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Abstract Background The World Health Organization recommends human papillomavirus (HPV) testing for primary cervical cancer screening, including among women living with HIV (WLWH). Low-and-middle-income countries account for 85% of the cervical cancer burden globally, yet have limited access to HPV-based screening, largely due to cost. This study aims to compare the performance of a rapid, isothermal amplification HPV assay (ScreenFire) to that of the Xpert HPV assay for the detection of HPV and cervical precancer among WLWH in Malawi. Methods We utilized stored self- and provider-collected specimens from a prospective cohort study of WLWH in Malawi from July 2020 to February 2022. Specimens were tested with both Xpert and ScreenFire HPV assays. The overall and within-channel non-hierarchical agreement between ScreenFire and Xpert was determined for both self- and provider-collected specimens. Hierarchical ScreenFire HPV positivity by channel was compared to Xpert for each histological diagnosis—cervical intraepithelial neoplasia grade 2 or worse (CIN2+) compared to

Abstract Background Adolescent girls in China have a low HPV vaccination rate. Although vaccination is recommended by the Chinese health authorities, the cost is not covered by the national immunisation programme. Vaccination delay, among other reasons such as supply shortage and poor affordability, may contribute to low uptake. This sequential mixed methods study aimed to identify potential factors of delayed HPV vaccination among Chinese adolescent girls. Methods Quantitative data about the attitudes and perceptions of HPV vaccination were collected from 100 caregivers of 14–18-year-old girls using an online survey in Chengdu, China. The survey data informed a subsequent qualitative study using four focus group discussions. We conducted a descriptive analysis of the survey data and a thematic analysis of the qualitative data. The findings were interpreted using a health behaviour model adapted from the Health Belief Model and the Andersen’s Behavioural Model for Health Services Use. Results A total of 100 caregivers – 85 were mothers and 15 were fathers – participated in the survey; 21 caregivers joined focus group discussions. When asked about their intended course of action if the 9vHPV vaccine was out-of-stock, 74% chose to delay until the 9vHPV vaccine is available while 26% would consider 2vHPV or 4vHPV vaccines or seek alternative ways to procure the vaccine. Qualitative results confirmed that caregivers preferred delaying HPV vaccination for adolescent girls. The intent to delay was influenced by systemic barriers such as supply shortage and individual-level factors such as a preference for the 9vHPV vaccine, safety concerns, inadequate health communication, and the belief that adolescents were unlikely to be sexually active. Conclusion In urban areas, Chinese caregivers’ intent to delay vaccination in favour of 9vHPV vaccine over receiving the more accessible options was influenced by a mix of individual and contextual factors. Focussed health communication strategies are needed to accelerate HPV vaccination among adolescents.

Abstract Background Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test. Methods A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR)

Abstract While 9-valent human papillomavirus (HPV) vaccination is approved by the US Food and Drug Administration for use in adolescents as young as age 9, providers typically recommend it at ages 11–12. Studies suggest that recommending HPV vaccination at 9 or 10 years of age could increase up-to-date vaccination by age 13, which could especially benefit rural populations with reduced access to primary health care and lower HPV vaccination coverage than urban areas. This study aimed to assess the feasibility of the age-9 recommendation of HPV vaccination in rural clinics. We conducted in-depth interviews with providers and staff from two primary care clinics in central North Carolina to understand attitudes toward recommending HPV vaccination to 9- and 10-year-olds. All interviewees agreed that HPV vaccination was important for cancer prevention and should be recommended before the onset of sexual activity, agreeing that HPV vaccination could be initiated before age 11 to improve timeliness and completion of the vaccination series. However, opinions were mixed on whether HPV vaccination should be initiated as young as 9 years old. Two key informants recruited from two university-affiliated clinics described their experiences recommending HPV vaccination to 9- and 10-year-olds, including a modified vaccination schedule that promotes HPV vaccination during routine well-child visits, prior to pubertal onset, and alongside other recommended adolescent vaccines. Age-9 recommendation and administration of HPV vaccination is possible with minimal changes to current clinical practices and could increase the convenience and acceptability of HPV vaccination in under-vaccinated settings.

Abstract Background Community health workers (CHWs) are essential field-based personnel and increasingly used to deliver priority interventions to achieve universal health coverage. Existing literature allude to the potential for detrimental effects of multi-tasking CHWs. This study objective was to assess the impact of integrating cervical cancer screening and prevention therapy (CCSPT) with family planning (FP) on time utilization among CHWs. Methods A time and motion study was conducted in 7 health facilities in Malawi. Data was collected at baseline between October-July 2019, and 12 months after CCSPT implementation between July and August 2021. CHWs trained to deliver CCSPT were continuously observed in real time while their activities were timed by independent observers. We used paired sample t-test to assess pre-post differences in average hours CHWs spent on the following key activities, before and after CCSPT implementation: clinical and preventive care; administration; FP; and non-work-related tasks. Regression models were used to ascertain impact of CCSPT on average durations CHWs spent on key activities. Results Thirty-seven (n = 37) CHWs were observed. Their mean age and years of experience were 42 and 17, respectively. Overall, CHWs were observed for 323 hours (inter quartile range: 2.8–5.5). Compared with the period before CCSPT, the proportion of hours CHWs spent on clinical and preventive care, administration and non-work-related activities were reduced by 13.7, 8.7 and 34.6%, respectively. CHWs spent 75% more time on FP services after CCSPT integration relative to the period before CCSPT. The provision of CCSPT resulted in less time that CHWs devoted towards clinical and preventive care but this reduction was not significant. Following CCPST, CHWs spent significantly few hours on non-work-related activities. Conclusion Introduction of CCSPT was not very detrimental to pre-existing community services. CHWs managed their time ensuring additional efforts required for CCSPT were not at the expense of essential activities. The programming and policy implications are that multi-tasking CHWs with CCSPT will not have substantial opportunity costs.

Abstract Background Opioid treatment programs (OTPs) serve as daily essential services for people with opioid use disorder. This study seeks to identify modifications to operations and adoption of safety measures at Pennsylvania OTPs during the COVID-19 pandemic. Methods A 25-min online survey to clinical and administrative directors at all 103 state-licensed OTPs in Pennsylvania was fielded from September to November 2020. Survey domains included: 1) changes to services, client volume, hours and staffing during the COVID-19 pandemic 2) types of services modifications 3) safety protocols to reduce COVID-19 transmission 4) challenges to operations during the pandemic. Results Forty-seven directors responded, for a response rate of 45%. Almost all respondents reported making some service modification (96%, n = 43). Almost half (47%, n = 21) of respondents reported reductions in the number of clients served. OTPs were more likely to adopt safety protocols that did not require significant funding, such as limiting the number of people entering the site (100%, n = 44), posting COVID-safety information (100%, n = 44), enforcing social distancing (98%, n = 43), and increasing sanitation (100%, n = 44). Only 34% (n = 14) of OTPS provided N95 masks to most or all staff. Respondents reported that staff’s stress and negative mental health (86%, n = 38) and staff caregiving responsibilities (84%, n = 37) during the pandemic were challenges to maintaining OTP operations. Conclusion OTPs faced numerous challenges to operations and adoption of safety measures during the COVID-19 pandemic. Funding mechanisms and interventions to improve adoption of safety protocols, staff mental health as well as research on patient experiences and preferences can inform further OTP adaptation to the COVID-19 pandemic and future emergency planning.

Abstract Background Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited. Methods Women (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race. Results Of the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03–2.36). Conclusions While the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.

Abstract Background Cervical cancer is the leading cause of cancer incidence and mortality among Malawian women, despite being a largely preventable disease. Implementing a cervical cancer screening and preventive treatment (CCSPT) program that utilizes rapid human papillomavirus (HPV) testing on self-collected cervicovaginal samples for screening and thermal ablation for treatment may achieve greater coverage than current programs that use visual inspection with acetic acid (VIA) for screening and cryotherapy for treatment. Furthermore, self-sampling creates the opportunity for community-based screening to increase uptake in populations with low screening rates. Malawi’s public health system utilizes regularly scheduled outreach and village-based clinics to provide routine health services like family planning. Cancer screening is not yet included in these community services. Incorporating self-sampled HPV testing into national policy could address cervical cancer screening barriers in Malawi, though at present the effectiveness, acceptability, appropriateness, feasibility, and cost-effectiveness still need to be demonstrated. Methods We designed a cluster randomized feasibility trial to determine the effectiveness, acceptability, appropriateness, feasibility, and budget impact of two models for integrating a HPV-based CCSPT program into family planning (FP) services in Malawi: model 1 involves only clinic-based self-sampled HPV testing, whereas model 2 includes both clinic-based and community-based self-sampled HPV testing. Our algorithm involves self-collection of samples for HPV GeneXpert® testing, visual inspection with acetic acid for HPV-positive women to determine ablative treatment eligibility, and same-day thermal ablation for treatment-eligible women. Interventions will be implemented at 14 selected facilities. Our primary outcome will be the uptake of cervical cancer screening and family planning services during the 18 months of implementation, which will be measured through an Endline Household Survey. We will also conduct mixed methods assessments to understand the acceptability, appropriateness, and feasibility of the interventions, and a cost analysis to assess budget impact. Discussion Our trial will provide in-depth information on the implementation of clinic-only and clinic-and-community models for integrating self-sampled HPV testing CCSPT with FP services in Malawi. Findings will provide valuable insight for policymakers and implementers in Malawi and other resource-limited settings with high cervical cancer burden. Trial registration ClinicalTrials.gov identifier: NCT04286243 . Registered on February 26, 2020.

Abstract Background Screening substantially reduces cervical cancer incidence and mortality. More than half of invasive cervical cancers are attributable to infrequent screening or not screening at all. The current study, My Body My Test (MBMT), evaluates the impact of mailed kits for self-collection of samples for human papillomavirus (HPV) testing on completion of cervical cancer screening in low-income, North Carolina women overdue for cervical cancer screening. Methods/design The study will enroll at least 510 US women aged 25–64 years who report no Pap test in the last 4 years and no HPV test in the last 6 years. We will randomize participants to an intervention or control arm. The intervention arm will receive kits to self-collect a sample at home and mail it for HPV testing. In both the intervention and control arms, participants will receive assistance in scheduling an appointment for screening in clinic. Study staff will deliver HPV self-collection results by phone and assist in scheduling participants for screening in clinic. The primary outcome is completion of cervical cancer screening. Specifically, completion of screening will be defined as screening in clinic or receipt of negative HPV self-collection results. Women with HPV-negative self-collection results will be considered screening-complete. All other participants will be considered screening-complete if they obtain co-testing or Pap test screening at a study-affiliated institution or other clinic. We will assess whether the self-collection intervention influences participants’ perceived risk of cervical cancer and whether perceived risk mediates the relationship between HPV self-collection results and subsequent screening in clinic. We also will estimate the incremental cost per woman screened of offering at-home HPV self-collection kits with scheduling assistance as compared to offering scheduling assistance alone. Discussion If mailed self-collection of samples for HPV testing is an effective strategy for increasing cervical cancer screening among women overdue for screening, this method has the potential to reduce cervical cancer incidence and mortality in medically underserved women at higher risk of developing cervical cancer. Trial registration ClinicalTrials.gov NCT02651883, Registered on 11 January 2016.

Abstract Objectives Self-collection of genital specimens for high-risk types of human papillomavirus (hrHPV) detection may increase cervical cancer screening uptake. We hypothesized that women would prefer self-collection to clinician-collection of genital specimens. To test this hypothesis, and women’s preference between two different self-collection approaches, a total of 199 women were enrolled in a cross-sectional study in Mombasa, Kenya. Materials and methods Participants provided self-collected specimens using the Evalyn cytobrush (Rovers) stored in a dry tube and the Viba cytobrush (Rovers) stored in wet Aptima media (Hologic). A clinician also collected cervical specimens for hrHPV testing and for cytology, and performed visual inspection using acetic acid. A post-examination questionnaire assessed preferences for the different methods of specimen collection. To test the difference in proportions for each collection method, we performed an exact binomial probability test, under the null hypothesis that women would prefer each specimen-collection method equally. Results Most women preferred clinician-collection over self-collection (68% versus 32%, p

Abstract Background Moral Reconation Therapy (MRT) is a cognitive-behavioral intervention aimed at reducing risk for criminal recidivism by restructuring antisocial attitudes and cognitions (i.e., “criminogenic thinking”). MRT has empirical support for reducing risk for criminal recidivism among civilian offenders. Recently, a version of MRT was developed for military veterans; however, no randomized controlled trials (RCT) have been conducted with the veteran-specific protocol, and the effectiveness and implementation potential of MRT outside of correctional settings has not been established. Methods Using a Hybrid Type 1 RCT design, this study will test the effectiveness of MRT to reduce risk for criminal recidivism and improve health-related outcomes among justice-involved veterans entering mental health residential treatment at three US Veterans Health Administration (VHA) Medical Centers. Upon admission to the treatment program, justice-involved veterans will complete a baseline assessment, be randomized to usual care (UC) or UC + MRT, and be followed 6 and 12 months post-baseline. A process evaluation will also be conducted to identify barriers and facilitators to implementation of MRT in residential treatment. Discussion The primary aim of this study is to evaluate the effectiveness of MRT with justice-involved veterans. If MRT proves effective in this trial, the findings can provide large healthcare systems that serve veterans with an evidence-based intervention for addressing criminogenic thinking among justice-involved adults, as well as guidance on how to facilitate future implementation of MRT in non-correctional settings. Trial registration This trial is funded by the VA Health Services Research & Development Program (IIR 14–081) and is registered with ClinicalTrials.gov (ID: NCT02524171).

Abstract Background Breast cancer survivors are at high risk for fracture due to cancer treatment-induced bone loss, however, data is scarce regarding the scope of this problem from an epidemiologic and health services perspective among Chinese women with breast cancer. Methods We designed a cross-sectional study comparing prevalence of vertebral fractures among age- and BMI-matched women from two cohorts. Women in the Breast Cancer Survivors cohort were enrolled from a large cancer hospital in Beijing. Eligibility criteria included age 50–70 years, initiation of treatment for breast cancer at least 5 years prior to enrollment, and no history of metabolic bone disease or bone metastases. Data collected included sociodemographic characteristics; fracture-related risk factors, screening and preventive measures; breast cancer history; and thoracolumbar x-ray. The matched comparator group was selected from participants enrolled in the Peking Vertebral Fracture Study, an independent cohort of healthy community-dwelling postmenopausal women from Beijing. Results Two hundred breast cancer survivors were enrolled (mean age 57.5 ± 4.9 years), and compared with 200 matched healthy women. Twenty-two (11%) vertebral fractures were identified among breast cancer survivors compared with 7 (3.5%) vertebral fractures in the comparison group, yielding an adjusted odds ratio for vertebral fracture of 4.16 (95%CI 1.69–10.21, p

Abstract Background Despite guidelines for cervical cancer prevention in low-resource countries, a very small proportion of women in these settings undergo screening, and even fewer women are successfully treated. Using pilot data from western Kenya and World Health Organization recommendations, we developed a protocol to implement evidence-based cervical cancer screening and linkage to treatment strategies to the rural communities. We describe the protocol for a cluster-randomized trial to compare two implementation strategies for human-papillomavirus (HPV)-based cervical cancer screening program using metrics described in the RE-AIM (reach, efficacy, adaption, implementation and maintenance) framework. Methods The study is a three-year, two-phase cluster-randomized trial in 18 communities in western Kenya. During Phase 1, six control communities were offered screening in health facilities; and six intervention communities were offered screening in community health campaigns. Screening was done with human-papillomavirus testing through self-collected specimens. Phase 1 ended and we are working in partnership with communities to further contextualize the implementation strategy for screening, and develop an enhanced linkage to treatment plan. This plan will be tested in an additional six communities in Phase 2 (enhanced intervention). We will compare the reach, efficacy, cost-effectiveness and adaptability of the implementation strategies. Discussion Effective low-cost cervical cancer prevention technologies are becoming more widely available in low- and middle-income countries. Despite increasing government support for cervical cancer prevention, there remains a sizeable gap in service availability. We will use implementation science to identify the most effective strategies to fill this gap through development of context-specific evidence-based solutions. This protocol design and results can help guide implementation of cervical cancer screening in similar settings, where women are most underserved and at highest risk for disease. Trial registration This trial is registered at ClinicalTrials.gov , NCT02124252 .

Following publication of the original article [1], we have been notified that another author should be added to the team of authors. The Name and affiliation details are below.