Human papillomavirus vaccination poses different risks for various cranial nerve disorders - a retrospective cohort study using a real-world database

Human papillomavirus vaccination poses different risks for various cranial nerve disorders - a retrospective cohort study using a real-world database | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Human papillomavirus vaccination poses different risks for various cranial nerve disorders - a retrospective cohort study using a real-world database Wen Chun Lin, Shiow-Ing Wang, Renin Chang, Cheng-Chung Wei This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4923637/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Human papillomavirus (HPV) vaccines act against HPV infection and some cancers. Various cranial nerve disorders are known to occur after HPV viral infections. However, studies on the relationship between human papillomavirus vaccination and cranial nerve disorders are limited. Here, we aimed to evaluate the association between human papillomavirus vaccination and risks of cranial nerve disorders in young girls. We enrolled 261,111 women aged between 9 and 26 years, and they had received HPV vaccination between January 2018 and December 2022. These subjects were compared with those controls who never received HPV vaccination using a propensity score-matched (1:1) based on the TriNetX U.S. Collaborative Network. Risks on incidences of various cranial nerve disorders were evaluated. Subgroup and sensitivity analyses were also performed. The HPV-vaccinated cohort, on one hand, had significantly lower risks on hearing loss (aHR:0.490, 95% CI:0.419-0.572), facial nerve disorders (aHR:0.690, 95% CI:0.522-0.912); disorders of vestibular function disorders (aHR:0.523, 95% CI:0.422-0.647); and similarly on other inner ear disorders (aHR:0.537, 95% CI:0.392-0.735) and trigeminal nerve disorders (aHR:0.328, 95% CI:0.200-0.538). On the other hand, the HPV-vaccinated cohort had significantly higher risks of odor and taste disorders (aHR: 3.136, 95% CI: 0 2.562-3.840). Kaplan-Meier curves of different cranial nerve disorders also revealed significant probability disparities between the two cohorts (Log–Rank test, p < 0.001). In conclusion, for females between 9 and 26 years old, their HPV vaccination was associated with on one hand, lower risks of cranial nerve disorders, like hearing loss, vestibular function/other diseases of the inner ear, facial nerve disorders, and disorders of the trigeminal nerve, and on the other hand, higher risks on smell and taste disorders, as revealed over a year-long follow-up period. Health sciences/Health care/Public health/Epidemiology Health sciences/Medical research/Epidemiology Human papillomavirus vaccine Cranial nerve disorders TriNetx Cohort study Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Human papillomavirus (HPV) is a small double-stranded DNA virus. HPV infection is becoming more common in recent years. Some specific subtypes of HPV infection are associated with various diseases, like cervical, head and neck, breast, lung, and anogenital cancers, and autoimmune diseases 1 – 4 . Today, 3 vaccines for Human papillomavirus have been reported prevent HPV infection and precancer lesions of cervical disease 4 . For example, Gardasil, a quadrivalent vaccine (Merck & Co., Kenilworth, NJ, USA), which targets HPV types 6,11,16, and 18, is the first commercially available HPV vaccine. It was licensed by the United States Food and Drug Administration (FDA) in 2006. Cervarix, a bivalent HPV vaccine (GSK, Brentford, UK) was also approved by FDA in 2009. It protects against the HPV type 16 and 18. Finally, Gardasil 9, a 9-valent vaccine (Merck & Co., Kenilworth, NJ, USA), was licensed by FDA in 2014. It protects against HPV 6, 11, 16, 18, 31, 33, 45, 53, and 58 2,4 . To date, the virus-like particle (VLP) of papillomavirus capsid protein L1, constitutes the HPV vaccines. VLP is produced from bacteria or yeast containing only protein without viral genomes. They are considered non-infectious and non-carcinogenic and are considered safer than those attenuated HPV vaccines. The World Health Organization currently recommends that girls aged 9 to 14 years are prioritized for HPV vaccination before their first sexual exposure 5 . Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccination can start at the age of 9 through 26 years old, for those not vaccinated before 6 . Viral infections are widespread and difficult to control. Various cranial nerve disorders due to viral infections are well-known, such as smell and taste dysfunction after COVID-19 infection 7 , 8 ; facial nerve paralysis after varicella-zoster virus infection, or human herpesvirus 6 infection 9 ; hearing impairment after human cytomegalovirus infection 10 , 11 ; and Zika virus infection after inner ear disease 12 . Knowledge on the relationship between human papillomavirus vaccination and cranial nerve disorders remains limited from the literature review. Here, we aimed to evaluate the association between young girls receiving the human papillomavirus vaccine and their risk of developing cranial nerve disorders. Results Characteristics of study subjects Table 1 shows baseline characteristics of the study subjects including their demographic characteristics, lifestyle, comorbidities, and medication usage of both the HPV-vaccinated cohort and the control cohort, before and after matching. Before matching, we found significant differences in two cohorts in terms of the following: age at index, race of white and black or African American, the emergency department services, comorbidities including certain infectious and parasitic diseases, noninflammatory disorders of female genital tract, disease of middle ear and mastoid, asthma, overweight and obesity, disorders of lipoprotein metabolism and other lipidemia, injuries to the head, depressive episode, anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders, sleep disorders, and Ibuprofen usage. After matching, the two cohorts were matched well as their differences were within the acceptable range (SMD < 0.1). After propensity score matching, the HPV-vaccinated cohort (N = 261,111) and the control group with no HPV vaccination (N = 261,111) were further compared. Table 1 Baseline characteristics of study subjects (before and after PSM matching) Variables Before PSM After PSM HPV vaccinated cohort (n = 263665) Control Cohort (n = 4350486) SMD HPV vaccinated cohort (n = 261111) Control Cohort (n = 261111) SMD Age at index Mean ± SD 13.8 ± 4.0 17.3 ± 5.4 0.721 13.9 ± 4.0 14.4 ± 4.4 0.135 Race, n (%) White 136212 (51.7) 2580103 (59.3) 0.154 135132 (51.8) 140876 (54.0) 0.044 Black or African American 53244 (20.2) 660689 (15.2) 0.132 52933 (20.3) 51453 (19.7) 0.014 Asian 13927 (5.3) 169841 (3.9) 0.066 13745 (5.3) 9484 (3.6) 0.079 American Indian or Alaska Native 1329 (0.5) 20119 (0.5) 0.006 1309 (0.5) 1476 (0.6) 0.009 Native Hawaiian or Other Pacific Islander 743 (0.3) 15503 (0.4) 0.013 741 (0.3) 790 (0.3) 0.003 Unknown Race 37454 (14.2) 627534 (14.4) 0.006 36911 (14.1) 39886 (15.3) 0.032 Other Race 20756 (7.9) 276697 (6.4) 0.059 20340 (7.8) 17146 (6.6) 0.047 Social economic status, n (%) Problems related to housing and economic circumstances 1096 (0.4) 909 (0.0) 0.085 983 (0.4) 673 (0.3) 0.021 Problems related to education and literacy 871 (0.3) 2011 (0.0) 0.066 854 (0.3) 723 (0.3) 0.009 Lifestyles, n (%) Tobacco use 263 (0.1) 2086 (0.0) 0.019 263 (0.1) 384 (0.1) 0.013 Nicotine dependence 666 (0.3) 11743 (0.3) 0.003 666 (0.3) 1169 (0.4) 0.033 Alcohol related disorders 230 (0.1) 2589 (0.1) 0.010 229 (0.1) 365 (0.1) 0.015 Cannabis related disorders 520 (0.2) 4722 (0.1) 0.023 515 (0.2) 904 (0.3) 0.029 Medical utilization, n (%) Office or Other Outpatient Services 129646 (49.2) 417488 (9.6) 0.965 127103 (48.7) 134647 (51.6) 0.058 Emergency Department Services 17336 (6.6) 119954 (2.8) 0.182 17144 (6.6) 20575 (7.9) 0.051 Hospital Inpatient Services 2092 (0.8) 17930 (0.4) 0.049 2084 (0.8) 3868 (1.5) 0.064 Preventive Medicine Services 52031 (19.7) 117556 (2.7) 0.560 49641 (19.0) 49346 (18.9) 0.003 Comorbidities, n (%) Neoplasms 3350 (1.3) 27516 (0.6) 0.066 3301 (1.3) 6027 (2.3) 0.079 Certain infectious and parasitic diseases 26480 (10.0) 85527 (2.0) 0.345 25882 (9.9) 29307 (11.2) 0.043 Inflammatory diseases of female pelvic organs 2636 (1.0) 15162 (0.3) 0.080 2623 (1.0) 4077 (1.6) 0.049 Noninflammatory disorders of female genital tract 15471 (5.9) 71106 (1.6) 0.224 15347 (5.9) 17643 (6.8) 0.036 Diseases of middle ear and mastoid 9361 (3.6) 33973 (0.8) 0.191 9234 (3.5) 10005 (3.8) 0.016 Asthma 16084 (6.1) 61698 (1.4) 0.248 15813 (6.1) 19297 (7.4) 0.053 Bronchitis, not specified as acute or chronic 982 (0.4) 4059 (0.1) 0.058 959 (0.4) 977 (0.4) 0.001 Overweight and obesity 13375 (5.1) 39462 (0.9) 0.246 13140 (5.0) 16244 (6.2) 0.052 Disorders of lipoprotein metabolism and other lipidemias 3599 (1.4) 10880 (0.3) 0.125 3502 (1.3) 3198 (1.2) 0.010 Diabetes mellitus 1293 (0.5) 19335 (0.4) 0.007 1292 (0.5) 1699 (0.7) 0.021 Essential (primary) hypertension 1112 (0.4) 9306 (0.2) 0.037 1104 (0.4) 1960 (0.8) 0.043 Cerebrovascular diseases 150 (0.1) 2305 (0.1) 0.002 149 (0.1) 509 (0.2) 0.039 Ischemic heart diseases 30 (0.0) 542 (0.0) 0.001 29 (0.0) 105 (0.0) 0.018 Injuries to the head 4525 (1.7) 23533 (0.5) 0.111 4479 (1.7) 6085 (2.3) 0.044 Transient cerebral ischemic attacks and related syndromes 11 (0.0) 167 (0.0) 0.001 11 (0.0) 30 (0.0) 0.008 Diseases of liver 457 (0.2) 4358 (0.1) 0.020 450 (0.2) 1039 (0.4) 0.042 Gingivitis and periodontal diseases 235 (0.1) 1263 (0.0) 0.025 234 (0.1) 353 (0.1) 0.014 Dental caries 903 (0.3) 9147 (0.2) 0.025 897 (0.3) 1575 (0.6) 0.038 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism 4577 (1.7) 34578 (0.8) 0.084 4511 (1.7) 8076 (3.1) 0.089 Systemic lupus erythematosus (SLE) 111 (0.0) 2275 (0.1) 0.005 110 (0.0) 476 (0.2) 0.042 Juvenile arthritis 196 (0.1) 3854 (0.1) 0.005 194 (0.1) 879 (0.3) 0.058 Rheumatoid arthritis with rheumatoid factor 15 (0.0) 283 (0.0) 0.001 15 (0.0) 45 (0.0) 0.011 Other rheumatoid arthritis 64 (0.0) 1056 (0.0) 0.000 64 (0.0) 182 (0.1) 0.021 Sjögren syndrome 43 (0.0) 430 (0.0) 0.006 41 (0.0) 83 (0.0) 0.010 Depressive episode 9601 (3.6) 38035 (0.9) 0.187 9485 (3.6) 15059 (5.8) 0.101 Anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders 19733 (7.5) 85352 (2.0) 0.263 19561 (7.5) 28899 (11.1) 0.123 Sleep disorders 4748 (1.8) 26541 (0.6) 0.109 4663 (1.8) 8107 (3.1) 0.085 Chronic kidney disease (CKD) 278 (0.1) 3271 (0.1) 0.010 276 (0.1) 698 (0.3) 0.037 Medications/ Procedures, n (%) Ibuprofen 19246 (7.3) 115066 (2.6) 0.215 18938 (7.3) 22851 (8.8) 0.055 Naproxen 2949 (1.1) 27959 (0.6) 0.051 2917 (1.1) 4935 (1.9) 0.064 Aminoglycoside antibacterials 2919 (1.1) 15540 (0.4) 0.088 2876 (1.1) 3179 (1.2) 0.011 Aspirin 552 (0.2) 6852 (0.2) 0.012 549 (0.2) 1261 (0.5) 0.046 Sulfonamides and potassium in combination 257 (0.1) 2369 (0.1) 0.016 257 (0.1) 305 (0.1) 0.006 Sulfonamides, plain 191 (0.1) 3145 (0.1) 0.000 191 (0.1) 605 (0.2) 0.041 Cyclophosphamide 19 (0.0) 463 (0.0) 0.004 18 (0.0) 121 (0.0) 0.024 Cisplatin 10 (0.0) 63 (0.0) 0.005 10 (0.0) 19 (0.0) 0.005 Carboplatin 10 (0.0) 78 (0.0) 0.004 10 (0.0) 25 (0.0) 0.007 Note: Bold font represents a standardized difference was more than 0.1. If the patient is less or equal to 10, results show the count as 10. PSM: Propensity Score Matching, HPV: Human Papillomavirus, SMD: Standardized Mean Difference, SD: Standard Deviation. *Propensity score matching was performed age at index, race, problems related to housing and economic circumstances (proxy to social economic status), lifestyles (including tobacco use, nicotine dependence), medical utilization (office or other outpatient services, preventive medicine services, hospital inpatient services), and comorbidities (hypertension, diabetes mellitus, overweight and obesity, asthma, inflammatory diseases of female pelvic organs, diseases of middle ear and mastoid, transient cerebral ischemic attacks and related syndromes, gingivitis and periodontal diseases, dental caries, depressive episode, anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders, certain infectious and parasitic diseases, injuries to the head). Incidence of cranial nerve disorders in the HPV-vaccinated and control groups Table 2 shows risks of cranial nerve disorders in both the HPV-vaccinated and control groups revealed during a yearlong follow-up. The HPV-vaccinated cohort had significantly lower risks of the following: hearing loss (aHR:0.490, 95% CI:0.419–0.572), including bilateral sensorineural hearing loss (aHR:0.472, 95% CI:0.384–0.581), sensorineural hearing loss, unilateral with unrestricted hearing (aHR:0.532, 95% CI:0.397–0.715), and sensorineural hearing loss, unspecified (aHR:0.472, 95% CI:0.351–0.634); facial nerve disorders (aHR:0.690, 95% CI:0.522–0.912); disorders of vestibular function (aHR:0.523, 95% CI:0.422–0.647); other diseases of inner ear (aHR:0.537, 95% CI:0.392–0.735) including labyrinthine dysfunction (aHR:0.382, 95% CI:0.246–0.591); and disorders of trigeminal nerve (aHR:0.328, 95% CI:0.200-0.538). At the same time, the HPV-vaccinated cohort showed significantly higher risks in disturbances of smell and taste (aHR: 3.136, 95% CI:0. 2.562–3.840), including anosmia/ parosmia (aHR: 3.212, 95% CI: 0.2.415–4.273) and parageusia (aHR: 5.416, 95% CI: 3.762–7.796). Kaplan–Meier curves of different cranial nerve disorders similarly revealed significant inter-cohort differences in probability (Log–Rank test, Table 2 Risk of outcome (1 days to 1y) Outcomes Patients with outcome Adjusted hazard ratio (95% CI) a HPV vaccinated cohort Control cohort Hearing loss 241 470 0.490 (0.419–0.572) Sudden idiopathic hearing loss 12 11 1.038 (0.458–2.352) Sensorineural hearing loss, bilateral 134 271 0.472 (0.384–0.581) Sensorineural hearing loss, unilateral with unrestricted hearing 69 124 0.532 (0.397–0.715) Sensorineural hearing loss, unspecified 66 133 0.472 (0.351–0.634) Disturbances of smell and taste 405 122 3.136 (2.562–3.840) Anosmia and Parosmia 208 61 3.212 (2.415–4.273) Parageusia 195 34 5.416 (3.762–7.796) Facial nerve disorders 85 117 0.690 (0.522–0.912) Disorders of vestibular function 131 238 0.523 (0.422–0.647) Meniere's disease 10 10 0.750 (0.201–2.793) Benign paroxysmal vertigo 77 92 0.791 (0.584–1.070) Vestibular neuronitis 10 10 3.313 (0.688–15.94) Other diseases of inner ear 61 108 0.537 (0.392–0.735) Labyrinthitis 10 15 0.567 (0.248–1.296) Labyrinthine dysfunction 28 70 0.382 (0.246–0.591) Other specified diseases of inner ear 10 10 0.707 (0.245–2.038) Disease of inner ear, unspecified 10 10 0.482 (0.088–2.632) Disorders of trigeminal nerve 21 61 0.328 (0.200-0.538) Note: If the patient is less or equal to 10, results show the count as 10. HPV: Human Papillomavirus, CI: Confidence interval. NA: Not applicable. a . Propensity score matching was performed age at index, race, problems related to housing and economic circumstances (proxy to social economic status), lifestyles (including tobacco use, nicotine dependence), medical utilization (office or other outpatient services, preventive medicine services, hospital inpatient services), and comorbidities (hypertension, diabetes mellitus, overweight and obesity, asthma, inflammatory diseases of female pelvic organs, diseases of middle ear and mastoid, transient cerebral ischemic attacks and related syndromes, gingivitis and periodontal diseases, dental caries, depressive episode, anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders, certain infectious and parasitic diseases, injuries to the head). * Proportionality < 0.001. p < 0.001, Figs. 2 to 7 ). To eliminate covariate biases, Table S1 shows risks of cranial nerve disorders between the HPV-vaccinated cohort and the control cohort analyzed according to different models. Compared with the controls, patients receiving HPV vaccination had a lower incidence of different cranial nerve disorders including hearing loss, facial nerve disorders, disorders of vestibular function, other disease of inner ear, and disorders of trigeminal nerve in all models. Conversely, disturbances of smell and taste risk were higher in the HPV-vaccinated cohort. To evaluate effects of different follow-up periods, Table S2 shows risks of different cranial nerve disorders incidences in the two cohorts at different follow-up periods after HPV vaccination. We found again significantly lower risks of different cranial nerve disorders, including hearing loss, facial nerve disorders, disorders of vestibular function, other diseases of the inner ear and disorders of trigeminal nerve across different durations of follow-up (i.e., 1 day to 1 month, 1 day to 3 months, 1 day to 6 months, 1 day to 1 year, and 1 day to 3 years). Also, risks of disturbances of smell and taste were higher in patients receiving HPV vaccination across 3 different durations (i.e., 1 day to 3 months, 6 months, 1 year and 3 years). Subgroup Analyses Table S3 shows risks of different cranial nerve disorders in subgroups stratified according to age. In the subgroup with ages from 9 to 17 years, HPV vaccinated subjects showed lower risks of all cranial nerve disorders, except disturbances of smell and taste (aHR:3.362, 95% CI: 2.662–4.246), when compared with controls. On the other hand, the same trend was only observed in the subgroup aged from 18 to 26 years in disturbances of smell and taste (aHR:1.998, 95% CI: 1.393–2.866). Patients who had received HPV vaccination showed lower risks of various cranial nerve disorders, including hearing loss, facial nerve disorders, vestibular function, and other diseases of the inner ear, and higher risks of disturbances of smell and taste in the white and African/American races, while only significantly lower risk in hearing losses was found in the Asian subgroup ( Table S4 ). We also divided the HPV-vaccinated cohort into the 9v and 4v vaccines subgroups, and assessed the incidence of different cranial nerve disorders from 1 day to 1 year after the index date. Table S5 showed that the 9v subgroup had significantly lower risks of hearing loss, facial nerve disorders, vestibular function, other diseases of inner ear diseases, and disorders of trigeminal nerve disorders, and higher risks of disturbances of smell and taste. However, in the 4v subgroup, we observed a significant difference only observed in the lower risk of hearing loss (aHR: 0.264, 95% CI: 0.098–0.711) and the higher risk of disturbances of smell and taste (aHR: 18.00, 95% CI: 2.410–134.4). Sensitivity analyses To confirm the consistency of results, we used the same study design to compare data with the influenza vaccination group. In this sensitivity analysis, we found similarly lower risks of various cranial nerve disorders, including hearing loss, other diseases of the inner ear and disorders of the trigeminal nerve, and higher risks of disturbances of smell and taste compared with the influenza vaccine cohort ( Table S6 ). Discussion In this current large retrospective cohort study using EMR of multi-HCOs from TriNetx Network, we discovered that in women, aged from 9 to 26 years old, who had received HPV vaccination showed significantly lower risks of cranial nerve disorders including hearing loss(cranial nerve (CN.) 8th), vestibular function disorders or other inner ear diseases of the inner ear(CN. 8th), facial nerve disorders(CN. 7th), and trigeminal disorders of the trigeminal (CN. 5th) nerve during the yearlong follow-up period after HPV vaccination. In contrast, these same vaccinated patients had relatively higher risks of disturbances of smell and taste (the CN. 1st/5th,7th/9th). Risks of disturbance of smell and taste were significantly higher in the subgroup analysis based on age, race, and vaccine value when compared with the non-vaccinated cohort. Again based on subgroup analyses, cranial nerve disorders, like hearing loss/inner ear disease/vestibular functions (CN. 8), facial nerve (CN. 7), and trigeminal nerve (CN. 5) showed significantly lower risks in the subgroup of patients with from age 9 to 17 years, the 9-value of the HPV vaccine, white, and African/American (except disorder of trigeminal nerve). Pathophysiological mechanisms of Herpes papillomavirus infection on nerve disorders remain elusive. Previous research by Tibor Füle et al 13 suggested that HPV-16 is likely present in neuronal cells in the vascular endothelium as HPV 16 E6 ORF sequences are found in neuronal cells and endothelial cells of oral and cervical cancers. Shi et al propose a molecular mimicry hypothesis in that HPV infection results in immune dysregulation to systemic lupus erythematosus. According to other studies on the Guillain-Barré syndrome 14 , 15 , the molecular mimicry is one mechanisms of Guillain–Barré syndrome related to post-virus infection. A variety of viruses, like Campylobacter jejuni, cytomegalovirus, Haemophilus influenzae, Mycoplasma pneumoniae, Epstein-Barr virus, hepatitis E virus, influenza A virus, Zika virus, and HPV B19 have been reported to trigger demyelinating neuropathy 16 , 17 . On the other hand, Guo et al proposed that HPV virus may be latent in the central nerve system and become reactivated when the host is immunocompromised resulting in central or peripheral nerve neuropathy 17 . Despite scarce evidence in support of the association of human papillomavirus infection and cranial nerve disorders. Our results indicated that HPV vaccination could reduce HPV infection and lower risks of cranial nerve disorders. Regarding the higher risks of smell and taste dysfunction after HPV vaccination, the underlying mechanism is unclear. It is widely believed that smell and taste disorders often develop in patients with allergic rhinitis 18 , 19 . According to the study by Afrin et al, allergic reactions like nasal congestion and dysosmia after HPV vaccination could have triggered cytokine storm, especially involving mast cells or auto-antibodies that can act directly or indirectly on the vascular endothelium via the humoral immune system, in a condition related to the mast cell activation syndrome 20 . This process may be used to explain the risk disparity between disturbances of smell and taste and other cranial nerve disorders. Our study has several strengths. We used the TriNetX network, one of the largest databases, to conduct this first large retrospective cohort study to investigate for the first time, the association between HPV vaccination and various cranial nerve disorders during a relatively long-term follow-up period. Confounding biases including age, lifestyle habits, social economic status, medical utilization, and comorbidities were all eliminated using propensity score matching between the two cohorts. In addition, we performed subgroup analyses to determine possible effects of age, race, and vaccine valence on the results. Finally, sensitivity analysis was conducted using an influenza vaccination cohort verify the reliability of our HPV findings. Our study has several limitations. First, the study design, which was based on data from the electronic health records, had inherent weak points. The definition of cranial nerve disorders was based on the ICD-10-CM codes reported by physicians. The information may be have been incorrect due to misdiagnosis, underdiagnosis, inaccurate coding and documentation errors. Second, the database had no record on HPV antibody titers in those vaccinated patients, therefore we could not perform a further evaluation of the relationship between the antibody titer and cranial nerve disorders. Third, the database was derived mainly from patients with medical records from HCOs in the United States, and the number of patients diagnosed with cranial disorder was relatively small. Therefore, the representation of our conclusions is limited. Forth, we did not include all 12 cranial nerve-related disorders in our study. Future research is needed to explore different ethnic groups or databases. In conclusion, our preliminary results had suggested that HPV vaccination was associated with lower risks of a variety of cranial nerve disorders, including hearing loss, disorders of vestibular function/other diseases of the inner ear, facial nerve disorders, and disorders of the trigeminal nerve, but higher risks of disturbances of smell and taste in female aged between 9 to 26 years old over a yearlong follow-up. In addition, results were prominent in subgroups aged from 9 to 17 years, white, African American, and in patients who had received the 9-value HPV vaccine. These findings were consistent across follow-up periods of different lengths, and again valid when compared with the influenza vaccination cohort. Future research is needed to further investigate the complete set of cranial nerve disorders and to explore the underlying pathophysiological mechanisms. Methods Data source We obtained data from the TriNetX Analytics Network platform, which is a global federated health collaborative research network that has derived data from electronic medical records (EMR). The network provides data for ~ 250 million patients across 120 global healthcare organizations (HCOs). These organizations have collected web-based, real-time, secure patient electronic medical records. Each medical record contains information on International Classification of Disease, 10th Revision (ICD-10) diagnostic codes, procedures (Current procedural Terminology (CPT) codes, medications, laboratory test results, genomic information, and demographic data such as geography, age, gender, race, income, and insurance group. In this study, we utilized the U.S. Collaborative Network, which is a subset of the TriNetX database. Our study period was from January 1, 2018, till December 31, 2022. For details of the TriNetX, please visit its website: https://trinetx.com/ . Because we only used de-identified patient records and did not involve the collection, use, or transmission of personally identifiable data, our study was exempt from approval from our institutional review board. Our study also followed the Reporting guidelines of the Strengthened Reporting of Observational Studies in Epidemiology (STROBE). Our study was approved by the Institutional Review Board of Chung Shan Medical University Hospital, Taiwan (CSMUH No: CS2-21176). Study Population The study population included female patients aged from 9 to 26 years with at least two medical visits between January 1, 2018 and December 31 2022 as documented in the TriNetx Network. We excluded those diagnosed with oral cancers, HPV infection, or pregnancy. Based on EMR in the TriNetx Network, patients were divided into two groups: with HPV vaccination or without. The index date of the HPV vaccinated group was the date of completing vaccination (2-valent, 4-valent, or 9-valent), and the control group was the date of the first visit during the study period. We used the current procedural terminology (CPT) codes: 2-valent (90650), 4-valent (90649), and 9-valent (90651) to identify patients in the HPV-vaccinated group. TriNetx methodology in TriNetx is presented in Fig. 1 . Outcomes Main outcomes were the incidence of certain cranial nerve disorders defined according to ICD-10 codes, These disorders were as follows: (1) Hearing losses (ICD10 code H91.2 or CPT code 69801, H90.3, H90.4, H90.5) Sudden idiopathic hearing loss (ICD10 code H91.2 or CPT code 69801) Sensorineural hearing loss, bilateral (ICD10 code H90.3) Sensorineural hearing loss, unilateral with unrestricted hearing (ICD10 code H90.4) Sensorineural hearing loss, unspecified (ICD10 code H90.5) (2) Disturbances of smell and taste (ICD10 code R43) Anosmia, Parosmia (ICD10 code R43.0, R43.1) Parageusia (ICD10 code R43.2) (3) Facial nerve disorders (ICD10 code G51) (4) Disorders of vestibular function (ICD10 code H81) Meniere's disease (ICD10 code H81.0) Benign paroxysmal vertigo (ICD10 code H81.1) Vestibular neuronitis (ICD10 code H81.2) (5) Other inner ear diseases (ICD10 code H83) Labyrinthitis (ICD10 code H83.0) Labyrinthine dysfunction (ICD10 code H83.2) Other specified diseases of inner ear (ICD10 code H83.8) Disease of inner ear, unspecified (ICD10 code H83.9) (6) Disorders of trigeminal nerve (ICD10 code G50) To identify the time effect of vaccination, we also divided the risk of outcomes after HPV vaccination, in terms of 5 partially overlapping time periods after the index date follow-ups, namely: (a) 1 day to 1 month, (b) 1 day to 3 months, (c) 1 day to 6 months, (d) 1 day to 1 year and (e)1 day to 3 years. Covariates Demographic variables were the following: age, race, problems related to housing and economic circumstances (ICD 10 code Z59), and problems related to education and literacy (ICD 10 code Z55). Lifestyle variables included nicotine dependence (smoking) (ICD10 code F17, tobacco use (smoking) (ICD10 code Z72.0, alcohol related disorders (ICD10 code F10), and cannabis related disorders (ICD10 code F12). Medical utilization variables were office or other outpatient services, preventive medicine services, emergency department services, and hospitalization. These variables were identified by the International, Classification of Diseases (ICD) procedure codes (1013626, 1013829, 1013711, 1013659). Comorbidities included essential hypertension (ICD-10 code I10), ischemic heart diseases (ICD-10 code I20–I25), cerebrovascular diseases (ICD-10 code I60–I69), obesity (ICD-10 code E66), disorders of lipoprotein metabolism and other lipidemia (ICD-10 code E78.5), diabetes mellitus (ICD10 code E08-13), Other chronic obstructive pulmonary disease (ICD-10 code J44), asthma (ICD-10 code J45),chronic kidney diseases (ICD-10 code N18), liver diseases (ICD-10 code K70–K77), sleep disorders (ICD-10 code G47), transient cerebral ischemic attacks and related syndromes (ICD10 code G45), vascular syndromes of brain in cerebrovascular diseases (ICD10 code G46), periodontitis(ICD10 code K05), depression (ICD10 code F32), anxiety, traumatic past experiences, stress (ICD10 code F40-F48), certain infectious and parasitic diseases (ICD10 code A00-B99), neoplasms (ICD10 code C00-D49), blood diseases and disorders involving immune mechanisms (ICD10 code D50-D89), injuries to the head(ICD10 code S00-S09), rheumatoid arthritis (ICD10 code M05, M06, M08), systemic lupus erythematosus (SLE) (ICD10 code M32), and Sjogren’s syndrome (ICD10 code M35.0) To detect the presence of comorbidities, we traced back for one-year preceding period preceding the index date. The variables of medication usage included gentamicin (Anatomical Therapeutic Chemical (ATC) code S01AA11), streptomycin (ATC code J01GA01), cisplatin (ATC code L01XA01), carboplatin (ATC code L01XA02), cyclophosphamide (ATC code L01AA01), ibuprofen (ATC code G02CC01), naproxen (ATC code G02CC02), salicylates (aspirin, ATC code B01AC06), and sulfonamides (ATC code C03CA). Pure tone audiometry was identified by Current Procedural Terminology (CPT) code 1012899. Statistical Analyses All data analyses were performed on the TriNetX built-in platform and with the Advanced Analytics. Propensity score matching (PSM)was a 1:1 ratio, to balance all covariates between the two cohorts regarding demographics, lifestyles, medical utilization, comorbidities, and medication usage. The procedure was to reduce the impact of intervention selection bias. The balance of baseline characteristics in the propensity score-matched populations was evaluated based on standardized mean difference (SMD). With an absolute value of < 0.1, it was considered well-matched between the two cohorts. Kaplan–Meier analysis and log-rank tests were used to evaluate the probability of the outcomes and the difference of the survival curves between the two cohorts. The adjusted hazard ratio (aHR) was calculated to evaluate the relative risks of different cranial nerve disorders based on the time-to-event analysis for both the HPV-vaccinated and control groups. We used Cox proportional hazards models to calculate the hazard ratio (HR) and the associated 95% confidence interval (95%CI). R's Survival package v3.2–3 was used to calculate HR, 95% CIs, and the test for proportionality. The two-sided p-value < 0.05 was considered statistically significant. To evaluate the possible variables on the results after adjustment, we created 4 models for comparison. Subgroup analyses were based on age (≤ 9 to 17 years, and 18 to 26 years), race (white, African American and Asian), and different vaccine values (9v and 4v). We assessed differences in the risk of cranial nerve disorders across these subgroups during a year of follow-up following the index date. Finally, we also conducted a sensitivity test to compare the HPV vaccination and the influenza vaccination cohort with the same study design to verify the consistency of the results. Declarations DATA AVAILABILITY Data is available from the TriNetX global network. Requests for data can be sent as logging on TriNetX platform (https://live.trinetx.com/). CODE AVAILABILITY Data is available from the TriNetX global network. Requests for data can be sent as logging on TriNetX platform (https://live.trinetx.com/). AUTHOR CONTRIBUTIONS W.-C.L. and S.-I.W. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition and analysis of data, statistical analysis: S.-I.W. Interpretation of data, concept and design, and drafting of the manuscript: W.-C.L. Critical revision of the manuscript for important intellectual content: J.C-C.W. R.-C. Supervision: J.C-C.W., R.-C. W.-C.L. and S.-I.W.is the co-first author. COMPETING INTERESTS The authors declare no competing interests. References Chen, T. Y.-T. et al. Recent Human Papillomavirus Vaccination is Associated with a Lower Risk of COVID-19: A US Database Cohort Study. Drugs , 1-12 (2023). Cheng, L., Wang, Y. & Du, J. Human papillomavirus vaccines: an updated review. Vaccines 8 , 391 (2020). Chen, M.-L., Kao, W.-M., Huang, J.-Y., Hung, Y.-M. & Wei, J. C.-C. Human papillomavirus infection associated with increased risk of new-onset psoriasis: a nationwide population-based cohort study. International Journal of Epidemiology 49 , 786-797 (2020). Phillips, A., Patel, C., Pillsbury, A., Brotherton, J. & Macartney, K. Safety of human papillomavirus vaccines: an updated review. Drug safety 41 , 329-346 (2018). Yoon, D., Lee, J.-H., Lee, H. & Shin, J.-Y. Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study. Bmj 372 (2021). Meites, E. et al. Vol. 19 3202-3206 (Wiley Online Library, 2019). Mehraeen, E. et al. Olfactory and gustatory dysfunctions due to the coronavirus disease (COVID-19): a review of current evidence. European Archives of Oto-Rhino-Laryngology 278 , 307-312 (2021). Kanjanaumporn, J., Aeumjaturapat, S., Snidvongs, K., Seresirikachorn, K. & Chusakul, S. Smell and taste dysfunction in patients with SARS-CoV-2 infection: A review of epidemiology, pathogenesis, prognosis, and treatment options. Asian Pacific Journal of Allergy and Immunology 38 , 69-77 (2020). Papan, C. et al. Infectious causes of peripheral facial nerve palsy in children—a retrospective cohort study with long-term follow-up. European Journal of Clinical Microbiology & Infectious Diseases 38 , 2177-2184 (2019). Martinez-Gomez, E., Perez-Carpena, P., Flook, M. & Lopez-Escamez, J. A. A systematic review on the Association of Acquired Human Cytomegalovirus Infection with hearing loss. Journal of Clinical Medicine 9 , 4011 (2020). Shi, X., Liu, X. & Sun, Y. The Pathogenesis of Cytomegalovirus and Other Viruses Associated with Hearing Loss: Recent Updates. Viruses 15 , 1385 (2023). Yee, K. T., Neupane, B., Bai, F. & Vetter, D. E. Zika virus infection causes widespread damage to the inner ear. Hearing research 395 , 108000 (2020). Füle, T. et al. The presence of human papillomavirus 16 in neural structures and vascular endothelial cells. Virology 348 , 289-296, doi:10.1016/j.virol.2005.12.043 (2006). Shahrizaila, N., Lehmann, H. C. & Kuwabara, S. Guillain-Barré syndrome. Lancet 397 , 1214-1228, doi:10.1016/s0140-6736(21)00517-1 (2021). Yuki, N. & Hartung, H. P. Guillain-Barré syndrome. N Engl J Med 366 , 2294-2304, doi:10.1056/NEJMra1114525 (2012). Li, K. Y. et al. The Potential Role of Human Papillomavirus Infection in Bell's Palsy: A Hypothesis-Generating Study Based on a Nationwide Cohort. Front Med (Lausanne) 8 , 616873, doi:10.3389/fmed.2021.616873 (2021). Guo, J. et al. Human parvovirus B19 infection in hospitalized patients suspected of infection with pathogenic microorganism. Front Cell Infect Microbiol 12 , 1083839, doi:10.3389/fcimb.2022.1083839 (2022). Guilemany, J. M. et al. Persistent allergic rhinitis has a moderate impact on the sense of smell, depending on both nasal congestion and inflammation. The Laryngoscope 119 , 233-238 (2009). Henkin, R. I., Levy, L. M. & Fordyce, A. Taste and smell function in chronic disease: a review of clinical and biochemical evaluations of taste and smell dysfunction in over 5000 patients at The Taste and Smell Clinic in Washington, DC. Am J Otolaryngol 34 , 477-489, doi:10.1016/j.amjoto.2013.04.006 (2013). Afrin, L. B., Dempsey, T. T. & Weinstock, L. B. Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease? Vaccines 10 , 127 (2022). Additional Declarations (Not answered) Supplementary Files Additionalfile1.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Reject after peer review 05 Feb, 2025 Review # 2 received at journal 01 Jan, 2025 Reviewer # 2 agreed at journal 30 Dec, 2024 Review # 1 received at journal 11 Oct, 2024 Reviewer # 1 agreed at journal 25 Sep, 2024 Reviewers invited by journal 25 Sep, 2024 Editor assigned by journal 09 Sep, 2024 Submission checks completed at journal 22 Aug, 2024 First submitted to journal 16 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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occurrence\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/0e3806de824ab2935e38ac83.png"},{"id":65063366,"identity":"0cbaf4ca-483c-467e-bb87-eddb46d9784b","added_by":"auto","created_at":"2024-09-23 08:24:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":131950,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of disturbances of smell and taste incidence\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/cb36e998ec35c988e1649027.png"},{"id":65063372,"identity":"7f8bdb4d-b503-409a-b1d7-18fd91e4ffa6","added_by":"auto","created_at":"2024-09-23 08:24:11","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":106428,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of facial nerve disorders incidence\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/9c5019a2b359a2e7854575ce.png"},{"id":65063370,"identity":"3c86206b-5680-40f2-b6b3-218e8e7aa5e0","added_by":"auto","created_at":"2024-09-23 08:24:11","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":113191,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of vestibular function disorders incidence\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/b8bfd2a31fbec79c09009bf4.png"},{"id":65064065,"identity":"cc44939c-5e19-432c-8ac9-5955fcf6e375","added_by":"auto","created_at":"2024-09-23 08:32:11","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":109494,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of other inner ear diseases incidence\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/9618004f05eb63678f533268.png"},{"id":65063368,"identity":"a3f4b744-c49f-4118-8ec2-4d85f719438a","added_by":"auto","created_at":"2024-09-23 08:24:11","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":103664,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of trigeminal nerve disorders inci\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/55895c7ebc3ac24c2db4a152.png"},{"id":65064866,"identity":"f23b2369-b8fd-4fb5-8dd1-ee696360b6b0","added_by":"auto","created_at":"2024-09-23 08:40:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1927808,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/9afc4899-3f04-4ea6-8d2a-fdeafb7d52af.pdf"},{"id":65064066,"identity":"9f0eccd4-d9b1-4765-ad64-bb4974ce8896","added_by":"auto","created_at":"2024-09-23 08:32:11","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":43751,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4923637/v1/603d4ad14db9f7ac452b44b7.docx"}],"financialInterests":"(Not answered)","formattedTitle":"Human papillomavirus vaccination poses different risks for various cranial nerve disorders - a retrospective cohort study using a real-world database","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman papillomavirus (HPV) is a small double-stranded DNA virus. HPV infection is becoming more common in recent years. Some specific subtypes of HPV infection are associated with various diseases, like cervical, head and neck, breast, lung, and anogenital cancers, and autoimmune diseases\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Today, 3 vaccines for Human papillomavirus have been reported prevent HPV infection and precancer lesions of cervical disease\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. For example, Gardasil, a quadrivalent vaccine (Merck \u0026amp; Co., Kenilworth, NJ, USA), which targets HPV types 6,11,16, and 18, is the first commercially available HPV vaccine. It was licensed by the United States Food and Drug Administration (FDA) in 2006. Cervarix, a bivalent HPV vaccine (GSK, Brentford, UK) was also approved by FDA in 2009. It protects against the HPV type 16 and 18. Finally, Gardasil 9, a 9-valent vaccine (Merck \u0026amp; Co., Kenilworth, NJ, USA), was licensed by FDA in 2014. It protects against HPV 6, 11, 16, 18, 31, 33, 45, 53, and 58\u003csup\u003e2,4\u003c/sup\u003e. To date, the virus-like particle (VLP) of papillomavirus capsid protein L1, constitutes the HPV vaccines. VLP is produced from bacteria or yeast containing only protein without viral genomes. They are considered non-infectious and non-carcinogenic and are considered safer than those attenuated HPV vaccines. The World Health Organization currently recommends that girls aged 9 to 14 years are prioritized for HPV vaccination before their first sexual exposure\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Centers for Disease Control and Prevention\u0026rsquo;s (CDC) Advisory Committee on Immunization Practices (ACIP) recommends that HPV vaccination can start at the age of 9 through 26 years old, for those not vaccinated before\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eViral infections are widespread and difficult to control. Various cranial nerve disorders due to viral infections are well-known, such as smell and taste dysfunction after COVID-19 infection\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e; facial nerve paralysis after varicella-zoster virus infection, or human herpesvirus 6 infection\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e; hearing impairment after human cytomegalovirus infection\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e; and Zika virus infection after inner ear disease\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Knowledge on the relationship between human papillomavirus vaccination and cranial nerve disorders remains limited from the literature review. Here, we aimed to evaluate the association between young girls receiving the human papillomavirus vaccine and their risk of developing cranial nerve disorders.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eCharacteristics of study subjects\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows baseline characteristics of the study subjects including their demographic characteristics, lifestyle, comorbidities, and medication usage of both the HPV-vaccinated cohort and the control cohort, before and after matching. Before matching, we found significant differences in two cohorts in terms of the following: age at index, race of white and black or African American, the emergency department services, comorbidities including certain infectious and parasitic diseases, noninflammatory disorders of female genital tract, disease of middle ear and mastoid, asthma, overweight and obesity, disorders of lipoprotein metabolism and other lipidemia, injuries to the head, depressive episode, anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders, sleep disorders, and Ibuprofen usage. After matching, the two cohorts were matched well as their differences were within the acceptable range (SMD\u0026thinsp;\u0026lt;\u0026thinsp;0.1). After propensity score matching, the HPV-vaccinated cohort (N\u0026thinsp;=\u0026thinsp;261,111) and the control group with no HPV vaccination (N\u0026thinsp;=\u0026thinsp;261,111) were further compared.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics of study subjects (before and after PSM matching)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore PSM\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter PSM\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHPV vaccinated cohort\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;263665)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;4350486)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHPV vaccinated cohort\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;261111)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003cp\u003eCohort\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;261111)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at index\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.721\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.135\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRace, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e136212 (51.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2580103 (59.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.154\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135132 (51.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e140876 (54.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlack or African American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53244 (20.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e660689 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.132\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52933 (20.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51453 (19.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13927 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e169841 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13745 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9484 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerican Indian or Alaska Native\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1329 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20119 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1309 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1476 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNative Hawaiian or Other Pacific Islander\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e743 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15503 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e741 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e790 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown Race\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37454 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e627534 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36911 (14.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39886 (15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther Race\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20756 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e276697 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20340 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17146 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSocial economic status, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProblems related to housing and economic circumstances\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1096 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e909 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e983 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e673 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProblems related to education and literacy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e871 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2011 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e854 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e723 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLifestyles, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTobacco use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e263 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2086 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e263 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e384 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNicotine dependence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e666 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11743 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e666 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1169 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlcohol related disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e230 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2589 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e229 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e365 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCannabis related disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e520 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4722 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e515 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e904 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedical utilization, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOffice or Other Outpatient Services\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e129646 (49.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e417488 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.965\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e127103 (48.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e134647 (51.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmergency Department Services\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17336 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e119954 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.182\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17144 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20575 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHospital Inpatient Services\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2092 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17930 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2084 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3868 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePreventive Medicine Services\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52031 (19.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e117556 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.560\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49641 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49346 (18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeoplasms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3350 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27516 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3301 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6027 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCertain infectious and parasitic diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26480 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85527 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.345\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25882 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29307 (11.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInflammatory diseases of female pelvic organs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2636 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15162 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2623 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4077 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNoninflammatory disorders of female genital tract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15471 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71106 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.224\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15347 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17643 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiseases of middle ear and mastoid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9361 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33973 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.191\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9234 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10005 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16084 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61698 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.248\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15813 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19297 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBronchitis, not specified as acute or chronic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e982 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4059 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e959 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e977 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOverweight and obesity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13375 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39462 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.246\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13140 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16244 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.052\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisorders of lipoprotein metabolism and other lipidemias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3599 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10880 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.125\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3502 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3198 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1293 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19335 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1292 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1699 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEssential (primary) hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1112 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9306 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1104 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1960 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCerebrovascular diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e150 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2305 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e149 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e509 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIschemic heart diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e542 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e105 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInjuries to the head\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4525 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23533 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.111\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4479 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6085 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTransient cerebral ischemic attacks and related syndromes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e167 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiseases of liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e457 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4358 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e450 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1039 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGingivitis and periodontal diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e235 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1263 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e234 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e353 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDental caries\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e903 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9147 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e897 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1575 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiseases of the blood and blood-forming organs and certain disorders involving the immune mechanism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4577 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34578 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4511 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8076 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSystemic lupus erythematosus (SLE)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2275 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e476 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJuvenile arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e196 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3854 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e194 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e879 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRheumatoid arthritis with rheumatoid factor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e283 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther rheumatoid arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1056 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e182 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSj\u0026ouml;gren syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e430 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDepressive episode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9601 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38035 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.187\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9485 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15059 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.101\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19733 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85352 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.263\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19561 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28899 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.123\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSleep disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4748 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26541 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.109\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4663 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8107 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChronic kidney disease (CKD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e278 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3271 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e276 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e698 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedications/ Procedures, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIbuprofen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19246 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e115066 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.215\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18938 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22851 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNaproxen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2949 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27959 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2917 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4935 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAminoglycoside antibacterials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2919 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15540 (0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2876 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3179 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAspirin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e552 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6852 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e549 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1261 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSulfonamides and potassium in combination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e257 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2369 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e257 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e305 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSulfonamides, plain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e191 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3145 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e191 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e605 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCyclophosphamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e463 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e121 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCisplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCarboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eNote:\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eBold font represents a standardized difference was more than 0.1.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eIf the patient is less or equal to 10, results show the count as 10.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003ePSM: Propensity Score Matching, HPV: Human Papillomavirus, SMD: Standardized Mean Difference, SD: Standard Deviation.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003e*Propensity score matching was performed age at index, race, problems related to housing and economic circumstances (proxy to social economic status), lifestyles (including tobacco use, nicotine dependence), medical utilization (office or other outpatient services, preventive medicine services, hospital inpatient services), and comorbidities (hypertension, diabetes mellitus, overweight and obesity, asthma, inflammatory diseases of female pelvic organs, diseases of middle ear and mastoid, transient cerebral ischemic attacks and related syndromes, gingivitis and periodontal diseases, dental caries, depressive episode, anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders, certain infectious and parasitic diseases, injuries to the head).\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eIncidence of cranial nerve disorders in the HPV-vaccinated and control groups\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows risks of cranial nerve disorders in both the HPV-vaccinated and control groups revealed during a yearlong follow-up. The HPV-vaccinated cohort had significantly lower risks of the following: hearing loss (aHR:0.490, 95% CI:0.419\u0026ndash;0.572), including bilateral sensorineural hearing loss (aHR:0.472, 95% CI:0.384\u0026ndash;0.581), sensorineural hearing loss, unilateral with unrestricted hearing (aHR:0.532, 95% CI:0.397\u0026ndash;0.715), and sensorineural hearing loss, unspecified (aHR:0.472, 95% CI:0.351\u0026ndash;0.634); facial nerve disorders (aHR:0.690, 95% CI:0.522\u0026ndash;0.912); disorders of vestibular function (aHR:0.523, 95% CI:0.422\u0026ndash;0.647); other diseases of inner ear (aHR:0.537, 95% CI:0.392\u0026ndash;0.735) including labyrinthine dysfunction (aHR:0.382, 95% CI:0.246\u0026ndash;0.591); and disorders of trigeminal nerve (aHR:0.328, 95% CI:0.200-0.538). At the same time, the HPV-vaccinated cohort showed significantly higher risks in disturbances of smell and taste (aHR: 3.136, 95% CI:0. 2.562\u0026ndash;3.840), including anosmia/ parosmia (aHR: 3.212, 95% CI: 0.2.415\u0026ndash;4.273) and parageusia (aHR: 5.416, 95% CI: 3.762\u0026ndash;7.796). Kaplan\u0026ndash;Meier curves of different cranial nerve disorders similarly revealed significant inter-cohort differences in probability (Log\u0026ndash;Rank test,\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRisk of outcome (1 days to 1y)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePatients with outcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAdjusted hazard ratio\u003c/p\u003e\n \u003cp\u003e(95% CI) \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHPV vaccinated cohort\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl cohort\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHearing loss\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e241\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e470\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.490 (0.419\u0026ndash;0.572)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSudden idiopathic hearing loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.038 (0.458\u0026ndash;2.352)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSensorineural hearing loss, bilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.472 (0.384\u0026ndash;0.581)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSensorineural hearing loss, unilateral with unrestricted hearing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.532 (0.397\u0026ndash;0.715)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSensorineural hearing loss, unspecified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.472 (0.351\u0026ndash;0.634)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisturbances of smell and taste\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.136 (2.562\u0026ndash;3.840)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnosmia and Parosmia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.212 (2.415\u0026ndash;4.273)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParageusia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.416 (3.762\u0026ndash;7.796)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFacial nerve disorders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.690 (0.522\u0026ndash;0.912)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisorders of vestibular function\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.523 (0.422\u0026ndash;0.647)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMeniere\u0026apos;s disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.750 (0.201\u0026ndash;2.793)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBenign paroxysmal vertigo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.791 (0.584\u0026ndash;1.070)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVestibular neuronitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.313 (0.688\u0026ndash;15.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOther diseases of inner ear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.537 (0.392\u0026ndash;0.735)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLabyrinthitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.567 (0.248\u0026ndash;1.296)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLabyrinthine dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.382 (0.246\u0026ndash;0.591)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther specified diseases of inner ear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.707 (0.245\u0026ndash;2.038)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease of inner ear, unspecified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.482 (0.088\u0026ndash;2.632)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisorders of trigeminal nerve\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.328 (0.200-0.538)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eNote:\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eIf the patient is less or equal to 10, results show the count as 10.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eHPV: Human Papillomavirus, CI: Confidence interval. NA: Not applicable.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e. Propensity score matching was performed age at index, race, problems related to housing and economic circumstances (proxy to social economic status), lifestyles (including tobacco use, nicotine dependence), medical utilization (office or other outpatient services, preventive medicine services, hospital inpatient services), and comorbidities (hypertension, diabetes mellitus, overweight and obesity, asthma, inflammatory diseases of female pelvic organs, diseases of middle ear and mastoid, transient cerebral ischemic attacks and related syndromes, gingivitis and periodontal diseases, dental caries, depressive episode, anxiety, dissociative, stress-related, somatoform and other nonpsychotic mental disorders, certain infectious and parasitic diseases, injuries to the head).\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e* Proportionality\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Figs. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e to \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e). To eliminate covariate biases, \u003cstrong\u003eTable \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/strong\u003e shows risks of cranial nerve disorders between the HPV-vaccinated cohort and the control cohort analyzed according to different models. Compared with the controls, patients receiving HPV vaccination had a lower incidence of different cranial nerve disorders including hearing loss, facial nerve disorders, disorders of vestibular function, other disease of inner ear, and disorders of trigeminal nerve in all models. Conversely, disturbances of smell and taste risk were higher in the HPV-vaccinated cohort. To evaluate effects of different follow-up periods, \u003cstrong\u003eTable S2\u003c/strong\u003e shows risks of different cranial nerve disorders incidences in the two cohorts at different follow-up periods after HPV vaccination. We found again significantly lower risks of different cranial nerve disorders, including hearing loss, facial nerve disorders, disorders of vestibular function, other diseases of the inner ear and disorders of trigeminal nerve across different durations of follow-up (i.e., 1 day to 1 month, 1 day to 3 months, 1 day to 6 months, 1 day to 1 year, and 1 day to 3 years). Also, risks of disturbances of smell and taste were higher in patients receiving HPV vaccination across 3 different durations (i.e., 1 day to 3 months, 6 months, 1 year and 3 years).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eSubgroup Analyses\u003c/h2\u003e\n \u003cp\u003e\u003cstrong\u003eTable S3\u003c/strong\u003e shows risks of different cranial nerve disorders in subgroups stratified according to age. In the subgroup with ages from 9 to 17 years, HPV vaccinated subjects showed lower risks of all cranial nerve disorders, except disturbances of smell and taste (aHR:3.362, 95% CI: 2.662\u0026ndash;4.246), when compared with controls. On the other hand, the same trend was only observed in the subgroup aged from 18 to 26 years in disturbances of smell and taste (aHR:1.998, 95% CI: 1.393\u0026ndash;2.866).\u003c/p\u003e\n \u003cp\u003ePatients who had received HPV vaccination showed lower risks of various cranial nerve disorders, including hearing loss, facial nerve disorders, vestibular function, and other diseases of the inner ear, and higher risks of disturbances of smell and taste in the white and African/American races, while only significantly lower risk in hearing losses was found in the Asian subgroup (\u003cstrong\u003eTable S4\u003c/strong\u003e).\u003c/p\u003e\n \u003cp\u003eWe also divided the HPV-vaccinated cohort into the 9v and 4v vaccines subgroups, and assessed the incidence of different cranial nerve disorders from 1 day to 1 year after the index date. \u003cstrong\u003eTable S5\u003c/strong\u003e showed that the 9v subgroup had significantly lower risks of hearing loss, facial nerve disorders, vestibular function, other diseases of inner ear diseases, and disorders of trigeminal nerve disorders, and higher risks of disturbances of smell and taste. However, in the 4v subgroup, we observed a significant difference only observed in the lower risk of hearing loss (aHR: 0.264, 95% CI: 0.098\u0026ndash;0.711) and the higher risk of disturbances of smell and taste (aHR: 18.00, 95% CI: 2.410\u0026ndash;134.4).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eSensitivity analyses\u003c/h2\u003e\n \u003cp\u003eTo confirm the consistency of results, we used the same study design to compare data with the influenza vaccination group. In this sensitivity analysis, we found similarly lower risks of various cranial nerve disorders, including hearing loss, other diseases of the inner ear and disorders of the trigeminal nerve, and higher risks of disturbances of smell and taste compared with the influenza vaccine cohort (\u003cstrong\u003eTable S6\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this current large retrospective cohort study using EMR of multi-HCOs from TriNetx Network, we discovered that in women, aged from 9 to 26 years old, who had received HPV vaccination showed significantly lower risks of cranial nerve disorders including hearing loss(cranial nerve (CN.) 8th), vestibular function disorders or other inner ear diseases of the inner ear(CN. 8th), facial nerve disorders(CN. 7th), and trigeminal disorders of the trigeminal (CN. 5th) nerve during the yearlong follow-up period after HPV vaccination. In contrast, these same vaccinated patients had relatively higher risks of disturbances of smell and taste (the CN. 1st/5th,7th/9th). Risks of disturbance of smell and taste were significantly higher in the subgroup analysis based on age, race, and vaccine value when compared with the non-vaccinated cohort. Again based on subgroup analyses, cranial nerve disorders, like hearing loss/inner ear disease/vestibular functions (CN. 8), facial nerve (CN. 7), and trigeminal nerve (CN. 5) showed significantly lower risks in the subgroup of patients with from age 9 to 17 years, the 9-value of the HPV vaccine, white, and African/American (except disorder of trigeminal nerve).\u003c/p\u003e \u003cp\u003ePathophysiological mechanisms of Herpes papillomavirus infection on nerve disorders remain elusive. Previous research by Tibor F\u0026uuml;le et al\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e suggested that HPV-16 is likely present in neuronal cells in the vascular endothelium as HPV 16 E6 ORF sequences are found in neuronal cells and endothelial cells of oral and cervical cancers. Shi et al propose a molecular mimicry hypothesis in that HPV infection results in immune dysregulation to systemic lupus erythematosus. According to other studies on the Guillain-Barr\u0026eacute; syndrome\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, the molecular mimicry is one mechanisms of Guillain\u0026ndash;Barr\u0026eacute; syndrome related to post-virus infection. A variety of viruses, like Campylobacter jejuni, cytomegalovirus, Haemophilus influenzae, Mycoplasma pneumoniae, Epstein-Barr virus, hepatitis E virus, influenza A virus, Zika virus, and HPV B19 have been reported to trigger demyelinating neuropathy\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. On the other hand, Guo et al proposed that HPV virus may be latent in the central nerve system and become reactivated when the host is immunocompromised resulting in central or peripheral nerve neuropathy\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Despite scarce evidence in support of the association of human papillomavirus infection and cranial nerve disorders. Our results indicated that HPV vaccination could reduce HPV infection and lower risks of cranial nerve disorders.\u003c/p\u003e \u003cp\u003eRegarding the higher risks of smell and taste dysfunction after HPV vaccination, the underlying mechanism is unclear. It is widely believed that smell and taste disorders often develop in patients with allergic rhinitis\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. According to the study by Afrin et al, allergic reactions like nasal congestion and dysosmia after HPV vaccination could have triggered cytokine storm, especially involving mast cells or auto-antibodies that can act directly or indirectly on the vascular endothelium via the humoral immune system, in a condition related to the mast cell activation syndrome \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. This process may be used to explain the risk disparity between disturbances of smell and taste and other cranial nerve disorders.\u003c/p\u003e \u003cp\u003eOur study has several strengths. We used the TriNetX network, one of the largest databases, to conduct this first large retrospective cohort study to investigate for the first time, the association between HPV vaccination and various cranial nerve disorders during a relatively long-term follow-up period. Confounding biases including age, lifestyle habits, social economic status, medical utilization, and comorbidities were all eliminated using propensity score matching between the two cohorts. In addition, we performed subgroup analyses to determine possible effects of age, race, and vaccine valence on the results. Finally, sensitivity analysis was conducted using an influenza vaccination cohort verify the reliability of our HPV findings.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, the study design, which was based on data from the electronic health records, had inherent weak points. The definition of cranial nerve disorders was based on the ICD-10-CM codes reported by physicians. The information may be have been incorrect due to misdiagnosis, underdiagnosis, inaccurate coding and documentation errors. Second, the database had no record on HPV antibody titers in those vaccinated patients, therefore we could not perform a further evaluation of the relationship between the antibody titer and cranial nerve disorders. Third, the database was derived mainly from patients with medical records from HCOs in the United States, and the number of patients diagnosed with cranial disorder was relatively small. Therefore, the representation of our conclusions is limited. Forth, we did not include all 12 cranial nerve-related disorders in our study. Future research is needed to explore different ethnic groups or databases.\u003c/p\u003e \u003cp\u003eIn conclusion, our preliminary results had suggested that HPV vaccination was associated with lower risks of a variety of cranial nerve disorders, including hearing loss, disorders of vestibular function/other diseases of the inner ear, facial nerve disorders, and disorders of the trigeminal nerve, but higher risks of disturbances of smell and taste in female aged between 9 to 26 years old over a yearlong follow-up. In addition, results were prominent in subgroups aged from 9 to 17 years, white, African American, and in patients who had received the 9-value HPV vaccine. These findings were consistent across follow-up periods of different lengths, and again valid when compared with the influenza vaccination cohort. Future research is needed to further investigate the complete set of cranial nerve disorders and to explore the underlying pathophysiological mechanisms.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eData source\u003c/h2\u003e\n \u003cp\u003eWe obtained data from the TriNetX Analytics Network platform, which is a global federated health collaborative research network that has derived data from electronic medical records (EMR). The network provides data for ~\u0026thinsp;250 million patients across 120 global healthcare organizations (HCOs). These organizations have collected web-based, real-time, secure patient electronic medical records. Each medical record contains information on International Classification of Disease, 10th Revision (ICD-10) diagnostic codes, procedures (Current procedural Terminology (CPT) codes, medications, laboratory test results, genomic information, and demographic data such as geography, age, gender, race, income, and insurance group. In this study, we utilized the U.S. Collaborative Network, which is a subset of the TriNetX database. Our study period was from January 1, 2018, till December 31, 2022. For details of the TriNetX, please visit its website: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trinetx.com/\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eBecause we only used de-identified patient records and did not involve the collection, use, or transmission of personally identifiable data, our study was exempt from approval from our institutional review board. Our study also followed the Reporting guidelines of the Strengthened Reporting of Observational Studies in Epidemiology (STROBE). Our study was approved by the Institutional Review Board of Chung Shan Medical University Hospital, Taiwan (CSMUH No: CS2-21176).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Population\u003c/h2\u003e\n \u003cp\u003eThe study population included female patients aged from 9 to 26 years with at least two medical visits between January 1, 2018 and December 31 2022 as documented in the TriNetx Network. We excluded those diagnosed with oral cancers, HPV infection, or pregnancy. Based on EMR in the TriNetx Network, patients were divided into two groups: with HPV vaccination or without. The index date of the HPV vaccinated group was the date of completing vaccination (2-valent, 4-valent, or 9-valent), and the control group was the date of the first visit during the study period. We used the current procedural terminology (CPT) codes: 2-valent (90650), 4-valent (90649), and 9-valent (90651) to identify patients in the HPV-vaccinated group. TriNetx methodology in TriNetx is presented in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eOutcomes\u003c/h2\u003e\n \u003cp\u003eMain outcomes were the incidence of certain cranial nerve disorders defined according to ICD-10 codes, These disorders were as follows:\u003c/p\u003e\n \u003cp\u003e(1) Hearing losses (ICD10 code H91.2 or CPT code 69801, H90.3, H90.4, H90.5)\u003c/p\u003e\n \u003cp\u003eSudden idiopathic hearing loss (ICD10 code H91.2 or CPT code 69801)\u003c/p\u003e\n \u003cp\u003eSensorineural hearing loss, bilateral (ICD10 code H90.3)\u003c/p\u003e\n \u003cp\u003eSensorineural hearing loss, unilateral with unrestricted hearing (ICD10 code H90.4)\u003c/p\u003e\n \u003cp\u003eSensorineural hearing loss, unspecified (ICD10 code H90.5)\u003c/p\u003e\n \u003cp\u003e(2) Disturbances of smell and taste (ICD10 code R43)\u003c/p\u003e\n \u003cp\u003eAnosmia, Parosmia (ICD10 code R43.0, R43.1)\u003c/p\u003e\n \u003cp\u003eParageusia (ICD10 code R43.2)\u003c/p\u003e\n \u003cp\u003e(3) Facial nerve disorders (ICD10 code G51)\u003c/p\u003e\n \u003cp\u003e(4) Disorders of vestibular function (ICD10 code H81)\u003c/p\u003e\n \u003cp\u003eMeniere\u0026apos;s disease (ICD10 code H81.0)\u003c/p\u003e\n \u003cp\u003eBenign paroxysmal vertigo (ICD10 code H81.1)\u003c/p\u003e\n \u003cp\u003eVestibular neuronitis (ICD10 code H81.2)\u003c/p\u003e\n \u003cp\u003e(5) Other inner ear diseases (ICD10 code H83)\u003c/p\u003e\n \u003cp\u003eLabyrinthitis (ICD10 code H83.0)\u003c/p\u003e\n \u003cp\u003eLabyrinthine dysfunction (ICD10 code H83.2)\u003c/p\u003e\n \u003cp\u003eOther specified diseases of inner ear (ICD10 code H83.8)\u003c/p\u003e\n \u003cp\u003eDisease of inner ear, unspecified (ICD10 code H83.9)\u003c/p\u003e\n \u003cp\u003e(6) Disorders of trigeminal nerve (ICD10 code G50)\u003c/p\u003e\n \u003cp\u003eTo identify the time effect of vaccination, we also divided the risk of outcomes after HPV vaccination, in terms of 5 partially overlapping time periods after the index date follow-ups, namely: (a) 1 day to 1 month, (b) 1 day to 3 months, (c) 1 day to 6 months, (d) 1 day to 1 year and (e)1 day to 3 years.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eCovariates\u003c/h2\u003e\n \u003cp\u003eDemographic variables were the following: age, race, problems related to housing and economic circumstances (ICD 10 code Z59), and problems related to education and literacy (ICD 10 code Z55). Lifestyle variables included nicotine dependence (smoking) (ICD10 code F17, tobacco use (smoking) (ICD10 code Z72.0, alcohol related disorders (ICD10 code F10), and cannabis related disorders (ICD10 code F12). Medical utilization variables were office or other outpatient services, preventive medicine services, emergency department services, and hospitalization. These variables were identified by the International, Classification of Diseases (ICD) procedure codes (1013626, 1013829, 1013711, 1013659). Comorbidities included essential hypertension (ICD-10 code I10), ischemic heart diseases (ICD-10 code I20\u0026ndash;I25), cerebrovascular diseases (ICD-10 code I60\u0026ndash;I69), obesity (ICD-10 code E66), disorders of lipoprotein metabolism and other lipidemia (ICD-10 code E78.5), diabetes mellitus (ICD10 code E08-13), Other chronic obstructive pulmonary disease (ICD-10 code J44), asthma (ICD-10 code J45),chronic kidney diseases (ICD-10 code N18), liver diseases (ICD-10 code K70\u0026ndash;K77), sleep disorders (ICD-10 code G47), transient cerebral ischemic attacks and related syndromes (ICD10 code G45), vascular syndromes of brain in cerebrovascular diseases (ICD10 code G46), periodontitis(ICD10 code K05), depression (ICD10 code F32), anxiety, traumatic past experiences, stress (ICD10 code F40-F48), certain infectious and parasitic diseases (ICD10 code A00-B99), neoplasms (ICD10 code C00-D49), blood diseases and disorders involving immune mechanisms (ICD10 code D50-D89), injuries to the head(ICD10 code S00-S09), rheumatoid arthritis (ICD10 code M05, M06, M08), systemic lupus erythematosus (SLE) (ICD10 code M32), and Sjogren\u0026rsquo;s syndrome (ICD10 code M35.0)\u003c/p\u003e\n \u003cp\u003eTo detect the presence of comorbidities, we traced back for one-year preceding period preceding the index date. The variables of medication usage included gentamicin (Anatomical Therapeutic Chemical (ATC) code S01AA11), streptomycin (ATC code J01GA01), cisplatin (ATC code L01XA01), carboplatin (ATC code L01XA02), cyclophosphamide (ATC code L01AA01), ibuprofen (ATC code G02CC01), naproxen (ATC code G02CC02), salicylates (aspirin, ATC code B01AC06), and sulfonamides (ATC code C03CA). Pure tone audiometry was identified by Current Procedural Terminology (CPT) code 1012899.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analyses\u003c/h2\u003e\n \u003cp\u003eAll data analyses were performed on the TriNetX built-in platform and with the Advanced Analytics. Propensity score matching (PSM)was a 1:1 ratio, to balance all covariates between the two cohorts regarding demographics, lifestyles, medical utilization, comorbidities, and medication usage. The procedure was to reduce the impact of intervention selection bias. The balance of baseline characteristics in the propensity score-matched populations was evaluated based on standardized mean difference (SMD). With an absolute value of \u0026lt;\u0026thinsp;0.1, it was considered well-matched between the two cohorts. Kaplan\u0026ndash;Meier analysis and log-rank tests were used to evaluate the probability of the outcomes and the difference of the survival curves between the two cohorts. The adjusted hazard ratio (aHR) was calculated to evaluate the relative risks of different cranial nerve disorders based on the time-to-event analysis for both the HPV-vaccinated and control groups. We used Cox proportional hazards models to calculate the hazard ratio (HR) and the associated 95% confidence interval (95%CI). R\u0026apos;s Survival package v3.2\u0026ndash;3 was used to calculate HR, 95% CIs, and the test for proportionality. The two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. To evaluate the possible variables on the results after adjustment, we created 4 models for comparison.\u003c/p\u003e\n \u003cp\u003eSubgroup analyses were based on age (\u0026le;\u0026thinsp;9 to 17 years, and 18 to 26 years), race (white, African American and Asian), and different vaccine values (9v and 4v). We assessed differences in the risk of cranial nerve disorders across these subgroups during a year of follow-up following the index date. Finally, we also conducted a sensitivity test to compare the HPV vaccination and the influenza vaccination cohort with the same study design to verify the consistency of the results.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is available from the TriNetX global network. Requests for data can be sent as\u003c/p\u003e\n\u003cp\u003elogging on TriNetX platform (https://live.trinetx.com/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCODE AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is available from the TriNetX global network. Requests for data can be sent as\u003c/p\u003e\n\u003cp\u003elogging on TriNetX platform (https://live.trinetx.com/).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eW.-C.L. and S.-I.W. had full access to all of the data in the study and take responsibility\u003c/p\u003e\n\u003cp\u003efor the integrity of the data and the accuracy of the data analysis. Acquisition and\u003c/p\u003e\n\u003cp\u003eanalysis of data, statistical analysis: S.-I.W. Interpretation of data, concept and design,\u003c/p\u003e\n\u003cp\u003eand drafting of the manuscript: W.-C.L. Critical revision of the manuscript for important\u003c/p\u003e\n\u003cp\u003eintellectual content: J.C-C.W. R.-C. Supervision: J.C-C.W., R.-C. W.-C.L. and S.-I.W.is the co-first author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eChen, T. Y.-T.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Recent Human Papillomavirus Vaccination is Associated with a Lower Risk of COVID-19: A US Database Cohort Study. \u003cem\u003eDrugs\u003c/em\u003e, 1-12 (2023).\u003c/li\u003e\n \u003cli\u003eCheng, L., Wang, Y. \u0026amp; Du, J. Human papillomavirus vaccines: an updated review. \u003cem\u003eVaccines\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 391 (2020).\u003c/li\u003e\n \u003cli\u003eChen, M.-L., Kao, W.-M., Huang, J.-Y., Hung, Y.-M. \u0026amp; Wei, J. C.-C. Human papillomavirus infection associated with increased risk of new-onset psoriasis: a nationwide population-based cohort study. \u003cem\u003eInternational Journal of Epidemiology\u003c/em\u003e \u003cstrong\u003e49\u003c/strong\u003e, 786-797 (2020).\u003c/li\u003e\n \u003cli\u003ePhillips, A., Patel, C., Pillsbury, A., Brotherton, J. \u0026amp; Macartney, K. Safety of human papillomavirus vaccines: an updated review. \u003cem\u003eDrug safety\u003c/em\u003e \u003cstrong\u003e41\u003c/strong\u003e, 329-346 (2018).\u003c/li\u003e\n \u003cli\u003eYoon, D., Lee, J.-H., Lee, H. \u0026amp; Shin, J.-Y. Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study. \u003cem\u003eBmj\u003c/em\u003e \u003cstrong\u003e372\u003c/strong\u003e (2021).\u003c/li\u003e\n \u003cli\u003eMeites, E.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Vol. 19 3202-3206 (Wiley Online Library, 2019).\u003c/li\u003e\n \u003cli\u003eMehraeen, E.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Olfactory and gustatory dysfunctions due to the coronavirus disease (COVID-19): a review of current evidence. \u003cem\u003eEuropean Archives of Oto-Rhino-Laryngology\u003c/em\u003e \u003cstrong\u003e278\u003c/strong\u003e, 307-312 (2021).\u003c/li\u003e\n \u003cli\u003eKanjanaumporn, J., Aeumjaturapat, S., Snidvongs, K., Seresirikachorn, K. \u0026amp; Chusakul, S. Smell and taste dysfunction in patients with SARS-CoV-2 infection: A review of epidemiology, pathogenesis, prognosis, and treatment options. \u003cem\u003eAsian Pacific Journal of Allergy and Immunology\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, 69-77 (2020).\u003c/li\u003e\n \u003cli\u003ePapan, C.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Infectious causes of peripheral facial nerve palsy in children\u0026mdash;a retrospective cohort study with long-term follow-up. \u003cem\u003eEuropean Journal of Clinical Microbiology \u0026amp; Infectious Diseases\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, 2177-2184 (2019).\u003c/li\u003e\n \u003cli\u003eMartinez-Gomez, E., Perez-Carpena, P., Flook, M. \u0026amp; Lopez-Escamez, J. A. A systematic review on the Association of Acquired Human Cytomegalovirus Infection with hearing loss. \u003cem\u003eJournal of Clinical Medicine\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 4011 (2020).\u003c/li\u003e\n \u003cli\u003eShi, X., Liu, X. \u0026amp; Sun, Y. The Pathogenesis of Cytomegalovirus and Other Viruses Associated with Hearing Loss: Recent Updates. \u003cem\u003eViruses\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 1385 (2023).\u003c/li\u003e\n \u003cli\u003eYee, K. T., Neupane, B., Bai, F. \u0026amp; Vetter, D. E. Zika virus infection causes widespread damage to the inner ear. \u003cem\u003eHearing research\u003c/em\u003e \u003cstrong\u003e395\u003c/strong\u003e, 108000 (2020).\u003c/li\u003e\n \u003cli\u003eF\u0026uuml;le, T.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e The presence of human papillomavirus 16 in neural structures and vascular endothelial cells. \u003cem\u003eVirology\u003c/em\u003e \u003cstrong\u003e348\u003c/strong\u003e, 289-296, doi:10.1016/j.virol.2005.12.043 (2006).\u003c/li\u003e\n \u003cli\u003eShahrizaila, N., Lehmann, H. C. \u0026amp; Kuwabara, S. Guillain-Barr\u0026eacute; syndrome. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e397\u003c/strong\u003e, 1214-1228, doi:10.1016/s0140-6736(21)00517-1 (2021).\u003c/li\u003e\n \u003cli\u003eYuki, N. \u0026amp; Hartung, H. P. Guillain-Barr\u0026eacute; syndrome. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e366\u003c/strong\u003e, 2294-2304, doi:10.1056/NEJMra1114525 (2012).\u003c/li\u003e\n \u003cli\u003eLi, K. Y.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e The Potential Role of Human Papillomavirus Infection in Bell\u0026apos;s Palsy: A Hypothesis-Generating Study Based on a Nationwide Cohort. \u003cem\u003eFront Med (Lausanne)\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 616873, doi:10.3389/fmed.2021.616873 (2021).\u003c/li\u003e\n \u003cli\u003eGuo, J.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Human parvovirus B19 infection in hospitalized patients suspected of infection with pathogenic microorganism. \u003cem\u003eFront Cell Infect Microbiol\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 1083839, doi:10.3389/fcimb.2022.1083839 (2022).\u003c/li\u003e\n \u003cli\u003eGuilemany, J. M.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Persistent allergic rhinitis has a moderate impact on the sense of smell, depending on both nasal congestion and inflammation. \u003cem\u003eThe Laryngoscope\u003c/em\u003e \u003cstrong\u003e119\u003c/strong\u003e, 233-238 (2009).\u003c/li\u003e\n \u003cli\u003eHenkin, R. I., Levy, L. M. \u0026amp; Fordyce, A. Taste and smell function in chronic disease: a review of clinical and biochemical evaluations of taste and smell dysfunction in over 5000 patients at The Taste and Smell Clinic in Washington, DC. \u003cem\u003eAm J Otolaryngol\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 477-489, doi:10.1016/j.amjoto.2013.04.006 (2013).\u003c/li\u003e\n \u003cli\u003eAfrin, L. B., Dempsey, T. T. \u0026amp; Weinstock, L. B. Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease? \u003cem\u003eVaccines\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 127 (2022).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-vaccines","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjvaccines","sideBox":"Learn more about [npj Vaccines](http://www.nature.com/npjvaccines/)","snPcode":"41541","submissionUrl":"https://submission.springernature.com/new-submission/41541/3?","title":"npj Vaccines","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Human papillomavirus vaccine, Cranial nerve disorders, TriNetx, Cohort study","lastPublishedDoi":"10.21203/rs.3.rs-4923637/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4923637/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHuman papillomavirus (HPV) vaccines act against HPV infection and some cancers. Various cranial nerve disorders are known to occur after HPV viral infections. However, studies on the \u0026nbsp;relationship between human papillomavirus vaccination and cranial nerve disorders are limited. Here, we aimed to evaluate the association between human papillomavirus vaccination and risks of cranial nerve disorders in young girls.\u003c/p\u003e\n\u003cp\u003eWe enrolled 261,111 women aged between 9 and 26 years, and they had received HPV vaccination between January 2018 and December 2022. These subjects were compared with those controls who never received HPV vaccination using a propensity score-matched (1:1) based on the TriNetX U.S. Collaborative Network. Risks on incidences of various cranial nerve disorders were evaluated. Subgroup and sensitivity analyses were also performed.\u003c/p\u003e\n\u003cp\u003eThe HPV-vaccinated cohort, on one hand, had significantly lower risks on hearing loss (aHR:0.490, 95% CI:0.419-0.572), facial nerve disorders (aHR:0.690, 95% CI:0.522-0.912); disorders of vestibular function disorders (aHR:0.523, 95% CI:0.422-0.647); and similarly on other inner ear disorders (aHR:0.537, 95% CI:0.392-0.735) and trigeminal nerve disorders (aHR:0.328, 95% CI:0.200-0.538). On the other hand, the HPV-vaccinated cohort had significantly higher risks of odor and taste disorders (aHR: 3.136, 95% CI: 0 2.562-3.840). Kaplan-Meier curves of different cranial nerve disorders also revealed significant probability disparities between the two cohorts (Log–Rank test, p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eIn conclusion, for females between 9 and 26 years old, their HPV vaccination was associated with on one hand, lower risks of cranial nerve disorders, like hearing loss, vestibular function/other diseases of the inner ear, facial nerve disorders, and disorders of the trigeminal nerve, and on the other hand, higher risks on smell and taste disorders, as revealed over a year-long follow-up period.\u003c/p\u003e","manuscriptTitle":"Human papillomavirus vaccination poses different risks for various cranial nerve disorders - a retrospective cohort study using a real-world database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-23 08:24:06","doi":"10.21203/rs.3.rs-4923637/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Reject after peer review","date":"2025-02-05T09:25:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-01-01T16:35:51+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-12-30T18:25:28+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-10-11T09:49:58+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-09-25T19:24:58+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-09-25T18:47:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-09T19:11:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-22T11:04:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Vaccines","date":"2024-08-16T08:28:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-vaccines","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjvaccines","sideBox":"Learn more about [npj Vaccines](http://www.nature.com/npjvaccines/)","snPcode":"41541","submissionUrl":"https://submission.springernature.com/new-submission/41541/3?","title":"npj Vaccines","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2544684-8bbf-47e1-8e2f-b24e780052ac","owner":[],"postedDate":"September 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":37347620,"name":"Health sciences/Health care/Public health/Epidemiology"},{"id":37347621,"name":"Health sciences/Medical research/Epidemiology"}],"tags":[],"updatedAt":"2025-02-26T10:53:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-23 08:24:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4923637","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4923637","identity":"rs-4923637","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}