TLu31ZsLtOakUtxRusIaBl1BsTQxeerzRZRlNdi90-bR05PGZ7dvWfNlw8X15tte3n18dPm_WVreMfX1mHHsOx6joV1TGjCpBvM4ACM7QSzxkgugNbVTNfRnslhEFr0jGPJ5eAEO2veHblLGWawBsKa9KSW5Ged9ipqr_6uBD-qm7hTQrKed7gCXt0BUvxWIK9q9tnANOkAsWRFGaV1Kk4OvV7-I72NJYW6nqK0O-9qGIxUFT2qTIo5J3D3wxCsDimrY8qqpqx-pqwO6Bd_rnFv-RVrFbCjINdSuIH0u_d_sD8AsBKzcA</recordid><startdate>20191201</startdate><enddate>20191201</enddate><creator>Viscusi, E.</creator><creator>Minkowitz, H.</creator><creator>Winkle, P.</creator><creator>Ramamoorthy, S.</creator><creator>Hu, J.</creator><creator>Singla, N.</creator><general>Springer Paris</general><general>Springer Nature B.V</general><scope>C6C</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20191201</creationdate><title>HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study</title><author>Viscusi, E. ; Minkowitz, H. ; Winkle, P. ; Ramamoorthy, S. ; Hu, J. ; Singla, N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-f0f30978406df36a139fbcbfeecd763dcc946e2290c772839bb6a68340949bf63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Abdominal Surgery</topic><topic>Adult</topic><topic>Analgesia</topic><topic>Analgesics, Opioid - administration &amp; dosage</topic><topic>Anesthetics</topic><topic>Anesthetics, Local - administration &amp; dosage</topic><topic>Bupivacaine</topic><topic>Bupivacaine - administration &amp; dosage</topic><topic>Chronic Pain</topic><topic>Double-Blind Method</topic><topic>Female</topic><topic>Hernia, Inguinal - surgery</topic><topic>Herniorrhaphy</topic><topic>Humans</topic><topic>Local anesthetics</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine &amp; Public Health</topic><topic>Meloxicam</topic><topic>Meloxicam - administration &amp; dosage</topic><topic>Middle Aged</topic><topic>Narcotics</topic><topic>Opioids</topic><topic>Original</topic><topic>Original Article</topic><topic>Pain</topic><topic>Pain Management</topic><topic>Pain Measurement</topic><topic>Pain perception</topic><topic>Pain, Postoperative - diagnosis</topic><topic>Pain, Postoperative - etiology</topic><topic>Pain, Postoperative - prevention &amp; control</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Viscusi, E.</creatorcontrib><creatorcontrib>Minkowitz, H.</creatorcontrib><creatorcontrib>Winkle, P.</creatorcontrib><creatorcontrib>Ramamoorthy, S.</creatorcontrib><creatorcontrib>Hu, J.</creatorcontrib><creatorcontrib>Singla, N.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</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</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>Hernia : the journal of hernias and abdominal wall surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Viscusi, E.</au><au>Minkowitz, H.</au><au>Winkle, P.</au><au>Ramamoorthy, S.</au><au>Hu, J.</au><au>Singla, N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study</atitle><jtitle>Hernia : the journal of hernias and abdominal wall surgery</jtitle><stitle>Hernia</stitle><addtitle>Hernia</addtitle><date>2019-12-01</date><risdate>2019</risdate><volume>23</volume><issue>6</issue><spage>1071</spage><epage>1080</epage><pages>1071-1080</pages><issn>1265-4906</issn><eissn>1248-9204</eissn><abstract>Purpose Currently available local anesthetics have not demonstrated sufficient analgesia beyond 12–24 h postoperatively. The purpose of the study was to assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer ® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl). Methods A phase 3, randomized, double-blind, active-controlled multi-center study (EPOCH 2; NCT03237481) in subjects undergoing unilateral open inguinal herniorrhaphy with mesh placement was performed. Subjects randomly received a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl, or saline placebo prior to closure. Results The study evaluated 418 subjects, and the primary and all key secondary efficacy endpoints were in favor of HTX-011. HTX-011 reduced mean pain intensity by 23% versus placebo (primary endpoint; p  &lt; 0.001) and by 21% versus bupivacaine HCl ( p  &lt; 0.001) with significant reductions in the number of patients experiencing severe pain. Opioid consumption over 72 h was reduced by 38% versus placebo ( p  &lt; 0.001) and 25% versus bupivacaine HCl ( p  = 0.024). Overall, 51% of HTX-011 subjects were opioid-free through 72 h (versus 22% for placebo [ p  &lt; 0.001] and 40% for bupivacaine HCl [ p  = 0.049]). HTX-011 was generally well-tolerated with fewer opioid-related adverse events reported compared to the bupivacaine HCl and placebo and no evidence of local anesthetic systemic toxicity. Conclusions HTX-011 demonstrated significant improvement in postoperative pain control and a clinically meaningful reduction in opioid consumption when compared to the most widely used local anesthetic, bupivacaine HCl.</abstract><cop>Paris</cop><pub>Springer Paris</pub><pmid>31429023</pmid><doi>10.1007/s10029-019-02023-6</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1265-4906
ispartof Hernia : the journal of hernias and abdominal wall surgery, 2019-12, Vol.23 (6), p.1071-1080
issn 1265-4906
1248-9204
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6938470
source MEDLINE; SpringerNature Complete Journals
subjects Abdominal Surgery
Adult
Analgesia
Analgesics, Opioid - administration & dosage
Anesthetics
Anesthetics, Local - administration & dosage
Bupivacaine
Bupivacaine - administration & dosage
Chronic Pain
Double-Blind Method
Female
Hernia, Inguinal - surgery
Herniorrhaphy
Humans
Local anesthetics
Male
Medicine
Medicine & Public Health
Meloxicam
Meloxicam - administration & dosage
Middle Aged
Narcotics
Opioids
Original
Original Article
Pain
Pain Management
Pain Measurement
Pain perception
Pain, Postoperative - diagnosis
Pain, Postoperative - etiology
Pain, Postoperative - prevention & control
Toxicity
title HTX-011 reduced pain intensity and opioid consumption versus bupivacaine HCl in herniorrhaphy: results from the phase 3 EPOCH 2 study
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T09%3A53%3A03IST&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=HTX-011%20reduced%20pain%20intensity%20and%20opioid%20consumption%20versus%20bupivacaine%20HCl%20in%20herniorrhaphy:%20results%20from%20the%20phase%203%20EPOCH%202%20study&rft.jtitle=Hernia%20:%20the%20journal%20of%20hernias%20and%20abdominal%20wall%20surgery&rft.au=Viscusi,%20E.&rft.date=2019-12-01&rft.volume=23&rft.issue=6&rft.spage=1071&rft.epage=1080&rft.pages=1071-1080&rft.issn=1265-4906&rft.eissn=1248-9204&rft_id=info:doi/10.1007/s10029-019-02023-6&rft_dat=%3Cproquest_pubme%3E2275700831%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=2275700831&rft_id=info:pmid/31429023&rfr_iscdi=true