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Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial
Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an...
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Published in: | EClinicalMedicine 2023-03, Vol.57, p.101849-101849, Article 101849 |
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creator | Chen, Chen Ouyang, Menglu Ong, Sheila Zhang, Luyun Zhang, Guobin Delcourt, Candice Mair, Grant Liu, Leibo Billot, Laurent Li, Qiang Chen, Xiaoying Parsons, Mark Broderick, Joseph P. Demchuk, Andrew M. Bath, Philip M. Donnan, Geoffrey A. Levi, Christopher Chalmers, John Lindley, Richard I. Martins, Sheila O. Pontes-Neto, Octavio M. Venturelli, Paula Muñoz Olavarría, Verónica Lavados, Pablo Robinson, Thompson G. Wardlaw, Joanna M. Li, Gang Wang, Xia Song, Lili Anderson, Craig S. |
description | Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130–140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target 150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018.
All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24–36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616.
There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24–36 h. Mean achieved systolic blood pressures over 1–24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24–36 h (0.3 [IQR 0.0–16.6] in the intensive group and 0.9 [0.0–12.5] in the guideline group; log Δmean −0.17, 95% CI −0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses.
Intensive blood pressure lowering treatment to a systolic target |
doi_str_mv | 10.1016/j.eclinm.2023.101849 |
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All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24–36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616.
There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24–36 h. Mean achieved systolic blood pressures over 1–24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24–36 h (0.3 [IQR 0.0–16.6] in the intensive group and 0.9 [0.0–12.5] in the guideline group; log Δmean −0.17, 95% CI −0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses.
Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity.
National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.</description><identifier>ISSN: 2589-5370</identifier><identifier>EISSN: 2589-5370</identifier><identifier>DOI: 10.1016/j.eclinm.2023.101849</identifier><identifier>PMID: 36820100</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acute ischaemic stroke ; Blood pressure ; Brain imaging ; Cerebral infarction ; Clinical trial ; Thrombolysis</subject><ispartof>EClinicalMedicine, 2023-03, Vol.57, p.101849-101849, Article 101849</ispartof><rights>2023 The Author(s)</rights><rights>2023 The Author(s).</rights><rights>2023 The Author(s) 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-472d2b71cb8f00de9607574ee9472810606326ffe711b6b6e915b9e9bf35dcfc3</citedby><cites>FETCH-LOGICAL-c463t-472d2b71cb8f00de9607574ee9472810606326ffe711b6b6e915b9e9bf35dcfc3</cites><orcidid>0000-0003-1009-2124 ; 0000-0002-8960-8797 ; 0000-0002-6105-1720 ; 0000-0002-7248-4863</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9938155/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S2589537023000263$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3548,27923,27924,45779,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36820100$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Chen</creatorcontrib><creatorcontrib>Ouyang, Menglu</creatorcontrib><creatorcontrib>Ong, Sheila</creatorcontrib><creatorcontrib>Zhang, Luyun</creatorcontrib><creatorcontrib>Zhang, Guobin</creatorcontrib><creatorcontrib>Delcourt, Candice</creatorcontrib><creatorcontrib>Mair, Grant</creatorcontrib><creatorcontrib>Liu, Leibo</creatorcontrib><creatorcontrib>Billot, Laurent</creatorcontrib><creatorcontrib>Li, Qiang</creatorcontrib><creatorcontrib>Chen, Xiaoying</creatorcontrib><creatorcontrib>Parsons, Mark</creatorcontrib><creatorcontrib>Broderick, Joseph P.</creatorcontrib><creatorcontrib>Demchuk, Andrew M.</creatorcontrib><creatorcontrib>Bath, Philip M.</creatorcontrib><creatorcontrib>Donnan, Geoffrey A.</creatorcontrib><creatorcontrib>Levi, Christopher</creatorcontrib><creatorcontrib>Chalmers, John</creatorcontrib><creatorcontrib>Lindley, Richard I.</creatorcontrib><creatorcontrib>Martins, Sheila O.</creatorcontrib><creatorcontrib>Pontes-Neto, Octavio M.</creatorcontrib><creatorcontrib>Venturelli, Paula Muñoz</creatorcontrib><creatorcontrib>Olavarría, Verónica</creatorcontrib><creatorcontrib>Lavados, Pablo</creatorcontrib><creatorcontrib>Robinson, Thompson G.</creatorcontrib><creatorcontrib>Wardlaw, Joanna M.</creatorcontrib><creatorcontrib>Li, Gang</creatorcontrib><creatorcontrib>Wang, Xia</creatorcontrib><creatorcontrib>Song, Lili</creatorcontrib><creatorcontrib>Anderson, Craig S.</creatorcontrib><creatorcontrib>ENCHANTED investigators</creatorcontrib><title>Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial</title><title>EClinicalMedicine</title><addtitle>EClinicalMedicine</addtitle><description>Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130–140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018.
All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24–36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616.
There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24–36 h. Mean achieved systolic blood pressures over 1–24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24–36 h (0.3 [IQR 0.0–16.6] in the intensive group and 0.9 [0.0–12.5] in the guideline group; log Δmean −0.17, 95% CI −0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses.
Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity.
National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.</description><subject>Acute ischaemic stroke</subject><subject>Blood pressure</subject><subject>Brain imaging</subject><subject>Cerebral infarction</subject><subject>Clinical trial</subject><subject>Thrombolysis</subject><issn>2589-5370</issn><issn>2589-5370</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9UU1PGzEQtSqqglL-QYV85JLgj13vmgMSSlOohOiFni3bO04cedfB3gTl0t9eR6GUXnryyG_em3nzEPpCyYwSKq7WM7DBD_2MEcYPX20lP6AzVrdyWvOGnLyrT9F5zmtCCCNVKwX5hE65aBmhhJyhXwvnwI4ZR4f9MMKQ_Q6wCTF2eJMg520CHOILJD8scRywhQQm6YB9tisNvdeFh8dVir2JYZ-h8PToYRjzdUGyX66KuitwaQK8eJzf3z4-Lb7iMXkdPqOPTocM56_vBP38tnia308fftx9n98-TG0l-DitGtYx01BrWkdIB8VFUzcVgCxIS4kggjNRnDSUGmEESFobCdI4XnfWWT5BN0fdzdb00NmyXvGgNsn3Ou1V1F79iwx-pZZxp6TkLa3rInD5KpDi8xbyqPpyAAhBDxC3WbGmkbxqD4tMUHVstSnmnMC9jaFEHdJTa3VMTx3SU8f0Cu3i_YpvpD9Z_fUA5VA7D0llW-5sofOpRKi66P8_4Tfk36-e</recordid><startdate>20230301</startdate><enddate>20230301</enddate><creator>Chen, Chen</creator><creator>Ouyang, Menglu</creator><creator>Ong, Sheila</creator><creator>Zhang, Luyun</creator><creator>Zhang, Guobin</creator><creator>Delcourt, Candice</creator><creator>Mair, Grant</creator><creator>Liu, Leibo</creator><creator>Billot, Laurent</creator><creator>Li, Qiang</creator><creator>Chen, Xiaoying</creator><creator>Parsons, Mark</creator><creator>Broderick, Joseph P.</creator><creator>Demchuk, Andrew M.</creator><creator>Bath, Philip M.</creator><creator>Donnan, Geoffrey A.</creator><creator>Levi, Christopher</creator><creator>Chalmers, John</creator><creator>Lindley, Richard I.</creator><creator>Martins, Sheila O.</creator><creator>Pontes-Neto, Octavio M.</creator><creator>Venturelli, Paula Muñoz</creator><creator>Olavarría, Verónica</creator><creator>Lavados, Pablo</creator><creator>Robinson, Thompson G.</creator><creator>Wardlaw, Joanna M.</creator><creator>Li, Gang</creator><creator>Wang, Xia</creator><creator>Song, Lili</creator><creator>Anderson, Craig S.</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1009-2124</orcidid><orcidid>https://orcid.org/0000-0002-8960-8797</orcidid><orcidid>https://orcid.org/0000-0002-6105-1720</orcidid><orcidid>https://orcid.org/0000-0002-7248-4863</orcidid></search><sort><creationdate>20230301</creationdate><title>Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial</title><author>Chen, Chen ; Ouyang, Menglu ; Ong, Sheila ; Zhang, Luyun ; Zhang, Guobin ; Delcourt, Candice ; Mair, Grant ; Liu, Leibo ; Billot, Laurent ; Li, Qiang ; Chen, Xiaoying ; Parsons, Mark ; Broderick, Joseph P. ; Demchuk, Andrew M. ; Bath, Philip M. ; Donnan, Geoffrey A. ; Levi, Christopher ; Chalmers, John ; Lindley, Richard I. ; Martins, Sheila O. ; Pontes-Neto, Octavio M. ; Venturelli, Paula Muñoz ; Olavarría, Verónica ; Lavados, Pablo ; Robinson, Thompson G. ; Wardlaw, Joanna M. ; Li, Gang ; Wang, Xia ; Song, Lili ; Anderson, Craig S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-472d2b71cb8f00de9607574ee9472810606326ffe711b6b6e915b9e9bf35dcfc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Acute ischaemic stroke</topic><topic>Blood pressure</topic><topic>Brain imaging</topic><topic>Cerebral infarction</topic><topic>Clinical trial</topic><topic>Thrombolysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chen</creatorcontrib><creatorcontrib>Ouyang, Menglu</creatorcontrib><creatorcontrib>Ong, Sheila</creatorcontrib><creatorcontrib>Zhang, Luyun</creatorcontrib><creatorcontrib>Zhang, Guobin</creatorcontrib><creatorcontrib>Delcourt, Candice</creatorcontrib><creatorcontrib>Mair, Grant</creatorcontrib><creatorcontrib>Liu, Leibo</creatorcontrib><creatorcontrib>Billot, Laurent</creatorcontrib><creatorcontrib>Li, Qiang</creatorcontrib><creatorcontrib>Chen, Xiaoying</creatorcontrib><creatorcontrib>Parsons, Mark</creatorcontrib><creatorcontrib>Broderick, Joseph P.</creatorcontrib><creatorcontrib>Demchuk, Andrew M.</creatorcontrib><creatorcontrib>Bath, Philip M.</creatorcontrib><creatorcontrib>Donnan, Geoffrey A.</creatorcontrib><creatorcontrib>Levi, Christopher</creatorcontrib><creatorcontrib>Chalmers, John</creatorcontrib><creatorcontrib>Lindley, Richard I.</creatorcontrib><creatorcontrib>Martins, Sheila O.</creatorcontrib><creatorcontrib>Pontes-Neto, Octavio M.</creatorcontrib><creatorcontrib>Venturelli, Paula Muñoz</creatorcontrib><creatorcontrib>Olavarría, Verónica</creatorcontrib><creatorcontrib>Lavados, Pablo</creatorcontrib><creatorcontrib>Robinson, Thompson G.</creatorcontrib><creatorcontrib>Wardlaw, Joanna M.</creatorcontrib><creatorcontrib>Li, Gang</creatorcontrib><creatorcontrib>Wang, Xia</creatorcontrib><creatorcontrib>Song, Lili</creatorcontrib><creatorcontrib>Anderson, Craig S.</creatorcontrib><creatorcontrib>ENCHANTED investigators</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EClinicalMedicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chen</au><au>Ouyang, Menglu</au><au>Ong, Sheila</au><au>Zhang, Luyun</au><au>Zhang, Guobin</au><au>Delcourt, Candice</au><au>Mair, Grant</au><au>Liu, Leibo</au><au>Billot, Laurent</au><au>Li, Qiang</au><au>Chen, Xiaoying</au><au>Parsons, Mark</au><au>Broderick, Joseph P.</au><au>Demchuk, Andrew M.</au><au>Bath, Philip M.</au><au>Donnan, Geoffrey A.</au><au>Levi, Christopher</au><au>Chalmers, John</au><au>Lindley, Richard I.</au><au>Martins, Sheila O.</au><au>Pontes-Neto, Octavio M.</au><au>Venturelli, Paula Muñoz</au><au>Olavarría, Verónica</au><au>Lavados, Pablo</au><au>Robinson, Thompson G.</au><au>Wardlaw, Joanna M.</au><au>Li, Gang</au><au>Wang, Xia</au><au>Song, Lili</au><au>Anderson, Craig S.</au><aucorp>ENCHANTED investigators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial</atitle><jtitle>EClinicalMedicine</jtitle><addtitle>EClinicalMedicine</addtitle><date>2023-03-01</date><risdate>2023</risdate><volume>57</volume><spage>101849</spage><epage>101849</epage><pages>101849-101849</pages><artnum>101849</artnum><issn>2589-5370</issn><eissn>2589-5370</eissn><abstract>Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130–140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018.
All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24–36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616.
There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24–36 h. Mean achieved systolic blood pressures over 1–24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24–36 h (0.3 [IQR 0.0–16.6] in the intensive group and 0.9 [0.0–12.5] in the guideline group; log Δmean −0.17, 95% CI −0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses.
Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity.
National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>36820100</pmid><doi>10.1016/j.eclinm.2023.101849</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-1009-2124</orcidid><orcidid>https://orcid.org/0000-0002-8960-8797</orcidid><orcidid>https://orcid.org/0000-0002-6105-1720</orcidid><orcidid>https://orcid.org/0000-0002-7248-4863</orcidid><oa>free_for_read</oa></addata></record> |
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source | ScienceDirect; PubMed Central |
subjects | Acute ischaemic stroke Blood pressure Brain imaging Cerebral infarction Clinical trial Thrombolysis |
title | Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T20%3A24%3A27IST&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=Effects%20of%20intensive%20blood%20pressure%20lowering%20on%20cerebral%20ischaemia%20in%20thrombolysed%20patients:%20insights%20from%20the%20ENCHANTED%20trial&rft.jtitle=EClinicalMedicine&rft.au=Chen,%20Chen&rft.aucorp=ENCHANTED%20investigators&rft.date=2023-03-01&rft.volume=57&rft.spage=101849&rft.epage=101849&rft.pages=101849-101849&rft.artnum=101849&rft.issn=2589-5370&rft.eissn=2589-5370&rft_id=info:doi/10.1016/j.eclinm.2023.101849&rft_dat=%3Cproquest_pubme%3E2779348606%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c463t-472d2b71cb8f00de9607574ee9472810606326ffe711b6b6e915b9e9bf35dcfc3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2779348606&rft_id=info:pmid/36820100&rfr_iscdi=true |