To achieve the Sustainable Development Goals (SDGs) target 2030, the United Nations (UN) endorsed tobacco use reduction, which is essential in decreasing unnecessary deaths caused by tobacco-induced disease. This study investigates the association between tobacco use and Human Papillomavirus (HPV) infection in clinically normal uterine cervix populations from the SDGs perspective.This study is a 7-year cross-sectional study of a clinically normal uterine cervix population, based on negative Visual Inspection of Acetic Acid (VIA). Subjects were recruited consecutively from the medical records of several public and private health providers in Jakarta. The Statistical Product and Service Solutions (SPSS) for Windows version 20.0 were used to analyze the data.A total of 1397 negative VIA subjects were collected, consisting of 4.9% (69/1397) tobacco users, and 95.1% (1328/1397) non-users. HPV-DNA positive were 4.3% (3/69) in the tobacco user group and 3.7% (49/1328) in the non-user group. Statistical analysis showed unadjusted OR was 1.19  and adjusted OR was 1.18 . High-risk HPV (hrHPV) infections of tobacco and non-tobacco users’ groups were found in 2/3 and 27/49 (55.1%), respectively.This study showed an insignificant statistical association between tobacco use and HPV infection in normal uterine cervix. However, the proportion of hrHPV infection was higher in tobacco users than non-users. From the SDGs perspective, cervical cancer is closely related to tobacco use and poverty. Further study is needed to support this result and evaluate other co-factor role-related cervical cancer history to achieve SDGs in 2030. A collaborative reanalysis of 12 studies also supported that current tobacco smoking was associated with an increased risk of squamous cell carcinoma (SCC), but not adenocarcinoma (AC)5. Risk factors associated with an increased incidence of severe dysplasia include sexual intercourse within five years of menarche (OR 3.32–4.09)6, lifetime smoking exposure (OR=7.2)7, and multiple sexual partners (OR=2.1) with four or more sexual partners8.International Agency for Research on Cancer (IARC), in 2004, listed cervical cancer among those causally related to smoking9. Increasing the number of HPV infections has been associated with tobacco use. Tobacco can affect the replication of HPV-DNA and accelerate the HPV life cycle. As a consequence, it can increase the ability of the virus to damage the cervical epithelium. Some cigarette components and their metabolites such as Benzo[a]pyrene, nicotine, and nicotine derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone were found to damage the local defence mechanism in the cervical epithelium10. Women who smoke tend to become infected with HPV with a 1.7 odds ratio (95% CI: 1.2–2.2)11. An estimated 19.33% of the global population (133 countries)12, 29% of the South-East Asia Region (SEAR) population13, and 24.3% of the Indonesian population smoke14. Although the most active smokers are men, women also contribute, especially as passive smokers, resulting in the same negative effects of smoking15.Understanding the history of HPV infection in the uterine cervix enables mapping out strategies to prevent cervical cancer16, compared to 14.1% in America17. The proportion of female smokers in the same year in SEAR and Indonesia were 10.8% and 4.8%, respectively14. In Indonesia, smoking cigarettes, the most popular tobacco usage, starts from the age of 12–13 years and higher in the rural than the urban areas18. Nevertheless, an increasing number of sexual partners of smoking women might be a potent risk factor10. In America, 42% of female teenagers had had sexual intercourse by the age of 15–19 years19. On the other hand, in Indonesia, based on a study by Rizkianti et al.20, most women delayed (>18 years) sexual onset (98.8%) while only 1.2% of 3943 samples had early (≤18 years) sexual onset.In 2018, the proportion of women smokers worldwide was at 6.1%21. Tobacco use prevalence is highest in low-income countries, while tobacco use contributes to increasing poverty21. Consequently, tobacco control, smoking cessation and poverty elimination are becoming some of the United Nation’s main concerns regarding the Sustainable Development Goals (SDGs). Smoking habits and poverty are part of a vicious circle that is difficult to break. This is an important study because there are no data in Indonesia. This study aimed to discover the association between tobacco use and HPV infection in normal uterine cervix from the SDGs perspective.The SDG 3 is sustained by WHO Framework Convention on Tobacco Control (FTCT) with some ambitious targets including reduction of the prevalence of current tobacco use, reduction of premature mortality from non-communicable diseases and the prevalence of several smokingrelated diseases, and strengthening of research capacity, particularly developing countriesThe cross-sectional study data were collected from the medical records for approximately seven years (January 2012 to July 2018). Subjects were women of reproductive age who were admitted to Primary Health Care (PHC) appointed in ‘See and Treat’ Female Cancer Program (FCP) Jakarta, in outpatients of the private clinic of the Obstetrics and Gynecology Department of Dr. Cipto Mangunkusumo General Hospital .After approval by University of Indonesia Review Board, the data were collected by consecutive sampling and presented with a percentage table from each risk factor. The inclusion criteria were married or sexually active and a negative VIA test. The exclusion criteria were diagnosed with cervical cancer or a pre-cancerous lesion, pregnancy, or genital infection when the study was conducted.The authors collected data from the medical records of the patients involved in the FCP program and other study sites. Tobacco users were defined as patients who had been ever and/or active cigarette smokers in their lifetime. HPV-DNA status was defined as a positive or negative HPV-DNA test result (PCR SPF10-DEIA-LiPA25 and hybridization for detecting and genotyping HPV-DNA). The samples were collected from cervicovaginal mucus taken before the VIA test. HPV types 16, 18, 31, 39, 51, 52, 53, 56, 58, 68, 69, 73 and 74 were classified as high-risk or probably high-risk types, while HPV 6, 11, 44, 54, 66 and 71 were classified as low-risk. Age was considered as the confounding factor in this study.The data were processed using Statistical Product and Service Solutions (SPSS) for Windows version 20.0. Association between smoking status and HPV infection was analyzed using chi-squared, and the confounding variable was analyzed using logistic regression.A total of 1504 subjects  for seven years met the inclusion criteria. Among these subjects, 62 subjects from FCP and PHC, and 42 subjects from Cipto Mangunkusumo Hospital, were excluded due to incomplete data on age, while three subjects were excluded due to duplicate patient data. Thus, 1397 subjects  with complete data were processed. Of 1345 subjects with a negative HPV-DNA test, 66 were tobacco users, while 1279 were non-users. Of 52 subjects with a positive HPV-DNA test, 3 were tobacco users, while 49 were non-users.The subject characteristics are described in The prevalence of HPV infection of the negative VIA population in this study was 52 subjects (3.7%). Based on tobacco user status, a positive HPV-DNA result was found in 3 (4.3%) tobacco users and 49 (3.7%) non-users. Data analysis showed that the odds ratio of tobacco use was 1.19 , and adjusted OR was 1.18  controlling for age, as described in Most of the study subjects (95.1%) were non-tobacco users, and only a small number (4.9%) were users. A positive HPV-DNA test was found in 4.35% (3/69) of the tobacco users and 3.93% (45/1145) in the non-users. The difference of 0.6% between these groups was considered significant because it exceeded the effect size (0.5%). However, analysis showed statistically insignificant result . This statistically insignificant result may be due to an inadequate sample size. Power calculations showed that to have 80% power to analyze the association between tobacco use and HPV infection with minimum effect size 0.5%, type I error 5% and the proportion of positive HPV in tobacco users was assumed 4%, and the ratio of non-users and users was 20, thus a minimum 11884 tobacco users and 237678 non-users were required. However, the available data were only 1397 subjects.22 in Mexico presented statistically similar results  with a total sample of 1340 subjects. The majority of the sample (76%) in their study had one lifetime sexual partner, and only 3% had multiple sexual partners during the previous years22. The study of Chatzistamatiou et al.11 observed that there was an association between smoking habits and high-risk HPV (hrHPV) infection in genitals in those aged 25–34 years  while there was no association in other age groups.A study by Lazcano-Ponce et al.23 with 1741 samples, showed an inverse association between tobacco consumption and HPV infection. This study reported a lower risk  of HPV-DNA infection in women with a history of tobacco smoking (19.8%). The smoking prevalence of women in Songkla, however, is low (6.1%), and in Lampang, it was reported higher in women aged >35 years (40.7%) than in younger women (2.3%). These data are similar to the prevalence of women smokers in Indonesia (4.8%) and the population in this study (5.68%). In the Sukvirach et al.23 study, a low participation rate was noticed because of limited screening (Pap smear) coverage in Thailand, and the proportion of women who refused to participate in the study was substantial. This study described the condition and obstacles of cervical cancer prevention in Asia, including in Indonesia.A population-based study in Songkla and in Lampang, Thailand, conducted by Sukvirach et al.24. Higher HPV 16 and HPV 18 DNA load was also associated with current smokers , but not with former smokers 10. This study found that 2 of 3 tobacco users with positive HPV DNA were infected with HPV 16 or 18 as the predominant hrHPV group. In contrast, only 9 of 49 (18.4%) non-tobacco users were infected with HPV 16 or 18. Smoking can increase the oncogenic HPV infections duration and decrease the probability of oncogenic infections clearance25. Besides, HPV infection risk increased with the intensity of smoking, while the risk of former smokers (OR=0.95) is similar to non-smokers. Secondhand smoking and alcohol drinking women might be at high risk of hrHPV persistence, but active or secondhand smoking independently did not affect the risk26. However, the association between smoking and the persistence of HPV is still controversial and has not been fully clarified27.Current smoking was a risk factor for squamous intraepithelial neoplasia if the HPV infection was persistent29. Although the specific mechanism of HPV infection-related tobacco use is unclear, it is presumed that tobacco has a harmful effect, particularly by direct carcinogenic process and local immuno-suppression in the cervix by reducing the number of Langerhans cells and CD4 lymphocytes, the local immune response in the uterine cervix. In addition, smoking can decrease natural killer cells’ activity, affecting the innate immune system27. However, the immunity status of the patients in this study could not be determined.Tobacco use, as one of the environmental/ exogenous factors, was not the only modifying factor contributing to the carcinogenesis of cervical cancer21. Tobacco use and poverty have a marked correlation. It is believed that tobacco use has a detrimental impact on individuals, countries, and nations’ health and economy21. Moreover, higher poverty was also related to increased HPVassociated cancers30. Tobacco’s participation in increasing poverty has been confirmed, particularly in developing countries. Nevertheless, we observed that the number of smokers in Indonesia was much lower than in high-income countries. In this study, the total number of smoking women was 69/1397 (4.93%), consistent with the Indonesian data in 2018 (4.8%)14, while in SEAR, United States, and the world, these were 10.8%, 14.1%, and 6.1%, respectively17. In this study, poverty as a strong risk factor for cervical HPV infection could not be controlled for.In the SDGs 2030, the UN includes tobacco control and poverty elimination31.It has been recognized that the squamocolumnar junction (SCJ) is essential in VIA testing because an invisible SCJ can lead to false-negative results. However, in this study, we included subjects aged >50 years to show that postmenopausal women do not always have an invisible SCJ. In this study, women over 50 years were considered as post-menopause. The number of subjects over 50 years was 228, including only 79 subjects (35%) with an invisible SCJ, while 65% (149 subjects) still had a visible SCJ. In addition, all subjects with invisible SCJ were HPV-negative. These findings supported the conclusion that there was no probability of false-negative results in the invisible SCJ group of this study. Another study in the Indonesian population in 2016 found that 38.4% of post-menopausal subjects still had a visible SCJ 32 and a low false-negative rate (3.21%)33. As a result, the false positive rate is high. In this study, each subject examination was performed by a trained general practitioner, midwife, or nurse, under the supervision of an expert and highly experienced gynecological oncologist to avoid bias due to false-positive and false-negative cases.The VIA is an excellent single screening tool with a sensitivity of over 90%In this study, the distribution of positive HPV-DNA tests in the clinically normal uterine cervix was considered a rare study population. However, this study has some limitations. Firstly, although there was a slightly high proportion of HPV infection in tobacco users, it is not statistically significant. Secondly, we did not distinguish former versus active tobacco users and the severity or the amount of tobacco use which may confound the biology of HPV infection. Thirdly, the persistency of the HPV infection was not evaluated due to difficulty in contacting the subjects. Fourthly, sexual behavior, socioeconomic status as well as poverty, OCs use, Pap result, as well as tobacco consumption frequency as confounding factors were not controlled for due to limited information obtained in the medical records. Finally, the power of this study was not sufficient to prove statistically significance because of the insufficient sample size. Therefore, further research is still needed to improve the weaknesses in this study. Although this study has some limitations, we believe it can be generalized to the normal uterine cervix population in Indonesia.This study showed that there is no significant statistical association between tobacco use and HPV infection in normal uterine cervix. However, this result needs to be carefully interpreted. Moreover, the proportion of hrHPV infection was higher in tobacco users than in non-users. Tobacco use is still believed to increase the progression to cervical cancer in the current dysplasia of uterine cervix. From the SDGs perspective, cervical cancer is closely related to tobacco use and poverty. Tobacco contributes to increasing poverty, particularly in developing countries. We only discussed cervical cancer risk factors due to tobacco use. In addition, further research is still needed to improve the weaknesses in this study. Thus, further evaluation of other co-factor roles related to cervical cancer history is necessary to achieve the SDGs in 2030.


I have always felt that connecting with others in my community would give me the support structure needed to succeed—both personally and professionally. Today, I am a research project manager in Veterans Affairs (VA), a social worker, and an Army veteran—three pieces of my identity that help me quickly connect to my community and the veterans within it. Building relationships with these folks gives me strength, and I hope to always do the same for them.In 2003, I enlisted and served in the Field Artillery for three years on active duty and deployed for 15 months as a truck driver. Shortly after returning home, I reenlisted with the New Jersey National Guard and deployed again for another year as an aide to the commanding general of detainee operations in Baghdad, Iraq. I’ve spent every year, post-service, working to help my fellow veterans make sense of the VA, a system that was built exclusively to care for them for the remainder of their lives. As a social worker, I see how the barriers within their healthcare system can help them or harm them. As a vet, I draw on personal experience to empathize with them. As a researcher, I dive deeper into those barriers and try to help break them down. Like many veterans before and after me, my desire to help other vets have a better experience drives my efforts to ensure we do our best for them.From War to Home: Through the Veterans Lens—a photovoice project that described the challenges of transition from military to civilian life. I took a picture of the two years of weekly unemployment I collected when I left the military in 2009, just one year after the recession. I wanted other Veterans to take advantage of this benefit instead of struggling to pay bills, like I did after completing my first tour of duty in 2006. Participating in From War to Home was my first experience with community-engaged research, and it gave me a platform to advocate for others like me. I first saw the flyer on the director’s desk at the West Chester University Veterans Center in 2011. He usually tossed flyers from the VA into the trash, but this time, he vouched for the researcher, saying he’d “grilled her for hours and she was legit.” If the researcher had not taken the time to explain the study to him, and he couldn’t see the impact, he would have never displayed a flyer for her. He built the center to support veterans and provide a safe space for them. The flyer mentioned compensation and a free camera, which appealed to me as a broke college student, but without hearing his perspective, I probably would have dismissed it.Figure From War to Home was a public-facing advocacy project. The data collected comprised a traveling exhibition of photos with corresponding quotes from photo-elicitation interviews. Gala made it clear that my words and photos would be displayed at many public-facing venues across the United States, including many VA Medical Centers. I had participated in other studies where I had never seen the results, or if what I contributed had made any kind of impact. The photovoice project felt very different.I expressed my interest over a short phone call and Dr. Gala True drove from Philadelphia to my home in Delaware, where we spent hours going over consent forms and talking about the project. From War to Home. At first, I talked about my experiences in the project, how it was similar to art or narrative therapy, and how it helped me talk about things that I previously had trouble expressing. As my career and my experience as a veteran evolved, the conversations began to shift into why collaborating with VA researchers was important. Veterans needed a stronger voice in the research that affected their care. Researchers were having trouble making connections to veterans outside the VA. I found myself speaking more about accessing the veteran community outside of VHA rosters and how best to approach them.For many years, Gala kept in touch and asked me to speak on webinars and travel for conferences to help present From War to Home helped me think about how I could make a broader impact through community engagement and research. Shortly after the photovoice project was first exhibited, I accepted a job at Portland State University to build and direct their new Veterans Resource Center. During my years there, we enrolled up to 1100 unique veterans annually, most of whom had just left the military and were using their education benefits. Aside from my advising duties, my students and I created a needs assessment for our community and collaborated with other student centers to increase diversity and inclusion in our space. I made it my mission to educate the public about the war and the value of the people who experienced it—in the classroom, on the stage, on the radio, or through community service. I hosted storytelling and art-making workshops, developed a peer-mentor program, and networked with every service aimed at veterans in the Portland metro area. Eventually, we created a space for VA to come to us—a closet in our student lounge that we turned into an office for our visiting VA Vocational Rehabilitation counselors. On the days they weren’t on campus, we opened the office to other veteran service officers and VA researchers looking to connect to our students. When researchers approached me, I asked them to first build trust with us. Instead of hanging flyers, we invited researchers to present information about their studies and gave them time to answer questions from veterans.The work I did with In 2014, Dr. Sarah Ono, a research investigator at VA, asked me to be a part of her seed committee for a new veteran engagement group, and I helped her identify some members who I believe are still advising research today. From working with Gala and Sarah, I saw a lot of the research being conducted as beneficial to the veteran community, so I took on the work of connecting them.In 2015, I was co-presenting with Gala and Sarah at the VA Health Sciences Research and Development Quality Enhancement Research Initiative National Meeting, and Gala told me she was relocating to New Orleans and starting another 3-year photovoice project. I asked if she needed a project manager, and soon enough, we began the year -long process of hiring and onboarding. Upon arriving in New Orleans, I began identifying veteran organizations and started meeting with whoever would give me the time. I volunteered. I helped create and organize events for veterans, their friends and families. I showed up for meetings. We get to meet a lot of people through community-engaged research, so we create opportunities to connect. In my experience, most communities of veterans grew organically, and friendships were formed from common experience and storytelling.1 We have another paper, co-authored with veterans with a traumatic brain injury, that is forthcoming in a special issue of the Journal of Community Engagement and Scholarship.2 They serve on our advisory boards and continue to connect us to other vets in their communities. We continue to call on them when we need their voices, and they always answer.A lot of the folks who collaborated on the projects I worked on became friends. We don’t just eat together—we have co-authored a paper with Veterans and caregivers that appeared in a special issue of the Journal of Humanistic Psychology.“Veterans helping veterans” has been the mantra of almost every veteran-focused organization I’ve worked with over the past decade, and I have heard many folks say that we are the only ones who can truly understand other veterans. The American Legion, Veterans of Foreign Wars, and similar groups seem like the most common places that researchers look for veterans—but there don’t seem to be many researchers in the ranks of their membership. If the VA could hire more veterans into research roles, and prioritize engagement with these groups, we may be able to make a bigger impact. They could easily protect time for veterans working in research to be liaisons and build bridges to groups like The Mission Continues, Team Rubicon, Veterans For Peace, About Face, and other veterans groups who could broaden the spectrum of diversity and inclusion. The future of VA research depends on VA’s commitment to support and push collaborative health services research forward. Together, veterans, and veteran or civilian researchers can truly break new scientific ground, not only for the betterment of VA health care, but potentially for health care systems in general.


Stenotrophomonas, Streptococcus, and Pseudomonas, and a concomitant paucity of Dialister, unidentified Prevotellaceae, Faecalibacterium, Bifidobacterium, and Bacteroides, were related with HSIL, which can be used to predict the development of HISL in high-risk HPV infected patients. The relative abundance of Stenotrophomonas being over 0.0090387%, or Faecalibacterium being under 0.01420015%, or Bifidobacterium being under 0.0116183% maybe a good predictor for HSIL for those infected with HPV 16 and/or 18. The relative abundance of Stenotrophomonas being over 0.01549105%, or Streptococcus being over 0.48409585%, or Bacteroides being under 0.0296912% maybe a good predictor for HSIL for those infected with the 12 other high-risk types of HPV with concurrent abnormal TCT results. This study revealed that potential vaginal microbiome biomarkers may relate to HSIL, and can facilitate the cervical cancer screening.Vaginal microbiome may have a role in HPV infection and cervical neoplasm. To explore potential vaginal microbiome biomarkers for high-grade squamous intraepithelial lesion (HSIL), and to find the best scheme to facilitate the current cervical cancer screening strategy. This study enrolled 272 women, including 83 confirmed with HSIL, 86 with HPV infection but without cervical neoplasm, and 103 without HPV infection as controls. Vaginal microbiome composition was determined by sequencing of barcoded 16S rDNA gene fragments (V4) on Illumina HiSeq2500. The relative increasing abundance of  Human Papillomavirus (HPV) is one of the most common causes of sexually transmitted diseases (STDs) in women around the world . The incThe vaginal ecosystem exists as a finely tuned balance between microorganisms and the host. Modern next-generation sequencing-based characterization of the VMB has provided a more in-depth and detailed composition of the microbiota. There is emerging evidence that VMB may play a crucial role in HPV induced cervical lesions –6 and isCervical cytology and HPV tests are widely used for cervical cancer screening and thus early detection of underlying disease. However, although the current screening strategy is highly sensitive for high-grade cervical neoplasm, it holds a limited specificity. Therefore, the objective of our current pilot study is to explore the most closed specific compositions of the VMB (defined by molecular techniques) associated with high-grade squamous intraepithelial lesion (HSIL), and thus facilitate the current screening strategy by decreasing the proportion of cases receiving invasive examination and overtreatment.clinicaltrials.gov is NCT03548740. Written informed consent was obtained from all participants.Ethical approval was obtained from the Ethics Committee of Peking Union Medical College Hospital (PUMCH), Beijing, China . All experiments were performed in accordance with relevant guidelines and regulations. The registration No. on This prospective observational cohort study was implemented in a tertiary teaching hospital. The sample size was referred to the previous reported study. According to the results of HPV test and pathology of cervical biopsy, the participants were divided into three groups. Group A: 83 cases with HPV infection confirmed with HSIL by cervical biopsy . Group B: 86 cases with HPV infection but confirmed without cervical neoplasm (LSIL were excluded) . Group C: 103 cases without HPV infection or abnormal TCT result . All the patients enrolled haven't been treated with physiotherapy such as laser therapy, cryotherapy, or surgical treatment like loop electrosurgical excision or cold knife conization. The flow diagram of this study is showed in The participants engaged in this research were those who visited the department of Obstetrics & Gynecology of PUMCH between July 2018 and March 2019. All of the participants enrolled are women presenting for cervical cancer screening. Inclusion criteria: Those aged 20 to 72 years old, having had vaginal intercourse for more than 3 years, and aren't in menstrual, pregnancy or puerperium period. Exclusion criteria: Those who are virgin, having had total or subtotal hysterectomy, or patients who were diagnosed with acute genital tract inflammation. Women who are HIV positive, have autoimmune disorders, or have a history of malignant tumors are also excluded. At the same time, all the participants should meet the following requirements: no vagina douching within the last 2 days, no vaginal intercourse within the last 3 days, no systemic application of antifungal agents, antibiotics or pessaries within the last 14 days before sampling.® Pap testing  and DNA capture via the Cobas® 4800 System HPV Genotyping Test  which is based on real-time qualitative PCR (RQ-PCR).A sterile, disposable speculum was inserted without lubricant, and a sterile swab sample was taken from the posterior vaginal fornix and stored immediately under −80°C for DNA extraction. At the same time, each patient was given a liquid Pap test with ThinPrepDNA extraction and the amplification of bacterial 16S rRNA V4 gene region and Illumina sequence were shown in the P < 0.05 was interpreted to be statistically significant.Statistical analysis of the clinical data was performed using the SPSS 23.0 software . Continuous variables were analyzed with rank sum test, and categorical variables were analyzed with Chi-Square Test. P = 0.773), Gravidity (P = 0.057), parity (P = 0.541), phase of menstrual cycle (P = 0.177) and the method of contraception  Curve to find the cut-off relative abundance of potential microbiome biomarkers to help avoid unnecessary invasive cervical biopsy. Among the 63 cases infected with HPV type 16 and/or 18, 15 cases were confirmed to have no cervical lesions by cervical biopsy. The positive predictive value (PPV) of HSIL can reach from 76.19 to 82.54% with the relative abundance of e biopsy .Stenotrophomonas being over 0.01549105%, or Streptococcus being over 0.48409585%, or Bacteroides being under 0.0296912%. That is, 11 cases could avoid the invasive biopsy   . In our Stenotrophomonas, Streptococcus, and Pseudomonas, as well as concomitant paucity of Dialister, unidentified_Prevotellaceae, Faecalibacterium, Bifidobacterium, and Bacteroides. Numerous epidemiological studies have shown associations between the non-Lactobacillus-dominant (NLD) cervicovaginal microenvironment and HPV infection, development of precancerous dysplasia and progression to cervical cancer   and one being in high abundance (Gardnerella) is associated with cervical lesions  , 14, 17. lesions . Patientneoplasm , 14, 19.ysplasia , 14. Thul genera , 22, couLactobacillus intestinalis, Lactobacillus reuteri, Lactobacillus iners, Streptococcus agalactiae, and a concomitant paucity of Lactobacillus jensenii, Dialister micraerophilus, Moryella sp KHD1, Prevotella disiens, Sneathia amnii, Veillonellaceae bacterium DNF00626, and Prevotella sp S7-1-8. A study conducted with Korean women also showed that a cervical microbial pattern characterized by high abundance of Atopobium vagiane, Lactobacillus iners, and Gardnerella vaginalis and a concomitant paucity of Lactobacillus crispatus causes an almost 6× higher risk of cervical neoplasm , Beijing, China . The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.SW and JL developed the ideas for this study, designed and performed this scheme. XC, LW, XT, HS, and QF collected the samples and clinical data. The manuscript was drafted by XC and LW, revised by SW, and approved by all authors.This study was funded by National Key R&D Program of China (2017YFC1001200).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The precipitation of large amounts of intermetallic compounds along the grain boundaries were found to be corroded preferentially. The internal surface of the used pipe was covered with many fine cracks. The corrosion and cracking of grain boundary precipitates accounted for the short service life of the C-276 pipe. Compositional measurements by electron probe micro-analyzer (EPMA) and phase identification by electron backscatter diffraction (EBSD) confirmed the presence of δ and μ phases in the ruptured pipe. The coarse intergranular precipitates were the δ phase (Mo7Ni7), which were enriched in Mo and Cr. Moreover, the fine precipitates dispersed intergranularly and intragranularly were the μ phase (Mo6Ni7), which were abundant in Mo and W. The numerous precipitates present in the matrix and along the grain boundaries were responsible for an obvious loss in the strength and ductility of the used C-276 pipe.Failure analysis was carried out on a ruptured C-276 pipe heated externally at 1050 °C, which had been used for a few months in a controlled decomposition reactor (CDR) system. To catch the decomposed perfluorinated compounds (PFCs, e.g., CF Precipitation of the Mo-enriched μ phase is known to produce a moderate loss of room-temperature tensile ductility [Hastelloy C (Ni-based) alloys are used extensively in the chemical and aerospace industries and in marine applications due to their excellent resistance to harsh corrosion and high temperature oxidation. Hastelloy C-276, a typical Ni-Cr-Mo-W alloy , is knowuctility  but resuuctility ,4. Impac4, SF6, NF3, C3F8 and C4F8) are extensively used by semi-conductor companies [3) is known to be an extremely strong greenhouse gas for it has a global warming potential thousands of times greater than that of CO2 [3 gas and other harmful species. Failure analysis was carried out on a failed C-276 pipe which ruptured after just a few months of service. A detailed investigation, including visual inspection, microstructural evaluation and phase identification, was performed to determine the causes of the fast failure of the C-276 pipe. In a prior study, the wear resistance and the hardness of Inconel 625 alloy could be increased by reinforcing with TiC particles with no harm to corrosion resistance, if less than 25% TiC was added [Nowadays, perfluorinated compounds . The tensile test follows the ASTM E8M specification. To evaluate the degradation in strength/ductility of the used pipe, some tensile specimens were cut from the ruptured pipe in two different zones located at distinct distances away from the broken zone. Because of non-uniform thickness and geometry constriction of the round pipe, tensile test samples cut from the ruptured pipe showed a slight curved profile. To reduce the deviation in tensile properties of the tested sample, the sample thickness was measured at five locations within the 25 mm gage length before tensile tests. The microstructures of the precipitates were inspected in detail with a Tecnai G2 transmission electron microscope . The samples for TEM examination were cut from the ruptured pipe by FIB. The specimens were also examined with a SEM equipped with a NordlysMax2 electron backscatter diffraction  detector to identify the phases present in the specimens.The microstructures of the ruptured pipe were investigated after it was cut into small samples, which were then subjected to metallographic preparations. A JSM-7100F field emission scanning electron microscope  was used to examine the changes in the microstructure in the ruptured C-276 pipe. The chemical compositions of the precipitates were determined with a JXA-8200 electron probe micro-analyzer . The reactive products that had formed on the inner and outer surfaces of the ruptured C-276 pipe were investigated by D2 Phaser X-ray diffraction  under Cu Kα radiation. The precipitates at the grain boundaries of the ruptured pipe were cut with a Helios NanoLab 600i focused ion beam  for further examination. The tensile properties of the solution-annealed plate and samples cut from the ruptured pipe were determined at a strain rate of 6 × 103, NH3, SiH4, SiO2 was decomposed in the pipe at elevated temperature and pressure lower than atmospheric pressure. To catch the decomposed harmful species, the pipe was purged periodically with water mist, which caused a temperature gradient from the external to the inner surface of the pipe. It was expected that HNO3 and HF would be the reaction products of the decomposed exhausted gas. Thus, the inner side of the pipe would be corroded severely by the reaction products of the decomposed exhausted gas.As shown in The tensile properties of the as-received C-276 plate were as follows: yield strength of 370 MPa, ultimate tensile strength of 782 MPa and 56% elongation. As shown in 2O4 mixed with Cr2O3, which was consistent with EPMA measurements  and the large precipitate was Mo7Ni7 (δ) in the γ matrix 5Ni6 [7Ni7 (δ) phase.A bright field (BF) TEM micrograph and the selected area diffraction patterns (SADP) of the coarse precipitates at the grain boundaries, which were cut by FIB from the C-276 sample, are shown in 0.2)5Ni6  or Mo7NiSEM micrographs of typical fracture morphology and microstructure around the outer and inner surfaces of the tensile samples are shown in 6Ni7 (μ) phase. As listed in 6C carbide and a few P phases were found in C-276 alloy aged in the temperature range of 650 to 900 °C [Several different kinds of precipitates can be present in thermally aged C-276 alloy, depending on the aging conditions. It is reported that L + σ → P transformation occurs at above 1200 °C in Ni-Fe-Mo alloy . With in7Ni7 (δ) phase. The XRD pattern revealed the coexistence of δ and μ phase in the γ matrix. The difference in the chemical compositions of the two precipitates was that the W tended to segregate to the μ phase but the δ contained a higher Cr concentration. Because the μ phase contained much more W than did the δ phase, the SEM-BSE image of the former was brighter than that of the latter. It was also reported that the P phase has the same crystal structure as the δ phase [Coarse precipitates distributed in the γ matrix and along the grain boundaries were also inspected. Those coarse precipitates were rich in Mo and Cr, as listed in  δ phase . Figure 2O3/NiCr2O4 mixed layer developed for C-276 alloy exposed in supercritical water at 500–600 °C/25 MPa [2O3 to form NiCr2O4 [2O4 mixed with Cr2O3, whereas the reactive products on the inner surface of the ruptured pipe were identified as NiO. It is reported that the higher diffusivity of Ni than that of Cr contributes to the formation of the outer NiO layer in a Ni-based alloy [2O3/NiCr2O4 mixed layer can effectively protect the C-276 alloy in supercritical water [2O3 and NiCr2O4 layers, leaving many pin-holes in the substrate adjacent to the oxide/metal interface.Dual oxide scales consisting of an outer NiO layer and an inner CrC/25 MPa ,21, and  NiCr2O4 . In thised alloy . As comped alloy , the comal water . The exaThe ruptured C-276 pipe was found to consist of many fine cracks around the hole and extending into the surrounding substrate and displayed a non-uniform reduction in thickness around the pipe. The reaction products of the decomposed perfluorinated compounds and the oxidizing environment in the pipe were the reasons for severe corrosion of the pipe. After carefully examining the ruptured pipe, the large amounts of IG precipitates were corroded preferentially, resulting in the formation of fine pores within the coarse precipitates. Moreover, the periodical purge with water mist introduced a temperature gradient between the outer and inner regions of the pipe, which inevitably induced high thermal stress. Therefore, thermal stress assisted the severe cracking of the grain boundary precipitates, resulting in the formation of microcracks along the grain boundaries. The coalescence of micro-pores into micro-cracks and the linkage of micro-cracks resulted in the fast crack growth along the grain boundaries of the pipe. Furthermore, the combination of thermal stress and corrosion attack caused spalling of the corroded segments, which was responsible for the rapid thinning in the wall of the used C-276 pipe. The C-276 pipe used in a CDR system to catch decomposed perfluorinated compounds was etched to uneven thickness. The zone near the external surface had a porous structure, whereas the microcracks tended to initiate and grow from the inner surface of the pipe. The induced thermal stress in the pipe caused severe cracking of the grain boundary precipitates. Moreover, the grain boundary precipitates were corroded preferentially, resulting in the formation of fine pores within the precipitates and around them. The spalling of the corroded segments was responsible for the rapid thinning in the wall of the C-276 pipe.7Ni7 (δ) phase, which was rich in Mo and Cr. By contrast, the fine precipitates dispersed intragranularly or embedded in the δ phase were the μ phase (Mo6Ni7) enriched in Mo and W.Two kinds of precipitates were present in the ruptured C-276 pipe; the intergranular (IG) precipitates were coarser and greater in amount than the intragranular (IT) precipitates. The coarse precipitates at the grain boundaries were MoAfter service at elevated temperature, the aggregation of W assisted the transformation of δ to μ phase in the aged C-276 pipe. Therefore, fine μ precipitates were found to be embedded in the coarse δ in the ruptured pipe. Moreover, numerous precipitates present in the matrix and along the grain boundaries caused a significant loss in the strength and ductility of the C-276 pipe.The causes of the rupture of a C-276 pipe used in a controlled decomposition reactor for catching the perfluorinated compounds in the exhaust gas of a foundry were investigated. The main findings are as follows:


Despite the substantial scientific evolution in cervical cancer prevention and related infrastructures, a plethora of women still miss the opportunity to detect their precancerous lesions at a curable stage by not participating in existing screening programs. Implementing sensitive screening modalities combined with easy sampling methods with minimal pain or discomfort such as self-sampling of vaginal and urine samples is increasingly applied. Self-sampling HPV modalities aimed to address this inequity, besides facilitating HPV genotyping as well as the measurement of related biomarkers in HPV-caused lesions and genital cancer. The low costs inflicted, the non-invasive nature, and the favorable acceptability profile of urine HPV detection give the potential to become a most promising tool that could expand the possibilities in changing genital and cervical cancer prevention strategies as well as in the surveillance and management of genital precancer.Within the previous decades, following the widespread implementation of HPV-related biomarkers and computerization in liquid-based cytology, screening for lower genital tract malignancies has been optimized in several parts of the world. Many organized anogenital cancer prevention systems have reached a point at which efficacy is more a matter of population coverage and less of available infrastructures. Meanwhile, self-sampling modalities in which biologic material  is obtained by the individual and not the clinician and subsequently undergoes examination for HPV biomarkers enjoy appreciating acceptance. Bygone the initial skepticism that vaginal or urine HPV represents “passenger” transient infections, extensive scientific work has been conducted to optimize high-risk HPV (hrHPV) detection from this “novel” biologic material. Nowadays, several state-of-the-art meta-analyses have illustrated that self-sampling techniques involving urine self-sampling represent a feasible alternative strategy with potentially enhanced population coverage possessing excellent performance and sensitivity. Recently published scientific work focusing on urine HPV was reviewed, and after a critical appraisal, the following points should be considered in the clinical application of hrHPV urine measurements; (i) use of first-void urine (FVU) and purpose-designed collection devices; (ii) using a preservation medium to avoid human/HPV DNA degradation during extraction and storage; (iii) using polymerase chain reaction (PCR) based assays, ideally with genotyping capabilities; (iv) processing of a sufficient volume of whole urine; and (v) the use of an analytically sensitive HPV test/recovery of cell-free HPV DNA in addition to cell-associated DNA. Despite the substantial scientific evolution in cervical cancer prevention and related infrastructures, millions of “at-risk” women miss the opportunity to detect their precancerous lesions at a curable stage by not participating in screening programs. Sometimes, this happens because a large proportion of the population is lost to cervical cancer screening due to poor resources, cultural barriers, or avoidance of a pelvic exam . AdditioDuring the previous decades, the progressive implementation of HPV-related cervical screenings has transformed the whole paradigm in cervical cancer prevention. HPV-based molecular screening modalities proved to be highly sensitive, thus offering better protection from cervical cancer than cytology ,6,7,8,9.Older and recent studies have illustrated that self-sampling is highly acceptable among women ,12,13,14Persistent high-risk HPV (hrHPV) infections are the leading cause of more than 90% of cervical and anal cancers, approximately 70% of vaginal and vulvar cancers, and more than 50% of penile cancers . Based oIn conjunction with the extensive research which has been performed in the field of self-sampling of vaginal secretions for cervical screening, detection or HPV-related biomarkers in urine have also emerged as a reliable and less invasive approach than a traditional cervical screening ,16. As eLater, in 2014, the first important meta-analyses had been published; Pathak et al. conclusively regarded urine HPV testing as a feasible and acceptable alternative in established cervical screening modalities suggesting it as a possible complementary organized screening method . SensitiIn a subsequent meta-analysis by the same author on self-samples that included 56 accuracy studies and 25 participation trials, Arbyn et al. focused primarily on vaginal self-sampling and illustrated that hrHPV assays based on polymerase chain reaction were as sensitive on self-samples as on clinician samples to detect CIN2+ or CIN3+, with hrHPV assays based on signal amplification showing less sensitivity on self-samples  18]. Ta. Ta18]. Aiming to address the poor reproducibility of HPV-related assays in self-samples, Arbyn launched the VALHUDES protocol and encouraged focusing on the development of tailored molecular tests that allow reflex testing of hrHPV in self-samples . AccordiSeveral authors have recently published their contributions in urine self-sampling. In this perspective, their early innovation with the development of a special apparatus for the scope of urine collection represented a mainstay development . The pioAdditionally, the importance of HPV genotyping in HPV lesions, genital cancer, and also cervical screening with self-samples was increasingly emphasized ,34,35,36A recent study by Oliveira et. al. assessed HPV16/18-E6 expression prior to the treatment of cervical lesions and evaluated the concordance between urinary, vaginal, and cervical HPV16/18-E6 and hrHPV DNA testing . OverallMethylation biomarkers, as suggested by Arbyn et al., represent a promising and attractive approach  18]. Va. Va18]. Two further recent studies have also been published by a research group that developed an ultrasensitive nanowire assay ,39. BothThree recent studies have assessed the performance of the APTIMA hrHPV E6/E7mRNA assay in urine. In the study of Asciutto et al., the sensitivity of the APTIMA HPV assay in detecting HSIL/AIS/cancer for the clinician-taken cervical HPV samples was 100.0%; however, the corresponding value for urine self-sampling was a disappointing 44.8%  40]. In. In40]. ® 4800 & GENOMICA CLART® HPV4S). Urine samples showed good concordance in hrHPV detection compared with vaginal and cervical samples when assessed with the COBAS assay and moderate with CLART. Additionally, urinary hrHPV detection by COBAS illustrated a sensitivity of 63.9% and a specificity of 96.5% compared with 51.6% and 92.4%, respectively, for CLART. While underscoring that participating individuals considered home-based urine collection as well-accepted and ranked it as the most preferred future screening procedure, the authors urge for improvement in accuracy rates of urinary hrHPV detection before urine can serve as an alternative screening option  and a Dacron swab (WD)), or more complicated inventions (a HerSwab (HS) and Qvintip (QT) device). Women harboring irregular colposcopic findings underwent cervical biopsies; for these patients, histology results were also available. The authors assessed for HPV positivity and user preference and confidence in the collection; they also conducted additional analyses to examine the effect of adjusting for sample cellularity and different positivity thresholds . In. In42]. resholds . Summariresholds .The recent study by Östensson et al. that focused on a special population of patients who had previously undergone conization is of special interest. The authors studied 531 women and utilized the Abbott RealTime High-Risk HPV assay to examine how well the HPV findings from self-sampled vaginal (VSS) and urine specimens containing transport medium correctly identified women with recurrent CIN2+ compared to samples collected by clinicians. At the first follow-up approximately six months post-treatment, all patients with recurrent CIN3 had positive HPV results by all methods. At the second follow-up approximately one-year post-treatment, all seven newly-detected CIN2/3 recurrences were associated with HPV positivity on VSS and clinician-samples. Only clinician-collected samples detected HPV positivity for the two adenocarcinoma-in-situ recurrences, which were both HPV18 positive . For oveFinally, in a very recent Danish cross-sectional study in colposcopy referred individuals, Ørnskov et al. compared the absolute and relative sensitivity as well as the specificity of two self-collected specimens  and a clinician-taken Cervical Sample (CS) to detect high-grade cervical intraepithelial lesions (CIN2+/CIN3+), by using the Cobas HPV assay [Cobas 4800™ ]. They illustrated that both urine and vaginal self-collected sampling are non-inferior to the clinician-taken CS in identifying CIN2+/CIN3+ . FurtherThe assessment of HPV-related biomarkers detection in vaccinated populations is a continuing challenge ,46. In tp ≤ 0.017). This study illustrated that vaccine-induced HPV antibodies are detectable in the first-void urine of young women, while significant positive correlations were documented between HPV6/11/16/18-antibodies in first-void urine and paired sera.A recent study by Van Keer et al. investigated the properties of HPV-specific antibody transudates from systemic circulation in first-void urine of (un)vaccinated subjects and the agreement with paired sera . Strong The second study compared the measurement of HPV antibodies in FV urine using a multiplex L1/L2 virus-like particles (VLP)-based ELISA (M4ELISA) with previously reported results using a glutathione S-transferase (GST)-L1- based immunoassay (GST-L1-MIA) . As expeThe non-invasive nature and favorable acceptability profile of urine HPV detection are most promising. However, currently, no HPV assay is specifically modified and marked for first-void urine, although devices to collect it have been developed and preservation mediums have been identified. Therefore, more investigation, focusing mainly on urine HPV DNA measurements with PCR-based methods and possible implementation in vaccination programs and HPV screening strategies, is required .Several emerging possibilities for the implementation of urine HPV detection require further research. In the field of monitoring HPV vaccinations and primary genital and cervical cancer prevention, the assessment of uptake in HPV vaccination programs using proxy HPV antibody concentrations in FVU is an attractive approach and cost-effective policy as previously illustrated, especially in difficult to reach populations or special minorities ,16.In the quest for an accurate reflection of vaccination coverage in diverse populations, the choice of the particular assay to be used in HPV urine detection is important and deserves evaluation with carefully designed prospective trials. It must be emphasized that these candidate assays should be able to detect shifts in HPV genotype prevalence in the context of identifying possible type replacements in a cohort.The assessment of urine HPV represents an invaluable tool that should not be confined to the primary vaccination cohorts of preadolescent girls, but it should be used for screening men and women of all ages.Regarding urine self-sampling HPV tests, it is necessary for future research to describe the implementation status in the different parts of the world and the acceptance status of examinees in more detail, which will help design future screening strategies. In developing these screening strategies, it is desirable to consider the effect of using self-sampling HPV detection methods like urine sampling in the sufficiency of medical resources that can focus on the prevention of cervical cancer in countries around the world, including developing countries.In the area of secondary cervical cancer prevention, the incorporation of urine HPV detection assays might vary depending on the settings. Studies have illustrated that primary cervical cancer prevention strategies can be individually deployed in various health systems and different target populations (a) maximal- and enhanced-resource settings, (b) limited-resource settings, and (c) basic-resource settings ,9,17,51.Patients attending colposcopy clinics who have been vaccinated following a local cervical treatment  or in thUrine HPV detection due to the low costs inflicted by bypassing the doctors’ visit, the non-invasive nature, and the favorable acceptability profile has the potential to become the most promising tool that could expand the possibilities in a changing genital and cervical cancer prevention screening as well as in the surveillance and management of genital precancer and vaccination surveillance. The following points should be considered in clinical applications of HPV urine measurements or future trials; (i) Use of first-void urine (FVU) and purpose-designed collection devices; (ii) using a preservation medium to avoid human/HPV DNA degradation during the extraction and storage; (iii) using PCR-based assays, ideally with genotyping capabilities; (iv) processing of a sufficient volume of whole urine; and (v) the use of an analytically sensitive HPV test/recovery of cell-free HPV DNA in addition to cell-associated DNA.


Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to some patients and represent a significant step forward in our knowledge of the biology of skin cancer. In this paper, we review the viral agents responsible for different types of skin cancer, especially for solid skin tumors. We focus on human papillomavirus and squamous cell cancers, Merkel cell polyomavirus and Merkel cell carcinoma, and human herpesvirus 8 and Kaposi’s sarcoma.  In 1910, Peyton Rous demonstrated that a spontaneous spindle cell sarcoma derived from a Plymouth Rock hen could be transmitted to healthy chickens using filtered cell-free tumor extracts . At firsThe International Agency for Research on Cancer (IARC) divides carcinogenic agents, including biological agents, into five categories according to their potential carcinogenicity . Group 1HPVs are small non-enveloped viruses with an icosahedral capsid in the Papillomaviridae family (PV). More than 200 serotypes have been identified so far . HPVs haClassification of HPVs is based on the nucleotide sequence of the ORF coding for capsid protein L1. HPV types belonging to different genera have less than 60% similarity within the L1 part of the genome. Different viral species within a genus share between 60 and 70% similarity. A novel HPV type has less than 90% similarity to any other HPV type .HPV infection targets undifferentiated keratinocytes in the basal layer of the epithelia, at the cutaneous and mucosal levels . AlthougIn the mid-1970s, some authors began to postulate that HPVs could be involved in the development of cervical cancer ,5,6. In More specifically, in 1983, the DNA of a type of a previously undescribed papillomavirus was identified in 60% of all cervical cancer biopsies . The autBy the end of the 1970s, some types of HPV were known to be involved in the development of verrucous lesions seen in epidermodysplasia verruciformis ,14 and iThe genome of HPVs is made up of circular double-stranded DNA, approximately 8 kb in size A. The viThe HPV genome is organized in three main regions: (1) an upstream regulatory region (URR), which contains transcriptional factor binding sites and regulates the gene expression of the virus; this region is not transcribed and acts as a promoter ; (2) an The infective cycle of the virus is linked to the differentiation program of the keratinocytes  Figure B. The viUnder normal circumstances, as keratinocytes migrate upwards and begin the differentiation process, they stop replicating and undergo a series of changes until they form the corneal layer. The E6 and E7 proteins hijack the checkpoint mechanisms and allow the keratinocytes to enter a phase of uncontrolled proliferation ,27. MoreIn the upper layers of the epithelium, viral gene expression shifts towards the L2 and L1 capsid proteins, which are targeted to the nucleus and auto-assemble into virions, encapsidating the viral genome . FinallyA reciprocal correlation between pRb and p16 has been established, which explains p16 overexpression in carcinomas and premalignant lesions of cervical cancer associated with HPV infection. In the case of β-HPVs, the activity related to proteins E6 and E7 is not the same as that in α-HPVs, but instead involves the degradation of Bcl-2. The hair follicle is regarded as the natural reservoir for cutaneous β-HPVs. HPV is present in hair follicles from different body sites including the scalp, eyebrows, arms, trunk, legs, and pubic region . The β-HIt is estimated that more than half of all sexually active people will be infected with HPV at some point in their lives. In most cases, HPV infection clears up spontaneously, without any associated health disorders. However, some lesions may develop into genital warts, precancerous lesions, and cancer. The HPV types that cause genital warts are different from those that cause anogenital cancer . HPVs arGenital warts are the most common clinical symptom associated with HPV infection. In general terms, the diagnosis of genital warts is reached by visual inspection . The HPVThere are multiple treatment options for genital warts  whose analysis lies beyond the scope of this review . Women wEpidemiology: Cervical cancer has an estimated incidence of 12,000 cases in the US, with 4000 estimated deaths in 2016 and an incidence of 7.7 per 100,000 people. It is, however, a huge health concern in developing counties. Cervical cancer is the fourth most common cancer affecting women worldwide after breast, colorectal, and lung cancers, with 604,127 new cases in 2020. It is also the fourth most common cause of cancer death  in women worldwide. Almost 70% of the global burden occurs in developing countries where it is the second most commonly diagnosed cancer and third leading cause of cancer death among women . Oncogenic (high-risk) HPVs are responsible for almost all cases of cervical and anal cancer, and for a smaller fraction of cases of penile, vaginal, vulvar, and oropharyngeal cancers . ProgresDiagnosis: Clinical presentation depends mainly on the location and extent of disease. Precancerous changes or very early-stage disease are usually asymptomatic. Advanced stages can cause vaginal bleeding, foul smelling, vaginal discharge, dyspareunia, pelvic or back pain, and inguinal lymphadenopathy . Colposcopy is a diagnostic procedure that can visually detect dysplastic changes and guide biopsies to obtain a histologic diagnosis . The mosAfter initial colposcopy, lesions are graded as cervical intraepithelial neoplasia (CIN) 1, 2, or 3 based on the degree of cellular and epithelial abnormality. The majority of CIN 1 are spontaneously cleared by the immune system; hence, surveillance rather than treatment is recommended. CIN 3 lesions represent a full-thickness neoplastic lesion with a high likelihood of progressing to cancer. CIN 2 lesions are intermediate, with up to 40% regressing if left untreated. The cornerstone of cervical cancer prevention is the detection of CIN 2 and CIN 3 lesions through screening and their eradication through treatment ,41. Treatment: In the era before colposcopy, the traditional treatments for CIN used to be conization and hysterectomy. After the introduction of colposcopy in the 1970s, more conservative treatments such as cryotherapy, electrocautery, and laser ablation were adopted. In the 1990s, an office-based excisional procedure known as loop electrosurgical excision procedure (LEEP) became available and was widely adopted ,42,43. UPotential treatment modalities for invasive cancer include surgery ; lymph node evaluation/dissection; radiotherapy (brachytherapy or systemic therapy) .Prevention: The CDC recommends that cervical cancer screening should begin at the age of 25 years due to the low incidence of cervical cancer and limited utility of screening in younger women. HPV infection is very common in adolescents, in whom it typically clears up spontaneously . ConventTests for different types of HPV are used for cervical cancer screening in conjunction with a Pap test, for the triage of abnormal cervical cytology results, and for follow-up after treatment of cervical precancers. These tests are only approved for use with cervical  specimens. Testing for non-oncogenic HPV types (6 and 11) is not recommended. Tests for oncogenic types of HPV are now being incorporated into cervical cancer screening recommendations with Pap tests (co-testing) to reduce the need for follow-up visits by women over 30 years of age. Sexual partners do not need to be tested for HPV. In the future, oncogenic (high-risk) HPV tests might be considered for primary cervical cancer screening, but no such recommendation has so far been made by any medical organization . A quadrivalent vaccine, which combines the L1 protein from HPV6/11/16/18, and a 9-valent vaccine, which contains the L1 protein of HPV6/11/16/18/31/33/45/52/58, are currently available; the bivalent vaccine is no longer marketed. All three vaccines protect against HPV16 and HPV18, which account for over 70% of cervical cancer cases. The quadrivalent and 9-valent vaccine also protect against other types of HPV, including those responsible for the development of genital warts. The success of cervical cancer screening programs is evident from the sharp decrease in cervical cancer incidence rates observed in the US between the 1970s and 2012 . The majority of anal carcinomas, roughly 80% of cases, are caused by HPV. Men that have sex with men, HIV+ individuals and women with cervical or vulvar cancer are at greatest risk . ClinicaVulvar SCCs tend to appear in postmenopausal women, and it begins as vulvar intraepithelial neoplasms ,46,47. TPenile SCC has been linked both to long-lasting inflammatory conditions (such as sclerotic and atrophic lichen) and to HPV infections . HPV is Bowen’s disease consists of an intraepithelial dysplasia which may appear anywhere in the skin and that has been linked to HPV as well, e.g., to HPV56  and HPV5HPV has been observed in other forms of anogenital cancer, including verrucous cSCC of the anogenital region, which is also known as Buschke-Löwenstein tumor. From a histopathological perspective, this tumor presents an abundant proportion of clear cells, an exo–endophytic pattern, with tumor lobules that may show dyskeratotic cells, but generally display a low level of differentiation. It has been associated with HPV6 and HPV11 infection  . The reaIn 1902, Lewandowsky and Lutz described a hereditary disease in which patients developed multiple verruca-like lesions and had an increased risk of developing cSCC . This coAt the end of the 1970s, DNA from two types of papillomavirus was identified in EV lesions ,14. ShorPatients with EV (1) have difficulties clearing their β-HPV infection; (2) do not have a higher risk of infection caused by bacteria and other viruses (including α-HPVs); (3) do not have a higher risk of developing other types of cancer; (4) feature UV radiation as a cofactor in the development of cSCC . In shorBeta HPV types are etiological agents that are potentially involved in the development of non-melanoma skin cancer (NMSC) in immunocompromised patients  ,62. The The higher incidence of keratinocyte carcinomas in immunocompromised patients points to a possible viral origin. A comparison with the rates in the general population shows that the risk of developing NMSC (particularly cSCC) is much higher in immunocompromised than in normal patients (65 times more in solid OTRs) . Two thiCases of cSCC in transplanted patients may exhibit clinical and morphological characteristics similar to those of viral warts (induced by HPV). Generally, cSCC coexists with viral warts, which suggests that persistent viral warts may evolve in these patients . More imThe prevalence of β-HPV in actinic keratosis is higher than in cSCC, which suggests that β-HPV may play a role in the initial stages of carcinogenesis (contrary to what occurs with α-HPV). In addition, recent sequencing studies have failed to find HPV in cSCC, which contrasts with observations in cervical cancer. A transgenic mouse model provides evidence of the causal role of HPV in the development of skin cancer. Mice that express the region of HPV8 under the simultaneous control of human keratin-14 promoter develop skin cancer spontaneously . STAT3 sIn 1895, Friedrich Sigmund Merkel described skin cells that he called Tastzellen (“touch cells”). These cells were found in the basal layer of the skin, connected to nerve endings and present in hair follicles, on some mucosal surfaces, and in touch-sensitive areas, which explains why their function was initially thought to be due to touch sensation. In 1972, Toker described a tumor made up of small polygon-shaped and highly basophilic cells that were organized as trabeculae, which prompted the entity to be named trabecular carcinoma . Five yeAfter the development of cytokeratin 20 (CK20) as an antibody in the early 1990s, the diagnosis of MCC became simpler and more reliable, and the reported incidence of MCC increased significantly, partly explaining why this rate has tripled in the last 20 years . Until tMerkel cell polyomavirus (MCPyV) is part of the polyomavirus family. As such, it has double-stranded DNA and a short circular genome. That of MCPyV is 5389 base pairs long and comprises early- and late-coding regions separated by a non-encoding regulatory region containing the origin of viral replication. The early genes, namely, the products of the T antigen locus , are expressed immediately upon infection and are generally involved in replication of the viral DNA genome A. FollowThe MCPyV genome is similar to other human polyomaviruses in that it includes a conserved replication origin, as well as opposing early and late gene regions. The early region contains small and large T antigens (sT and LT) and a 57 kT antigen (57kT). The late region expresses the major capsid protein viral protein 1 (VP1) and the minor capsid protein 2 and 3 (VP2 and VP3) antigens B. MCPyV Polyomavirus origins of replication typically contain pentanucleotide consensus sequences that help direct assembly of LT proteins on the DNA by specifically binding the origin-binding domain (OBD), which initiates replication. Early region gene products of polyomavirus generally target cellular proteins that function in cell cycle regulation and tumor suppression. These gene products are designated as tumor antigens, or T antigens, so the early region is frequently referred to as the T antigen locus. The polyomavirus T antigens also perform key functions during the initiation of viral DNA synthesis. The MCPyV early region expresses three T antigen . All three share a short amino-terminus, but alternative splicing downstream of the first exon is ultimately responsible for determining their unique nature. The late region of the MCPyV genome contains open reading frames for VP1, VP2, and VP3. MCPyV LT is the main viral oncoproteins, while sT plays an accessory role in transformation.MCC is a rare and often fatal neuroendocrine skin cancer. It has an incidence of approximately 1500 cases per year in the US, similar to those of cutaneous T cell lymphoma and dermatofibrosarcoma protuberans . AlthougThe population at risk includes the elderly and patients who are immunocompromised ,88,89, eThe most common clinical features of MCC can be summarized in an acronym: AEIOU : asymptoThis cancer has a higher five-year relative mortality rate than malignant melanoma (46% vs. 15%), and the cases presenting without clinical evidence of nodal disease have a 32% chance of microscopic nodal involvement . In geneSurgery is the treatment of choice for localized Merkel cell carcinoma. The recommended resection margins for MCC have not been assessed, although for functional reasons, 1–2 cm margins are recommended. Several retrospective studies have shown that adjuvant radiotherapy is very likely to have benefits for survival and is therefore recommended ,105,106.SLNB is recommended when possible regardless of the size of the primary tumor ,110. If Avelumab is an anti-PD-L1 monoclonal antibody that showed a response rate of 32% in a phase 2 study of patients with metastatic MCC who had been refractory to conventional chemotherapy; 82% of those patients were still responding at a 10-month follow-up . The datPneumocystis carinii, but subsequently renamed as Pneumocystis jirovecii) [In 1872, Moritz Kaposi described five patients who had what he called primary idiopathic pigmented sarcoma . The patrovecii) ,118,119.rovecii) . Kaposi’s sarcoma-associated herpesvirus (KSHV) is the eighth member of the herpesvirus family (HHV8) to be identified. Its genome is complex but similar to those of other human herpesviruses . As withKSHV has a biphasic life cycle comprising latent and lytic infections . Its DNAHHV8 has broad cellular tropism and interacts with several cell proteins, including molecules such as heparan sulfate, integrins, DC-SIGN, and the heteromeric amino acid transporter (xCT) ,132,133.Viral latency is associated with proteins such as LANA, vCyclin, vFLIP, vIRF4, kaposin, and viral microRNAs . LANA  have revealed the importance of epigenetic regulation and of the MAPK signaling pathway [There are several ways to induce change in the KSHV cycle. Studies with artificial inductors such as 12- pathway ,148. Rea pathway .An immediate-early gene encoded by ORF50 and homolog of RTA  activates the lytic cycle gene expression from the latent viral genome . The DNAUpon completion of RTA-dependent viral replication, late gene synthesis proceeds by expressing structural proteins and glycoproteins, such as K8.1 glycoprotein. Finally, infectious virions are assembled that subsequently disseminate to other individuals . LANA, aHHV8 is responsible for Kaposi’s sarcoma . Kaposi’Understanding the transmission mechanisms of the virus was a challenge in the years immediately after its identification. Considering the epidemiological context of the epidemic outbreaks of Kaposi’s sarcoma with regard to HIV, sexual transmission was considered as a hypothesis ,158,159,The risk factors associated with the development of KS and HHV8-related malignant lesions are age (whereby risk increases with age) and an immunocompromised status  .Clinical features: Kaposi’s sarcoma lesions are predominantly present in the skin and mucosa, mostly affecting lower extremities, face, trunk, genitalia, and oropharyngeal mucosa, but in severe cases may also involve lymph nodes and visceral organs, including the respiratory and gastrointestinal tracts . From a KS is an AIDS-defining illness and remains the most prevalent malignancy among patients with AIDS. In HIV-infected persons, AIDS–KS is a much more aggressive disease that typically manifests itself with disseminated lesions and visceral involvement. Kaposi’s sarcoma exhibits a less aggressive presentation in patients already receiving highly active antiretroviral therapy (HAART). Exacerbation  can occur after therapy  or subsequently to the immune reconstitution inflammatory syndrome that may occur when initiating HAART in HIV-infected persons . All these forms have common virological, histological, and clinical features . Kaposi’2 laser) or topical . In the more severe forms, anthracycline-based regimens  are the treatment of choice. The expectant approach is taken for mild classic cases. In immunocompromised or HIV+ patients, improving the immunocompromising conditions by treating HIV is the best strategy [Treatment: The disease can be managed expectantly, or the treatment may be physical (e.g., cryotherapy or COstrategy .Several viral agents have been associated with different forms of skin cancer. There is clear evidence on the pathogenetic implication of certain types of HPV in cervical cancer, but also in anal, vulvar, penile carcinomas and in verrucous carcinoma of the anogenital region. Moreover, HPV5 and HPV8 have been associated with cSCC in individuals with epidermodysplasia verruciformis, and HPV has been associated with cSCC in immunocompromised patients, and some evidence has postulated its potential association with cSCC in immunocompetent individuals. Merkel cell polyomavirus has been linked to the development of Merkel cell carcinoma more recently, and HHV8 is responsible for Kaposi’s sarcoma. Proper knowledge of the mechanisms underlying these forms of cancer open opportunities for prevention in the future.


Compared to other regions of the world, sub-Saharan Africa has made limited progress in the implementation and performance of nationwide human papillomavirus (HPV) vaccination programmes. Without urgent intervention, this will serve to undermine cervical cancer elimination efforts in this region. The primary intent of this narrative review is to highlight the programmatic successes and challenges of the school-based HPV vaccination programme in South Africa since its inception in 2014, with the aim of contributing to the evidence base needed to accelerate implementation and improve programme performance in other sub-Saharan African countries. As of 2020, the proportion of adolescent girls aged 15 years who had received at least one dose of the HPV vaccine at any time between ages 9–14 years was 75%, while 61% had completed the full recommended two-dose schedule. This gives some indication of the reach of the South African HPV vaccination programme over the past 6 years. Despite this, vaccine coverage and dose completion rates have persistently followed a downward trend, slowing progress toward attaining global elimination targets. There is evidence suggesting that declining public demand for the HPV vaccine may be a result of weakening social mobilization over time, inadequate reminder and tracking systems, and vaccine hesitancy. Another concern is the disproportionate burden of HPV and HIV co-infections among adolescent girls and young women in South Africa, which predisposes them to early development of invasive cervical cancer. Moving forward, national policy makers and implementers will have to explore reforms to current age eligibility criteria and vaccine dose schedules, as well as implement strategies to support vaccine uptake among populations like out-of-school girls, girls attending private schools, and HIV positive young women. Additional opportunities to strengthen the South African HPV vaccination programme can be achieved by scaling up the co-delivery of other adolescent health services such as comprehensive sexual and reproductive health and rights education, deworming, and health screening. This calls for reinforcing implementation of the integrated school health policy and leveraging existing adolescent health programmes and initiatives in South Africa. Ultimately, establishing tailored, adolescent-centered, integrated health programmes will require guidance from further operational research. Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related death among women worldwide . The bruRecognizing the devastating impact of cervical cancer on public health, the World Health Assembly passed a resolution in August 2020 to accelerate the elimination of cervical cancer, calling for all member states to adopt multi-sectoral and integrated healthcare approaches aimed at achieving the following triple-intervention coverage targets by 2030; (i) vaccination: 90% of adolescent girls fully vaccinated with the HPV vaccine by the age of 15 years, (ii) screening: 70% of women screened using a high-performance test by the age of 35, and again by the age of 45 years, and (iii) treatment: 90% of women with cervical pre-cancer treated and 90% of women with invasive cervical cancer managed . CurrentThree licensed prophylactic HPV vaccines – the bivalent, quadrivalent and nonavalent HPV vaccines – with excellent safety profiles and relatively similar effectiveness in preventing cervical cancer are currently available for use. As of June 2020, the proportion of countries that had introduced the HPV vaccine partially or nationwide as part of their national immunization programme per region was as follows: 85% in the Americas, 77% in Europe, 56% in Oceania, 40% in Asia, and finally 31% in Africa . Where tIn South Africa, the bivalent and quadrivalent HPV vaccines were first approved for use in 2008, although only available at a cost through the private health sector at the time. In April 2014, South Africa joined countries like Rwanda and Seychelles as one of the first few sub-Saharan African countries to roll-out nationwide HPV vaccination, offered free of charge to grade 4 adolescent girls ≥9 years of age, attending public schools across the country . The schIt is also worth noting that adolescents in South Africa constitute about 19% of the overall population . The burOf the 503,507 eligible grade 4 girls aged ≥9 years attending South African public schools in April 2014, 419,520 were vaccinated with the first dose of the bivalent HPV vaccine during the first round of the nationwide HPV vaccination programme, achieving a high coverage rate of 83% . The secThe disparity in coverage rates between the first and last vaccine doses is also worth noting and suggests an increasing dropout rate over time, ranging from 18% in 2014 to as high as 26% in both 2018 and 2019 . The chaWhere South Africa's progress toward achieving the 2030 vaccine coverage target is concerned, the WHO-UNICEF cumulative data collected by 2020 show that the proportion of adolescent girls aged 15 years who had received at least one dose of the HPV vaccine at any time between ages 9–14 years was 75% while 61% had received the full recommended schedule . It is iOverall, coverage rates over the past 6 years of the nationwide HPV vaccination programme in South Africa are lower than anticipated, given the high uptake rates (>90%) reported during early demonstration projects and feasibility studies , 30. ThiThe successful implementation of the nationwide HPV vaccination programme in South Africa has been largely attributed to the strong political commitment, intersectoral collaboration among the National Departments of Health, Basic Education and Social Development, careful planning and coordination at provincial and district levels, and strong leadership from the National Department of Health . This stOn the supply side, factors such as appropriate vaccine dose schedules, eligibility, cost, vaccine delivery strategies, vaccine availability and accessibility, partnerships with key stakeholders, quality of health infrastructure, and capacity of vaccinators including staffing, capability, and level of knowledge, can all influence HPV vaccine uptake and completion rates. Although the bivalent and quadrivalent HPV vaccines were initially licensed as three-dose vaccines, a two-dose schedule was widely adopted following demonstration of non-inferior immunogenicity between both schedules , 31. ThePolicy decisions on the eligibility for the HPV vaccine is another critical supply-side factor as limited and missed opportunities for vaccination could contribute to suboptimal vaccine uptake and compromise elimination efforts. There have been calls to expand the reach of the South African HPV vaccination programme given the unique epidemiology of HPV infection and co-burden of other sexually transmitted infections  among AGYW >15 years of age . SeveralIn terms of HPV vaccine availability and accessibility in South Africa, providing free HPV vaccination to eligible girls continues to be a major driver of vaccine uptake. According to the 2019 School Realities Report by the Department of Basic Education , of the Given the current context, it is worth highlighting how South Africa has approached the school-based HPV vaccination programme during the COVID-19 pandemic. Intermittent school closures in response to multiple waves of the COVID-19 pandemic disrupted HPV vaccine delivery particularly in 2020 and may have even led to wasted doses. Without appropriately adapting the HPV vaccination programme amid the COVID-19 context, South Africa would have gone on to lose a year's worth of the programme with half a million eligible girls missing out on lifesaving vaccination. Fortunately, the South African National Advisory Group on Immunization recommended pivoting the HPV vaccination programme to prioritize adolescent girls in grade 5, most of whom may have missed their scheduled doses in 2020 due to the pandemic . It is aPublic demand for the HPV vaccine may be influenced by the level of knowledge, awareness and attitudes of the various stakeholders involved in the HPV vaccination programme. These stakeholders include, the parents or caregivers of adolescent girls, adolescent girls themselves, their peers, teachers, and healthcare providers. The influence of these stakeholders on the performance of the vaccination programme stresses the need for sustained, inclusive, and strengthened vaccine communication, education and promotional campaigns aimed at increasing stakeholders' knowledge and awareness about the life-time risk of HPV infection and the risks and benefits of the HPV vaccine in an effort to increase public trust and encourage positive attitudes toward the vaccination programme. Previous systematic reviews , 45 haveTo improve HPV vaccine acceptance and uptake, the WHO recommends that national immunization programmes invest in effective vaccine communication strategies and provides clear guidance on developing and delivering such strategies . In SoutOne of the persistent reasons for reluctance or non-acceptance of the HPV vaccine among stakeholders has been the misconceptions about the safety of the vaccine. Even among parents and caregivers with high levels of education, unaddressed safety concerns about the HPV vaccine may fuel negative attitudes like hesitancy or unacceptance . Our revWithout easy access to careful and transparent information about the safety and benefits of the HPV vaccine, stakeholders may not be able to demand lifesaving HPV vaccines, instead turning to readily available false and often dangerous information in making the decision to refuse the vaccine altogether. Although difficult to quantify, it has been suggested that vaccine hesitancy may play an important role in the suboptimal HPV vaccine coverage and completion rates observed in South Africa, however this is yet to be comprehensively researched . Among ahttp://sheconquerssa.co.za/) and B-Wise , as well as others with similar mandates.Demand generation for the HPV vaccine in South Africa can be improved through continued multi-level engagements with the full scope of stakeholders. Such engagements should adopt tailored, community-based communication and sensitization campaigns with the goal of increasing public awareness and trust in the HPV vaccine. In the current COVID-19 context, clear and effective communication strategies will be important in ensuring that adolescent girls and their parents or caregivers do not confuse ongoing COVID-19 vaccine roll-out with the HPV vaccination programme. The need to empower adolescent girls to demand lifesaving HPV vaccines cannot be overstated. Opportunities exist for creating national spaces and platforms which encourage adolescent girls to be at the forefront of HPV and cervical cancer advocacy and awareness campaigns which can be linked with existing initiatives like the She Conquers campaign   makes prThere is limited evidence in the published literature on the co-delivery of HPV vaccines and other adolescent health services in South Africa. Further operational research studies are required to improve our limited understanding of the successes and challenges of such integrated programmes. Evidence from elsewhere suggests that while delivering the HPV vaccine alongside other adolescent health services in schools offers significant prospects in terms of adolescent health and wellbeing, such programmes come with substantial financial, logistical, and operational challenges . In thisWe present recommendations for expanding current research and practice aimed at scaling up the delivery and uptake of adolescent health services alongside the HPV vaccination programme in South Africa . DrawingAlthough a systematic literature search was performed as part of this narrative review, it is possible that the strategy used may have excluded key literature sources. While we attempted to adequately capture core themes and trends emerging from the pre-HPV vaccine introduction era to date by expanding the scope of the review to include literature sources published between 2010 and 2021, the findings may not comprehensively capture the real-world experiences of the HPV vaccination programme in South Africa. In addition, the review findings may not be generalizable to all settings and calls for further systematic reviews and syntheses to be conducted.Overall, sustained implementation of a nationwide school-based HPV vaccination programme in South Africa has been successful, at least over the past 6 years. Moving forward, improving demand generation will be crucial in recovering optimal HPV vaccine coverage and completion rates among eligible adolescent girls. This will have to be supported by up-to-date research evidence on the determinants of HPV vaccine uptake and dose completion. Maximizing the utility of the HPV vaccination programme as an entry point for delivering comprehensive adolescent health care will require, (i) further high-level political commitment and multi-sectoral collaboration, aimed at scaling up the HPV vaccination programme with the local unique disease epidemiology in mind, (ii) reinforcing the implementation of the integrated school health policy, and (iii) appropriately linking adolescents to existing programmes and initiatives which meet their expressed healthcare needs.As more countries in sub-Saharan Africa prepare to introduce nationwide HPV vaccination programmes, policymakers and immunization managers will rely on the lessons learned in countries with existing and mature programmes. While the South African HPV vaccination programme may be unique for several reasons including the fact that it is fully funded by the national government, the experiences gained over the past 6 years are worth sharing and could make useful contributions to the body of evidence needed to accelerate HPV vaccination and cervical cancer elimination efforts across sub-Saharan Africa. Future HPV vaccination programmes in sub-Saharan Africa will have to secure the involvement of policy makers and influencers, including adolescents, to support and sustain implementation. Furthermore, future, and existing HPV vaccination programmes in sub-Saharan Africa will need to strengthen the implementation of context-specific and adolescent-centered strategies needed to maintain high demand for HPV vaccination and reduce missed opportunities for vaccination and dropout rates. It is also important to stress the need for adaptable HPV vaccination programmes which can withstand acute and prolonged health systems shocks such as those caused by disease outbreaks and pandemics. Finally, given that the widely observed inequitable distribution of COVID-19 vaccines has strengthened calls to invest in scaling up vaccine manufacturing capacity within sub-Saharan Africa, it is imperative that the production of low-cost generic HPV vaccines form part of this regional policy agenda as an avenue to address vaccine supply challenges.EA-D developed the review concept and wrote the initial draft of the manuscript. EA-D, NB, VVN, and VC contributed to the overall review process, including the literature search, screening, data extraction, and analysis. All authors approved the final version of the manuscript.EA-D was supported by funding from the Harry Crossley Postdoctoral Research Fellowship, 2021. The funder had no role in the conception of the review, data collection and analysis, preparation of the manuscript, or the decision to publish.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.