The clinical and economic impact of cervical cancer consistently become a serious burden for all countries, including Indonesia. The implementation of HPV vaccination policy for a big country such as Indonesia requires a strong commitment from several decision-makers. The aim of this study was to provide a comprehensive description on cost-effectiveness and the budget-impact of HPV vaccination policy in Indonesia.A cohort Markov model was used to evaluate the cost and the clinical impact of HPV vaccination for 10 years old girls in Indonesia. The researchers consider two doses of all three available HPV vaccines adjusted with the HPV infection profilewith 95% vaccination coverage to estimate the national cervical cancer incidence and mortality. The Budget impact analysis explores three different scenarios covering (1) Two districts per year expansion, (2) oneprovince per year expansion and (3) achieving the National Immunization Program in 2024.Upon fully vaccinating almost 2.3 million 10-year-old girls, 34,723; 43,414; and 51,522 cervical cancer cases were prevented by Quadrivalent, Bivalent and Nonavalent vaccines, consecutively. Furthermore, the highest (591 cases) and lowest (399 cases) mortality were prevented by Nonavalent and Quadrivalent vaccines, respectively. Most of the vaccines were considerably cost-effective and only the Bivalent vaccine with the GAVI/UNICEF price which will be considered a cost-saving strategy.To provide national coverage of HPV vaccination in Indonesia, the government has to provide an annual budget of about US$49 million and US$22 million using the government contract price and GAVI/UNICEF price, respectively.HPV vaccination shows a cost-effective strategy and the budget required to provide this policy is considerably affordable for Indonesia. The high clinical and economic burden of cervical cancer has been experienced by many countries in the world, particularly developing countries such as Indonesia. The latest global cancer survey showed that cervical cancer is the second-highest incidence and mortality rates among women with the age-standardized incidence and mortality rate of 13.1 and 6.9 per 100,000, respectively . CurrentAlthough the cause of cervical cancer and its prevention strategy has been clearly explained and recommended by several bodies including WHO, the comprehensive implementation of the recommendation, covering HPV vaccination, cervical screening, and cancer treatment as the primary, secondary and tertiary intervention, consecutively, faces some substantial milestone due to several issues for example parent’s acceptance, availability of skilled human resources, and most importantly, the required budget.However, several health economic studies showed that the implementation of HPV vaccination and cervical screening are cost-effective strategies in most countries in the world –5. MoreoThe current prices of HPV vaccines are considerably expensive. In addition, since Indonesia entered the GAVI accelerated transition phase in 2016, Indonesia is currently not eligible for co-financing policy implementation scheme where vaccines is funded by both Indonesia and GAVI. Therefore, self-financing of HPV vaccination policy by the government of Indonesia requires a huge amount of national budget since the government has to provide about five million (two doses x 2.5 million girls on age 10) doses annually. On the other hand, the pilot project that has been initiated since 2016 in Jakarta Province and it was followed by several regions/regencies, such as Yogyakarta, Bali, Makassar, and Manado, in the next following years. The results of this pilot was promising since the vaccination coverage was mostly higher than 90%.Since these prevention programs require strong political commitment from several stakeholders, including the ministry of health, ministry of planning and most importantly, ministry of finance, an evidence-based policy recommendation is required in order to provide a comprehensive clinical and economic impact of HPV vaccination policy in Indonesia. Therefore, this study objectives was to provide not only the updated cost-effectiveness analysis of cervical cancer prevention using HPV vaccines in Indonesia but also its required budget in order to provide this particular strategies nationwide.A cohort Markov model, that has been developed previously, was updVaccine efficacies on preventing cervical cancer incidence were derived from efficacies data and then adjusted with the HPV infection profile in Indonesia,12. OnlyAlthough Indonesia has been included as GAVI Accelerated Transition Countries since 2016, GAVI vaccine prices are still applicable for Indonesia as long as the procurement is implemented through UNICEF until 2025. GAVI Vaccine price for Bivalent, Quadrivalent and Nonavalent vaccines are US$4.6, US$4.5, and US$6.9, respectively. CurrentThe initial and recurrent cervical cancer costs were adopted from previous studies  and screet. Al., (2018) about the Quality of Life of the Indonesian General Population [et.al., (2018)evaluating the Health-Related Quality of Life of HPV-related cancer patients including cervical cancer [The utility values for the susceptible population was derived from a study by Purba et. Al., 18 about l cancer  and the l cancer .The clinical impacts of all three HPV vaccines on the Indonesian population were presented as the incidence- and mortality-rate reduction in the cohort. While the incremental cost and utility were presented as the differences in cost and utility between each vaccine compared to the current situation in Indonesia. Moreover, the Incremental Cost-Effectiveness Ratio (ICER) is calculated by dividing the incremental cost with the incremental effectiveness, utility or Quality Adjusted Life Years (QALYs) is used in this study.Univariate sensitivity analysis was performed in order to investigate the robustness of the ICER. This analysis was performed by implementing the minimum and maximum values of several variables; including vaccine coverage (99.70% - 99.90%), cervical cancer treatment cost , discount rate for cost and utility (0% - 5%), vaccine cost (US$8.84 –US$14.74), utility for susceptible population (0.80–1.00), and  vaccine effectiveness (0.48–0.80).The HPV vaccination program has been implemented in one province (DKI Jakarta) and other five regions  in 2018. In 2019, the expansion program has been executed to add three additional districts of Yogyakarta  in order to provide HPV vaccination for all districts in Yogyakarta Province. The impacts of the HPV vaccination policy for 2020 to 2024 were described comprehensively according to the Ministry of Health plan and proposed scenario. The budget impact was estimated according to the projected population of Indonesia 2010–2025 from the Indonesian Central Bureau of Statistics  and the The target population was divided into (1) new population, representing the population who get the first dose of vaccination, and (2) recurrence population, representing the population who get the second dose of vaccination. Based on these criteria, the required budget for HPV vaccination was calculated annually. In this BIA, we also calculated the potential cost reduction, potential incidence, and mortality reduction by running the scenario of HPV vaccination implementation for every 10 years old cohort annually from 2020 to 2024 and compared it with the no-vaccination policy in Indonesia.There were three scenario of HPV vaccination policy implementation: (1) introduction to two district per year based on the province with high cervical cancer incidence, (2) introduction to 1 province per year based on the cervical cancer incidence rate, (3) introduction to several province excluding the province with Regional Gross Domestic Product (GDP) equal or higher than GDP of Bali province that has to be self-funded. The third scenario was chosen since the province of Bali introduced an HPV vaccination program in one of the districts in the region in 2017. According to this finding, we assume that if a region has sufficient budget, synergistic collaboration between local and central government will speed up the National Immunization Program for HPV in Indonesia.HPV vaccines show a promising clinical impact on the Indonesian women population . The higThe profile of cervical cancer incidence and mortality reduction caused by all three different HPV vaccines showed a comparable patterns. While Nonavalent vaccines potentially eliminates cervical cancer by providing 93.78%, reduction on cervical cancer incidence, currently available vaccines in Indonesia will only reduce the incidence up to 63% and 79% for Quadrivalent and Bivalent, respectively.All three vaccines generate additional discounted QALYs in the Indonesian women population due to cervical cancer incidence and mortality reduction. Under the GAVI-price, the implementation of HPV vaccination policy using the Bivalent vaccine generates lower discounted-total cost compared to the current situation (-US$3.48M), while the other two vaccines require an additional cost of US$0.95M and US$2.45M for Quadrivalent and Nonavalent vaccine, consecutively. Furthermore, only the bivalent vaccine is considered as a cost-saving vaccination program while the other two vaccines show a small value of ICER .If the Government contract price is implemented in the country, a substantial increase of discounted-costs are required (>US$30M) for all three vaccines with the highest addition is required by the Nonavalent vaccine (US$53.36M). However, since there is a huge amount of benefits represented by QALYs value, the ICER generated by all three vaccines are considerably highly-cost-effective (US$562-US$830/QALYs).One-way sensitivity analysis was used to evaluate the impact of each parameter on the ICER . Our stuTo describe the budget impact of the HPV vaccination implementation program in Indonesia, we performed a budget impact analysis (BIA) for the next five years of implementation (2024). The first scenario is intended to introduce HPV vaccination program for two districts per year based on the province incidence rate in Indonesia . This scAnother plan on the HPV vaccination expansion plan in Indonesia is to add one province per year according to the cervical cancer incidence rate. This imThe synergistic role between central and local governments will possibly enhance the achievement of the National Immunization Program (NIP) in Indonesia . While sHPV vaccination coverage will reach almost 100%  coverage in 2024 using this scenario. However, the required budget substantially increases up to US$22.3M and US$48.9M using GAVI/UNICEF and government contract price, consecutively. The estimated clinical benefits from this strategy will reduce both the incidence and mortality of about 63%.In this study, three different expansion scenarios, (1) two districts per year, (2) one province per year, and (3) achieving National Immunization Programin 2024, were simulated in order to describe the impact of these strategies on the national budget, potential cost of treatment reduction, incidence rate and mortality rate. In this budget impact analysis, two different prices, GAVI or UNICEF price, and the government contract price were considered since Indonesia is still eligible to get the vaccines using the GAVI price if the procurement processes are done through UNICEF until 2025.Generally, higher vaccination coverage will generate more benefits for both Indonesian governments and the population since there will be fewer incidence and death due to cervical cancer and therefore cost of cervical cancer treatment is also reduced substantially and surely, the higher vaccination coverage will generate a substantial required budget. The further question is about how much the Indonesian government will increase the allocation of their current health budget for the HPV vaccination program since the required budget in order to provide a nationwide HPV vaccination program would be about US$22.4 and US$49 Million using GAVI and contract price, respectively in 2024. This value is considerably high since the projected annual budget of vaccination in 2019 is about US$200 Million.Additionally, this study shows that the provision of HPV vaccines on top of the current situation, VIA screening and pap smear are accessible for free, are considerably cost-saving to cost-effective intervention since the ICER US$-64 –US$830) lies far below the Indonesian GDP per capita,25.These4 –US$830One of the limitation on this study is that the use of 1–3 times GDP as a normative threshold or willingness to pay to decide whether an intervention is cost-effective in a country is debatable and sometimes questionable. This statement was initially published by the WHO Commission on Macroeconomics and Health and recommends that an ICER lay beyond three times GDP and one time GDP is cost-effective and highly-cost-effective, respectively . HoweverFormalized WTP or threshold in a country is crucial in order to ensure the transparency of decision making process. For example, using 1 to 3 times GDP-per-capita recommendation, all three vaccines are cost-effective strategies and therefore Bivalent vaccine will be selected since it has the lowest ICER. However, since all those three ICERs are located far below GDP, the decision-maker can choose Nonavalent vaccine since it has the highest effectiveness among all those three vaccines.However, a question about how much budget is required to implement HPV vaccination as a national policy has to be addressed and it has been explained in this study as well.Although several vaccines  have considered not only HPV16 and HPV18 but also the most oncogenic types of HPV , another limitation of this study is that several serotypes which are commonly found in Indonesia; including HPV39, HPV51, HPV56 and HPV59,35. ThisAnother limitation of this study was the use of Static Markov model since it generally underestimates the protection of the HPV vaccine in the population. This model fairly describe the impact of herd immunity of the HPV vaccine and therefore the non-linear relationship between age and HPV vaccine effectiveness was also created. For example, irrespective of the type of HPV, the incidence and mortality rates of cervical cancer have the same trends. Therefore, the best type of model to explain the nature of infection and its prevention is using a dynamic model. The dynamic model could also explain the interaction among the susceptible population, through sexual contact (matrix), and therefore the effectiveness of vaccines on preventing the infection can be explained comprehensively,37. HoweAlthough several limitations, mainly lack of the formalized WTP or threshold in Indonesia, not all serotypes are covered in the study and the use of static Markov Model, are exist in this study, this budget impact analysis of cervical cancer prevention program in Indonesia showed that HPV vaccines are affordable especially when it is procured using GAVE/UNICEF prices.S1 Appendix(DOCX)Click here for additional data file.


External genital lesions (EGL) are the most common sexually transmitted infections (STIs). We aimed to evaluate the prevalence, determinants and sex differences in EGL among young adults from Brazil.Overall, 7694 participants (aged 16 to 25 years) underwent an interview, genital examination and sampling for HPV genotyping.p <  0.001). Genital lesions were significantly associated with male sex, infection by high-risk and multiple HPV types, having more than two sexual partners in the last year, smoking status and the presence of other STI. While alcohol use was associated with a higher prevalence of EGL in women, same-sex sexual relationship increase the prevalence in men. In the EGL group, 67.79% (p = 0.032) were positive for HPV infection and the types HPV6 and HPV11 were the most prevalent ones.The prevalence of EGL was 4.08% (234) and is more frequent in men (5.72%) than women (2.31%) (The prevalence of EGL in young adults was consistently high, and most cases were associated with genital HPV infection and STIs. Although men have a higher prevalence, both sexes share most genital lesion determinants. The promotion of sexual education and vaccination especially focus in young men, who are usually outside the targets of primary health care programmes, can prevent EGL in Brazilian young adults. Human papillomavirus (HPV) lesions of the external genital region, which are commonly identified as genital warts (GW), are the most common outcome of HPV infection, followed by low-grade squamous intraepithelial lesions and cervical, penile, anal and head and neck cancers , 2. The The presence of EGL is commonly associated with the presence of HPV genital infection; however, the diagnosis of HPV is often difficult, and the treatment is usually performed in a syndromic approach . AdditioHPV immunization provides direct protection against HPV types included in the vaccine. Currently, the national HPV vaccination programme in Brazil provides the quadrivalent HPV vaccine HPV 6/11/16/18) for girls and boys between 9 and 14 years old. Although the types commonly associated with genital lesions are included in the quadrivalent vaccine, multiple infection types can cause an increase in genital lesion incidence; therefore, it is important to understand the type distribution in the Brazilian population /16/18 fo.To date, few studies investigating the association among EGL, the presence of genital HPV infection and genotype in Latin America have been conducted . The curConsidering that data regarding the prevalence of EGL and associated factors are scarce in Brazil, the purpose of this study is to evaluate the prevalence, determinants and sex differences in EGL among sexually active young adults from Brazil.We used data from the POP-Brazil study, a cross-sectional, multicentric, nationwide study designed to evaluate HPV infection and its associated factors among sexually active women and men aged between 16 and 25 years in all geographic regions of Brazil , 18, to All individuals consenting to participate were invited to answer a standardized questionnaire based on validated instruments to provide information regarding sociodemographic factors and prior and current sexual health and behaviours. The presence of STIs  was self-reported. Additionally, the participants were invited to undergo a rapid HIV and syphilis test. During the sampling, the presence of any lesion in the external genital region was investigated and reported by the health care professional. Genital HPV infection was assessed in cervical samples collected with a digene® HC2 DNA Collection Device  and by supervised penile auto-collection using a digene® Female Swab Specimen Collection Kit (Qiagen). Genital  samples were analysed to detect HPV infection by DNA extraction with a MagNA Pure LC 2.0 Instrument and DNA Isolation Kit III ; the HPV detection and genotyping were conducted with a Linear Array® HPV Genotyping Test (LA HPV) . The LA HPV is based on PCR amplification [450 base pair (bp) fragment of the polymorphic region of the L1 gene of HPV], followed by specific hybridization and colorimetric detection according to the manufacturer’s instructions. The test can detect thirteen types of high-risk HPV (HR-HPV)  and twenty-four types of LR-HPV . The test include the amplification of the human β-globin (268 bp fragment) gene was used as an internal control for sample adequacy. An AutoBlot instrument  was used to automate the hybridization and wash steps. The LA HPV test probes against HPV types 33, 35, 52, and 58 are cross-reactive; therefore, if the tests using these probes were positive, we performed additional analyses using a specific real-time PCR assay as previously described . The samp <  0.05.The data were analysed using SAS software  version 9.4. The descriptive data are presented as frequencies (%), means and confidence interval (CI). ANOVA, Chi-squared or Student’s t-test were used to compare the characteristics between the groups. To compare proportions, a chi-square test was used. Normal distribution was determined through the Anderson-Darling test, and Student’s t-test was applied to compare the continuous variables when appropriate. A Poisson regression with robust variance was conducted to examine the factors associated with EGL. A theoretical framework was structured as follows with the associated variables differentiated in hierarchical blocks: HPV presence (Model 1); model 1 + age (Model 2); model 2 + alcohol consumption (Model 3); model 3 + condom use, having more than 2 partners in the prior year, and STI presence (Model 4) . To adjup <  0.001).Of the 7694 participants included in the study, the prevalence of EGL was 4.08% (95% CI: 3.22–4.94), and significant differences in prevalence were observed according to sex. Men have a higher prevalence of EGL (5.72%) than women . The EGL group were also associated with current smoking (24.41%), alcohol consumption (82.68%), having two or more sexual partners in the prior year (50.68%) and having a same-sex relationship (14.87%). A higher prevalence of lesions was observed in the Southeast region . Significant differences were not observed in the variable “age at first sexual intercourse” between the groups [15.38 mean age in years of individuals with lesions (95% CI: 15.09–15.67) versus 15.35 without lesions (95% CI: 15.30–15.40)]. Age, race/skin colour, relationship status, and condom use were not associated with the presence of EGL (Table The group of participants with lesions had a higher frequency of STIs (42.97%) than the groups of participants without lesions . The frequency of infection by HR-HPV (50.20%) and multiple genotype infection (43.71%) were higher among the people with lesions than among those without lesions . There was no statistically significant difference in LR-HPV infection between the groups  ; of these individuals, 67.79% (132) were positive for HPV DNA compared to 53.03% positivity among those without lesions (p < 0.001) and HPV6  were significantly higher in the group with lesions. There was no difference in the prevalence of specific HPV types according to sex (data not shown).The most frequently identified HPV genotypes in the participants with lesions were HPV16 (12.55%), HPV6 (9.22%), HPV11 (8.82%), HPV62 (8.67%), HPV58 (8.36%), HPV52 (8.19%) and HPV51 (8.01%). By comparing the groups with and without lesions, HPV11 ]. However, HPV lost significance after incorporating STIs into the model, and no interaction was observed between HPV and STI. Alcohol consumption was independently associated with the presence of lesions in the women [PR 1.91 (95% CI: 1.09–3.33)]. HPV was not associated with lesions in men, and those with STI were 3.13 times (95% CI: 1.57–6.24) more likely to have genital lesions than non-exposed subjects  than women (2.31%) and was associated with HPV infection only when STIs were not considered. The viruses commonly associated with lesions, HPV6 and HPV11,  were alsThe prevalence rates found are high, similar to that reported in Mexico 5.10%), Hungary (4.03%) and the USA (4.10%), and much higher than that in most countries, such as Italy (0.05%), Canada (1.10%)  and Viet0%, HungaData regarding the prevalence of genital lesions in men from low/middle income countries are scarce , 24–26. We found a statistically significant association between alcohol consumption and the presence of EGL. An association between alcohol and HPV prevalence has been previously reported. Alcohol intake was associated with a higher positivity of HPV infection and HR-HPV types in men . In womeThe rate of HPV infection in the participants with EGL (67.79%) was similar to that reported in other studies , but lower than the results obtained in Thailand (88.3%), Turkey (75.8%), Colombia (88.9%), China (97.0%) and Ireland (78%) , 33–36. Among the participants with genital lesions positively genotyped to HPV, 52.37% were positive for LR-HPV, and 50.20% were positive for HR-HPV. Although our study population had a much lower rate of HPV6 and/or HPV11 (24.55%) than other populations, , 39 we fOur study has both strengths and limitations. Because of the potential to report socially desirable responses or lack of knowledge, self-reported data have inherent biases that could lead to the underreporting of alcohol consumption or overreporting of STI. Additionally, we do not have enough data to address deeply some specific population as men and women who have same sex relationship. We also performed HPV testing of all the genital region in the men - including areas without lesions - while in the women, the cervix and external areas with lesions were tested. This strategy allowed for the identification of all HPV types present in the genitalia in addition to the area with EGL. This strategy could lead to an increase in other HPV genotypes not related to the lesion in the men and a decrease the types associated with lesions in the women. Additionally, the diagnosis of HPV-related lesions was performed only through visual inspection, leading to misclassification bias. Although we did not perform histological testing to confirm the clinical diagnosis, Hernandez-Suarez et al. concluded that only 19% of clinically diagnosed HPV-related lesion cases were not confirmed by microscopy .Some specific populations as men who have sex with men and the impact of vaccination in this population compared to heterosexual men regarding the prevalence of EGL could not be addressed in this study and deserves further investigation as well as the impact of vaccination in EGL lesion in the Brazilian population.Our data provide important information regarding the prevalence of external genital lesions and their determinants while also exploring the differences between the sexes. The results can be used for the development of public health strategies to focus on the affected groups, such as young men, who are usually outside the targets of primary health care programmes. Furthermore, these data reinforce the importance of sexually transmitted infections prevention and the need to include boys in HPV vaccination programmes.


Higher knowledge (β = 0.062 and p < 0.000) and perceived susceptibility (β = 0.043 and p = 0.002) were also predictors of HPV vaccine uptake. Of those who had not received the HPV vaccine, 53.5% expressed a willingness to do so. Likewise, social economic status indicators were associated with the willingness to receive the HPV vaccine. Total knowledge score (β = 0.138 and p < 0.001), both perceived susceptibility (β = 0.092 and p < 0.001) and perceived benefit (β = 0.088 and p < 0.001), and sexual experience (β = 0.041 and p = 0.007) had a positive and significant direct effect on the willingness to receive the HPV vaccine, while perceived barriers (β = −0.071 and p < 0.001) had a negative effect on the willingness to receive the HPV vaccine. Conclusions: Geographical region and socioeconomic disparities in the HPV vaccination uptake rate and willingness to receive the HPV vaccine provide valuable information for public health planning that aims to improve vaccination rates in underserved areas in China. The influence of knowledge and perceptions of HPV vaccination suggests the importance of communication for HPV immunization.Background: This study aimed to determine human papillomavirus (HPV) vaccine uptake and willingness to receive HPV vaccination among female college students, in China, and its associated factors. Methods: An online cross-sectional survey of female college students across the eastern, central, and western regions of China was undertaken between April and September 2019. Partial least squares structural equation modeling (PLS-SEM) was used to examine factors associated with the HPV vaccine uptake and willingness to receive the HPV vaccine. Results: Among the total 4220 students who participated in this study, 11.0% reported having been vaccinated against HPV. There are direct effects of indicators of higher socioeconomic status, older age (β = 0.084 and  Cervical cancer is the most common cancer of the female genital system, in China. It ranks as the eighth most frequent cancer among women in China and is the second most prevalent cancer in women aged between 15 and 44 years . The NatThe introduction of the HPV vaccine in many countries has resulted in major decreases in the specific human papillomavirus (HPV) infection rates. More than 10 years after the licensure of the first HPV vaccines, 99 countries and territories worldwide have introduced HPV vaccination programs . A recenSeveral studies have examined willingness and intention to receive HPV vaccines among Chinese females prior to the availability of the HPV vaccine in the Chinese market ,12. Now Currently, three years after the introduction of the HPV vaccine in China, information about vaccine uptake and its acceptance among young adult Chinese women, particularly those at college or university, is scarce. However, to the best of our knowledge, no study has reported real HPV vaccine uptake among young women in China since it became available in the Chinese market. Information about HPV vaccination rates is crucial to enable the Chinese government to plan or carry out effective strategies necessary to optimize uptake of the HPV vaccine.The purpose of this study was to explore the uptake of HPV vaccination among young adult college women in China and its associated factors. The second objective was to identify factors associated with the willingness to receive the HPV vaccine among the unvaccinated female college students.Using a cross-sectional design and convenience sampling method, young female college students were recruited from a total of 136 universities throughout eastern (78 universities), western (31 universities), and central (27 universities) regions of China. Participating universities were those that responded positively to an invitation to assist with data collection. A survey was conducted between April and September 2019. The inclusion criteria were all female students from the participating universities. The survey was administered online. The link to the survey questions was sent to administrators and lecturers from all invited universities for dissemination to registered female students. In an attempt to achieve comprehensive recipient coverage, the link to the survey was also sent to students’ social media groups or forums. Students who had received the survey link were also encouraged to forward the link to their peers.The questionnaire consisted of sections that assessed demographic characteristics, risk behaviors, knowledge, and health beliefs related to HPV infection and vaccination, HPV vaccine uptake, and willingness to receive the HPV vaccine.Personal details including age, ethnicity, study program, and year of study were collected. The participants were asked to indicate whether they had partaken in any sexual activity, including vaginal, oral, and anal sex. The participants who had done so were asked about safe sex practice and their number of sexual partners. Safe sex was defined as sexual intercourse with the use of a male condom.The participants’ knowledge was assessed using a series of questions regarding HPV infection, the relationship of HPV infection with the development of cervical cancer and genital warts, and HPV vaccination . The response options were “true”, “false”, or “don’t know”. A correct response was given a score of 1 and an incorrect or “don’t know” response was scored 0. The possible total knowledge score ranged from 0 to 20, with higher scores representing higher levels of knowledge.Health belief model (HBM) derived items were used to measure the participants’ beliefs about HPV vaccination ,20,21. TThe participants were asked to indicate their HPV vaccination status. Those who had not received the HPV vaccination were asked about their willingness to receive the HPV vaccine in the near future. The response option was “yes” or “no”.The items in the questionnaire were content validated by several panel experts to ensure the relevance and clarity of the questions. After minor amendments, the questionnaire was pilot tested on randomly sampled students who were not included in the main study.This study was approved by the Medical School of Ningbo University Review Board, China (reference number 20190506). The students were informed that their participation was voluntary, and consent was implied on completion of the questionnaire. All responses were collected and analyzed without identifiers.All statistical analyses were performed using the Statistical Package for the Social Sciences, version 20.0 . A p-value of less than 0.05 was considered statistically significant. The reliability of knowledge items was evaluated by assessing the internal consistency of the items representing the knowledge score. The 20 knowledge items in the study sample had a reliability (Kuder–Richardson 20) of 0.931. Partial least squares structural equation modeling (PLS-SEM) was used to quantify the contributing factors of HPV vaccine uptake and willingness to receive the HPV vaccination. All variables showing statistically significant associations with HPV vaccine uptake and willingness to receive the HPV vaccination in the univariate analyses were included in the PLS-SEM. A bootstrapping approach was used to evaluate the significance of associations in the proposed model. Bootstrapping includes the random resampling of the original dataset to generate new samples of the same size as the original dataset. This technique not only assesses the reliability of the dataset but also the statistical significance of the coefficients and the error of the estimated path coefficients . All PLSn = 78), central (n = 27), and western (n = 31) regions of China responded to the invitation to assist in recruiting participants for this survey. A total of 4220 completed responses were received between April and September 2019. The majority of the responses were from western China (40.8%), followed by eastern (38.4%), and central China (20.8%). A summary of the characteristics of the respondents is provided in the first column of A total of 136 universities from eastern  than the mean total knowledge score of the participants who had not received the HPV vaccine (11.5 ± 5.1).A total of 463 participants  10.1 to 11.9) reported that they had been vaccinated against HPV, and 3757 participants  reported that they did not have the vaccination. Univariate analyses indicated that HPV vaccine uptake was associated with older age, being in a higher year of study, place of birth in a city area, residing in eastern China, higher maternal and paternal education levels, a higher monthly disposable fund, perceived family economic status being rich or intermediate, having ever had sexual experience, a higher total knowledge score, a higher perception of susceptibility, and perceived effectiveness of the HPV vaccine .p = 0.006), being born in a city area (β = 0.058 and p = 0.002), residing in eastern China (β = 0.033 and p = 0.024), a higher monthly disposable fund, a higher total knowledge score (β = 0.062 and p < 0.001), and a higher perceived susceptibility (β = 0.043 and p = 0.002) had a positive and significant direct association with HPV vaccine uptake. The adjusted R2 for vaccination status in this model was 0.04, which indicates that 4% of HPV vaccination uptake could be explained by this model.n = 2010) responded “yes” and 46.5% (n = 1747) answered “no” to willingness to receive the HPV vaccine. As shown in Among the 3757 participants who had not received the HPV vaccination, 53.5% (p = 0.039), a higher monthly disposable fund (β = 0.045 and p = 0.007), higher maternal education (β = 0.038 and p = 0.004), attending a large scale university (β = 0.037 and p = 0.012), and a higher year of study (β = 0.094 and p < 0.001) had significant direct associations with willingness to receive the HPV vaccine. Total knowledge score had the highest beta coefficient (β = 0.138 and p < 0.001), indicating significant relevance of knowledge in predicting willingness to receive the HPV vaccination. For the HBM construct, both perceived susceptibility (β = 0.092 and p < 0.001) and perceived benefit (β = 0.088 and p < 0.001) had positive and significant direct associations with willingness to receive the HPV vaccine, while perceived barriers (β = −0.071 and p < 0.001) had a negative association with willingness to receive the HPV vaccine. Having had sexual experience (β = 0.041 and p < 0.007) had a positive significant association with willingness to receive the HPV vaccine. The adjusted R2 was 0.094, indicating that 9.4% of willingness to receive the HPV vaccination could be explained by this model.This study provides the first evidence of female college students’ HPV vaccine uptake rate in mainland China. Nearly three years after the introduction of the HPV vaccines in China, the uptake rate of 11.0% (95% CI 10.1 to 11.9) among the surveyed participants implies the need to enhance HPV vaccine uptake among young women in China. Nevertheless, the rate is slightly higher than reported among young women in Hong Kong (9.7%), in 2008, when the vaccines were newly introduced to the country . The HPVThis study also observed a greater likelihood of HPV vaccination among older than among younger female college students. This highlights the need to promote HPV vaccination among younger age college students by informing them of the importance of early protection against HPV infections. It is important to inform them of recent evidence indicating that young women in China aged 25 and below presented the highest HPV infection rate . They shAnother important highlight of the finding was the lower proportion of correct responses for all knowledge items among those who had not taken the vaccine as compared with those who had received the HPV vaccination. The PLS-SEM also revealed a strong influence of knowledge on HPV vaccine uptake. This indicates that increasing knowledge or awareness is an important factor in raising HPV vaccination rates. Perceived susceptibility was found to have a positive association with HPV vaccine uptake, which has likewise been found in many other studies on young adults in Asia and in Western countries ,30,31,32The proportion of nearly 54% female college students willing to receive HPV vaccination in this study is similar to that found in a recent smaller-scale study conducted among young women in China . The modThe model also revealed that among all factors investigated, knowledge was identified as a strong driver of willingness to be vaccinated against HPV infection. A recent publication revealed that school-based education was effective and appropriate for increasing HPV-related knowledge and acceptability of HPV vaccines among junior middle school students in China . Campus-Our study suggests that imparting perceived susceptibility and perceived benefits could increase students’ willingness to take the HPV vaccine. Having a good understanding of the potential benefits of the HPV vaccination could outweigh perceived barriers to receiving the HPV vaccination . InformaOur model indicated that students who have had sexual experience are more likely to express a willingness to receive the HPV vaccination. Further studies need to be conducted to find reasons for unwillingness to be vaccinated against HPV. These could include a perceived lack of risk due to not having had sexual intercourse or social stigma associated with seeking HPV vaccines, as found in other studies ,38. The This study is not without limitations. The main limitations are the nature of the cross-sectional study, which was unable to provide inferential causality, and the use of self-reported data, which can be subject to self-reporting bias. Of note, the HPV vaccine uptake rate found by this study may not be nationally representative, and therefore warrants cautious interpretation. The results should be interpreted with caution. Despite these limitations, the sample was large with diverse sociodemographic backgrounds representative of female college students from the eastern, central, and western regions of China.This study found that HPV vaccination rates remain critically low among female college students approximately three years after the licensure of the HPV vaccines in China. Despite the low vaccination rate, the overall acceptability of the vaccine among the unvaccinated was moderate. Most importantly, the study found associations between geographical region, socioeconomic status, and young college women’s knowledge and beliefs about both HPV vaccine uptake and willingness to receive the HPV vaccine. The findings suggest that it is essential to establish a campus-based HPV immunization delivery program.


Cervical cancer is the fourth cancer worldwide. The Human Papilloma Virus is responsible for 99% of the cases but the distribution of its genotypes varies among populations. We aimed to identify HPV genotypes distribution in women with grade 2/3 cervical intraepithelial dysplasia or invasive cervical cancer in Guadeloupe, a French Caribbean territory with a population mainly of African descent.We used paraffin-embedded tumors for viral DNA extraction from women diagnosed between 2014 and 2016 and identified by the population-based cancer registry. The HPV Genotyping was performed with the InnoLIPA HPV Genotyping Extra kit®.Overall, 213 samples out of the 321 eligible records were analyzed. The HPV status was positive for 94% of the cases. The five most common oncogenic HPV genotypes were HPV31 (47%), HPV33 (38%), HPV16 (32%), HPV44 (31%) and HPV26 (28%). HPV18 was found in only in 5% of the cases. Among the studied cases, 94% had multiple infections. More than 60% of single infections were HPV16-related, accounting for 35% of HPV16 infections.These results show a different distribution of oncogenic HPVs in Guadeloupe with “31 >  33 > 16” and a high frequency of multiple infections. Despite a lower coverage, the nine-valent vaccine is nevertheless adequate. Cervical cancer is the 4th cancer worldwide, accounting for 3.2% of all new cancer cases and for 7.5% of cancer deaths in women in 2018 [The Human Papilloma Virus (HPV) is responsible for the development of precancerous and cancerous cervical lesions, and up to 99% of cervical cancers are estimated to be HPV related . HoweverCervical cancer screening is implemented in Martinique since 1991 as part of national population-based pilot programs conducted in four regions . DespiteThe HPV vaccine is available since 2015 in both territories and is recommended for young girls under 14 years. Unfortunately, vaccination coverage remains very low in both Guadeloupe and Martinique. In 2018, the full HPV vaccination coverage among girls at 16 years old was 11.9% in Guadeloupe and 8.2% in Martinique . The popIndeed, national policies for cervical cancer prevention may not be appropriate for the Guadeloupean context. Recent work among healthy Guadeloupean women  has alreThe objective of this study was to determine the prevalence of circulating HPV genotypes in cervical cancers in Guadeloupe using paraffin embedded blocks of tissue from cervical tumours..A retrospective study was conducted on women with invasive cervical cancer or high grade cervical intraepithelial neoplasm (CIN 2/3) identified by the cancer registry between 2014 and 2016. Eligible participants’ tumour blocks and slides for which informed consent was obtained were included in the study. Ethics approval was granted by the local ethics committee of the University hospital of Guadeloupe Paraffin-embedded blocks containing cervical tumour tissue were accessed from the only two existing pathology labs in Guadeloupe. The blocks were de-archived, re-read by the referent pathologists to mark-off the tumor rich zone on the slides, and sent to Karubiotec™, the Biological resource center of University Hospital of Guadeloupe for processing. Karubiotec’s™ activities consist of receiving, conserving, and ensuring the availability of human biological resources. It is authorized by the French Ministry of Education, Higher Education and Research and is approved by a national research ethics committee, under the numbers AC-2018-3313, and DC-2013-1941 modified. Karubiotec™ is also dually certified according to NF S 96–900 and ISO 9001 standards under the number 150197/1289F. The dedicated software used for the management of biological collections, ModulBio®, is declared to the French Data protection authority, CNIL, under the number 1682116v0.The HPV genotyping carried out on the Karubiotec™ molecular biology platform was validated by the expert microbiologist of the University Hospital of Guadeloupe. For each person with identified material, a 5-10 μm thick section block was extracted, in accordance with the richest zone of tumor cells marked by the pathologist.Before processing for DNA extraction, the successive steps were performed: 1) Incubation at 56 °C for 3 min with 320 μL of deparaffinization solution ; 2) Reduction of the temperature down to 15–25 °C 3) Addition of 180 μL of ATL Buffer and mixing by vortexing; 4) Centrifugation 1 min at 11000 g; 5) Addition of 20 μl proteinase K to the lower phase and mixing by pipetting up and down; 6) Incubation 1 h at 56 °C; 7) New 1 h incubation at 90 °C.After the last incubation, and centrifugation to remove drops on the lid, the lower clear phase was transferred into a new tube to continue the DNA purification step, with the QIAamp DNA FFPE tissue kit . All samples were processed according to manufacturer’s protocols and were eluted in a 100 μL final ATE Buffer. For all DNA, Optical Density (OD) was measured for Quality Control with OD260nm/ OD280nm ratio on a nanodrop® One (Thermofisher®).The HPV Genotyping was performed with the InnoLIPA HPV Genotyping Extra kit® (ID 81533: amplification kit and ID 81534: hybridization kit) . In thisQuality controls of extraction and hybridization,HPV High risk genotypes (HR-HPV): HPV16 HPV18 HPV31 HPV33 HPV35 HPV39 HPV45 HPV51 HPV52 HPV56 HPV58 HPV59 HPV68.HPV potentially High-risk genotypes (pHR-HPV): HPV26 HPV53 HPV66 HPV70 HPV73 HPV82HPV Low risk and non-categorized genotypes (LR-HPV): HPV06 HPV11 HPV42 HPV40 HPV43 HPV44 HPV54 HPV61 HPV62 HPV67 HPV81 HPV83 HPV89.In the same reaction tube, 2 other primers specific to the HLADPB1 gene provided supplementary quality control for the DNA extraction. All probes were first immobilized on a membrane strip. After hybridization, stringent washes, addition of alkaline phosphatase conjugated streptavidin and incubation with BCIP/NBT chromogen, the revealed parallel lines corresponded to:Each technical run had a positive and negative control.For 25 patients with negative HPV tests, the data collected for P16 and Koilocytes from the pathology reports were used to confirm the negative result. Out of the 25 patients, 13 had insufficient tumor materials for HPV genotyping but were positive for either P16 of Koilocytes. P16 overexpression is a surrogate biomarker of HPV infection with a high specificity to detect high grade dysplasia , 18. HPVClinical and demographic data was extracted from the Guadeloupe cancer registry database which has been recording incident cancer cases since 2008. The registry is part of the national program for epidemiological surveillance of cancer in France, within the French network of cancer registries (FRANCIM). International and standardized data collection and coding procedures with International Classification of Diseases for Oncology (ICD-O3) are used in compliance with International Agency for Research on Cancer (IARC) and European Network of Cancer Registries (ENCR). For cervical cancer, we use the revised IARC/WHO 2014 classification. The pathology reports for all cases are collected in our database and the diagnosis is based on primary histology in more than 95% of cases. High grade cervical intraepithelial neoplasms (CIN 2/3) are characterized by at least more than 2/3 of the epithelium, or the entire epithelium, replaced by abnormal cells.This Registry is authorized by the National Authority for the protection of privacy and personal data . For each case, the data collected are: date of birth, date of diagnosis, and tumor characteristics . Place and date of first treatment and type of treatment are also recorded.Descriptive analyses were performed to compare patients’ characteristics at diagnosis between histological grades, age groups and HPV status. The prevalence of each HPV genotype (in single or multiple concurrent infections) was given for the overall population, by histological grade and by age group. Our combinations were classified as HR/LR/pHR independently of their genotype. The resulting classification yielded 48 combinations involving between 1 and 6 HR types. We further classified these combinations into three categories according to the number of HR types involved: 1 HR, 2–3 HR and more than 3 HR.P values were considered significant under 0.05. All analyses were performed with R software version 3.6.0.The quantitative variables are presented as means (accompanied by their standard deviation) and qualitative variables as frequencies (percentage). Chi-squared test and Student t-test were used to assess the association between variables. When the assumptions for Chi-squared test were not met, an Exact Fisher test was performed. p = 0.0001).Figure Table The frequencies of HR-HPV, pHR-HPV and LR-HPV did not differ between histological grades or age groups. HR-HPV was found in 91% in the overall population whereas pHR-HPV and LR-HPV were found respectively in 52% and 51% of all cases.We analyzed the number of HR-HPV genotypes, regardless of the pHR or LR-HPV status. The most frequent combinations of HR-HPV (i.e. 2 to 3) was found in 48.4% of the overall samples without any difference between histological grades or age groups.p = 0.01).Table The most frequent combination involving 3 viruses were HPV26–31-52 and HPV26–31-33. The association of HPV06 with invasive cancer was based on the consistency of its association with HPV16 (33% of the cases). Table Among patients infected with 2 or 3 viruses but with only one high-risk genotype, HPV16 remained the most frequently involved, both in CIN 2/3 and invasive cancer (respectively 22% and 24%). When in combination of 2 or 3, the most frequent HR-HPV association involved was HPV31–52 (respectively 29% of CIN 2/3 and 6% of invasive cancer), and to a lesser extent HPV31–33.n = 14) or HPV33 (n = 32) were the most frequent high-risk genotypes involved. HPV31 and HPV33  were involved in more than 60% of the cases. A combination involving 31–33–56-68 was found in invasive cancer among patients with more than 3 concurrent infections (p = 0.01). The most frequent HR-HPV combinations are shown in Fig. For patients infected with more than 3 viruses, no single HR-HPV was found. In the different combinations, HPV31 along with either HPV52 , confirming the importance of non-HPV16/18 types on our territory. The most frequent HR-HPV types involved in our samples excluding HPV16, were HPV31, HPV33 and HPV52. Our results coincide with a previous study conducted on healthy women attending cervical cancer screening in Guadeloupe. A lower frequency of HPV16 or HPV18 (7.3%) was reported compared to other HR-HPV (28.8%) considered as a pooled category . In our These results show similarities with other Caribbean and Central American countries. In Mexico, the study by Gallegos-Bolaños et al. reported that, with respect to the HPV16/18 combination, HPV16 was present at the third position after HPV51 and 52 but before HPV33 while HPV 18 was far behind . In CuraA meta-analysis and a French study conducted on women with invasive cervical cancer and high-grade cervical lesions showed that HPV16 and HPV18 were the most common in all continents , 15. In The role of multi-infection in aggravation of cervical lesions has already been highlighted in several studies. The sequence of primary infection/clearance/re-infection or over-infection seems to be decisive in the evolution of intra-epithelial lesions towards cancer. In a Brazilian cohort study, Trottier et al. suggested that the cumulative number of HPV genotypes were relevant in the evolution of cervical lesions . LikewisWe found a higher frequency of 2–3 viruses in patients with invasive cancer cases compared to CIN 2/3 cases. We also documented the distribution of multiple infections with combined high-risk genotypes (i.e. 2 or more combined HR-HPV genotypes) and found that HPV31 and HPV52 were associated with CIN 2/3, whereas HPV35 and HPV33 did not show differences between CIN 2/3 and cancer. Our data on multiple infections were consistent with the results from Soto-De Léon et al., in Colombian women  but in oAlthough our study was not designed to investigate the natural history of HPV infections on cervical cancer, our results provide valuable insight on the frequency of certain HR-HPV genotypes specific to the Afro-Caribbean population. In our sample, HPV31–33 seems to have similar frequency than HPV16. HPV16, HPV31, HPV33 and HPV52 are all in a same group of alpha papilloma virus (A9).The high prevalence of the non-HPV16 types could be explained by a synergy between them as suggested by other studies . Thus, SOur findings will also provide insights for the ongoing implementation of the national cervical screening program in Guadeloupe. Early detection of high-grade lesions is expected with the program, resulting in a reduction of age at diagnosis. The identification of the involved HPV genotypes, and the delivery of comprehensive information could reduce the mistrust toward HPV vaccine and improve coverage. HPV vaccines are produced to prevent cervical cancer and the latest nonavalent vaccine targeting HPV16–18–06-11-31-33-45-52-58, is available since 2016. Although the potential immunization coverage of this vaccine could be considered appropriate for 75% of  CIN 2/3 patients and 69% of cancer patients in our population, it remains slightly lower compared to data from mainland France (81 and 90% respectively).The limitations of our study are firstly, our small sample size. Nevertheless, the cases included were representative of all the cancer cases diagnosed in Guadeloupe for the study period and recorded through the population-based cancer registry. The volume of biological specimens was sometimes insufficient to perform adequately HPV genotyping, resulting in the exclusion of subjects for certain analyses. The removal of these subjects however is thought to be at random thus the possibility of attrition bias is kept to a minimum. Nevertheless, the method was carried out in good conditions and the results obtained for a large proportion of our blocks prove the feasibility of using FFPE block for the detection of HPV despite the humid tropical climate.This study describes for the first time the distribution of HPV genotypes in women from Guadeloupe with cervical cancer and CIN2/3 lesions. The most frequent genotypes were HPV31, HPV33, HPV16 and HPV52. Therefore, the coverage of the nine-valent HPV vaccine is adequate despite being lower than in European populations. Further studies are needed to understand the role of the multiple concurrent infections observed in our Afro-Caribbean population.


The Bland–Altman plot is the most common method to analyze and visualize agreement between raters or methods of quantitative outcomes in health research. While very useful for studies with two raters, a limitation of the classical Bland–Altman plot is that it is specifically used for studies with two raters. We propose an extension of the Bland–Altman plot suitable for more than two raters and derive the approximate limits of agreement with  In health research, it is often desired to determine to what degree different raters or methods (either persons or devices) agree on the measurement of a continuous outcome on the same subject . The main aim is to ensure that the variability between raters is small enough to use observations from a single rater in future studies or clinical practice and that it does not make any difference which rater conducted the single measurement.Typically this situation will be dealt with by applying a mixed effect regression model or related methods ,2,3. In m raters result in One of the drawbacks of the classical Bland–Altman plot is that it only applies to a situation with two raters or methods, while for both practical reasons (distributing workload to multiple raters) and statistical reasons , it is desirable to use more than two raters for carrying out agreement studies. The standard suggestion is usually to present multiple Bland–Altman plots for each pairwise comparison of raters ,8, but tSome suggestions include presenting all observations in the same plot, with one marker for each observation instead of each subject, either connecting observations for the same subject by lines  or by distandard  or reducstandard .The aim of this paper is to present a novel extension of the classical BA plot together with a generalized LOA, which only requires one plot and one marker per observed subject. While the main aim of this proposal is the comparison of multiple raters, the plot can be applied to comparisons of multiple methods as well. Especially for this case, it is important to be aware of the assumption of homoscedasticity, which our proposal inherits from the classical Bland–Altman plot; deviations from this assumption damage the interpretation of the Bland–Altman limits of agreement ,13.m raters who observe each of n subjects once, resulting in We are interested in investigating a situation with In this setting, we assume a data generating process similar to the assumptions made by Bland and Altman  for the Each subject’s true value In the classical Bland–Altman plot  and constant variance is While it is intuitive where the sample should be placed, the placement of a 95% LOA requires some additional considerations. Here, we use the property that the empirical variance of Applying this to our model, we observe asymptotically:Therefore, we propose to place our LOA at:s, which in the classical Bland–Altman plot is taken into account by using the t-quantile), nor that the coverage achieved by the LOA should correspond to a n. To communicate the uncertainty of the LOA, we suggest plotting 95% confidence intervals around the line. Here, we did this by applying bootstrapping in each sample with 1000 repetitions and reporting a Note that this formula only takes into account the number of raters, but neither the number of subjects observed  to distinguish which rater was responsible for the largest deviation from this subject’s mean; hence, a color/symbol very common in the plot would indicate a rater with larger uncertainty than the remaining raters, violating the assumption of j. Algorithm 1Extended Bland–Altman plot for multiple raters.m and number of subjects n and individual ratingsObserve number of raters Determine each subject’s mean and standard deviation:Determine the position of the LOA: Estimate the 95% confidence interval for the LOA by bootstrappingDetermine bias indicators for each rater:L with the confidence interval, and Plot One limitation of our suggested plot is losing the information on a possible bias of a specific rater, as well as possible heterogeneity between the uncertainty of raters. To include information on this phenomenon in the plot, we suggest adding tick marks on the y-axis corresponding to:n observations used to produce the plot and for one new observation (To determine how reasonably our LOA agrees with the desired nominal s et al. . Data wennet [boot [R Version 3.6.1  with thennet  and bootet [boot ,20 was uTo investigate the usefulness of the extended BA plot, we applied it to two datasets with multiple raters from the literature. For the first application  left, weFor the second application, we applied the extended BA plot to the glucose measurement data from a method comparison study  with fouWe showed that it is possible to present the agreement of more than two methods or raters in one combined plot and to obtain similar information as can be obtained from a classical BA plot including LOA and the corresponding confidence intervals; moreover, we indicated the possibility of detecting inhomogeneity in variance, as well as bias among raters. We showed by simulation that our suggested formula for the LOA of the extended BA obtains approximately The main strength of this study is that we combined a closed formula for the LOA based on mathematical arguments with transparent simulations documenting that the method behaves well even with small sample sizes. Moreover, we showed that our suggested plot can combine information presented in multiple plots in applications from the literature. A weakness of this study is that the LOA is only an approximation, as it does not fully capture the uncertainty of new observations, as well as only being equipped with approximate bootstrapped confidence intervals.Compared to the literature, the main strength of our approach is that only one plot is required for the comparison of multiple methods or raters and that only one dot is included in the plot for each observation unit, resulting in plots that are easier to comprehend. Moreover, these facts imply that the points on our plot are independent observations facilitating the estimation of accurate LOA and confidence intervals. Although it is possible to indicate bias and variance heterogeneity in our plot, it might be less clear than in some of the methods presented in the literature. Additionally, as our plot is only one-sided due to the non-negativity of standard deviations, this might impede its interpretation for readers used to classical BA plots.An additional weakness of the proposed method is that it shares the assumption of homoscedasticity with the classical BA plot. It is well known from the literature that this assumption can be problematic, especially in the case of method comparison studies ,13. TherThe possibility to present agreement information for more than two raters hopefully increases the possibility to report this information in agreement studies and to better inform the readers. Indirectly, this also might increase the inclination to include multiple raters in agreement studies, improving the generalizability of such studies. This implies that researchers can include the same observations in a graphical presentation as in more advanced analyses in studies with multiple raters, e.g., mixed models, improving the transparency of the studies. The fact that our LOA is presented with BA plots . One of There are still some outstanding questions with regard to our suggested extension of the BA plot. Firstly, it would be desirable to obtain a more precise, non-asymptotic formula for the LOA taking into account the full amount of uncertainty in the observations. Secondly, a closed formula for the confidence interval would be preferable to our bootstrap approach. Finally, implementations of our plot in standard software packages will improve its applicability.


Human papilloma virus (HPV) is a renowned cause of cervical cancer, which has resulted in high mortality of individuals. Cervical cancer could be reduced by screening and HPV vaccination. This study investigated knowledge, attitudes and perceptions of parents towards HPV vaccines in Ibadan, South-West L.G.A, Oyo State, Nigeria.A cross-sectional descriptive design was used with a multi-stage sampling technique to select 186 parents from Ibadan South-West local government area of Oyo state. A validated structured questionnaire (r=0.78) was used for data collection.The mean age of the respondents was 30.2 years. The parents had good knowledge of the HPV vaccine (mean=3.12) and most had a high level of knowledge (98.9%). Parents demonstrated negative attitude (mean=2.97) and positive perception to HPV vaccines. Major factors affecting their attitude towards the uptake of HPV vaccines were: finance (86%), level of education (81%), distance to health facilities (83%), inadequate knowledge about the vaccine (89%), fear of promiscuity (82%), and concern about adverse effect (80%).Factors responsible for a negative attitude were the high cost, distance from vaccination site, inadequate knowledge, fear of subsequent adolescent promiscuity and concern about adverse effects. In light of the benefits of HPV vaccination, the Nigerian government should make HPV vaccines available, affordable, and accessible to the public. Cervical cancer is one of the leading causes of death with about 0.27 million deaths occurring yearly1. In Nigeria, cancer of the cervix accounted for 62.3% and 65.7% of histologically confirmed gynaecological cancers, respectively3. Cervical cancer is a major health problem globally, especially in sub-Saharan Africa including Nigeria4.Cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 20184. It is a renowned cause of cervical cancer but also other cancers including of the vulva, anus, vagina, penis, head and neck. Globally, HPV-associated infection incidence is very high, with about 14 million cases in 20086.HPV is the most common viral infection, especially in Nigeria7.WHO has endorsed the HPV vaccine as the prime approach for the prevention of cervical cancer, to be administered before first sexual contact. Certain countries have also initiated vaccination against HPV in males, as the vaccines available are found to be effective for the prevention of anal pre-cancers and genital warts in both sexes9.The vaccines are approved for administration to females aged 9–26 years. They were licensed and introduced in Nigeria in 2009, but are being utilized by few privileged populations. Several studies have reported low knowledge of HPV vaccination against the infection and high cost beyond the reach of average NigeriansHence, this study was carried out to assess the knowledge, attitudes and perceptions of parents to HPV vaccination in Ibadan, Oyo state, Nigeria.A cross-sectional convenience study design was used. The study was carried out on parents in Ibadan South-West local government area of Oyo state. A multi-stage sampling technique was used to select calculated sample size of 186 participants who met the inclusion criteria, using the Kish & Leslie formula.Face and content validity were performed to ascertain the validity of the instrument. A pilot test was carried out, and a test-retest method of reliability was carried out using ten parents twice within a time interval of two weeks. The result was correlated using Pearson moment-correlation coefficient analysis; the resulting reliability coefficient was 0.78, which shows the instrument is reliable. The validated structured questionnaire (r=0.78) was then used for data collection on sociodemographics, knowledge, attitudes and perceptions of HPV vaccine amongst parents and factors affecting attitudes towards the uptake of HPV vaccine (Supplementary file).Responses of ‘knowledge’ and ‘attitudes’ were analyzed using the mean. The responses were assigned scores as follows: Very True of me=4, True of me=3, Untrue of me=2, Very Untrue of me=1. The mean of each item that assessed knowledge was calculated, and a weighted grand mean was obtained from these means and then used to compare the cut off of 2.5. A weighted grand mean ≥2.5 was defined as a good level of knowledge and vice versa. The level of knowledge was analyzed by assigning scores to the responses as follows: Very True of me=4, True of me=3, Untrue of me=2, Very Untrue of me=1. A total score ≥32 means high level of knowledge and vice versa. Responses of ‘perception’ were also analyzed using the mean. The responses were assigned scores as follows: Strongly agree=4, Agree=3, Disagree=2, and Strongly disagree=1. The mean of each item that assessed perception was calculated and a weighted grand mean was obtained from these means, and then used to compare the cutoff. A weighted grand mean ≥2.5 was noted as a positive perception and vice versa.Ethical approval was obtained from Oyo State Ministry of Health Ethical Review Committee, for permission to carry out the research in Ibadan South-West Local Government Area. The ethical principles of research were maintained. The consent of the respondents was sought by first explaining the purpose of the research and informing them that their participation was voluntary. They were assured of their anonymity and confidentiality, informed of their freedom to withdraw at any time without any penalty or punishment and then informed consent was obtained.Data entry, coding and running of data was done using Statistical Package for Social Sciences (SPSS) Version 22. Data were analyzed using descriptive statistics of mean, frequencies and percentages, and inferential statistics.The mean age of the respondents was 30.2 years, the majority were females (71.5%), of Yoruba ethnic group (75.3%) and Christians (79.6%) . The parThe majority (72%) reported that they have some reservations for the HPV vaccines, 69% reported that their moral upbringing contradicts HPV vaccines, and their faith contradicts HPV vaccines (61%). Factors affecting their attitude towards the uptake of HPV vaccine were financial barriers (86%), level of education (81%), distance to health facilities (83%), preference for vaccinating girls (79%), lack of awareness that vaccine can be given to males (82%), and inadequate knowledge or information about vaccine (89%) .Overall, parents had positive perception towards uptake of HPV vaccines with a weighted grand mean of 3.08.12.The findings of the study revealed that the parents that responded to our survey in Ibadan, Nigeria, have good knowledge of HPV vaccine. A similar finding reported awareness of HPV vaccine and its relevance to development of cervical carcinoma among parents10. However, a low level of awareness of HPV vaccine was reported by some studies13. However, a study showed a contrary report on attitude towards HPV vaccine among parents14. It could be inferred that the negative attitude demonstrated by the respondents towards HPV vaccine uptake based on their religious belief is not unexpected, as Nigeria, with its diverse religions and their practices, has religions that forbid the uptake of drugs, vaccines and even certain health-care procedures.Parents demonstrated negative attitude to HPV vaccines. This finding is in line with a study that reported negative attitude to HPV vaccine among parents11 where favourable opinions were found about sexually transmitted infection (TSI) prevention messages for vaccination, including at young ages, and that sexual health is a topic of conversation between adolescents and healthcare providers. In contrast to this study, a negative perception was reported among female adolescents in selected secondary schools in Ibadan, Nigeria15. This presents an opportunity to strengthen vaccination channels, especially for adolescents, in order to prevent HPV.The parents had positive a perception towards HPV vaccine uptake, as in another study17. Even though the parents in Ibadan South-West have good knowledge and perception about the HPV vaccine, there were several factors identified that impeded them and their children from taking the HPV vaccine. This might explain why there is an increase in the incidence of cervical cancer in Ibadan18. There is, therefore, a need to tackle these factors by means of proper information, subsidization of vaccination, as well as availability of vaccines.Factors such as financial barriers, level of education, distance to health facilities, preference for vaccinating girls, misconception about the effect of the vaccines, religion and cultural beliefs, fear of promiscuity, ignorance that males can take the vaccines, and the longevity of dose interval, are the major factors influencing the attitudes of the parents towards uptake of the HPV vaccines. Similar studies reported that ignorance of vaccination availability for boys, safety concerns, belief, physician recommendation, health insurance coverage and cost of vaccination had a significant effect on uptake of vaccinationA strength of the study was the ability of the researchers to get the parents to participate in the study given that in our society the discussion of such sensitive topics is usually difficult because of religion and culture. The limitations of the study are the inability to generalize findings to the overall population of Ibadan, because of the small sample size used  and also the cross-sectional design used for the study, which only collects data at a point in time.The study revealed that respondents had good knowledge, high level of knowledge and positive perception of HPV vaccine. Negative attitudes demonstrated by the parents and factors responsible were the expense and distance to health facilities, inadequate knowledge about the vaccine, fear of subsequent adolescent promiscuity and concern about adverse effects. There is a need to make HPV vaccine accessible, available, affordable, and to educate parents more about HPV vaccine and dispel fears about adverse effects through education.Click here for additional data file.


Anal cancer, usually driven by an oncogenic Human Papillomavirus, remains a leading cause of morbidity in men who have sex with men (MSM) living with HIV, despite combined antiretroviral therapy. Various recommendations advocate to perform regular examination and proctologist-performed samples to anticipate this risk and treat locally before cancer occurrence, an efficient strategy which has the drawback of requiring the proctologist’s availability. This study evaluates the acceptability, feasibility, and efficiency of self-performed samples to screen for HPV-infection and HPV-related anal dysplasia among MSM living with HIV followed in Hôtel-Dieu Hospital.Between February 2015 and June 2015, MSM living with HIV and referred to the day-care hospital were offered to perform an anal self-sampling for cytologic and virologic evaluation. A self-sampling kit was provided, and a tutorial video was shown. A subset of participants had a proctology appointment after they did the self-sampling, and thus had a clinical examination and an anal swab sampling performed by the proctologist, using the same sampling material.Anal self-sampling was offered to 103 patients, and 100 accepted. Sixty-three samples were interpretable, of which 36 (57%) were normal and 27 (43%) showed abnormal results. Virologic analysis was performed for 60 (95%) interpretable samples: 50/60 (83%) of them were positive for HPV. Among HPV-carrier patients, 42/50 (84%) were infected with at least one HR-HPV. Twenty patients had a proctologist consultation. All clinician-performed samples were interpretable and 14 (70%) self-samples were interpretable.This study highlights the acceptable accuracy of self-sampling screening method among MSM living with HIV and try out its acceptability and feasibility as a secondary prevention device. Although it cannot replace a proctologist consultation for high risk patients, self-sampling should be studied further as one of the ways of screening for anal cancer among low-risk outpatients. Combined antiretroviral therapy (cART) has dramatically reduced HIV/AIDS-related mortality and morbidity . Anal caIn most cases, anal cancer is a squamous cell carcinoma, driven by an oncogenic, or High Risk Human Papillomavirus (HR-HPV), most commonly HPV type 16 and type 18 . SimilarDespite the use of cART, MSM living with HIV are especially at risk of anal cancer , with anFrench guidelines recommend an annual day-care hospitalization to screen for non-communicable, non-AIDS comorbidities in PLWHIV . CurrentYet, the regular examination of an intimate part can raise acceptability issues among PLWHIV  and requThe purpose of our study was to reassess the acceptability, feasibility, and efficiency of anal self-sampling to screen for HPV-infection and HPV-related anal dysplasia among MSM living with HIV.OVHID is an outpatient cohort of PLWHIV followed in our clinical center. The inclusion in the cohort occurred on the day of admission in the day-care hospital for comprehensive screening of non-communicable, non-AIDS comorbidities according to French guidelines. The OVHID study protocol was approved by the Ethics Committee « Ile de France II » (N° ID RCB: 2010-A00417-32) and by the French general data protection regulation (CNIL). All participants signed written informed consent. MSM living with HIV and referred to the day-care hospital between February 2015 and June 2015 were offered to perform an anal self-sampling. If they were willing to perform such a self-sampling, a short educational video on how to perform the sampling was shown. Patients were advised to introduce the swab for 2 centimeters, to spin it and then to rub the brush against the wall of the preserving vial.The sampling material was a sterile Dacron swab with a brush dedicated to this kind of anal sampling . The transport medium was a preserving PreserCyt® vial with ThinPrep® liquid, Hologic . The tutAll samples were analyzed in the Pathology department of the Cochin Hospital, Paris. Cytologic analyzes were performed using ThinPrep® slides as well as the Papanicolaou staining. The results were reported according to the Bethesda System 2014 used for HPV-linked cervical cancer . All samA subset of participants who had a planned proctology appointment as part of their day-care hospital, because of past anal dysplasia or systematic consultation scheduled every 3 years, did the self-sampling first and then had a clinical examination with high-resolution anoscopy and an anal swab sampling performed by the proctologist, using the same sampling material as described above.3, median CD4+ nadir was 251/mm3 (1/mm3 to 912/mm3). Ninety-four percent of patients had an undetectable plasma viral load and the maximal viral was 550 copies/mL. A history of previous sexually transmitted infections, besides HIV and HPV, was found in 48% of patients, and 19% had a past episode of condyloma.Anal self-sampling was offered to 103 patients, and 100/103 accepted (97.1%). Their median age was 56 years . Median CD4+ count was 704/mmOut of 100 samples, 63 were interpretable, of which 36 (57%) were normal and 27 (43%) showed abnormal results. Among the samples unsatisfactory for evaluation, 19 (51%) evidenced intestinal glandular cells, 17 (46%) were acellular and 1 (3%) was agglutinated . Among tVirologic analysis was performed for 60 (95%) interpretable samples: 50 (86%) of them were positive for HPV, 8 (13%) were negative, 2 (3%) failed to provide a result . Among H3 (227–1476) and 865/mm3 (164–1760) (Student’s Test p<0.05).No significant differences were found between patients with cytological lesions and patients with normal self-sample except the CD4+ count, respectively at 690 /mmTwenty patients had an examination with a proctologist consultation planned for their day hospitalization, and thus had both self-sample and clinician-performed samples on the same day . All clinician-performed samples were interpretable. Fourteen (70%) self-samples were interpretable and 6 (30%) were not . Among tThe 3 biopsies evidenced 1 low-grade dysplasia (self-sample showed LSIL), 1 low-grade dysplasia with condyloma (self-sample showed ASC-US) and 1 normal biopsy (self-sample showed ASC-US).Only 1 patient had an HSIL according to the clinician-performed sample. Self-sample concluded to LSIL without being able to exclude HSIL and advised to perform a biopsy. The virologic sample evidenced HPV 16, HPV 26, HPV 58, HPV 70 and HPV 82.According to the studies we reviewed, the prevalence of histologically-proven squamous intra epithelial neoplasia in MSM living with HIV is around 20%  which isHereby, in a cohort of 100 patients, followed according to French guidelines with consultations and day hospitalization, we found a strong acceptability (97%), like in previous studies concerning PLWHIV , 13, 14,This study reports a prospective systematic screening cohort of 100 ambulatory patients, with cytologic and virologic results of self-samples for most of the patients. Despite being single-centered, it provides a viewing of the prevalence of AINs among MSM living with HIV. It corroborates the previously obtained data studies, concerning an important topic for MSM living with HIV which lacks cost-efficient screening methods. Furthermore, it provides an overview of HPV carriage among MSM living with HPV. This preliminary study does not aim to establish anal self-sampling as substitute for proctologist consultation. However, it does highlight the acceptable accuracy of this screening method among MSM living with HIV and try out anew its acceptability and feasibility as a secondary prevention device. Besides, considering the cost of screening and treating HPV infection, investigations for the efficiency of the HPV vaccine among MSM living with HIV. Just as it was recently investigated among women living with HIV , it shouTo conclude, considering the high prevalence of HR-HPV among MSM living with HIV and the satisfactory accuracy of this low-priced ambulatory test, self-sampling strategy should be studied further as one of the ways of screening for anal cancer, among others. Further prospective studies are needed to evaluate its use among PLWHIV and to distinguish the respective usefulness of cytologic and virologic samples. Caution should be taken for high-risk patients, for instance those with history of condyloma, before skipping the visit with the proctologist. Higher performance of a clinician-performed sample and absence of direct visual control during a self-sample should be kept in mind. Yet, acceptability and proctologist availability being the main barriers to the consultation, positive anal sampling could help to convince the patient to attend proctologist’s consultation and should help to target the higher risk MSM living with HIV.


The rates of the mothers who replied they would not inoculate were significantly lower at 9 months and 23 months, but at 76 months was significantly higher . We found that intervention with a leaflet that could be used under the current suspension of the governmental recommendation did not increase the mothers’ intention to inoculate their daughters. A leaflet that actively encourages vaccination may increase the intent of vaccination. It is strongly recommended that the MHLW promptly resume its recommendations for HPV vaccination.The trend for cervical cancer in younger women has been increasing recently in Japan. However, as a result of the suspension of governmental recommendation, Japan’s HPV (human papillomavirus) vaccination rate for girls born since 2000 has dropped sharply. We conducted an internet survey in December of 2019, 76 months after the suspension of recommendation, to verify the intention of mothers to inoculate their daughter under current circumstances and compared with our previous surveys and leaflet intervention effect. The rates of mothers who replied that they would “inoculate” were significantly higher at 9 and 23 months, but by 32 months after the suspension the rate was significantly lower ( The incidence of cervical cancer is one of the few cancers that could potentially be almost entirely eliminated by current medical practices, that the WHO  has made its Draft Global Strategy for achieving that lofty goal one of its global public health policies. “Elimination” in this case would mean that the age-adjusted incidence rate of cervical cancer would fall to less than four reported cases per 100,000 women. By the time of this publication, this WHO Policy Proposal should have been approved by the World Health Assembly . WHO’s Draft Global Strategy has three main pillars, “Prevent, Screen and Treat”. These emphasis points capture WHO’s comprehensive approach to cervical cancer that includes sustained cancer prevention efforts, early and effective screening for the cancer, affordable and achievable optimal treatment options for all pre-cancerous lesions, and, as a final effort, early diagnosis and aggressive, efficacious programs for the management of invasive cervical cancers [Australia has already promoted several such national programs and has reported scenarios for cervical cancer elimination . Other cIn direct contrast, the status of Japan’s cervical cancer countermeasures has been disastrous and seemingly going in reverse. Since around 2000 the trend for cervical cancer in younger women has been increasing in Japan . EspeciaThe subsidies local governments provided for the national HPV vaccination programs commenced in 2010; this became a routine public vaccination program in April of 2013. However, due to repeated news reports regarding so-called adverse post-vaccination events, the Ministry of Health, Labor and Welfare (MHLW) announced the “Suspension of its active inoculation recommendation for the cervical cancer prevention vaccine” in June of 2013 . This suThe second strategy of WHO was for achieving a cervical cancer screening rate of 70%, The cervical cancer screening rate among Japanese women is currently roughly 40%. This 40% is low compared to the 70% to 80% rate in most/all other OECD countries, so the achievement of this target will be very difficult for Japan to reach ,11.We have previously conducted three different surveys on “the intention of mothers to inoculate their daughters with the HPV vaccine”. Our newest report discusses the results of our fourth such internet survey, conducted in December 2019. In particular, we reveal the changes over time in the mothers’ “awareness of the HPV vaccine”, “their awareness of news reports regarding the so-called “adverse vaccine events” and “the intention of mothers to inoculate their daughters with the HPV vaccine” by comparing the results of our four sequential internet surveys. In addition, we examined the effectiveness of supporting the mothers’ decisions by interventions using three types of leaflets. This survey comparison spans the period of 76 months since the announcement of the government’s suspension of its HPV-vaccination recommendation.This latest internet survey was conducted in December of 2019, 76 months after the suspension of recommendation. The respondents were 1545 mothers who had HPV-unvaccinated daughters who were aged 12–16 . SimilarFor the main survey, we analyzed for correlations between the following questions related to cervical cancer, the HPV vaccine, and the intention of the mothers to inoculate their daughters: (1) Knowledge of cervical cancer: Do you know that cervical cancer more often affects women in their 20′s and 30′s?, (2) Knowledge about the HPV vaccine: Do you know about the HPV vaccine? Do you know the HPV vaccine can prevent cervical cancer? Do you know that there were news reports regarding the so-called adverse events of the HPV vaccine, such as chronic pain and motor impairment, which were discussed in relation to HPV vaccination in the Council of the MHLW?  (3) HealThe contents of the three different leaflets that we presented on the screen are shown in The following two questions were compared to ascertain how many mothers who had answered “Unsure” or “Won’t inoculate” changed their intention to inoculate because of the leaflet intervention: (1) Would you inoculate your daughter with the HPV vaccine under the current circumstances? (2) Would you inoculate your daughter if the MHLW restarted its recommendation? In addition, we asked the following question to examine the factors that better promote inoculation under the recommendation suspension: While the MHLW has not yet restarted its recommendation, would you inoculate your daughter if any of the following events occur?—A recommendation by the family doctor, a recommendation by the school, a recommendation by local government, or an inoculation of a daughter’s friend.We compared our current survey results with the internet surveys we had conducted at 9 months, 23 months, and 32 months after the initial suspension of recommendation ,14,15. Tp < 0.05. In comparison between multiple groups, Dunnett’s test was conducted, where the significant difference was set to p < 0.025 in comparison between the control group and the two test groups.Univariate analysis  was used for the statistical analysis. The level of statistical significance was set at This study was approved by the Institutional Review Board and Ethics Committee of the Osaka University Medical Hospital (14361-9).The characteristics of the internet survey respondents are shown in Regarding the collective mothers’ responses—before viewing our leaflet interventions, 11.1% (171/1545) had at first replied that their intentions regarding their daughters were to “inoculate under the current circumstances” . Meanwhip < 0.05, respectively). The percentage who had no knowledge of cervical cancer or who had no knowledge of the HPV vaccine, or was significantly higher in the group who replied “unsure” than for the other two groups . Furthermore, regardless of the pre-intervention intention of the mothers to inoculate, each rate of the mothers who were aware of cervical cancer, the HPV vaccine and the effects of the vaccine were high: 82.6% (1276/1545), 91.7% (1416/1545), and 88.9% (1374/1545), respectively. The percentage of mothers who knew about the negative news reports regarding the so-called adverse events in the groups of mothers who replied they would “inoculate“ or “unsure” were significantly lower, while the rate of that in the group of the mothers who replied they would “won’t inoculate” was significantly higher: 91.0% (120/171), 80.3% (446/578), and 93.5% (774/796) . No correlation was observed with the mothers’ health behavior, including the mother’s previous cervical cancer screening pattern and influenza vaccination status, and their intention to inoculate their daughters.The percentage of mothers who knew about cervical cancer, the HPV vaccine, and that the HPV vaccine could prevent cervical cancer was significantly higher in the group of mothers who initially replied that they would not inoculate their daughters than in the other groups . If the MHLW restarted their recommendation, 3.3% (14/424) of Group 2 and 8.5% (35/412) of Group 3 turned willing to inoculate their daughters after intervention with the leaflets. Compared to 3.7% (16/434) of Group 1, the increase in the rate of Group 3 was significantly higher (p = 0.0037).In the mothers who had no intention to suggest vaccination to their daughter under the current circumstances, 5.0% (23/463) of Group 2 and 9.2% (41/448) of Group 3 became newly willing to inoculate their daughters after intervention with our leaflets . Comparep < 0.05, respectively)  .p < 0.05, p < 0.05, respectively), but at least 90% or more of the mothers knew about the HPV vaccine throughout the four surveys , but about 80% of the mothers knew “about” the HPV vaccine throughout all the surveys.The rate of the mothers who knew about the HPV vaccine was significantly higher at 23 months after the suspension, and those in the surveys responding after 32 and 76 months after the suspension were significantly lower . The rates of the mothers who replied “unsure” were significantly higher at 9 and 32 months and that at 76 months was significantly lower . The rates of the mothers who replied they would not inoculate were significantly lower at 9 months and 23 months, but at 76 months was significantly higher .The rates of mothers who replied that they would “inoculate” under the current circumstances were significantly higher at 9 and 23 months, but by 32 months after the suspension the rate was significantly lower . The rates of the mothers who replied “unsure” were significantly higher at 9, 23 and 32 months, but at 76 months was significantly lower . The rates of mothers who replied that they wouldn’t inoculate were significantly lower at 9 and 23 months, and that at 76 months was significantly higher .The rates of the mothers who replied they would “inoculate” if the MHLW restarted their recommendation were significantly higher at 9 and 23 months, and that at 32 months after the suspension was significantly lower  . The rate of the mothers who replied that they would not inoculate even if many girls of the same age group have been inoculated, and the MHLW restarted their recommendation, was 28.2% at 23 months, and practically unchanged, 26.9%, at 76 months.The rate of the mothers who replied they would “inoculate without any specific preconditions” or would “inoculate immediately after a restart of the recommendation” was significantly lower at 23 months, and that at 76 months after the suspension was significantly higher (ctively) . The ratIn 2018, approximately 570,000 women developed cervical cancer worldwide, and 311,000 women died from this now easily avoidable disease . It is eJapan is not the only country whose vaccination rate had once dropped due to a deep public distrust of the HPV vaccine. In Ireland, the activity of anti-vaccine lobbying groups established in 2015 deeply reduced that nation’s HPV inoculation rate too, but in 2016 and 2017, first a steering group of concerned organizations, and then a pro-HPV Vaccination Alliance was established, forming powerful cross-sectoral alliances that rapidly led to improvements in HPV vaccine uptake . DenmarkUNICEF has reported that the once novel HPV vaccine has now been introduced into 90 different countries . EstimatIn our internet survey, we found that about 80 to 90% of the mothers surveyed were already aware of cervical cancer and the HPV vaccine and its effects, regardless of their own intentions for vaccination of their daughter . The ratIt is clear that Japanese mothers do not have low health awareness; 85.2% of the mothers had received both cervical cancer screening and an influenza vaccine . HoweverWe believe that the one leaflet we created is a positive recommendation for the vaccine, and that, shown by our survey, it could significantly increase the percentage of mothers intending to recommend that their daughter receive the HPV vaccination, both under the current circumstances and in a theoretical scenario where the governmental recommendation would be restarted . HoweverWhat will happen to the HPV vaccination rate after such an information provision is improved? In the changes over time regarding the question of preconditions which mothers might require prior to their daughters’ HPV vaccination, the rates of the mothers who replied they would “inoculate without any specific conditions” or “inoculate immediately after a restart of the recommendation” were increased significantly . The ratSimms et al. have made predictions regarding the lifetime cervical cancer morbidity and mortality rates in the population of young Japanese girls born between 1994 and 2007; their predictions were based on the current extremely low rate of HPV vaccination . They prWe have already complained that the following efforts are needed as soon as possible: (1): Provide opportunities for immunization for younger women who are already older than the normally targeted ages of 12–16 years, this is because they were not immunized during the vaccine recommendation hiatus, and thus are at greater risk, (2): Start inoculating young boys, (3): Introduce the newer, more comprehensive nine-valent HPV vaccine, (4): Enhance local, national and public health recommendations for cervical cancer screening as a way to reduce the health damage incurred by the suspension of recommendation, (5): Create a special national action plan to re-promote HPV immunization, and (6): Provide more accurate and pro-vaccine information for the media to report . We haveThe rate of mothers who are confused about their daughters’ inoculation has decreased and that of mothers who would not inoculate has significantly increased in this current study. It was clear that a leaflet that could be used under the current suspension of the MHLW recommendation could not increase mothers’ intention to inoculate their daughters. These results suggested strongly that the resumption of recommendations is essential for the future re-emergence of the vaccine. The MHLW promptly should resume its recommendations for HPV vaccination.