The human papillomavirus (HPV) vaccine protects adolescents and young adults from 9 high-risk HPV virus types that cause 90% of cervical and anal cancers and 70% of oropharyngeal cancers. This study extends our previous research analyzing online content concerning the HPV vaccination in social media platforms used by young adults, in which we used Pathfinder network scaling and methods of distributional semantics to characterize differences in knowledge organization reflected in consumer- and expert-generated online content. The current study extends this approach to evaluate HPV vaccine perceptions among young adults who populate Reddit, a major social media platform. We derived Pathfinder networks from estimates of semantic relatedness obtained by learning word embeddings from Reddit posts and compared these to networks derived from human expert estimation of the relationship between key concepts. Results revealed that users of Reddit, predominantly comprising young adults in the vaccine catch up age-group 18 through 26 years of age, perceived the HPV vaccine domain from a virus-framed perspective that could impact their lifestyle choices and that their awareness of the HPV vaccine for cancer prevention is also lacking. Further differences in knowledge structures were elucidated, with implications for future health communication initiatives. The recommendation to vaccinate males extends to age 26 if they have compromised immune systems  or are gay, bisexual, transgender, or have sex with other men.1 While clinical guidelines encourage vaccination for both males and females, in the United States, young adult women are much more likely than their male counterparts to have been vaccinated.36 However, the HPV vaccination coverage rate is alarmingly low for both males and females .An estimated 1 in 4 people in the United States are currently infected with the human papillomavirus (HPV) and 14 million additional people are infected with HPV each year. While most HPV infections (90%) are cleared within 2 years, persistent infection with high-risk HPV infections causes 90% of cancers of the cervix and anus and 79% of throat cancers. Consequently, Gardasil 9 9 Studies have also uncovered other patterns surrounding HPV vaccination uptake among US young adults. Health-care access plays a role in vaccine uptake; studies have found that access to free vaccination was strongly predictive of vaccine uptake, cost was a barrier to vaccination, and knowledge of where to receive vaccinations was correlated with a more favorable view of vaccination effectiveness and safety.1012 Other studies found that having an established relationship with a primary doctor, having received a non-HPV vaccine, and having received HIV testing were predictive of vaccination, but having health insurance was not always associated with vaccine completion.1315 Furthermore, being of a racial/ethnic minority, having lower educational attainment, and preferring a language other than English for communicating health information was associated with less vaccination.16 There are also geographic variations in vaccination rates, with areas of more poverty seeing less HPV vaccination.17 More research is needed about factors that encourage vaccination initiation among US young adults  and series completion because studies suggest that barriers for initiation are likely different than the barriers for completion.1618In the United States, while parents typically are the decision makers regarding vaccination for minors (up to age 18), young adults make the decision to vaccinate themselves. However, research has shown that parental opinion may still influence vaccine uptake in this population.19 Studies also found that while knowledge of HPV infection among young adults has improved over the past decade, misconceptions about vaccine safety and shortcomings in HPV literacy still exist.12 Misunderstandings differ among young adult subpopulations. One study by Klosky et al20 on HPV vaccination among young adult cancer survivors found them to be more HPV vaccine naive than the general population despite their experience with cancer. In another study, Vanderpool et al17 found that in a rural area with high cancer rates, fatalism about developing cancer predicted nonvaccination. Studies suggest that in the United States, provider education and recommendation of vaccination to young adults could encourage uptake, but research also suggests the need for more culturally tailored messaging, both in delivery and in format.21Studies of HPV vaccine acceptability, beliefs, and knowledge among young adults in the United States found low perceived susceptibility to HPV, especially among those in committed relationships.22 Use of social media to seek health information, facilitate social support, and promote greater psychological well-being is higher among young adults,24 making it a novel information source to understand personal determinants of health-seeking behaviors. A study of HPV-related posts in a social media found that information and misinformation influence vaccine acceptance.25 Another study on HPV vaccination content on social media found both male and female discussants, highlighting how both genders participate in discourse surrounding this topic on social media.26One potential outlet for HPV vaccination information is through social media. The term “social media” refers to Internet-based platforms that allow users to contribute and share information. The majority of Americans now access social media and young adults are particularly heavy users.2734 Some, like Pananos and others35 and Tangherlini and colleagues,36 used Google searches and website blogs, respectively. The former relied on a mathematical model that looked at near elimination of a disease and measles mumps and rubella (MMR) vaccine high uptake as signals for impending reduced vaccination and disease outbreak. Several studies specifically examined the HPV-related domain.2834While many studies have analyzed social media using such as word embeddings, we selectively reviewed previous work applying machine learning (ML) methods to vaccine-related social media content. This review was conducted on PubMed in November 2018 using the following search query: “social media AND  AND “vaccine” and sorted by best match. Most research within this area focused on classification-related tasks  using various ML approaches and using Twitter as a data source.The aforementioned studies focused on ML methods to classify information, yet this is only useful if categories are known beforehand. Text categorization of this nature can determine whether or not a previously identified concept has been mentioned or not, but this doesn’t provide any information about how concepts might relate to one another in the text or in the mind of its author. In studies that examined sentiment and emotion in text, there is nuance in bifurcated positive and negative emotion classification. If we were to show the association of data, or the structure of knowledge, more meaningful representation of the data would evince expressive information that can be utilized by researchers and experts. Our work makes use of the combination of distributional semantics and network graphs that can elicit interpretable representations of conceptual relationships from large amounts of unstructured text. Instead of Twitter, we focus on the Reddit social media platform, evoking structures of knowledge from 2 different populations—young adults and health experts. To the best of our knowledge, this is the first study that examines at Reddit on consumer vaccine research.37 Social media platforms differ particularly in the demographics of their users.22 Reddit is a popular social media platform whose users are mostly in the United States (54%) and younger than 35 years of age (87%).38 Reddit is currently the fifth most accessed website in the United States and the seventh most accessed website in the world.39 Referring to itself as “The Frontpage of the Internet,” Reddit is the first source of news for a sizable number of its users.40 Signing up for a Reddit account is free and allows the user to participate in subreddit communities that share and discuss content on a common interest. Reddit account holders can post and “vote” on content. They “upvote” posts that they find interesting and “downvote” posts that they do not like. A post with more “upvotes” rises to the top of a subreddit home page. As such, the Reddit platform is a real-time proxy for trending interests and values among its users.38 Data from Reddit have been used by researchers to examine health behaviors,41 obtain information about patient experiences,42 track patient outcomes,43 and identify common health information needs, perceptions, concerns, and health beliefs.4347 Our study used Reddit to examine the perceptions, concerns, and beliefs of Reddit users as they pertain to HPV vaccination. Findings from our study will increase understanding of factors influencing young adults’ decision-making regarding obtaining the HPV vaccination and will help guide future interventions targeting HPV vaccination uptake in this population. Ultimately, methods used and findings from this work will inform future approaches to conducting Internet-based formative work and e-behavioral intervention research targeting online groups, such as young adults.Social media sites’ data are accessible to evaluators and researchers and can be used to access first-hand, real-time information about experiences and outcomes of patients with cancer.48 Take, for example, the words “cancer” and “neoplasm” that appear frequently in a hypothetical corpus with the word “cervical.” The 2 terms mentioned may be related on account of their frequent presence in similar contexts. Since the 1990s, several distributional semantic approaches have been introduced that derive geometric representations of terms (word vectors or word embeddings) from their occurrence across large text corpora.50 Often referred to as word space (or semantic space) models, these models have been widely used because (1) they represent words and their meanings as a geometric representation that is amendable to further computation, (2) they utilize a data-driven approach to understand meaning from context without any prior linguistic or semantic knowledge, (3) they permit application of simple vector operations to extrapolate information and generate representations of larger units of text, and (4) estimates of relatedness between words can be derived from their vector representations.Distributional semantics is predicated on the notion that words that appear in similar contexts across large bodies of free text (corpora) may be semantically related to each other.51 Hyperspace Analogue to Language (HAL)52 is a related approach where, instead of a word-by-document matrix, each row (word) in a term-by-term co-occurrence matrix captures its frequency of co-occurrence with other words in a sliding window moved through the text. The Skip-Gram model53 is another window-based approach that uses artificial neural networks to predict terms that occur in context with a target term and derives estimates of semantic relatedness from the neural network weights for each term in a trained model.Latent semantic analysis is a seminal word space model that generates a reduced dimensional approximation of a statistically weighted term-by-document matrix and estimates relatedness between words from the distance between the resulting word vector representations.54 a stochastically implemented distributional semantic method based on the notion of sparse distributed memory,55 and Reflective Random Indexing (RRI),56 an extension of RI that aims to enhance its ability to recover meaningful implicit associations between terms from a corpus,57 were used. One benefit of RI is the reduced dimensionality of the vectors which are obtained without the need to represent a full term-by-context matrix explicitly, enhancing scalability. Another unique benefit is that it is not reliant on a specific data structure , which means it is adaptable to any word context scheme.In this study, Random Indexing (RI),With RI, each unique document in a target corpus is denoted by a stochastically generated random index vector with a predefined dimensionality and seed length. The vector is initialized as a vector of zeros, but a small number of elements (on the order of 10) are randomly assigned to “1” or “−1.” In addition to the random index vector, each unique term in the corpus is assigned a semantic vector. This semantic vector represents semantic information derived from random index vectors representing the contexts in which a term occurs.54 To add one qualification to the summary, instead of random index vectors for documents, we can also alternatively assign random index vectors to terms which would permit us to apply RI to approximate sliding window-based approaches such as HAL.58 Directional models further extends the sliding window approach through permutation of the random vectors of terms that appear before or after certain terms, such that terms are encoded differently depending on their orientation to a focus term in a sliding window.59The training of the semantic vectors is accomplished by traversing the documents in a corpus. In 60Reflective Random Indexing involves additional steps depending on the type—Document-Based Reflective Random Indexing (DRRI) or Term-Based Reflective Random Indexing. For DRRI, another allocation step occurs after the standard RI method where another set of document vectors is derived from the semantic vectors previously produced in standard RI by adding together the vectors for terms that occur in documents . This in turn can be used to generate another set of semantic vectors, as shown in 61 Pathfinder network scaling—the method used to derive PFNETS—is a psychometric method that harnesses graph theory approaches to identify salient links between concepts in order to represent mental models or knowledge structures of groups or individuals. The underlying idea is that the links preserved between network nodes representing concepts reflect the cognitive and psychological structures representing these concepts in the minds of individuals. Typically, these network links are based on individual judgments of similarity between concepts , but networks have also been obtained from estimates of semantic relatedness derived using methods of distributional semantics. The core network structure of the PFNETs is a minimal weighted subgraph  of a network derived from an algorithm to filter less essential links. It has been shown that these minimal subgraphs express the core relationships of the network that reflect memory and knowledge structures.62Pathfinder networks were introduced by Roger Schvaneveldt and his colleagues in the 1980s.r and q noted as PFNET. The q parameter constrains the number of steps an alternative link  may have. This allows control over the density of the graph by regulating the number of links in the PFNET. From a representational standpoint, the q value also modulates the number of links for psychological interpretation and expressiveness. Often the parameter of q = n − 1 is selected, imposing no limit on the number of links considered. The r parameter governs the distance metric used to determine the length of each path. This is important because the pruning aspect of the PFNET uses the weights of individual links in a network path. This aspect is predicated on the Minkowski distance measurement where if the r parameter is ∞, we take the maximum weight of links  to determine the length of a path comprising these links  from topic-related submissions posted on Reddit, a social media platform. The results were expected to show how young adults who utilize Reddit conceive of the HPV vaccine and its related concepts. Understanding preconceptions of this group could inform health-care professionals to better engage target vaccine audience users on social media platforms such as Reddit.In a previously published study,65 conceives of this domain. We also derived a PFNET from expert ratings of concepts instead of curating a corpus of expert-authored content. We enlisted the help of participating health experts  to provide their ratings for pairs of HPV vaccine concepts to produce an expert knowledge structure of the HPV vaccine domain as a PFNET. We proposed, by using the generated knowledge structures of PFNETs for experts (ratings based) and Reddit community members , to understand:1: What are the principal notions about the HPV vaccine domain in the Reddit community?R2: What are differences in HPV and HPV vaccination knowledge and perceptions between Reddit users and HPV vaccine experts?RThe following study utilized PFNETs to interpret the set of relationships existing between extracted keywords from submissions posted on Reddit over a duration of 10 years (2007-2017). Unlike our previous work, this study addresses a specific type of vaccine, namely the HPV vaccine, and how a young adult demographic, a demographic that is at risk for HPV,38 With this in mind, a list of concepts from a review of the literature on HPV vaccination and young adults was compiled. PubMed was searched for articles with keywords “HPV” and “vaccination.” Given the Reddit user demographics, articles were chosen if they described data from the United States and described the issue from the perspective of those who were considering vaccination for themselves . After identifying an article of interest from this list, articles PubMed had suggested as “articles like this one” and “articles that cited this” were also examined. Concepts, based on the ConceptNet knowledge base66 (a semantic knowledge graph of “commonsense” information), were extracted based on repetition and similarities across articles. Concept identification continued until themes appeared to be saturated . Researchers then met with medical and public health content experts in the Texas Children’s Hospital and the University of Texas Health Science Campus to prepare a final list of terms for the analysis. As we will explain later, the concept pap screen was excluded from analysis due to its absence from the Reddit corpus. The final list of 23 concepts (including pap screen) was:To derive PFNET for entities in the domain knowledge structure of Reddit contributors, a list of concepts that would serve as the nodes was required. Demographically, Reddit users are a distinct user group from those of other social media sites. Most Reddit users reside in the United States and are younger than 35 years of age.Pushshift.io.67 Submissions (topic starters) and comments (responses to the topic) that contained the case-insensitive expressions of “hpv,” “papillomavirus,” “cervarix,” or “gardasil” were extracted and stored in a PostgreSQL database. The entire subset of HPV-related content was then exported to plain text files. The entire Reddit corpus was also processed with word2phrase68 to identify and concatenate multiworded tokens . In total, the number of documents from the corpus was 88 836.The Reddit corpus for HPV-related content was derived from a data set from 69 facilitated the collection of pair-wise relatedness ratings. The seed term concepts were presented individually with a prompt asking the rater to determine how related the 2 concepts are . Four HPV vaccine experts who were either an MD and/or held an MPH in public health volunteered to rate the association of the seed terms. Using JRate70 (prerelease version 5.9) was used to derive the proximity data from the seed terms with word space models. Then several word space models were created—RI and its variant models and a neural embedding model derived using the Skip-Gram with negative-sampling algorithm.53 For sliding window models, we utilized a contextual window size of 10 (radius = 10) to capture both synonymous and associative relationships.71Term by document RITerm-based RRIDocument-based RRISliding window Directional window Skip-Gram neural embedding The Semantic Vectors software package72 Inverse document frequency weighting was utilized for the RRI models.For each of the models, we incorporated a stop word list from Cornell University researchers’ SMART information retrieval system.73 a freely available software tool to explore and visualize PFNETs. http://bit.ly/2sOBZkc.After the 6 abovementioned word space models were built, the vector space with each seed term (concept) was extracted from each model and the cosine distance between each concept calculated. The data were formatted in a proximity data file (similar to the JRate export). The exported proximity data were analyzed and used to generate the PFNET (discussed in Results) through JPathfinder,The coherence score for each of the models produced was measured see . The cohComparing all of the Reddit proximity word models, the directional (with RI) model yielded the highest coherence (0.723) compared to the rest, with document RRI model with the second highest rating (0.719). The mean and median version of expert rating produced similar results (0.726 and 0.715). From 63pap screen concept did not appear in the Reddit network due to not appearing in the Reddit corpus. Hence, we removed that concept from the expert network and recomputed the network to provide comparable networks with equal number of nodes. The Reddit PFNET exhibited 22 nodes and 21 links connecting the nodes, while the expert PFNET exhibited 22 nodes and 25 links within its network.Network visualizations and meta-data were generated from JPathfinder. hpv, while the expert PFNET was hpv. The Reddit PFNET concept of hpv has the maximum number of links to it, and hpv vaccine has the maximum number of links within the expert PFNET. Finally, between PFNETs of Reddit and expert, the only two shared links are risk ↔ hpv and hpv ↔ genital warts.Calculating eccentricity value  for a network representation can indicate a node that is central within an entire network: the node with minimum eccentricity. A central concept in a network structure could indicate the arrangement of knowledge based on a particular core concept, and in the case of representing knowledge, it could indicate the important unifying belief of the network. Aside from eccentricity, the maximum of number of links to a concept (maximum degree) can also emphasize an important concept. For example, for the Reddit PFNET, the central concept, based on eccentricity calculation, was unsafe and myth are a set of concepts, disconnected from the larger expert network. No isolated subnetworks exist for the Reddit network . Concept pairs such as risk ↔ scientific evidence, health ↔ hpv vaccine, death ↔ inaccessible, and prevention ↔ recommendation (weakly associated pairings) are 1 standard deviation below the average similarity(μ − 1σ).The most and least close association of concept pairs among the Reddit model had similarity and dissimilarity distances beyond 1 standard deviation among all pairwise associations. The pair-wise similarities of hpv vaccine ↔ health, inaccessible ↔ health, recommendation ↔ hpv, and scientific evidence ↔ death has indistinct associative pairings among the Reddit pairings. With the expert, the concept pairs with weak associations are highlighted in red. These “weaker” pairs are also 1 standard deviation below the average (μ − 1σ).Among the experts , the conR1: What are the principal notions about the HPV vaccine domain for the Reddit community?From the various data generated from word space models of the Reddit corpus and the Likert ratings for the pair-wise comparison of terms, we discovered discrepancies in the concept similarity and network data that may have implications for future research and communication efforts.hpv is the primary concept, which is different from Expert PFNET where hpv and hpv vaccine are the primary concepts. Of interest, the seed terms were intended to be related to the hpv vaccine, so a Reddit PFNET centered on hpv illustrates how Reddit users implicitly arrange their knowledge around virus- rather than vaccine-related topics. In contrast, HPV vaccine experts abstracted their knowledge using professional understanding of the HPV vaccine and HPV. This is further supported when observing the placement of hpv vaccine in relation to other concepts from the Reddit PFNET. hpv vaccine has one link to the network of the Reddit PFNET. As we had noted earlier, this link is one of the weak associations from that network.As shown in hpv and genital warts has the highest similarity (0.823). risk is another concept with high similarity to hpv, and health (0.628) has a moderate association with hpv. When exploring the nearest neighboring concepts other than the seed concepts , but the concept sexual is one of its nearest neighboring concept outside of the seed concepts. Overall, the PFNET for Reddit expresses young people’s domain understanding from the perspective of STD transmission and the impact of contracting this virus.R2: What are some differences in knowledge structures between Reddit users and HPV vaccine experts?Furthermore, epts see , the conAside from the salient concepts, comparing the associations between the various concepts in the expert PFNET and the Reddit PFNET revealed some additional understanding of young people’s perception of the HPV vaccine domain.The expert PFNET has numerous concept associations that are highly related, yet many of them do not coincide with the Reddit PFNET. These concepts that are strongly associated are highlighted in green on hpv ↔ genital warts and hpv ↔ risk, none of these pair-wise associations coincides with the Reddit PFNET. We assert that professional knowledge structures concerning the HPV vaccine are notions that are generally not known or not thought of by young people, especially the association of hpv vaccine ↔ cancer, which is an important relation in this domain. However, hpv ↔ genital warts appears to be a common association with this specific population, perhaps because of its important impact on young people’s lifestyle choices. The same can be said for hpv ↔ risk, which is also another shared pair-wise association. While hpv vaccine ↔ cancer is associated closely in the expert PFNET structure, we find that hpv ↔ cancer is highly associated (0.798), indicating some evidence of HPV cancer awareness with this population.With the exception of The pap screen concept is absent in the Reddit PFNET structure, as it has no relation/co-occurrence with the other concepts in the word space models for Reddit. Pap screening is an important preventive measure for HPV among females, yet this concept does not appear to be reflected or understood to be important by the younger and predominantly male Reddit population in the context of HPV.75 Moreover, health-care providers often struggle to effectively educate individuals about HPV-related diseases and vaccine.75 Social media platforms are widely utilized among the younger population and serve as an informational tool for this group. Through the availability of many platforms and their APIs, social media data provide researchers a storehouse of behavioral data collected from a large population.76 If experts want to directly communicate and understand this population, researchers need to better wield these platforms for maximum benefit and know the users’ knowledge, attitudes, and beliefs on a specific health topic to refine communication efforts.Lack of knowledge and misinformation about HPV and the HPV vaccine are common.77 In particular, young adults are also a population who engage in high risk behavior,78 which makes them susceptible to HPV transmission. Currently, there is no screening test available for HPV for men (CDC79), who may be asymptotic carriers and likely to have a higher number of sexual partnerships.One overarching theme that emerged from this study method was an important difference between the young adult population that use Reddit and the HPV vaccine experts. In our examination of Reddit data, we identified common themes including a preoccupation with virus transmission and risk versus awareness of the HPV vaccine. Young adults have high rates of HPV infection.80 Also, vaccination rates for the HPV vaccine are not meeting the targeted 80%, as HPV vaccination coverage of females and males is at 43%. The HPV vaccine is best administered between the ages of 11 to 25 to attain the benefit of its immunity against the HPV viruses that lead to adulthood cancers, such as cervical cancer and head and neck cancer. While there is strong evidence from our study to support our claims concerning the lack of HPV vaccine awareness, there is awareness for HPV-related cancers and the risks they pose.Another finding is that of lack of knowledge about the HPV vaccine among young adults, possibly due to lack of informational interventions to raise awareness. While experts associate HPV vaccine with cancer and prevention, in our Reddit PFNET, these associations do not emerge. Pap screening was also missing from the Reddit PFNET, possibly because of the predominantly male user population with low knowledge of pap screening to detect cervical cancer or precancerous lesions caused by HPV. To date, few cancer prevention interventions target young adults.This study’s method to mine large corpora on social media to assess consumers’ knowledge of a health-related topic provides a new approach to conducting formative work. What individuals express on social media platforms may be examined qualitatively and quantitatively to identify themes related to how a subgroup may perceive or understand health recommendations, including vaccination. This is particularly helpful for health communication and public health researchers planning e-health interventions targeting online users in specific social media domains. Our approach not only brings to light knowledge structures of a population around certain concepts but also provides insight regarding how these concepts are linked to one another.82 the risk of sexually transmitted diseases and their prevention appeared to resonate more with the sexually active young adults. Future studies are needed to confirm these findings, particularly among young adult non-Reddit users, such as young women and those with less educational attainment.Findings from this work indicate HPV vaccination messaging for young adults should focus on genital warts and prevention of HPV infection, followed by education on HPV vaccination for cancer prevention. While cancer prevention may be more acceptable and salient for parents considering the HPV vaccine,In this article, we utilized distributional semantics and PFNETs to understand the knowledge structures of Reddit users, reported to be young adults. This enabled creation of PFNETs to discover how closely related certain concepts within the HPV vaccine domain were and to compare them with PFNETs generated from HPV vaccine experts’ ratings. Results show Reddit users do not conceptualize HPV vaccine the same way as experts and that they are mostly concerned with the immediate consequences of the virus itself. Our results have implications for public health as they stress the need to reach out to a young adult population that can still be vaccinated. Also, our work provides researchers a method to better use social media or large amounts of textual information to understand and communicate based on how a certain population represents domain knowledge of a health topic.


As Veterans age, they may experience an emergence or exacerbation of stress symptomatology. Later-Adulthood Trauma Reengagement (LATR) is an intervention that provides psychoeducation on the LATR process, teaches mindfulness and coping, facilitates trauma re-integration, and fosters meaning-making in late life. This program evaluation project evaluated the LATR group offered in the Geriatric Mental Health Clinic at VA Boston. Twenty-one Vietnam Veterans with PTSD symptomatology were referred to the group between 2017-2018. Fifteen completed the 10-week group, and 12 completed pre- and post-intervention assessments and offered feedback. At the conclusion of the group, Veterans reported a decrease in depressive and PTSD symptoms. Of the 4 Veterans who endorsed suicidal ideation at the start of the group, 3 reported a decrease post-group. Veterans endorsed slightly more positive appraisals of their military service. Veterans reported that the group offered support, connection, and a sense of belonging with other Veterans, helped increase coping, and increased insight into thoughts, feelings, and behaviors. A suggested improvement to the group was to offer more sessions. Eleven Veterans sought continued mental health services following the group; three newly sought trauma-focused interventions. Four Veterans reported that their trauma-related symptoms were resolved and declined referral. Veterans found the LATR group helpful as evidenced by reduction in symptoms and responses to open-ended questions. A small number sought additional trauma-focused treatment; others reported that their symptoms were resolved and did not require additional treatment. Findings support the continued offering of the LATR group within this clinical setting.


The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose. Further, in the CVT stable antibody responses were documented at levels between five- and ninefold higher for HPV 16 and 18 than those induced by natural immunity; yet, they were fourfold lower compared with levels elicited by three doses The Costa Rica Vaccine Trial (CVT) At present, HPV vaccine uptake and cervical cancer screening implementation has been insufficient in most world regions and the expected number of cervical cancers is projected to increase over the coming decades post hoc analysis of the CVT, review the validity of these findings by discussing potential biases, and present our future efforts to additionally address critical questions around single-dose protection afforded by the HPV vaccines.The objective of this manuscript is to summarize the evidence to date for single-dose efficacy of the bivalent HPV vaccine from 22.1CVT was a publicly funded, four-year, community-based, randomized phase III clinical trial  2.2At enrollment and follow-up visits, participants provided a serum sample, and for sexually-experienced women, a pelvic exam was performed at which time cervical cells were collected for cytology and HPV DNA testing. At the end of the four-year trial, participants were offered the vaccine they had not received at enrollment (cross-over vaccination) and were invited to stay in a long-term follow-up observational study As part of the study design, time windows for each vaccine dose were pre-defined based on the first vaccination date. Women who became pregnant during the vaccination phase or who were referred to colposcopy were deferred, and missed that dose if the vaccination window was closed; this occurred in roughly 20% of women in the CVT In this report, we summarize the published data to date. We compared multiple vaccine groups with their corresponding control groups, as follows: (i) women who received one HPV16/18 vaccine dose; (ii) women who received two HPV16/18 vaccine doses at enrollment and 1 month later; (iii) women who received two HPV16/18 vaccine doses at enrollment and 6 months later; (iv) women who received all three HPV16/18 vaccine doses; (v) women randomized to the original control arm; and (vi) women from the new unvaccinated control group. We evaluated these groups for virologic and serologic endpoints.2.3HPV DNA detection and genotyping from cervical specimens were performed at DDL Diagnostic Laboratory HPV16 and HPV18 serum antibody levels were measured by ELISA using HPV16 and HPV18 virus like particle (VLP) at the NCI HPV Immunology Laboratory, as previously described HPV16 avidity was measured in serum by coating plates with HPV16 L1 VLP. Each serum sample was tested at a dilution that yielded an absorbance reading of 1.0 ± 0.5 as previously determined in an HPV16 VLP ELISA. Guanidine-HCl (GuHCl) was added to the samples at various concentrations (0.5–3.5 M); the concentration of GuHCl that reduced the optical density by 50%, compared with sample wells without GuHCl treatment, defined the Avidity Index.HPV16 and HPV31 neutralization titers were determined using a previously described pseudovirion-based secreted alkaline phosphatase neutralization (SEAP) assay 2.4For analyses of the efficacy of <3 doses during the randomized, blinded phase (first four years of study), the primary endpoint was newly detected HPV 16 or 18 infection that persisted for at least 6 months. Endpoint definition required detections of the same genotype consecutively at least four months apart with no intervening negatives. We required detection of the first infection to start at the 12-month study visit or later to avoid prevalent infections at enrollment and differential assessment by missed visits during the vaccination phase . We additionally investigated 12-month persistent HPV16/18 infections, and HPV 31/33/45 infections , HPV types with prior evidence of vaccine cross-protection.The analytic cohort excluded women who were both HPV16 and 18 DNA positive at enrollment, and women with no follow-up visits post-enrollment . Within each dose group, the complement of the ratios of the attack rates for the HPV arm and the control arm are the vaccine efficacy (VE) estimates. Instead of conducting a direct comparison by number of doses within the HPV arm only, data from the randomized control arm were used, because we were uncertain whether the underlying HPV attack rates would vary by vaccine dose (i.e.: are women who missed dose(s) riskier in some way, and therefore have a higher HPV attack rate?).For analyses occurring at the seven-year study visit, multiple endpoints were assessed, including year-7 incident and prevalent HPV infections. This focus on the year seven results and not cumulative assessment of the endpoints over the seven years of the study follow-up was meant to ensure the assessment of the longevity of the protection against HPV infections, instead of allowing the early-term protection to potentially drive the longer-term findings. Comparisons of endpoints are made between the HPV dose groups and the new, non-randomized unvaccinated control group, since the original control group was exited by this time point. For each of the endpoints, we reported the number (n) of women with the endpoint, the total number (N) of eligible women, and corresponding percentage (%) by each of the four HPV vaccine groups. We also report the p-values comparing rates in the 2-dose (0/6 month), 2-dose (0/1 months), and 1-dose groups with the rate in the 3-dose group using Fisher’s test. Given the use of the non-randomized control group, we present a comparison of HPV prevalence by group in lieu of VE.33.1Data generated from CVT and other sources on single-dose HPV vaccine protection are being used to make decisions about future studies. While dose-specific data were obtained in the context of a randomized clinical trial, they are observational in nature. A concern is that one-dose protection is not actually a function of the HPV vaccine, but instead related to an underlying characteristic shared by women who received only one dose. We provide the following example: perhaps women who received a single dose did so because they had a strong adverse reaction to the vaccine, but are actually better able to mount an immune response to the first dose. If this were the case, then our findings on single-dose protection would not generalize to the majority of women who can tolerate multiple HPV vaccine doses.•Demographic and HPV-related differences at enrollment, including sexual behavior and presence or absence of Chlamydia trachomatis by dose group;•Reasons for missed doses;•Vaccine antibody response elicited one month after the first dose, when all women received the same number of doses irrespective of the total number of doses they received; and,•Prevalence of HPV genotypes not protected by the vaccine, as an indicator of HPV exposure, accumulated over the four-years of follow-up.To confirm the validity of the findings to date, several metrics have been used to evaluate potential biases and confounding in our data , includi3.1.1Based on the enrollment characteristics, we evaluated whether balance was present by vaccine received (i.e.: comparing participants randomized to the HPV arm versus the control arm) within a dose group. There were no differences by arm in the one dose group by age at vaccination (p = 0.9), number of clinic visits attended , or HPV16/18 DNA (p = 0.8) or serologic status (p = 0.5). We also did analyses to investigate sexual risk-taking behavior using presence or absence of Chlamydia trachomatis (Ct)- the prevalence of Ct was balanced within a dose group by arm p = 0.8; .Table 2BSome differences are noted across HPV-vaccinated groups, with single-dose recipients having more HPV16/18 DNA positivity at enrollment compared to three-dose HPV vaccine recipients (p = 0.01 for the HPV arm); HPV16/18 seropositivity was not different across the dose groups.3.1.2Among all vaccinated women, reasons for not receiving all doses were similar in both HPV and HAV arms conditional on the number of doses received , ref 11.3.1.3The antibody levels measured at one-month following the initial doses, when all women received the same number of doses irrespective of the total number of doses they received, were not significantly different (13). Specifically, the HPV16 GMTs were 419.7 (95% CI 251.0 to 701.7) for 1 dose, 646.2 (95% CI 478.2 to 873.4) for 2 doses, and 597.0 (95% CI 454.1 to 784.8) for 3 doses (p = .4); the respective data for HPV18 were 207.0 (95% CI 114.9 to 372.8), 244.1 (95% CI 184.2 to 323.4), and 207.9 (95% CI 163.3 to 264.5) (p = .7). This allayed concerns that the one-dose recipients may have had a more robust intrinsic ability to respond to the vaccine.3.1.4After four years of follow-up, in the HAV arm, the attack rates of incident HPV16 or HPV18 infections that persisted for at least six months were similar among women who received three doses , two doses , or one dose  indicating that they were at similar risk for acquiring HPV infections regardless of the number of HAV doses they received 3.2In evaluations of single-dose efficacy using the bivalent HPV vaccine, the data were assessed at two timepoints: first, during the initial four-year randomized blinded phase that included the randomized control arm  to assess background rates of HPV infection, and then at seven years in our long-term follow up study that included a new observational control arm. The analytic strategy changed between the two timepoints. At four years, we cumulatively assessed HPV infections over the four-year follow up. At the seven-year data point, we assessed point prevalence as the outcome. The goal was to assess continued duration of protection; so, it was important to avoid having protection documented in the initial four years’ drive findings in the latter years. In future analyses, we will continue to use this approach of assessing protection at the far-out time point.Four years after initial vaccination, a single dose of the bivalent HPV vaccine had comparable efficacy to three doses of the vaccine using an endpoint of cumulative persistent HPV infection (11). The four-year efficacy against HPV16 or 18 infections (that persisted for at least six months) among women who were HPV DNA negative for these types at first vaccination: for three doses = 84% ; two doses = 81% (95% CI: 53–94%); 5 and 24 events among HPV [n = 422] and control [n = 380] arms, respectively); and one dose = 100%  were substantially higher than those among naturally-infected unvaccinated women (approximately ninefold higher for HPV16 and fivefold higher for HPV18) four years after initial vaccination. Titers remained stably elevated at our latest assessment, seven years post-vaccination, albeit still at four- to fivefold lower levels than for two or three doses Neutralizing antibodies, the presumed mediators of protection, were measured via SEAP at year 4. They were highly correlated with levels measured by ELISA: spearman correlations were high for three (0.87), two , two , and 1 (0.79) dose groups, although decreased correlation was noted for the fewer-dose groups HPV16 VLP antibody avidity, a measure of the quality of the antibody response, was measured at years four and seven. In years four and seven, one dose recipients had 80% of the avidity index compared to those who received three-doses, thus suggesting that HPV16 antibody quality was stable over time 4Since 2011, the CVT and PATRICIA trials have provided evidence that a single dose of the bivalent HPV vaccine provides strong and lasting protection against HPV16 and 18, and suggest there may be the additional benefit of cross-protection against phylogenetically-related HPV types. Much work has been done to rule out bias and confounding by dose group. Most recently, we extended the documentation on the duration of protection against virologic and immunologic endpoints out to seven years. Yet, we acknowledge that the group of women receiving one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was relatively small, and that they were not randomized to a reduced-dosing schedule. Based on compelling data together with both the fact that they challenge the prevailing dogma that protein-based subunit vaccines require a prime-boost regimen, and the potential public health impact of an effective one-dose strategy, we contend that further studies are warranted.Thus, the next phase of our research has three complementary component parts, aimed at providing the rigorous, long-term data to drive HPV vaccine recommendations to one dose if warranted. The three parts include (1) extension of the follow-up of the one-dose women from the original Costa Rica HPV Vaccine Trial (“CVT EXTEND”), (2) a new RCT that formally evaluates the protection of a single dose of the HPV vaccines , and (3) immunobridging trials to other populations around the world. Short introductions to these efforts are provided below.4.1It is critical to continue to evaluate the long-term stability of antibody responses among reduced dose recipients. To do so, we extended the follow-up time of women in the original CVT who received one or two doses and a subset who received three doses of the HPV vaccine out to 15 years (note that women enrolled into CVT were between the ages of 18 and 25). The main aim of this extension is to describe, by dose, the long-term positivity and stability of the antibody response to HPV vaccination. These 15-year data on the durability of the antibody response for a single dose of the HPV vaccine will be available prior to the completion of four-years of follow-up of the ESCUDDO study (described below). Thus, results from both studies will be paired for presentation to recommending bodies.4.2The US NCI, again in collaboration with the Costa Rica Agencia Costarricense de Investigaciones Biomédicas (formerly Proyecto Epidemiologico Guanacaste), is conducting a large, 20,000 subject, randomized, controlled, non-inferiority efficacy trial in Costa Rica  of two FDA- and WHO-approved HPV vaccines: the bivalent vaccine Cervarix (GSK) and the nonavalent vaccine Gardasil 9 (Merck). The main goals of the trial are to evaluate whether, in adolescent girls (ages 12 to 16), one dose or two doses of the bivalent or nonavalent vaccines can confer strong, durable protection against persistent HPV infections. Virologic endpoints are necessary in the evaluation of a one-dose schedule, as the antibody levels are inferior to those of two doses, and, as yet, we do not know the minimum level required for protection. Separately for each vaccine, one-dose will be tested for non-inferiority against the two-dose regimen. Analyses will also be conducted to estimate vaccine efficacy versus no vaccination using a concurrent population survey of comparable, unvaccinated age-matched females in the same region, who will be tested for HPV DNA and then immediately vaccinated. The population survey will be used to estimate vaccine efficacy against incident persistent infection by subtracting off estimates of HPV infection prevalence four years earlier. The effort is intended to provide definitive results that can drive widespread recommendations by agencies such as the World Health Organization.4.3The overall aim of our immunobridging work is to compare dose- and vaccine-induced HPV-specific antibody levels among girls in multiple other countries to the antibody levels observed to provide protection against HPV infection in the Costa Rica ESCUDDO study (described above). These data will address the hypothesis that girls in other countries, such as those in sub-Saharan Africa where more co-morbidities may exist, including parasites, other infections, malnutrition, and general decreased immune status, mount an immune response to the HPV vaccines that is not significantly less than that observed in women in a Western, middle-income country, in this case, Costa Rica. These studies are running in parallel with the ESCUDDO study, to accumulate the necessary data simultaneously.In addition to the immunobridging potential of the one-dose trial to other world populations, it also creates the needed biobank in which to evaluate/immunobridge to one-dose regimens of future VLP-based biosimilar HPV vaccines.4.4From the global perspective, women who are at the greatest lifetime risk of cervical cancer are not being vaccinated. Our data showing that a single dose of the HPV vaccine continued to protect against HPV infection, with documented stability of antibody and avidity up to 7 years, augments other data supporting the hypothesis that one dose may be sufficient. Continued demonstration of the protection afforded by one dose will be provided by the CVT cohort for 15 years post initial HPV vaccination. This durability data is intended to complement the ESCUDDO study, a formal trial of the bivalent and nonavalent HPV vaccines. Finally, the immunobridging studies will focus on regions that may have additional comorbidities to ensure the findings from Costa Rica are generalizable to other world populations. Combined, we intend to provide sufficient evidence to motivate policy change, in the event one-dose HPV vaccination continues to demonstrate robust protection.From a public health perspective, it is important to plan further studies in light of the current data and the likelihood of the planned trial demonstrating the validity of a single-dose strategy. In this regard, the efficacy of a single-dose strategy could have dramatic public health implications, particularly as it could establish substantial herd immunity and thus protect not only vaccinees but also other against the world’s third leading cause of cancer death in women.The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the NCI. The trial is sponsored and funded by the NCI , with funding support from the National Institutes of Health Office of Research on Women's Health. GlaxoSmithKline Biologicals (GSK) provided vaccine and support for aspects of the trial associated with regulatory submission needs of the company under a Clinical Trials Agreement (FDA BB-IND 7920) during the four-year, randomized, blinded phase of our study.The NCI and Costa Rica investigators are responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. John T. Schiller and Douglas R. Lowy report that they are named inventors on US Government-owned HPV vaccine patents that are licensed to GlaxoSmithKline and Merck and for which the National Cancer Institute receives licensing fees. They are entitled to limited royalties as specified by federal law. The other authors declare that they have no conflicts of interest.Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica—Bernal Cortés (specimen and repository manager), Paula González , Rolando Herrero , Silvia E. Jiménez , Carolina Porras (co-investigator), Ana Cecilia Rodríguez (co-investigator).United States National Cancer Institute, Bethesda, MD, USA—Allan Hildesheim , Aimée R. Kreimer , Douglas R. Lowy (HPV virologist), Mark Schiffman , John T. Schiller (HPV virologist), Mark Sherman (CVT: QC pathologist), Sholom Wacholder (statistician).Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA (HPV Immunology Laboratory)—Ligia A. Pinto, Troy J. KempGeorgetown University, Washington, DC, USA—Mary K. Sidawy (CVT: histopathologist)DDL Diagnostic Laboratory, Netherlands (HPV DNA Testing)—Wim Quint, Leen-Jan van Doorn, Linda Struijk.University of California, San Francisco, CA, USA- Joel M. Palefsky , Teresa M. Darragh University of Virginia, Charlottesville, VA, USA- Mark H. Stoler (QC pathologist)


Nearly all the research on appraisals of military service and homecoming experiences have been done on World War II veterans. However, Spiro et al. (2016) hypothesized that there were war cohort differences in military experiences that could affect life-long adaptation. For example, Boscarino et al. (2018) found that Vietnam veterans reported less welcoming homecoming experiences than OEF/OIF/OND veterans. We examined war cohort differences among OEF/OIF/OND, Persian Gulf, and Vietnam combat veterans in military service appraisals and homecoming experiences. We used pilot data from Veterans Aging: Longitudinal studies in Oregon (VALOR) from an online survey. The sample included male and female combat veterans : 39 from the OEF/OIF/OND, 68 from the Persian Gulf War, and 60 from the Vietnam War cohorts. Comparable to earlier studies , combat veterans were surprisingly much more likely to endorse desirable appraisals than the undesirable ones, with each of the 14 desirable appraisals endorsed by over 90% of the veterans. Fewer endorsed the undesirable experience items; the most common was separation from loved ones and loss of friends. Most also reported positive homecoming experiences. Contrary to expectations, ANOVAs revealed that there were no significant differences in appraisals of desirable and undesirable military service experiences, nor in homecoming experiences among the war cohorts. In this small sample, military experiences were perceived similarly among combat veterans despite differences in wartime experiences. Most felt that positive experiences resulted from their desirable military service.


Compared to HPV-negative head and neck squamous cell carcinomas (HNSCCs), HPV-positive HNSCCs are associated with a favorable prognosis in part due to their improved treatment sensitivity. Inactivating mutations in NSD1 were shown to be a favorable prognostic biomarker in laryngeal cancers. Here, we characterize NSD1 mutations from the expanded The Cancer Genome Atlas (TCGA) HNSCC cohort (n = 522) and examine their prognostic implications based on HPV status of the tumor. We also begin to examine if NSD1 regulates response to platinum-based drugs and other DNA-damaging agents.TCGA HNSCC samples were segregated by HPV and NSD1 mutations using cBioPortal and patient survival was determined. Pathogenicity of mutations was predicted using UMD-Predictor. NSD1-depleted cell lines were established by transfection with control or shRNAs against NSD1, followed by puromycin selection, and confirmed by qRT-PCR. Cell sensitivity to DNA damaging agents was assessed using short-term proliferation and long-term clonogenic survival assays.Among 457 HPV(−) tumors, 13% contained alterations in the NSD1 gene. The majority (61.3%) of NSD1 gene alterations in HPV(−) specimens were truncating mutations within or before the enzymatic SET domain. The remaining alterations included homozygous gene deletions (6.7%), missense point mutations (30.7%) and inframe deletions (1.3%). UMD-Predictor categorized 18 of 23 missense point mutations as pathogenic. For HPV(+) HNSCC (n = 65), 6 NSD1 mutations, comprised of two truncating (33%) and 4 missense point (66%) mutations, were identified. Three of the 4 missense point mutations were predicted to be pathogenic or probably pathogenic by UMD-Predictor. Kaplan-Meier survival analysis determined significantly improved survival of HPV(−) HNSCC patients whose tumors harbored NSD1 gene alterations, as compared to patients with wild-type NSD1 tumors. Interestingly, the survival effect of NSD1 mutations observed in HPV-negative HNSCC was reversed in HPV(+) tumors. Proliferation and clonogenic survival of two HPV(−) cell lines stably expressing control or NSD1 shRNAs showed that NSD1-depleted cells were more sensitive to cisplatin and carboplatin, but not to other DNA damaging drugs.Genetic alterations in NSD1 hold potential as novel prognostic biomarkers in HPV(−) head and neck cancers. NSD1 mutations in HPV(+) cancers may also play a prognostic role, although this effect must be examined in a larger cohort. NSD1 downregulation results in improved sensitivity to cisplatin and carboplatin, but not to other DNA-damaging agents, in epithelial cells. Increased sensitivity to platinum-based chemotherapy agents associated with NSD1 depletion may contribute to improved survival in HPV(−) HNSCCs. Further studies are needed to determine mechanisms through which NSD1 protects HPV(−) HNSCC cells from platinum-based therapy, as well as confirmation of NSD1 effect in HPV(+) HNSCC. Head and neck squamous cell carcinomas (HNSCCs) comprise a diverse group of tumors, which are classified into various anatomical sites , with unique epidemiology, anatomy, clinical behavior, and association with human papilloma virus (HPV) or Epstein-Barr Virus infection , 2. HPV-For HPV(−) cancers, which are significantly more deadly than HPV(+) cancers, understanding their molecular diversity is critical to developing and selecting appropriate treatments to improve mortality. Comprehensive genomic profiling of head and neck squamous cell carcinomas by The Cancer Genome Atlas (TCGA) has identified a distinct subgroup of HPV(−) cancers with inactivating mutations in the nuclear receptor-binding SET domain protein 1 (NSD1), a methyltransferase and chromatin modifier , 16. In In this study, we characterize NSD1 mutations in HPV(+) and HPV(−) cohorts from the expanded TCGA HNSCC dataset and examine prognostic implications of NSD1 mutations in the TCGA dataset. Finally, we investigate response of NSD1-depleted cells to platinum-based chemotherapy drugs and a variety of agents that have different mechanisms of DNA damage.cbioportal.org). Figure TCGA HNSCC database was mined for HPV(−) and HPV(+) samples (HPV(+) defined as ≥100 HPV reads per million human reads in whole-genome sequencing. Of the initial group of HPV(+) cases detected, those with p53 mutations were redesignated as HPV(−) cases, as the HPV DNA detected was likely not a driver of carcinogenesis. NSD1 mutations were identified with cBioPortal  and HPV(+) HNSCC with and without mutations in NSD1 were produced and downloaded from cBioPortal, and the log-rank (Mantel-Cox) test was used for statistical analyses.FaDu (human HPV(−) hypopharyngeal HNSCC) and SCC35 (human HPV(−) pharyngeal HNSCC) cells were cultured in DMEM/F12 medium supplemented with 0.4 μg/mL hydrocortisone. HaCat (spontaneously transformed non-tumorigenic human keratinocyte) cells were grown in DMEM with nonessential amino acids. All media was supplemented with 10% FBS (Invitrogen), 50 μg/mL penicillin, and 50 μg/mL streptomycin (Invitrogen). All cell lines tested negative for Mycoplasma and microsatellites authenticated.FaDu , SCC35, Primer pairs:Total RNA was extracted by Qiagen RNA extraction kit and cDNA was synthesized using iScript cDNA Synthesis Kit (Bio-Rad) according to the manufacturer’s instructions. Quantitative real-time reverse transcription (qRT-PCR) was done using iQ SYBR Green Supermix (Bio-Rad) and indicated primer pairs on the iCycler iQ Real-Time PCR Detection System (Bio-Rad). Each qRT-PCR reaction was done in duplicate at least, and the ΔΔCt method was used to analyze the data; relative expression (% from GPDH) is presented.Cells (3000 cells/well) were plated in 96-well plates and treated with increasing doses of cisplatin (0–16 μM), carboplatin (0–20 μg/ml), etoposide (0–25 μM), zeocin (0–480 μg/ml), paclitaxel (0–160 nM), or mirin (0–80 μM) in triplicate. Proliferation was determined 72 h after treatment using the Cell Titer Glo reagent (Promega).Cells (1000 cells/well) were plated in 6-well plates and treated with carboplatin  in duplicates. After cell growth for 10 days for HaCat cells and 14 days for FaDu cells, colonies were fixed and stained with methylene blue in methanol for 1 h. Colonies consisting of at least 50 cells were counted.n = 273 [In the previously published TCGA HNSCC cohorts (n = 273  or n = 4n = 273 ), NSD1 wn = 273 . FurtherStatistical analysis of clinical characteristics of the HPV(−) cohort demonstrated that the NSD1 mutant and wild-type groups did not differ significantly in terms of average age at diagnosis or sex, race, alcohol use, or clinical stage Table . Thus, NClassification of the TCGA HPV(−) cohort by site revealed that laryngeal cancers were overrepresented amongst those with mutant NSD1: 25% of HPV(−) tumors arose in the larynx but almost 60% of HPV(−) tumors with NSD1 mutations occurred in the larynx Fig. . In contWe next performed Kaplan-Meier survival analysis of head and neck patients in the expanded TCGA cohort based on HPV and NSD1 mutation status. Interestingly, patients with HPV-negative HNSCC whose tumors contain alterations in the NSD1 gene (n = 60), showed significantly improved overall (p = 0.006) and disease-free (p = 0.007) survival compared to patients with tumors that harbor wild-type NSD1 (n = 397) Fig. A. ImprovCancerrxgene.org, a database in which > 1000 genetically characterized human cancer cell lines have been screened against a wide range of anti-cancer drugs [To begin exploring the factors underlying the survival differences between patients harboring tumors with wild-type and mutant NSD1, we used er drugs . Althouger drugs . Increaser drugs ; etoposier drugs , 26; andn = 6 for NSD1 mutants), there was no difference in ERCC5 expression between those tumors with wild-type and mutated NSD1 (q = 0.975)  and NSD1-depleted (NSD1 sh) FaDu cells showed that NSD1 knockdown rendered cells more sensitive to increasing concentrations of carboplatin and cisplatin Fig. E. Thus, As opposed to platinated drugs, cell viability assays showed that depletion of NSD1 did not sensitize cells to etoposide, zeocin , paclitaxel, or mirin, an MRE11 inhibitor that prevents activation of a DNA damage sensor molecule Ataxia Telangiectasia Mutated (ATM) and DNA damage signaling Fig.  and B. CExpression of ERCC5 was decreased in HPV(−) tumors with NSD1 mutations, compared to HPV(−) tumors with wild-type NSD1 Fig. A. ERCC5 A histone H3 lysine 36 (H3K36) methyltransferase and chromatin modifier, NSD1 plays a role in epigenetic DNA regulation and is essential in normal human development . NSD1 isAlterations in NSD1 expression have already shown promise as a prognostic biomarker in various cancers. In neuroblastomas and gliomas, NSD1 promoter methylation-associated gene silencing predicts worse survival . In laryUnique epidemiological, molecular, biological and clinical differences have led to the increasing recognition of HPV-positive head and neck cancer as distinct from HPV-negative HNSCC. Our data examined NSD1 mutations in both HPV(+) and HPV(−) tumors in the expanded TCGA HNSCC dataset and identified a subgroup of inactivating NSD1 mutations in both the HPV(+) and HPV(−) cohorts Figs. . NSD1 muInterestingly, NSD1 mutations were associated with decreased survival in patients with HPV(+) HNSCCs Fig.  B. No diNSD1 mutations were associated with differences in gene expression of ERCC5 based on HPV status Fig. . We demoUsing isogenic cell lines, our data showed that even partial downregulation of NSD1 , zeocin (radiomimetic), paclitaxel , and mirin (MRE11 inhibitor). Together, these data suggest that platinum-based chemotherapy better targets HPV(−) tumors with NSD1 mutations, while those without NSD1 mutations  may require alternative treatments.In this study, we identify in the expanded TCGA HNSCC database a subgroup of inactivating NSD1 mutations in both the HPV(+) and HPV(−) cohorts. NSD1 mutations appear to be associated with opposite survival effects in HPV(+) and HPV(−) tumors, with NSD1 mutations correlating with improved survival in HPV(−) tumors but worse survival in HPV(+) tumors. However, the prognostic role of NSD1 mutations in HPV(+) tumors must currently be taken with caution, as it has yet to be examined in a larger cohort. In HPV(−) tumors, the survival advantage of NSD1 mutations can in part be explained by increased sensitivity to the DNA-crosslinking agents cisplatin and carboplatin.


A positive impact of bivalent HPV vaccine was observed, both on direct and cross protection. Sexual habits could have changed in the post-vaccination period.Bivalent human papillomavirus (HPV) vaccine was incorporated into the childhood vaccination calendar in Galicia, Spain in 2008. The objectives of this study were to estimate direct, indirect and total effectiveness of HPV vaccine and to identify sexual habits changes in the post-vaccination period in Galicia, Spain.Endocervical scrapings of 745 women attending 7 Health Areas of the Galician Public Health Service were collected in the post-vaccination period, from 2014–2017. Two groups were studied: women born between 1989 and 1993 (n = 397) and women born in 1994 or later (n = 348). Twelve high-risk human papillomavirus (HR-HPV) genotypes were detected by Cobas® 4800 HPV test . The Linear Array® HPV Genotyping Test (Roche Diagnostics) was used for HR-HPV genotype detection other than HPV 16/18. Information about sexual habits was collected by a self-filled questionnaire. Post-vaccination data were compared to previously published pre-vaccination data obtained between 2008 and 2010 in Galicia from women of the same age . The Stata 14.2 software was employed for statistical analyses.Data from 392 unvaccinated and 353 vaccinated women were compared. For unvaccinated and vaccinated women, HPV 16/18 prevalence was 9.2% and 0.8%, respectively, and HPV 31/33/45 prevalence was 8.4% and 1.1%, respectively. Direct, indirect and total effectiveness of the HPV vaccine were : 94 (72−99), 30 (-11−56) and 95 (79−99), respectively, for HPV 16/18 and 83 (46−94), -10 (-88−33) and 84 (54−94), respectively, for HPV 31/33/45. The number of women with first intercourse before 17 years old and 3 or more sexual partners along life was higher in the post-vaccination period ( Persistent infection of high-risk human papilloma virus (HR-HPV) is thought to be responsible for about 100% of cervical cancer cases  and causTo reduce the incidence of these pathologies, mainly of cervical cancer, several vaccines against HPV have been developed. HPV 16 and 18 are responsible for approximately 70% of world cervical cancer  and HPV In Galicia, the bivalent vaccine was introduced in the official immunization schedule for girls at the end of 2008. Three doses (0–1–6 months) were administered to girls born after the 1st of January of 1994 when they were 14 years old. In March 2014, there was a change to the two-dose schedule (0–6 months) authorized by the Spanish Agency of Medicines and Medical Devices. In January of 2016, the vaccination of 12 years old girls was introduced.In Galicia, the pre-vaccination prevalence of HR-HPV genotypes was estimated to be around 10% in female general population, 19% in women 16–19 years old and 23% in women 20–24 years old. The most frequent genotype was HPV 16, with a prevalence of 3.5% [In different countries, the introduction of HPV vaccination programs produced a decrease in the prevalence of HPV genotypes targeted by the vaccine (HPV 16 and 18) ,12. ThisTherefore, in order to evaluate the vaccine effectiveness and its impact on our population, it is essential to compare pre and post vaccine HPV prevalence. As HPV transmission route is sexual, this comparison should take into account any change in women's sexual behavior.The objective of this paper was to estimate direct, indirect and total effectiveness of bivalent HPV vaccine and to identify changes in sexual habits after the introduction of the vaccination program in Galicia, Spain.In the post-vaccination period, the study population comprised women of 18–26 years old, born in 1989 or later, living in Galicia (Spain), attending a primary care center, gynecology department or family counseling center belonging to the Galician Public Health Service from 2014 to 2017. The exclusion criteria considered were: no previous intercourse with penetration, current consultation for a sexually transmitted infection (including HPV related lesion follow-up), pregnancy, giving birth in the previous 40 days, hysterectomy, psychiatric disorders or inability to fill in a self-filled questionnaire.Twenty-three collaborators working throughout the seven Health Areas of Galicia (Spain) were selected by convenience criteria in order to cover the entire territory. Women were offered to participate following an established system based on appointment schedule and year of birth. Two cohorts were established according to the HPV vaccine recommendation stated by 2008 official immunization schedule in Galicia, Spain: women born between 1989 and 1993 (older cohort) and women born in 1994 or later (younger cohort). Collaborators were asked to include the same number of women from both groups . This paDuring this post-vaccination period, HPV detection cervical scrapings were collected in ThinPrep PreservCyt Solution  in 6 Health Areas and in BD SurePath™ Collection Vial  in one Health Area. Twelve HR-HPV genotypes were detected by Cobas® 4800 HPV test : HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. The Linear Array® HPV Genotyping Test , which identifies eighteen HR-HPV , was used in case of HR-HPV genotype detection other than HPV 16/18.On the other hand, in the pre-vaccination period 2008–2010), the study population comprised women of 18–26 years old, living in Galicia (Spain) and attending the Galician Public Health Service at Pontevedra, which is one of the seven Health Areas of Galicia (Spain). The exclusion criteria were the same as in the post-vaccination period. The HR-HPV prevalence observed in these patients were previously published [, the stuIn both periods, sexual habits information was collected by a self-filled written questionnaire  were calculated for each HPV genotype group. In case of detection of any HR-HPV, other than HPV 16/18, that could not be analyzed by the Linear Array test, the assignment to the HPV 31/33/45 group or to the other HR-HPV group was performed using the system of chained equations  by logistic regression .vs. unvaccinated women from post-vaccination period (direct effectiveness), (2) unvaccinated women from post-vaccination period vs. women from pre-vaccination period (indirect effectiveness), (3) vaccinated women from post-vaccination period vs. women from pre-vaccination period , (4) women from post-vaccination period vs. women from pre-vaccination . The model was estimated unadjusted and adjusting by age group , by first intercourse > 16 years old, 3 or more partners along life, and 2 or more partners in the last year. In the post-vaccination period, a comparison was also performed by inclusion year: first biennium (2014–15) and second biennium (2016–17). The variance was estimated using the Huber and White sandwich estimator.For each HPV genotype group, vaccine effectiveness was estimated as 1 –prevalence ratio (1 –PR). PR was calculated using a Poisson regression model considering the HPV status (positive or negative) as the dependent variable and the groups to be compared as independent variable: (1) vaccinated Epidemiological data were compared by vaccination status and time period. The qualitative variables were compared using Fisher's exact test. The concordance between two methods of vaccination status estimation was measured by Cohen's kappa coefficient.To assess the statistical significance, a level of significance of 5% was considered (p < 0.05). The Stata 14.2 software was used for statistical analysis.This study received approval from the Ethics Committee of Clinical Investigation of Galicia . All study participants were informed about the purpose of the survey and were asked to sign a consent form before taking part in the study. Confidentiality was ensured during data collection and subsequent publication of the results.A total of 745 women (average age 21.7 years ± 2.2 SD) from all Health Care Areas of Galicia were included in the post-vaccination period: 447 (60%) in the first biennium (2014–2015) and 298 (40%) in the second biennium (2016–2017). The older cohort (53.3%) was born between 1989 and 1993. The younger cohort (46.7%) was born in 1994 or later. Eighty two percent was born in Galicia. Fifty seven percent had their first sexual relationship before age 17 and 71% declared to have had a sexual partner in the last year. The average age at the first intercourse was 16.4 years ± 1.7 SD. The vaccination coverage information was available in the electronic clinical history in 480 cases. It was only available in questionnaires in 209 cases and it was not available in 56 cases. The global vaccination coverage was 47% (10% with two doses and 90% with three doses). The vaccination coverage was 43% and 53% in the first and second biennium, respectively. A 96% concordance (Kappa 0.90) was observed between women knowledge about their vaccination status and the information registered in the clinical history.vs. 20.4 for vaccinated women. The number of partners along life was 2 or more for 84.5% of unvaccinated women vs. 5 or less in 83.3% of vaccinated women (p = 0.022). The proportion of women having their first sexual relationship before age 17 was 54% in unvaccinated women vs. 61% in vaccinated women (p = 0.022).vs. 57.8% of women studied in the post-vaccination period (p < 0.001). The proportion of women having their first sexual relationship before age 17 was 36.9% in the pre-vaccination period vs. 57.5% in the post-vaccination women (p < 0.001).HPV 16/18 was detected by the Cobas® 4800 HPV test (Roche Diagnostics) in 39 (5.2%) samples and other HR-HPV different than 16/18 in 199 (26.7%). Among these 199 samples, 128 (64.3%) were genotyped by the Linear Array® HPV genotyping test (Roche Diagnostics) and the genotype was automatically assigned in the rest of samples as described in the statistical analysis section. The calculated prevalence of three groups of HR-HPV in the studied populations is reported in vs. 0.8% (95% CI: 0.2−2.5) in vaccinated women  in unvaccinated women ed women , giving ed women . The adjvs. 1.1% (95% CI: 0.3−2.9) for vaccinated women  for unvaccinated women ed women . The adjed women . The adjThe prevalence of other HR-HPV is shown in Regarding sexual habits changes in the Galician population, it was observed that women included in the post-vaccination period started sexual activity earlier and had a higher number of sexual partners along life than women included in the pre-vaccination period. In addition, analyzing only women included in the post-vaccination period, the youngest women (vaccinated group) were younger at first intercourse than the older women (unvaccinated group). Despite of this, an important decrease in HPV 16/18 prevalence and a high direct immunization effectiveness (94%) was observed in vaccinated women in comparison with unvaccinated women in the same period of time (post-vaccination period).et al. [et al. [On the other hand, the estimated unadjusted PR for HPV 16/18 between the post-vaccination and the pre-vaccination period was 0.5 (50% decrease), reaching values previously reported by Markowitz et al.  or Kavan [et al. .p = 0.145). This suggests a herd immunological effect of this vaccine already observed in other studies by Cameron et al. [et al. [et al. [Although unvaccinated women at the post-vaccination period started sexual risk behaviors earlier than women at the pre-vaccination period, the indirect vaccination effectiveness was 29.7% . This supports that results of this study are representative of the Galician population. Although 90% of vaccinated women included in this study received three doses, those receiving two doses were also considered as vaccinated. This criterion allowed us to increase the sample size relying on data on two doses vaccination effectiveness observed in other studies ,21.et al. [This study has several strengths. As stated by Cameron et al. , there aFour limitations of this study could be listed: (i) the small sample size; (ii) the impossibility of verifying the external validity of the sample; (iii) the imputation of data on 71 samples; and (iv) the fact that two different methods were used for HPV detection in pre-vaccination and post-vaccination periods, although these two tests have previously shown a very high agreement for the detection of HR-HPV genotypes .In conclusion, this study highlights the achievements of the vaccination program followed in our community. A high direct effectiveness previously described for HPV 16/18 was also supported by this study. A possibly relevant result is the high direct cross effectiveness (83%) shown for some other genotypes (HPV 31/33/45) not targeted by the bivalent vaccine. An indirect effectiveness of 30% was observed for genotypes 16/18; although statistical significance was not achieved with our sample size, the information could be of interest, as it supports an expected result not yet demonstrated. Our results seem to indicate that there was no common HPV replacement by other types. Continuous surveillance importance lies not only in the evaluation of vaccine effectiveness but also in the future assessment of genotype replacement or cross protection persistence along time.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOC)Click here for additional data file.S6 Table(DOC)Click here for additional data file.S7 Table(DOC)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOC)Click here for additional data file.S10 Table(DOC)Click here for additional data file.S11 Table(DOC)Click here for additional data file.S12 Table(DOCX)Click here for additional data file.


Current cervical cancer screening guidelines recommend a Pap test every 3 years for women age 21–65 years, or for women 30–65 years who want to lengthen the screening interval, a combination of Pap test and high-risk human papilloma virus testing (co-testing) every 5 years. Little population-based data are available on human papilloma virus test utilization and human papilloma virus infection rates. The objective of this study was to examine the patient-level, cervical cancer screening, and area-level factors associated with human papilloma virus testing and infection among a diverse sample of uninsured and underinsured women enrolled in the New Jersey Cancer Early Education and Detection (NJCEED) Program.We used data for a sample of 50,510 uninsured/underinsured women, age ≥ 29 years, who screened for cervical cancer through NJCEED between January 1, 2009 and December 31, 2015. Multivariable logistic regression models were used to estimate associations between ever having a human papilloma virus test or a positive test result, and individual-  and area-level covariates , and number of screening visits.Only 26.6%  of the sample had at least one human papilloma virus test. Among women who underwent testing, 13.3% (1792) tested positive for human papilloma virus. Most women who were positive for human papilloma virus (99.4%) had their first test as a co-test. Human papilloma virus test utilization and infection were significantly associated with age, race/ethnicity, birthplace (country), and residential area-level poverty. Rates of human papilloma virus testing and infection also differed significantly across counties in the state of New Jersey.These findings suggest that despite access to no-cost cervical cancer screening for eligible women, human papilloma virus test utilization was relatively low among diverse, uninsured and underinsured women in New Jersey, and test utilization and infection were associated with individual-level and area-level factors. Approximately 80 million people are currently infected and 14 million people are newly infected annually with human papillomavirus (HPV) in the United States (US) . AlthougIn 2004, HR-HPV DNA tests were approved by the US Food and Drug Administration (FDA) for use concurrently with cytology (co-testing) as a primary cervical cancer screening test for women age ≥ 30 years –7. Most Little population-based data exist on the utilization of and barriers/facilitators to HPV DNA testing in the US, particularly for minority and medically underserved women with a higher risk of developing cervical cancer. The limited population-based studies on HPV co-test utilization have generally demonstrated low utilization across various population subgroups (approximately ≤20% testing rates) –12; howeAlthough rates of cervical cancer incidence in New Jersey has been declining dramatically from 1990  to 2014  at approximately 2.7% per year  [The NJCEED Program is housed within the New Jersey Department of Health (NJDOH) and is funded primarily by the NJDOH and the Centers for Disease Control and Prevention (CDC) to provide screening, diagnostic, and treatment services to eligible individuals for breast, cervical, prostate and colorectal cancers. Eligibility for receipt of NJCEED program services, include low-income  and lack of adequate health insurance (uninsured or underinsured). NJCEED has been providing breast and cervical cancer outreach, education, early detection, screening and follow-up to eligible individuals in New Jersey since 1993 with initial funding through the CDC’s Preventive Health and Health Services Block Grant. Statewide coverage, with services being provided in all 21 counties, began on September 1, 1997. Currently, NJCEED program services are provided through 21 contracted lead agencies, with at least one lead agency in each county. The lead agencies work directly with providers within their county to provide services to eligible program participants. Between January 1, 2000 and December 31, 2015, a total of 116,313 unique and eligible women, age 21 to 64 years, received cervical cancer screening services through NJCEED. Among these, 55,827 were enrolled during the study period of interest . We further restricted our study sample to women age ≥ 29 years, who had available data on race/ethnicity and residential zip code , which includes data on invasive cancer cases ascertained through annual data linkages with the New Jersey State Cancer Registry (NJSCR). CaST allows the user to track patients through the length of the study and collect information on screening and diagnostic procedures done for breast and cervical cancer (NBCCDEP) and colorectal cancer (CRCCP). Individual-level data for this study were obtained from the Minimum Data Elements (MDEs) of the CaST based on inclusion criteria described above. All identifiers were removed prior to providing the limited data set to study investigators for analysis. Use of the data and all related study activities were approved by the New Jersey Department of Health, Rutgers Biomedical Health Sciences Institutional Review Board, and the Scientific Review Board of Rutgers Cancer Institute of New Jersey.Age at enrollment was defined as the age at the earliest cervical cancer screening visit during the study period (2009–2015). Race/ethnicity and place of birth were based on patient self-report and stored in CaST. A total of 166 unique countries of birth were reported among participants, which were collapsed into 7 categories: (1) USA, (2) Central and South America, (3) Caribbean, (4) Africa, (5) Asia and the Middle East, (6) Europe, Russia, Australia and Oceania, and (7) Other Countries. In terms of cervical cancer screening variables, number of cervical cancer screening visits was defined as the total number of unique visits to NJCEED providers for any cervical cancer screening procedures at any time during the study period ; and number of HR-HPV DNA tests was defined as the total number of unique visits where an HPV test was performed during the study period. HR-HPV DNA test results were only available as positive result or negative result. Specific HR-HPV DNA types  for positive results were not available. Age at first Pap test and HPV test were defined as study participant’s age at the earliest Pap test or HPV test, respectively, reported during the study period.Residential zip code tabulation area (ZCTA) for each study participant was linked to the 2010–2014 American Community Survey (ACS) 5-year ZCTA-level estimates collected by the US Census Bureau. The following ACS estimates were obtained to derive area-level sociodemographic factors: (1) poverty status in the past 12 months; (2) race/ethnicity; (3) health insurance coverage type; and (4) language spoken at home. Proportions of participants falling into quintiles  of each of the above sociodemographic factors (based on ZCTA population estimate distributions within the NJCEED population in our study cohort) were estimated. The proportion of minority residents per ZCTA was calculated as the difference of 1 minus the proportion of non-Hispanic White (NHW) residents. Age-adjusted cervical cancer incidence and mortality rates by New Jersey county were obtained from the National Cancer Institute (NCI) State Cancer Profiles [P < 0.05 level. County level rates of HR-HPV DNA testing, positive results for HR-HPV DNA test, and invasive cervical cancer incidence and mortality were also examined. Data were analyzed using SAS v9.4  and STATA v14 .Our primary outcomes of interest are having at least one HR-HPV DNA test and having ever received a positive HR-HPV DNA test. Descriptive statistics were used to summarize the individual sociodemographic and screening characteristics. Chi-square tests were used to compare these variables by HR-HPV DNA test receipt and receipt of a positive HR-HPV DNA test result. We conducted bivariate logistic regression models to examine the relationship between individual-level covariates , number of screening visits, and area-level measures with our primary outcomes. Full models were based on significant relationships in the unadjusted models. Tests for multicollinearity were also conducted, with negative results. We ran multivariate models adjusting for year, which was significantly associated with HR-HPV DNA testing rates but not HR-HPV positivity. Upon inclusion of year in the full model, the associations remained mostly consistent. Study participants with missing demographic or zip codes were excluded from analysis. We estimated odds ratios (OR) and 95% confidence intervals (CI) using robust standard errors and defined significance as Among the 50,510 women included in the analysis, 26.6%  had at least one HR-HPV DNA test through NJCEED over the 6-year study period from 2009 to 2015. Among those who ever had a HR-HPV DNA test, 13.3% (1792) had received a positive test result. Characteristics of the analytic cohort overall, as well as among those ever tested for HR-HPV and among those who ever received a positive HR-HPV test result are shown in Table P < 0.0001). Compared to women who were never tested for HR-HPV test, those who were tested were more likely to be younger at enrollment into NJCEED, younger at their first Pap and HR-HPV tests, to have more cervical cancer screening visits, to have more Pap tests, and were less likely to be NHW and US-born . Almost all women who had a HR-HPV DNA test through NJCEED had their first test as a co-test with Pap test (99.8%) and the first test result was positive among 12.7% of these women. Like women who had a HR-HPV test, participants who tested positive for HR-HPV were also more likely to be younger at enrollment in NJCEED, younger at their first Pap and HR-HPV DNA tests, to have more cervical cancer screening visits, and to have more Pap tests compared to those who never tested positive for HR-HPV . However, unlike the women who were tested, HR-HPV positive women were more likely to be NHW and US-born. Almost all women who had ever received a positive HR-HPV test results (99.4%) had their first test as a co-test with a Pap test and for 95.5% of them their first HR-HPV test was positive.In terms of cervical cancer screening, most women had only one screening visit (59.1%) and had only one Pap test (70.6%) over 6 years. Additionally, they had their first NJCEED Pap test an older age . In terms of HR-HPV testing, 73.4% of the sample were never tested. HR-HPV DNA testing rates among women age ≥ 29 years increased from 7.4% in 2009 to 35.4% in 2015  , while several other counties had HR-HPV infection rates that were 2- to 3-fold higher than the sample average . Figure In our analysis of HR-HPV DNA testing and HR-HPV infection by New Jersey county of residence, we found that the rates of HR-HPV DNA testing among residents of eight counties were significantly higher than the 26.6% overall rate of testing in the study sample  among this sample of eligible women. We also observed wide variation in HR-HPV DNA test utilization and HR-HPV infection by individual-level  and area-level characteristics (poverty), as well as by county of residence. Of note, while non-Hispanic Black and Hispanic patients had higher odds of HR-HPV DNA test use, they were significantly less likely to be HR-HPV-infected compared to NHWs.Few studies have examined the rates of HR-HPV DNA testing in cervical cancer prevention –12, but Similar to our current study, another study  examininWe observed wide variation in HR-HPV DNA test utilization and HR-HPV infection by individual-level and area-level characteristics. After controlling for covariates, NHBs, APIs, and Hispanics (compared to NHWs) and residents of ZCTAs with larger proportions of residents living below FPL (quintile 5 vs. quintile 1) had higher odds of ever being tested for HR-HPV. The higher odds of HR-HPV DNA testing among NHBs, Hispanics, and women living in high poverty areas were particularly interesting given that there are striking disparities in the cervical cancer burden in these groups, despite widespread reductions in incidence and mortality. Minority, uninsured and low socioeconomic status (SES) women tend to be screened less often and this lower screening tends to result in increased cervical cancer morbidity and mortality –21. ThesWe also found that the odds of HPV testing decreases as age increases, a finding which has been reported by other investigators . AdditioWe found that among women who ever had a HPV DNA test, 13.3% of them had at least one positive test, indicating infection with one or more HR-HPV types. Our finding that NHB and Hispanics had lower odds of ever having a positive HPV test, although having higher odds of ever having a HPV DNA test, was unexpected, given existing data that show higher rates of HPV infection among low SES, minority women, which has been linked to their disproportionate burden of cervical cancer , 35–38. The observed variation in HR-HPV DNA test utilization by New Jersey county of residence identified several counties with rates higher than the average of the study sample, which indicates that NJCEED providers covering these areas are doing relatively well at providing guideline cervical cancer screening in medically underserved populations in the state. However, we also identified several counties that had HPV screening rates that were quite low. While we did not examine provider characteristics in the current study, we hypothesize that they are important to understanding variation in cervical cancer screening and HPV DNA testing across counties and by NJCEED providers. Prior studies have shown that variation exists in providers’ adherence to screening guidelines and specifically in recommendations for HPV testing , 39–42.The strengths of this study include its large sample size of diverse, uninsured and underinsured women who sought cervical cancer screening services through NJCEED during the study period. Availability of cervical cancer screening history through large administrative data for several years was also a strength. An additional strength is that our findings will contribute to the dearth of population-based data related to HR-HPV test utilization and HR-HPV infection in a diverse sample of women. There were also some limitations of this study that should be considered in the interpretation of our findings. First, the use of administrative data from the NJCEED Program limited the availability of additional covariates of interest, including specific individual-level SES measures and more detailed information on sexual behaviors and other risk factors for HR-HPV infection and HPV vaccination status among study participants. Additionally, we cannot confirm that women included in this study did not seek cervical cancer screening outside of NJCEED during the study period. We also saw a high proportion of women who were only screened once within the program, based on their encrypted participant ID number. While some of these women may have repeat screenings within NJCEED across our study years, they may have been assigned a different participant ID due to screening at a different location or other reasons. Another limitation was that we don’t know if any of the NJCEED providers or sites targeted screening for high-risk groups (and the variation among providers), which could explain some of the observed differences in county-level testing rates. We also don’t know if NJCEED is reaching all of the women who are eligible for the program and if all of these women are seeking cervical cancer screening services through the program, if providers are meeting their catchment area targets for the NJCEED Program, and how much funding they have to meet the needs of the women in their catchment area. Thus, generalizability of these data to women not eligible for NJCEED services is not possible. And finally, lack of data on specific HR-HPV genotypes prevented us from examining the type specific prevalence of HR-HPV by subgroup of women, which would really enhance our assessment of cervical cancer risk in this population.This is one of the few studies to examine utilization of HR-HPV DNA testing and HR-HPV DNA infection among a sample of medically underserved women who are at high-risk for cervical cancer. These study findings provide insight to individual, area-level factors associated with testing and positive testing results as well as geographic variation across the state in HR-HPV DNA testing, which can inform further exploration of barriers to low utilization of HR-HPV DNA testing, particularly among high risk populations and to develop strategies to increase the utilization rates of this important cervical cancer screening test.