Although interleukin-2 (IL-2) has long been associated with cancer development, its roles in the development of cervical cancer remains unclear. Few studies examined the associations between IL-2 and high-risk human papillomavirus (HPV) with risk of cervical intraepithelial neoplasia (CIN).We aimed to assess the association of IL-2 and high-risk HPV infection with risk of CIN as well as their interactions on the risk of CIN.We performed a cross-sectional analysis of screening data in 2285 women aged 19-65 years who participated in an ongoing community-based cohort of 40,000 women in Shanxi, China in 2014-2015. Both categorical and spline analyses were used to evaluation the association between IL-2 in the local vaginal fluids and prevalence of CIN. In addition, 1503 controls were followed up until January 31, 2019), the nested case-control study design was adopted to evaluate the association of vaginal lavage IL-2 levels and the risk of CIN progression.After adjusting for potential confounders, IL-2 levels were statistically inversely associated with prevalence of CIN . Increased IL-2 levels were inversely associated with prevalence of CIN . The highest prevalence of CIN was observed in women with high-risk HPV, who also had the lowest IL-2 levels (P-interaction < 0.01). Nested case-control study observed an inverse association between IL-2 levels and risk of CIN progression .IL-2 levels in the local vaginal fluids were inversely associated with the risk of CIN in Chinese women either with or without high-risk HPV infection. HoweverCytokines are low-molecular-weight soluble proteins that act as a medium of the immune system. They are induced by immunogens or other factors that are stimulated by immune or other cells, and have various functions such as regulating the development and function of the body’s immune and non-immune systems. HPV infection in the body is mainly depend on the cellular immunity of CD4+ T helper cells (Th) and cytotoxic T cells (CTL) to eliminate the virus . After tVaginal microecology includes vaginal flora, endocrine regulation, local immunity, and anatomy. Local immunity may play an important role in maintaining microecological balance. As the cervix is located in the vagina, the vaginal micro-ecological imbalance can have a direct impact on the cervix. Local immunity may also have a more significant role in cervical lesions than systemic immunity. Moreover, as the cervix can be easily exposed; it can easily adjust local immunity and prevent disease progression. However, limited research has been conducted on the effects of local immunity on diseases; Therefore, measuring the cytokine IL-2 levels in the local vaginal fluids can be an effective way of assessing immune changes that accurately reflect the cervix’s environment. This approach may prove to be more sensitive and specific than the blood and other body fluids.To better understand the potential risk factors associated with CIN and to develop effective strategies for preventing its progression to cervical cancer, we launched a large population-based cervical cancer screening program and a prospective cohort study (Shanxi CIN Cohort) in Shanxi, China in 2014-2015 . In the 22.1This study was conducted based on the data obtained from the Shanxi CIN Cohort Study in 2014-2015. The rationale, design, and methods of the cohort have been detailed elsewhere. BrieflyAdditionally, 1503 women of the control group had followed up until January 3, 2019. Twenty-five women  with abnormal biopsy results were selected as the case group. The research carried out a follow-up on women with negative pathological examination results. During the follow-up period, patients who progressed to CIN I, CIN II or CIN III were the case group, and those who did not progress to the control group were matched at a ratio of 1:3. The matching condition included no disease progression occurred on the latest follow-up date of the case group, age ± 1 year old, and high-risk HPV infection. We finally matched to 25 cases and 75 controls. The study was approved by the ethical committees of the Second Hospital of Shanxi Medical University, and registered in the Chinese Clinical Trial Register (ChiCTR) (registration number: ChiCTR-ROC-15006479).2.22.2.1Face-to-face interviews were conducted by trained interviewers using a standardized and structured questionnaire. The interviewers were trained to administer the questionnaire in a standardized style. The survey mainly includes the demographic characteristics, such as age, educational years, smoking, alcohol drinking, and yearly income; characteristics of cervical lesion-related factors, such as parity, first sexual intercourse age, and family history of cancer.2.2.22.2.2.1All participants were instructed to abstain from sexual intercourse and not perform vaginal lavage or medications for 48 h prior to the sampling. After exposing the cervix, the cervical detachment cells were collected by rotating the cervical cell brush five times, and the sampler was rinsed 10 times with the preservation solution, and then tightened after capping. The samples were stored at 4°C and tested within 1 week. Dissatisfactory cervical cell specimens were re-acquired after reading the films, and satisfactory specimens were obtained from each participant.2.2.2.2The HPV test special brush was inserted into the cervical canal, and gently rotated for 3-5 turns; the brush head was left in the sample tube, and stored in −20°C refrigerator for inspection.2.2.2.3The vaginal lavage fluid was taken before the colposcopy biopsy. The speculum was opened, 5 ml of normal saline was taken using a disposable sterile syringe, 1/3 of the vagina and cervix was rinsed, and 5 ml of vaginal lavage was extracted, stored in a sterile centrifuge tube, and tested for the cytokine IL-2 levels. The collected vaginal lavage fluid was centrifuged for 10 min (2000 rpm), and the supernatant was dispensed and stored inside a refrigerator at −80°C until use.2.2.2.4Cervical tissue specimens were collected by a physician with colposcopy. The cervical mucus was gently wiped using a sterile cotton ball, and the suspicious part of cervix was taken using a colposcopy sterile biopsy forceps. The clamped tissue was immediately sent to the pathology department of our hospital for pathological diagnosis.2.2.32.2.3.1All Pap tests were performed using an LBC method. Two cytopathologists from the Second Hospital of Shanxi Medical University performed the cytologic evaluation according to Bethesda System 2001 terminology. All slides with abnormal cytological results were further reviewed by a senior cytopathologist blinded on the previous pathological results for quality control.2.2.3.2Colposcopy was performed by gynecological specialists at the Second Hospital of Shanxi Medical University according to a standard protocol, within 12 weeks from the Pap test. Video colposcopy was performed using the SLC-2000 device . During the colposcopy, the cervix was divided into quadrants, and each quadrant was examined. All visually abnormal areas were biopsied, and the quadrants without a visible lesion were biopsied at the squamocolumnar junction (“random biopsy”). Women with abnormal cytological results and negative or inadequate colposcopic findings also underwent endocervical curettage. Cervical biopsy and endocervical curettage results were evaluated by two gynecologic pathologists from the Second Hospital of Shanxi Medical University. The cases were classified as negative, CIN I, CIN II, CIN III, or squamous cell carcinoma. The pathologists were blinded to the Pap test results when they read the cervical biopsy or endocervical curettage tissue specimens. If the two pathologists had different diagnoses, the cases were reviewed by a third senior pathologist. The three pathologists reviewed difficult or equivocal cases together to reach a consensus diagnosis.2.2.3.3HPV genotyping by HybriMax was performed using an HPV GenoArray Test Kit (HybriBio Ltd) with the residual Pap test specimens. HPV types were divided into high-risk HPV types and others (including low-risk HPV types and negative) based on their oncogenic potential. This assay can identify 21 types of HPV, including 15 high-risk  and 6 low-risk  types through the use of a flow-through hybridization technique performed with a TC-96/G/H6 HPV DNA Amplification Analyzer and an HMM-2 fast nucleic acid molecule hybridization instrument (HybriBio Ltd).2.2.3.4IL-2 levels were measured using the enzyme-linked immunosorbent assay (ELISA) kits (Jinma company in Shanghai) according to the manufacturer’s instructions.2.3The EpiData 3.1 software was used to enter and manage the datasets. Descriptive statistics were used to describe the frequency, proportion, mean, median, and quartile and the characteristics of demographic and cervical lesion-related factors. Participants’ characteristics were examined for significant difference(s) using the Pearson’s chi-square test for categorical variables and t-test for continuous variables. Logistic regression models were used to test odds ratios (ORs) and confidence intervals (CIs) of CIN II/III for each IL-2 quartile compared with the highest quartile. Tests of linear trends across the increasing quartiles of IL-2 levels were conducted by assigning the medians of quartiles treated as continuous variables. Interaction between IL-2 levels and high-risk HPV infections with prevalence of CIN were evaluated by including the terms in the model. After the crude analysis, we adjusted for the demographic characteristics such as age, educational level, yearly income, smoking, alcohol drinking, parity, first sexual intercourse age, family history of cancer, and high-risk HPV infection fitted simultaneously. Smoking was defined as those who smoked at least 1 cigarette/day in the past 6 months. Alcohol drinking was defined as those who drank hard liquor, beer, or wine at least 1/week in the past 6 months.We further performed the spline analysis with a three-knot  restricted cubic spline function to deter3Among the 2285 women, 1563 were high-risk HPV negative, and 15 of them were low-risk HPV infected. The mean ± SD of IL-2 in 15 women with low-risk HPV infection was 181.64 ± 49.46pg/ml with the median was 178.55pg/ml. Among 722 women with high-risk HPV infections the mean ± SD of 194.58 ± 99.86pg/ml; 1548 negative cases, with a mean ± SD of 204.82 ± 108.21pg/ml and a median of 183.60 pg/ml. We did not observe he statistically significant difference between negative, low-risk HPV and high-risk HPV patients (P = 0.075). After adjusting for all potential confounders including high-risk HPV infections, we observed the inverse linear dose-response associations between IL-2 levels and prevalence of CIN , CIN I , and CIN II/III  Figure 1The highest prevalence of CIN was observed in women with high-risk HPV infections, who also had the lowest IL-2 levels  Figure 2In the nested case-control study, we compared IL-2 expression levels before and after follow-up. The mean ± SD of IL-2 level before follow-up in the progression group (n=25) was 205.4 ± 93.84 pg/ml, the median value was 202.0 pg/ml. The mean ± SD IL-2 level at end of follow-up was 142.0 ± 58.44 pg/ml (media= 137.0 pg/ml). The mean ± SD of IL-2 level before follow-up in the non-progressive population (n=75) was 207.1 ± 123.8 pg/ml (median = 177.0 pg/ml). The mean ± SD of IL-2 level at end of follow-up was 170.3 ± 42.11 pg/ml (median=172.0 pg/ml). After adjusting the potential confounders, those with local vaginal IL-2 ≤ 169.00pg/ml (median) had a 3.43 (1.17-10.03) times risk of progression to CIN than those with IL-2>169.00pg/ml Table 3.4In this large-scale population-based study, we found that IL-2 levels in the local vaginal were associated with higher prevalence of CIN, with a non-linear dose-response associations in Chinese women in the Shanxi CIN cohort. Women with high-risk HPV infections and the lowest IL-2 levels in the vaginal lavage fluid had the highest prevalence of CIN. These results indicate the potential role of IL-2 levels in vaginal lavage in the development of CIN, regardless of high-risk HPV infections.Passmore J A et al.  (registration number: ChiCTR-ROC-15006479). The patients/participants provided their written informed consent to participate in this study.RZ and WHW designed the analysis pipeline and wrote the manuscript. AY revised the manuscript critically. WZ, WW, ZLW, and JW performed atherosclerotic plaque collection and sorting. BF, JY, ZW, and XN created figures. MH reviewed and revised the paper in detail. All authors contributed to the article and approved the submitted version.


TM HPV assay (Sentis) , an isothermal amplification-based HPV assay, on self-collected and clinician-collected samples and the agreement of Sentis on self-collected samples with the BD OnclarityTM HPV assay (Onclarity) , a PCR-based HPV assay, on clinician-collected samples. This was a prospective study of 104 women attending the colposcopy clinic for abnormal smears. After informed consent, participants self-collected vaginal samples before having clinician-collected cervical samples. Self-collected samples underwent HPV testing with Sentis (Self-Sentis HPV) and clinician-collected samples were tested with Sentis (Clinician-Sentis HPV) and Onclarity (Clinician-Onclarity), which was used as a reference standard. The concordance was assessed using Cohen’s kappa. The prevalence of HPV and the acceptability of self-sampling were also evaluated. The concordance rate between Self-Sentis HPV and Clinician-Sentis HPV was 89.8% with a kappa of 0.769. The concordance rate between Self-Sentis HPV and Clinician-Onclarity was 84.4% with a kappa of 0.643. The prevalence of HPV was 26.0% on Clinician-Onclarity, 29.3% on Clinician-Sentis HPV, and 35.6% on Self-Sentis HPV. Overall, 65% of participants would undergo self-sampling again. This was attributed to mainly not feeling embarrassed (68%) and being convenient (58%). Our study showed a substantial agreement between Self-Sentis HPV with Clinician-Sentis HPV and Clinician-Onclarity. Self-sampling was also shown to be a generally well-accepted method of screening.This study aimed to evaluate the concordance of HPV results between the Sentis Cervical cancer ranks fourth amongst the most common female cancers in the world with around 604,000 women diagnosed with the disease and caused 342,000 deaths in 2020 . In HongThe World Health Organisation (WHO) has recently developed a global strategy for cervical cancer elimination to be achieved by 2030. One action of this strategy is to utilise a high-performance test in at least 70% of women with at least two screenings at 35 and 45 years of age . The advTM HPV assay (Sentis) is an isothermal amplification real-time fluorescent HPV detection assay. The test is based on assays that have been shown to have similar sensitivity to PCR-based HPV tests between self-sampled and clinician-sampled results for the detection of CIN2+  and Onclarity, which was used as a reference standard. The self-sampled specimens were processed with Sentis only. Of the three HPV tests performed, participants were only informed of their HPV results from the clinician-collected samples analysed using Onclarity. HPV results from Sentis were performed for research purposes and were not used for direct patient care.Any abnormal results were managed according to the Hong Kong College of Obstetricians and Gynaecologists (HKCOG) cervical cancer prevention and screening guidelines 2016) [16 [20]. Data were collected and analysed using Statistical Package for the Social Sciences version 26 . Women with incomplete data  were excluded from the analysis. The concordance rate of HPV between self-collected samples and clinician-collected samples was calculated by absolute agreement and Cohen’s kappa statistics, which was interpreted as no agreement (≤0), slight (0.01–0.20), fair (0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80) and almost perfect agreement (0.81–1.00).Sentis is an isothermal amplification real-time fluorescent HPV detection assay, developed by BGI Group, Shenzhen, China. The assay is based on the AmpFire HPV assay and was supplied by Atila Biosystems . Specific primers and probes are used to amplify regions of viral genomic DNA including E6/E7 regions. The assay detects 14 high-risk (hr) HPV subtypes . The self-sampling kits were provided by Sunrise Diagnostic Centre (SDC) Limited and Sentis was performed by BGI Health (HK) Company Limited in Hong Kong according to the manufacturer’s instructions. The accuracy and reproducibility of AmpFire HPV assay for primary cervical cancer screening have previously been validated .Onclarity  is a United States Food and Drug Administration (FDA) approved HPV assay and is used as the reference standard. It is a fully automated real-time PCR assay that detects 14 hrHPV subtypes. The test specifically identifies 6 hrHPV for types 16, 18, 31, 45, 51, and 52 while concurrently detecting 8 other hrHPV types . Along with the cytological and histological samples, Onclarity was performed by the Department of Pathology, at the University of Hong Kong according to standard protocols and the manufacturer’s instructions.A total of 104 eligible women were recruited between April and July 2022. The median age of participants was 45 years (range 30–64) and 81% were Chinese. Of these, 101 women had self-collected samples processed with Sentis (Self-Sentis HPV), 100 had clinician-collected samples processed for cytology and Onclarity (Clinician-Onclarity), and 99 had clinician-collected samples processed with Sentis (Clinician-Sentis HPV). Between 3–5 women in each group did not have their samples processed due to missing samples.The concordance of Self-Sentis HPV and Clinician-Sentis HPV samples was 89.8% with a positive agreement of 93.1%, a negative agreement of 88.4%, and a kappa of 0.769, indicating substantial agreement. The concordance of Self-Sentis HPV and Clinician-Onclarity samples was 84.4% with a positive agreement of 88.5%, a negative agreement of 82.9%, and a kappa of 0.643, also indicating substantial agreement. The concordance of Clinician-Sentis HPV and Clinician-Onclarity samples was 95.8% with a positive agreement of 96.1%, a negative agreement of 95.6%, and a kappa of 0.897, indicating almost perfect agreement .For the reference standard test using Onclarity on clinician-collected samples, the prevalence of hrHPV amongst our study population was 26.0%. For Clinician-Sentis HPV and Self-Sentis HPV samples, the prevalence of hrHPV was 29.3% and 35.6%, respectively .A total of 3 patients had a high-grade squamous intraepithelial lesion (HSIL) diagnosed on cervical biopsy, and all had positive hrHPV results on Self-Sentis HPV and Clinician-Sentis HPV. However, one out of the three patients did not have hrHPV detected on Clinician-Onclarity. For patients with a histological low-grade squamous intraepithelial lesion (LSIL) on cervical biopsy, 12 (63.2%), 8 (44.4%), and 6 (31.6%) patients had hrHPV detected on Self-Sentis HPV, Clinician-Sentis HPV, and Clinician-Onclarity, respectively. For patients who had normal histology on cervical biopsy, 6 (50.0%), 7 (63.6%), and 7 (58.3%) had hrHPV detected on Self-Sentis HPV, Clinician-Sentis HPV, and Clinician-Onclarity, respectively. Cytology results were available for 95 patients (5 had unsatisfactory results or the test was not completed) .There were 100 acceptability questionnaires received. Four patients did not return the questionnaires. Of the 100 respondents, 68% were not embarrassed or not embarrassed at all, 58% found it convenient or very convenient, and 46% found it an easy or very easy process. However, only 34% were confident or very confident about collecting the sample correctly, and 31% had an overall good or very good experience with self-sampling . FurtherTo justify the use of HPV self-sampling in a local screening program, it is important to show adequate accuracy of such screening methods before considering its application. It is also paramount to validate a specific HPV assay according to sample collection methods in order to obtain reliable and reproducible results . PCR-basThe AmpFire HPV assay developed by Atila Biosystems, USA, is an isothermal amplification assay designed to detect hrHPV. The use of the assay has shown promising data in providing similar accuracy in self-collected and clinician-collected samples when compared with PCR-based assays. Zhang et al. showed that the AmpFire HPV assay had similar sensitivity when compared to PCR-based assays in a large cohort . Desai eIn our study, the concordance rate between clinician-collected samples for Sentis and Onclarity was 95.8% with a kappa of 0.89, which is the same as that found by Zhang et al. More importantly for the purpose of our study, we found a substantial agreement between Self-Sentis HPV with Clinician-Sentis HPV (concordance of 89.8% and a kappa of 0.769) as well as with Clinician-Onclarity (concordance of 84.4% and a kappa of 0.643). To our knowledge, this is the first concordance study between self-collected and clinician-collected samples using an AmpFire-based assay for hrHPV detection. This substantial agreement provides preliminary support for the use of isothermal amplification techniques for HPV testing in cervical screening and has the potential to reach non-attenders by use of self-sampling.As we move away from the COVID-19 pandemic, the possibilities in terms of telemedicine have been broadened and accepted in many parts of the world. Self-sampling kits for rapid antigen testing and telemedicine consultations were commonplace, reducing the workload on healthcare professionals and allowing patients to be managed remotely . The dawThe prevalence of hrHPV in our study population ranged from 26 to 36%, depending on the method of sample collection and test performed. This number is much higher than that observed in other local studies, which ranged from 4.5% to 12.9% ,39. ThisTM HPV assay detected hrHPV associated with HSIL in all three patients whereas clinician-collected samples tested with Onclarity only detected hrHPV in two out of three patients. HPV 16 was detected in four patients, and the results were consistent regardless of the collection method or HPV assay used. Another patient had a double positive result with HPV 16 and another hrHPV type detected on Self-Sentis HPV, but not detected on Clinician-Sentis HPV or Clinician-Onclarity. According to our findings, it seems that the HPV result of both self- and clinician-collected samples analysed using Sentis is at least as accurate as the reference standard of clinician-collected samples tested with Onclarity. Furthermore, HPV testing on both self- and clinician-collected samples seems to be better in detecting CIN2+ than the traditional cytology as one of the three HSIL patients returned a negative cytology result. Although limited by the small number of patients, our findings are consistent with the available evidence supporting the use of HPV self-sampling using isothermal amplification techniques in cervical cancer screening [In the current study, three patients who underwent colposcopy and cervical biopsy had HSIL on histology. Both self- and clinician-collected samples tested with Sentiscreening .Our study found that the majority of patients (65%) would undergo self-sampling again. Women found it an easy and convenient method of cervical cancer screening which minimized embarrassment. However, the majority of participants who would not consider self-sampling again cited a lack of confidence in taking self-sampling accurately. Therefore, measures that may increase confidence in performing self-collection, such as the appropriate instructions and design of the collection kits, are important. Our participants were women who were already attending colposcopy services for abnormal cervical smears. These women are attenders and their attitudes to self-sampling may differ from those who have never been screened or are long-term non-attenders. Ngu et al. had previously shown that the acceptability of self-sampling in the local never- or under-screened population was similar in terms of previous smear experience, parity, and educational background. The uptake rate of self-sampling was up to 62% . Given tOne of the limitations of this study is its small sample size and short recruitment time. However, given the available data on isothermal amplification techniques for HPV testing, our data suggests a similar almost perfect agreement between clinician-collected samples for Sentis and PCR-based Onclarity. More significantly, we found a substantial agreement between Self-Sentis HPV and Clinician-Sentis as well as Self-Sentis HPV and Clinician-Onclarity. This study has provided preliminary evidence for the use of self-sampling using isothermal amplification techniques for HPV testing in our local population. Another limitation is that the participants were recruited from the colposcopy clinic rather than in the primary screening setting. Nonetheless, given that the aim of our study was to compare the concordance of HPV results between self- and clinician-collected samples with different HPV assays, we would require an adequate number of HPV-positive women to achieve this.Our study has shown a substantial agreement between self- and clinician-collected samples for HPV screening using isothermal amplification techniques, which has also been shown to be comparable to the reference standard. Self-sampling was also shown to be a generally well-accepted method of screening. In a population that is prone to socio-cultural barriers, it is important to provide an alternative to traditional clinician-led screening methods. This study has provided preliminary evidence to support self-sampling using self-sampling kits and isothermal amplification assays in the local cervical screening program.


N6-methyladenosine (m6A) methylation is the most prevalent mRNA modification in eukaryotes, and it is defined as the methylation of nitrogen atoms on the six adenine (A) bases of RNA in the presence of methyltransferases. Methyltransferase-like 3 (Mettl3), one of the components of m6A methyltransferase, plays a decisive catalytic role in m6A methylation. Recent studies have confirmed that m6A is associated with a wide spectrum of biological processes and it significantly affects disease progression and prognosis of patients with gynecologic tumors, in which the role of Mettl3 cannot be ignored. Mettl3 is involved in numerous pathophysiological functions, such as embryonic development, fat accumulation, and tumor progression. Moreover, Mettl3 may serve as a potential target for treating gynecologic malignancies, thus, it may benefit the patients and prolong survival. However, there is a need to further study the role and mechanism of Mettl3 in gynecologic malignancies. This paper reviews the recent progression on Mettl3 in gynecologic malignancies, hoping to provide a reference for further research. Gynecologic malignancies are major diseases that pose a threat to the health of women worldwide; and among them, cervical cancer (CC), ovarian cancer (OC), and endometrial cancer (EC) are the most common malignancies. In recent years, patients diagnosed with these diseases are more likely to be younger . SurgicaN6-methyladenosine (m6A) modification in RNA is defined as the methylation of nitrogen atoms on the six adenine (A) bases of RNA in the presence of methyltransferases . AlthougTherefore, Mettl3 may be a new target for treating gynecological malignancies. Conducting a comprehensive investigation into the specific mechanism of Mettl3 in gynecologic malignancies could provide substantial benefits to a diverse patient population by facilitating the development of effective diagnostic and therapeutic strategies. This article reviews the latest research progress of Mettl3 in gynecologic malignancies, as well as the detailed mechanisms behind, to offer insights into innovation in the diagnosis and treatment of gynecologic malignancies.Mettl3 comprises a zinc finger structural domain (ZFD) and a methyltransferase domain (MTD) construct containing 358–580 residues, both of which are essential for enzymatic activity  Wang et. The MTDPrevious investigations have shown that Mettl3 plays a critical role in promoting cancer development in diverse tissue types of cancer, such as affecting the development of gastrointestinal malignancies by affecting tumor proliferation, angiogenesis, apoptosis, and metastasis  Wang et. AnalogoCC has the fourth highest incidence and mortality rate among women, constituting a significant public health problem that endangers women’s health globally , Cohen . AccordiIn vitro, transcription is activated due to TATA-binding protein (TBP) binding to the Mettl3 promoter to the point at which Mettl3 expression levels are significantly increased , leading to cellular proliferation, migration, invasion, and tumor formation . BesidesIn summary, all current studies suggest that high expression of Mettl3 in OC causes adverse biological behaviors and promotes tumor development. Regrettably, despite the promising role of Mettl3 as a therapeutic target in OC, no treatments targeting Mettl3 have been developed to date. Further exploration of the underlying mechanisms of Mettl3 in OC is warranted, and there is a need for the active design and development of Mettl3 inhibitors to provide potential benefits for patients.EC, ranked among the three most prevalent gynecologic malignancies, was responsible for 41,700 newly diagnosed cases globally in 2020. Furthermore, its incidence has demonstrated a gradual increase over a 30-year period, with an overall rise of 132% . The curWhile there have been some studies investigating the role of Mettl3 in EC, the number of studies is relatively limited compared to other gynecological malignancies. This may be due to the status that endometrial cancer is less common than CC and OC, and the understanding of the molecular mechanisms underlying endometrial cancer is still incomplete. However, the studies conducted so far suggest that Mettl3 may play a key role in EC tumorigenesis and progression, and therefore further research is warranted. Liu et al. used immunohistochemical staining to compare tumor samples from patients with EC with adjacent tissues, and they found that Mettl3 expression was downregulated in tumor samples. Inhibited expression of Mettl3 was detected along with the loss-of-function mutation of Mettl14 and reduced m6A levels in EC tissues, and it was correlated with the proliferative effects of tumor cells . MechaniAlthough evidence suggests that dysregulated m6A methylation is involved in the development and progression of EC, the exact association between m6A methylation and EC remains unclear . InteresMettl3 affects various biological behaviors of tumor cells by regulating m6A methylation, such as cell proliferation, apoptosis, invasion, and metastasis . Additioin vitro, which is an exciting achievement in the field of Mettl3 research (Due to the broad involvement of m6A methylation in numerous stages of tumorigenesis, the regulatory proteins of m6A are increasingly being recognized as promising therapeutic targets . Accordiresearch . HoweverCancer is a daunting global health challenge, and its unique biological behaviors, such as infinite proliferation, immune escape, angiogenesis, and individual tumor microenvironment, have resulted in numerous difficulties in its diagnosis and treatment . M6A metAlthough this manuscript focuses on the role of Mettl3 in gynecologic malignancies, m6A methylation is a dynamically regulated process, and other regulatory proteins’ functions are equally important . NotablyIn summary, the m6A methylation process, regulated by a writer-eraser-reader complex, plays a significant role in gynecologic malignancies. Among the regulatory proteins, Mettl3, a writer, has been found to have multiple roles and extensively affects various biological behaviors of tumor cells. Its dysregulation has been associated with oncogenic transformation, metastasis, chemoresistance, and poor prognosis in gynecologic malignancies. However, current research on Mettl3’s role in tumors may only scratch the surface, and the development of drugs targeting Mettl3 is still in its infancy; there is a need to study its mechanism of action in depth and work on designing new treatments to provide more benefits to a great quantity of patients with gynecologic malignancies.


The control group (n = 120) received routine instructions, and the intervention group (n = 118), printed message cards about the quadrivalent HPV vaccine. A pre- and post-intervention knowledge, attitude and practice survey was applied to both groups. The McNemar test, to analyze knowledge, attitude and pre- and post-intervention practice, the chi-square test, to compare compliance in relation to knowledge and attitude, and a logistic regression model, to assess vaccine compliance, were carried out. A significance level of 5% was adopted.pre-intervention, knowledge was inadequate and attitude was adequate in both groups. Post-intervention, adequate knowledge and practices became greater in the intervention group. Adequate post-intervention knowledge and attitude, in addition to being 12 years of age or older, increase the chance for vaccination, explaining 70% of the practice.the educational intervention was effective for adolescents’ knowledge and compliance with the quadrivalent HPV vaccine. UTN: U1111-1254-5546; ReBEC: RBR-107hzdqt. The oncogenic subtypes that are most commonly associated with cervical cancer (CC) are subtypes 16 and 18.Human papillomavirus (HPV) is a sexually transmitted infection (STI) caused by a DNA virus in which its persistent cervical infection increases the risk of acquiring cancer and its precursor lesions. Globally, the highest prevalence of HPV is observed at young ages, peaking in women under 25 years of age, decreasing at older ages.HPV vaccination represents an effective strategy for primary CC prevention, given its high efficacy against precancerous cervical lesions. Although the vaccine has been available in the Brazilian National Immunization Program  since 2014, it is difficult to maintain the expected vaccine coverage, especially for the second dose, weakening actions to combat cancer.In the European context, Infection rates and HPV incidence have dropped considerably since the vaccination license in 2006, which makes it possible to control the occurrence of cervical neoplasm.Currently, the vaccine is administered in two doses, with an interval of 180 days between the first and second dose, in girls aged between nine and 14 years and in boys between 11 and 14 years old.A study that estimated the HPV 6, 11, 16, 18 (Recombinant) vaccine coverage in Brazil in adolescent girls in the year 2017 found that the first dose had high coverage in most cases, with the exception of the Federal District and Amazonas. However, for the second dose, the opposite was observed, with low vaccination coverage in all states.It appears that the main reasons for refusal occur due to lack of information, followed by psychogenic reaction, which is the set of symptoms that develop in response to stress associated with vaccination, such as fear of injection and adverse events, in addition to of finding that the vaccine was not effective.Thus, the use of attractive educational technologies that arouse curiosity about the subject and that are practical and easy to read is a form of learning support to enhance appropriate health practices aimed at vaccinating adolescents against HPVIt is noteworthy that the strategy based on printed message cards provides advantages, as it is an easily replicable, simple-to-use and low-cost technology compared to other types of technologies, being a palpable alternative for application, in addition to presenting adapted design and language, according to the target audience, with short and objective texts..An American study used printed cards as an educational intervention to reduce the risk of STIs, concluding a decrease in risk behaviors (p < 0.001). Therefore, the data support the feasibility of providing a risk reduction intervention focused on card education, indicating that exposure to information on the subject may be associated with the acquisition of healthier practicesIn this context, an educational health intervention through printed message cards, aimed at schoolchildren about HPV vaccination, can be a strategy for the development or reinforcement of capacities, in order to promote compliance with vaccination and continuity of the vaccination schedule, in addition to collaborating with care actions in Primary Health Care, focusing on adolescent health promotion and neoplasm prevention. The relevance of educational intervention as a health-promoting resource is highlighted, as it favors the action of adolescents as active agents of care. The relationship between health professionals and the target population, mediated by the message cards, enables knowledge promotion and attitudes towards healthy behaviors and adolescent health care.Sai fora, HPV), through printed message cards to increase the knowledge, attitude and compliance of school adolescents with HPV vaccination.In view of this, the objective is to assess the effects of “Piss off, HPV!” , with the purpose of promoting knowledge about HPV and its vaccine for adolescents and parents and/or guardians, in order to sensitize them about the importance and practice of immunization through playful activities.It is noteworthy that the intervention named “Piss off, HPV” is part of an educational project linked to the Research Group on Sexual and Reproductive Health at the This is an experimental study and a randomized clinical trial. There was a comparison between two groups: one with an educational intervention (IG), consisting of “Piss off, HPV!”, and educational project, with delivery of printed message cards about compliance with HPV vaccination for two consecutive months; and one with standard intervention, called control (CG), with only usual care, routine guidelines during nursing consultations at the health unit or guidelines passed on by the adolescent’s educational institution for the same period.To ensure scientific rigor, the Consolidated Standards of Reporting Trials (CONSORT) guideline for non-pharmacological interventions was adopted as a methodological framework.The study took place in six elementary schools in two municipalities in the state of Ceará, northeastern Brazil, from August 2019 to January 2020. The study population consisted of female adolescents regularly enrolled in schools, which is justified due to the recent inclusion of male adolescents for HPV vaccination, in 2017.To calculate the sample, we used the formula for studies with comparative groups. With the HPV vaccination rate as the outcome variable, the following values were adopted: Zα = 95%, Zβ = 80%, p = 59.1%, d = 20%, with 95 participants per group. Adding a margin of 10% for possible losses, there were at least 105 adolescents in each group. We included adolescent school girls aged 9 to 14 years who had received the quadrivalent HPV vaccine, attested by the vaccination card. We excluded adolescents with physical conditions that compromised school attendance, making it impossible to respond directly to the data collection instrument.Recruitment took place through visits to schools, and the vaccine card was requested, through the coordination, to verify the number of doses taken of the HPV vaccine. Subsequently, a communication was sent to parents and/or guardians, in order to explain the purpose of the research and request authorization to participate.We opted for randomization of the sample by clusters. The municipalities were divided into conglomerates with their school. The random allocation of clusters was defined by the simple random allocation process.On that occasion, a lottery was used with numbered papers, sequentially, in recipients among the conglomerates, and then a random allocation was carried out to choose the schools. Thus, cluster A, municipality 2, was part of the IG, and cluster B, municipality 1, of the CG. It is worth noting that the schools were randomly selected to compose the Ig and the CG within the respective conglomerate. Moreover, adolescents were blind about the group they participated.. It is subdivided into seven sessions: 1. Personal data; 2. Sociodemographic, economic and cultural aspects; 3. Habits and health care; 4. Sexual and reproductive aspects; 5. Knowledge on HPV and its vaccination; 6. Attitude towards quadrivalent HPV vaccine; 7. Practice on quadrivalent HPV vaccine (exclusively completed by the researcher).The Knowledge, Attitude and Practice (KAP) survey used in the study was validated and pre-testedIts measurement took place as follows: a) Adequate knowledge: if participants have already heard about HPV and are able to inform at least one of these response alternatives about HPV: “It is a STI”, “Causes cervical/penis cancer/can turn into cancer”, or “Causes warts/disease/infection”; b) Inadequate knowledge: if participants had never heard about HPV or if they had heard about it, but could not say any of the information mentioned above about HPV; c) Appropriate attitude: if an adolescent mentions that she intends to be vaccinated; d) Inappropriate attitude: if an adolescent mentions that she does not intend to be vaccinated; e) Appropriate practice: if an adolescent receives the dose of the vaccine; f) Inappropriate practice: if an adolescent does not receive the vaccine dose.The pre-test data collection took place in August and September 2019. Standard and educational interventions took place in October and November 2019. Finally, the post-test was collected in December 2019 and January 2020.First, CG adolescents were individually invited in the classroom to go to a private place at the school and respond to the pre-test of the KAP survey. After two months of standard intervention, these adolescents answered the post-test of the KAP survey via telephone, being asked again for information on the vaccination card about the doses of quadrivalent HPV vaccine to assess the outcome. Adolescents with whom there was no possibility of telephone contact or who did not respond to the requested instruments were discontinued from the study.In the IG, the summoning of adolescents and the KAP survey pre-test application were carried out in the same way as in the CG. However, shortly after that moment, adolescents received the welcome message card. During the following two months, the educational intervention “Piss off, HPV!” was offered, in addition to the standard intervention.Message card delivery was carried out by school professionals, collaborators who were blind as to the insertion group, to each adolescent, personally, in the classroom, twice a week, from Monday to Friday, on non-fixed days, in shifts. morning and afternoon, referring to the school’s opening hours, totaling 16 cards. At the end of this period, they received an acknowledgment message card for participating in the educational project.The outcome considered was compliance with the quadrivalent HPV vaccine by adolescents, i.e., the administration of a vaccine dose proven in the vaccination card. The outcome assessment took place later with vaccination card checking at the time of carrying out the KAP survey post-test in person at school. Not responding to the KAP survey again or not taking the post-intervention vaccination card were considered study discontinuation criteria.Descriptive analysis was performed according to the frequency distribution of respondents’ responses. We performed the chi-square test to check homogeneity and compare the responses of individuals from the CG and IG, in order to find or not significant differences, in addition to comparing compliance with the quadrivalent HPV vaccine in relation to knowledge and attitude. The McNemar Test was used to analyze whether there was any change in the assessment of knowledge, attitude and practice before and after the intervention, in order to observe its effectiveness.The practice assessment variable was used as the dependent variable, in which a regression model was used to analyze it. The statistical model used was the multiple logistic regression. The Hosmer and Lemeshow test was also carried out, for the adequacy of the model, and the stepwise variable selection method, to arrive at the final model.The statistical significance level was set at 5% p < 0.05. The Statistical Package for the Social Sciences (SPSS), version 24.0, and software R were used for statistical data analysis.. It is registered at the International Clinical Trials Registry Platform, under Universal Trial U1111-1254-5546 and Brazilian Clinical Trials Registry RBR-107hzdqt.The study was approved by the UFC Research Ethics Committee, under Opinion 2,645,679/2018, according to Resolution 466/2012 of the Brazilian National Health CouncilThe comparison of sociodemographic data and adolescents’ life habits found homogeneity, in general, between the groups (p < 0.05). With regard to age, the CG had a higher proportion of girls under 12 years of age (65.8%) than the IG (40.7%). Regarding race, the IG had a higher proportion of girls who considered themselves non-white (89%) than the CG (72.5%). As for religion, 47.5% of the CG considered themselves Catholic and 43.2% of the IG reported being Evangelical.It is noteworthy that most participants in both groups had an income of up to US$363.63 , did not use cigarettes , alcohol  and illicit substances , used the public health service  and almost all adolescents  had not started their sexual life.Of those who had started , the majority were over 12 years old  and did not manage . Of these, only one of the CG had become pregnant (25%), but spontaneously miscarried. None of them reported having an STI (100% in both groups), however 50% of the IG did not use any contraceptive method and 75% of the CG used condoms as the main method. Moreover, 75% of the CG and 50% of the IG did not perform gynecological prevention.The questions assessed about knowledge  were positively influenced post-intervention.Regarding the post-intervention attitude, there was no significant difference when compared to the pre-test (p = 0.087). However, in the specific questions about thoughts about vaccines in general and whether they would take the HPV vaccine, there was an influence after the educational project implementation, becoming more effective in the IG (p < 0.005).However, a relevant fact to be highlighted is that the CG showed a higher percentage of inadequate knowledge and attitude after the intervention, when compared to the IG.Regarding the practice, it is highly associated with the groups, verifying that IG presented a frequency of practice assessed as adequate higher than the CG (p = 0.000), inferring that the intervention was significant.Also related to compliance with the quadrivalent HPV vaccine, Adequate knowledge (p = 0.004) and attitude (p = 0.010) after intervention were also significant for the model, indicating that adolescents with adequate knowledge are 2.5 times more likely to comply with the quadrivalent HPV vaccine than those with inadequate knowledge (OR = 2.516) as well as adolescents with an adequate post-intervention attitude are 5.5 times more likely to be vaccinated (OR = 5.510).After the intervention, it was observed that adequate knowledge was greater in the IG, especially regarding hearing about HPV and its vaccine and what HPV is. The difference between the groups’ knowledge at the beginning of the research is also noteworthy, being lower in the IG, i.e., adolescents had less knowledge, and the result after the intervention could have been influenced by the higher percentage of inadequate initial knowledge. However, even with less initial knowledge, at the end of the intervention, they had adequate knowledge and much better than the CG, which reinforces the effectiveness of the intervention in terms of knowledge..Corroborating with the present study, when asked about what HPV was in an experimental research with educational intervention, also carried out in Brazil, Rio Grande do Sul, the level of knowledge of school adolescents was also higher in the IG, showing a significant increase of 23.5% when compared to the CG (p < 0.000). Another study, carried with Korean-American women, who also used written language as an educational strategy, showed significant differences in knowledge about HPV and post-intervention HPV vaccination.Internationally, a study with an educational session on HPV in Bamako, Mali, found that knowledge about the virus was very incipient and that only 3.4% of adolescents knew that HPV is an STI, and 7% of participants correctly stated that HPV is one of the main causes of CC before the educational session. Thus, participants’ knowledge increased significantly after the intervention, about 30%.Differing from what was found in the present study, a research carried out in southeastern Brazil, with the aim of assessing an educational intervention on knowledge and attitude of adolescents about the vaccine, did not identify a statistically significant difference in terms of adequate knowledge. In the assessment of previous knowledge about HPV and its vaccine, it was observed that 8.5% of women knew about the topic, and, in the comparison of this item, there were also no differences (p > 0.05)It appears that, in the studies described, knowledge may vary according to the population’s region and personal characteristics, such as age and education, as well as the context in which they are being assessed, i.e., public or private school, health unit, among others, and the moment, if it occurred soon after the intervention or weeks later.When talking about attitude, it is observed, in the current research, that it was adequate in both pre- and post- intervention groups. However, thoughts about vaccines in general and whether to take the quadrivalent HPV vaccine were positively influenced after the intervention in the IG, resulting in an increase in the percentage of adequate attitude.. This vaccination-related attitude was also high among study participants in Mali; however, after the educational session, there was an increase in vaccine acceptance, especially among adolescents (from 75.3% to 91.8%).A study carried out in Malaysia showed that the number of schoolchildren who intended to be vaccinated against HPV was quite high (86.6%), and this desire to be vaccinated was significantly associated with knowledge about CC (p = 0.042).The intervention through text message also presented significant increase statistical, intending that study participants receive the HPV vaccine (p < 0.001), with the percentage of participants who indicated an intention to receive the HPV vaccine within a one-year period increased from 63.3% to 96.7% (p = 0.009).In the comparative analysis regarding the attitude towards the quadrivalent HPV vaccine in a Brazilian experimental study, the group submitted to the educational action showed the correct attitude in 37% of interviewees, against 23% of those who had not received intervention through the preliminary educational action (p = 0.044), in line with data evidenced in this research.Research carried out with Italian pre-adolescents to assess knowledge, practices and attitudes regarding HPV infection and vaccination, showed that there is an overall positive attitude towards the importance of getting the vaccine and the severity of HPV-related illnesses even before educational sessions, demonstrating how this public is open to new knowledge about the HPV vaccine and should be a constant target of health education in different contexts, such as family, school and health.It can also be seen that, according to the results presented in the present study, even adolescents who do not have adequate knowledge are willing to learn, as they seem to consider the subject as something important. Attitude is to interpret events according to certain predispositions. It is a trend, characterized as an intermediate variable between the situation and the response to that situationIt is observed that educational interventions are capable of improving participants’ attitude towards HPV vaccination. However, it is important to emphasize that, from the beginning, there is already positive adolescents’ attitude towards the vaccine. This attitude, however, is not associated with adequate knowledge. Thus, it is believed that adequate information promotion, through effective educational strategies, significantly contributes to the acquisition of knowledge necessary for vaccine compliance..In an Italian study, which assessed the possible association between the characteristics of young adults and the scores of knowledge and attitude, the variables significantly related to the highest scores were attending a health university, using social networks for up to two hours a day, history of STIs and HPV-related lesions, having heard about HPV prior to the survey, and reporting good economic status.Furthermore, family members and the mass media as a source of information about HPV are significantly related to worse knowledge scores. On the other hand, professionals specialized in the gynecological area are reported as a source of information, with significantly higher knowledge scores. Although there are non-modifiable factors, such as age, in the process of compliance with HPV vaccination, studies reinforce how fundamental the implementation of school and home education is, ensuring that effective information about the vaccine is shared among students and between adolescents and their families.Regarding the source of information about the quadrivalent HPV vaccine, individuals who reported teachers, information material and health professionals had significantly higher attitude scores. Thus, it is understood that there must be investment in the dissemination of clear, objective and attractive information to the adolescent public, in order to promote effective communication aimed at promoting health.In addition, social networks can be allies in promoting sexual and reproductive health, as they reach a wide audience, including adolescents. Faced with the reality of using the virtual environment as a means of searching for information and communicating among peers, social networks need to be considered as a strategic environment for promoting adolescent healthHowever, a finding evidenced in the present research is worrying, because the inadequate knowledge of the CG, which received standard guidelines from the school/health service, increased in the post-test, as well as the inadequate attitude, despite adolescents’ attitude have been generally adequate.. However, such data raises doubts about the quality and the way in which these guidelines are being passed on in the current scenario.It is a fact that when adolescents are oriented at school by health professionals and teachers about HPV and the importance of vaccination, their knowledge, attitude and practice, they tend to become more effective.According to a review, which aimed to describe the factors related to receptivity to the quadrivalent HPV vaccine, knowledge can act as a barrier or facilitator of this receptivity. Fear and increased refusal may be motivated by distorted information or insufficient secure data. In contrast, knowledge derived from science can be applied to educate individuals and increase receptivity. Another context, which generates permanent negative repercussions that are difficult to reverse, causing difficulty in receptivity to vaccines, is the dissemination of data without scientific evidence by social networks or by groups against vaccination.The school is a strategic place of orientation in health. It is also worth mentioning its fundamental role in promoting the sexual education of young people, as the school environment can be a place of relevant transformations in adolescents’ lives and health The integration between schools and health services needs to be implemented in order to address the health needs of students, generating empowerment of information and autonomy in their attitudes and practices for safe sexual initiation and STI prevention. However, for this to become effective, it requires understanding the family and its culture, since this understanding is considered a determining factor for health problems and the health education processWith regard to practice, the current survey results revealed that the educational intervention was significant for compliance with the quadrivalent HPV vaccine in the IG. The use of message cards as a means of sharing information resulted in the acquisition of adequate knowledge, and such knowledge, associated with the adequate attitude already presented by adolescents and strengthened by the intervention, seems to have influenced the decision in favor of the vaccine..In a randomized study aimed at parents and adolescents aged 11 to 17 years, with the aim of encouraging HPV vaccination through a digital video, it was found that, between the intervention and control clinics, adolescents who participated in the intervention were almost twice as likely to receive a vaccine dose .Another study that tested the feasibility and effectiveness of a seven-day text message intervention to increase knowledge, attitude, and practice of HPV vaccination in 30 Korean-American women concluded that 16.7% of them reported having received the first HPV vaccine dose one week after completing the intervention program. Others, 13.3%, reported receiving the first dose of vaccine at the three-month follow-up visit, indicating that 30% of participants received the HPV vaccine after intervention.A Swedish study that aimed to promote HPV vaccination among students, in addition to increasing the use of condoms, found that face-to-face educational intervention in schools increased the likelihood that students would actually be vaccinated. The proportion of girls vaccinated in the IG was 52.5% before and 59% after the intervention, while no difference over three months was observed in the CG (60.9%) (p = 0.02)In line with the data found in this research, scientific studies bring the association between HPV vaccination and educational intervention. When there is something that reinforces information, motivates participants and stimulates memory, the trend is for action, and this is the role of educational intervention, to empower individuals on the subject for positive decision-making..A review carried out with the aim of investigating educational technologies constructed and/or used to promote HPV vaccination identified printed materials, such as flyers, messages from electronic devices, internet pages, computer programs, videos and radio soap operas. The development of these materials gave rise to creative, reliable and useful tools for health education, showing a positive impact on knowledge and compliance from their application with the target audienceRegardless of the type of educational technology used during an intervention, it is essential that this practice is encouraged in health education processes, in a participatory way, and that the target audience is an active agent in the promotion of their health, such as the intervention analyzed in the present study..It is important to emphasize the school’s educational role, together with these health professionals, since vaccination practice is linked to this environment, confirmed in an Italian study, which investigated factors associated with the refusal of HPV vaccination in 141 young women. In this investigation, it was observed that one of the factors associated with not receiving the vaccine were lower participation in school seminars on HPV  and lower perception of the benefits of vaccination Undoubtedly, educational health technologies can be promising tools to promote health, given the satisfaction and increase in individuals’ knowledge, attitude and practice. Educational interventions using message cards as technology help in compliance with HPV vaccination, reducing the burden of CC and other types of associated neoplasms for younger populations, as it is simple, attractive and easy to read.Despite being carried out with methodological rigor and showing valid results, the study had as main limitations: establishing effective communication via telephone with adolescents, but with the aim of mitigating losses; reinforce communication between school, parents and researchers for continuity of the research, in addition to other options for telephone contacts; punctually delivering the message cards in a relatively short period of time between the intervention and the post-test with vaccination card double-checking; and suggesting the development of further research to follow participants for a longer period of time, in order to assess the continuity of the educational intervention’s confirmed effectiveness.As it is a low-cost technology that is simple to apply, it can be incorporated into the care process in different environments, such as schools, in periods that precede the vaccination campaign and health institutions in consultations and actions, as well as by Community Health Workers at home, being an important tool for building knowledge, not only of adolescents, but also of the family.In nursing care, it can be a useful tool for the development of educational actions about HPV vaccination and to improve care at the primary level with regard to the prevention of pathologies associated with the virus.It is concluded that the educational project “Piss off, HPV”, using message cards, was effective for adolescents’ knowledge and compliance with the quadrivalent HPV vaccine. The variables age, knowledge and attitude explain approximately 70% of the practice. Adequate post-intervention knowledge and attitude, in addition to age greater than or equal to 12 years, increase the chance of compliance with the quadrivalent HPV vaccine.Given the positive effects of educational intervention, it can be incorporated into the care process in different environments, as it is low-cost and simple to apply, such as in schools, especially in the periods before the vaccination campaign, such as in health institutions, by the team responsible for consultations and actions, as well as in households, being an important tool for building knowledge, not only for adolescents, but also for the family.


The Heart Rhythm Society strongly recommends remote monitoring (RM) of cardiovascular implantable electronic devices (CIEDs) because of the clinical outcome benefits to patients. However, many patients do not adhere to RM and, thus, do not achieve these benefits. There has been limited study of patient-level barriers and facilitators to RM adherence; understanding patient perspectives is essential to developing solutions to improve adherence.We sought to identify barriers and facilitators associated with adherence to RM among veterans with CIEDs followed by the Veterans Health Administration.We interviewed 40 veterans with CIEDs regarding their experiences with RM. Veterans were stratified into 3 groups based on their adherence to scheduled RM transmissions over the past 2 years: 6 fully adherent (≥95%), 25 partially adherent (≥65% but <95%), and 9 nonadherent (<65%). As the focus was to understand challenges with RM adherence, partially adherent and nonadherent veterans were preferentially weighted for selection. Veterans were mailed a letter stating they would be called to understand their experiences and perspectives of RM and possible barriers, and then contacted beginning 1 week after the letter was mailed. Interviews were structured  and focused on 4 predetermined domains: knowledge of RM, satisfaction with RM, reasons for nonadherence, and preferences for health care engagement.Of the 44 veterans contacted, 40 (91%) agreed to participate. The mean veteran age was 75.3 (SD 7.6) years, and 98% (39/40) were men. Veterans had been implanted with their current CIED for an average of 4.4 (SD 2.8) years. A total of 58% (23/40) of veterans recalled a discussion of home monitoring, and 45% (18/40) reported a good understanding of RM; however, when asked to describe RM, their understanding was sometimes incomplete or not correct. Among the 31 fully or partially adherent veterans, nearly all were satisfied with RM. Approximately one-third recalled ever being told the results of a remote transmission. Among partially or nonadherent veterans, only one-fourth reported being contacted by a Department of Veterans Affairs health care professional regarding not having sent a remote transmission; among those who had troubleshooted to ensure they could send remote transmissions, they often relied on the CIED manufacturer for help . Most nonadherent veterans felt more comfortable engaging in RM if they received more information or education. Most veterans were interested in being notified of a successful remote transmission and learning the results of their remote transmissions.Veterans with CIEDs often had limited knowledge about RM and did not recall being contacted about nonadherence. When they were contacted and troubleshooted, the experience was positive. These findings provide opportunities to optimize strategies for educating and engaging patients in RM. Cardiovascular implantable electronic devices (CIEDs: pacemakers and implantable cardioverter-defibrillators [ICDs]) are life-saving devices that provide heart rhythm therapy for patients at risk or with malignant brady- or tachyarrhythmias. CIEDs also generate important diagnostic information, which can be transmitted to clinicians through remote monitoring (RM). RM is strongly recommended by the Heart Rhythm Society  and is the standard of care for all patients with CIEDs . This isUnfortunately, adherence to RM is suboptimal. Within the Department of Veterans Affairs (VA), the largest US health system performing RM, caring for more than 60,000 veterans with CIEDs who are monitored centrally by the Veterans Affairs National Cardiac Device Surveillance Program (VANCDSP), fewer than one-third of veterans had complete adherence to scheduled transmissions over a 2-year period . For patTo improve RM adherence among patients with CIEDs, we must first understand the reasons for nonadherence. Although previous research has quantitatively examined RM adherence, data about patient perspectives are limited to a single focus group study of 9 patients from 1 county in the Midwestern US . To bettUsing the VANCDSP database of all veterans with CIEDs who had agreed to participate in RM as of October 23, 2020, we created this study’s sample. Veteran contact information was identified through the Veterans Affairs Corporate Data Warehouse. According to best practices for qualitative methods, our goal was to select a representative sample of veterans to understand their perspectives about barriers and facilitators associated with RM, and we continued this study until we reached saturation of information to ensure adequate data .Veterans were stratified into 3 groups based on their adherence to RM transmissions over the past 2 years: fully adherent (≥95%), partially adherent (≥65% but <95%), and nonadherent (<65%). Each time that a veteran sent an RM transmission, the veteran was considered adherent for the past number of days equivalent to their transmission interval, plus an additional 10 days in order to provide a buffer for any brief delays in transmission . Thus, aAmong the entire population of veterans who had agreed to participate in RM, we randomly selected veterans from each of the 3 groups  in a 2:6:3 ratio, respectively, through purposive sampling . First, The structured interview guide was developed to learn about veteran experiences with care for CIEDs. In developing the interview guide, we sought input from clinicians with expertise in RM and researchers with expertise in qualitative methods. The structured interview guide used a fixed order and number of questions with predetermined categorical answer choices. A few questions allowed for open-ended responses to dive deeper into themes. The interview guide was pretested on 3 randomly selected veterans to determine acceptability, improve clarity, and fine-tune length.Veteran interviews covered 4 predetermined domains: knowledge, satisfaction, reasons for nonadherence, and preferences for health care engagement. The first domain asked all veterans about their understanding of RM and its benefits. The second domain asked veterans who were fully or partially adherent about their perspectives, satisfaction, and adherence to RM. The third domain was limited to veterans who were partially or nonadherent to RM; these questions asked about reasons for nonadherence, contact with the health care system or CIED manufacturer, and reminders about missed transmissions. The final CIED-related domain asked questions about preferences for engagement around home monitoring, including stopping in-person clinic visits, confirmation of transmission success, and learning the results of remote transmissions. We also asked veterans about demographics, social determinants of health, and location of care. Veterans could decline to answer any questions.All veterans were mailed a letter in November 2020 stating that they would be reached by phone to understand their experiences and perspectives of RM technology as well as possible barriers. They were also provided with contact information if they wanted to schedule an interview.Approximately 1 week after the letters were mailed, veteran contact began. Veterans were reached at one of their 2 primary numbers within the electronic health record, one of which is usually a mobile phone number. Attempts were made to reach veterans a minimum of 3 times, leaving a message after the first attempt with a call-back number.The structured interviews were conducted by 1 author (SM), who has experience conducting telephone interviews with veterans. Once saturation across responses was reached, no further interviews were conducted. During the interview, veterans were also provided with education about RM, and those who were not actively transmitting were provided reference information to support starting or restarting remote transmissions.Study data were analyzed deductively using content analysis within the 4 study domains. The data are presented using descriptive statistics. Where available, quotations are used to illustrate themes.This project did not constitute research. In accordance with the VA’s Office of Research & Development Program Guide: 1200.21, “VHA  Operations Activities That May Constitute Research,” data were collected as part of a quality improvement study to assess and improve the quality of RM care for veterans with CIEDs and did not require institutional review board approval. Veterans consented to participation; no compensation was provided.Overall, we contacted 44 veterans . A total of 2 veterans declined to be interviewed, and another 2 could not be reached despite multiple attempts. We concluded participant recruitment after reaching saturation.Among the 40 veterans interviewed , the mean age for veterans was 75.3 (SD 7.6) years, and 98% (39/40) were men . A totalOf the 40 veterans, a total of 22 (55%) had pacemakers, and 18 (45%) had ICDs. A total of 30 (75%) CIEDs were wireless-capable, while 10 (25%) were manual transmission only. The veterans had been implanted with their current CIED for an average of 4.4 (SD 2.8) years and had a mean of 1.6 (SD 0.7) generators in their history. Of the 40 respondents, 37 (92%) received all their cardiology care within VA, and all but one received at least half of their health care within VA.Of the 40 veterans, 23 (58%) reported that home monitoring had been discussed with them, and 5 (12%) were not sure. Among these 23 veterans, only 5 (22%) recalled learning about RM at the initial implant, with 14 (61%) learning about it at follow-up for in-person CIED checks . The perOnly 18 (45%) of the 40 veterans thought that they had a good understanding of RM. However, when these 18 veterans were asked an open-ended question to describe their understanding, some potential misconceptions were identified. A veteran said, “machine (remote transmitter) will buzz, call (name of clinician) at the VA.” Other veterans did have an understanding:"Every 90 days, transmitter reads ICD, transmits to Boston Scientific. They decode and send results to (the) doctor."When these 40 veterans were asked to describe the clinical benefits of RM, 19 (48%) reported detection of abnormal rhythms and 5 (12%) reported detection of device malfunction. However, 8 (20%) veterans were unable to report any benefits. Of the 40 veterans, 33 (82%) recognized that it was safer to be participating in RM than not participating, while 4 (10%) felt that it was the same, and 3 (8%) declined to answer.Among the 31 fully or partially adherent veterans, a total of 27 (87%) were satisfied with RM . Of thesOf these 31 veterans, 11 (35%) reported having ever been told the results of a remote transmission. Only 18 (58%) veterans had an idea of the next steps if their RM transmitter was not working; approximately half said that they would contact their VA clinic and the other half would contact the manufacturer of their CIED.Of the 25 veterans who were partially adherent to RM, when asked about possible barriers to adherence, a total of 3 (12%) reported forgetting about monitoring, and 3 (12%) reported losing a monitor . A totalAmong these 25 veterans, only 6 (24%) reported being contacted by a VA health care professional regarding not having sent a transmission, and the same number recalled being offered help in transmitting. A total of 14 (56%) veterans had called the manufacturer of their CIED about RM, and all but 2 reported a positive experience; one of them asked for a new remote transmitter but reported that the request was declined, and the other replied that they were unable to reach anyone.Among 9 veterans who were nonadherent, the barriers identified were not knowing how to transmit (n=4), not recalling being informed about RM (n=4), preferring in-person visits to RM (n=2), forgetting (n=2), privacy concerns (n=1), and difficulty with using a home monitor (n=1).Of these 9 veterans, only 4 reported that they had been contacted by a VA health care professional about not sending a transmission. However, a total of 5 veterans felt that they would feel more comfortable engaging if they received more information or education; all 5 preferred to learn from VA clinicians, and an additional 2 were amenable to informational postcards. Of these 9 veterans, a total of 3 had called the manufacturer of their CIED; of which 2 reported positive experiences, while 1 reported that no solution was possible because of a lack of cell coverage. Of these 9 veterans, a total of 3 were not sure about their interest in starting RM, and 1 was not interested in starting RM, stating, “If it’s my time, it’s my time.”When all 40 veterans were offered the hypothetical possibility of stopping routine in-person CIED evaluations in favor of an RM-only approach, a total of 10 (25%) were interested in the possibility, while 25 (62%) were not, another 4 (10%) were not sure, and 1 (2%) declined to answer . A majorOf the 40 veterans, a total of 25 (62%) were interested in a smartphone or tablet app notifying them of a successful transmission, and 24 (60%) had a smartphone or tablet. And 33 (82%) veterans, including majorities in all 3 categories, were willing to receive a reminder if they had missed their transmission by at least 3 days. A total of 34 respondents  reported their preferred mechanism: SMS text messaging (n=12), email (n=11), phone call (n=13), and n=1 each through a letter or a mobile app.A total of 33 (82%) veterans were interested in learning the results of their remote transmissions; of these, a total of 26 (79%) wanted to know just if the transmission was normal or abnormal, while 7 (21%) were interested in all device details. When these 33 veterans were asked the mechanism through which they would like to learn these results, 8 (24%) stated SMS text message, 9 (27%) email, 4 (12%) mobile app, 8 (24%) other and reported that they wanted either a letter or phone call, and 5 (15%) mentioned multiple options.Among the 13 veterans who needed to send manual transmissions, a total of 10 (77%) were interested in electronic reminders through either SMS text message, email, or both. Similarly, among the 27 veterans with wireless CIEDs, a total of 22 (81%) were interested in a reminder the day before their automatic scheduled transmission, and some of these veterans were also interested in a phone call or letter reminder.In this qualitative study of veterans with CIEDs, we found that most veterans reported being satisfied with RM, but they often had limited understanding about the need for and clinical benefits of RM. Some veterans did not recall receiving counseling about RM. Among veterans who were not fully adherent to RM, few recalled being contacted by clinicians about nonadherence. Nonadherent veterans welcomed the opportunity to learn more about RM and engage in monitoring. These findings are important because they demonstrate gaps in veterans’ knowledge about RM and opportunities to support veterans in increasing RM engagement so that they can achieve the many clinical outcome benefits of RM that lead to its strong professional society recommendation ,2.Previous single-center survey and interview research has shown that patients have limited understanding about their CIED ,17. ThisA previous survey of patients in CIED clinics found variation in the amount of detail patients request about their remote transmissions, ranging from most patients being interested in learning about battery life to a smaller proportion being interested in sensing and impedance data . To dateTo ensure minimal knowledge gaps about RM among patients, the standard of care should be patient education before device implant, as recommended by the Heart Rhythm Society ,2. In thOur findings also demonstrate that patients should be informed about nonadherence. The Heart Rhythm Society gives a Class 1 recommendation for device clinics to have an established process with dedicated clinic staff to facilitate reconnection . HoweverAddressing these gaps in patient education and addressing nonadherence is particularly important because the number of patients implanted with CIEDs has been growing globally ; more thWe also found that veterans were interested in learning about their remote transmissions—both if a transmission was successfully received and varying levels of details about the transmissions. In 2019, the Heart Rhythm Society issued a Call to Action about transparent sharing of digital health data, including data from CIEDs , and thiOur findings should also be considered within the context of their limitations. First, this study is limited to 40 randomly selected veterans followed by the VA and may not generalize to other populations. However, as there are more than 60,000 veterans with CIEDs followed by VA, these findings generalize to a large population, and we had a 91% response rate among veterans who we attempted to reach. Additionally, patients outside VA may face financial burdens for participating in RM. Second, this study population was enriched for veterans with intermittent or low adherence and may not reflect the views and perspectives of more adherent veterans, although veterans who are not fully adherent are those for whom understanding barriers and facilitators is most important. Third, social desirability bias may have led participants to provide answers that are inconsistent with their true viewpoints. Future studies can directly address patient viewpoints, such as through a validated questionnaire about satisfaction with RM .Among a population of veterans with CIEDs enriched for those intermittently or nonadherent, we found that veterans often had limited understanding of RM. Most veterans did not recall being contacted about nonadherence, but when they were contacted and troubleshooted, they found the experience to be positive. These findings demonstrate important opportunities to engage patients in RM, thereby improving both their quality of care and clinical outcomes.


Amongst participants reporting a sexual history (67%), intentions to get vaccinated significantly increased by 10.75 points on a 100-point scale (p < 0.01) after they received information about the risks of HPV for both themselves and their female partner, compared to receiving information about only their own HPV risk. These findings provide valuable guidance for public health officials and policymakers into the effectiveness of different messaging strategies in promoting HPV vaccination amongst adult male populations to increase vaccination rates.Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STIs). However, despite widespread under-vaccination amongst men and the importance of vaccinating both sexes to curb the spread of HPV, research has focused on promoting HPV vaccination predominantly amongst women. Therefore, the current study examines the effectiveness of different informational interventions in promoting vaccination intentions amongst heterosexual men. In a preregistered study of 583 unvaccinated adult men, we randomly assigned participants to one of four informational interventions aimed at promoting awareness of HPV risks and vaccine uptake: (1) risks to oneself ( Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STIs) worldwide. Currently, over 43 million Americans are infected with HPV, and an estimated 13 million Americans become infected each year . While mDespite the effectiveness and availability of the HPV vaccine, uptake remains low, particularly among eligible men. Among eligible men, only 27.0% have opted to receive at least one dose of the HPV vaccine, and among those only a dismal 9.0% ended up completing all the recommended doses. In contrast, among eligible women, 53.6% have received at least one dose of the HPV vaccine, with 27.0% completing all the recommended doses . TherefoWhile informational interventions have been found to be effective in promoting HPV vaccine uptake, these interventions have focused on adult women . In a syThe current research evaluated the effectiveness of different informational interventions in promoting HPV vaccination intentions for adult heterosexual men. We achieved this by experimentally investigating the effectiveness of different information interventions that highlight the risk of HPV for themselves, their female partner, or both themselves and their female partner. Our rationale for these different informational interventions is linked to the sex-specific nature of certain cancer types linked to HPV. Because some cancers linked to HPV are male-specific (penile cancer), female-specific , or apply to both sexes , understanding whether it is important to highlight the cancer risks of HPV for oneself, one’s partner, or both is of theoretical interest. Following the informational intervention, we measured HPV vaccination intentions in each condition.To date, only a limited number of studies have addressed the extent to which self- and partner-oriented informational interventions influence HPV vaccination. These studies have yielded mixed results. While one study suggested that both self- and partner-oriented HPV risk information can be more effective than general HPV risk information in promoting HPV vaccine acceptance amongst heterosexual adults , other sIn light of the limited research on male-specific HPV vaccine interventions, the current randomized experiment aimed to systematically examine the impact of providing HPV risks for oneself as compared to one’s female partner on HPV vaccination intentions among heterosexual adult men. To do so, we employed a full randomized experimental design, testing the impact of an informational intervention that highlights the HPV risks to oneself (Self), the HPV risks to one’s female partner (Partner), the HPV risks to both oneself and one’s partner (Both: Self and Partner), and a condition that highlights neither the risk to oneself nor to one’s partner (Control). From this experimental design, we can test two competing theories for the impact of self-oriented or partner-oriented informational interventions on HPV vaccine intentions of male participants.On the one hand, partner-oriented HPV risk information may be less effective in boosting vaccination rates compared to offering information that is more directly self-relevant. This is because men tend to be less communally oriented than their female counterparts . Hence, In sum, our objective was to experimentally assess whether including partner-oriented risk information increases HPV vaccination intentions among adult heterosexual men. In doing so, we provide valuable insight for public health officials into what informational intervention methods may be most effective in boosting HPV vaccination amongst an under-vaccinated and often understudied male population.This research was approved by the University of Chicago Institutional Review Board (IRB21-2010). The study design, including the number of participants, number of conditions, exclusion criteria, and planned analyses were preregistered on the Open Science Framework .We conducted a randomized experiment in which we randomly assigned participants of a convenient online sample to one of four HPV vaccine informational interventions .f = 0.15) with four experimental groups at a power of 95%, yielded a total sample size of 580 participants (145 participants per condition). We therefore preregistered 580 participants (after exclusion). We anticipated ~5% exclusions (based on previous studies using online samples) and therefore requested slightly more online participants.An a priori calculation of the required sample size, anticipating a medium sized effect  and CloudResearch . Of these, 23 participants (3.8%) were excluded according to our preregistered exclusion criteria. Participants were excluded if they did not pass the attention check (n = 7), indicated that they did not pay attention to the intervention messages (n = 8), or failed to provide any relevant information regarding HPV or the HPV vaccine in the open response question (n = 8).Participants were first prescreened to ensure they (1) were heterosexual males between 18 and 26 years old currently residing in the United States, (2) were eligible to receive the HPV vaccine, (3) had not been previously vaccinated or currently had an appointment to get vaccinated against HPV , and (4) currently had health insurance. Eligible participants were invited to participate in the main online experiment. After consenting to participate, each eligible participant was randomly assigned to one of four informational intervention conditions. See AgeM = 22.48 years, SD = 2.46, age range: 18 to 26 years). We tested adults aged 18 to 26 with and without a prior history of sexual activity because HPV vaccination is recommended for all individuals up to the age of 26 regardless of their sexual history ; Partner: M = 43.06, SD = 32.21, 95% CI ; Both: M = 48.60, SD = 30.15, 95% CI ; Control: M = 44.56, SD = 30.31, 95% CI ; F  = 1.16, p = 0.32) .Overall, the four intervention conditions did not differ significantly from each other (Self: .32) See . Furtherb = 4.21, t [530] = 1.97, p = 0.05, 95% CI ). There were no significant differences in vaccine intentions between participants in the Self condition and participants in the Partner condition, both with and without controls for demographic characteristics . There was also no significant difference in vaccine intentions between participants in the Both condition and participants in the Self condition if demographic factors were not accounted for .However, among the three intervention conditions , an interesting pattern emerged. When controlling for demographic characteristics of the sample (see details above), participants in the Both condition reported significantly higher HPV vaccination intention than participants in the Self condition . When including sexual history  as a covariate in the model, participants in the Both condition reported significantly higher HPV vaccination intentions than participants in the Self condition . However, participants of all intervention conditions reported similar vaccination intentions as participants in the Control condition . Also, participants in the Partner condition reported similar intentions to vaccinate to participants in the Self condition .Sexual history had a significant main effect on intentions to get vaccinated . Here, participants who had sexual experiences (67.2%) in the Both condition  reported significantly higher HPV vaccination intentions than participants with sexual experience in the Self condition . Participants without sexual experiences (28.3%) in the Both condition reported similar HPV vaccination intention  as participants without sexual experiences in the Self condition   also significantly interacted with intervention conditions (Both vs. Self) . When including sexual activity in the model, participants in the Both condition reported significantly higher HPV vaccination intention compared to participants in the Self condition . With sexual activity in the model, participants in all three intervention conditions reported similar vaccine intentions as participants in the Control condition ; and participants in the Self condition reported similar vaccine intentions as participants in the Partner condition . Furthermore, current sexual activity did not significantly interact with any of the planned comparisons (p > 0.05) and hence did not influence the strength of the effect of intervention type on vaccination intentions.Next, we examined sexual activity , which also significantly influenced intentions to get vaccinated (p > 0.05).Lastly, we examined the impact of relationship status on vaccination intentions. There was neither a significant main effect nor interaction of relationship status on vaccination intentions across conditions , they did not significantly interact with intervention conditions across any of the planned comparisons .Along with relationship and sexual history, we also measured general attitudes regarding vaccines more broadly. Because there is variance in the extent to which individuals are open to getting vaccinated, one possibility is that only individuals who are generally open to getting preventative vaccinations will be impacted by different informational interventions. However, while general attitudes around vaccination significantly predicted HPV vaccination intentions . However, endorsements of agentic values did not interact with intervention conditions across any of the planned comparisons . Surprisingly, there was no significant effect of endorsement of communal values on vaccination intentions , with its interaction with each of the planned comparisons failing to reach significance as well .Finally, we tested whether general endorsement of agentic or communal values influenced vaccine intentions. It is possible that informational interventions describing impacts of HPV infections on others are more effective among people who are generally more communal (or partner-oriented) as compared to people who are generally more agentic (or self-oriented). We found that agentic value significantly predicted vaccination intentions . It may be the case that while the participants had a relatively high intention to get vaccinated in the near future, they may have not necessarily had the time to sign up for a vaccination appointment immediately after completing the study. Additionally, it may be the case that certain populations, such as those found on online survey platforms, may be generally less willing to click external links than they otherwise would be if they had encountered the link in another setting. Both of these possibilities warrant future research.In sum, these findings have important practical implications for future public health campaigns to promote HPV vaccination uptake. Since adult male populations are often overlooked when examining interventions to boost HPV vaccination despite their far lower vaccination rates, this experiment bridges a gap in the current HPV vaccination literature while offering actionable informational interventions. Additionally, this study samples a more representative demographic beyond that of male college students used in prior studies, making these findings more broadly generalizable. There are possible limitations when considering the implications of this work. First, the current experiment did not directly measure vaccination uptake. However, under the Theory of Planned Health Behavior, expressed intentions are the stronger predictor of behavioral outcomes . AdditioThis study tested the effectiveness of different informational interventions on HPV vaccination intentions amongst eligible unvaccinated heterosexual men in the United States. We found that for men with sexual experiences, highlighting how HPV affects themselves and their partner boosted reported vaccination intentions by 10.75 points on a 100-point scale compared to when highlighting information on their personal risks alone. This result demonstrates that combining information about the benefits for oneself and their partner has a compounding impact on HPV vaccination intentions. Thus, this randomized experiment offers valuable guidance for public health officials and policymakers. We demonstrate how a low-cost informational intervention may be implemented to boost vaccination rates amongst a largely under vaccinated population to more effectively combatting HPV transmission.