{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:21:42Z","timestamp":1792513302000,"version":"4.5.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"\n Background<\/jats:title>\n \n Biofilm formation is a major clinical challenge contributing to treatment failure of periprosthetic joint infection (PJI). Lytic bacteriophages (phages) can target biofilm associated bacteria at localized sites of infection. The aim of this study is to investigate whether combination therapy of phage and vancomycin is capable of clearing\n Staphylococcus aureus<\/jats:italic>\n biofilm-like aggregates formed in human synovial fluid.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this study,\n S. aureus<\/jats:italic>\n BP043, a PJI clinical isolate was utilized. This strain is a methicillin-resistant\n S. aureus<\/jats:italic>\n (MRSA) biofilm-former. Phage Remus, known to infect\n S. aureus<\/jats:italic>\n , was selected for the treatment protocol. BP043 was grown as aggregates in human synovial fluid. The characterization of\n S. aureus<\/jats:italic>\n aggregates was assessed for structure and size using scanning electron microscopy (SEM) and flow cytometry, respectively. Moreover, the formed aggregates were subsequently treated\n in vitro<\/jats:italic>\n with: (a) phage Remus [\u223c10\n 8<\/jats:sup>\n plaque-forming units (PFU)\/ml], (b) vancomycin (500 \u03bcg\/ml), or (c) phage Remus (\u223c10\n 8<\/jats:sup>\n PFU\/ml) followed by vancomycin (500 \u03bcg\/ml), for 48 h. Bacterial survival was quantified by enumeration [colony-forming units (CFU)\/ml]. The efficacy of phage and vancomycin against BP043 aggregates was assessed\n in vivo<\/jats:italic>\n as individual treatments and in combination. The\n in vivo<\/jats:italic>\n model utilized\n Galleria mellonella<\/jats:italic>\n larvae which were infected with BP043 aggregates pre-formed in synovial fluid.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Scanning electron microscopy (SEM) images and flow cytometry data demonstrated the ability of human synovial fluid to promote formation of\n S. aureus<\/jats:italic>\n aggregates. Treatment with Remus resulted in significant reduction in viable\n S. aureus<\/jats:italic>\n residing within the synovial fluid aggregates compared to the aggregates that did not receive Remus (\n p<\/jats:italic>\n &lt; 0.0001). Remus was more efficient in eliminating viable bacteria within the aggregates compared to vancomycin (\n p<\/jats:italic>\n &lt; 0.0001). Combination treatment of Remus followed by vancomycin was more efficacious in reducing bacterial load compared to using either Remus or vancomycin alone (\n p<\/jats:italic>\n = 0.0023,\n p<\/jats:italic>\n &lt; 0.0001, respectively). When tested\n in vivo<\/jats:italic>\n , this combination treatment also resulted in the highest survival rate (37%) 96 h post-treatment, compared to untreated larvae (3%;\n p<\/jats:italic>\n &lt; 0.0001).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We demonstrate that combining phage Remus and vancomycin led to synergistic interaction against MRSA biofilm-like aggregates\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fmed.2023.1134912","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T01:16:39Z","timestamp":1686273399000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Combining bacteriophage and vancomycin is efficacious against MRSA biofilm-like aggregates formed in synovial fluid"],"prefix":"10.3389","volume":"10","author":[{"given":"Mariam","family":"Taha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tia","family":"Arnaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasia J.","family":"Lightly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangxue","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley W. M.","family":"Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven S.","family":"Theriault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesham","family":"Abdelbary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1007\/s10654-018-0377-9","article-title":"One-and two-stage surgical revision of peri-prosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies.","volume":"33","author":"Kunutsor","year":"2018","journal-title":"Eur J Epidemiol."},{"key":"B2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1302\/0301-620X.102B6.BJJ-2019-1582.R1","article-title":"Complications in the treatment of prosthetic joint infection.","volume":"102","author":"Hartzler","year":"2020","journal-title":"Bone Joint J."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2016-014056","article-title":"Description of the rates, trends and surgical burden associated with revision for prosthetic joint infection following primary and revision knee replacements in England and Wales: an analysis of the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.","volume":"7","author":"Lenguerrand","year":"2017","journal-title":"BMJ Open."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1016\/j.molimm.2009.01.020","article-title":"Host defence against Staphylococcus aureus biofilms infection: phagocytosis of biofilms by polymorphonuclear neutrophils (PMN).","volume":"46","author":"Gunther","year":"2009","journal-title":"Mol Immunol."},{"key":"B5","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1093\/jac\/dkq257","article-title":"Penetration of antibiotics through Staphylococcus aureus and Staphylococcus epidermidis biofilms.","volume":"65","author":"Singh","year":"2010","journal-title":"J Antimicrob Chemother."},{"key":"B6","doi-asserted-by":"publisher","first-page":"6585","DOI":"10.4049\/jimmunol.1002794","article-title":"Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo.","volume":"186","author":"Thurlow","year":"2011","journal-title":"J Immunol."},{"key":"B7","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1128\/CMR.00111-13","article-title":"Prosthetic joint infection.","volume":"27","author":"Tande","year":"2014","journal-title":"Clin Microbiol Rev."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.2106\/JBJS.G.00838","article-title":"Direct demonstration of viable Staphylococcus aureus biofilms in an infected total joint arthroplasty. A case report.","volume":"90","author":"Stoodley","year":"2008","journal-title":"J Bone Joint Surg Am."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/Spectrum.00267-21","article-title":"Synovial fluid-induced aggregation occurs across Staphylococcus aureus clinical isolates and is mechanistically independent of attached biofilm formation.","volume":"9","author":"Staats","year":"2021","journal-title":"Microbiol Spectr."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.01368","article-title":"Identification and characterization of planktonic biofilm-like aggregates in infected synovial fluids from joint infections.","volume":"11","author":"Bidossi","year":"2020","journal-title":"Front Microbiol."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.655873","article-title":"Staphylococcus aureus floating biofilm formation and phenotype in synovial fluid depends on albumin, fibrinogen, and hyaluronic acid.","volume":"12","author":"Knott","year":"2021","journal-title":"Front Microbiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1093\/infdis\/jiv096","article-title":"Biofilm-like aggregation of Staphylococcus epidermidis in synovial fluid.","volume":"212","author":"Perez","year":"2015","journal-title":"J Infect Dis."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0221012","article-title":"Equine or porcine synovial fluid as a novel ex vivo model for the study of bacterial free-floating biofilms that form in human joint infections.","volume":"14","author":"Gilbertie","year":"2019","journal-title":"PLoS One."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1007\/s00253-009-2386-9","article-title":"Antibacterial and biofilm removal activity of a podoviridae Staphylococcus aureus bacteriophage SAP-2 and a derived recombinant cell-wall-degrading enzyme.","volume":"86","author":"Son","year":"2010","journal-title":"Appl Microbiol Biotechnol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1007\/s11274-014-1655-7","article-title":"Natural solution to antibiotic resistance: bacteriophages \u2018The Living Drugs\u2019.","volume":"30","author":"Jassim","year":"2014","journal-title":"World J Microbiol Biotechnol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1128\/AEM.02304-07","article-title":"Fluorescence correlation spectroscopy to study diffusion and reaction of bacteriophages inside biofilms.","volume":"74","author":"Briandet","year":"2008","journal-title":"Appl Environ Microbiol."},{"key":"B17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2174\/1381612820666140905112311","article-title":"Bacteriophages and their enzymes in biofilm control.","volume":"21","author":"Chan","year":"2015","journal-title":"Curr Pharm Des."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2805","DOI":"10.1128\/IAI.70.6.2805-2811.2002","article-title":"The in vitro interaction of Streptococcus pyogenes with human pharyngeal cells induces a phage-encoded extracellular DNase.","volume":"70","author":"Broudy","year":"2002","journal-title":"Infect Immun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1002\/jbm.b.35220","article-title":"Combining povidone-iodine with vancomycin can be beneficial in reducing early biofilm formation of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus on titanium surface.","volume":"111","author":"Taha","year":"2023","journal-title":"J Biomed Mater Res B Appl Biomater."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3237","DOI":"10.1128\/JVI.02763-12","article-title":"Romulus and Remus, two phage isolates representing a distinct clade within the Twortlikevirus genus, display suitable properties for phage therapy applications.","volume":"87","author":"Vandersteegen","year":"2013","journal-title":"J Virol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/0022-1759(90)90029-u","article-title":"Removal of endotoxin from protein solutions by phase separation using Triton X-114.","volume":"132","author":"Aida","year":"1990","journal-title":"J Immunol Methods."},{"key":"B22","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/978-1-60327-164-6_9","article-title":"Enumeration of bacteriophages using the small drop plaque assay system.","volume":"501","author":"Mazzocco","year":"2009","journal-title":"Methods Mol Biol."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107307","article-title":"Effective removal of staphylococcal biofilms by the endolysin LysH5.","volume":"9","author":"Gutierrez","year":"2014","journal-title":"PLoS One."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0211132","article-title":"The peptidoglycan and biofilm matrix of Staphylococcus epidermidis undergo structural changes when exposed to human platelets.","volume":"14","author":"Loza-Correa","year":"2019","journal-title":"PLoS One."},{"key":"B25","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/0022-2836(84)90232-8","article-title":"Structural comparison of the two distinct sugar binding sites in wheat germ agglutinin isolectin II.","volume":"178","author":"Wright","year":"1984","journal-title":"J Mol Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.3390\/md8092493","article-title":"N-acetylglucosamine: production and applications.","volume":"8","author":"Chen","year":"2010","journal-title":"Mar Drugs."},{"key":"B27","first-page":"207","article-title":"Staphylococcal biofilms.","volume":"322","author":"Otto","year":"2008","journal-title":"Curr Top Microbiol Immunol."},{"key":"B28","doi-asserted-by":"crossref","DOI":"10.6064\/2012\/489208","article-title":"N-acetylglucosamine (GlcNAc) functions in cell signaling.","volume":"2012","author":"Konopka","year":"2012","journal-title":"Scientifica."},{"key":"B29","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/j.tim.2020.05.017","article-title":"Wall teichoic acid in Staphylococcus aureus host interaction.","volume":"28","author":"van Dalen","year":"2020","journal-title":"Trends Microbiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1002\/1522-2683(20000701)21:12<2509::AID-ELPS2509>3.0.CO;2-9","article-title":"Background-free, high sensitivity staining of proteins in one- and two-dimensional sodium dodecyl sulfate-polyacrylamide gels using a luminescent ruthenium complex.","volume":"21","author":"Berggren","year":"2000","journal-title":"Electrophoresis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1093\/cid\/cir034","article-title":"Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary.","volume":"52","author":"Liu","year":"2011","journal-title":"Clin Infect Dis."},{"key":"B32","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1055\/s-0034-1396906","article-title":"Combination antibiotic treatment of serious methicillin-resistant Staphylococcus aureus infections.","volume":"36","author":"Davis","year":"2015","journal-title":"Semin Respir Crit Care Med."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotobiol.2022.112563","article-title":"Dramatic destruction of methicillin-resistant Staphylococcus aureus infections with a simple combination of amoxicillin and light-activated methylene blue.","volume":"235","author":"Feng","year":"2022","journal-title":"J Photochem Photobiol B."},{"key":"B34","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1111\/j.1745-7254.2007.00564.x","article-title":"Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines.","volume":"28","author":"Xu","year":"2007","journal-title":"Acta Pharmacol Sin."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0168615","article-title":"Synergy and order effects of antibiotics and phages in killing Pseudomonas aeruginosa Biofilms.","volume":"12","author":"Chaudhry","year":"2017","journal-title":"PLoS One."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e1652","DOI":"10.1128\/mBio.01652-19","article-title":"Resistance evolution against phage combinations depends on the timing and order of exposure.","volume":"10","author":"Wright","year":"2019","journal-title":"mBio."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0231791","article-title":"Investigation of synovial fluid induced Staphylococcus aureus aggregate development and its impact on surface attachment and biofilm formation.","volume":"15","author":"Pestrak","year":"2020","journal-title":"PLoS One."},{"key":"B38","doi-asserted-by":"publisher","first-page":"419","DOI":"10.4161\/viru.24930","article-title":"Galleria mellonella larvae as an infection model for group A streptococcus.","volume":"4","author":"Loh","year":"2013","journal-title":"Virulence."},{"key":"B39","doi-asserted-by":"publisher","first-page":"D344","DOI":"10.1093\/nar\/gkaa977","article-title":"The InterPro protein families and domains database: 20 years on.","volume":"49","author":"Blum","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1093\/bioinformatics\/btu031","article-title":"InterProScan 5: genome-scale protein function classification.","volume":"30","author":"Jones","year":"2014","journal-title":"Bioinformatics."},{"key":"B41","doi-asserted-by":"publisher","first-page":"3292","DOI":"10.1099\/mic.0.051987-0","article-title":"Structure-function analysis of HsiF, a gp25-like component of the type VI secretion system, in Pseudomonas aeruginosa.","author":"Lossi","year":"2011","journal-title":"Microbiology."},{"key":"B42","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/infdis\/jiu514","article-title":"Effect of biofilms on recalcitrance of staphylococcal joint infection to antibiotic treatment.","volume":"211","author":"Dastgheyb","year":"2015","journal-title":"J Infect Dis."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173919","article-title":"Determining bacteriophage endopeptidase activity using either fluorophore-quencher labeled peptides combined with liquid chromatography-mass spectrometry (LC-MS) or Forster resonance energy transfer (FRET) assays.","volume":"12","author":"Lood","year":"2017","journal-title":"PLoS One."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02252","article-title":"Phage lysins for fighting bacterial respiratory infections: a new generation of antimicrobials.","volume":"9","author":"Vazquez","year":"2018","journal-title":"Front Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2743","DOI":"10.1128\/AAC.02526-12","article-title":"Novel bacteriophage lysin with broad lytic activity protects against mixed infection by Streptococcus pyogenes and methicillin-resistant Staphylococcus aureus.","volume":"57","author":"Gilmer","year":"2013","journal-title":"Antimicrob Agents Chemother."},{"key":"B46","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1016\/j.drudis.2018.01.026","article-title":"Phage-derived lysins as potential agents for eradicating biofilms and persisters.","volume":"23","author":"Sharma","year":"2018","journal-title":"Drug Discov Today."},{"key":"B47","doi-asserted-by":"crossref","DOI":"10.3390\/antibiotics9050268","article-title":"Phages for biofilm removal.","volume":"9","author":"Ferriol-Gonzalez","year":"2020","journal-title":"Antibiotics."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/625341","article-title":"Bacteriophage-derived peptidase CHAP(K) eliminates and prevents Staphylococcal biofilms.","volume":"2013","author":"Fenton","year":"2013","journal-title":"Int J Microbiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1128\/AEM.01616-06","article-title":"Lytic activity of recombinant bacteriophage phi11 and phi12 endolysins on whole cells and biofilms of Staphylococcus aureus.","volume":"73","author":"Sass","year":"2007","journal-title":"Appl Environ Microbiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1099\/mic.0.2007\/013292-0","article-title":"Wall teichoic acids are dispensable for anchoring the PNAG exopolysaccharide to the Staphylococcus aureus cell surface.","author":"Vergara-Irigaray","year":"2008","journal-title":"Microbiology."},{"key":"B51","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1006\/mpat.2001.0469","article-title":"Teichoic acid enhances adhesion of Staphylococcus epidermidis to immobilized fibronectin.","volume":"31","author":"Hussain","year":"2001","journal-title":"Microb Pathog."},{"key":"B52","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1093\/infdis\/141.4.463","article-title":"Role of teichoic acid in the binding of Staphylococcus aureus to nasal epithelial cells.","volume":"141","author":"Aly","year":"1980","journal-title":"J Infect Dis."},{"key":"B53","doi-asserted-by":"publisher","first-page":"S341","DOI":"10.1093\/clinids\/9.supplement_4.s341","article-title":"Adherence of Staphylococcus aureus to squamous epithelium: role of fibronectin and teichoic acid.","author":"Aly","year":"1987","journal-title":"Rev Infect Dis."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/foods11213438","article-title":"Correlation analysis between GlpQ-regulated degradation of wall teichoic acid and biofilm formation triggered by lactobionic acid in Staphylococcus aureus.","volume":"11","author":"Hou","year":"2022","journal-title":"Foods."},{"key":"B55","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1111\/j.1574-6968.1993.tb05867.x","article-title":"The slime of coagulase-negative staphylococci: biochemistry and relation to adherence.","volume":"10","author":"Hussain","year":"1993","journal-title":"FEMS Microbiol Rev."},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.00127","article-title":"Does treatment order matter? Investigating the ability of bacteriophage to augment antibiotic activity against Staphylococcus aureus biofilms.","volume":"9","author":"Kumaran","year":"2018","journal-title":"Front Microbiol."},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3390\/v11010054","article-title":"Characterization and genome analysis of Staphylococcus aureus podovirus CSA13 and its anti-biofilm capacity.","volume":"11","author":"Cha","year":"2019","journal-title":"Viruses."},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0209390","article-title":"Adjunct phage treatment enhances the effectiveness of low antibiotic concentration against Staphylococcus aureus biofilms in vitro.","volume":"14","author":"Dickey","year":"2019","journal-title":"PLoS One."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00695","article-title":"Using bacteriophages as a trojan horse to the killing of dual-species biofilm formed by Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus.","volume":"11","author":"Tkhilaishvili","year":"2020","journal-title":"Front Microbiol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1134912\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T01:16:50Z","timestamp":1686273410000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1134912\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,9]]},"references-count":59,"alternative-id":["10.3389\/fmed.2023.1134912"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2023.1134912","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.05.15.540793","asserted-by":"object"}]},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,9]]},"article-number":"1134912"}}