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Background: Human papillomavirus (HPV) persistence is the pivotal event in cervical carcinogenesis. We followed a large-scale community-based cohort for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer including invasive and in situ carcinoma.Methods: At the baseline examination in 1991-1992, 11,923 participants (aged 30-65 years) consented to HPV testing and cytology; 6923 participants were reexamined in 1993-1995. For HPV testing, we used a polymerase chain reaction-based assay that detected 39 HPV types. Women who developed cervical cancer were identified from cancer and death registries. Cumulative risks for developing cervical cancer among infected and persistently infected women were calculated by the Kaplan-Meier method.Results: Of 10,123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV16, HPV58 (without HPV16), or other carcinogenic HPV types (without HPV16 or HPV58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV-negative at both visits (hazard ratio = 75.4, 95% confidence interval = 31.8 to 178.9). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age: The risks were 5.5%, 14.4%, and 18.1% for women aged 30-44 years, 45-54 years, and 55 years and older, respectively. However, newly acquired infections were associated with a low risk of cervical cancer regardless of age.Conclusions: HPV negativity was associated with a very low long-term risk of cervical cancer. Persistent detection of HPV among cytologically normal women greatly increased risk. Thus, it is useful to perform repeated HPV testing following an initial positive test. [ABSTRACT FROM AUTHOR]

Background: We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection.Methods: We tested serum samples from 3463 HM aged 16-24 years with 1-5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated.Results: The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having >3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1-4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3-6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence.Conclusion: Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence. [ABSTRACT FROM AUTHOR]

Background: We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)-seronegative men who have sex with men (MSM).Methods: Data were analyzed from 602 MSM aged 16-27 years with ≤ 5 lifetime sexual partners. Serum samples were tested for antibodies to HPV6/11/16/18. Swab samples were collected separately from several anogenital areas for detection of HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 DNA.Results: The prevalence of any tested HPV type was 18.5% at the penis, 17.1% at the scrotum, 33.0% at the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. Overall, 415 MSM (69.7%) were negative to HPV 6, 11, 16, and 18 at enrollment by both serology and DNA detection. Men residing in Europe and Latin America had significantly increased risk of HPV infection at external genital sites and the anal canal compared to men from Australia. Tobacco use and greater number of lifetime sexual partners was associated with higher HPV infection prevalence.Conclusions: The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection. Lifetime number of sexual partners was the most important modifiable risk factor for anogenital HPV infection. [ABSTRACT FROM AUTHOR]

Background: Symptomatic treatment for Alzheimer's disease (AD) dementia could temporarily slow symptom worsening and improve the quality of life for both AD dementia patients and their caregivers. A comprehensive evaluation of symptomatic treatment patterns using recent data for newly diagnosed AD dementia has not been performed and compared across different countries., Methods: The drug name, time to the first therapy, duration, discontinuation or switches were described in newly diagnosed AD dementia patients in two databases (a major U.S. health plan [US] and UK-Clinical Practice Research Datalink [CPRD GOLD]). This analysis included patients with newly diagnosed AD dementia in 2018-2019, who initiated symptomatic AD drug therapy, with ≥ 1 year baseline period and ≥ 1 year of follow-up., Results: Over median follow-ups of 698 and 645 days, 63% and 65% of AD dementia patients used symptomatic treatments, with 34% and 77% newly initiating therapy, constituting analytic samples of 7637 patients in the US database and 4470 patients in the CPRD, respectively. The median time to the first therapy was 14 days for US and 49 days for CPRD; donepezil ranked the as most frequently used (69% vs 61%), followed by memantine (19% vs 28%) in the US database and CPRD, respectively. Median time on first therapy was 213 and 334 days, and 30% and 12% of patients proceeded to a second treatment in the US and CPRD databases, respectively., Conclusion: Approximately two thirds of newly diagnosed AD dementia patients utilized approved symptomatic treatment. Time on first therapy was relatively short (< 1 year) and the majority did not move to a second therapy, highlighting the need for better adherence and persistence to existing AD symptomatic therapies and the need for additional therapies to alleviate the significant burden of AD dementia., (© 2023. The Author(s).)

Abstract: Insomnia is a common sleep disorder characterized as dissatisfaction with sleep quantity or quality resulting in distress or impairment of social, occupational, or other daily functioning. It is unknown if there are medical conditions that have strong associations with insomnia but are unrecognized in previous literature. In this cross-sectional study based on IBM Marketscan Research Databases, we measured insomnia and 78 medical conditions in patients with 2-year continuous enrollment during 2018-2019. We selected important comorbidities associated with insomnia for eight age-sex groups and built logistic regression models to measure the associations. The prevalence of diagnosed insomnia increased with age, from <0.4% in the age group 0-17 to 4%-5% in the age group ≥65. Females had a higher prevalence of insomnia than males. Anxiety and depression were two important comorbidities across all age-sex subgroups. Most odds ratios of comorbidities remained significant after adjusting for other comorbidities in regression models. We did not find any new medical conditions that had strong associations with insomnia but were unrecognized in previous literature. The findings can help physicians use comorbidities to identify patients with high risk of insomnia., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Although randomized controlled trials (RCTs) are the gold standard for establishing the efficacy and safety of a medical treatment, real-world evidence (RWE) generated from real-world data has been vital in postapproval monitoring and is being promoted for the regulatory process of experimental therapies. An emerging source of real-world data is electronic health records (EHRs), which contain detailed information on patient care in both structured (eg, diagnosis codes) and unstructured (eg, clinical notes and images) forms. Despite the granularity of the data available in EHRs, the critical variables required to reliably assess the relationship between a treatment and clinical outcome are challenging to extract. To address this fundamental challenge and accelerate the reliable use of EHRs for RWE, we introduce an integrated data curation and modeling pipeline consisting of 4 modules that leverage recent advances in natural language processing, computational phenotyping, and causal modeling techniques with noisy data. Module 1 consists of techniques for data harmonization. We use natural language processing to recognize clinical variables from RCT design documents and map the extracted variables to EHR features with description matching and knowledge networks. Module 2 then develops techniques for cohort construction using advanced phenotyping algorithms to both identify patients with diseases of interest and define the treatment arms. Module 3 introduces methods for variable curation, including a list of existing tools to extract baseline variables from different sources (eg, codified, free text, and medical imaging) and end points of various types (eg, death, binary, temporal, and numerical). Finally, module 4 presents validation and robust modeling methods, and we propose a strategy to create gold-standard labels for EHR variables of interest to validate data curation quality and perform subsequent causal modeling for RWE. In addition to the workflow proposed in our pipeline, we also develop a reporting guideline for RWE that covers the necessary information to facilitate transparent reporting and reproducibility of results. Moreover, our pipeline is highly data driven, enhancing study data with a rich variety of publicly available information and knowledge sources. We also showcase our pipeline and provide guidance on the deployment of relevant tools by revisiting the emulation of the Clinical Outcomes of Surgical Therapy Study Group Trial on laparoscopy-assisted colectomy versus open colectomy in patients with early-stage colon cancer. We also draw on existing literature on EHR emulation of RCTs together with our own studies with the Mass General Brigham EHR., (©Jue Hou, Rachel Zhao, Jessica Gronsbell, Yucong Lin, Clara-Lea Bonzel, Qingyi Zeng, Sinian Zhang, Brett K Beaulieu-Jones, Griffin M Weber, Thomas Jemielita, Shuyan Sabrina Wan, Chuan Hong, Tianrun Cai, Jun Wen, Vidul Ayakulangara Panickan, Kai-Li Liaw, Katherine Liao, Tianxi Cai. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 25.05.2023.)

Importance: Temporal shifts in clinical knowledge and practice need to be adjusted for in treatment outcome assessment in clinical evidence., Objective: To use electronic health record (EHR) data to (1) assess the temporal trends in treatment decisions and patient outcomes and (2) emulate a randomized clinical trial (RCT) using EHR data with proper adjustment for temporal trends., Design, Setting, and Participants: The Clinical Outcomes of Surgical Therapy (COST) Study Group Trial assessing overall survival of patients with stages I to III early-stage colon cancer was chosen as the target trial. The RCT was emulated using EHR data of patients from a single health care system cohort who underwent colectomy for early-stage colon cancer from January 1, 2006, to December 31, 2017, and were followed up to January 1, 2020, from Mass General Brigham. Analyses were conducted from December 2, 2019, to January 24, 2022., Exposures: Laparoscopy-assisted colectomy (LAC) vs open colectomy (OC)., Main Outcomes and Measures: The primary outcome was 5-year overall survival. To address confounding in the emulation, pretreatment variables were selected and adjusted. The temporal trends were adjusted by stratification of the calendar year when the colectomies were performed with cotraining across strata., Results: A total of 943 patients met key RCT eligibility criteria in the EHR emulation cohort, including 518 undergoing LAC (median age, 63 [range, 20-95] years; 268 [52%] women; 121 [23%] with stage I, 165 [32%] with stage II, and 232 [45%] with stage III cancer; 32 [6%] with colon adhesion; 278 [54%] with right-sided colon cancer; 18 [3%] with left-sided colon cancer; and 222 [43%] with sigmoid colon cancer) and 425 undergoing OC (median age, 65 [range, 28-99] years; 223 [52%] women; 61 [14%] with stage I, 153 [36%] with stage II, and 211 [50%] with stage III cancer; 39 [9%] with colon adhesion; 202 [47%] with right-sided colon cancer; 39 [9%] with left-sided colon cancer; and 201 [47%] with sigmoid colon cancer). Tests for temporal trends in treatment assignment (χ2 = 60.3; P < .001) and overall survival (χ2 = 137.2; P < .001) were significant. The adjusted EHR emulation reached the same conclusion as the RCT: LAC is not inferior to OC in overall survival rate with risk difference at 5 years of -0.007 (95% CI, -0.070 to 0.057). The results were consistent for stratified analysis within each temporal period., Conclusions and Relevance: These findings suggest that confounding bias from temporal trends should be considered when conducting clinical evidence studies with long time spans. Stratification of calendar time and cotraining of models is one solution. With proper adjustment, clinical evidence may supplement RCTs in the assessment of treatment outcome over time.

Background: Challenges in identifying microsatellite instability (MSI)/mismatch repair (MMR)-tested colorectal carcinoma (CRC) patients in electronic health records have led to gaps in the understanding of MSI-high/deficient mismatch repair prevalence. Methods: An algorithm to identify MSI-/MMR-tested Veterans Affairs patients was developed and an observational study of adult CRC patients with MSI/MMR testing from 2010 to 2018 was undertaken. Results: An optimized model to identify MSI-/MMR-tested patients yielded high positive predictive value (89.0%) and specificity (97.8%). The authors observed MSI-high/deficient mismatch repair CRC in 54 of 291 patients (18.6%); highest frequencies were observed in stages II (25.9%) and III (22.6%) and lowest in stage IV (5.8%). Conclusions: In this real-world study, the authors proposed a novel method of identifying MSI-/MMR-tested patients. Further validation and refinement of this model, and study in a larger CRC cohort, is warranted.

Importance: Coronavirus disease 2019 patients have an increased risk of thrombotic complications that may reflect immunothrombosis, a process characterized by blood clotting, endothelial dysfunction, and the release of neutrophil extracellular traps. To date, few studies have investigated longitudinal changes in immunothrombosis biomarkers in these patients. Furthermore, how these longitudinal changes differ between coronavirus disease 2019 patients and noncoronavirus disease septic patients with pneumonia are unknown., Objectives: In this pilot observational study, we investigated the utility of immunothrombosis biomarkers for distinguishing between coronavirus disease 2019 patients and noncoronavirus disease septic patients with pneumonia. We also evaluated the utility of the biomarkers for predicting ICU mortality in these patients., Design Setting and Participants: The participants were ICU patients with coronavirus disease 2019 ( n = 14), noncoronavirus disease septic patients with pneumonia ( n = 19), and healthy age-matched controls ( n = 14)., Main Outcomes and Measures: Nine biomarkers were measured from plasma samples (on days 1, 2, 4, 7, 10, and/or 14). Analysis was based on binomial logit models and receiver operating characteristic analyses., Results: Cell-free DNA, d-dimer, soluble endothelial protein C receptor, protein C, soluble thrombomodulin, fibrinogen, citrullinated histones, and thrombin-antithrombin complexes have significant powers for distinguishing coronavirus disease 2019 patients from healthy individuals. In comparison, fibrinogen, soluble endothelial protein C receptor, antithrombin, and cell-free DNA have significant powers for distinguishing coronavirus disease 2019 from pneumonia patients. The predictors of ICU mortality differ between the two patient groups: soluble thrombomodulin and citrullinated histones for coronavirus disease 2019 patients, and protein C and cell-free DNA or fibrinogen for pneumonia patients. In both patient groups, the most recent biomarker values have stronger prognostic value than their ICU day 1 values., Conclusions and Relevance: Fibrinogen, soluble endothelial protein C receptor, antithrombin, and cell-free DNA have utility for distinguishing coronavirus disease 2019 patients from noncoronavirus disease septic patients with pneumonia. The most important predictors of ICU mortality are soluble thrombomodulin/citrullinated histones for coronavirus disease 2019 patients, and protein C/cell-free DNA for noncoronavirus disease pneumonia patients. This hypothesis-generating study suggests that the pathophysiology of immunothrombosis differs between the two patient groups., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Nationwide healthcare registries are potential important real-world data (RWD) sources for assessing drug effectiveness in oncology. However, it is unclear whether registry-derived RWD are suitable for clinical development. In this study, we replicate results from the comparator arm of two previously published oncology randomized controlled trials (RCTs) using RWD from Swedish nationwide healthcare registries. For replication 1, the RCT included 553 patients and the RWD included 283 patients treated with sorafenib for advanced hepatocellular cancer. The median overall survival (OS) was 11.2 (95% confidence interval (CI): 10.1-13.2) months in the RCT and 8.2 (95% CI: 7.0-9.9) months in the RWD, unadjusted hazard ratio (HR) 0.75 (95% CI: 0.63-0.88). For time-to-treatment discontinuation (TTD), the HR was 1.00 (95% CI: 0.87-1.16). For replication 2, the RCT included 154 patients and the RWD included 704 patients treated with melphalan, prednisone, and thalidomide for untreated multiple myeloma. The median OS was 52.6 (95% CI: 40-not applicable) months in the RCT and 36.9 (95% CI: 33.8-40.5) months in the RWD, unadjusted HR 0.67 (95% CI: 0.51-0.87). For TTD, the HR was 0.89 (95% CI: 0.74-1.06). The results were similar when applying various propensity-based confounding adjustments. In conclusion, OS was shorter in the RWD, whereas TTD was similar. Importantly, the data necessary (ex: eligibility criteria and baseline confounders) for replicating RCTs was mostly not available and these results further underscore the importance of developing frameworks for capturing relevant patient-level RWD for clinical and regulatory decision making in oncology., (© 2021 Merck Sharp & Dohme Corp. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Background: The prevalence of treatment-resistant depression (TRD) among patients with pharmaceutically treated depression (PTD) varies greatly in publications. The aim of this study is to estimate the prevalence of TRD using 2 large claims databases in the US., Methods: This cross-sectional study used data from the Humana and Optum databases. Patients aged ≥ 18 years who had at least 1 diagnosis of major depressive disorder ( ICD-10 - CM codes: F32.xx, F33.xx) and 1 antidepressant prescription filled in 2018 were identified as having PTD. Among patients with PTD, TRD was defined as experiencing failure of treatment with at least 2 antidepressants with ≥ 4 weeks of adequate treatment. We estimated the age- and gender-standardized prevalence of TRD and then used logistic regression to investigate if TRD risk varies by age, sex, race, and geographic region. Finally, we described the timeline of TRD development in incident PTD patients., Results: We identified 296,055 and 277,941 patients with PTD in the Humana and Optum databases, among whom 17,640 (6.0%) and 16,131 (5.8%) had TRD. After age and sex standardization, TRD prevalence among PTD patients was 6.8% in Humana vs 5.8% in Optum. Females, middle-aged adults, and White patients had higher risk of TRD. The median time from index antidepressant use to TRD was about 6 months in incident PTD patients., Conclusions: The prevalence of TRD among patients with PTD was similar in the 2 databases. TRD prevalence varies by sex, race, and age, with a higher prevalence in females, White patients, and those in the age group of 45-64 years. However, the absolute differences were small., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Purpose: To compare and characterize baseline characteristics and overall survival (OS) differences by key oncology eligibility criteria for real-world patients from the Flatiron Health database with advanced non-small-cell lung cancer (NSCLC) who received pembrolizumab monotherapy., Methods: Real world data (RWD) were from the Flatiron Health advanced NSCLC database and include patients who initiated pembrolizumab monotherapy (first, second, or third line of therapy) by November 30, 2019. At the data cutoff (May 31, 2020), the median survival follow-up time was 8.4 months. Eligible patients satisfy the criteria of Eastern Cooperative Oncology Group performance status of 0/1 and laboratory values indicative of adequate organ function. RWD were analyzed for all patients and patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%. Patients were divided into three categories: ineligible, eligible, and unknown (who satisfy all observed criteria, with at least one missing). An augmented population was also formed, which combines the latter two groups through a propensity-based adjustment., Results: At the data cutoff, N = 3,877 patients with NSCLC received pembrolizumab monotherapy (1L = 2,682, 2L = 946, and 3L = 249). OS was consistently lower for the ineligible with similar survival for the eligible and augmented. Among all patients, the median OS in months (95% CI) was 8.2 (7.5 to 9.6), 16.3 (14.5 to 18.4), 16.4 (15.1 to 19.3), and 16.8 (15.6 to 18.5) for the ineligible (47%, n = 1,827), unknown (27%, n = 1,045), eligible (26%, n = 1,005), and augmented, respectively. The results were similar for patients with a programmed cell death ligand-1 tumor proportion score ≥ 1%., Conclusion: Real-world patients who received pembrolizumab monotherapy and meet key clinical eligibility criteria exhibited similar baseline characteristics and OS profiles as the unknown and augmented patient groups. Population augmentation is a feasible approach for improving the power of RWD analysis., Competing Interests: Thomas JemielitaEmployment: Merck & Co, IncStock and Other Ownership Interests: Merck & Co, Inc Xiaoyun (Nicole) LiEmployment: Merck & Co, IncStock and Other Ownership Interests: Merck & Co, Inc Thomas BurkeEmployment: Merck & Co, IncStock and Other Ownership Interests: Merck & Co, Inc Kai-Li LiawEmployment: Merck & Co, IncStock and Other Ownership Interests: Merck & Co, IncResearch Funding: Merck & Co, IncTravel, Accommodations, Expenses: Merck & Co, Inc Wei ZhouEmployment: Merck & Co, IncStock and Other Ownership Interests: Merck & Co, IncResearch Funding: Merck & Co, IncTravel, Accommodations, Expenses: Merck & Co, Inc Cong ChenEmployment: Merck & Co, IncStock and Other Ownership Interests: Merck & Co, IncNo other potential conflicts of interest were reported.

Background: Behavioral disturbance (BD) is common in dementia patients, with no FDA approved medications for this condition. Little data exists on the real-world medication use in this population., Objective: To describe real-world medications use in this population., Methods: A cross-sectional study was conducted using the MarketScan database for outpatient medications and the Cerner database for inpatient medications. The study period was Oct 2015-Jun 2018. Patients with dementia and BD were identified through ICD-10-CM. We examined outpatient medications prescribed during 6-month before or after BD event date, and inpatient medications during inpatient visits, especially on central nervous systems (CNS) drugs including antidementia drugs, antidepressants, antipsychotics, anxiolytics, and anticonvulsants., Results: A total of 56,544 outpatients and 34,245 patient hospitalizations were assessed separately. Among outpatients, patients filled more medications after a BD event. The use of the five CNS drug classes generally increased after a BD event, and the largest increase was seen in antipsychotics (23%to 33%). Among inpatients, the median number of medications used in each hospitalization was 14. The use of antipsychotics was particularly high (64%), followed by anxiolytics (51%). A list of 60 unique medications were suggested to be the commonly used drugs in dementia patients with BD., Conclusion: In dementia patients with BD, anti-dementia medications, antidepressants, anticonvulsants, hypnotics and antipsychotics were the most used drug classes. Antidepressants and antipsychotics use were more frequent after a BD event, which suggests a need for safe drugs targeting BD in dementia patients., Competing Interests: All the authors are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, all of whom may own stock and/or hold stock options in the Company., (© 2021 – The authors. Published by IOS Press.)

There is increasing interest in utilizing real-world data (RWD) to produce real-world evidence (RWE) on the benefits and risks of medical products that could support regulatory approval decisions. The field of pharmacoepidemiology has a long history of focusing on data and evidence that would now be termed "real-world," including evidence from healthcare claims, registries, and electronic health records. However, several emerging trends over the past decade are converging to support the use of these and other RWD sources for approval decisions, and there are several recent examples and ongoing research that demonstrate how RWE may be used to support regulatory approval of new or expanded indications. The goal of this article is to review the current landscape and future directions of the use of RWE in this context. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE)., (© 2021 John Wiley & Sons Ltd.)

Prevalence of different HPV genotypes is changing after HPV vaccination. The associated risks are needed for optimizing cervical cancer screening.To estimate HPV type-specific prevalence, odds ratio (OR), and positive predictive value (PPV) for cervical cytological abnormalities, we determined 41 different HPV genotypes in cervical samples from a population-based sample of 8351 women aged 18-51 years before HPV vaccination era (V501-033; NCT01077856).Prevalence of HPV16 was 4.9% (95% CI: 4.4-5.5) with the PPV for high-grade cytology 11.2%, and OR 11.9 (95% CI: 8.5-16.5). Carcinogenic HPVs included in the nonavalent vaccine (HPV16,18,31,33,45,52,58) had a population prevalence of 14.4% (95% CI: 13.5-15.4), with PPV of 8.0% (95% CI: 6.8-9.3) and OR 23.7 (95% CI: 16.0-63.5) for high-grade cytology. HPV types currently included in most screening tests, but not vaccinated against (HPV35,39,51,56,59,66,68) had a joint prevalence of 8.5% (95% CI: 7.8-9.2) with PPV of 4.4% (95% CI: 3.3-5.7) and OR of 2.9 (95% CI: 2.0-4.0) for high-grade cytology. The other 27 non-carcinogenic genotypes had a prevalence of 11.8%, PPV of 2.9% (95% CI:2.1-3.9), and OR 1.5 (95% CI: 1.1-2.2.) for high-grade cytology.These results suggest that HPV screening tests in the post-vaccination era might perform better if restricted to the HPV types in the nonavalent vaccine and screening for all 14 HPV types might result in suboptimal balance of harms and benefits.

Purpose: Given regulatory approval of immune checkpoint inhibitors in patients with mismatch repair-deficient (MMR-D) cancers agnostic to tumor type, it has become important to characterize occurrence of MMR-D and develop cost-effective screening approaches. Using a next-generation sequencing (NGS) panel (OncoPanel), we developed an algorithm to identify MMR-D frequency in tumor samples and applied it in a clinical setting with pathologist review., Methods: To predict MMR-D, we adapted methods described previously for use in NGS panels, which assess patterns of single base-pair insertion or deletion events occurring in homopolymer regions. Tumors assayed with OncoPanel between July 2013 and July 2018 were included. For tumors tested after June 2017, sequencing results were presented to pathologists in real time for clinical MMR determination, in the context of tumor mutation burden, other mutational signatures, and clinical data., Results: Of 20,301 tumors sequenced, 2.7% (553) were retrospectively classified as MMR-D by the algorithm. Of 4,404 samples with pathologist sign-out of MMR status, the algorithm classified 147 (3.3%) as MMR-D: in 116 cases, MMR-D was confirmed by a pathologist, five cases were overruled by the pathologist, and 26 were assessed as indeterminate. Overall, the highest frequencies of OncoPanel-inferred MMR-D were in endometrial (21%; 152/723), colorectal (9.7%; 169/1,744), and small bowel (9.3%; 9/97) cancers. When algorithm predictions were compared with historical MMR immunohistochemistry or polymerase chain reaction results in a set of 325 tumors sequenced before initiation of pathologist assessment, the overall sensitivity and specificity of the algorithm were 91.1% and 98.2%, respectively., Conclusion: We show that targeted, tumor-only NGS can be leveraged to determine MMR signatures across tumor types, suggesting that broader biomarker screening approaches may have clinical value.

Introduction: Emergency contraceptive pill (ECP) use is reported to have increased in several countries over time. In this multi-country population-based questionnaire study, we aimed to describe the patterns of ECP use and identify factors associated with its use., Material and Methods: In 2011-2012, women aged 18-45 years were randomly selected from national registers in Denmark, Norway and Sweden and invited to respond to questions related to lifestyle and contraceptive use. We used generalized logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CI) comparing women who had used ECP with women who had never used ECP., Results: Of the 45 445 women, 33.9% (Denmark = 32.3%, Norway = 35.1%, Sweden = 34.6%) had used ECP at least once in their lifetime. Among ECP users, 15.8% had used ECP within the last year and 50.0% had used ECP more than once in their life. After adjusting for country, age at response and response type, ECP use was associated with higher education (OR 2.09, 95% CI 1.54-2.84) and being single, divorced or widowed (OR 3.17, 95% CI 2.87-3.49). Binge drinking and smoking increased the odds of ECP use. Furthermore, early age at first intercourse (OR 1.29, 95% CI 1.08-1.55), having a new partner in the last 6 months (≥3 partners: OR 6.44, 95% CI 5.46-7.60) and lack of condom use with a recent new partner (OR 1.42, 95% CI 1.22-1.66) were found to be associated with ECP use., Conclusions: Our study shows that ECP use is common among Scandinavian women. Higher education and being single were associated with increased odds of ECP use. Risk behaviors such as smoking and early age at first sex were also associated with increased odds of ECP use. Since ECP use is not protective against sexually transmitted infections, our findings highlight the need to encourage awareness and regular use of condoms to prevent sexually transmitted diseases in women., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Aim: PD-L1 expression and high levels of microsatellite instability (MSI-H) may predict response to checkpoint inhibitors, but their prevalence and prognostic value are unknown in many cancers., Methods: We retrospectively evaluated PD-L1 combined positive score (CPS) and MSI-H and their association with clinical outcomes among patients with ten advanced uncommon cancers., Results: 398 of 426 patients (93%) had a valid PD-L1 result; most (242; 61%) had CPS ≥1. Prevalence of MSI-H tumors was 8/360. Median overall survival was shorter among patients with PD-L1 CPS ≥1 tumors after first-line treatment (23.0 vs 39.7 months, p = 0.014)., Conclusion: PD-L1 was commonly expressed in solid tumors, and CPS ≥1 was associated with shorter overall survival. Prevalence of MSI-H was low., Competing Interests: Financial & competing interests disclosure W Zhou, M Marton, SK Pruitt, F Jin, K-L Liaw are employees of and stakeholders in Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.)

Introduction: Sexual behavior at the population level impacts on public health. Recent representative sexual behavior data are lacking., Material and Methods: Cross-sectional surveys in 2005 and 2012 on women age 18-45 years randomly selected from the general population in Denmark (n = 40 804), Norway (n = 30 331) and Sweden (n = 32 114)., Results: Median (interquartile range) age at first intercourse was 16 (15-18) years in Denmark, 17 (16-18) years in Norway, and 17 (15-18) years in Sweden. Women in the most recent birth cohort had sexual debut at the lowest age, and were most likely to have sexual debut before the legal age of consent. Proportions with debut age ≤14 years among women born 1989-1994 vs 1971-1976, odds ratio (95% confidence interval) were: 18.4% vs 10.9%, 1.95 (1.74-2.18) in Denmark, 12.9% vs 6.3%, 2.38 (2.01-2.82) in Norway, 17.8% vs 11.4%, 1.75 (1.55-1.98) in Sweden. Median (interquartile range) number of lifetime sexual partners was 6 (3-10) in Denmark, 5 (2-10) in Norway, and 6 (3-11) in Sweden. The proportion of women reporting >10 sexual partners was also highest in the most recent survey. The percentage with odds ratio (95% confidence interval) in 2012 vs 2005 surveys were: 24.9% vs 22.8%, 1.13 (1.07-1.18) for Denmark; 23.8% vs 19.8%, 1.27 (1.19-1.34) for Norway; and 28.3% vs 23.8%, 1.31 (1.24-1.38) for Sweden. Similarly, the proportion of women reporting ever having had a sexually transmitted infection among women age <30 years were: 29.4% vs 26.4%, 1.21 (1.13-1.31) in Denmark, 28.9% vs 25.0%, 1.20 (1.10-1.31) in Norway, and 29.4% vs 22.2%, 1.45 (1.33-1.58) in Sweden., Conclusions: Scandinavian women reported lower age at first intercourse in younger birth cohorts. Moreover, they reported more lifetime sexual partners and a higher prevalence of ever having a sexually transmitted infection in 2012 than in 2005. Our findings may inform the interpretation of trends in outcomes associated with sexual health, and public health policies., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

To determine if a set of time-varying biological indicators can be used to: 1) predict the sepsis mortality risk over time and 2) generate mortality risk profiles., Design: Prospective observational study., Setting: Nine Canadian ICUs., Subjects: Three-hundred fifty-six septic patients., Interventions: None., Measurements and Main Results: Clinical data and plasma levels of biomarkers were collected longitudinally. We used a complementary log-log model to account for the daily mortality risk of each patient until death in ICU/hospital, discharge, or 28 days after admission. The model, which is a versatile version of the Cox model for gaining longitudinal insights, created a composite indicator (the daily hazard of dying) from the "day 1" and "change" variables of six time-varying biological indicators (cell-free DNA, protein C, platelet count, creatinine, Glasgow Coma Scale score, and lactate) and a set of contextual variables (age, presence of chronic lung disease or previous brain injury, and duration of stay), achieving a high predictive power (conventional area under the curve, 0.90; 95% CI, 0.86-0.94). Including change variables avoided misleading inferences about the effects of day 1 variables, signifying the importance of the longitudinal approach. We then generated mortality risk profiles that highlight the relative contributions among the time-varying biological indicators to overall mortality risk. The tool was validated in 28 nonseptic patients from the same ICUs who became septic later and was subject to 10-fold cross-validation, achieving similarly high area under the curve., Conclusions: Using a novel version of the Cox model, we created a prognostic tool for septic patients that yields not only a predicted probability of dying but also a mortality risk profile that reveals how six time-varying biological indicators differentially and longitudinally account for the patient's overall daily mortality risk., Competing Interests: Drs. Liaw, Dwivedi, and Medeiros received support for article research from the Canadian Institutes of Health Research (CIHR). Drs. Liaw and Medeiros disclosed government work. Dr. Fox-Robichaud’s institution received funding from CIHR, CIHR/Natural Sciences and Engineering Research Council of Canada, and Hamilton Academic Hospital Fund. Dr. Dodek’s institution received funding from McMaster University. Dr. Winston received grant support from the Alberta Lung Association and the Canadian Intensive Care Foundation. Dr. Lellouche received compensation for patient inclusions in the study, and he disclosed he is a co-founder, administrator, and consultant of Oxynov, R&D company. Dr. Marshall received patient recruitment fees per CIHR grant, and he received funding from Data Monitoring Committee, Asahi Kasei Pharmaceuticals and Baxter. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objective: Women's contraceptive use at first sexual intercourse (FSI) may be associated with subsequent sexual behaviors. We examined associations between contraceptive methods used at FSI and subsequent number of lifetime partners, induced abortions and sexually transmitted infections (STIs)., Study Design: During 2011-2012, we collected questionnaire data from a random sample of women aged 18-45 years from Denmark, Norway and Sweden. We used logistic regression and discrete-time proportional hazards models to estimate odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs), comparing different contraceptive methods used at FSI in the whole study sample and in women with FSI in 2001 or later [when emergency contraceptive pills (ECPs) were available without prescription]., Results: Of 45,361 women in the study sample, those who did not use contraception at FSI (n=8155; 18.0%) were more likely than condom users to have ≥11 lifetime partners (OR=1.34; 95% CI 1.27-1.42), induced abortions (HR=1.62; 95% CI 1.53-1.71) and STIs (HR=1.15; 95% CI 1.10-1.20). ECP users (n=440, 1.0%) were more likely than condom users to have ≥11 lifetime partners (OR=1.76; 95% CI 1.40-2.22), induced abortions (HR=1.44; 95% CI 1.11-1.86) and STIs (HR=1.84; 95% CI 1.56-2.16). A similar pattern was seen in safe periods/withdrawal users. The associations did not change among women with FSI in 2001 or later (n=14,445)., Conclusions: Compared with condom use, contraceptive nonuse, safe periods/withdrawal use and ECP use at FSI were associated with subsequent number of sexual partners, induced abortions and STIs., Implications: Contraceptive method used at first intercourse was associated with subsequent sexual behaviors in women. This study highlights the importance of early sexual behaviors and may help understand patterns of women's sexual behaviors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It is valuable to establish a population-based prevaccination baseline distribution of human papillomavirus (HPV) types among women with high-grade cervical intraepithelial neoplasia (CIN) grade 2 or 3 and cervical cancer in order to assess the potential impact of HPV vaccination. In four countries (Denmark, Norway, Sweden, and Iceland), we collected consecutive series of cervical cancers (n = 639) and high-grade precancerous cervical lesions (n = 1240) during 2004-2006 before implementation of HPV vaccination and subjected the specimens to standardized HPV genotyping. The HPV prevalence was 82.7% (95% confidence interval [CI] 79.0-86.4) in CIN2, 91.6% (95% CI 89.7-93.5) in CIN3, and 86.4% (95% CI 83.7-89.1) in cervical cancer. The most common HPV types in CIN2/3 were HPV16 (CIN2: 35.9%, 95% CI 31.2-40.6; CIN3: 50.2%, 95% CI 46.8-53.6) and HPV31 (CIN2: 10.9%, 95% CI 7.8-13.9; CIN3: 12.1%, 95% CI 9.9-14.3), while HPV16 and HPV18 were the most frequent types in cervical cancer (48.8%, 95% CI 44.9-52.7 and 15.3%, 95% CI 12.5-18.1, respectively). The prevalence of HPV16/18 decreased with increasing age at diagnosis in both CIN2/3 and cervical cancer (P < 0.0001). Elimination of HPV16/18 by vaccination is predicted to prevent 42% (95% CI 37.0-46.7) of CIN2, 57% (95% CI 53.8-60.5) of CIN3 and 64% (95% CI 60.3-67.7) of cervical cancer. Prevention of the five additional HPV types HPV31/33/45/52/58 would increase the protection to 68% (95% CI 63.0-72.2) in CIN2, 85% (95% CI 82.4-87.2) in CIN3 and 80% (95% CI 77.0-83.2) in cervical cancer. This study provides large-scale and representative baselines for assessing and evaluating the population-based preventive impact of HPV vaccination., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: This study examined the associations between current behaviours/characteristics and self-perceived risk for STIs, among randomly selected women aged 18-45 years from Denmark, Norway and Sweden., Method: A population-based, cross-sectional, questionnaire study (paper based, web based and telephone based) was conducted during 2011-2012. We compared medium-high STI risk perception with no/low risk perception. The associations were explored for women who had ever had sexual intercourse and for women with a new partner in the last 6 months using multivariable logistic regression., Result: The overall prevalence of medium-high STI risk perception was 7.4%. It was highest among women aged 18-24 years (16.2%) and among the Danish women (8.8%). Number of new sexual partners in the last 6 months (≥3vs 0 partners, OR 14.94, 95% CI 13.20 to 16.94) was strongly associated with medium-high STI risk perception. Among women with a new partner in the last 6 months, lack of condom use increased medium-high STI risk perception (OR 1.73, 95% CI 1.52 to 1.96). Genital warts in the last year, binge drinking and being single were associated with increased risk perception and remained statistically significant after additional adjustments were made for number of new partners and condom use with new partners in the last 6 months., Conclusion: Subjective perception of risk for STI was associated with women's current risk-taking behaviours, indicating women generally are able to assess their risks for STIs. However, a considerable proportion of women with multiple new partners in the last 6 months and no condom use still considered themselves at no/low risk for STI., Competing Interests: Competing interests: CM received lecture fees and support for conference participation from Sanofi Pasteur MSD. MN has received research grants from MSD/Merck through the affiliating institute. LA-D has received grant support from Merck, Sanofi Pasteur MSD and GlaxoSmithKline. K-LL is an employee at Merck Sharp & Dome Corp, a subsidiary of Merck & Co, Inc, Whitehouse Station, New Jersey, and may own stock or stock options in Merck. SKK has received lecture fees, scientific advisory board fees from Merck and Sanofi Pasteur MSD and unrestricted research grants through the affiliating institute from Merck., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To monitor the changes in prevalence of human papillomavirus (HPV) infections in women <50 years of age, participating in cervical screening programs of Denmark, Norway, and Sweden, before and after introduction of quadrivalent HPV (qHPV) vaccination., Methods: Liquid-based cytology samples were collected from 6538 women who attended cervical screening in Denmark, Norway, and Sweden in 2006-2008 and from 6332 similarly enrolled women in 2012-2013. Denmark started organized qHPV vaccination in 2008, Norway in 2009, and Sweden in 2012. All HPV testing and genotyping was performed using identical enrollment and analysis methods, by accredited general primer polymerase chain reaction methods with typing using the Luminex system., Results: Overall HPV positivity declined slightly from 36.5% in 2006-2008 to 34.5% in 2012-2013. The decline was most pronounced among women 18-26 years of age: from 54.4% to 48.1% (P < 0.001). The decline was substantial for vaccine HPV types (HPV6/11/16/18: decline from 22.3% to 16.6%; P < 0.001) and was seen for both low-risk vaccine types (HPV6/11 declined from 5.0% to 2.5%) and high-risk vaccine types (HPV16/18 declined from 18.9% to 14.9%). Among women 27-50 years of age, there was no change between the time periods (22.5% and 21.6%, respectively). The significant decline in the younger age group was different in the 3 countries., Conclusion: This population-based study enrolling >12,000 women participating in cervical screening in the 3 Nordic countries before and after introduction of organized qHPV vaccination demonstrated a marked decline in HPV infection in the younger population in the 2 countries where qHPV vaccination programs started in 2008-2009, suggesting that organized HPV vaccination programs resulted in a decrease of HPV types circulating in the general population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV-exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV-exposed miscarriages.

Introduction: The active component of the herpes zoster vaccine (ZVL), licensed for people ≥50 years of age, is a live attenuated varicella-zoster virus. ZVL is contraindicated for immune compromised individuals, with limited regard to the degree of immunosuppression. Areas covered: This review evaluates phase I and II and observational studies for ZVL, and published reports of the off-label use of ZVL, for conditions and therapies for which investigators considered the risk-benefit for using ZVL to be favorable. It also discusses exploratory trials of ZVL for additional immune compromising conditions, and summarizes clinical guidelines from many countries and professional societies that are based upon recent investigations. Studies in immune compromised patients of investigational vaccines that do not contain live virus are reviewed. Expert commentary: It is likely that past and ongoing research with ZVL will define immune compromising diseases and/or therapies for which the risk-benefit for using ZVL vaccine is favorable. The main variables to consider in this assessment in immune compromised patients are safety, immunogenicity, protection against herpes zoster, and persistence of protection. Vaccination against herpes zoster prior to suppressing immunity is an important clinical strategy, although efficacy of this approach has not been evaluated in a clinical trial.

Using a large, population-based survey, we assessed the levels and correlates of human papillomavirus (HPV) awareness among Scandinavian women after introduction of HPV vaccination. In 2011-2012, a random sample of women aged between 18 and 45 years from Denmark, Sweden and Norway received a questionnaire on lifestyle, health and HPV awareness. We included 47 895 women (response rate 60.6%) in our study. Country-specific and age-specific proportions of women who had heard of HPV in 2011-2012 (postvaccination survey) were compared with corresponding proportions in an identical survey from 2004-2005 (prevaccination survey, n=54 079, response rate 71.3%). Correlates of HPV awareness in the postvaccination survey were assessed by logistic regression. In all countries and age groups, awareness of HPV increased from the prevaccination to the postvaccination survey. In the postvaccination survey, HPV awareness was higher in Denmark (75.8%) and Sweden (74.8%) compared with Norway (62.4%), with greatest discrepancy among women aged between 18 and 19 years (Denmark: 74.9%, Sweden: 70.4%, Norway: 39.6%). Variables associated with low HPV awareness included the following: low education [≤12 vs. >16 years of schooling: odds ratio (OR)=0.45, 95% confidence interval (CI): 0.42-0.48], being a virgin (vs. nonvirgins: OR=0.74, 95% CI: 0.66-0.83), never having used condoms (vs. ever: OR=0.62, 95% CI: 0.56-0.67), nonuse of contraception at first intercourse (vs. use: OR=0.83, 95% CI: 0.79-0.88) and daily smoking (vs. never: OR=0.86, 95% CI: 0.80-0.92). HPV awareness in Scandinavia has increased since the introduction of HPV vaccination. However, 24-38% of Scandinavian women still have never heard of HPV. Future information efforts should target groups with low HPV awareness.

Introduction: The aim of this study was to describe recent patterns of contraceptive use at first sexual intercourse and to examine whether selected factors are associated with non-use and emergency contraceptive pill use at first sexual intercourse, among 18- to 26-year-old women from Denmark, Norway and Sweden., Material and Methods: This was a population-based, questionnaire study of randomly chosen 18- to 26-year-old Scandinavian women. The prevalence of contraception methods used at first sexual intercourse was calculated. Factors associated with contraceptive non-use and emergency contraceptive pill use at first sexual intercourse were determined using log binomial models., Results: The prevalence of contraceptive non-use and emergency contraceptive pill use was lowest in Denmark (9.6 and 2.1%, respectively) compared with Norway (14.1 and 4.4%) and Sweden (16.6 and 4.5%). The risk of contraceptive non-use increased in women who had first sexual intercourse at or before 14 years of age (13-14 years: prevalence ratio 1.40; 95% confidence interval 1.24-1.58). The risk of both non-use and emergency contraceptive pill use increased when the partner at first sexual intercourse was 20 years or older, and with increasing age difference between the partner and the woman at her first sexual intercourse. Smoking initiation prior to first sexual intercourse increased risk of contraceptive non-use (prevalence ratio 1.70; 95% confidence interval 1.50-1.92), and alcohol initiation prior to first sexual intercourse increased risk of emergency contraceptive pill use at first sexual intercourse (prevalence ratio 1.95; 95% confidence interval 1.49-2.54)., Conclusions: Contraceptive non-use at first sexual intercourse was strongly associated with early age at first sexual intercourse. Emergency contraceptive pill and contraceptive non-use at first sexual intercourse were both strongly associated with increasing partner age and an increasing difference in age between the woman and her partner. Hence, young women should be educated to negotiate contraceptive use with their partners., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

The epidemiology of herpes zoster (HZ) in contemporary autologous hematopoietic cell transplant (HCT) recipients, and the impact of acyclovir (ACV)/valacyclovir (VACV) prophylaxis, is not well described. In this observational study from 2002 to 2010, we retrospectively identified 1000 varicella zoster virus (VZV)-seropositive autologous HCT recipients with up to 5 years of follow-up. The incidence of HZ and use of ACV/VACV prophylaxis were determined through review of medical records and mailed questionnaires. Risk factors for HZ were determined by multivariable Cox regression. Over a period of 5 years after autologous HCT, 194 patients developed at least 1 HZ episode, with a cumulative incidence of 21%; 159 of 194 (82%) were not on prophylaxis at the time of HZ. A second episode of HZ occurred in 31 of 194 (16%) patients. Patients taking ACV/VACV had reduced risk for HZ (adjusted hazard ratio [aHR], .59; 95% confidence interval [CI], .37 to .91), whereas those older than the median age (≥55.5 years) had increased risk (aHR, 1.42; 95% CI, 1.05 to 1.9). Disseminated VZV was reported in 8% and postherpetic neuralgia in 13% of patients. We demonstrate a high burden of HZ late after autologous HCT, despite long-term antiviral prophylaxis. Improved prevention strategies are needed to provide sustained protection against HZ after autologous HCT., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Cervical cancer is the most common cancer among women of reproductive age in Thailand. However, information on the prevalence and correlates of anogenital HPV infection in Thailand is sparse., Methods: HPV genotype information, reproductive factors, sexual behavior, other STI and clinical information, and cervical cytology and histology were assessed at enrollment among one thousand two hundred and fifty-six (n=1,256) HIV negative women aged 20-37 from Thailand enrolled in a prospective study of the natural history of HPV. The type-specific prevalence of HPV was estimated using cervical swab specimens from healthy women and women with a diagnosis of CIN 2/3 at baseline. Prevalence ratios (95% CI) were estimated using Poisson regression to quantify the association of demographic, behavioral, and clinical correlates with prevalent HPV infection., Results: Overall, 307 (24.6%) and 175 (14.0%) of women were positive for any HPV type and any HR-HPV type, respectively; the most common types were 72, 52, 62, and 16. Among women diagnosed with CIN 2/3 at enrollment (n=11), the most prevalent HPV types were 52 and 16. In multivariate analysis, HPV prevalence at enrollment was higher among women with: long-term combined oral contraceptive use, a higher number of lifetime sexual partners, a prior Chlamydia infection, and a current diagnosis of Bacterial Vaginosis., Conclusion: The study findings provide important information that can be used in the evaluation of primary and secondary interventions designed to reduce the burden of cervical cancer in Thailand.

Objective: To assess whether recipients and non-recipients of the human papillomavirus (HPV) vaccine subsequently differ in terms of sexual risk taking behaviour., Design: Cross-sectional survey. Sequential analyses constructed from self-reported age at vaccination, age at first intercourse and age at response., Setting: A random selection of women aged 18-46 years living in Denmark, Norway and Sweden in 2011-2012, eligible for opportunistic or organized catch-up HPV vaccination., Participants: A total of 3805 women reported to have received the HPV vaccine and 40,247 reported not to have received it. Among vaccinees, 1539 received the HPV vaccine before or at the same age as sexual debut, of which 476 and 1063 were eligible for organized catch-up and opportunistic vaccination, respectively., Main Outcome Measures: Self-reported sexual behaviour, compared by hazard ratios and odds ratios for women who received the HPV vaccine before or at the same age as sexual debut versus women who did not receive the HPV vaccine., Results: HPV vaccination did not result in younger age at first intercourse. Women who received the HPV vaccine before or at the same age as sexual debut did not have more sexual partners than did non-vaccinees. Non-use of contraception during first intercourse was more common among non-vaccinees than among HPV vaccinees. The results were similar for organized catch-up and opportunistic vaccinees., Conclusion: Women who received the HPV vaccine before or at the same age as sexual debut did not subsequently engage more in sexual risk taking behaviour than women who did not receive the HPV vaccine., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: First intercourse at the age of 14 years or younger is usually considered high-risk behaviour for sexually transmitted infections (STIs). It has been linked to other types of risky behaviour in women, while conflicting results have been obtained for men. The aim of the study was to estimate the prevalence of first intercourse at a young age in various birth cohorts of men and to determine any association with later risky behaviour., Methods: We studied 22,979 randomly selected men aged 18-45 years from the Danish general male population who responded to a self-administered questionnaire. Multiple sexual partners over a lifetime, multiple new sexual partners within the past 6 months, intercourse with a commercial sex worker, having an STI, binge drinking and current smoking were considered risky behaviour., Results: First intercourse at the age of 14 years or younger was more prevalent in younger (14%) than in older (10%) birth cohorts and among men with shorter schooling. Young age at sexual debut was associated with a more than twofold increase in the risks for subsequent risky behaviour., Conclusions: More than 10% of Danish men first had sex at an early age, and this was closely related to subsequent risk-taking behaviour., (© 2014 the Nordic Societies of Public Health.)

Background: Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a chronic disease caused by human papillomavirus types 6 and 11. It is associated with significant morbidity that places intense physical, psychological, and financial strain on patients and their families. Few studies have assessed the incidence and prevalence of JORRP in the United States., Methods: This retrospective, longitudinal cohort study was performed using data from a pair of large insurance claims databases in the United States. The Optum Clinformatics and Truven MarketScan Medicaid databases represent a sample of privately and publicly insured children, respectively. Cohorts of children aged 0 to 17 years were created within each database to estimate the incidence and prevalence of JORRP in 2006. Claims-based algorithms were designed to capture as many potential cases as possible. To improve the accuracy of the incidence and prevalence estimates, chart validation was performed to estimate the positive predictive value (PPV) of the claims-based algorithms., Results: The overall PPV-adjusted incidence of JORRP in 2006 was 0.51 per 100,000 in Optum and 1.03 per 100,000 in the MarketScan Medicaid population. Peak incidence was observed among 0- to 4-year-olds in both databases. The PPV-adjusted prevalence of JORRP in 2006 was 1.45 and 2.93 per 100,000 in the Optum and MarketScan Medicaid cohorts, respectively., Conclusions: Although relatively uncommon, JORRP represents a disease with significant morbidity. The incidence and prevalence of JORRP in publicly insured children were consistently higher than those covered by private insurance plans, suggesting an increased burden of illness among those with lower socioeconomic status.

Background: Infection with high-risk human papillomavirus (HPV) is causally related to cervical, vulvar and vaginal pre-invasive neoplasias and cancers. Highly effective vaccines against HPV types 16/18 have been available since 2006, and are currently used in many countries in combination with cervical cancer screening to control the burden of cervical cancer. We estimated the overall and age-specific incidence rate (IR) of cervical, vulvar and vaginal cancer and pre-invasive neoplasia in Denmark, Iceland, Norway and Sweden in 2004-2006, prior to the availability of HPV vaccines, in order to establish a baseline for surveillance. We also estimated the population attributable fraction to determine roughly the expected effect of HPV16/18 vaccination on the incidence of these diseases., Methods: Information on incident cervical, vulvar and vaginal cancers and high-grade pre-invasive neoplasias was obtained from high-quality national population-based registries. A literature review was conducted to define the fraction of these lesions attributable to HPV16/18, i.e., those that could be prevented by HPV vaccination., Results: Among the four countries, the age-standardised IR/10⁵ of cervical, vaginal and vulvar cancer ranged from 8.4-13.8, 1.3-3.1 and 0.2-0.6, respectively. The risk for cervical cancer was highest in women aged 30-39, while vulvar and vaginal cancers were most common in women aged 70+. Age-standardised IR/10⁵ of cervical, vulvar and vaginal pre-invasive neoplasia ranged between 138.8-183.2, 2.5-8.8 and 0.5-1.3, respectively. Women aged 20-29 had the highest risk for cervical pre-invasive neoplasia, while vulvar and vaginal pre-invasive neoplasia peaked in women aged 40-49 and 60-69, respectively. Over 50% of the observed 47,820 incident invasive and pre-invasive cancer cases in 2004-2006 can be attributed to HPV16/18., Conclusion: In the four countries, vaccination against HPV 16/18 could prevent approximately 8500 cases of gynecological cancer and pre-cancer annually. Population-based cancer and vaccination registries are essential to assess the predicted public health effects of HPV vaccination.

Purpose: To estimate the burden of human papillomavirus (HPV) infection and cervical disease among sexually active women in a sample of Chinese women., Methods: A multicenter, population-based study was conducted between May 2006 and April 2007. A total of 4215 sexually active women aged 17-54 years were surveyed from five geographical sites representing both urban and rural areas: Beijing, Shanghai, Shanxi, Henan and Xinjiang. Women were referred for colposcopy on the basis of results of Pap testing and HPV screening. HPV genotyping of the CIN1+ specimens was performed with INNO-LiPA. Attribution of HPV types to lesions was estimated using a fractional contribution approach., Results: 13.3% of the women (559/4215) were referred for colposcopy; 4.3% (183/4215) of these were diagnosed with CIN1+. Of the latter, 88.5% (162/183) were typed and 94.4% (153/162) were HPV-positive. HPV16 was the most prevalent type in lesions in both urban and rural settings. Combined, HPV16 and 18 were attributable to 71.4% of HPV-positive CIN2+ lesions. In addition, HPV31, 33, 52 and 58 were prevalent in CIN1+ lesions, with HPV33, 52, and 58 combined accounting for 24.1% CIN2+ lesions. Though prevalent, HPV31 always occurred as a co-infection with another HPV type and therefore was attributed minimal causality., Conclusions: HPV16 and 18 are associated with the majority of cervical lesions in Chinese women from which this population-based sample was drawn. In addition, other HPV types, such as 33, 52, and 58, also play an important role in cervical disease., (Copyright © 2013. Published by Elsevier Ltd.)

The associations between variants of human papillomavirus (HPV) 16 and risk of cervical neoplasia have been reported, but nucleotide variations of HPV 16 in Asian populations and their association with cervical neoplasia have not been evaluated extensively. During 1991-1992, 11,923 women from seven townships in Taiwan were enrolled. The HPV DNA in cervical cells was detected and genotyped using EasyChip HPV blot. Nucleotide variations in the long control region (LCR), E6, and E7 genes were determined using DNA sequencing for 170 HPV 16-positive cervical samples. The Asian variant was the most prevalent variant (81.8%) of HPV 16 in Taiwan, and was also associated with increased prevalence of histologically confirmed cervical intraepithelial neoplasia grade 3 or worse, showing an age-adjusted odds ratio (exact confidence limits) of 10.70 (1.62-451.05; P = 0.0049) compared to the HPV 16 European variant. Similar significant associations with cervical intraepithelial neoplasia grade 3 or worse were also observed for distinct nucleotide substitutions, including T178A/G, A647G, A7730C/G, T7781C, G7842A, and C24T/G. These results demonstrate that non-European variants (non-E) of HPV 16, predominantly Asian variants, are associated with increased risk for severe cervical neoplasia, compared with European variants. Molecular mechanisms accounting for varied cervical neoplasia risk among different HPV 16 variants warrant further investigation., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: To estimate the burden of human papillomavirus (HPV) infection among sexually active women in China., Methods: We conducted a multi-center, population-based study between May 2006 and April 2007. A total of 4,215 women aged 17-54 years were surveyed from five geographical sites: Beijing, Shanghai, Shanxi, Henan, and Xinjiang. Direct endocervical exfoliated cells were collected from consenting participants for Sure Path liquid-based cytology (BD) and HPV testing. HPV testing was performed with Hybrid Capture II (Qiagen) with high-risk and low-risk probes, and Linear Array (Roche) was utilized for HPV genotyping., Results: Approximately 11 % of the study population had a cytological abnormality (ASCUS or worse). HPV prevalence in the entire study population was 14.3 % (age-standardized to the world standard female population 14.5 %). The most prevalent types found were HPV16 (2.9 %), HPV52 (1.7 %), HPV58 (1.5 %), HPV33 (1 %), and HPV18 (0.8 %). Patterns of HPV prevalence differed by age, geographic region, and cytology findings. However, HPV16 was predominant among all grades of cytological abnormalities for all areas., Conclusions: Although HPV18 appeared to be less frequent among population-based samples of China, given the high prevalence of HPV 16 and 18 in high-grade squamous intraepithelial lesion (HSIL) or worse pap abnormalities, prophylactic HPV16/18 vaccines should substantially reduce the burden of cervical cancer in China.

Objectives: To estimate the occurrence of and risk factors associated with genital warts in Danish men, Methods: We conducted a cross-sectional, questionnaire-based study among almost 23 000 men aged 18-45 years, randomly sampled from the general population of Denmark. Data was collected on self-reported clinically diagnosed genital warts, and various lifestyle habits., Results: Ever having had clinically diagnosed genital warts was reported by 7.9% of the men. The median age at first occurrence was 22 years. Genital warts within the previous 12 months were reported by 0.92% of the men, with a peak of 1.83% among men aged 21-24 years. The likelihood of reporting genital warts was strongly correlated with the lifetime number of sex partners (OR 8.0; 95% CI 6.0 to 10.8 for ≥15 partners vs 1-2 partners). Other factors associated with an increased risk for genital warts included ever having smoked and having had other sexually transmitted infections., Conclusions: Almost 8% of Danish men aged 18-45 years reported having had a diagnosis of genital warts. The results provide baseline information for developing and monitoring prevention strategies against genital warts, such as vaccination against human papillomavirus types 6 and 11.