{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:38:02Z","timestamp":1792255082141,"version":"4.4.0"},"reference-count":62,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: in recent years, many studies were carried out to explore the role of vaginal microbiota in HPV infections and cervical intraepithelial neoplasia (CIN) progression. The aim of this study was to conduct a review of the literature to analyze the interaction between the vaginal microbiota, the CIN, and the immunological response. Methods: we performed a literature search, considering papers published between November 2015 and September 2021. Results: despite significant evidence suggesting a role of vaginal microbiota in the pathogenesis of HPV-related lesions, some studies still struggle to demonstrate this correlation. However, the vaginal microbiota of HPV-positive women shows an increased diversity, combined with a reduced relative abundance of Lactobacillus spp. and a higher pH. In cervical dysplasia progression, a strong association is found with new bacteria, and with the deregulation of pathways and hyperexpression of cytokines leading to chronic inflammation. Conclusions: in HPV progression, there is a strong correlation between potential biomarkers, such as Sneathia and Delftia found in community state types IV and II, and chronic inflammation with cytokine overexpression. Better analysis of these factors could be of use in the prevention of the progression of the disease and, eventually, in new therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms23137174","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T23:59:22Z","timestamp":1656460762000},"page":"7174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["The Complex Interplay between Vaginal Microbiota, HPV Infection, and Immunological Microenvironment in Cervical Intraepithelial Neoplasia: A Literature Review"],"prefix":"10.3390","volume":"23","author":[{"given":"Barbara","family":"Gardella","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3744-7888","authenticated-orcid":false,"given":"Marianna Francesca","family":"Pasquali","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6071-0245","authenticated-orcid":false,"given":"Marco","family":"La Verde","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Unit, Department of Woman, Child and General and Specialized Surgery, University of Campania, Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Cianci","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Torella","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Unit, Department of Woman, Child and General and Specialized Surgery, University of Campania, Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6322-607X","authenticated-orcid":false,"given":"Mattia","family":"Dominoni","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, IRCCS Foundation Policlinico San Matteo, 27100 Pavia, Italy"},{"name":"Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/aje\/kwn036","article-title":"Persistent human papillomavirus infection and cervical neoplasia: A systematic review and meta-analysis","volume":"168","author":"Koshiol","year":"2008","journal-title":"Am. J. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1002\/cam4.538","article-title":"Early-life exposures to infectious agents and later cancer development","volume":"4","author":"Vedham","year":"2015","journal-title":"Cancer Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.ygyno.2008.07.045","article-title":"Natural history and epidemiology of HPV infection and cervical cancer","volume":"110","year":"2008","journal-title":"Gynecol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1056\/NEJMp058171","article-title":"The Promise of Global Cervical-Cancer Prevention","volume":"353","author":"Schiffman","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1158\/1055-9965.EPI-14-0410","article-title":"Attribution of 12 High-Risk Human Papillomavirus Genotypes to Infection and Cervical Disease","volume":"23","author":"Joura","year":"2014","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.semcancer.2013.11.002","article-title":"The human papillomavirus family and its role in carcinogenesis","volume":"26","author":"Tommasino","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S0140-6736(13)60022-7","article-title":"Human papillomavirus and cervical cancer","volume":"382","author":"Crosbie","year":"2013","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.vaccine.2005.09.054","article-title":"The epidemiology of genital human papillomavirus infection","volume":"24","author":"Trottier","year":"2006","journal-title":"Vaccine"},{"key":"ref_10","first-page":"405","article-title":"Epidemiology of cervical cancer with special focus on India","volume":"7","author":"Sreedevi","year":"2015","journal-title":"Int. J. Womens Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.ajog.2012.09.007","article-title":"Human papillomavirus: What every provider should know","volume":"208","author":"Erickson","year":"2014","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1093\/infdis\/jir341","article-title":"Prevalence of Genital Human Papillomavirus Among Females in the United States, the National Health and Nutrition Examination Survey, 2003","volume":"204","author":"Hariri","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1080\/0092623X.2019.1586019","article-title":"Sexual Behavior of Women With Diagnosed HPV","volume":"45","author":"Caruso","year":"2019","journal-title":"J. Sex Marital Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.3390\/v7072802","article-title":"Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia","volume":"7","author":"Egawa","year":"2015","journal-title":"Viruses"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1386-6532(00)00125-6","article-title":"Human papillomavirus and cancer: The epidemiological evidence","volume":"19","author":"Munoz","year":"2000","journal-title":"J. Clin. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1093\/oxfordjournals.aje.a010166","article-title":"Mathematical Model for the Natural History of Human Papillomavirus Infection and Cervical Carcinogenesis","volume":"151","author":"Myers","year":"2000","journal-title":"Am. J. Epidemiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e0153274","DOI":"10.1371\/journal.pone.0153274","article-title":"Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study","volume":"11","year":"2016","journal-title":"PLoS ONE"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1038\/s41598-021-81931-z","article-title":"A clinical pilot study on the effect of the probiotic Lacticaseibacillus rhamnosus TOM 22.8 strain in women with vaginal dysbiosis","volume":"11","author":"Pino","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1093\/infdis\/jiw184","article-title":"The Vaginal Microbiome: Current Understanding and Future Directions","volume":"214","author":"Martin","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4680","DOI":"10.1073\/pnas.1002611107","article-title":"Vaginal microbiome of reproductive-age women","volume":"108","author":"Ravel","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1177\/1933719111418379","article-title":"Importance of Vaginal Microbes in Reproductive Health","volume":"19","author":"Li","year":"2012","journal-title":"Reprod. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"551","DOI":"10.3389\/fmicb.2020.00551","article-title":"Crosstalk Between Female Gonadal Hormones and Vaginal Microbiota Across Various Phases of Women\u2019s Gynecological Lifecycle","volume":"11","author":"Kaur","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1146\/annurev-micro-092611-150157","article-title":"Vaginal Microbiome: Rethinking Health and Disease","volume":"66","author":"Ma","year":"2012","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1093\/infdis\/jiu330","article-title":"Interplay Between the Temporal Dynamics of the Vaginal Microbiota and Human Papillomavirus Detection","volume":"210","author":"Brotman","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5837","DOI":"10.1038\/s41598-017-05699-x","article-title":"Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillo-mavirus infection","volume":"7","author":"Duchi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fpubh.2017.00140","article-title":"Mycoplasma hominis and mycoplasma genitalium in the vaginal microbiota and persistent high-risk human papillomavirus infection","volume":"5","author":"Adebamowo","year":"2017","journal-title":"Front. Public Health"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15479","DOI":"10.1038\/s41598-018-33750-y","article-title":"Association of cervical microbial community with persistence, clearance and negativity of Human Papillomavirus in Korean women: A longitudinal study","volume":"8","author":"Arokiyaraj","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1086\/427777","article-title":"Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women","volume":"191","author":"Watts","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1471-2334-11-10","article-title":"Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: A meta-analysis","volume":"11","author":"Gillet","year":"2011","journal-title":"BMC Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16865","DOI":"10.1038\/srep16865","article-title":"Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity","volume":"5","author":"Mitra","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7593","DOI":"10.1038\/s41598-018-25879-7","article-title":"Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women","volume":"8","author":"Barnes","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9787","DOI":"10.1038\/s41598-018-27980-3","article-title":"HPV infection and bacterial microbiota in the placenta, uterine cervix and oral mucosa","volume":"8","author":"Tuominen","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Plisko, O., Zodzika, J., Jermakova, I., Pcolkina, K., Prusakevica, A., Liepniece-Karele, I., Donders, G.G.G., and Rezeberga, D. (2021). Aerobic Vaginitis\u2014Underestimated Risk Factor for Cervical Intraepithelial Neoplasia. Diagnostics, 11.","DOI":"10.3390\/diagnostics11010097"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1136\/ijgc-2020-001341","article-title":"Characterization of vaginal microbiota in Chinese women with cervical squamous intra-epithelial neoplasia","volume":"30","author":"Wu","year":"2020","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.ygyno.2021.08.016","article-title":"The feature of cervical microbiota associated with the progression of cervical cancer among reproductive females","volume":"163","author":"Wu","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chen, Y., Qiu, X., Wang, W., Li, D., Wu, A., Hong, Z., Di, W., and Qiu, L. (2020). Human papillomavirus infection and cervical intraepithelial neoplasia progression are associated with increased vaginal microbiome diversity in a Chinese cohort. BMC Infect. Dis., 20.","DOI":"10.1186\/s12879-020-05324-9"},{"key":"ref_37","first-page":"109","article-title":"Vaginal Douching: Evidence for Risks or Benefits to Women\u2019s Health","volume":"23","author":"Martino","year":"2012","journal-title":"Epidemiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"132ra52","DOI":"10.1126\/scitranslmed.3003605","article-title":"Temporal Dynamics of the Human Vaginal Microbiota","volume":"4","author":"Gajer","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Vitale, S.G., Ferrari, F., Ciebiera, M., Zgliczy\u0144ska, M., Rapisarda, A.M.C., Vecchio, G.M., Pino, A., Angelico, G., Knafel, A., and Riemma, G. (2022). The Role of Genital Tract Microbiome in Fertility: A Systematic Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010180"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Vodstrcil, L.A., Hocking, J.S., Law, M., Walker, S., Tabrizi, S.N., Fairley, C.K., and Bradshaw, C.S. (2013). Hormonal Contraception Is Associated with a Reduced Risk of Bacterial Vaginosis: A Systematic Review and Meta-Analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073055"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Brotman, R.M., He, X., Gajer, P., Fadrosh, D., Sharma, E., Mongodin, E.F., Ravel, J., Glover, E.D., and Rath, J.M. (2014). Association between cigarette smoking and the vaginal microbiota: A pilot study. BMC Infect. Dis., 14.","DOI":"10.1186\/1471-2334-14-471"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.resmic.2015.03.009","article-title":"Complementary seminovaginal microbiome in couples","volume":"166","author":"Punab","year":"2015","journal-title":"Res. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1574-695X.2009.00618.x","article-title":"The vaginal bacterial communities of Japanese women resemble those of women in other racial groups","volume":"58","author":"Zhou","year":"2010","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1093\/jjco\/hyu112","article-title":"Human papillomavirus genotype distribution in cervical intraepithelial neoplasia grade 2\/3 and invasive cervical cancer in Japanese women","volume":"44","author":"Azuma","year":"2014","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1158\/1940-6207.CAPR-15-0350","article-title":"Cervical Microbiota Associated with Higher Grade Cervical Intraepithelial Neoplasia in Women Infected with High-Risk Human Papillomaviruses","volume":"9","author":"Piyathilake","year":"2016","journal-title":"Cancer Prev. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Curty, G., de Carvalho, P.S., and Soares, M.A. (2019). The Role of the Cervicovaginal Microbiome on the Genesis and as a Biomarker of Premalignant Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010222"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/1471-0528.15854","article-title":"The vaginal microbiota, human papillo-mavirus and cervical dysplasia: A systematic review and network meta-analysis","volume":"127","author":"Norenhag","year":"2020","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lee, J.E., Lee, S., Lee, H., Song, Y.-M., Lee, K., Han, M.J., Sung, J., and Ko, G. (2013). Association of the Vaginal Microbiota with Human Papillomavirus Infection in a Korean Twin Cohort. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063514"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/ijc.31342","article-title":"Cervicovaginal microbiota composition correlates with the acquisition of high-risk human papillomavirus types","volume":"143","author":"Huang","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.tim.2014.02.009","article-title":"M\u00e9nage \u00e0 trois: An evolutionary interplay between human papillo-mavirus, a tumor, and a woman","volume":"22","author":"Shulzhenko","year":"2014","journal-title":"Trend. Microbiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s40168-016-0203-0","article-title":"The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: What do we know and where are we going next?","volume":"4","author":"Mitra","year":"2016","journal-title":"Microbiome"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6199","DOI":"10.1158\/0008-5472.CAN-05-0455","article-title":"Activation of the Canonical Wnt Pathway during Genital Keratinocyte Transformation: A Model for Cervical Cancer Progression","volume":"65","author":"Fallen","year":"2005","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"So, K.A., Yang, E.J., Kim, N.R., Hong, S.R., Lee, J.-H., Hwang, C.-S., Shim, S.-H., Lee, S.J., and Kim, T.J. (2020). Changes of vaginal microbiota during cervical carcinogenesis in women with human papillomavirus infection. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238705"},{"key":"ref_54","first-page":"4","article-title":"A meta-analysis of the relationship between vaginal microecology, human papillomavirus infection and cervical intraepithelial neoplasia","volume":"14","author":"Liang","year":"2019","journal-title":"Infect. Agent. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s10147-014-0680-8","article-title":"Cytokine profile in cervical mucosa of Japanese patients with cervical intraepithelial neoplasia","volume":"20","author":"Iwata","year":"2014","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/oxfordjournals.jncimonographs.a003478","article-title":"Chapter 4: Genital Tract Infections, Cervical Inflammation, and Antioxidant Nutrients--Assessing Their Roles as Human Papillomavirus Cofactors","volume":"2003","author":"Castle","year":"2003","journal-title":"J. Natl. Cancer Inst. Monogr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.humimm.2012.06.003","article-title":"Local cytokine profiles of patients with cervical intraepithelial and invasive neoplasia","volume":"73","author":"Peghini","year":"2012","journal-title":"Hum. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1158\/1055-9965.EPI-10-0184","article-title":"Elevated systemic levels of inflammatory cytokines in older women with persistent cervical human papillo-mavirus infection","volume":"19","author":"Kemp","year":"2010","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., and PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_60","unstructured":"(2022, April 28). Chapter 8: Assessing risk of bias in a randomized trial. Cochrane Training. Available online: https:\/\/training.cochrane.org\/handbook\/current\/chapter-08."},{"key":"ref_61","unstructured":"(2022, April 28). Chapter 14: Completing \u2018Summary of findings\u2019 tables and grading the certainty of the evidence. Cochrane Training. Available online: https:\/\/training.cochrane.org\/handbook\/current\/chapter-14."},{"key":"ref_62","unstructured":"(2022, April 28). Chapter 7: Considering bias and conflicts of interest among the included studies. Cochrane Training. Available online: https:\/\/training.cochrane.org\/handbook\/current\/chapter-07."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7174\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:48Z","timestamp":1760139588000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,28]]},"references-count":62,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23137174"],"URL":"https:\/\/doi.org\/10.3390\/ijms23137174","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,28]]}}}