Loading…

Epigenome-wide association analyses of active injection drug use

Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized. 401 participants (Mage = 47.9; 68% male; 90% African Ameri...

Full description

Saved in:
Bibliographic Details
Published in:Drug and alcohol dependence 2022-06, Vol.235, p.109431-109431, Article 109431
Main Authors: Shu, Chang, Jaffe, Andrew E., Sabunciyan, Sarven, Ji, Hongkai, Astemborski, Jacquie, Sun, Jing, Bakulski, Kelly M., Sosnowski, David W., Mehta, Shruti H., Kirk, Gregory D., Maher, Brion S.
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c452t-a28ffea65f143c36b97f32e15399e070479c7e0867eab2f467c45c9320ff4e023
cites cdi_FETCH-LOGICAL-c452t-a28ffea65f143c36b97f32e15399e070479c7e0867eab2f467c45c9320ff4e023
container_end_page 109431
container_issue
container_start_page 109431
container_title Drug and alcohol dependence
container_volume 235
creator Shu, Chang
Jaffe, Andrew E.
Sabunciyan, Sarven
Ji, Hongkai
Astemborski, Jacquie
Sun, Jing
Bakulski, Kelly M.
Sosnowski, David W.
Mehta, Shruti H.
Kirk, Gregory D.
Maher, Brion S.
description Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized. 401 participants (Mage = 47.9; 68% male; 90% African American) over several timepoints (1054 visits) were drawn from a longitudinal cohort of people who inject drugs. DNA methylation was measured among buffy coat samples from the 1054 visits. Compared to samples collected after ≥ 6 months of abstinence, separate EWAS were conducted for active injecting of any drug, quantitative injection frequency, injecting of heroin and injecting of cocaine. Linear mixed effect models were used and analyses were adjusted for repeated measurements and key technical, biological, and sociodemographic characteristics. We found epigenome-wide significant CpG sites associated with active injection (cg10636246, AIM2, p = 2.33 × 10−8) and injection intensity (cg13117953, p = 4.30 × 10−8). We found converging evidence that cg10636246 (AIM2), cg23110600 (PRKCH), cg03546163 (FKBP5), cg04590956 (GMCL1), and cg16317961 (MAPRE2) were among the top 0.1% significantly differentially methylated CpG sites shared across the five EWAS. Top ranked CpGs among the five EWAS were enriched (p 
doi_str_mv 10.1016/j.drugalcdep.2022.109431
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2648894790</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0376871622001685</els_id><sourcerecordid>2675247691</sourcerecordid><originalsourceid>FETCH-LOGICAL-c452t-a28ffea65f143c36b97f32e15399e070479c7e0867eab2f467c45c9320ff4e023</originalsourceid><addsrcrecordid>eNqFkMtKAzEUhoMoWi-vIANu3EzNbZLJTi31AoIbXYc0cyIZppOadCp9e1NbFdyYTSDn-885-RAqCB4TTMRVO27i8GY628BiTDGl-VlxRvbQiNRSlRhzsY9GmElR1pKII3ScUovzEQofoiNWMVVVmI3Q9XTh36APcyg_fAOFSSlYb5Y-9IXpTbdOkIrgCmOXfgWF71uwX8XNAsWQ4BQdONMlONvdJ-j1bvoyeSifnu8fJzdPpeUVXZaG1s6BEZUjnFkmZko6RoHkRRRgiblUVgKuhQQzo44LmXNWMYqd44ApO0GX276LGN4HSEs998lC15kewpA0FbyuVW6DM3rxB23DEPNnNpSsKJdCkUzVW8rGkFIEpxfRz01ca4L1xrJu9a9lvbGst5Zz9Hw3YJjNofkJfmvNwO0WgGxk5SHqZD30Fhofsz_dBP__lE94OZGW</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2675247691</pqid></control><display><type>article</type><title>Epigenome-wide association analyses of active injection drug use</title><source>Applied Social Sciences Index &amp; Abstracts (ASSIA)</source><source>Elsevier ScienceDirect Journals</source><source>Elsevier:Jisc Collections:Elsevier Read and Publish Agreement 2022-2024:Freedom Collection (Reading list)</source><creator>Shu, Chang ; Jaffe, Andrew E. ; Sabunciyan, Sarven ; Ji, Hongkai ; Astemborski, Jacquie ; Sun, Jing ; Bakulski, Kelly M. ; Sosnowski, David W. ; Mehta, Shruti H. ; Kirk, Gregory D. ; Maher, Brion S.</creator><creatorcontrib>Shu, Chang ; Jaffe, Andrew E. ; Sabunciyan, Sarven ; Ji, Hongkai ; Astemborski, Jacquie ; Sun, Jing ; Bakulski, Kelly M. ; Sosnowski, David W. ; Mehta, Shruti H. ; Kirk, Gregory D. ; Maher, Brion S.</creatorcontrib><description>Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized. 401 participants (Mage = 47.9; 68% male; 90% African American) over several timepoints (1054 visits) were drawn from a longitudinal cohort of people who inject drugs. DNA methylation was measured among buffy coat samples from the 1054 visits. Compared to samples collected after ≥ 6 months of abstinence, separate EWAS were conducted for active injecting of any drug, quantitative injection frequency, injecting of heroin and injecting of cocaine. Linear mixed effect models were used and analyses were adjusted for repeated measurements and key technical, biological, and sociodemographic characteristics. We found epigenome-wide significant CpG sites associated with active injection (cg10636246, AIM2, p = 2.33 × 10−8) and injection intensity (cg13117953, p = 4.30 × 10−8). We found converging evidence that cg10636246 (AIM2), cg23110600 (PRKCH), cg03546163 (FKBP5), cg04590956 (GMCL1), and cg16317961 (MAPRE2) were among the top 0.1% significantly differentially methylated CpG sites shared across the five EWAS. Top ranked CpGs among the five EWAS were enriched (p &lt; 0.0001) in AIM2 inflammasome complex, T cell migration, insulin regulation and epinephrine synthesis pathways. During periods of active injection, samples had 0.46 years of epigenetic age acceleration relative to the abstinence period, within the same subject (p = 0.03). Findings from this study demonstrate modest, common, and specific effects on DNA methylation during a relatively short time between periods of active drug injection and abstinence. •Multiple DNA methylation sites are associated with active injection drug use•Top methylation sites are enriched in AIM2 inflammasome complex pathway•Within the same subjects, there was approximately a half year acceleration in biological age when comparing blood DNA methylation profiles during periods of active injection vs. abstinence</description><identifier>ISSN: 0376-8716</identifier><identifier>EISSN: 1879-0046</identifier><identifier>DOI: 10.1016/j.drugalcdep.2022.109431</identifier><identifier>PMID: 35395503</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Abstinence ; Adrenaline ; African Americans ; Biological effects ; Blood ; Buffy coat ; Cell migration ; Cocaine ; Cohort Studies ; CpG islands ; CpG Islands - genetics ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; Drug abuse ; Drug use ; Epigenesis, Genetic ; Epigenetics ; Epigenome ; Epinephrine ; Female ; Genome-Wide Association Study ; Health risks ; Heroin ; Humans ; Inflammasomes ; Injection ; Injection drug use ; Insulin ; Lymphocytes ; Lymphocytes T ; Male ; Microtubule-Associated Proteins - genetics ; Middle Aged ; Morbidity ; Sociodemographics</subject><ispartof>Drug and alcohol dependence, 2022-06, Vol.235, p.109431-109431, Article 109431</ispartof><rights>2022 Elsevier B.V.</rights><rights>Copyright © 2022 Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier Science Ltd. Jun 1, 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c452t-a28ffea65f143c36b97f32e15399e070479c7e0867eab2f467c45c9320ff4e023</citedby><cites>FETCH-LOGICAL-c452t-a28ffea65f143c36b97f32e15399e070479c7e0867eab2f467c45c9320ff4e023</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0376871622001685$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3547,27922,27923,30997,45778</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35395503$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shu, Chang</creatorcontrib><creatorcontrib>Jaffe, Andrew E.</creatorcontrib><creatorcontrib>Sabunciyan, Sarven</creatorcontrib><creatorcontrib>Ji, Hongkai</creatorcontrib><creatorcontrib>Astemborski, Jacquie</creatorcontrib><creatorcontrib>Sun, Jing</creatorcontrib><creatorcontrib>Bakulski, Kelly M.</creatorcontrib><creatorcontrib>Sosnowski, David W.</creatorcontrib><creatorcontrib>Mehta, Shruti H.</creatorcontrib><creatorcontrib>Kirk, Gregory D.</creatorcontrib><creatorcontrib>Maher, Brion S.</creatorcontrib><title>Epigenome-wide association analyses of active injection drug use</title><title>Drug and alcohol dependence</title><addtitle>Drug Alcohol Depend</addtitle><description>Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized. 401 participants (Mage = 47.9; 68% male; 90% African American) over several timepoints (1054 visits) were drawn from a longitudinal cohort of people who inject drugs. DNA methylation was measured among buffy coat samples from the 1054 visits. Compared to samples collected after ≥ 6 months of abstinence, separate EWAS were conducted for active injecting of any drug, quantitative injection frequency, injecting of heroin and injecting of cocaine. Linear mixed effect models were used and analyses were adjusted for repeated measurements and key technical, biological, and sociodemographic characteristics. We found epigenome-wide significant CpG sites associated with active injection (cg10636246, AIM2, p = 2.33 × 10−8) and injection intensity (cg13117953, p = 4.30 × 10−8). We found converging evidence that cg10636246 (AIM2), cg23110600 (PRKCH), cg03546163 (FKBP5), cg04590956 (GMCL1), and cg16317961 (MAPRE2) were among the top 0.1% significantly differentially methylated CpG sites shared across the five EWAS. Top ranked CpGs among the five EWAS were enriched (p &lt; 0.0001) in AIM2 inflammasome complex, T cell migration, insulin regulation and epinephrine synthesis pathways. During periods of active injection, samples had 0.46 years of epigenetic age acceleration relative to the abstinence period, within the same subject (p = 0.03). Findings from this study demonstrate modest, common, and specific effects on DNA methylation during a relatively short time between periods of active drug injection and abstinence. •Multiple DNA methylation sites are associated with active injection drug use•Top methylation sites are enriched in AIM2 inflammasome complex pathway•Within the same subjects, there was approximately a half year acceleration in biological age when comparing blood DNA methylation profiles during periods of active injection vs. abstinence</description><subject>Abstinence</subject><subject>Adrenaline</subject><subject>African Americans</subject><subject>Biological effects</subject><subject>Blood</subject><subject>Buffy coat</subject><subject>Cell migration</subject><subject>Cocaine</subject><subject>Cohort Studies</subject><subject>CpG islands</subject><subject>CpG Islands - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>Drug abuse</subject><subject>Drug use</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Epigenome</subject><subject>Epinephrine</subject><subject>Female</subject><subject>Genome-Wide Association Study</subject><subject>Health risks</subject><subject>Heroin</subject><subject>Humans</subject><subject>Inflammasomes</subject><subject>Injection</subject><subject>Injection drug use</subject><subject>Insulin</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Microtubule-Associated Proteins - genetics</subject><subject>Middle Aged</subject><subject>Morbidity</subject><subject>Sociodemographics</subject><issn>0376-8716</issn><issn>1879-0046</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>7QJ</sourceid><recordid>eNqFkMtKAzEUhoMoWi-vIANu3EzNbZLJTi31AoIbXYc0cyIZppOadCp9e1NbFdyYTSDn-885-RAqCB4TTMRVO27i8GY628BiTDGl-VlxRvbQiNRSlRhzsY9GmElR1pKII3ScUovzEQofoiNWMVVVmI3Q9XTh36APcyg_fAOFSSlYb5Y-9IXpTbdOkIrgCmOXfgWF71uwX8XNAsWQ4BQdONMlONvdJ-j1bvoyeSifnu8fJzdPpeUVXZaG1s6BEZUjnFkmZko6RoHkRRRgiblUVgKuhQQzo44LmXNWMYqd44ApO0GX276LGN4HSEs998lC15kewpA0FbyuVW6DM3rxB23DEPNnNpSsKJdCkUzVW8rGkFIEpxfRz01ca4L1xrJu9a9lvbGst5Zz9Hw3YJjNofkJfmvNwO0WgGxk5SHqZD30Fhofsz_dBP__lE94OZGW</recordid><startdate>20220601</startdate><enddate>20220601</enddate><creator>Shu, Chang</creator><creator>Jaffe, Andrew E.</creator><creator>Sabunciyan, Sarven</creator><creator>Ji, Hongkai</creator><creator>Astemborski, Jacquie</creator><creator>Sun, Jing</creator><creator>Bakulski, Kelly M.</creator><creator>Sosnowski, David W.</creator><creator>Mehta, Shruti H.</creator><creator>Kirk, Gregory D.</creator><creator>Maher, Brion S.</creator><general>Elsevier B.V</general><general>Elsevier Science Ltd</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>7QJ</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20220601</creationdate><title>Epigenome-wide association analyses of active injection drug use</title><author>Shu, Chang ; Jaffe, Andrew E. ; Sabunciyan, Sarven ; Ji, Hongkai ; Astemborski, Jacquie ; Sun, Jing ; Bakulski, Kelly M. ; Sosnowski, David W. ; Mehta, Shruti H. ; Kirk, Gregory D. ; Maher, Brion S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c452t-a28ffea65f143c36b97f32e15399e070479c7e0867eab2f467c45c9320ff4e023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Abstinence</topic><topic>Adrenaline</topic><topic>African Americans</topic><topic>Biological effects</topic><topic>Blood</topic><topic>Buffy coat</topic><topic>Cell migration</topic><topic>Cocaine</topic><topic>Cohort Studies</topic><topic>CpG islands</topic><topic>CpG Islands - genetics</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Methylation</topic><topic>Drug abuse</topic><topic>Drug use</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Epigenome</topic><topic>Epinephrine</topic><topic>Female</topic><topic>Genome-Wide Association Study</topic><topic>Health risks</topic><topic>Heroin</topic><topic>Humans</topic><topic>Inflammasomes</topic><topic>Injection</topic><topic>Injection drug use</topic><topic>Insulin</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Microtubule-Associated Proteins - genetics</topic><topic>Middle Aged</topic><topic>Morbidity</topic><topic>Sociodemographics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shu, Chang</creatorcontrib><creatorcontrib>Jaffe, Andrew E.</creatorcontrib><creatorcontrib>Sabunciyan, Sarven</creatorcontrib><creatorcontrib>Ji, Hongkai</creatorcontrib><creatorcontrib>Astemborski, Jacquie</creatorcontrib><creatorcontrib>Sun, Jing</creatorcontrib><creatorcontrib>Bakulski, Kelly M.</creatorcontrib><creatorcontrib>Sosnowski, David W.</creatorcontrib><creatorcontrib>Mehta, Shruti H.</creatorcontrib><creatorcontrib>Kirk, Gregory D.</creatorcontrib><creatorcontrib>Maher, Brion S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Applied Social Sciences Index &amp; Abstracts (ASSIA)</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Drug and alcohol dependence</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shu, Chang</au><au>Jaffe, Andrew E.</au><au>Sabunciyan, Sarven</au><au>Ji, Hongkai</au><au>Astemborski, Jacquie</au><au>Sun, Jing</au><au>Bakulski, Kelly M.</au><au>Sosnowski, David W.</au><au>Mehta, Shruti H.</au><au>Kirk, Gregory D.</au><au>Maher, Brion S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epigenome-wide association analyses of active injection drug use</atitle><jtitle>Drug and alcohol dependence</jtitle><addtitle>Drug Alcohol Depend</addtitle><date>2022-06-01</date><risdate>2022</risdate><volume>235</volume><spage>109431</spage><epage>109431</epage><pages>109431-109431</pages><artnum>109431</artnum><issn>0376-8716</issn><eissn>1879-0046</eissn><abstract>Injection drug use (IDU) is prevalent in the US and is associated with substantial risk of blood-borne infections, morbidity, and mortality. However, the spectrum of its biologic effects on DNA methylation in blood is not well characterized. 401 participants (Mage = 47.9; 68% male; 90% African American) over several timepoints (1054 visits) were drawn from a longitudinal cohort of people who inject drugs. DNA methylation was measured among buffy coat samples from the 1054 visits. Compared to samples collected after ≥ 6 months of abstinence, separate EWAS were conducted for active injecting of any drug, quantitative injection frequency, injecting of heroin and injecting of cocaine. Linear mixed effect models were used and analyses were adjusted for repeated measurements and key technical, biological, and sociodemographic characteristics. We found epigenome-wide significant CpG sites associated with active injection (cg10636246, AIM2, p = 2.33 × 10−8) and injection intensity (cg13117953, p = 4.30 × 10−8). We found converging evidence that cg10636246 (AIM2), cg23110600 (PRKCH), cg03546163 (FKBP5), cg04590956 (GMCL1), and cg16317961 (MAPRE2) were among the top 0.1% significantly differentially methylated CpG sites shared across the five EWAS. Top ranked CpGs among the five EWAS were enriched (p &lt; 0.0001) in AIM2 inflammasome complex, T cell migration, insulin regulation and epinephrine synthesis pathways. During periods of active injection, samples had 0.46 years of epigenetic age acceleration relative to the abstinence period, within the same subject (p = 0.03). Findings from this study demonstrate modest, common, and specific effects on DNA methylation during a relatively short time between periods of active drug injection and abstinence. •Multiple DNA methylation sites are associated with active injection drug use•Top methylation sites are enriched in AIM2 inflammasome complex pathway•Within the same subjects, there was approximately a half year acceleration in biological age when comparing blood DNA methylation profiles during periods of active injection vs. abstinence</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>35395503</pmid><doi>10.1016/j.drugalcdep.2022.109431</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0376-8716
ispartof Drug and alcohol dependence, 2022-06, Vol.235, p.109431-109431, Article 109431
issn 0376-8716
1879-0046
language eng
recordid cdi_proquest_miscellaneous_2648894790
source Applied Social Sciences Index & Abstracts (ASSIA); Elsevier ScienceDirect Journals; Elsevier:Jisc Collections:Elsevier Read and Publish Agreement 2022-2024:Freedom Collection (Reading list)
subjects Abstinence
Adrenaline
African Americans
Biological effects
Blood
Buffy coat
Cell migration
Cocaine
Cohort Studies
CpG islands
CpG Islands - genetics
Deoxyribonucleic acid
DNA
DNA Methylation
Drug abuse
Drug use
Epigenesis, Genetic
Epigenetics
Epigenome
Epinephrine
Female
Genome-Wide Association Study
Health risks
Heroin
Humans
Inflammasomes
Injection
Injection drug use
Insulin
Lymphocytes
Lymphocytes T
Male
Microtubule-Associated Proteins - genetics
Middle Aged
Morbidity
Sociodemographics
title Epigenome-wide association analyses of active injection drug use
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T12%3A32%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Epigenome-wide%20association%20analyses%20of%20active%20injection%20drug%20use&rft.jtitle=Drug%20and%20alcohol%20dependence&rft.au=Shu,%20Chang&rft.date=2022-06-01&rft.volume=235&rft.spage=109431&rft.epage=109431&rft.pages=109431-109431&rft.artnum=109431&rft.issn=0376-8716&rft.eissn=1879-0046&rft_id=info:doi/10.1016/j.drugalcdep.2022.109431&rft_dat=%3Cproquest_cross%3E2675247691%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c452t-a28ffea65f143c36b97f32e15399e070479c7e0867eab2f467c45c9320ff4e023%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2675247691&rft_id=info:pmid/35395503&rfr_iscdi=true