Incremental cost-effectiveness analysis (CEA) using a Markov model would be used to determine the cost of clinic-based HPV self-sampling. We believe that screening approaches to disease stratification could provide an insight into the merits and limitations of current approaches to the diagnosis of cervical cancer, and how these could eventually be implemented into HIV clinics in Uganda and other developing African countries. It is anticipated that the findings would guide the development of step-by-step guidelines for the HPV self-sampling approach. In Uganda, the uptake of cervical cancer (CC) screening services is low, at 46.7%, among HIV-infected women, and only 9% of these women adhere to annual CC screening. Some studies have evaluated the possibility of community or home-based human papillomavirus (HPV) self-collected vaginal swabs, but not clinic-based HPV self-collected vaginal swabs. Therefore, we propose a study to determine the efficacy of clinic-based versus home-based HPV DNA self-sampling among HIV-infected women attending a rural HIV clinic in Uganda. We believe that a randomized, single-blinded trial would achieve this objective, and so we have chosen it to guide the study. Including a total of 382 participants from a rural HIV clinic, randomized into a ratio of 1:1 for clinic- and home-based HPV self-sampling, would allow us to appropriately ascertain the difference in the uptake of HPV self-sampling between the two arms. The Integrated Biorepository of H3 Africa Uganda Laboratory would be used as a reference laboratory for the HPV DNA extraction, typing, and sequencing. At baseline, modified Poisson regression models would be used to measure factors associated with the prevalence of HPV and uptake in both arms at baseline. Visual inspection under acetic acid (VIA), as a gold-standard test for CC to grade for CIN, would be performed at 0 and 6 months among a random sample of 75 women with a self-collected HPV sample. The difference in uptake could be determined using the intention-to-treat analysis. The difference in the groups by each variable would be summarized as the standardized mean difference . The predictors of the time for which participants would continue with HPV self-sampling in both arms, recovery, and Cox proportional hazards regression would be used. At the bivariate level, the associations between each independent variable and time, with the time of continuing HPV self-sampling, would be computed. Crude hazard ratios and their 95% confidence interval would be used in the presentation of the results, with  The highest burden of cervical cancer (CC) disease is mainly observed in Sub-Saharan Africa ,2. In AfCervical cancer is the commonest cancer among Ugandan women. Annually, 3915 women in Uganda are afflicted by CC and, of these, 2160 die . The maiCervicography, Pap smears, and VIA are mainly performed by health providers via a colposcopy ,13. HPV Uganda faces many barriers to provider-led CC screening, and these include health workers who do not know the importance of CC screening , inadequHPV testing is globally recommended instead of Pap testing, because it is also conducted on patient-collected samples ,28. The Countries in SSA, such as Uganda, bear a high burden of the HIV/AIDS epidemic, and 50% of HIV-infected women barely access CC screening. Repeated HPV infection, and the cervix’s inability to shade off the HPV virus due to reduced immunity, occur mostly in HIV-positive women. As a result, they easily progress to pre-invasive cervical lesions . In UganThis increased risk among HIV-infected women requires them to screen for CC annually. However, there is a paucity of studies that have determined the effectiveness of clinic-based versus home-based HPV self-sampling approaches among HIV-infected women. It is anticipated that HPV patient-led CC screening would be effective, and would increase the uptake of CC screening and, hence, the early detection and treatment of CC. Additionally, there is no clear policy or organized structure for a nationwide cervical cancer screening program in Uganda. Therefore, there is an opportunity to increase the interest among rural HIV-infected women in going for HPV testing, through the promotion of programs that involve self-sampling approaches to HPV sampling among women. This could contribute to a reduction in the incidence of invasive CC, and in the health and community consequences of the disease. There is a lack of studies determining the effectiveness of patient-led HPV screening at an HIV clinic, compared to home-based vaginal HPV self-sampling, among HIV-infected women. We predict that if HIV-infected women conducted self-sampling at the HIV clinic using a vaginal collection kit method that was reliable, efficient, and acceptable, it would reduce the waiting time to access CC screening from the HW, enhance the prompt receipt of results, reduce attrition, and further address barriers to CC screening in rural communities. The results from the study will direct us to the appropriate HPV self-sampling approach for disease stratification, which will be published, and used to design policy briefs. Additionally, the findings will also be used to develop health promotion programs related to the prevention of HPV and CC among women. The health promotion model (HPM) has been chosen as the conceptual framework to guide this study, because health-promoting behavior is interpreted as a broad conceptualization, including the secondary prevention of CC. The theory could be used to interpret the effectiveness of clinic-based HPV self-sampling, in comparison with home-based HPV self-sampling approaches. It could be used to assess the difference in the uptake, HPV prevalence, associated factors, performance of clinic-based screening among HIV-infected women and their experiences, and costs related to patient-led HPV screening. The HPM would be used to interpret the factors affecting the uptake of clinic-based versus home-based HPV self-sampling among HIV-infected women. It was chosen because it suits the tailoring of public health interventions and dissemination . Public The three concepts that were chosen to guide this study were the concept of personal factors, the concept of situational influences, and the concept of health-promoting behavior. The concept of personal factors could be used to identify the demographic characteristics , knowledge, sexual history, reproductive health history, social factors, economic factors, and culture, concerning the prevention of HPV and eventually cervical cancer. The concept of situational influences could support the identification of the personal, family, community , and health system factors , and the cost-effectiveness, of the clinic-based versus home-based HPV self-sampling approach.Health-promoting behavior could be interpreted as activities related to HPV self-sampling, at the clinic or at home, among HIV-infected women. The model could also examine the relationship between personal factors and health-promoting behavior; situational influences and health-promoting behavior; and personal factors and health promotion. Additionally, the HPM has been widely used in health promotion research involving people of different age groups regarding participation in HPV self-sampling and CC screening . Figure Geographical areas where women have multiple sexual partners are key risk factors for HIV and HPV transmission. Luwero district is found in the central region of Uganda, where 19% of women have multiple sexual partners, which is a key risk factor for HIV and HPV transmission . This provides the basis used to justify the HIV clinic at Luweero Hospital, Luweero district  being coAs shown in The study approach would be to enroll all women attending the HIV clinic aged 25–49 years who had never been screened, had not been screened within the last year , or had abnormal screening results at the clinic, and to obtain their consent to participate.We propose using a phased approach, to allow step-by-step learning, as we implement the study procedures to determine the effectiveness of the clinic-based HPV self-sampling approach. The three phases that would guide this study are detailed below. To understand the dynamics of testing the tools, randomization, and recruitment procedures, and the specimen collection, handling, transportation, and storage before shipment to the central laboratory, it is important to pilot the tools. A three-day pilot of the tools could be conducted at Mukono General Hospital, Mukono District, which is not part of the study. We would aim to pretest 30 questionnaires among 15 HIV-infected women per arm. Per arm, three women would undergo HPV self-sampling and a visual inspection of the cervix under acetic acid (VIA) at the clinic and would also participate in an IDI. The main purpose of the pilot phase would be to test the tools, randomization, and recruitment procedures, and the specimen collection, handling, transportation, and storage before shipment to the central laboratory. At baseline, a cross-sectional study design would be used to determine the factors associated with the prevalence of, and those associated with the uptake of, HPV testing in both arms. We could, further, estimate the differences in the viability of the samples between the clinic-based and control groups. A prospective randomized controlled single-blinded trial has been considered to estimate the efficacy of clinic-based versus home-based HPV self-sampling among HIV-infected women at the HIV clinic. As women came to the HIV clinic, they could prospectively be randomized to clinic-based or home-based HPV self-sampling. This would be a single-blinded randomized controlled trial, in which the study participants would not know the arm to which they had been assigned. After recruitment and consent, a randomization Excel list would be generated, and participants randomized to the two study arms in the ratio of 1:1. However, a random sample of HPV-positive women who took up HPV testing in both arms at baseline could also be subjected to VIA. The women would be followed up at 6 months, to measure their continued uptake rate of HPV self-sampling. The period of six months has been considered as is the time for their refill treatment for ART. As the study is tailored so that the findings could be used to design screening approaches that were public, feasible, and cost-effective, a modified societal perspective could be used to model the cost-effectiveness analysis. Non-medical costs would be obtained from the interviews that we conducted with the women, and from the secondary data analysis of the budgets. However, comparisons for the transport costs, personnel time, patient waiting time, and time spent in the facility would be considered. To obtain robust outcomes, all midwives involved in the study would be initially trained in the study procedures. All eligible women attending the HIV clinic would be educated on the different procedures for the collection of samples for HPV testing. Women could prospectively be recruited and randomized as they came to the HIV clinic. The midwives would obtain women’s consent to HPV testing and VIA screening. The women randomized to the clinic-based HPV self-sampling group who had consented to and accepted the screening would be provided with an HPV sample collection kit to collect the vaginal swab and return it to the laboratory for HPV testing. The women randomized to home-based HPV self-sampling, who had consented to, and accepted, the screening, would receive the HPV testing kit from the community linkage personnel (CLP). The CLP could collect all the collected samples from the women and transport them to the laboratory at Luweero Hospital. As recommended by the World Health Organization  all women who took up screening in each group would need to first undergo a pregnancy test called human chorionic gonadotropin (HCG). The randomly selected sample of 150 HPV-positive women who took up HPV testing in both arms would further be subjected to a VIA, which is accepted as a gold-standard test for grading CIN in low-income settings such as Uganda. All women with suspected CIN2 and CIN3 could be referred to Uganda Cancer Institute for further management. The study would leverage the existing referral systems for cancer patients. UCI is the only national center for cancer treatment in Uganda and, therefore all identified cases are referred to that center as a norm; hence, there is no need for a memorandum of understanding. This is as shown in It has been estimated that a total of 382 HIV-infected women would determine the effectiveness of the clinic-based HPV sampling approach. In each arm, i.e., the clinic-based and the home-based HPV self-sampling, there would be 191 participants. The required powered sample for this sub-study has been determined based on the formula for comparative studies where the outcome is categorical (or a proportion) . To answer the question of the facilitators and barriers to HPV screening in the rural HIV clinic, we would conduct 24 in-depth interviews (IDIs) among women aged 25–35 years and 36–49 years, including women who would decline CC screening, with or without a history of STIs, as indicated in The phenomenology design would be used to explore the deeper facilitators and barriers toward women regarding self-sampling, either at home or in clinical settings, in Luweero District Hospital, Uganda. The in-depth interview (IDI) guide would be translated from English to Luganda. Qualitative data analysis would be guided by content analysis techniques. The transcripts would be coded in NVivo 20.7.0. The coded text would then be used to generate categories of analytically meaningful data that guided the formation of themes, the interpretation of results, and the final write-up.An electronic sampling frame of women aged from 25 to 49 years would be obtained via the Luweero district hospital HIV clinic. The women’s history of CC screening could be reviewed in their files. All women who had not been screened at all, not been screened within the last three years, had abnormal screening results, or had been screened more than 1 year ago with normal results, attending the HIV clinic, could be included in the sampling frame. The first participant would be randomly selected, and the subsequent women would be systematically selected using an interval of 2. Purposive sampling would be used to allocate women for IDIs, and expert opinions would be used to collect cost data from key informants and documents.Those who took up screening in both groups would be educated on the sampling procedure, and given a Qvintip kit to collect their samples. The Qvintip dry-based sample collection kit can be transported at room temperature, and is, therefore, appropriate to use in developing countries, as it does not require cold-chain transportation. Therefore, it would be appropriate to collect samples using the Qvintip kit, because would be is user-friendly in our settings. The samples stored at the HIV clinic lab would be transported to the Integrated Biorepository of H3 Africa Uganda as a reference laboratory for the HPV DNA extraction, PCR amplification, testing, and genotyping. To determine the factors associated with the uptake, and HPV prevalence at baseline (0 months) in clinic-based versus home-based HPV self-sampling from the baseline data, descriptive statistics, as well as univariate, bivariate, and multivariate logistic regression would be considered. The difference in uptake over the study period (effectiveness of clinic-based versus home-based HPV self-sampling) could be determined using the intention-to-treat analysis. We could further determine predictors of the time to continue with HPV self-sampling in both arms, and recovery, and Cox proportional hazards would be used. Content analysis could be used to analyze the qualitative data regarding the facilitators and barriers to HPV self-sampling. To estimate the cost-effectiveness of the clinic-based HPV self-sampling approach, an Excel model could be built and validated to check for the logical flow of events. Ethical approval was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC), Makerere University, School of Public Health Higher Degrees Research and Ethics Committee (MaKSPH-HDREC), and the Uganda National Council of Science and Technology (UNCST). The UNSCST has guidelines that support primary data collection, and the COVID-19 risk management plan for this project has been developed within the required guidelines. HPV self-sampling at the HIV clinic could be effective, and would increase the number of women using the service. The prospective implementation of the study will provide insights into the merits and disadvantages of the HPV self-sampling approaches for disease stratification, hence contributing to the best service design for Sub-Saharan Africa. The findings will also be used to guide a step-by-step process for providing HPV self-sampling services at HIV clinics.


To understand the HPV infection profiles among Chinese HIV/AIDS patients and the HPV vaccine acceptance among unvaccinated Chinese people with different HIV infection statuses after the HPV vaccine launch in China, this study searched Web of Science, PubMed, Cochrane Library, Embase, Scopus, CNKI, WANFANG, SinoMed, and VIP databases up to 23 June 2023, according to the registered protocol (CRD42023449913). A total of 58 studies were included. The results showed that the HPV infection rate among Chinese HIV/AIDS patients was 52.54% (95% CI: 42.11–62.86%) and higher in males than in females (74.55% vs. 41.04%); meanwhile, the rate was higher in the anus than in the cervix (69.22% vs. 41.71%). Although there was no statistical difference, the high-risk HPV infection rate (38.98%) was higher than low-risk HPV (23.86%), and single infections were more common (28.84%) than multiple infections (19.23%). HPV vaccine acceptance among the unvaccinated Chinese population was 59.19% (95% CI: 52.50–65.89%), and was slightly higher among HIV-infected rather than non-HIV-infected individuals (67.72% vs. 59.58%). There was a difference in acceptance among respondents from different regions. Although the difference in acceptance rate between males and females was not statistically significant (61.10% vs. 61.18%), MSM had a higher acceptance rate than non-MSM (84.28% vs. 59.05%). HPV infection is prevalent among HIV patients, demonstrating the need to increase the frequency of HPV screening for PLWH. The HPV vaccine acceptance rate is higher than that of non-HIV-infected individuals. Male acceptance is almost the same as female’s, with MSM acceptance higher than non-MSM, suggesting that using MSM, especially MSM in PLWH, as an entry point may be a practical avenue to explore to further expand the scope of HPV vaccination. Acquired Immunodeficiency Syndrome (AIDS) is caused by infection with the Human Immunodeficiency Virus (HIV) and is characterized by severe immunosuppression and infection. According to data reported by The Joint United Nations Programme on HIV/AIDS (UNAIDS), there were 1.5 million newly reported HIV infections in 2021, of which 49% were women and girls. Approximately 4900 young women aged 15–24 were infected with HIV each week, with People Living with HIV (PLWH) reaching 38.4 million by the end of 2021 . In addiStudies have confirmed that HIV infection increases the risk of HPV infection; for example, cervical HPV infection is significantly elevated in female PLWH , and anaCurrently, available HPV vaccines mainly include the bivalent vaccine , quadrivalent vaccine , and the 9-valent vaccine ; the bivalent and quadrivalent vaccines have shown promising safety and efficacy in previous research studies ,16,17. IChina’s State Food and Drug Administration (SFDA) approved the bivalent and quadrivalent HPV vaccines for marketing in July 2016 and May 2017, respectively, and then conditionally approved the 9-valent HPV vaccine for marketing in April 2018; two domestically produced bivalent vaccines have subsequently been approved. Previous surveys on HPV vaccine acceptance have mainly been conducted among age-appropriate women. One study summarized the results of several surveys conducted in China from 2009–2016 and found that the HPV vaccine acceptance among women under age 45 was 76.12% . AnotherIn this study, we hope to understand the HPV infection profiles among PLWH by summarizing the results of related studies and further analyzing them according to different genders, infection sites, HPV types, and other characteristics to find out the differences in HPV infection profiles among different subgroups of PLWH. Meanwhile, we will comprehensively analyze the HPV vaccine acceptance level among unvaccinated people after the launch of the HPV vaccine in China, and analyze the specific situations among individuals with different HIV infection statuses, gender, and other characteristics, not only to provide reference information for accurately grasping the actual acceptance of the HPV vaccine among unvaccinated women who are still in a wait-and-see state in China, but also to explore possible entry points for further expanding the scope of HPV vaccination in the future, especially in its application for males or PLWH.The review protocol was registered on PROSPERO (CRD42023449913). The databases Web of Science, PubMed, Cochrane Library, Embase, Scopus, CNKI, WANFANG, SinoMed, and VIP served as the study’s data sources. Search terms included HIV, AIDS, HPV, Human Immunodeficiency Virus, Acquired Immune Deficiency Syndrome, Human Papillomavirus, Acceptability, Willingness, Attitude, Intention, and China. Before the formal search, all the search terms were also searched in the Chinese Theme Word List and Mesh Word List, and several commonly used expressions were added. An additional manual retrieval strategy was used to retrieve and supplement the related literature that was listed in the review. Without regard to the article type, the retrieval time was from the earliest year provided by the database to 23 June 2023.Inclusion criteria: (1) The literature was a cross-sectional observational study, published in English or Chinese before 23 June 2023. (2) The study population was Chinese PLWH who underwent HPV testing. (3) The investigation was conducted in mainland China. (4) The article reported the accurate number of patients included in the study as well as HPV detection. (5) The sample size was not less than 100.Exclusion criteria: (1) Non-original studies . (2) Studies limited to patients with obvious symptoms of HPV infection. (3) Cohort studies with therapeutic interventions for patients.Because men have not yet been included in the HPV vaccination program in China, only women were limited by prior vaccination history; for example, the survey respondents had to be explicitly unvaccinated women, or the acceptance of unvaccinated women was reported separately in the results section. However, if the text did not explicitly describe that the men included in the survey were previously vaccinated with the HPV vaccine, the default was that the men had not been vaccinated against HPV.Inclusion criteria: (1) The literature was of cross-sectional observational studies published in English or Chinese before 23 June 2023. (2) The study population was Chinese people (who had not received the HPV vaccine) who were surveyed on HPV vaccine acceptance. (3) The survey was conducted in mainland China. (4) The survey was conducted after July 2016. (5) The article explicitly reported the number of unvaccinated patients as well as the number of people who were willing to receive the HPV vaccine.Exclusion criteria: (1) Non-original studies . (2) Studies which measured the respondents’ willingness to vaccinate others (spouses/children) with the HPV vaccine. (3) Studies in which educational interventions with relevant knowledge were provided to the patients. (4) Studies carried out under the condition of assuming a variety of prerequisites .If different articles were reported using the same data, only the article with the most detailed data description was included.The software Endnote (version X9) is used to manage the retrieved bibliographies. Data will be extracted independently by two writers. Any disagreements will be settled through debate until an agreement is reached or a third author is consulted. The following information will be extracted: the first author, the year of publication, the title (Chinese and English), the sample source, the investigation time, the collection sample, the study population, the number of HIV patients, the HPV infection profiles, the number of distributed and valid questionnaires, the number of unvaccinated and willingly vaccinated individuals, etc. If they included subjects with different affected areas or genders in one study and accurate data were available, they were extracted for multiple data points. The STROME-ID statement and features of the related studies were considered when we modified the literature-quality-assessment items, following the AHRQ’s requirements for evaluating cross-sectional studies. A total of 11 assessment items were eventually set for each component .Publication Language: Chinese; English. Gender: Male; Female. HPV type: High-risk HPV; Low-risk HPV. Infection type: Multiple-infection (MI); Single-infection (SI). HIV infection statuses: HIV infection; Non-HIV infection. Sample source: North China , Northeast , East China , Central China , South China , Southwest , Northwest . Multi-region . Meanwhile, the HPV vaccination policies in Hong Kong, Macao, and Taiwan differ from mainland China; studies about those regions are also excluded.2 test. When p ≤ 0.10 or I2 ≥ 25%, it indicated study heterogeneity. The combined effect size was determined using the random-effects model when p ≤ 0.10 or I2 ≥ 50%; otherwise, the fixed-effects model was used. Subgroup analyses and meta-regression analyses were also conducted. For the investigation of publication bias, Egger’s test was employed. If the p value > 0.05, it was assumed that there was no substantial publishing bias; if there was, the clipping and complement approach was employed to rectify it. Sensitivity analyses were also conducted by eliminating studies one by one to evaluate the stability of the combined effect values.Software R (version 4.2.3) and Stata (version 16.0) were used for the statistical analysis. The meta package evaluated the combined effect value of the HPV infection rate among PLWH and the HPV vaccine acceptance among unvaccinated Chinese people. The heterogeneity test employed the Q test and IIn this study, the HPV infection rate among PLWH was the number of HIV/AIDS patients infected with HPV (without distinguishing the type of HPV) divided by the number of PLWH who were successfully tested for HPV, hereinafter referred to as the infection rate; the HR-HPV infection rate, LR-HPV infection rate, single-infection rate, and multi-infection rate were similar. HPV vaccine acceptance among unvaccinated Chinese people is the number of people willing to receive the HPV vaccine as a proportion of the unvaccinated population who completed a valid survey, hereinafter referred to as acceptance; male acceptance and female acceptance are similar.A total of 24 relevant studies were included in this section. Because one study collected samples from both the cervix and the anus of patients and reported the results separately, the study was extracted into two data points, resulting in a total of 25 data points, among which 17 studies (18 data points) reported infection profiles without differentiating between the types of HPV, and 7 studies reported only high-risk or low-risk HPV infection.p > 0.05) but there was in different genders and sampling site groups (p ≤ 0.05).In calculating the combined effect value for HPV infection rate in Chinese PLWH, data from 17 studies (18 data points) that did not differentiate between HPV types were included, in which the reported infection rate ranged from 34.00% to 98.96%, and the meta-analysis  showed aB = 13.40, p ≤ 0.05).The combined infection rate among male PLWH was 74.55%, which was higher than among female PLWH (41.04%), and the detection rate of HPV was also higher in samples collected from the anus rather than the cervix of women (69.22% vs. 41.71%). When focusing on infection profiles in male PLWH, the results showed a higher HPV infection prevalence in MSM than in the general male population , the HR-HPV infection rate was 38.98%, which was higher than that of LR-HPV (23.86%), and the single-infection rate was higher than the multiple-infection rate (28.84% vs. 19.23%).Although the differences between groups of different HPV types and infection types were not statistically significant , with Northeast China having a higher level of acceptance (75.00%) than the other regions, followed by Southwest China and East China, with 66.11% and 64.95%, respectively, and North China having the lowest level of acceptance (30.68%). One study investigated acceptance in Shanxi and Sichuan and reported the data separately of the nine studies involving multiple regions, which offer two data points, with the remaining 25 studies conducted within a single province, constituting a total of 27 data points. When divided by the seven major geographic subregions of China A, the HPp > 0.05), and further comparison of acceptance among men between the MSM and the non-MSM rates revealed that acceptance was significantly higher among MSM (84.28% vs. 59.05%). When the cumulative meta-analysis was performed separately by gender, using the publication time of the included studies (p < 0.05), which slowly increased from 45.83% reported in 2019 and continued to fluctuate around 60%, and showed an upward trend among males , increasing from 38.46% to 61.10%.Five studies that did not limit the initial respondents’ gender provided HPV vaccine acceptance rates for males and females separately at the time of reporting, with 27 other studies that limited the respondents to a single gender, providing 37 data points. Meta-analysis  and subg studies , the res1 = 0.5186; P2 = 0.5322). The sensitivity analysis results showed that the maximum change value of the combined infection rate was 3.86%, when removing a study published in 2015 conducted in the Shaanxi MSM population, and the change amount was within 2.00% when excluding other studies. The maximum change value of combined acceptance was 1.12%, when excluding a study published in 2021 among students in Guangdong province, and the change amount was less than 1.12%, after removing other studies, suggesting that the combined effect values of both components were relatively stable.Egger’s test showed no publication bias in both components  in HIV-negative women in previous studies . In addi3), also reported were no significant differences in HPV IgG concentrations between the PLWH and HIV-negative individuals over time [Two meta-analyses in China, with search times ending in April and June 2020, have reported the HPV infection rates of male and female PLWH in China, which were 85.1%  and 45.8ver time . Additiover time , and malver time . These rAlthough single-infection is more common when grouped by the number of HPV subtypes infected, the pooled multi-infection rate is also nearly 20%. HIV infection makes it difficult for patients with impaired immune function to clear infected HPV automatically. As the organism continues to be infected with HPV, the degree of the lesion at the infection site will continue to deepen, and the likelihood of multi-infection will also continue to rise as the lesion’s severity increases, which in turn exacerbates the malignant lesion. Some studies have concluded that ART for HIV fails to affect HPV infection rates , but thiThis study summarized data from studies that focused only on the unvaccinated Chinese population and studies that mixed the HPV-vaccinated population but provided separate information on the acceptance of the unvaccinated individuals, and the results showed that the HPV vaccine acceptance among unvaccinated Chinese people was 59.19% after the HPV vaccine was permitted in China. Except for a few individuals, the majority of Chinese people in mainland China had not been HPV vaccinated prior to the marketing permission. However, the acceptance obtained from pre-permission studies was still higher than this study ,22, whicIt is worth mentioning that although there was no difference in acceptance between males and females, according to the results of cumulative meta, both unvaccinated males and females had an increase in HPV vaccine acceptance after the HPV vaccine was permitted in China, reflecting a series of measures that have been taken, since the HPV vaccine has been approved and marketed, one after the other in China since the start of 2016, such as increased publicity of HPV vaccine-related knowledge, increase in the types of vaccines that can be administered, expansion of the age range that can be vaccinated, and lowering of the cost of the vaccine, have achieved good results. These measures have been effective among females and impacted the HPV vaccine acceptance among males. China currently only vaccinates females against HPV, and the United Kingdom has provided HPV vaccine for girls aged 12–13 years old since 2008 to prevent cervical cancer caused by HPV infection and has provided a catch-up vaccination program for females aged 14–18 years old from 2008–2010. On the one hand, this female-only vaccination program has resulted in a significant reduction in the incidence of cervical cancer and cervical intraepithelial neoplasia type 3 (CIN3) in young women and has even almost succeeded in eliminating the incidence of cervical cancer in females born since 1 September 1995 . On the To the best of our knowledge, this study is the first meta-analysis in China to include both male and female HIV/AIDS patients and to provide a comprehensive description of the infection profiles with different sampling sites, HPV species, and HPV subtypes. At the same time, we found that a large number of previous HPV vaccine acceptance surveys conducted in China, or even meta-analysis within a specific population, did not differentiate between patients’ previous HPV vaccination status and reported the acceptance of individuals with different vaccination histories in a mixed manner, which may have resulted in an overestimation of the acceptance from the unvaccinated population. Therefore, this study focused on unvaccinated individuals and compared the acceptance of individuals with different HIV statuses for the first time in China, providing more accurate reference information for further promoting the HPV vaccine in the unvaccinated population. There are also some limitations. Firstly, the heterogeneity is high, as the data of this study are all derived from published articles, much information about the study individuals’ characteristics could not be extracted. Although the subgroup analysis has found that there are differences in HPV infection profiles among PLWH of different genders and sampling sites, and also found that there are differences in HPV vaccine acceptance among individuals in different regions and with different behavioral characteristics among the same gender, but this is not enough to explain all the heterogeneity. Different HPV testing methods and tested-HPV-subtype numbers may impact the combined value. Meanwhile, this study did not include studies with sample sizes less than 100, due to concerns of the limitations of sample sizes in previous meta-analyses, which may also provide certain information, but this study could not analyze those factors in depth. More factors contributing to heterogeneity need to be further explored in subsequent studies. Secondly, although some of the studies involved respondents from multiple regions, the distribution of the source regions ultimately included in this study was not sufficiently balanced, and there are still missing data from some provinces, which may make the results of the study deviate from the actual situation to a certain extent. Thirdly, some of the subgroups included fewer study cases, which may also have an impact on the results of the relevant analysis. Finally, due to the lack of qualification of specific HPV subtypes in many studies, the extracted information about HPV subtypes is limited, whether in the infection rate or acceptance, so this study was unable to carry out a detailed analysis for a particular HPV subtype, and there is a need to continue to track the literature to analyze the effect of different HPV subtypes on these components in subsequent studies.The HPV infection profiles among Chinese HIV/AIDS patients are prominent, with a significantly higher infection rate in men than in women, and more HR-HPV infections than LR-HPV, suggesting that increasing the HPV screening frequency for PLWH and initiating treatment as early as possible may help reduce the disease burden, improve quality of life, and prolong survival cycles. Meanwhile, the HPV vaccine acceptance among PLWH is higher than the non-PLWH; the HPV vaccine acceptance among unvaccinated males was almost equal to that of females and was higher among MSM than non-MSM, suggesting that using MSM, especially MSM in PLWH, as an entry point may be a practical attempt to explore and further expand the scope of HPV vaccination.


Background: Routine human papillomavirus (HPV) vaccine uptake continues to be suboptimal since its recommendation in 2006 for girls and in 2011 for boys. This paper aims to review published quality improvement (QI) methodologies on interventions to improve HPV vaccine uptake among adolescents. Methods: Science Direct and Scopus databases were searched for QI initiatives evaluating the effect of multimodal interventions to improve HPV vaccination rates (initiation and/or completion of series) among adolescents. Studies that included an outcome of interest among adolescents aged 10 to 18 years old were included. Two investigators worked independently to screen for potential articles and a designated investigator extracted data on study characteristics and evaluated the outcomes. Results: A preliminary search yielded a total of 523 articles and 13 were included in the final analysis. Common strategies were provider-specific  and patient- and/or parent-specific interventions , with an emphasis on education and knowledge empowerment. System-level interventions such as policy changes and revised protocols were less commonly prescribed despite being associated with a more significant weight on the overall outcome. Conclusions: Creative, sustainable, and economical multilevel interventions that focus not only on provider training and public education but also incorporate local policies and system enhancements can substantially improve HPV vaccination coverage among adolescents. Human papillomavirus (HPV) vaccine administration is recommended for adolescents by the age of 11 or 12 years to protect them from cancer-causing infections and precancers caused by HPV infection. HPV vaccination has been shown to be an effective primary prevention method to reduce the associated healthcare costs .In the United States (US), recent data on the coverage of at least one dose of HPV vaccine among adolescents aged 13 to 17 years showed an increase from 71.5% in 2019 to 75.1% in 2020 . DespiteGlobally, a multitude of quality improvement (QI) strategies has been devised to improve HPV vaccination rates: focusing on provider education on effective communication and HPV vaccine recommendations, prioritizing HPV vaccination along with other scheduled vaccinations, establishing strong partnerships between local healthcare facilities and departments, as well as developing and disseminating HPV-related resources for the public and providers . In MalaTo date, the barriers to complete HPV vaccine administration among adolescents largely stem from a lack of knowledge or misinformation among the public. A study among 400 women aged 17 to 26 years old in Krakow, Poland showed that nearly 70% of the respondents were aware that HPV vaccination may help prevent cervical cancer and yet only 8.5% were vaccinated against HPV . This siThis review involved a database search using a pre-defined search strategy on the Scopus and Science Direct databases. The keywords ‘human papillomavirus’ OR ‘HPV’ AND ‘vaccination’ AND ‘quality improvement’ were used.Eligible studies were included if they met the inclusion criteria, i.e., published QI reports aiming to boost the HPV vaccination rate among adolescents 10 to 18 years old, with the primary outcome analyzed statistically, published between 1 January 2019 and 25 March 2023. Review articles, letters to the editor, comments, and case reports were excluded. The references of the included articles were also checked to ensure inclusivity. Only articles published in the English language were included. If data of interest were unavailable for a particular study, the corresponding author was contacted for detailed information.A single author (K.K.) independently collected and collated search results based on predefined search strategies. Pooled abstracts from the citations were combined using Mendeley Desktop Version 1.19.8 and independently examined by two authors for article selection (K.Y.L. and N.F.M.) for final analysis. Discrepancies were resolved by the third author (O.W.). Final articles included for analysis were reviewed, the information extracted, and analyzed by a single author whose primary interest lies in QI methodology (K.K.) using a designated data extraction sheet. The data included the name of the first author, publication year, QI target population, mode of QI initiative, and results . At the end of the data extraction, the two researchers (K.Y.L. and N.F.M.) reviewed all key data and qualitatively assessed article quality.The primary study outcome was the overall HPV vaccination rate (not limited to either first injection or completed injection series). The secondary outcomes included the effect of specific intervention on any focus group .The study protocol was registered with the National Medical Research Register of the Ministry of Health Malaysia (NMRR ID-23-01062-XDU). The study was exempted from institutional review board based on the Malaysian National Institutes of Health Guidelines for Conducting Research in Ministry of Health (MOH) Institutions and Facilities 3rd ed. (2021).The article selection process followed the recommendation by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines .From the papers included in this review, improving the knowledge and communication skills of healthcare providers (HCP) through education sessions was the most common QI initiative undertaken to empower the HCPs, and subsequently boost the HPV vaccination rate in healthcare settings ,21,22,23In addition, for the QI activities to be successful, HCPs should have access to reliable resources on ways to improve HPV vaccination among adolescents in the primary care settings. More importantly, these resources should be developed based on the recommendations of key stakeholders such as the CDC, the American Academy of Pediatrics (AAP), the Henry F. Kaiser Family Foundation, etc. . FurtherAs for the QI coaches, in addition to playing an important role in educating the participants, they should also be actively involved in the project to continually motivate and provide feedback about on-site performance to the team members. A dynamic team is vital to sustain the momentum and continuum of the QI project to achieve the desired objectives . For exaIt is well established that risk communication and community engagement are fundamental to achieve high public acceptance and uptake of vaccinations. This can be achieved by empowering the public with adequate knowledge, awareness, and confidence through effective communication and strategic social media approaches.In this review, one of the QI strategies employed to prime the parents and/or caregivers in preparation for their child’s vaccination was to send a pre-visit email with information about the HPV vaccine prior to their child’s scheduled visit ,15. SomeFurthermore, social events to improve awareness and health literacy among the public were also organized, for example the HPV vaccination poster contest and ‘HPV T-shirt Fridays’ . By provLast but not least, effective healthcare policy changes may also bolster public health initiatives in improving HPV vaccination uptake. For example, a QI project conducted in a private pediatric practice in suburban New England found that the inclusion of HPV vaccination along with other vaccines contributed to an increase in HPV vaccination rates among adolescents from 17.8% to 63.6% in three months . SeveralThis review summarizes various QI methodologies used as evidence-based strategies in enhancing the uptake of HPV vaccination among adolescents. While most of the QI projects have shown a certain level of success, the implementation of these strategies in the real-world practice required careful planning and execution to ensure the feasibility and impact of the strategies.Based on this review, most of the implemented interventions to improve HPV vaccination uptake and completion focused on advancing HCPs’ knowledge so that they can educate the patients and parents/caregivers. Additionally, the important role of HCPs in providing effective communication is further highlighted in a study in which as many as 80% of the parents agreed that the provider’s recommendation during the clinic session was the main reason for them to approve their children’s vaccination . ProvideDespite HCPs being the most frequently targeted intervention group, a study conducted at three family practice clinics in Florida, US, to evaluate the use of a provider-based intervention  showed only a slight improvement of HPV vaccination rates . A succeOur study amplifies the significant role of social networking in healthcare. Provision of educational resources for patients/caregivers, regular reminders about clinic visits for scheduled vaccination via various available media, and awareness-raising campaigns and events were proven to be compelling efforts in boosting vaccination rates. Knowledge empowers adolescents (and their caregivers) to make proactive and appropriate decisions regarding the HPV vaccination. Hence, transparency in providing information regarding vaccine safety will also alleviate fears and misperceptions and guide their decision to get vaccinated ,14. AparIn comparison, some of the less commonly implemented interventions often require systematic changes, such as the establishment of an integrated patient-tracing system and scheduled follow-ups after missed appointments, facilitated through electronic health records. These multi-mode reminders via regular mail, telephone calls, e-mails, and text messages can be used to reach the young adult population . The samApart from the aforementioned strategies, a study found that including HPV vaccination together with other vaccinations during adolescence  also improved the overall vaccination rate . This woApart from these evidence-based QI approaches, potential cultural factors may also influence the decision to vaccinate. A relevant study across 12 clinics in Ohio, US, found that Latino children recorded the highest HPV vaccination completion rate (80%) while White children showed the lowest rate at 64% . HoweverIt is important to highlight the healthcare cost burden of preventable diseases caused by human papillomavirus. A recent review paper by Chesson et al. (2019) applying the current cancer cost estimates noted a substantial impact on the estimated medical costs that may be averted by HPV vaccination, with a moderate influence on the estimated cost per quality-adjusted life year (QALY) from HPV vaccination. In their example, a catch-up vaccination for adolescents and young adults was able to reduce the estimated cost per QALY by about USD 12,400 . This fuThe findings from our review highlighted that QI initiatives for the improvement of HPV vaccine uptake among adolescents require holistic efforts that incorporate improvement in any given measure to overcome conventional practices . Due attMultilevel interventions that focus not only on provider training, but also incorporates local policy and system refinements can substantially improve HPV vaccination uptake. Provider-based QI interventions are instrumental in improving the communication between clinicians and their patients with the aim of straightening HPV vaccine awareness and uptake. However, the implementation of these QI strategies in the real world can be challenging due to limited resources and demanding commitment. Therefore, a consistent and continuous HPV vaccination communication, supplemented by low-cost sensory rewards, as well as dynamic engagement between clinicians, supporting clinical staff, and the community are needed to ensure a high HPV vaccination uptake and completion among adolescents and young adults.


Gallbladder cancer (GBC) is among the most lethal malignancies in the world, with a prognosis that is extremely poor. The results of previous studies suggest that tripartite motif containing 37 (TRIM37) contributes to the progression of numerous types of cancer. Nevertheless, there is little knowledge about the molecular mechanisms and functions of TRIM37 in GBC.A clinical significance assessment was conducted on TRIM37 following its detection by immunohistochemistry. In vitro and in vivo functional assays were performed to investigate the role of TRIM37 in GBC.In this study, TRIM37 is upregulated in GBC tissues, which is associated with decreased histological differentiation, advanced TNM stage, and shorter overall survival rates. In vitro, TRIM37 knockdown inhibited cell proliferation and promoted apoptosis, and in vivo, TRIM37 knockdown suppressed GBC growth. Contrary to this, cell proliferation is increased in GBC cells when overexpression of TRIM37 is expressed. Mechanistic investigations revealed that TRIM37 promotes GBC progression through activation of the Wnt/β‑catenin signaling pathway via degradation of Axin1.The present study suggests that TRIM37 contributes to the development of GBC and thus provides an important biomarker for predicting GBC prognosis and an effective target for therapeutic intervention.  Among the biliary system tumors, gallbladder cancer (GBC) is the most common and most aggressive with an extremely poor prognosis Cancer progression may be caused by abnormal activation of the Wnt/β-catenin pathway in several cancer types, such as GBC ,6. Wnt lTripartite motif-containing 37 (TRIM37) belongs to the tripartite motif (TRIM) family and displays a conserved RING finger, B-box, and coiled coil regions The immunohistochemistry specimens used for immunohistochemistry were obtained from 124 radical cholecystectomy patients who underwent no preoperative chemotherapy or radiotherapy from January 2008 to January 2017 at the Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College. As shown in Paraffin-embedded GBC tissues were sectioned for immunohistochemical (IHC) analysis. Deparaffinization in xylene and rehydration in ethanol with varying concentrations were performed on the sections. In accordance with the standard procedure, the specimens were stained with an anti-TRIM37 antibody  followed by an anti-IgG antibody A0208  coupled to horseradish peroxidase (HRP). A maximum of four points was given to each sample in the immunohistochemistry evaluation, which was conducted independently by two pathologists without any knowledge of the patient's clinical or pathological characteristics. In total, 124 GBC patients were divided into two groups according to their IHC results: low TRIM37 expression group (0–2) and high TRIM37 expression group (3–4).Genechem  provided the human GBC cell lines GBC-SD and NOZ on October, 2019. An analysis of short tandem repeats has been performed on the GBC-SD and NOZ cells to validate their authenticity. The cells used in this study were regularly tested for contamination with mycoplasma. GBC‐SD cells were cultured in high‐glucose DMEM , and NOZ cells were cultured in William's medium E . In addition to 10% fetal bovine serum , 1% antibiotics were added to the medium to maintain all of the cells at 37°C in a humidified atmosphere with 5% CO2. From Selleck, we obtained cycloheximide (CHX) and MG132, which inhibit protein synthesis and proteasome activity, respectively.The TRIM37-overexpressed and TRIM37-short-hairpin RNA (shTRIM37) lentiviruses, as well as their negative controls, were obtained from Genechem . The guiding strand site and sequences of shTRIM37, according to the literature report In order to perform the subsequent treatment, the transfected cells are plated on either six or 96-well plates, and they are cultured for the indicated period of time. An assay for evaluating cell proliferation was measured using the Cell Counting Kit-8 . A cellular colony assay was performed by plating 1000 cells per well in 6-well plates and culturing them for two weeks at 37°C, in the following step, the cells were fixed in 70% ethanol and stained with crystal violet (0.5% in ethanol). An Annexin V-FITC Apoptosis Detection Kit was used to determine the degree of apoptosis among the cells. (Beyotime). Three independent assays were performed for each assay.−∆∆ct method, real-time reverse transcription PCR was conducted to measure the expression levels of target genes. Normalization of expression results for genes was achieved using the internal control, β-actin. The primer sequences were as follows: TRIM37, forward: 5′TATGGAGAAATTGCGGGATGC 3′ and reverse: 5′GTCAGCCAGCGCCTAATACAG3′; Axin1, forward: 5′GACCTGGGGTATGAGCCTGA3′ and reverse: 5′GGCTTATCCCATCTTGGTCATC3′; β-Actin, forward: 5′CATGTACGTTGCTATCCAGGC3′ and reverse: 5′CTCCTTAATGTCACGCACGAT 3′.The total RNA was extracted from tissues or cell lines of GBC using Trizol reagent (Invitrogen). In reverse transcription, cDNA was synthesized using the iScript™ cDNA synthesis kit (Bio-Rad). With the ABI Prism 7500 system  and SYBR Premix Ex Taq  using the 2Following the extraction of the total protein, it was separated by SDS-PAGE and then transferred to a polyvinylidene fluoride membrane. After that, we blocked the membrane with 5% non-fat milk in 0.1% PBST and incubated it with the indicated antibodies. The primary antibodies used were as follows: TRIM37, Axin1, β-Catenin , Active β-Catenin , C-Myc , Cyclin D1, β-Actin . Afterward, A secondary antibody  conjugated to HRP was then used to probe the membranes. Finally, enhanced chemiluminescence (Bio-Rad) was used to visualize the membranes.Lysates of cells were collected and immunoprecipitated overnight at 4°C with indicated or anti-IgG antibodies with gentle rotation. Over a two-hour period, we pulled down the antibodies using protein A/G-agarose beads (Santa Cruz). After extensive washing, immunocomplexes were resuspended in SDS loading buffer, followed by western blotting and IP assay. In the ubiquitination assay, Transfections with the HA-ubiquitin plasmid were performed on shTRIM37 stable transfected cells or on shControl cells. 48 hours after transfection, either two mg of HA-tag or IgG antibody was used to pull down the cell lysates. Separation of the immunoprecipitates by SDS-PAGE and immunoblotting with each antibody were performed.6 GBC-SD cells infected shTRIM37 or shControl was performed under the armpits by subcutaneous injection. The sizes of tumors were measured twice a week with calipers. Excision, weighing, and photography of the tumors were performed after the mice were sacrificed on the 21st day.In the present study, two randomly selected groups of female BALB/c nude mice (4-5 weeks old) were purchased from Shanghai Laboratory Animal Company. Inoculation of 1 × 10Statistical analysis was conducted with SPSS 22.0 and GraphPad Prism 6 software. Student's t-tests were used to compare groups, while Pearson's correlation test was performed to analyze data relating TRIM37 expression to clinicopathological characteristics. As part of the survival analysis, the Kaplan-Meier method and the Log-Rank test were used. The prognostic factors that were independent have been identified using multivariate and univariate Cox proportional hazard regression models. P values of less than 0.05 were classified as statistically significant.An examination of TRIM37 expression in clinical GBC tissue led us to speculate about its possible role in the disease. An analysis of 10 pairs of GBC and adjacent non-cancerous tissues performed using qRT-PCR revealed that the mRNA levels were higher in GBC than in adjacent non-cancerous tissues A. FurtheAn evaluation of the associations between TRIM37 expression and clinicopathological characteristics was conducted to clarify the clinical significance of TRIM37 expression in GBC. Based on the results of the IHC staining, the 124 patients with GBC were grouped into a low expression TRIM37 group (59 patients) and a high expression TRIM37 group (65 patients). According to To elucidate whether TRIM37 affected the biological characteristics of GBC, we examined two GBC cell lines (GBC-SD and NOZ) for TRIM37 expression as a first step. In GBC-SD cells, TRIM37 expression levels were higher than in NOZ cells according to qRT-PCR and western blot analysis A and B. In order to determine whether TRIM37 affects the proliferation of GBC cells, CCK-8 and colony formation assays were performed. TRIM37 knockdown significantly reduced the proliferation of GBC-SD cells, whereas TRIM37 overexpression increased the proliferation of NOZ cells A and B. As part of our investigation into a deeper understanding of the molecular mechanisms underlying the process, we explored the role of TRIM37 in the activation of the Wnt/β-catenin signaling pathway. As shown in http://www.hitpredict.org/) to explore its molecular mechanism on regulating Wnt/β-catenin signaling pathway. The predicted substrates for TRIM37 include Axin1 which encodes a cytoplasmic protein that functions as a negative regulator of Wnt/β-catenin signaling, was studied in detail. As shown in The bioinformatic analysis of TRIM37 was performed using HitPredict , 10.13039/501100003995Natural Science Foundation of Anhui Province in China (2108085QH342) and Science Fund for Outstanding Young Scholars of the First Affiliated Hospital of Bengbu Medical College (2021byyfyyq03).This study was supported by the There are no conflicts of interest reported by the authors.


This research is a preliminary study to observe the high-risk HPV infection profile among asymptomatic women, as a basis for developing Indonesian-specific reagents and implementing a national vaccination program.® 6800 platform for HPV identification and INNO Lipa (Fujirebio) kit for identification of the genotype.The research subjects were female employees/families of BUMN (state-owned enterprises) who underwent annual routine medical check-up. The research sample was a cervical swab which was examined using the CobasOut of 858 cervical swab samples collected in this study, 31 samples were excluded as they had invalid results from the initial examination, so the remaining 827 samples continued this study protocol. Of those samples, 69 (8%) samples gave positive results, giving an overall HPV prevalence of 8%. Among HPV-positive samples, HPV 52 was the most common genotype  found as both single-infection and multiple infections. The median age of subjects was 38 years. There were nine samples (13%) with multiple infections of two or more genotypes and seven samples (10.1%) with no specific genotype identified.HPV prevalence was 8%, with HPV 52 being the most common high-risk type, making it a necessity to develop a diagnostic kit and vaccine for national vaccination program that is specific for Indonesian population which includes this genotype. Cervical cancer is the fourth most common malignancy in women worldwide and remains as a global health problem. Based on data from the World Health Organization (WHO), in 2020 there are approximately 604,000 new cases and 342,000 deaths from cervical cancer worldwide, and around 90% of them came from low-middle-income countries . In geneNonetheless, cervical cancer can be prevented. As Human Papillomavirus (HPV) is found in >95% of cervical cancer lesions, HPV infection is considered an important etiological factor. There is no treatment for the virus itself, although some topical microbicides have been proposed for an intrinsic antiviral activity . AlthougHuman Papillomavirus (HPV) belongs to the Papillomaviridae family. Based on various genomic studies, more than 200 genotypes have been identified. HPV is able to infect the stratum basalis squamous epithelium of the skin and mucous membrane, so it can be classified into cutaneous and mucosal types. In addition, based on its relationship with cancer and pre-cancerous lesions, HPV is also grouped into high-risk types associated with malignant lesions, and low-risk types associated with benign lesions .HPV infection is one of the most common sexually transmitted infections in both men and women. Global prevalence rates of genital HPV infection in men range from 3.5 to 45% compared to 2–44% in women, with similar transmission rates . Most caHIV-infected individuals are reported to have a higher, up to six times the risk of contracting HPV. However, most infections among immunocompetent individuals will undergo spontaneous elimination. Persistent infections are thought to be associated with neoplastic progression. Persistent low-risk infection can cause benign lesions, such as condyloma, while persistent high-risk infection can cause precancerous lesions, such as CIN  in cervical tissues, which subsequently may develop into invasive cancer , 9.As an effort to eliminate cervical cancer, the WHO mandated all countries by 2030 to have achieved the 90-70-90 target, namely: 90% of young girls to have received full vaccination at 15 years old, 70% of women to have undergone screening using high-performance tests at 35 years old and a repeat testing at 45 years old, and for 90% of women with cervical cancer to be managed  . HoweverThis cross-sectional, community-based study was conducted between May–December 2022 as a part of a research for diagnostic kit development project. All subjects were female employees and their families belonging to state-owned enterprises (BUMN) in areas of Jakarta, Bogor, Bandung, or Semarang cities who underwent routine medical check-ups and were subjected to a Pap test with no apparent clinical symptoms. A total of 858 subjects participated in this study.®—Hologic, Inc. Malborough, MA, USA). The sample was immediately sent to the Immunology and Biomolecular Laboratory, Clinical Laboratory Department, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta.The sample used in this study was a cervical swab, which was taken by trained health workers using a cytobrush and promptly preserved in a liquid transport medium , designed for the identification of 32 different genotypes of HPV , including 13 HR types on 65 bp fragments. This kit amplifies a 65 bp long region on the open reading frame L1, producing a biotin-labeled amplicon. Genotype detection was based on reverse hybridization. Amplicons were reacted with various genotype-specific oligonucleotide probes attached parallel to the nitrocellulose membrane strips. Subsequently, the conjugate was added in the form of streptavidin-alkaline phosphatase to bind to the biotin-labeled amplicon, which was bound to the probe. The addition of the BCIP/NBT chromogen substrate formed a colored band on the strip.Data were analyzed using Microsoft Excel 2018 (version 16.16.14 or higher). Categorical variables were summarized using absolute values and percentages. The normality of the distribution of continuous variables was tested by Kolmogorov-Smirnov (K-S) test. Continuous variables with normal distribution were presented as mean (standard deviation [SD]), and non-normal variables were reported as median (interquartile range [IQR]). The difference in age between HPV-positive subjects and HPV-negative subjects was analyzed using the Mann-Whitney U test. Statistical analyses were performed using Statistical Package for Social Science (SPSS) software version 23 . A p-value (two-tailed) <0.05 was considered statistically significant.This study was approved by the Ethical Clearance Committee of the Faculty of Medicine, University of Indonesia (No. 674/UN2.F1/ETIK/PPM.00.02/2022). The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from subjects before enrolment.Out of 858 cervical swab samples collected in this study, there were 31 samples excluded as they had invalid results from the initial examination, so the remaining 827 samples continued this study protocol. Of those samples, 69 (8%) samples gave positive results. Based on the K-S test, data distribution for age variables does not follow a normal distribution (p<0.05). Therefore, we presented the age variable as median (IQR). The median age of HPV-negative subjects was 38.0 years (IQR: 31–43 years), which was not significantly different from the HPV-infected subjects whose median age was 38.0 (IQR: 32–42 years), with Mann-Whitney p-value of 0.841.Fourteen genotypes were identified in this study , and theMultiple infections occurred due to coinfection of two or more HPV genotypes, either high-risk types or coinfection with low-risk types. HPV 52 was the most frequently found high-risk type in coinfection with other high-risk types, such as 35, 16, and others. Coinfection of high-risk and low-risk types occurred in 1 sample, which was coinfected by HPV 59 and 44. There was one patient who was coinfected by 4 types of HR .Until 2021, more than 200 HPV genotypes have been identified. Based on their ability to trigger the development of precancerous lesions, these HPV genotypes are grouped into high-risk types associated with the risk of precancerous lesions, and low-risk types associated with benign lesions. High-risk types have been widely reported in at least 13 genotypes , but HPV 16 and 18 are considered the most prevalent. However, the distribution of commonly found genotypes can vary, depending on geographical areas and different cultural characteristics –13. ThisIn this study, the prevalence of HPV infection in the asymptomatic female population was found to be 8%. This is similar to de Sanjosé’s previous report, which stated that the average prevalence of HPV in 13 European countries infection in women with normal cervical cytology was 6.6%, ranging between 1.4–25.6% . LikewisIn this study, the most common high-risk genotype was HPV 52, both as single and multiple infections. These results are different from other studies, which generally reported HPV 16 as the most common high-risk type , 16. ThiBecause the commercial HPV vaccines in the circulation generally incorporate HPV 16 as the main target, such as monovalent (HPV16), divalent (HPV16/18), and quadrivalent (HPV 6/16/18/11) vaccines. While the vaccine might be able to prevent infection against HPV 16 and 18 , it is not enough to protect against other high-risk types . The samThere is already a nonavalent vaccine commercially available, which protects against HPV 52 among eight other high-risk genotypes (6/11/16/18/31/33/45 and 58), but the vaccine routinely used in Indonesia’s HPV program is the quadrivalent type, which only covers against HPV 6, HPV 11, HPV 16, and HPV 18. By adding HPV 31/33/45/52 and 58 to the genotypes already included in the quadrivalent vaccines, up to 90% of high-grade cervical lesions can be prevented. Using high-estimate calculations, Capra et al. demonstrated that the nonavalent HPV vaccine has a significant additional impact on both LSIL and HSIL, with a 23.8–32.8% increase in the proportion of cases effectively prevented by the second-generation HPV vaccine  [Another data found in this study was that 10.1% of samples were positive for HPV with an undeterminable genotype. This was possible because reagent kits generally used primers designed to amplify the most conserved DNA sequences and covered most of the HPV genotypes. The region considered to be the most conserved in the HPV genome is the L1 region. Genotype detection was then carried out by adding specific oligonucleotide probes for each known genotype. In this case, the failure to identify the HPV genotype was due to the limitations of the oligonucleotide probes used in the reagent kit.HPV is generally transmitted through sexual contact, but some suggest that HPV can also live in the environment, as HPV is a stable virus and can survive on fomites and surfaces for days. However, much work is needed to confirm the non-sexual transmission of HPV , 18. MosEven though this research was conducted on a demographic of middle socioeconomic status, HPV infection was still detected in significant proportion. This is consistent with previous reports, which were hardly contested, which stated that at least 80% of sexually active women will acquire HPV. But this is not the only factor that causes precancerous lesions. Persistent infection is an important factor for cervical carcinogenesis, and multiple infections proved to be an important factor in the persistence of infection , 19, 20.This study has several limitations. First, we only include subjects with relatively homogenous demographic characteristics, representing women of mid to high- social economy and education status living in three big cities; therefore, they may not represent general Indonesian women HPV prevalence status, in which population living in rural areas or low economic rate may encounter younger age of marriage (<15 years old) and thus are more vulnerable to HPV infection. Second, we could not determine the genotype of 7 HPV-positive samples due to the limitations of the oligonucleotide probes used in the reagent kit. Whole-genome sequencing may be a preferable method for assigning HPV genotypes. However, these strategies are associated with higher costs, and only variable portions of the genome are informative for HPV genotyping. Third, we did not collect the results of the Pap test, and therefore, the association of cervical cytology with HPV genotypes could not be inferred in this current study.The prevalence of HPV infection among the female population in four major cities of Indonesia is 8%, with a median age of 38 years. The most commonly found high-risk genotype was HPV 52, either as a single infection or co-infection.It is essential to develop more suitable reagent kits for Indonesian population. Vaccine selection for the national vaccination program needs to consider the high-risk genotype profile with high prevalence in Indonesia.S1 Data(XLSX)Click here for additional data file.


SDC2 were significantly related to the HPV susceptibility. And rs2575712  in SDC2 was associated with increased HPV 16/18 susceptibility. Four SNPs  were significantly associated with persistent HPV infection. Importantly, the genotypes of rs16894821 under recessive model  in SDC2 and rs11199993 under dominant model  in FGFR2 were significantly associated with the disease progression. Finally, SNPs showed comparable efficacy in detecting CIN2+ for the women infected with non-HPV16/18 compared with cervical cytology . SNPs in HPV receptor related genes may influence HPV susceptibilities and clinical outcomes in Chinese women.To investigate the relationship between single nucleotide polymorphisms (SNPs) in human papillomavirus (HPV) receptor associated genes and HPV susceptibility and clinical outcomes in Chinese women, from October 2016 to March 2020, a total of 3,066 women were recruited for a 3-year prospective population-based cervical cancer screening clinical trial. The primary endpoint was histological cervical intraepithelial neoplasia 2 and worse (CIN2+). Twenty-nine SNPs of HPV receptor associated genes on women with available cytology residual samples at baseline were detected using MALDI-TOF MS. Eligible data were available for 2,938 women. Rs16894821  and rs724236  in IMPORTANCE Virus receptors are known to mediate virus attachment and further lead to virus infection of the host cells. In the current study, we investigated the relationship between single nucleotide polymorphisms (SNPs) in human papillomavirus (HPV) receptor associated genes and HPV susceptibility and clinical outcomes in Chinese women, and to explore the new triaging strategy for non-16/18 high-risk HPV infection. Cervical cancer (CC) is the fourth leading cause of worldwide cancer death for women with more than 300,000 deaths annually . High-riAs we know, the development of CC is a complex, multistep process, including HPV infection, genetic, and environmental factors , 7. Viru10–13–16–Totally 2,938 women with sufficient cytology samples received SNP detection, and 23.11%  women were lost after 3 years of follow-up. Among 313 women with HPV infection at baseline, 57 were HPV 16/18 positive and 256 were non-16/18 HPV positive. Baseline characteristics of 2938 participants were listed in Table S2. Among 255 women with HPV positive at 3rd year, 160 women were newly infected who were HPV negative at baseline, while 95 were persistent HPV infection after excluding loss of follow-up. Among HPV positive at baseline, 107 women were spontaneously cleared at 3rd year and 62 cases were diagnosed as CIN2+. Totally 66 patients were diagnosed as CIN2+ during 3 years  and all of them were HPV positive at diagnosis.HWE) (P > 0.05). The SNP’s genotype and allele distribution were analyzed between groups with and without HPV infection (SDC2 had significantly increased HPV susceptibility compared with AA genotype (odds ratio (OR) = 1.71, 95% confidence interval (CI) = 1.08-2.69, P = 0.0473). Similarly, the carriers of allele G had significantly increased HPV susceptibility compared with allele A . Further analysis demonstrated that the recessive model for rs16894821  was a significant association with HPV infection instead of the dominant model. TT genotype of rs724236 in SDC2 had significantly increased HPV susceptibility compared with AA genotype . Similarly, the carriers of allele T had significantly increased HPV susceptibility compared with allele A . We also found a significant increase in HPV susceptibility both under the dominant model  and recessive model for rs724236 .The genotype distribution of 29 SNPs was in Hardy-Weinberg equilibrium . This observation was consistent with the increased frequency of the allele T compared with G  and the dominant model .HPV16 and HPV18 were the two most carcinogenic HPV genotypes. Thus, we further analyzed the SNPs for HPV 16/18 susceptibility  and founFGFR2, rs2575735 in SDC2, and rs878949 in HSPG2) were significantly associated with persistent HPV infection (Table S5). For rs1047057, HPV positive women carried AG genotype  and dominant model  were prone to HPV cleared compared with GG genotype. For rs10510097, allele T increased the risk of persistent HPV infection  compared with C, while rs2575735  and rs878949  had the opposite tendency. Dominant model analysis of rs10510097 revealed that CT/TT was more likely to turn to persistent HPV infection compared to CC genotype , while rs878949  had the opposite tendency.Due to immune mechanisms, most HPV infections spontaneously cleared within one to 2 years . In the SDC2, and rs11199993 in FGFR2) were significantly associated with the disease progression . Recessive model analysis revealed that genotype GG also increased the risk of disease progression compared with AA/AG . For rs11199993, dominant model of rs11199993 carried CG/CC genotype  and allele C  were also risk factors for developing to CIN2+.The baseline characteristics of participants of current study between <CIN2 and CIN2+ groups were listed in Table S4. As expected, the proportion of HPV positive women in CIN2+ group was higher than <CIN2 group, and there were no differences in age, smoking status, alcohol drinking, and education between <CIN2 and CIN2+ groups. The frequencies of genotype and allele of two SNPs  and 0.44 (0.30 to 0.60), specificities were 0.96 (0.96 to 0.97) and 0.98 (0.97 to 0.99), positive predictive values (PPVs) were 0.23 (0.15 to 0.33) and 0.33 (0.22 to 0.47), and negative predictive values (NPVs) were 0.99 (0.98 to 0.99) and 0.99 (0.98 to 0.99) for SNPs and cytology, respectively , which iHPV infection was recognized as the principal factor in the development of CC. More than 80% of women who in sexually active might be infected by the virus, but only a very few persist and eventually cause cancer . In pracSDC2 was one of the syndecan family of proteins, which could promote cell adhesion and was associated with cell proliferation. Previous studies have reported that SDC2 was overexpressed and enhanced invasion in several cancers  had a similar effect in detecting disease progression as cervical cytology in women with non-HPV16/18 infection. To the best of our knowledge, our study was the first to provide evidence that SNPs of HPV host cell receptor gene can be used to identify the disease progression in women with non-HPV16/18 infection.As we know, women with HPV16/18 infection would be directly referred to colposcopy, while women with non-16/18 HPV infection would receive cervical cytology triage, and abnormal results  required further colposcopy. However, the performance of cytology was heavily dependent on the experience and abilities of trained cytologists. In addition, a lack of well-trained cytologists had limited the application of cytology in developing countries. eceptors , which peceptors . Increasn cancer –39. Studll lines . Sun et ing FGFR , and FGF therapy . In presUnderstanding the role of genetic variants could promote the development of early detection biomarkers, predict the outcome of HPV infection and disease progression, and make aggressive management to reduce the incidence of adverse outcomes in a high-risk population. Our findings suggested that SNPs could effectively identify CIN2+ in women with non-HPV16/18 infection and had comparable PPV and NPV with cytology triage strategy. Due to the small sample size, additional prospective large-sample studies are needed to address the functional consequence of this genetic alteration in the natural course of HPV infection.Between October 2016 and March 2020, 3,066 women were enrolled in a 3-year prospective clinical trial on CC screening in Lishui, Zhejiang, China approved by the National Medical Products Administration clinical trial . Eligibility criteria for clinical trial included: aged 21 to 65 years and informed consent were obtained. Exclusion criteria included as follows: pregnancy or within 2 months of the postpartum period; previous total hysterectomy; surgical history of cervix uteri; a history of CIN or worse, vulvar intraepithelial neoplasia or worse, or vaginal intraepithelial neoplasia or worse, invalid HPV results/invalid or unsatisfactory cytology. Women with insufficient residual cytology samples were further excluded from current study. This study was approved by the Ethics Committee of Women’s Hospital, School of Medicine, Zhejiang University .The flow chart was shown in Subsequently, women with positive HPV or abnormal cytology at baseline would be recalled for cytology test every 1 year for 2 years and all enrolled women would be recalled for cytology and HPV test at 3rd year. Women with positive HPV or ≥ASC-US were referred to colposcopy in follow-up. All women with histological abnormalities at each visit were managed according to the Guideline for Comprehensive Prevention and Control of Cervical Cancer in China . The endGenomic DNA was extracted using the AxyPrep Multisource Genomic DNAMinprep kit . The genotypes of 29 SNP sites of HPV receptor related genes, including EGFR, FGFR2, HSPG2, INTEGRIN, and SDC2, were determined using the MassARRAY System  at Sangon Biotech Company . The detection system was based on MALDI-TOF MS, and the following procedures were applied: PCR amplification of genomic DNA containing the SNP sites, dNTP degradation using shrimp alkaline phosphatase (SAP), single base extension, desalinization with Spectro CLEAN resin, sample dispensation on Nano dispenser Spectro CHIP, data acquisition and analysis with MassARRAY TYPER software. Primers used for PCR amplification, single base extension, and 29 SNP sites were listed in Table S1. The detection of 29 SNP sites for each sample was carried out simultaneously in one well.2 test. The χ2 or Fisher exact tests were utilized to analyze the differences in genotypic and allelic distributions between groups. The correlation of genotypic and allelic with the risk of CIN2+ was evaluated via OR and 95% CI by unconditional logistic regression. The HWE was estimated by the goodness-of-χ2 test. All statistical tests were two-sided, and P < 0.05 was considered statistically significant. We used SAS 9.4 for all statistical analyses.Categorical variables were expressed as absolute numbers with percentages and compared with the χ


Cervical cancer (CxCa) is preventable and treatable via vaccination and screening. Cervicovaginal fluid (CVF) represents the physiological components of the female genital tract. These components are suitable to be utilized for clinical purposes, therefore, making CVF a suitable material for disease screening approaches.Due to high false-negative result rates and low attendance of current expensive routine CxCa screening methods, it has become more important to develop a point-of-care (POC) screening method that every single woman could reach worldwide. For this purpose, various self-usage apparatus have been developed for screening of the human papilloma virus (HPV) infection.Furthermore, due to the low specificity of HPV tests and the high clearance rate of HPV infections, many patients undergo overtreatment. Since proteins play an important role in cellular process and carcinogenesis, it is appropriate to use proteins in a simple screening test for the detection of carcinogenesis.In this article, POC screening tests and the studies of discovery of CVF protein biomarkers will be overviewed to consider the development of a method that can be used for the rapid and conceivable screening method of CxCa. The cervix, consisting of the ectocervix and endocervix, is the muscle where the uterus opens into the vagina. The endocervix is composed of columnar mucus-secreting cells, while the ectocervix consists of squamous epithelial cells. Under unfavorable conditions, the squamous epithelial cells in the ectocervix undergo various morphological and metabolic changes. The area where such transformation occurs is referred to as the “transformation zone” and is where carcinogenesis begins . TypicalManagement of cervical cancer screening follows the current guidelines. Since these cervical pathologies usually do not cause any symptoms, the cervix is routinely screened through Pap-smear test, and HPV genotyping for sexually-active female adults, regardless of any complaint. However, due to the frequent false-negative results of Pap-smear tests for screening CxCa, and the reduced availability of medical follow-up in low- and middle-income countries (LMICs), the development of self-screening tests is critical for improving the health of women worldwide. In addition, HPV infection has a high self-clearance rate, and in most cases, HPV positivity does not predict cancer development leading to overtreatment in HPV-positive patients. Therefore, a novel screening method with novel biomarkers for the detecting and prognosis of CxCa is critical to improve the wellness of women worldwide . Concerning this, studies for the investigation of new alternative screening approaches have been conducted for the last 20 years .HPV is the most common viral infection of the female reproductive tract, and HPV is mainly transmitted through sexual intercourse. An average adult has an 80% risk of contracting the HPV infection by the age of fifty. Every year, 570,000 cases among females and 60,000 cases among males can be attributed to HPV infection among cancer cases. Despite advances in HPV vaccination, vaccines cannot provide full protection due to the diversity of the virus in nature. To date, more than 170 HPV types have been identified; 40 of which cause various infectious diseases and 20 of which settle in genital tissues in humans. Vaccines are developed only against the most common and risky types of HPV.In particular, vaccines have been developed against HPV-6, 11, 16, and 18 types, which have most commonly been detected in CxCx cases . Although the HPV vaccine has 100% protection against the antigen types contained in children and adults who have never been exposed to the virus, it may also be effective in infected individuals . The vaccine protection is known for a maximum of 10 years. Therefore, an effective competent screening method for cervical cancer is required, which is a disease caused by this common infection and is highly treatable .Current diagnostic methods include Pap-smear test , HPV genotyping (based on (PCR) polymerase chain reaction), colposcopic imaging, cervicographic imaging, speculoscopic imaging, needle biopsy, and cone biopsy. Pap-smear test detects abnormal cells, produced by the infected transformation zone, in cervical smear samples . Pap-smePap-smear screening has been documented to decrease both the incidence and mortality rates of CxCa . NeverthCxCa screening and vaccination programs are effective in lowering the public risk of developing this disease ; howeverPoint-of-care (POC) diagnosis is a promising approach for screening certain diseases. The goal of this approach must be to detect disease-related specific biomarkers from easily accessible body fluids that were obtained through self-sampling apparatus. The device must serve as an easy-to-use, inexpensive, and noninvasive method.Generally, POC devices can be microfluidic electrochemical biosensors; they may contain fluorescent, nanoparticles, or quantum dots technology, or they may consist of simple paper-based microfluidic immunochromatographic tests . The typSince many people in LMICs do not have access to full healthcare services, early diagnosis of certain diseases is depend on the POC tests, under those circumstances. Currently, there are numerous POC tests available for the detection of various communicable diseases, especially viral or bacterial infections .Clinical laboratories offer high-quality diagnostic tests, such as PCR, genome sequencing, blood or urine culture, immunoassays, and mass spectrometry analysis, which are time-consuming, expensive, and rely on sophisticated instruments and well-trained personnel. In contrast, POC tests offer low-cost, portable solutions that are simple to administer and along with providing rapid results, which allows better short-term care, such as glucometers. Furthermore, as the most critical point, routine screening of certain diseases through self-tests emphasizes preventive medicine rather than treatment. Therefore, it has been reported that POC tests provide immediate results, can thus act as a personal indicator for medical intervention . ConsequAccording to the World Health Organization, POC tests that address disease control needs, especially in developing countries, must meet the “ASSURED” criteria: (1) affordable, (2) sensitive, (3) specific, (4) user-friendly, (5) rapid and robust, (6) equipment-free, and (7) deliverable to end-users .In recent years, several studies have focused on developing a novel sampling method for CxCa screening. 2) is 0.97 with a 4% coefficient of variation (CV). However, since the CA-125 marker is also overexpressed in CxCa and endometrial cancer  was significantly overexpressed in CIN-II, CIN-III, and CxCa tissues (p < 0.005) than the healthy tissue, and they confirmed its overexpression using both Western blotting and immunohistochemistry . This fiTo address the issue of limited financial resources, Inan et al. created a POC device that detects the HPV viral oncoprotein in whole blood using a noninvasive, inexpensive, rapid, and easy-to-perform method . This teAnother example of HPV self-screening test is nucleic acid amplification-based: Rodriguez et al. developed a POC chip for the risk detection of CxCa, made entirely out of paper and adhesive sheets, making it equipment-free, low-cost, portable, disposable, easy to manufacture, and simple to use. This chip can operate directly with cervical cytological specimens in less than 1 h using isothermal loop-mediated amplification (LAMP) to detect the expression of the E7 oncogene of HPV-16 .Zhang et al. compared the immunological paper-based test “OncoE6/E7” with the widely used liquid-based Pap-smear test “ThinPrep”. They found that the OncoE6/E7 test is capable of detecting E6/E7 oncoproteins from HPV-16 and -18 which are the most common types of CxCa risk, in the cytological specimens . They sh4, followed by ascorbic acid reduction; therefore, this resulted in immediate color changes in the samples. They found that the control gold nanoparticles  were bright blue, while the test gold nanoparticles (formed with cancerous samples) were colorless. They reported that this color changing was due to the formation of Au nanoparticles and the size/shape/interparticle distance-dependent localized surface plasmon resonance (SPR) of those. The detection technique C-ColAur was validated for its sensitivity and specificity, by comparing to Pap-smear test and/or colposcopic biopsy as the gold standards. Out of 42 samples, cancerous samples were identified in 28/27 and healthy samples 14/10 were identified correctly. The technique was reported with a high confirmation rate (approximately 96%) and high sensitivity (of approximately 96%) and specificity (of approximately 87%) for the efficiency of the method for early CxCa screening  which exposes the characteristic color. CVF samples were mixed with HAuClcreening .Following the development of novel alternative screening methods through POC tests, alternative biological materials for CxCa screening started to be investigated. Concordantly, cervicovaginal fluid (CVF) has a higher quality concerning the context compared to the smear sample. Moreover, CVF collection provides the direct secretions of the cervicovaginal region which comprises the transformation zone. In addition, its collection does not require medical assistance. Accordingly, studies on the CVF content have been conducted through different methods for various gynecological conditions in terms of genome, transcriptome, proteome, metabolome, and microbiome since the 1970s .Traditionally, biological secretions can be used as clues to identify and evaluate the circumstances of the human body. With the rise of omics technologies, the opportunity for the early diagnosis of certain diseases parallelly rises in the use of liquid biopsy assays . In addiIn the case of CVF, this body fluid contains approximately 92%–95% of water and approximately 5%–8% of ions, soluble macromolecules, and proteins  were determined as 100% and 100%, which are reduced respectively to 77% and 94% in the second part. Even so, the AUC was 87%, and this study identified six potential proteins as candidate protein biomarkers for the early diagnosis of CxCa, particularly ACTN4.The third of these quantitative proteomics studies, the identification of candidate protein biomarkers for CIN2+ stages, was conducted by Gutiérrez et al. in 2021. They collected the CVF samples with an endocervical brush onto cotton-based FTA (Flinders Technology Associates) elute microcards and used the filter-based protein digestion method. They established the study with 40 samples for (HPV-negative) the control group, and 59 samples for the patient  group. The peptide separation was performed by RP-LC using a nano-LC system combined with Q-Exactive Plus Orbitrap for MS analysis. They stated that a “predictive 7-protein multivariate model” was developed to discriminate the 2+ neoplasia stages, with 90% of sensitivity and 55% of specificity. However, they did not perform the antibody-based validation, which is frequently required to confirm proteomics results quantitatively (Regarding three of these studies, only ACTN4 and ANXA2 proteins are common  as signiCVF has great potential as a source for biomarkers for pathologies of the female genital tract. It may yield plenty of information about the functioning of the female genital tract. The proteomic studies may improve the understanding of the microenvironmental changes due to the various physiological conditions mentioned earlier. Nonetheless, the issues about the reliability of the biomarkers and the development of biomarker-based screening tests often depend on their method validation. Potential biomarkers generally cannot survive further validation. The probable reason for this is that although quantitative analyzes were performed to identify the CVF, not much attention has been given to the contribution of its biophysiological and also inter- and intraindividual variation, so far.Proteomic studies using the latest technology can further expand the CVF proteome and reveal novel candidate biomarkers. This section summarizes the studies that suggest potential candidate protein biomarkers that must be validated and verified by further and larger clinical studies. The development of an algorithm of diagnosis through an immunoassay or integrated multiplex microfluidic cancer biochip with two or three of the protein biomarkers may be the alternative screening method of CxCa. We believe that there is a high probability about such noninvasive novel methods will eventually be replaced with traditional methods.CVF may yield information about the health, function, and current prognosis of female genital tract diseases with several parameters such as the microbiome, pH, protein, and metabolite composition of this region. A novel method may be developed by the applications of advanced proteomic analysis and may help expand our understanding of the molecular environmental changes associated with the menstrual cycle, fertility, age, pregnancy and preterm birth, infections, and cancers of the female genitourinary area. Findings of metaanalysis and systematic reviews  indicateIncreased attendance rates that have been tracked through self-sampling  promote POC devices should also focus on applying novel biosensing technologies, which may improve reliability and facilitate the use of several protein targets. There have been several significant advances in this field over the last 15 years, which suggests that it may soon be possible to start producing low-cost clinical diagnostic solutions for women around the world.


Melaleuca alternifolia, is used for the management of various dermatological conditions, including HPV [Warts (verruca vulgaris) are benign epithelial proliferations associated with human papillomavirus (HPV) infection. They are a DNA virus belonging to the Papillomaviridae family . Worldwiding HPV ,4, by naWe performed a comprehensive literature search to include original articles, case reports and case series, and abstracts that discussed the effect of TTO on HPV verruca vulgaris; in PubMed, Embase, and Google Scholar; and were published on April 9, 2022, or earlier. Reviews and articles that used TTO with other interventions were excluded. The following keywords were used: “tea tree oil” OR “aromatherapy” OR “naturopathy” AND “human papillomavirus” OR “HPV” OR “verruca vulgaris” OR “warts.”A total of 4 articles involving 5 patients with warts treated with aromatherapy were included . Warts wThis research letter indicates that TTO can be beneficial in treating warts, which are caused by HPV and commonly occur in pediatric and school-aged children. The potent anti-inflammatory and antiviral properties of TTO have been widely used to treat HPV infections. In vitro studies have also used TTO to treat herpes simplex virus . TerpineTTO should be considered a safe, cost-effective, noninvasive modality in the management of HPV warts. More research is necessary to understand the clinical applications and other long-term systemic effects.