This systematic review aims to provide a comprehensive understanding of the role of human papillomavirus (HPV) in head and neck cancer of unknown primary (HNCUP). HNCUP is a rare type of cancer with an unknown primary site, which makes it difficult to diagnose and treat. The review includes articles published between 2013 and 2023 that investigated the prevalence of HPV in HNCUP, its association with clinical outcomes, and its potential implications for diagnosis and treatment. The search was conducted in 11 electronic databases, and the gray literature: Cochrane, Cumed, IBECS, JAMA Network, LILACS, MEDLINE Ovid, MEDLINE-EBSCO, PubMed, Scopus, SciELO, and Taylor & Francis Online; a total of 23 studies met the inclusion criteria. The review found that HPV is present in a significant proportion of HNCUP cases, ranging from 15.5% to 100%. HNCUP incidence is increasing, and the presence of HPV was associated with improved clinical outcomes in some studies, such as overall survival and disease-free survival; but was found to have no association with outcomes in others. This may have implications for diagnostic and treatment strategies. The findings of this review suggest that further research is needed to better understand the role of HPV in HNCUP and to develop targeted therapies for this disease. Head and neck cancers of unknown primary (HNCUP) pose a diagnostic challenge for clinicians. They are characterized by the presence of metastatic disease in the neck lymph nodes without any evidence of a primary tumor in the upper aerodigestive tract, despite thorough investigation . These tSome studies have suggested a potential role for human papillomavirus (HPV) in the development of head and neck cancer of unknown primary (HNCUP); however, the exact mechanisms and prevalence of HPV in these tumors remain unclear . There iThe objective of this present study is to evaluate the existing literature regarding the role of HPV in HNCUP. Specifically, the study aims to assess the prevalence of HPV, its association with clinical outcomes, and its impact on patient prognosis. Through a systematic review of published and gray literature, studies meeting predetermined inclusion and exclusion criteria were selected. Relevant information was extracted, and subsequent analyses were performed to address the study objective. This systematic review is important as it provides a comprehensive overview of the current evidence on the role of HPV in HNCUP. The findings will have implications for therapeutic management in patients with this challenging condition and will guide future research by enhancing our understanding of the tumors' pathogenesis and identifying new avenues for diagnosis and treatment.Materials and methodsTo design this systematic review, a thorough literature search using the Critical Appraisal Skills Programme (CASP) guidelines were used , and to Descriptores en Ciencias de la Salud (DeCS) and Medical Subject Heading (MeSH) terms included the following: "head and neck", "unknown primary tumor", "occult primary", "HPV", "human papillomavirus", "virus del papiloma humano" "cabeza y cuello", "cáncer de origen desconocido", "primario oculto", and "VPH". Boolean operators "AND", "Y", "OR", and "O", were used as linking words. We only considered articles published between 2013 and 2023, and filters were applied to retrieve results in English or Spanish only. The articles that the databases yielded were then screened by title and abstract.Information was gathered from 11 databases and the gray literature: Cochrane, Cumed, IBECS, JAMA Network, LILACS, MEDLINE Ovid, MEDLINE-EBSCO, PubMed, Scopus, SciELO, and Taylor & Francis Online. Only studies with original data were considered when choosing the study types. Articles that assessed the link between HNCUP (or SCCUP) and HPV, their prevalence, correlation with clinical outcomes, and influence on patient prognosis were chosen. The analysis was limited to research in humans and only included case-control studies, randomized clinical trials, cross-sectional studies, retrospective or prospective cohort studies, and cohort studies.Mycoplasma hominis and HNCUP, Epstein-Barr and HNCUP, or microorganisms other than HPV; articles about HPV-negative carcinomas of the head and neck only, or oropharyngeal cancer (OPC) only; works on public policy; studies of HPV-related cancers of known origin; comments and letters to the editor; and texts on HPV-genotyping. Furthermore, only articles that satisfied all inclusion criteria had their full texts examined. Complete books, mini-reviews, meta-analyses, opinion pieces, systematic review articles, and letters to the editor were not considered.The exclusion criteria included: joint committees; guidelines; classifications; algorithms; studies about ResultsThrough database searching, a total of 3600 records were found. Forty-two were chosen for full-text review after deleting duplicates, records older than 10 years, and articles written in languages other than English and Spanish, in addition to examining titles and abstracts. Nineteen of the latter were eliminated using exclusion criteria. Twenty-three papers were consequently included in the systematic review. This process can be found in greater detail in Table Titles and abstracts were independently evaluated by two authors to determine eligibility for full-text review. Discussions were used to settle disagreements. To incorporate research that had not been found in the electronic or gray literature review, the references of pertinent reviews and those of chosen articles were manually examined. The studies -30, theiThe articles selected were mostly written in Europe and the United States: four articles in Sweden ,9,11,28,Each study had an average of 301.57 participants, ranging from 20 in the study with the fewest patients  to 972 iThe methods used to assess HPV status in the studies were p16 and DNA, and all studies but one  reportedDiscussionHNCUP IncidenceTwo studies evaluated this variable and suggested that the incidence of HNCUP is increasing , with onHPV is implicated in the pathogenesis of SCOPC due to mechanisms that are not fully understood, and a vast proportion of HNCUP end up being SCOPC when more information becomes available, which makes the assessment of HPV in patients with HNCUP even more imperative ,23,26,30Assessing the HPV Status of Patients with HNCUPScreening for association with HPV has been part of the HNCUP workup procedure since the 2017 8th edition of the American Joint Committee on Cancer (AJCC)'s Tumor Node Metastasis (TNM) classification ,31. It cMost of the studies in this review demonstrated positivity for HPV in a range between 15.5%  and 100%Two of the studies suggested additional benefits of using p16, such as acting as a predictor of added disease-free survival (DFS) independent of nodal status and treatment ,20. HoweThe use of direct or indirect techniques should be determined on a case-by-case basis and considering the availability of each, as there does not seem to be a significant difference in their overall performance . Many coOther Diagnostic ConsiderationsOther variables explored by the studies in this review included the reassessment of pathology slides by specialized head and neck pathologists when there were doubts about the diagnosis of HNCUP . The autAnother work explored the utility of biopsies performed in cervical lymph node metastases, using patients as their own controls by comparing the results to the histological material of the same patients . TestingAdvances are being made at the biomolecular level with the analysis of mutations of HPV-related tumors compared to HPV-negative tumors ,28. In aPrognosis and OutcomesPrognostic implications of HPV in the context of HNCUP are, perhaps, the point that brings up the most controversy within studies. Some authors did not find any difference in the prognosis of patients regarding HPV status ,10,17,19In addition to HPV, some studies have identified additional prognostic factors for survival, such as age over 70 and N3 stage, which are considered independent factors . Other sFurther studies or meta-analyses that include larger samples should be performed to delve further into this. Some studies also highlighted the lack of difference in the efficacy of treatment modalities (like neck dissection and definitive radiotherapy) in patients with HNCUP ,17.TNM StatusA lower age has been consistently linked to improved survival outcomes. Reports have varied in terms of the importance attributed to the N stage, with some authors finding statistically worse survival for N3, while others have identified N2b, N2c, and N3 as contributing factors. Additionally, decreasing survival trends have been observed for N1, N2, and N3 stages in certain studies ,16.The presence of extracapsular extension (ECE) in tumors has consistently been identified as a negative prognostic factor. Its occurrence has been associated with poorer outcomes and an increased likelihood of disease progression. Therefore, monitoring for the presence of ECE is crucial when assessing the prognosis of individuals with head and neck cancer ,16.Smoking and excessive alcohol consumption are well-known causal factors for head and neck cancer. These behaviors have been firmly established as major risk factors for the development of this type of cancer. Consequently, addressing and mitigating these risk factors through targeted interventions, such as smoking cessation programs and alcohol abuse prevention measures, are essential in reducing the incidence and impact of head and neck cancer in affected populations ,10,16.LimitationsThis systematic review has some limitations, such as its retrospective nature, the limited use of HPV testing in some studies, the inherent variability in staging workup in any multiple center series, and the inherent challenges of retrospective registry recorded data with a diagnosis of unknown primary of any disease site. Analyses that include information on local and regional control may be more valuable in determining the best treatment option. However, using these data sets makes it possible to analyze a larger population of this unusual entity than is possible with any single institution series. Another limitation of this study was that it only considered articles published in the last 10 years. Furthermore, as there was not an overwhelming amount of data on this topic, more in-depth research is necessary to draw more specific conclusions. This review may have missed articles in languages other than English and Spanish; however, despite a thorough search and usage of databases in Spanish, zero articles were found that were written in Latin America and the Caribbean, which further evidences the depth of the gaps in research on head and neck cancer in this population. Future studies should be conducted tailored to this community so that comparisons can be made and advancements can be implemented.Evaluation of Bias of Selected StudiesDue to the heterogeneity in measurements and methodology, especially in terms of therapeutic approaches that could impact overall survival and outcomes, or the lack of inclusion of smoking status, the studies used for the final synthesis may have had information biases that could have led to an overestimation of the effect of HPV status and prevalence on patient outcomes in HNCUP. Results with a magnitude bigger than the actual one might emerge from these studies' common lack of blinding for the assessor and the patients, as well as the inter-study heterogeneity in outcome measurement. However, in other more controlled circumstances, there would likely be a probable reduction in the apparent effect while keeping a clinically meaningful influence. The overall quality of the included research was evaluated and was determined to be moderate in all articles, using the Newcastle-Ottawa scale for quality assessment of nonrandomized studies , renderiIn conclusion, this systematic review provides important insights into the role of HPV in HNCUP. The review reveals that HPV is present in a significant proportion of HNCUP cases and highlights the relevance of considering HPV in diagnostic and treatment strategies, such as locating the primary tumor site. The findings also suggest a potential association between HPV and improved clinical outcomes in some studies, although the evidence is not consistent.Additionally, given the increasing incidence of HPV-related HNCUP, further research is necessary to better understand the impact of HPV on this disease. Exploring the potential implications of HPV prevention, especially HPV vaccination and its effects on HNCUP is an important area for future investigation. Understanding the long-term effectiveness of HPV vaccination and its potential role in reducing HPV-related cases of HNCUP can contribute to preventive measures and public health strategies.The importance of conducting additional research is crucial to enhance our knowledge about the role of HPV in HNCUP, particularly in diverse contexts, including developing countries. Such research efforts can lead to the development of innovative diagnostic approaches and treatment strategies that have the potential to improve the prognosis and outcomes of HNCUP patients. Therefore, ongoing research endeavors are essential to advance our understanding and refine our approaches to diagnosing and treating HNCUP.


Several leaks appeared in a mild steel (MS) pipe jet nozzle installed in a direct impact test rig after a few months of operation in erosive flow at the Centre for Erosion–Corrosion Research. The locations of perforation leaks were primarily upstream, but severe wall thinning was also noticed adjacent to the exit section. In this paper, a failure analysis was carried out on the leaking of a pipe jet nozzle, and the results are discussed in detail. The investigation carried out includes visual observation, scanning electron microscopy, 3D scanning, energy-dispersive spectroscopy, and laser profilometry measurements. In addition, numerical simulations based on computational fluid dynamics (CFD) and the discrete phase model (DPM) were conducted to investigate the root cause of the failure of leaks in the pipe jet nozzle. Further CFD-DPM simulations were performed on three different pipe jet designs for liquid–solid flow conditions, and were compared to find an alternative design to prevent the failure of the pipe jet nozzles. It was found that the increase in turbulence along with multiple impacts of particles on the wall generate leaks and cracks in the pipe jet nozzle. Moreover, the CFD-DPM showed a five-fold reduction in the maximum erosion rate; this was observed in the replacement of failed pipes with the proposed alternative nozzle pipe design featuring a chamfer reducer section. The CFD-DPM analysis of all geometric configurations showed that alteration of reducer section design has the greatest impact on erosive wear mitigation. A pipe jet nozzle is used to develop sufficient flow and momentum of fluid in a round jet configuration that can sustain fluid emerging at high speed across long distances . ErosionLeaks were found at locations adjacent to the inlet at the top of a Mild Steel (MS) pipe jet nozzle installed in a direct impact test rig for the testing of components in hydroabrasive flow conditions after a few months of operation in multiphase flow conditions at the Centre for Erosion–Corrosion Research, NUST, Pakistan. Visual inspection shows the presence of cracks and one leak location in the upstream location, and severe wall thinning was observed in the downstream section. Another small leak perforation was noticed on the inlet slightly shifted from the top of the pipe. Based on our analysis, the pipe jet nozzle made from mild steel (MS), which is prone to failure due to erosion–corrosion after operation for a short period; leaks were detected within 4 months of the operation.In the literature, several studies on the erosion–corrosion failure of pipe components under industrial operating conditions have been conducted ,11,12. YMoreover, some experimental studies on erosion using direct impact test apparatus have been conducted in the literature; unfortunately, there is still a lack of experimental studies on the erosion of nozzle pipes in liquid–solid flow conditions. A limited erosion study involving mitigation of erosion in nozzle pipes has been established to reduce particle–wall impaction , alongside alternative nozzle design suggestions for erosion prevention and mitigation.In this research, a root-cause-of-failure analysis was performed on a jet pipe nozzle connected to a direct impact test rig, as shown in The failed jet pipe nozzle material is mild steel, the nozzle pipe diameter is 10 mm, and the pipe wall thickness is 3 mm. The chemical composition of a mild steel pipe nozzle with (wt%) 0.22 C, 0.40 Mn, 0.012 S, <0.21 P, <0.03 Si and <0.4 Cu was obtained from the manufacturer. The carrier fluid contains sand microparticles with an average size of 300 µm. The flow velocity of the slurry is 6 m/s, with a particle concentration of 2 wt%. The nozzle pipe suddenly failed during normal operating conditions after 300 hrs. The leak location is found adjacent to the nozzle inlet at the top of the pipe. A failure analysis was performed, utilizing visual observation, microscopic analysis, thickness measurements, computational fluid dynamics (CFD), and the discrete phase model (DPM). In the current work, the erosion–corrosion behavior of the failed nozzle pipe was evaluated via 3D scanning and SEM-EDS. Besides, using SEM, the surface roughness of the samples was measured using a laser profilometer before further analysis. A portable roughness tester, Mitutoyo SURFTEST SJ-210, was used to measure the mean surface roughness (Ra). The failed nozzle pipe was cut into two sections in such a way that the Ra value was captured at different locations  and circumferential angles (α). After quantification of Ra values, a 3D Olympus DSX1000 confocal microscope was used to obtain a 3D surface profile of the location with the maximum Ra value, which is given in The ANSYS fluent CFD-DPM module was used to evaluate the erosion phenomena of the pipe jet nozzle. Computational fluid dynamics (CFD) and the discrete phase model (DPM) were coupled to simulate and track the motion of discrete phases, such as solid particles, in a fluid flow. The DPM uses a Lagrangian approach to track the motion of individual solid particles transported through the carrier fluid. A tetrahedral mesh was used to solve and produce the full flow domain in order to represent the numerical setup, providing reliable numerical simulations and minimizing numerical diffusion errors. As illustrated in The Oka  erosion Due to long-term exposure to the slurry, the surface of the failed nozzle pipe has serious perforation traces, and the leak is located adjacent to the inlet location. The macroscopic appearance of elbow leaks is depicted in A 3D scan of leak morphology in 2O3, as shown in Plastic deformation can also cause the breakage of the passive oxide film in the mild steel, increase the surface energy, and further accelerate the erosion–corrosion. Thus, small pits become large leak sites due to severe plastic deformation. According to Thickness at different locations  and circumferential angles (α) were quantified by employing a digital micrometer three times at each location . This quThe thickness plotted at different locations and annular angles (α) along the axial length is shown in The CFD-DPM simulation of the failed jet nozzle pipe is presented in As determined by the simulation results in This simulation analysis shows that particle impaction and turbulence are responsible for the development of the erosion pattern adjacent to the inlet that resulted in the development of leak perforation. In Design 3, the maximum erosion rate is five times less than in Design 1, which indicates Design 3 can be used as a choice of replacement to mitigate the erosion of the nozzle pipe, as shown in Additionally, the increase in turbulence in Design 1, as shown in To reduce the maximum erosion rate of the failed nozzle pipe, three geometric configurations are proposed for numerical analysis. Design 1 corresponds to the geometry of the failed nozzle pipe. Design 3, with a chamfer reducer section, was found to be the best choice for the replacement of the failed pipe. It can be found that the CFD-DPM simulations predict the maximum erosion rate locations in failed nozzle pipes with reasonable accuracy. However, to increase the accuracy of simulations, simply spherical solid particles should be replaced by non-spherical solid particles. Moreover, particle–particle interactions should also be considered during numerical simulations.2O3 formation on the worn surface results in difficulty in passing through oxygen molecules and an increase in oxygen concentration that may result in pitting corrosion and the development of leaks. The non-uniform corrosion characteristics of mild steel result in crack development at the borders of leak locations.The condition of the inlet section at the top of the pipe is more severely degraded, and leak perforations were located in a spherical and circular shape in the direction of flow. Pipe misalignment could be the reason for high turbulence, and could consequently enhance the severity of erosive wear on the internal surface. High turbulence means that the particles impact the wall with high frequency, and continuously move around in an annular pattern due to a larger inertia force. Therefore, high turbulence caused more erosion in Design 1 of the nozzle pipe, which is the main cause of leak failure. Based on the EDX assessment of corrosion products, FeIn the current study, the causes of failure in mild steel pipe jet nozzles were analyzed using visual observation, microscopy analysis, thickness loss assessment, surface roughness measurements, and computational fluid dynamics (CFD) simulation techniques.Microscopic and simulation analyses of nozzle pipes reveal that pitting corrosion, cutting, and wall thinning due to highly turbulent water flow carrying sand particles are the primary causes of pipeline failure.Erosion–corrosion is a progressive martial degradation phenomenon; it is recommended that ultrasonic non-intrusive inspection of nozzle pipes connected to direct impact test rigs is carried out at regular intervals. In addition, increased pipe thickness and the use of alloy materials are recommended.CFD-DPM shows that the flow of the carrier phase with the disperse phase impacts more frequently at the inlet location and results in high turbulence at the inlet of the pipe. The simulation results reveal that the maximum erosion rate in Design 3 is five times less than that in Design 1. Based on numerical analysis, Design 1 can be replaced with Design 3 to mitigate the erosion–corrosion rate and consequently decrease the severity of leak failure on the elbow surface during operation.Simulation results indicate that maximum erosion occurs in designs similar to failed pipe nozzles, while minimum erosion occurs in designs with a chamfer reducer section. CFD-DPM can effectively simulate the erosion zone and turbulence inside nozzle pipe configurations.It should be pointed out that the current study demonstrates that a nozzle pipe with a chamfer reducer section is useful for erosion mitigation in liquid–solid flow conditions. However, the industrial flow process may involve three-phase flow with highly viscous carrier fluids. It is necessary to confirm the proposed design’s erosive wear performance under multiphase flow conditions. For this purpose, experimental evaluations are needed to validate the findings herein, and the influence of design and flow parameters should be considered in future studies.


E7 gene, suggesting a limited ability to interfere with the differentiation of the host cells. These findings support the use of HPV vaccines that cover HPV6/11 not only for preventing genital warts but also for preventing specific types of cancers.Vaccination against human papillomavirus (HPV) helps prevent cancer caused by this virus. Determining which viral genotypes should be included is key for developing successful vaccination strategies. Low-risk genotypes, especially HPV6 and HPV11, are associated with benign warts. However, some studies also report their presence in cancers. We reviewed the scientific literature to estimate the proportion of cancers that bear single or dual HPV6/11 infections. HPV6 and HPV11 have been reported in up to 5.5% of penile and 87.5% of laryngeal cancers; however, they have not been reported in vulvar, vaginal or oral cancers. Next, we compared the HPV6/11 genomes with HPV16, the most common high-risk HPV genotype, and observed that the similarities mainly involved the E7 gene, indicating a limited ability to block cell differentiation. The presence of single or dual HPV6/11 infections in variable proportions of penile and laryngeal cancers support the vaccination strategies that cover these genotypes, not only for preventing genital warts but also for cancer prevention. Other risk factors and co-carcinogens are likely to participate in epithelial carcinogenesis associated with low-risk HPV.High-risk human papillomavirus (HPV) is etiologically related to cervical cancer, other anogenital cancers and oropharyngeal carcinomas. Low-risk HPV, especially HPV6 and HPV11, cause genital warts and laryngeal papillomas. However, the accumulating data suggests that HPV6 and HPV11 may cause malignant lesions at non-cervical anatomic sites. This review aims to estimate the proportions of single and dual HPV6/11 infections in multiple cancers reported in the last 10 years in the Cochrane, Embasa and PubMed databases. Secondly, the genomes of HPV6/11 were compared with the most common high-risk genotype, HPV16, to determine the similarities and differences. A total of 11 articles were selected, including between one and 334 HPV+ cancer patients. The frequencies of single or dual HPV6/11 infections ranged between 0–5.5% for penile and 0–87.5% for laryngeal cancers and were null for vulvar, vaginal and oral cancers. The genomic similarities between HPV6/11 and HPV16 mainly involved the  Infecti6 Da ,4. The H6 Da ,8,9,10. 6 Da ,12,13,146 Da . Quadriv6 Da . Low-ris6 Da . HPV6 an6 Da  and are 6 Da ,20. In c6 Da  and peni6 Da  cancers.The systematic review was performed in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines , accordiThe HPV6 and HPV11 genomes were compared with HPV16, the most commonly identified high-risk HPV in cancer, to identify the similarities and differences in the key genes involved in the cell transformation. The complete genomes of HPV16 (NC_001526.4) and HPV6 (NC_001355.1) were retrieved from the RefSeq database, available at NCBI. The RefSeq database was unavailable for HPV11. Therefore, its complete genome was retrieved from the GeneBank database, available at NCBI (MW404328.1). Then, the complete genomes of HPV16, HPV6 and HVP11 were uploaded to the Proksee/CGView Server online tool, which is a system for genome assembly, annotation and visualization . In thisMost of the initially screened publications were excluded since they dealt with benign lesions instead of cancer, which was in line with the known role of HPV6 and HPV11 in warts. Overall, after applying the inclusion and exclusion criteria, 11 articles were selected for further analysis . A totalThe selected publications  spanned These studies generally identified an extremely low prevalence of single HPV6/11 infections or infections with HPV6/11 in the context of other LR-HPV in cervical cancer. A single case of HPV11 mono-infection was reported by , which aINK4a was studied using immunohistochemistry in five articles. Two studies found that most penile cancers harboring HR-HPV were p16INK4a-positive [INK4a-positive. Three studies described p16INK4a immunostaining in laryngeal cancers [The HPV surrogate marker p16positive ,35. Howe cancers ,30,31 anHPV16 had a circular dsDNA with a total of 7906 bp and eight coding sequences . When peAccording to the data obtained, the protein with highest similarity between HPV16 and HPV6 was E7, while E5 was the protein with lowest similarity. Similar results were obtained for HPV16 and HPV11.High-risk (HR)-HPVs, particularly HPV16, have been identified as the etiologic agents of multiple anogenital and oropharyngeal cancers, as shown by numerous observational and experimental studies ,39,40,41It is possible that genomic similarities with high-risk HPV allow for HPV6 and HPV11 to interact with important cellular targets, conferring a limited carcinogenic potential. The HPV early proteins had regulatory functions and could be found in both high- and low-risk HPVs ,70,71,72Overall, the present review combined and analyzed the data concerning the frequency of HPV6 and HPV11 mono-infections across multiple types of cancer. This analysis was limited by the small caseload of some studies and also by the absence of data concerning possible carcinogenic co-factors that could synergize with HPV6 and HPV11 to promote their tumorigenic potential. HPV6 and HPV11 mono-infections were mostly associated with SCCs of the larynx and penis. SCCs of the cervix, vagina, vulva and the head and neck (apart from the pharynx) showed the lowest frequencies of HPV6 and HPV11 mono-infections. It is plausible that factors such as immune suppression and specific changes to the local microbiome may contribute to the enhancement of viral persistence, while chemical agents may also act as co-carcinogens in the pharyngeal and penile mucosae. Establishing the etiologic role of these LR-HPVs in the penis and pharynx and the contributions of other co-factors will require additional studies and experimental demonstrations.


We present a case of squamous cell carcinoma (SCC) in the setting of Waldenström macroglobulinemia (WM). A 68-year-old male and daily marijuana smoker with recently diagnosed WM presented via telemedicine in 2020 for a progressively worsening sore throat and unintentional weight loss. Immunotherapy for WM was delayed due to the COVID-19 pandemic. In the clinic, examination revealed an indurated, tender midline mass at the base of the tongue, not limiting tongue mobility. The left level-II and right level-III lymph nodes were enlarged. The oropharyngeal lesion was biopsied, and pathology was consistent with human papillomavirus-positive (HPV+) SCC. Four cycles of concurrent chemotherapy and radiation for SCC were administered without delay, with an initial response. However, on surveillance, metastases to the brain and lungs were detected, and the patient was placed on palliative treatment as he did not meet eligibility for a clinical trial due to his WM. Concurrent WM and HPV+ SCC may have a worse prognosis, due to disease progression and reduced therapeutic options. Waldenström macroglobulinemia (WM) is a rare indolent lymphoplasmacytic lymphoma, a non-Hodgkin's lymphoma (NHL). Lymphomas are the second most common malignancy of the head and neck, with 65-90% of head and neck lymphomas being NHL . WM may A 68-year-old male maintenance worker with a history of eyelid cancer and recently diagnosed WM presented with a complaint of a sore throat for two months. He had not received the rituximab prescribed for WM due to difficulties associated with the COVID-19 pandemic. He reported pain with tongue protrusion, swallowing, throat palpation, and intermittent left-sided otalgia. His throat pain reportedly worsened as the days progressed, especially with citrus drinks or cold drinks. He also reported fatigue, an unintentional six-pound weight loss, and a deepening voice. He reported smoking four to five hits of marijuana daily and previous tobacco smoking of less than one pack per day, with cessation 35 years ago.Due to concerns about the patient’s history from the telemedicine visit, he was immediately scheduled to be seen in clinic. A complete head and neck exam revealed an indurated, tender midline mass on palpation of the base of the tongue without limitations to the tongue’s mobility. He had a palpable right-sided 2 cm level-III lymph node and a left-sided level-II 3 cm lymph node. Flexible laryngoscopy was performed and was notable for a tongue base mass similar in appearance to a prominent lingual tonsil but with tortuous and speckled microvasculature Figure .Computed tomography of the neck with contrast revealed a large infiltrative lingual mass suspicious for carcinoma Figure .The patient underwent an office-based biopsy of the base of the tongue lesion, and pathology revealed human papillomavirus-positive (HPV+) SCC. DNA of HPV type 16 was detected. Because of his WM and treatment with rituximab, he did not meet the selection criteria for a clinical trial examining a novel combination of immunotherapy and chemotherapy for HPV+ SCC. Immunotherapy for WM continued to be deferred during the COVID-19 pandemic, though he received four cycles of chemoradiation without delay, with an adequate response, and without reported complications. He showed no signs of oropharyngeal disease at his last follow-up but unfortunately developed metastases to his brain and lungs and was placed on palliative treatment.Oropharyngeal cancer may present as a nonhealing red or white lump or ulcer. Particular attention should be given to regional lymph nodes during a thorough head and neck exam. When there is a history of heavy smoking or alcohol consumption, a flexible laryngoscopy helps to evaluate the oropharynx, hypopharynx, and larynx to identify the presence and superficial extent of any lesion. Clinically suspicious lesions with aberrant microvasculature should be biopsied. Even though HPV infection of the oral cavity has a bimodal age distribution at ages 30-34 and ages 60-64, HPV+ oropharyngeal SCC has a peak incidence at ages 60-64 [WM may present with symptoms of hyperviscosity and may also present with weight loss, neuropathy, and fatigue, all of which may be alleviated by cannabis use. In hematologic malignancies, cannabinoids may activate pathways of programmed cell death and may promote response to chemotherapy -6. In HPWM can present with head and neck lesions that present similarly to primary oropharyngeal SCC. Cannabinoids may have beneficial effects in the setting of hematologic malignancies, yet they are known to promote HPV+ SCC. Despite underlying hematologic malignancy, HPV+ oropharyngeal cancer should be high in the differential in patients who use marijuana daily and present with oropharyngeal lesions. Molecular links between WM and HPV+ oropharyngeal SCC are limited and must be further explored. HPV+ SCC in patients with WM may have a worse prognosis due to disease progression and reduced therapeutic options.


Veterans with posttraumatic stress disorder (PTSD) and moral injury can encounter several barriers to treatment, including limited access to care and low engagement with therapy. Furthermore, most treatment approaches focus on alleviating distress rather than cultivating positive experiences that could facilitate trauma recovery. A potential way to address these issues is through moral elevation: feeling uplifted and inspired by others’ virtuous actions.This study aimed to examine the feasibility and acceptability of a novel, web-based moral elevation intervention for veterans with PTSD symptoms and moral injury distress . This mixed methods study also examined potential changes in PTSD symptoms, moral injury distress, quality of life, and prosocial behavior.In this pilot trial, 48 participants were randomized to a MOVED or control condition (24 participants per condition). Both conditions included 8 sessions and lasted 1 month. The MOVED intervention and all survey components across both conditions were administered online. Participants completed self-report measures that assessed PTSD symptoms, moral injury distress, quality of life, and prosocial behavior at baseline and follow-up. Veterans in the MOVED condition also completed individual qualitative interviews at follow-up. We coded qualitative responses to interviews and identified emergent themes.d=1.44), approximately twice that of veterans in the control condition (Cohen d=0.78). Those in MOVED also reported medium-sized increases in physical (Cohen d=0.71) and psychological domains of quality of life (Cohen d=0.74), compared with no meaningful changes in the control condition. Unexpectedly, MOVED veterans reported no decrease in moral injury distress, whereas veterans in the control condition endorsed a medium-sized decrease in the total score. There were no changes in prosociality for either condition. Qualitative feedback further supported high levels of perceived acceptability and satisfaction and positive treatment outcomes across a range of domains, including behaviors, cognitions, emotions, and social functioning. Veterans also recommended adaptations to enhance engagement and maximize the impact of intervention content.Findings suggest the MOVED intervention was largely feasible, with evidence for moderate-to-high levels of participation, engagement, and retention in MOVED sessions. Both quantitative and qualitative results suggest veterans found MOVED to be acceptable and satisfactory at the overall treatment level. Furthermore, participants reported high scores for helpfulness and engagement at the session level. Veterans who completed MOVED reported large within-person decreases in PTSD symptoms (Cohen Overall, findings indicate that veterans with PTSD and moral injury distress were interested in an intervention based on exposure to and engagement with experiences of moral elevation. After further research and refinement guided by future trials, veterans may benefit from this novel approach, which may enhance treatment outcomes and increase treatment accessibility for those in need of additional trauma-focused care. Veterans are at increased risk for exposure to traumatic events and are, therefore, at risk for major mental health consequences, such as posttraumatic stress disorder (PTSD) and moral injury ,2. PTSD Although addressing PTSD and moral injury is a priority, there are several barriers to successful treatment. Barriers include difficulties with treatment retention and the existence of residual symptoms after treatment ,11, alonTargeting moral elevation may provide one such novel approach to addressing PTSD and moral injury. Moral elevation  is a positive emotion characterized by feeling inspired or moved after witnessing another person engage in a virtuous behavior . ElevatBroadly, past researchers have identified a series of benefits associated with elevation in nonclinical civilian populations, including increased prosocial behaviors, compassion, positive affect, and greater affiliation with others -26. AlthDespite initial support from naturalistic observations and experimental studies, elevation has yet to be tested as a structured treatment for veterans with trauma-related distress. As a potential therapeutic tool, elevation may be particularly well suited for use in a web-based intervention, given prior evidence of the capacity to elicit this emotion using web-based induction methods . ResMoral Elevation Online Intervention for Veterans Experiencing Distress Related to PTSD and Moral Injury (MOVED). Consistent with the Obesity-Related Behavioral Intervention Trials model for developing behavioral treatments for chronic diseases  you know, I’m struggling and I want help.” Several participants also indicated that the telehealth component contributed to their decision to enroll.Out of the 8 possible sessions, veterans randomized to the MOVED condition completed an average of 6  sessions, and those randomized to the control condition completed an average of 7  sessions; 63% (15/24) completed all 8 sessions in the treatment condition. The qualitative results indicated several strengths of the MOVED format that contributed to its high feasibility and engagement. Specifically, many veterans described the use of videos within sessions, self-administered format, and flexibility of completing sessions on their own as strengths. For example, “I am glad I had the opportunity to do it on my own time or when I had the time...being flexible with time was very good.” In addition, some reported enhanced openness and not fearing judgment because of the web-based format:The online interaction made it a little easier to be open and honest about things going on, and how I feel about them; It gives you more of a chance to honestly assess yourself without feeling judged.We also examined the feasibility of the goal-setting exercise by examining descriptive statistics for the number of weeks participants reported completing the previous session’s goal. On average, participants completed 4.32 (range 0-7) of 7 session goals. Notably, the highest rate of completion was found in goals from sessions 1  and 2 , that is, the predetermined goals assigned to veterans rather than the participant-generated goals.Although the number of goals completed by participants was more than the number of incomplete goals, the qualitative responses suggested that the experience of setting and completing goals was difficult for some participants. Several veterans noted difficulties in remembering their goals, experiencing difficulties in completing goals because of low motivation and PTSD symptoms, and challenges with balancing goal-oriented activities with other responsibilities or personal or work schedules.Among the 48 randomized participants, 36 (75%) completed the postsession survey: 16 (67%) out of 24 and 20 (83%) out of 24 from the treatment and control conditions, respectively. All participants who completed the postsession survey were included in subsequent analyses. Only 9 significant others completed the postsession survey: 19% of the desired sample size (N=48) and 39% of those who completed the baseline survey (n=23). Given the low response rate for significant other participants at follow-up, we did not examine change scores in observer ratings.For participants in the treatment condition, we examined descriptive statistics for self-reported state elevation to determine whether the induction exercises elicited elevation as intended. The mean score when all 12 items were included, aggregated across all sessions, was 1.63 (SD 1.12), with a median of 1.58 and a range of 0 to 4. Because the mean was below the midpoint score of 2—lower than expected for sessions designed to elicit elevation—we further inspected elevation scores by examining the distribution of endorsed items. Notably, several items were positively skewed, and most items did not appear to be normally distributed in this small sample . When itGiven the low response (and skew) with physical items, we recalculated the total state elevation scores after excluding the scores for physical items. The resulting 8-item mean score was 1.93 . Further breakdown of the state elevation scores by session and session type is available on the OSF page.Accordingly, veterans’ qualitative responses suggested mixed results regarding elevation responses to the videos and recall exercises. Several veterans described the exercises as helpful and reported experiencing positive emotions—consistent with the intended purpose of the induction exercises—such as feeling inspired and motivated in response to the exercises. With regard to the videos, in particular, veterans articulated the recognition of a wide range of virtues, including commitment, compassion, love, and selflessness—suggesting an awareness of elicitors that lead one to experience elevation. For instance, “He did it all out of the goodness of his heart,” and “Just watching that and seeing how the father just loved his son so much he was willing to put himself through these marathons, just to see his son smile.” Veterans also described motives consistent with the theoretical framework, including a desire to help and connect with others. For example, “It gave me the knowledge and the confidence to say, ‘You know what, I can help somebody else, and help them a lot.’”However, several veterans also described barriers to experiencing a positive response during the induction exercises. Regarding the videos, veterans with little to no positive responses indicated that some of the videos were not relatable, “cheesy,” or in some cases, elicited a negative response. For example, negative responses included being reminded of social disconnection, being reminded of a traumatic event, or endorsing negative judgments about the people featured in the video. Veterans also described challenges with identifying events that elicited elevation in their own life with respect to the recall exercises, particularly in the context of the COVID-19 pandemic:Because interpersonal communication is now very limited or is still non-existent for some, people are still not really going out and interacting with other people and having conversations because of what is going on.For the overall treatment, the mean and median scores across both the TEI-SF and CSQ-8 items were above the item range midpoint . These results suggest that veterans found the overall intervention acceptable and satisfactory .Regarding satisfaction with individual sessions and their content as assessed by the exercise-specific satisfaction measure, mean and median scores for items assessed at each session were above the item range midpoint (4 out of 0 to 8). Specifically, veterans indicated that the sessions were moderately helpful , that they moderately benefited from a session’s elevation exercise , that the goal-setting assignment was moderately helpful , and that they were highly engaged with the session . The scores were relatively similar across sessions and session types .Themes from the qualitative data further supported high levels of perceived acceptability and satisfaction. Veterans reported feeling comfortable with MOVED, described it as helpful, and stated that they looked forward to the sessions. Some veterans noted that they saw MOVED as a good first step in the process of recovering from trauma exposure, and several veterans mentioned that they explicitly endorsed the intervention when speaking to other veterans. Regarding the specific structure, many veterans reported being satisfied with features such as the session length, the web-based format, and having 2 sessions each week and highly endorsed the use of videos .d=1.44) and each symptom cluster (Cohen d range 0.83-1.60), whereas those in the control condition reported medium-sized effects for overall symptoms (Cohen d=0.78) and clusters (Cohen d range 0.51-0.62). Notably, the average change score for the treatment condition fell within the range of a 15-point decrease to 18-point decrease on the PCL-5—a marker of reliable change in PTSD symptoms  going through life not noticing the little goods in people or in myself. And I guess ultimately, that’s a good thing that I’m forced to think about it.Woman aged 33 yearsThere is a problem when you constantly relive your military experience, you relive them through a certain perspective. And when you are in the study, it kind of gives you the ability to analyze that perspective and look over it. Kind of look at it in a new light.Man aged 48 yearsI had a hatred for people for a very, very long time. I think this is what got me back to sort of seeing the good in folks that’s out there, you know? I say this taught me to be loving towards other people again.Man aged 37 yearsRegarding emotional changes, veterans reported improved emotion regulation and decreases in negative emotions :I encountered something not too long ago that normally is out of character for me, but I caused a little situation, an individual got mad at me, and I was like, ‘My bad. I’m sorry.’ And their attitude completely changed. And normally that would have been maybe me breaking the guy’s skull open or something, you know in my old days. But it was like, you know what, I was in the wrong. Sorry.Man aged 37 yearsI’m a little more mellow and a little more—I wouldn’t say relaxed—but I’m able to not be bothered by things.Man aged 48 yearsI’m not as angry or point fingers at myself you know?...I wasn’t disappointed at myself for the things I’ve seen or have had to do.Woman aged 50 yearsVeterans also described increases in positive emotional experiences , including feeling more empathy, gratitude, and humility. Importantly, changes in social functioning were also noted, including being more engaged with family, improved relationships and communication with both family and coworkers, and greater social awareness regarding how one might be perceived by others and their capacity to have an impact on others:Even with my children, they wouldn’t be as interactive, but now it’s different.Man aged 41 yearsI can have interactions with people and not just hate them automatically...Instead of just pushing on by, I should try to engage with people and not just be a loner for the rest of my life.Woman aged 33 yearsI actually talk to friends here and I’ve reached out to people that I haven’t talked to in years.Woman aged 50 yearsIt helped me engage a little bit more with my daughter.Woman aged 43 yearsIt helped, I guess, build a better bond with my son...and start sharing a little bit of things with him.Man aged 37 yearsI’ve noticed that my relationships with co-workers have improved tremendously.Man aged 36 yearsI used to do things without [my wife] and now, after seeing the first video, I told her I wanted to start doing workouts with her, so we started at least walking and jogging. This study has pushed me to do more things with her.Man aged 43 yearsA few veterans described negative experiences with MOVED, such as difficulties with the recall exercises and feeling less engaged in the second half of the intervention. In addition, some reported negative reactions to exercises such as exacerbating feelings of disconnectedness or ruminating on negative thoughts. Within this select subgroup, it should be noted that there was 1 outlier participant who reported no changes and even some negative reactions to the overall intervention. This veteran (aged 36 years) attributed his negative reaction to a contentious relationship with his identified significant other along with major cultural differences. He noted that because of his culture or race (self-identified as Black) and life experiences, he found it difficult to relate to the elevation induction exercises, which led to reluctance to complete the sessions because he did not think they would be helpful:As a Black male, like I don’t really see a lot of that kind of stuff [referencing video content] in my community you know? Like that kind of stuff doesn’t happen. And so, for me, it looked like White people doing their stuff that don’t happen to us.I mean to go further than the videos just themselves, the cultural differences, like those barriers, made it difficult for me to be able to see that happening in my day-to-day life. For it to be relatable.Man aged 36 yearsAll veterans also suggested some revisions to improve MOVED. One of the emergent themes was to integrate an explicit focus on negative experiences, such as traumatic and morally injurious events, to assist with processing negative experiences while also fostering positive experiences. Regarding the overall format, veterans suggested incorporating a military perspective throughout by using more military terms , structuring sessions and exercises like “missions,” and creating clear objectives for each week to help orient veterans to upcoming tasks:I think the best way to go about it is just go by the military definitions of things because that’s what most people already understand. You know, you look at the army core values or the marine core values, things of that nature.Man aged 37 yearsI think if we established more of a battle rhythm, it would have been helpful. When I went on a mission, they told me about the objective, how we get there, okay let’s come back safe. You know, where this could be like, hey look for kind acts, look for good people, think about it, remember it, so you can report about it.Man aged 43 yearsRegarding treatment length, veterans advocated for additional flexibility by suggesting that there should be options to continue the treatment beyond 8 sessions or booster sessions should be made available. Similarly, it was suggested that creating the flexibility to choose 1 or 2 sessions per week (rather than making everyone complete 2 sessions) might benefit veterans with differing work schedules and personal responsibilities.In terms of specific session content, veterans remarked that changes to the videos, recall exercises, and goals could further enhance the treatment. First, veterans who noted negative reactions to the videos recommended avoiding “cheesy” videos and encouraged using more videos that veterans can connect to or would find more relatable. Another common revision suggested was to change the way in which the videos were distributed across the program by either adding more videos as a component of the standard intervention, alternating between video and recall exercises , or adding extra or supplemental videos for use when needed. This recommendation was largely driven by veterans who described enjoying the videos but felt that they were presented too infrequently.Additional recommendations for the recall exercises focused on expanding the target of noticing virtuous behaviors to include more options. For example, the prompt encouraged veterans to recall something they witnessed in the past few days that may have elicited elevation in themselves; however, several veterans noted challenges with completing this task and suggested that the treatment encourage veterans to search existing media to find acts of virtue or to recall any previous event in their life that may have similarly elicited an elevation-like response. Consistent with other feedback regarding the helpfulness of reminders, several veterans also encouraged sending text or email reminders to participants during the days when they are asked to look for virtuous behaviors.An early suggestion for the goal-setting portion of MOVED, which was later endorsed by nearly all veterans, was to create a list of predetermined goals that might align with each induction exercise and allow veterans to choose the goal they would like to pursue from that list. Veterans suggested that this might reduce the burden of creating a brand-new goal and would likely increase engagement with the exercise. In addition to difficulties in creating a new goal, veterans reported challenges with remembering what goal was set and, in some cases, forgetting to complete the goal. Accordingly, they recommended adding text or email reminders that include the specific goal selected and task due the next session. Some veterans also suggested limiting goal setting to once per week  to increase the feasibility of completing that goal.A common theme among most veterans was that integrating some interactions with a therapist or another person would be helpful in conjunction with the current content, and some explicitly described wanting more human interactions. Suggestions for the potential involvement of a therapist ranged from optional, occasional consultation to scheduled weekly conversations with a therapist. Veterans indicated that they would have consulted a therapist to seek their help with identifying additional coping tools, processing emotions, processing traumatic or morally injurious events, and navigating goal-directed activities .Finally, the desire to access MOVED materials more easily during and after the intervention emerged as a theme. For example, veterans recommended providing video links in addition to displaying the videos within sessions, which would allow participants to watch the videos again or share them with others. Similarly, participants stated an interest in receiving access to previous session’s content for review, including psychoeducational materials, as well as information about what their previous goals were and their progress with the goals. Finally, some veterans requested the provision of feedback about participants’ progress during the course of treatment, which could include information regarding goals and recall exercises and results from self-report questionnaires about emotions and social interactions experienced during treatment.A few extant studies imply the possible benefits of experiencing elevation for veterans with PTSD symptoms and moral injury distress. However, no study has tested an intervention using elevation to target these concerns in this population. The purpose of this mixed methods study was to conduct a pilot trial of a web-based elevation intervention to assess the overall feasibility, acceptability, and potential changes in targeted outcomes. Overall, the findings suggest that the MOVED intervention was largely feasible and that veterans found it acceptable and satisfactory as a treatment. In addition, veterans who completed MOVED reported large decreases in PTSD symptoms and a moderate increase in quality of life.First, recruitment and retention data suggest that participation in this study, the MOVED intervention condition in particular, was largely feasible. In addition, we found evidence for moderate-to-high levels of participation and retention for the MOVED sessions. For example, 79% (19/24) of veterans completed ≥4 sessions, with the majority completing at least 7 sessions . However, a limitation of this study is the retention of veterans at the follow-up survey for the treatment condition: one-third of veterans randomized to the treatment condition were missing posttreatment data, which could have led to biased results and should be addressed in future replication studies.Overall, the quantitative and qualitative results suggest that veterans found MOVED to be acceptable and satisfactory at the overall treatment level, and participants reported high scores for helpfulness and engagement at the session level. Veterans who completed the treatment also highlighted several ways in which it could be improved, including integrating the processing of negative experiences, incorporating more military structure and terminology, increasing the flexibility of the treatment structure and duration, and ensuring that materials are culturally appropriate to veterans who identify as racial or ethnic minority individuals. Participants also identified specific improvements to the videos, recall exercises, and goal setting. Finally, participants suggested providing increased access to treatment materials throughout the intervention, additional accountability and feedback on progress, and some degree of integrated therapist interaction.Surprisingly, veterans in the MOVED condition endorsed lower state elevation scores following inductions than expected. A potential reason could be deficits in the measurement tool for state elevation, particularly with regard to the associated physical sensations. At the time of this study, there was no standard or widely used scale for state-level elevation with strong psychometric properties. However, a novel measure was recently developed and validated in both clinical and nonclinical samples ; therefoNotably, there is some discrepancy between the elevation scores and other responses in the treatment condition. For example, veterans reported low-to-moderate elevation scores after the induction exercises but high scores for engagement and perceived helpfulness of the exercises for the same sessions. This difference could further highlight the limitations of the measure used. It could also suggest that veterans perceived benefits to the sessions regardless of whether they experienced a strong elevation response. The role of elevation responses following the induction exercises should be explored in future research to clarify the potential mechanisms of action if participation in this treatment truly leads to meaningful improvements in the targeted outcomes.what elevation stimuli. Future work should aim to develop idiographic approaches with a more diverse set of elevation-eliciting stimuli, which could help tailor videos to the specific preferences and background of a given veteran. Such personalization may be important in general for efforts toward using elevation as a therapeutic tool.Moreover, the qualitative interviews suggested variability in individual responses to elevation inductions. This was highlighted by the contrast between veterans who described the videos as highly inspiring and even asked for more such videos compared with those who described the same videos as “cheesy” or unrelatable. The possibility of diverse reactions to video stimuli was underscored by a veteran sharing how his personal experiences and cultural background made it challenging to relate to the people in the videos, thereby preventing a strong elevation response. An important direction for this area of research is to better understand who is likely to respond to d=1.44), nearly twice that endorsed by the control condition (Cohen d=0.78). This finding is remarkable, given that the intervention did not directly or explicitly target trauma memories or distress symptoms. Nonetheless, the large effect within the MOVED condition paralleled veterans’ qualitative reports of positive pre-post changes in behaviors, cognition, and emotions consistent with trauma recovery . In addition, the treatment condition reported medium-sized increases in physical and psychological quality of life, in contrast to the control condition, which reported no meaningful changes.Veterans who completed MOVED reported a large decrease in PTSD symptoms. Although the small sample size for this pilot trial is not powered to test true treatment effects through group comparisons, the preliminary results of the MOVED condition are noticeably distinct from those of the control condition. Specifically, the MOVED group endorsed a large within-person decrease in symptoms . It is unclear why the control condition would report decreased distress, other than random error, regression to the mean, or perhaps assessment reactivity—a reduction in distress because of completing self-report measures and reflecting on symptoms without the influence of the intervention . HoweverFinally, veterans in neither condition displayed changes in prosocial behavior. It is unclear why this might be the case, but if replicated with a larger sample, a null finding might suggest that (1) perhaps the elevation dose was too mild to elicit prosocial motivations, (2) perhaps participants’ session goals did not sufficiently target helping others , or (3) perhaps contextual factors such as social distancing during the COVID-19 pandemic limited opportunities for prosocial acts. In addition, when considering findings for PTSD symptoms and quality of life, perhaps acting on motives for prosocial behavior may not be essential to attain benefits from MOVED.Given the pilot trial’s aim of testing feasibility and acceptability, statistical tests in this small sample should be interpreted with caution, particularly for the targeted outcomes. Future studies with larger samples that also account for external factors  are needed to replicate pre-post effects and formally test differences between groups that could be attributed to MOVED. Second, the state elevation measure did not perform optimally in this sample; accordingly, future studies should use the newly validated measure to further ensure the appropriate assessment of elevation at the state level. Third, despite substantial efforts, we were unable to obtain feedback from participants who dropped out or failed to complete the required sessions, and we could not inquire about their experiences with the intervention. Therefore, the initial pilot data are limited to those who completed the intervention. Future research should make additional efforts to explore the specific barriers and struggles for the subset of veterans who were unable to fully participate.and quality of life—important objectives, given the struggles of many veterans and findings that suggest patients rate functional aspects of recovery and improved quality of life as top targets for seeking mental health care [Despite these limitations, this study has several strengths with potential clinical implications. First, this web-based intervention was easy to access. In addition to descriptive statistics showing engagement, qualitative responses highlighted the ease and benefits of accessing this treatment alone, with one’s own devices and with scheduling flexibility. Thus, this approach might be useful for targeting some of the known barriers to initiating and staying engaged with trauma-focused treatment -16. Thislth care ,56. FollOverall, the findings provide preliminary evidence that veterans with PTSD and moral injury distress were interested in an intervention based on exposure and engagement with experiences of moral elevation. Future studies must further test and refine this novel approach for targeting trauma-related distress and quality of life, with the ultimate aim of increasing treatment access and inspiring veterans to improve their mental, social, and physical well-being.


Cervical carcinoma is the fourth female malignant tumor in the world, and the persistent infection of high-risk human papillomavirus (HPV) is recognized as the most common cause. This article studies the correlation between multiple HPV infections and the occurrence, development, and prognosis of cervical cancer in order to provide more references for clinical diagnosis and treatment. We conducted a retrospective analysis of the clinical data of 400 cervical carcinoma patients admitted to our hospital from 2015 to 2023. The collected patient data include age, HPV infection status, tumor size and morphology, local infiltration depth, diagnostic staging, surgical approach, vascular cancer thrombus status, lymph node status, and postoperative HPV follow-up status. We use SPSS statistical software for data analysis. Our research shows that the high-risk age group for cervical carcinoma is concentrated between 41 and 60 years old, which is basically consistent with the age range of the high incidence of HPV infection. In the statistics for HPV infection types, ~67.7% of patients are single HPV-infected, 25.29% are double infected, and 7.00% are infected with three or more types of HPV. Among the multiple HPV infections, most of the patients are younger than 40 years old and older than 70 years old, with double infection accounting for the majority. The top five HPV subtypes with high detection rates belong to high-risk subtypes, which are the HPV16, 18, 58, 33, and 52 subtypes, respectively. There was no significant relationship between multiple HPV infections and cervical cancer stage, lesion size, pathological tissue type, tissue differentiation degree/vascular cancer thrombus, and lymph node metastasis, and there was no significant difference in the results between the groups. In summary, multiple types of HPV infection in the cervix are common. We found that multiple infections, mainly HPV16, are closely related to cervical cancer. For the HPV16, 18, 58, 33, and 52 subtypes of infection, especially for patients younger than 40 years old and older than 70 years old, priority should be given to prevention and treatment. The relationship between multiple HPV infections and the progression and prognosis of cervical carcinoma requires further research, which could better guide cancer prevention and treatment. Cervical carcinoma is the fourth female malignant tumor in the world, and it is also the most usual malignant tumor of the female reproductive tract. Its morbidity is only next to breast cancer, colorectal cancer, and lung cancer , squamous cell carcinoma antigen (SCC), smoking history, postoperative adjuvant treatment, postoperative HPV follow-up status, tumor-free survival rate, follow-up interval, and mortality rate. All information is obtained by consulting medical records. This study was approved by the Ethics Committee of the Second Affiliated Hospital of Dalian Medical University. This study used SPSS software version 25.0 for statistical analysis. Heterogeneity comparison between groups was conducted using the chi-square test, and Fisher's exact test was used when a single sample size was < 4. For the remaining analyses, a We described the clinical data of 400 cervical carcinoma patients admitted to our hospital from 2015 to 2023, as shown in P < 0.05)  and older than 70 years (66.7%). We speculate that this may be related to factors such as sexual activity, fluctuations in hormone levels, decreased immunity, and an increased probability of causing latent viral infections. Among patients with multiple HPV infections, there are mainly 65 cases of double infection, 12 cases of triple infection, and fewer cases of four or more HPV infections. One patient is simultaneously infected with seven types of HPV. There is a significant difference in the distribution of HPV infection types among different age groups ( < 0.05) , 3.We analyzed the distribution of HPV infection subtypes and found that the top five HPV subtypes with high detection rates in this study belonged to high-risk subtypes, namely, the HPV16, 18, 58, 33, and 52 subtypes . Patientp-value of < 0.05 was considered statistically significant. We used SPSS software version 25.0 for statistical analysis of lymph node metastasis and vascular cancer thrombi. A heterogeneity comparison between the groups was conducted using the chi-square test, and Fisher's exact test was used when a single sample size was < 4. For the remaining analyses, a We conducted correlation analysis based on different groups of multiple infections and found that there was no significant relationship between HPV multiple infections and cervical cancer stage, lesion size, pathological tissue type, tissue differentiation degree, vascular cancer thrombus, and lymph node metastasis. There was no significant difference in the results between the groups , 9.Cervical carcinoma is a usual malignancy in the female reproductive system. It is one of the malignant tumors with high morbidity and mortality among women in developing countries, threatening the health of many women. According to the statistics, ~48,000 women die from cervical cancer every year  to detect HPV integration status and prognosis in 204 patients undergoing chemotherapy for cervical carcinoma. The authors found that HPV integration is a biomarker that predicts disease-free survival after cervical carcinoma (Joo et al., Joo et al. used In summary, multiple types of HPV infection in the cervix are common. However, there is currently no consensus at home or abroad on the occurrence, development, and impact of multiple HPV subtypes of infection on cervical lesions and cervical carcinoma. This study found that multiple infections, mainly HPV16, are closely interrelated to cervical carcinoma. For the HPV16, 18, 58, 33, and 52 subtypes of infection, especially for patients younger than 40 years and older than 70 years who have multiple infections with the HPV16, 18, 58, and 33 subtypes, priority should be given to close follow-up, prevention, and active treatment. The relation between multiple HPV infections and the evolvement and prognosis of cervical carcinoma requires a large sample study from multiple centers, which could better guide cancer prevention and treatment.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Dalian Medical University. The patients/participants provided their written informed consent to participate in this study.JL and SH processed the case and drafted the manuscript. JN and YL assisted in collecting case data and literature, and conducted all literature and article work. JW made many constructive suggestions during the revision and production process. XW contributes to the statistical analysis of case data. All authors contributed to the article and approved the submitted version.


Human papillomavirus (HPV) is a virus primarily transmitted through sexual contact. Little is known about the association between HPV infection or immunization and the risk for rheumatoid arthritis (RA). The purpose of this study was to evaluate whether HPV infection or immunization is related to the risk for RA in adults.Data were obtained from the 2007-2016 National Health and Nutrition Examination Survey (NHANES). We developed three independent multivariate logistic regression models to evaluate the association between HPV infection or immunization and the risk for RA in adults.Finally, we analyzed 15,677 and 8,944 subjects, respectively. In all models, HPV infection was positively associated with an increased prevalence of RA in adults aged 18-59 years, with the highest value of the odds ratio (OR) in model 2 , whereas HPV immunization significantly reduced the prevalence of RA in adults aged 18-59 years, with the lowest OR in model C . These associations persisted after correction for confounders such as age, sex, race, education level, marital status, smoking, diabetes, hypertension, hyperlipidemia, and BMI.In summary, our study suggests that HPV infection is positively associated with the prevalence of RA in adults, and HPV immunization can reduce the prevalence of RA in adults. However, our findings need more powerful to prove these associations through rigorously designed prospective studies. Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease characterized by synovitis. The prevalence of RA varies globally, with an age-standardized prevalence of 246.6 per 100,000, and has increased in recent years . In addiA population-based cohort study showed that the adjusted hazard ratio of human papillomavirus (HPV) infection to RA was 1.40, suggesting that HPV infection may be a predisposing factor for RA . The mecData used in this study were obtained from five survey cycles  of the National Health and Nutrition Examination Survey (NHANES). NHANES is a cross-sectional study conducted by the National Center for Health Statistics (NCHS) to assess the nutritional and health status of the non-institutional American civilian population. The survey is conducted every 2 years and collected information including demographic data, dietary data, examine data, laboratory data and questionnaire data. Details of participants’ demographics, socioeconomic, dietary factors, and medical and health conditions were collected through family interviews. Standardized medical and physical examinations are performed by trained medical personnel through the collection of biological samples such as serum and urine in specially equipped mobile examination centers (MECs). The protocol for the NHANES study was reviewed and approved by the NCHS Study Ethics Review Committee and all participants signed informed consent forms. Given the age range for HPV polymerase chain reaction (PCR) test data was 18-59 years, we included participants aged 18-59 years with complete data on HPV PCR test results, history of HPV vaccination and history of RA in our analysis.HPV infection was assessed by laboratory data. Samples included vaginal swabs and oral rinses. Participants with “positive” test results were classified as HPV infected group, those with “negative” test results were classified as HPV uninfected group, and those participants with “Inadequate” test results were excluded. Detailed procedures and methods can be found in the laboratory procedures manual.HPV immunization was assessed through a self-report questionnaire vaccination question. Participants who answered “yes” to the question on HPV vaccination were classified as the HPV vaccinated group, and those who answered “no” were classified as the HPV unvaccinated group, excluding those who answered “refused” and “don’t know”. Missing data were also excluded.The assessment of RA was determined by self-report questionnaire questions. These questions included “Has a doctor or other health professional ever told you that you had arthritis?” and “Which type of arthritis was it?”. Participants who answered “RA” to the latter question were classified in the RA group, while those who answered “no” to the former question and “osteoarthritis, degenerative arthritis, psoriasis, and others” to the latter question were classified in the non-RA group.We included confounding factors that might influence the relationship between proposed HPV infection or immunization and RA as covariates, based on other published studies , 13. TheDistribution characteristics were expressed as standard deviation (SD) for continuous variables and as the number of cases (n) and percentage (%) for categorical variables. The chi-square test was used to assess differences in categorical variables, and the Mann-Whitney test was used to assess differences in continuous variables. Risk ratio (RR) was used to evaluate the association between HPV infection or immunization with the risk for RA among all participants. Subsequently, we used the R package Matching for propensity score matching (1:1) to match HPV infection or HPV immunization corresponding controls to reduce heterogeneity and selection bias . Standar15,677 participants were included in the study of HPV infection and RA Figure 2In all participants, compared with the control group without HPV infection, the risk of RA in HPV infected group was significantly higher , however, this result has not been adjusted for confounding factors Figure 3In all participants, the risk of RA was significantly reduced in the HPV vaccinated group when compared with the HPV unvaccinated group  Figure 5HPV is a group of small, envelope-free DNA viruses that can infect human skin and mucosal epithelial tissues. It is mainly transmitted mainly through sexual contact and has become a global public health problem. HPV infection can cause a variety of diseases, including cancer, infertility, congenital malformation, and other diseases, the most common of which is cervical cancer . The peaThe HPV vaccine is highly effective in preventing HPV infection, therefore reducing the incidence of cervical cancer. A recent study have shown that HPV immunization programs have significantly reduced the incidence of cervical cancer, especially for women born after September 1, 1995, resulting in almost complete elimination of cervical cancer . ConsequThis study is based on the NHANES database and has several limitations. First, the data may be biased due to the exclusion of certain populations, including older adults living in nursing or retirement homes, military personnel living on military bases, prisoners living in federal prisons, the USA citizens living outside the USA, and foreigners living in the USA. Second, only existing data can be collected and analyzed, which may overlook certain important information. Finally, the quality of the data may affect the analysis. NHANES data are self-reported and do not contain comprehensive details such as physician diagnosis of RA, assessment of disease activity, and use of anti-rheumatic drugs. As with all health surveys, the accuracy of the data collected may be influenced by a variety of factors, including respondent honesty, subjective bias, memory, cultural background, social environment, language ability, and education level, making it susceptible to misclassification, nonresponse, and recall bias. Additionally, there are missing values in the data, which may affect the accuracy of the study results. Therefore, more comprehensive studies are needed to further evaluate the relationship between HPV infection or immunization and the risk for RA.In summary, our study provides new insights into the relationship between HPV infection or immunization and the risk for RA. Our findings indicate that HPV infection is positively associated with RA while HPV immunization reduces the prevalence of RA among adults. This suggests that HPV immunization not only reduce the prevalence of cervical cancer but also significantly reduce the prevalence of RA. Therefore, we recommend that HPV vaccination should be actively promoted, especially for young women, to reduce the risk of developing RA. However, our findings need further validation through rigorously designed prospective studies to provide more robust evidence for this association.Publicly available datasets were analyzed in this study. Data were obtained from the 2007-2016 National Health and Nutrition Examination Survey (NHANES).This study was based on non-identifying data collected from NHANES and did not include any experimental data from human or animal participants; participants were not directly involved in the submission and secondary data were used for analysis. This analysis was considered exempt from Institutional Review Board oversight.GY, ZR, and KW contributed to the conception and design of the study. GY and ZR performed data collection. KW performed data analyses. GY and KW wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.


The single HPV infections reveals significant differences from control group in bacterial vaginosis , fungal vaginitis , and cervical lesions . In the bacterial infection group, HPV51  and HPV58  showed significant differences in infection compared to the control group. In the fungal infection group, HPV39  showed a significant difference in infection compared to the control group. Cervical lesions, bacterial vaginosis, fungal vaginitis, and cervical lesions among Chinese population exhibit age-specified distribution. HPV infection rate in bacterial vaginitis, fungal vaginitis and cervical lesions was higher than that in normal group. HPV52 and HPV16 infection are different, and HPV39 is different between bacterial vaginitis and fungal vaginitis.The previous research has found that human papillomavirus (HPV) infection is the main cause of cervical cancer, but it is still unclear whether HPV infection, as well as the HPV genotypes, are related to reproductive tract infections in the Chinese population. Patients who underwent HPV screening at Shandong Maternal and Child Health Hospital were selected, and the HPV infection status was analyzed among patients with cervical lesions, bacterial vaginosis, cervical inflammation, fungal vaginitis, and pelvic infections. SPSS 22 statistical analysis was used to analyze the differences in HPV infection types and rates between the control group and the experimental group. The HPV infection rate of bacterial vaginosis (χ Previous studies have shown that HPV infection is associated with vaginal microbial imbalance, also, HPV infection changed the richness and diversity of the vaginal microbiota.,5 At same time, How vaginal microecology and HPV co-infection to affect human health need to be addressed.Human papillomavirus (HPV) is one of the most widely transmission DNA viruses worldwide, identified as prime culprit of cervical cancer.,7 Pelvic inflammatory disease is an inflammation of the fallopian tubes and cervix, caused by microecological imbalance in the reproductive tract triggered by pathogenic microorganisms including Neisseria gonorrhea, Chlamydia trachomatis, and Mycoplasma genitalium. Bacterial vaginitis is one of the most common vaginal microecological imbalance, caused by increasing in Gardnerella vaginalis, Prevotella, Atopobium vaginalis, Bacteroidetes, Streptococcus, and a decrease in the normal flora Lactobacillus.,10 Studies have shown that more than 75% of women have got vaginal candida and that Candida albicans is the main causative agent of fungal vaginitis. In conclusion, alterations in the microecology of the female genital tract are closely related to changes in HPV invasiveness.Previous studies have shown that HPV infection is associated with vaginal microbial imbalance. For example, the main HPV genotype causing cervical cancer are HPV18 and HPV52, while the main HPV genotype causing squamous cell carcinoma is HPV16.,15 Few studies have been carried out on invading bias of HPV genotype in genital tract microenvironment. Previous studies have shown that HPV58 and HPV52 is prone to invading the women got bacterial vaginitis in Northwest China, while further research on the relationship between HPV genotype with microecological dysregulation of the reproductive tract is required.More than 200 HPV genotype have been identified, and HPV genotype show different preference and specified in invading host.,18 Jinan, as the capital city of Shandong Province with a population size of more than 10 million, is a representative geographic area for epidemiologic investigations in East China. In this study, we investigated the subtypes of HPV infection under different vaginal microecological types in Shandong Province of China, to provide new knowledge of the dangers of reproductive tract microecological imbalance and HPV prevention.HPV transmission shows significant variability among ethnic, regional, and temporal.The research was approved by the Ethics Committee of Shandong Maternal and Child Health Hospital (No. 2021-024), in accordance with the China Ethical Principles for Biomedical Research Involving Human Subjects and the Declaration of Helsinki for Human Research. The content of the experiment (including the use of tissue samples), the significance of research, and confidentiality of the study have been well informed to the participants, the research was well-informed and supported by all subjects and/or their legal guardian(s) in case of minors.The data were collected from individuals who sought medical advice in Shandong Maternal and Child Health Hospital from January 2018 to August 2021. A total of 13,972 individuals were enrolled in this study. The enrolled individuals were aged from 15 to 83 years.There are separately 239,659,294,943 individuals enrolled in pelvic inflammatory, cervical lesions, fungal vaginitis, or bacterial vaginitis.Inclusion criteria for the pelvic inflammatory group: pressure pain in the lower abdomen and adnexal area; purulent discharge of cervical or vaginal mucus or the presence of leukocytes on microscopic examination of vaginal secretions; accelerated blood sedimentation or elevated levels of reactive protein.Inclusion criteria for cervical lesions: liquid-based thin-layer cytology examination and colposcopic histopathological diagnosis, cervical intraepithelial low-grade tumor-like lesions.Inclusion criteria for bacterial vaginitis: a. positive clue cells (>20%). b. positive ammonia test. c. vaginal pH > 4.5.Inclusion criteria for fungal vaginitis: a. wet film microscopy of vaginal secretions reveals budding spores, pseudomycorrhizae or mycelium. b. Fungal culture of vaginal secretions or commercial tests showing positive for Pseudomycetes.The control population group was the physical control group of the physical examination population. There are no gynecological diseases mentioned above among healthy individuals.No enrolled individuals with a basic disease  were included.α+Zβ)/(p1−p2)]2, assuming the same sample size for the experimental and control groups, α is taken as 0.05, Z value is two-sided, Zα = 1.96, β test efficacy is 0.8, Zβ = 0.84; p1 = 0.12, p2 = 0.22, N ≈ 221, so N > 221.According to the formula N = 2pq[. The kit was used to detect and genotype fifteen high-risk HPV genotypes  and two low-risk HPV genotypes (HPV6/HPV11). The experimental steps followed the kit instructions .P < .05 was considered statistically significant.The positive individuals were divided into single HPV genotype, double HPV genotype and triple genotype according to the infection genotype. The data were statistically analyzed using SPSS 22.0 software . Any differences between the groups in prevalence were assessed by chi-squared (χ2) tests, and The statistical sample was divided into 9 age groups, namely, <20 years group, 21 to 25 years group, 26 to 30 years group, 31 to 35 years group, 36 to 40 years group, 41 to 50 years group, 51 to 60 years group, and > 60 years group. The HPV infection prevalence in each group was presented using line chart.This study presents 2828 positive from 13,972 individuals, and the positive rate was 20.3%. The HPV single genotype group had 2100 cases, accounting for 74.3% of the positive individuals; the HPV double genotype group had 520 cases, accounting for 18.4% of the positive individuals; and the HPV triple genotype group had 208 cases, accounting for 7.4% of the positive individuals.In the statistics, the top fifth prevalent HPV genotypes were HPV52 , HPV16 (3.9%), HPV58 (3.2%), HPV51 (2.2%), and HPV39 (1.9%). The top fifth single infection types were HPV52 , HPV16 (15.9%), HPV58 (12.6%), HPV51 (8.6%), and HPV39 (7.1%); The top fifth double infection types were HPV52 , HPV16 (27.5%), HPV58 (21.7%), HPV51 (15.4%), and HPV39 (15.2%); the top fifth triple infection types were HPV52 , HPV16 (43.6%), HPV58 (43.6%), HPV51 (35.9%), and HPV39 (35.9%) . The infection rate of fungal vaginitis is 18.8%, which also shows a significant difference compared to the control group . The overall infection rate of cervical lesions is 40.1%, which is significantly different from the control group  , fungal vaginitis , and cervical lesions . Analysis of double HPV infections shows significant differences compared to the control group in bacterial vaginosis  and cervical lesions   and HPV58  showed significant differences in infection compared to the control group  showed a significant difference in infection compared to the control group. In the cervical lesion group, HPV16, HPV39, HPV51, HPV52, HPV56 are all significant differences from the control group.In the analysis of the most prevalent HPV subtypes in the reproductive tract, the main HPV subtypes in each group are the same as those in the control group. The infection rates of the top 6 types were compared between the control and experimental groups. In the bacterial infection group, HPV51 (1.9%; χ,20 In this study, the peak incidence of pelvic inflammatory disease was found 40 to 45 years old, which is a period after pregnancy and before menopause. High incidence of bacterial vaginitis in the 20 to 45 year group, this data is consisted with the Grenadian women, which showed high incidence of bacterial vaginitis in the 20 to 29 years. Pregnancy and sexual activity may explain infection during this period. The peak period for fungal vaginitis was found to be 30 to 35 years old, occurring mostly before pregnancy. This finding is consistent with a previous study by Ting Zhao, which found the highest incidence of fungal vaginitis at 20-29 years old in Yunnan provinces of Chinese. Cervical lesions exhibit a typical cumulative time effect, which is consistent with previous Chinese findings.The microecology of the reproductive tract changed with age, this phenomenon is related to factors such as age-related reproductive and marital status, hormones, and lifestyle habits. A study conducted in Northwest China found that HPV types 16 and 18 are commonly found in women with normal vaginal microecology, while HPV types 16 and 52 are common in women with vaginal infections. In this study, HPV types 52 and 58 showed significant differences in infection rates between bacterial group and control group, which may be due to the influence of bacterial infections on the infectivity of HPV types 52 and 58. This research found HPV 39 infection rate was significantly different between the fungal vaginitis group and the control group. Fungal vaginitis is mainly caused by C albicans, whether C albicans and HPV synergistically affect vaginal microecology requires further investigation. In adding, this study also found significant differences in HPV types 16, 39, 51, 52, and 56 between cervical lesions and the control group, providing new evidence for HPV vaccine administration.It has been discovered that HPV infection are closely related to the type and abundance of vaginal microorganisms.,27 Vaginal lactobacilli maintain a low pH, prevent HPV invasion, and produce bacteriocins, effectively inhibiting HPV entry into basal keratinocytes of the cervix. Anaerobic bacteria in vaginal bacterial vaginosis produce enzymes and metabolites that may disrupt the barrier of cervical epithelial cells and promote HPV entry.,30 In addition, colonization of C albicans in vaginal candidiasis can affect HPV infection by altering vaginal acidity and alkalinity.Interesting, vaginal microecology can affect the process of HPV infection through various mechanisms.The samples were taken from outpatient patients rather than a cohort population, which may result in bias in disease incidence compared to the general population. The overall sample size of the study was not large, especially the limited number of patients with pelvic inflammatory disease. On the data collection, upper reproductive tract infections such as and cervical lesions may be influenced by lower reproductive tract infections such as vaginal infections.This study characterized the HPV infection types and rates in common reproductive tract infections such as pelvic inflammatory disease, cervical lesions, bacterial vaginosis, and fungal vaginitis. Through scientific statistical analysis, not only the study found a correlation between HPV infection and cervical lesions, but also discovered associations between HPV infection and bacterial vaginosis and fungal vaginitis. This study provides new insights into the harmful effects of reproductive tract microecological imbalance and offers new perspectives for the prevention and treatment of HPV infections.The authors acknowledge all the people who participated in this work at Shandong Maternal and Child Health Hospital. We also thank all participants in the research.Data curation: Liang Wang, Ting-Ting Wang.Formal analysis: Liang Wang, Ting-Ting Wang.Investigation: Xiao-Li Qu.Writing – original draft: Yu-Xia Zhou, Xiao-Qian Zhang.Writing – review & editing: Yu-Xia Zhou, Xiao-Qian Zhang.