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Association of frequency of marijuana use, duration of marijuana, and joint years of marijuana use with oropharyngeal and oral tongue cancers

Background: The incidence of oropharyngeal and oral tongue cancers has increased over the last 20 years which parallels increased use of marijuana among individuals born after 1950.Methods: A pooled analysis was conducted comprising individual-level data from nine case–control studies from the United States and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls.Results: Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal [adjusted OR (aOR), 1.24; 95% confidence interval (CI): 1.06–1.47] and a reduced risk of oral tongue cancer (aOR, 0.47; 95% CI, 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer was reduced among never users of tobacco and alcohol. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR, 0.99; 95% CI, 0.71–1.25), but had no effect on the oral tongue cancer association.Conclusions: These results suggest that the association of marijuana use with head and neck carcinoma may differ by tumor site.Impact: The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anticarcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure. Cancer Epidemiol Biomarkers Prev; 23(1); 160–71. ©2013 AACR.

Description for sensitivity analysis to adjust for potential unmeasured confounding

Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities; however, data on the economic burden of cCMVi during early childhood are scarce. The primary objective of the study was to describe longitudinal patterns of health care resource utilization (HCRU) and direct medical costs among infants with cCMVi compared to infants unexposed to cCMVi.A retrospective cohort study was performed using data on infants born between 2013 and 2017, as captured in the database of Maccabi Healthcare Services, a 2.5 million-member health care organization in Israel. cCMVi cases were identified by physician diagnosis and/or dispensed valganciclovir within 90 days after birth. Infants born to mothers CMV-seronegative throughout pregnancy were selected for comparison (unexposed controls). Infants were retrospectively followed up through December 31, 2018, or 4 years of age (Y4). HCRU included physician visits, hospital admissions, audiology tests/procedures, imaging, and valganciclovir treatment. Direct medical costs, in US dollars per person per year (USD PPPY) were calculated from the health-system perspective. To compare costs of cCMVi cases and controls, direct medical costs were estimated using a generalized linear model with a log link function and γ distribution after adjustment for patient characteristics.A total of 351 cCMVi cases and 11,733 control infants with continuous follow-up during their first year of life (Y1) were included in the study. In Y1, cases were more likely to have a hospital admission (8.5% cases vs 4.5% control; P0.001) and higher numbers of pediatrician visits (median, 18 vs 15), audiology visits and tests, and cranial ultrasounds (all, P0.05). Longitudinally, incremental costs associated with cases were highest in Y1 (1686.7 USD PPPY; cost ratio = 2.6; P0.001) and remained elevated through Y4.cCMVi was associated with substantial increases in HCRU and economic burden during early childhood, and particularly during the first year of life.

The potential for vaccines to induce autoimmunity has been the subject of considerable investigation and autoimmune induction remains a common focus for vaccine safety research. This study assessed the risk of new onset autoimmune conditions among males receiving the 4-valent human papillomavirus (HPV) vaccine (4vHPV).Within a US health insurance claims database, we formed a cohort of male 4vHPV vaccine recipients between 2009 and 2016, along with a propensity score matched cohort of males who did not receive the 4vHPV vaccine. The study outcome was new onset autoimmune conditions (20 separate conditions) within four categories (rheumatologic/hematologic, gastroenterologic, endocrinologic and neurologic/ophthalmalogic). Outcomes identified using diagnosis codes were adjudicated through medical record review. Incidence rates (per 1,000 person-years) were estimated for the vaccinated and unvaccinated groups along with rate ratios (RRs).There were 65,606 males receiving at least one dose of 4vHPV vaccine, and 55,670 were matched to a comparator. The matched 4vHPV vaccine cohort provided 35 confirmed cases among 39,735 person-years, for an incidence rate of 0.88 (95% CI: 0.61-1.23), while the comparator cohort provided 47 confirmed cases among 58,215 person-years, an incidence rate of 0.81 (0.59-1.07), a RR of 1.09 (0.70-1.69). The RR within categories was 0.49 (0.10-2.42) for rheumatologic/hematologic, 1.26 (0.58-2.71) for gastroenterologic, 1.11 (0.61-2.02) for endocrinologic and 1.46 (0.21-10.40) for neurologic.The incidence of autoimmune conditions among males receiving the 4vHPV vaccine was similar to that among unvaccinated males. These results are consistent with other studies that have assessed autoimmunity with the 4vHPV vaccine.

Cancer incidence is higher in men than in women at most shared anatomic sites for currently unknown reasons. The authors quantified the extent to which behaviors (smoking and alcohol use), anthropometrics (body mass index and height), lifestyles (physical activity, diet, medications), and medical history collectively explain the male predominance of risk at 21 shared cancer sites.Prospective cohort analyses (n = 171,274 male and n = 122,826 female participants; age range, 50-71 years) in the National Institutes of Health-AARP Diet and Health Study (1995-2011). Cancer-specific Cox regression models were used to estimate male-to-female hazard ratios (HRs). The degree to which risk factors explained the observed male-female risk disparity was quantified using the Peters-Belson method.There were 26,693 incident cancers (17,951 in men and 8742 in women). Incidence was significantly lower in men than in women only for thyroid and gallbladder cancers. At most other anatomic sites, the risks were higher in men than in women (adjusted HR range, 1.3-10.8), with the strongest increases for bladder cancer (HR, 3.33; 95% confidence interval [CI], 2.93-3.79), gastric cardia cancer (HR, 3.49; 95% CI, 2.26-5.37), larynx cancer (HR, 3.53; 95% CI, 2.46-5.06), and esophageal adenocarcinoma (HR, 10.80; 95% CI, 7.33-15.90). Risk factors explained a statistically significant (nonzero) proportion of the observed male excess for esophageal adenocarcinoma and cancers of liver, other biliary tract, bladder, skin, colon, rectum, and lung. However, only a modest proportion of the male excess was explained by risk factors (ranging from 50% for lung cancer to 11% for esophageal adenocarcinoma).Men have a higher risk of cancer than women at most shared anatomic sites. Such male predominance is largely unexplained by risk factors, underscoring a role for sex-related biologic factors.

Congenital cytomegalovirus infection (cCMVi) is the leading cause of nonhereditary sensorineural hearing loss among newborns. Women newly acquiring cytomegalovirus infection (CMVi) during pregnancy have the highest risk of vertical transmission. This study aimed to describe the epidemiology of CMVi in pregnancy in a large healthcare database. A retrospective cohort study was performed using the Maccabi Healthcare Services database (Israel). Women aged 18-44 years old on July 1, 2013 with no record of pregnancy in the prior 6 months were followed through December 31, 2017 for first pregnancy occurrence. Pregnancy outcomes (live birth, spontaneous/therapeutic abortions, stillbirth, and uncertain outcomes) were captured. CMV test results were obtained to assess serostatus at the start of pregnancy (SoP) and primary CMV infection (CMVi) during pregnancy. Associations of demographic and reproductive factors with pCMVi were investigated (multivariable logistic regression). The study included 84 699 pregnant women (median age = 31 years; interquartile range = 28-35). Live birth, fetal loss, and uncertain pregnancy outcomes accounted for 76.8%, 18.2%, and 5.0%, respectively. The seroprevalence of CMV at the start of pregnancy in this cohort was 63.4% (95% confidence interval [CI]: 63.1-63.7). Among seronegative women with available test results (n = 10 657), CMVi incidence was 14.5 per 1000 (95% CI = 12.2-16.7). In multivariate logistic regression models adjusting for maternal age, CMVi was significantly associated with having one or more prior live births (odds ratio [OR]: 3.8 [95% CI: 2.6-5.4]) and having a child less than 6 years of age (OR: 4.3 [95%CI: 3.0-6.1]). One in three pregnant women in Israel is at risk for primary CMVi. This study demonstrates that real-world electronic healthcare data can be leveraged to support clinical management and development of interventions for congenital CMV by identifying women at high risk for CMVi during pregnancy.

Objective The quadrivalent human papillomavirus vaccine (4vHPV, GARDASIL®), was approved in the US in 2009 for use in males aged 9 to 26 for the prevention of HPV-related genital warts, and in 2010 for the prevention of certain HPV-related anogenital diseases. A regimen was approved in 2016 for those who initiate the vaccine series between the ages of 9 to 14 years. We describe patterns of 4vHPV administration among US males before this modification. Methods The study used a US health insurance claims database, and included males, age 9 to 26 years, who initiated 4vHPV between 2012 and 2016. Time from first dose to subsequent doses was estimated. Logistic regression identified factors associated with regimen completion. Results Among 100,786 males who initiated 4vHPV (corresponding to ∼ 13% of male birth cohorts), 50,573 (50.2%) and 25,763 (25.6%) received a second and third dose, respectively. Annual administration was common, with 47% of males receiving 3 doses over 3 years (1 dose per year) as compared to 12% receiving the 3-dose series in the recommended 6-month timeframe. Receipt of 4vHPV was 2.2 (range 1.5 to 2.9) times as likely to occur in summer months compared to other times of the year. Individuals aged 18 to 21 years and those living in Western states or rural regions were less likely to complete the 3-dose regimen. Conclusions The real-world patterns of 4vHPV vaccination observed, particularly the low uptake and regimen completion, suggest that better strategies are needed for males to improve 4vHPV vaccine use in males.

BACKGROUND: Viral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking. METHODS: We performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation. RESULTS: VL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir’s effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24. CONCLUSIONS: Our results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Background As the socioeconomic conditions in Jordan have improved over recent decades the disease and economic burden of Hepatitis A has increased. The purpose of this study is to assess the potential health and economic impact of a two-dose hepatitis A vaccine program covering one-year old children in Jordan. Methods We adapted an age-structured population model of hepatitis A transmission dynamics to project the epidemiologic and economic impact of vaccinating one-year old children for 50 years in Jordan. The epidemiologic model was calibrated using local data on hepatitis A in Jordan. These data included seroprevalence and incidence data from the Jordan Ministry of Health as well as hospitalization data from King Abdullah University Hospital in Irbid, Jordan. We assumed 90% of all children would be vaccinated with the two-dose regimen by two years of age. The economic evaluation adopted a societal perspective and measured benefits using the quality-adjusted life-year (QALY). Results The modeled vaccination program reduced the incidence of hepatitis A in Jordan by 99%, 50 years after its introduction. The model projected 4.26 million avoided hepatitis A infections, 1.42 million outpatient visits, 22,475 hospitalizations, 508 fulminant cases, 95 liver transplants, and 76 deaths over a 50 year time horizon. In addition, we found, over a 50 year time horizon, the vaccination program would gain 37,502 QALYs and save over $42.6 million in total costs. The vaccination program became cost-saving within 6 years of its introduction and was highly cost-effective during the first 5 years. Conclusion A vaccination program covering one-year old children is projected to be a cost-saving intervention that will significantly reduce the public health and economic burden of hepatitis A in Jordan. Electronic supplementary material The online version of this article (10.1186/s12879-018-3034-8) contains supplementary material, which is available to authorized users.

A live attenuated zoster vaccine was licensed in the United States in 2006 for prevention of shingles in persons aged 60 years or older; the indication was extended in 2011 to cover those aged 50–59 years. We assessed vaccine effectiveness (VE) against shingles for 8 years after immunization at Kaiser Permanente Northern California. VE was estimated by Cox regression with a calendar timeline that was stratified by birth year. We adjusted for demographics and time-varying covariates, including comorbidities and immune compromise. From 2007 to 2014, 1.4 million people entered the study when they became age eligible for vaccination; 392,677 (29%) received the zoster vaccine. During 5.8 million person-years of follow-up, 48,889 cases of shingles were observed, including 5,766 among vaccinees. VE was 49.1% (95% confidence interval (CI): 47.5, 50.6) across all follow-up. VE was 67.5% (95% CI: 65.4, 69.5) during the first year after vaccination, waned to 47.2% (95% CI: 44.1, 50.1) during the second year after vaccination, and then waned more gradually through year 8, when VE was 31.8% (95% CI: 15.1, 45.2). Unexpectedly, VE in persons vaccinated when they were aged 80 years or older was similar to VE in younger vaccinees, and VE in persons vaccinated when immune compromised was similar to VE in persons vaccinated when immune competent.

Introduction The paradigm for preventing clinically significant cytomegalovirus (CMV) infection and CMV disease after hematopoietic cell transplantation (HCT) has shifted from preemptive treatment to antiviral prophylaxis with the approval of letermovir. Previously, our group validated the use of quantitative CMV DNA viral load as a surrogate endpoint for tissue-invasive CMV disease (ASBMT 2018) in the pre-emptive treatment setting. Objectives To address whether CMV viral load kinetics could serve as valid surrogate endpoints for CMV disease in the prophylactic setting, we performed CMV viral load testing of frozen serum samples collected during a placebo-controlled randomized trial of ganciclovir (GCV) given at engraftment (Goodrich et al. Ann Intern Med 1993). Because this study pre-dated the approval of ganciclovir, CMV disease occurred in an extremely high proportion of patients, allowing us to link viral load kinetics with CMV disease, which would not be possible in the modern treatment environment. Methods We calculated each patient's CMV viral load kinetics (mean, peak, maximum change, percentage of positive viral loads) from samples collected during the first five weeks after randomization and analyzed their value as surrogates for CMV disease by 24 weeks after randomization. First, we tested each marker for fulfillment of the Prentice criteria for valid surrogate endpoints using multivariable logistic regression, including quantifying the degree to which each marker captured the effect of ganciclovir on CMV disease. Secondly, to determine the ability of the viral load markers to predict CMV disease, we developed a ‘SuperLearner' machine learning model and quantified prediction accuracy by cross-validated area under the receiver-operator characteristic curves (cv-AUCs). Results Mean, peak, change, and percentage of positive viral loads were significantly higher in the placebo group than in the ganciclovir group. See viral loads by group in Fig 1. Percentage of positive viral load satisfied Prentice criteria as a valid surrogate endpoint for CMV disease by week 24 after randomization (Fig 2). All kinetics explained greater than 80% of ganciclovir's reduction in CMV disease (mean: 86%, peak: 83%, maximum change: 95%, percent positive: 94%). We found that a SuperLearner model that included all four viral load kinetics, CMV donor serostatus, acute graft-versus-host disease, and baseline viral load predicted CMV disease with 91% cv-AUC in the placebo group, 78% in the ganciclovir group, and 82% in the combined groups (Fig 3). Conclusion We have shown for the first time in a clinical endpoint-rich, placebo-controlled antiviral prophylaxis trial that CMV viral load kinetics fulfill the Prentice criteria as valid surrogate endpoints and have high predictive value for CMV disease after HCT.

Historically in the United States, cancer incidence has been significantly higher in men than women. This disparity is often attributed to gender-related behavioral risk factors, such as smoking and drinking. The degree to which differences in age-adjusted cancer rates are due to sex (e.g., chromosomes, hormones) is unknown. We estimated the effect of sex on cancer risk by comparing cancer incidence at 21 shared sites between men and women while adjusting for known gender-related risk factors. We analyzed data from 122,826 women and 171,274 men enrolled in the NIH AARP Diet and Health Study (1995-2011), contributing 3.5 million person-years of follow-up. Cox proportional hazards models were used to estimate male-to-female (M:F) adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for each of the cancers, controlling for relevant baseline cancer-specific demographic (age, race, marital status, education), lifestyle (self-reported health status, family history of cancer, diet, body mass index, physical activity), and behavioral factors (tobacco, alcohol use). We used the Peters-Belson method to partition the observed differences between the sexes in cancer incidence into the proportion of the difference explained by the modifiable environmental and behavioral exposures (explained disparity) and the remaining proportion that cannot be explained by these exposures (unexplained disparity). After adjustment for cancer-specific risk factors, risks remained significantly higher in men for nearly all sites. The highest M:F aHR was for esophageal adenocarcinoma (aHR: 10.59, 95% CI: 7.19, 15.61) followed by gastric cardia (aHR: 4.55, 95% CI: 3.28, 6.31) and larynx (aHR: 3.73, 95% CI: 2.84, 4.89) cancers. In contrast, men had a lower adjusted incidence of thyroid (aHR: 0.57, 95% CI: 0.48, 0.68) and gallbladder (aHR: 0.55, 95% CI: 0.37, 0.82) cancers compared with women. Using the Peters-Belson method we found that, if men had the same exposure distribution as the women (under a counterfactual), the male predominance would remain for 12 cancers (bladder, skin, lung, colon, kidney, rectum, esophageal adenocarcinoma, larynx, gastric cardia, esophageal squamous cell carcinoma, pancreas, and oropharynx). For 4 cancers (liver, gastric non-cardia, oral cavity, and anus), if men had the exposure distribution of women, they would have experienced a higher cancer incidence than what was observed. This elevated risk in men compared with women, after adjustment for risk factors, indicates potential innate sex differences across nearly all shared cancer sites. Funding: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics Citation Format: Sarah S. Jackson, Morgan A. Marks, Hormuzd Katki, Barry I. Graubard, Michael D. Cook, Anil Chaturvedi. Estimating the influence of sex on cancer risk: An analysis in a large US prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 787.

Background Infants with congenital cytomegalovirus infection (cCMVi) may present with symptoms such as sensorineural hearing loss (SNHL) during the neonatal period and/or develop permanent disability. This study aims to identify infants with cCMVi using information available in an electronic healthcare database in Israel. Methods We performed a retrospective study in Maccabi Healthcare Services (MHS, 2.4-million-member healthcare system) among infants with ≥30 days’ continuous enrolment since birth and linked maternal data of women aged 18-44 years in 2013-2017. Data were obtained on diagnosis codes (‘Dx’; ICD-9-CM) of CMV and SNHL and dispensed valgancivlovir treatment (‘Tx’) within 90 days after birth. To help inform the timing of the CMV infection (congenital vs. postnatal) data on maternal CMV testing history were also obtained among infants whose earliest CMV Dx was at age 22-90 days. Results The study included 171,952 infants linked to 128,264 mothers (167,879 pregnancies). A total of 461 infants (0.3%) had a CMV Dx within 90 days, 81.3% of which (n=375) were diagnosed within 21 days. Among all infants with a CMV Dx within 90 days, 105 also had dispensed Tx (n=101) and/or SNHL Dx (n=16). Among infants diagnosed at age 22-90 days without evidence of prior Tx or SNHL (n=69), 12 had a record of primary maternal CMV infection in pregnancy, 8 had mothers who were CMV seronegative at the start of pregnancy without follow-up test results, and 49 did not have any maternal laboratory data available. A medical record review is being conducted to validate each cCMV case definition in the MHS database. Conclusion In large Israeli healthcare system, 0.3% of infants had a CMV Dx in their electronic health records suggestive of potential cCMVi. Case review is ongoing to validate these codes and help inform analyses on the clinical and economic burden of cCMVi in this population where awareness of CMV is high but newborn screening is not universal. Disclosures Morgan Marks, PhD, ScM, Merck and Co. Inc. (Employee, Shareholder) Wei Wang, PhD, Merck (Employee) Anushua Sinha, MD, MPH, Merck & Co. (Employee)Merck & Co. (Shareholder)Merck & Co. (Consultant)

Background Postherpetic neuralgia (PHN) occurs in 5–30% of individuals with herpes zoster (HZ) and is characterized by long-lasting pain. Zoster vaccine live (ZVL) is licensed for people 50 years and older to prevent HZ and PHN. This study evaluated vaccine effectiveness (VE) of ZVL against PHN. Methods We conducted an open cohort study within Kaiser Permanente Northern California with continuous accrual of people as they became age-eligible for ZVL. We defined PHN using a PHN diagnosis between 90 and 365 days after an incident episode of HZ. We estimated VE against PHN using Cox regression with a calendar timeline stratified by year of birth and adjusted for sex, race, influenza vaccination, outpatient visit frequency, comorbidities, and immune compromise status. Results From 2007 to 2016, 1·5 million people entered the study population and 33% received ZVL. During 7·6 million person-years of follow-up, there were 62,205 HZ cases, 4150 (6·7%) of which went on to develop PHN. Overall VE for PHN was 64·8% (95% CI 61·3, 68). VE was 82·8% (95% CI 77·6, 86·7) during the first year after vaccination, 58·3% (95% CI 50.1, 65.2) during the third year, and then waned more gradually to 48·7% (95% CI 30·2, 62·3) during the eighth year. VE in persons vaccinated when aged 80 years or older was similar to VE in younger vaccinees. VE in persons vaccinated when immune compromised was similar to VE in immune competent. Conclusions Overall, ZVL was 65% effective against PHN. It was effective in all age groups and provided moderate protection through 8 years.

Background Congenitally transmitted cytomegalovirus (CMV) is the leading infectious cause of deafness and intellectual impairment among infants. Due to lack of effective preventive and curative treatments, routine CMV screening of pregnant women is generally not recommended by clinical guidelines or public health authorities, but is conducted on an opportunistic basis by specific healthcare systems and providers. This targeted review describes the rate of reported maternal screening for CMV infection and subsequent pregnancy outcomes. Methods PubMed and Embase were searched to identify English-language articles reporting the rate of screening for CMV maternal infection (Objective 1), the acceptance rate for diagnostic amniocentesis (Objective 2), and the elective termination rates due to CMV infection (Objective 3) in Europe and Israel. No date limit was applied. Results Seventeen articles published between 2000 and 2018 were included. Routine CMV screening of pregnant women in the absence of country-level guidelines appears to be common in France and Israel (table). Conversely, in Portugal, where country-level guidelines exist for preconception screening, a high proportion of women are not screened (table). Acceptance rates of diagnostic amniocentesis among women with CMV infection vary considerably across countries, with the highest rates reported in Israel (73%) and the lowest in Italy (16%). Elective termination rates were higher among women who underwent amniocentesis vs. those who did not and those with primary CMV infection vs. those with nonprimary infection. Conversely, one study in Israel showed higher termination rates among patients who did not undergo amniocentesis vs. those who did (35.5% vs. 7.3%). Conclusion The available data indicate that routine screening is carried out in some countries to a variable degree. There is an unmet need for effective prevention and management options to help prevent unnecessary termination of pregnancy. Disclosures All authors: No reported disclosures.

Cervical cancer is caused by infection with high risk human papillomavirus (HR-HPV). Inducible nitric oxide synthase (iNOS), a soluble factor involved in chronic inflammation, may modulate cervical cancer risk among HPV infected women. The aim of the study was to measure and correlate plasma nitrite/nitrate levels with tissue specific expression of iNOS mRNA among women with different grades of cervical lesions and cervical cancer. Tissue biopsy and plasma specimens were collected from 120 women with cervical neoplasia or cancer (ASCUS, LSIL, HSIL and invasive cancer) and 35 women without cervical abnormalities. Inducible nitric oxide synthase (iNOS) mRNA from biopsy and plasma nitrite/nitrate levels of the same study subjects were measured. Single nucleotide polymorphism (SNP) analysis was performed on the promoter region and Ser608Leu (rs2297518) in exon 16 of the iNOS gene. Differences in iNOS gene expression and plasma nitrite/nitrate levels were compared across disease stage using linear and logistic regression analysis. Compared to normal controls, women diagnosed with HSIL or invasive cancer had a significantly higher concentration of plasma nitrite/nitrate and a higher median fold-change in iNOS mRNA gene expression. Genotyping of the promoter region showed three different variations: A pentanucleotide repeat (CCTTT) n, -1026T > G (rs2779249) and a novel variant -1153T > A. These variants were associated with increased levels of plasma nitrite/nitrate across all disease stages. The higher expression of iNOS mRNA and plasma nitrite/nitrate among women with pre-cancerous lesions suggests a role for nitric oxide in the natural history of cervical cancer.

Objective To determine whether the concentration and distribution of immune markers in paired oral samples were similar. Study type Clinical research. Study design Cross-sectional study. Methods Paired saliva and oral secretions (OS) samples were collected. The concentration of immune markers was estimated using Luminex multiplex assay (Thermo Fisher Scientific, Waltham, MA). For each sample, the concentration of respective immune markers was normalized to total protein present and log-transformed. Median concentrations of immune markers were compared between both types of samples. Intermarker correlation in each sampling method and across sampling methods was evaluated. Results There were 90 study participants. Concentrations of immune markers in saliva samples were significantly different from concentrations in OS samples. Oral secretions samples showed higher concentrations of immunoregulatory markers, whereas the saliva samples contained proinflammatory markers in higher concentration. Conclusion The immune marker profile in saliva samples is distinct from the immune marker profile in paired OS samples. Level of evidence 2b. Laryngoscope, 128:E214-E221, 2018.

A single dose, live attenuated zoster vaccine, is licensed in >50 countries for the prevention of herpes zoster and PHN. Duration of protection is being evaluated in a long-term observational study. We previously reported that vaccine effectiveness (VE) to prevent zoster tended to decline over time and was on average 45–50% over 5 years in people ≥60 (60+) years. We present here the results of VE against PHN. The study is conducted in a large US healthcare plan as an open cohort that members enter unvaccinated when they become age-eligible for vaccination. PHN cases among vaccinated and unvaccinated zoster cases were identified as having a PHN-specific diagnosis code ≥90 days after first zoster diagnosis code. VE against PHN was estimated using Cox regression adjusting for sex, birth year, race/ethnicity, healthcare use, comorbidities and immunocompromise status. From 2007 to 2013, >300,000 subjects were vaccinated (coverage >40% in 60+) and ~42,000 zoster episodes occurred. VE against PHN was 83% (95% CI 73–90%) in the first year, decreased in the second year, and then remained relatively stable through year 5, with an overall VE of ~70% in all 60+ age groups (60–69, 70–79, and 80+ years at vaccination); among people vaccinated at 80+, VE was 71% (54–82%). Overall VE against PHN was ~70% in all 60+ age groups. VE against PHN and zoster in people vaccinated at 80+ was similar to younger 60+ groups, supporting vaccination of all eligible people, including the elderly who are at increased risk of zoster and PHN.

Dengue virus (DENV) infection causes an acute febrile illness generally considered to result in either complete recovery or death. Some reviews describe persistent symptoms after the febrile phase, although empirical data supporting this phenomenon is scarce. We evaluated symptom persistence in acute febrile DENV-infected and DENV-negative (controls) individuals from Peru. Self-reported solicited symptoms were evaluated at an acute and a follow-up visit, occurring 10–60 days after symptom onset. Rate of persistence of at least one symptom was 7.7% and 10.5% for DENV infected and control subjects, respectively (P < 0.01). The DENV-infected individuals had lower rates of persistent respiratory symptoms, gastrointestinal symptoms, headache, and fatigue, but higher rates of persistent rash compared with controls. Older age and female gender were positively associated with symptom persistence. As dengue cases continue to increase annually, even a relatively low frequency of persistent symptoms may represent a considerable worldwide morbidity burden.

Background Zostavax™, a live zoster vaccine licensed as 1 dose, is indicated in the United States for the prevention of herpes zoster (HZ) in people 50 years or older. Real-world vaccine effectiveness (VE) and duration of protection are being evaluated in an ongoing study. Compared with randomized clinical trials, this large observational study includes a more diverse population and offers a unique opportunity to assess VE across sex and race/ethnic groups. Methods Kaiser Permanente Northern California members enter the ongoing cohort study when age-eligible for zoster vaccine, starting in 2007. Incident HZ is defined as a new HZ diagnosis accompanied by an antiviral prescription or a positive varicella-zoster virus test, with no HZ diagnosis in the preceding 12 months. VE by sex and race/ethnicity was estimated using Cox regression models controlling for age and adjusting for healthcare use, comorbidities and immunocompromise status. Results During 2007–2014, 1,355,720 individuals entered the study, including 724,283 (53.4%) females. Among the unvaccinated, the incidence rate of HZ was 7.5 and 10.2 cases per 1,000 person-years (PY) among males and females, respectively. VE was 51.6% [95% CI: 49.2, 53.9] in males and 47.7% [45.8, 49.6] in females. The study included 818,361 (60.4%) Whites, 208,248 (15.4%) Asian/Pacific Islanders, 171,949 (12.7%) Hispanics, 98,914 (7.3%) African Americans, and 58,248 (4.3%) with Other/Unknown race/ethnic group. HZ incidence among the unvaccinated was highest among Hispanics (10.1 per 1,000 PY) and lowest among African Americans (6.7 per 1,000 PY). VE was somewhat higher among Hispanics (57.0% [52.7, 61.0]) compared with Whites (48.1% [46.3, 49.9], Asian/Pacific Islanders (49.7% [46.0, 53.3]), and African Americans (50.5% [42.3, 57.6]). Conclusion Overall, VE against HZ was generally similar across sex and race/ethnic groups, except for a somewhat higher VE among Hispanics. This small difference in VE may be due to differences in time since vaccination, since VE tends to wane over time (e.g., average follow-up was 2.2 years for vaccinated Hispanics vs. 2.8 for Whites, resulting in Hispanics having relatively more follow-up closer to vaccination when VE is higher). Longer study follow-up may help to interpret these findings. Disclosures M. A. Marks, Merck and Co. Inc.: Employee and Shareholder, Salary. P. Saddier, Merck and Co. Inc.: Employee and Shareholder, Salary. N. P. Klein, Sanofi Pasteur: Investigator, Research grant. Merck: Investigator, Research grant. GSK: Investigator, Research grant. Pfizer: Investigator, Research support. Protein Science: Investigator, Research grant. MedImmune: Investigator, Research grant. Dynavax: Research Contractor, Grant recipient.

Background Congenital cytomegalovirus infection (cCMVi) is the leading viral cause of birth defects and developmental disabilities in newborns. The epidemiology of cCMVi in settings with high cytomegalovirus (CMV) seroprevalence, such as China, is not well studied. This study sought to describe maternal CMV seroprevalence and cCMVi prevalence at birth in Henan Province, China. Methods A multicenter prospective cohort study was conducted in three counties of Henan Province in China from June 2015 through May 2018. Pregnant women were enrolled early in pregnancy and followed up through delivery. Serum specimens were collected at enrollment for CMV immunoglobulin G serological testing. Saliva and urine specimens were collected in newborns within 72 hours after birth and tested with real-time polymerase chain reaction for CMV DNA. cCMVi was defined as CMV DNA positive in the infants’ urine or saliva specimens. Results A total of 6327 pregnant women underwent CMV serological testing and 6062 were CMV seropositive (95.8%). The maternal age was 26.8 ± 4.3 (mean ± SD) years. There were 49 (0.7%) newborns identified with cCMVi among 6705 newborns screened. Lower maternal education level (middle school or lower), younger maternal age ( Conclusion Despite a high maternal CMV seroprevalence in this large cohort study from China, the birth prevalence of cCMVi is similar to other studies in settings of high and medium CMV seroprevalence. In settings of high maternal CMV seroprevalence, additional research is needed to ascertain the relative contribution of non-primary CMV infections during pregnancy to congenital transmission. Disclosures All authors: No reported disclosures.

The United States Food and Drug Administration recently issued guidance that CMV DNAemia (quantitative CMV viral load as measured by PCR) could be used in a composite endpoint along with tissue-invasive CMV disease as the primary endpoint in allogeneic HCT CMV prophylaxis trials. However, the specific time points after antiviral treatment initiation at which to measure viral load and the viral load thresholds that most accurately predict clinical CMV disease have not been identified. In order to estimate the treatment effect of an antiviral agent on CMV clinical outcomes, placebo-controlled, randomized trial data with accompanying viral load measurements are needed. Unfortunately, in the modern era of PCR and early preemptive treatment, ethically, placebo-controlled, randomized trials that allow for the development of CMV disease after HCT can no longer be performed. To overcome this limitation, we performed CMV DNA PCR testing on frozen plasma samples collected during the first 100 days post-HCT in the only placebo-controlled, double-blind RCT of ganciclovir for the early treatment of CMV infection after HCT (Goodrich et al. NEJM 1991). We used three analytic methods (Cox proportional hazards models, machine learning, and a novel non-parametric method) to determine which of 14 viral load markers, measured in the first four weeks of treatment, are the most useful surrogates of antiviral treatment for the prevention of CMV disease. All methods identified peak viral load and percentage of positive samples by week 4 as highly associated with or predictive of tissue-invasive CMV disease by week 8 post-randomization. Cox proportional hazards models (Figure 1) yielded significant associations for peak viral load measured by week 4 (HR 1.4, 95% CI 1.1-1.9) and percentage of positive samples by week 4 (HR 1.6, CI 1.1-2.3). The machine-learning ensemble algorithm SuperLearner implemented in R (Figure 2) demonstrated cross-validated area under the receiver-operator curves of at least 75% for peak viral load (75%, CI 62-87%) and percentage of positive plasma samples (77%, CI 63-90%) measured by week 4. Using a novel statistical technique that allows direct estimation of biomarker surrogacy (Parast et al. Stat Med 2017), we estimated that the percentage of ganciclovir treatment effect explained by peak viral load and percentage of positive samples measured by week 4 was greater than 85%—peak viral load 89%, CI 56-100%; percent positive samples 91%, CI 60-100% (Figure 3). Peak viral load and percentage of positive samples by week 4 are highly predictive of CMV disease and the treatment effect of ganciclovir. Our analysis suggests that these may be the best surrogate markers of ganciclovir treatment and introduces novel methods for identifying optimal candidate biomarkers as surrogates for clinical endpoints.

Background: The incidence of oropharyngeal and oral tongue cancers has increased over the last 20 years which parallels increased use of marijuana among individuals born after 1950. Methods: A pooled analysis was conducted comprising individual-level data from nine case–control studies from the United States and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls. Results: Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal [adjusted OR (aOR), 1.24; 95% confidence interval (CI): 1.06–1.47] and a reduced risk of oral tongue cancer (aOR, 0.47; 95% CI, 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer was reduced among never users of tobacco and alcohol. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR, 0.99; 95% CI, 0.71–1.25), but had no effect on the oral tongue cancer association. Conclusions: These results suggest that the association of marijuana use with head and neck carcinoma may differ by tumor site. Impact: The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anticarcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure. Cancer Epidemiol Biomarkers Prev; 23(1); 160–71. ©2013 AACR.

Despite similar frequencies of exposure, the low prevalence of certain sexually transmitted infections such as Chlamydia, HPV and HIV-1 in the oral cavity relative to the cervix is poorly understood. This could be explained in part by differences in host immune microenvironments between these two anatomic sites.We compared the concentration and correlation of 27 different immune markers in paired secretion specimens collected from the oral and cervical mucosa of healthy women.Paired oral and cervical secretion specimens were collected from thirty-nine women. The concentration of twenty-seven different immune markers was estimated using a Luminex multiplex assay. Marker concentration was normalized to total protein present in the specimen. Median immune marker concentrations were compared across anatomic sites. Unsupervised hierarchical clustering analysis was utilized to identify groups of markers that shared similar patterns of relative concentrations across anatomic sites.The oral cavity had significantly higher concentrations of eotaxin, IFN-γ, IL-2, IL-4, IL-5, IL-7, IL-9, IL-13, IL-15, PDGF-BB, TNF-α, (p0.01 for each) while the cervix had higher concentrations of pro-inflammatory markers such as FGF-basic, IL-1ra, IL-1β, IL-6, IL-8, IP-10, G-CSF, GM-CSF, MCP-1, MIP-1β, VEGF (p0.01 for each). Hierarchical cluster analysis identified two groups of immune markers comprised of T-cell related immune markers with significantly higher concentrations in the oral cavity relative to the cervix, and a third cluster consisting of mostly inflammatory immune markers which were higher concentrations in the cervix. The oral cavity had a larger number of significant inter-marker correlations as compared to the cervix.The oral cavity and cervix have significantly different immune marker profiles, which may in part explain the significantly lower burden of sexually transmitted infections such as Chlamydia, HPV, and HIV-1 in the oral cavity vs. the cervix.

Background Few studies have evaluated the trends in head and neck cancer in developing countries. The purpose of this study was to estimate trends in incidence of human papillomavirus–related (HPV-R) and HPV-unrelated (HPV-U) head and neck cancer in Lima, Peru, from 1987 to 2008. Methods Registry data from a single public cancer hospital were used to estimate age and sex-specific incidence rates. Annualized percent change was estimated using Poisson regression. Results The rate of total head and neck cancers, HPV-U, and HPV-R was 11.9, 10.9, and 0.8, respectively, per 100,000 person-years. Significant increases in HPV-U head and neck cancer were observed in men aged 30 to 44 (2.5%/year) and women 15 to 29 (4.2%/year), 30 to 44 (3.4%/year), and 60 to 74 (2.0%/year). Significant increases in HPV-R head and neck cancer were observed only among men aged 45 to 59 (9.6%/year). Conclusion Although increased exposure to tobacco, occupational carcinogens, and changing sexual behaviors could be influencing these trends, additional analyses to assess generalizability of these findings to other regions of Peru are needed. © 2013 Wiley Periodicals, Inc. Head Neck 36: 729–734, 2014

BACKGROUND Depletion of gut-associated lymphocytes by HIV infection facilitates microbial translocation, which may contribute to non-Hodgkin lymphoma (NHL) risk via chronic immune activation and B-cell hyperstimulation. METHOD We therefore examined associations of four microbial translocation markers with subsequent NHL risk in a case-control study nested within four prospective cohort studies of HIV-infected individuals. Prediagnostic blood specimens for 56 NHL cases and 190 controls matched for age, sex, race, specimen type, cohort, and CD4 T-cell count were tested for the endotoxin lipopolysaccharide (LPS), antiendotoxin core antibody (EndoCab), LPS-binding protein (LBP), and soluble CD14 (sCD14). RESULTS Elevated levels of sCD14 were associated with significantly increased NHL risk [odds ratio (OR) 2.72 (95% confidence interval [95% CI] 1.29-5.76)]. In subgroup analyses, elevated LPS levels were also associated with significantly increased NHL risk [OR 3.24 (95% CI 1.10-9.53)]. EndoCab and LBP levels were not associated with NHL risk. CONCLUSION The association of sCD14 and LPS with NHL risk supports an etiologic role for gut microbial translocation in lymphomagenesis among HIV-infected individuals. Additional studies with larger sample sizes are needed to confirm these observations.

Ophthalmic sponges are used to collect undiluted cervical secretions for assessment of markers of genital tract immunity. Heterogeneity in absorbed and extracted sample volumes requires normalization in order to make valid inter-individual comparisons. We evaluated the performance of adjustment by weight and total protein on normalizing inter-individual variability of immune marker measurement due to differences in volume collection. Normalization to total protein resulted in a minimal loss of usable specimens and a significant reduction in the correlation of immune marker concentration to specimen weight compared to weight adjustment. Total protein normalization appeared to be more effective than weight adjustment in reducing the dependence of cervical immune marker concentrations on differences in specimen volume.

High-risk human papillomavirus (HR-HPV) testing is increasingly important. We therefore examined the impact on accuracy of repeated versus one-time testing, type-specific versus pooled detection, and assay analytic sensitivity. By using a nested case-control design from the ASCUS-LSIL Triage Study, we selected women with incident cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2/3; n = 325) and a random sample of women with n = 401). HPV DNA status was assessed using hybrid capture 2 (HC2), a pooled test for 13 HR-HPV types, and the linear array (LA) and the line blot assay (LBA), two PCR-based HPV genotyping assays, at enrollment and the 6-month follow-up visit. The relative sensitivity and specificity for different permutations of multiple measurements were compared to a single measurement using marginal regression models. We found that repeat detection of any HR-HPV (by HC2, LA, or LBA) and of type-specific persistence (by LA or LBA) were significantly more specific but less sensitive than use of a single time point measurement of any HR-HPV. Sensitivity decreased and specificity increased further when testing intervals were increased from 12 to 24 months. Including detection of borderline carcinogenic/noncarcinogenic HPV types with HR-HPV types decreased specificity for repeat measures of HPV with no impact on sensitivity. Similar patterns were observed when we used a CIN3 end point. We conclude that assay performance for detecting incident CIN2/3 was affected by which types were included, the analytic sensitivity of the assay, and the testing interval. These trade-offs need to be considered when assessing the potential overall clinical utility of repeated testing for HR-HPV DNA to identify women at risk for CIN2/3.

Background Several studies of the real-world effectiveness of Zostavax™, a live zoster vaccine (ZVL), have been published since its licensure in 2006. The objective of this review was to summarize available evidence on vaccine effectiveness (VE) of ZVL against herpes zoster (HZ) and post-herpetic neuralgia (PHN) in the general population. Methods An extensive literature search was performed in Embase and Medline for the period January 2007 to January 2018 to identify peer-reviewed, original, English study manuscripts reporting the results of observational studies of ZVL VE. In all studies, HZ cases were identified from HZ diagnosis codes, with only two studies also requiring HZ-specific antiviral use. For PHN, different case definitions were used across studies, usually without validation from medical chart review. Results Seven original effectiveness studies were identified (5 from the United States and 1 each from the UK and Canada) that assessed HZ effectiveness in the general population. Five of these studies also assessed PHN effectiveness. Vaccine effectiveness to prevent HZ was similar across studies in the early years following vaccination, but tended to diverge in the later years (overall VE against HZ ranged from 33% to 62%, clustering around ~50% across studies providing this information). Overall VE against PHN ranged from 55% to 88%, clustering around ~65%. Conclusion Real-world observational studies assessing the effectiveness of ZVL in preventing HZ and PHN in the general population reported generally similar results. Differences in VE estimates across studies were likely driven by differences in study design and methods, including sample size and age of study population, HZ and PHN case definition, duration of follow-up, and methods of covariate selection, definition and adjustment. We are currently conducting a meta-analysis to identify and quantify the potential heterogeneity across studies and calculate summary VE estimates. Disclosures P. Saddier, Merck and Co. Inc.: Employee and Shareholder, Salary. M. A. Marks, Merck and Co. Inc.: Employee and Shareholder, Salary. S. Calhoun, Merck and Co. Inc.: Employee, Salary. K. Johnson, Merck & Co., Inc.: Employee, Salary. Y. Moride, Merck: Research Contractor, Consulting fee.

Women diagnosed with cervical cancer report longer duration and more recent use of combined oral contraceptives (COCs). It is unclear whether COC use is associated with upstream events of human papillomavirus (HPV) infection prior to development of clinical disease. The objective of our study was to assess the association of contraceptive use on the risk for prevalent HPV infection in a cohort of long-term hormonal contraceptive (HC) users. One thousand and seventy (n = 1,070) HIV-negative women aged 20-37 from Thailand enrolled in a prospective study of the natural history of HPV. Baseline HPV genotype information, recency and duration of HC use, sexual behavior, other sexually transmitted infection (STI) information and cervical cytology and histology were assessed. At enrollment, 19.8% and 11.5% of women were infected with any HPV or any high-risk (HR)-HPV, respectively. After adjustment for age, current and past sexual risk behaviors, STI history and cytology, the use of COCs for >6 years was found to be associated with an increased risk of infection with any HPV [prevalence ratio (PR): 1.88 (1.21, 2.90)] and any HR-HPV [PR: 2.68 (1.47, 4.88)] as compared to never users. Recent, long-term COC use was associated with an increased risk for prevalent HPV infection independent of sexual behavior and cervical abnormalities. No similar association was observed for recent or long duration use of progestin-only contraceptives (i.e., depomedroxyprogesterone acetate). These data suggest that COC use may impact early upstream events in the natural history of HPV infection.

Summary Background Although cytomegalovirus viral load is commonly used to guide pre-emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We therefore investigated the association between cytomegalovirus viral load and mortality in the first year after haemopoietic stem cell transplantation. Methods In this retrospective cohort study, we included patients from the Fred Hutchinson Cancer Research Center, WA, USA, who received an allogeneic haemopoietic stem cell transplantation between Jan 1, 2007, and Feb 28, 2013, were cytomegalovirus seropositive or had a seropositive donor, and underwent weekly plasma cytomegalovirus monitoring by PCR through to day 100 post-transplantation. Cox proportional hazards models were used to estimate the association of cytomegalovirus viral load at different thresholds with overall mortality by 1 year post-transplantation, adjusting for the use of pre-emptive therapy and other factors such as neutropenia, and graft-versus-host disease. Findings Of the 1037 patients initially selected for inclusion in this cohort, 87 (8%) patients were excluded because of missing cytomegalovirus testing and 24 (2%) were excluded because of their participation in cytomegalovirus prophylaxis trials. In the remaining 926 patients included in this study, the cumulative overall mortality was 30·0% (95% CI 26·9–33·0) 1 year after haemopoietic stem cell transplantation. 95 patients developed cytomegalovirus disease; death was directly attributable to cytomegalovirus disease in three (1%) of 263 patients who died in the first year after transplantation. A cytomegalovirus viral load of 250 IU/mL or greater was associated with increased risk of early (day 0–60 post-transplantation) death (adjusted hazard ratio [HR] 19·8, 95% CI 9·6–41·1). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·3–2·3). Similar associations were noted for higher cytomegalovirus viral load thresholds. Interpretation Cytomegalovirus viraemia is associated with an increased risk of overall mortality in the first year after haemopoietic stem cell transplantation, independent of the use of pre-emptive therapy, and with evidence of a positive dose-response relationship. These data indicate the suitability of viral load as a surrogate clinical endpoint for clinical trials for cytomegalovirus vaccines, biologics, and drugs. Funding Merck and Co, National Institutes of Health.

Background: Chagas cardiomyopathy is a chronic sequela of infection by the parasite, Trypanosoma cruzi. Advanced cardiomyopathy is associated with a high mortality rate, and clinical characteristics have been used to predict mortality risk. Though multiple biomarkers have been associated with Chagas cardiomyopathy, it is unknown how these are related to survival.Objectives: This study aimed to identify biomarkers associated with mortality in individuals with severe Chagas cardiomyopathy in an urban Bolivian hospital.Methods: The population included individuals with and without T. cruzi infection recruited in an urban hospital in Santa Cruz, Bolivia. Baseline characteristics, electrocardiogram findings, medications, and serum cardiac biomarker levels (B-type natriuretic peptide [BNP], N-terminal proeB-type natriuretic peptide [NT-pro—BNP], creatine kinase-myocardial band [CK-MB], troponin I, matrix metalloproteinase [MMP]-2, MMP-9, tissue inhibitor of metalloproteinases [TIMP] 1 and 2, transforming growth factor [TGF] beta 1 and 2) were ascertained. Echocardiograms were performed on those with cardiac symptoms or electrocardiogram abnormalities at baseline. Participants were contacted approximately 1 year after initial evaluation; deaths were reported by family members. Receiver-operating characteristic curves (ROC) were used to optimize cutoff values for each marker. For markers with area under the curve (AUC) >0.55, Cox proportional hazards models were performed to determine the hazards ratio (HR) and 95% confidence interval (CI) for the association of each marker with mortality.Results: The median follow-up time was 14.1 months (interquartile range 12.5, 16.7). Of 254 individuals with complete cardiac data, 220 (87%) had follow-up data. Of 50 patients with severe Chagas cardiomyopathy at baseline, 20 (40%) had died. Higher baseline levels of BNP (HR: 3.1, 95% CI: 1.2 to 8.4), NT-proBNP (HR: 4.4, 95% CI: 1.8 to 11.0), CK-MB (HR: 3.3, 95% CI: 1.3 to 8.0), and MMP-2 (HR: 4.2, 95% CI: 1.5 to 11.8) were significantly associated with subsequent mortality.Conclusions: Severe Chagas cardiomyopathy is associated with high short-term mortality. BNP, NT-proBNP, CK-MB, and MMP-2 have added predictive value for mortality, even in the presence of decreased ejection fraction and other clinical signs of congestive heart failure.HighlightsOur study followed patients with severe Chagas cardiomyopathy who had a 40% mortality at 1- to 2-years follow-up.For those with severe Chagas cardiomyopathy, the characteristics between those who died and those who survived to follow-up were similar, except body mass index, which was significantly higher among the survivors.BNP, NT-proBNP, CK-MB, and MMP-2 were significantly higher among those that died than in those who survived.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12879-015-0886-z) contains supplementary material, which is available to authorized users.

The objective of this study was to assess the utility of a second generation human papillomavirus (HPV) virus-like particle (VLP)-based ELISA as an adjunct to HPV DNA testing to identify women at risk for high-grade cervical intraepithelial neoplasia (CIN). Participants provided blood, cervical samples and interviewer-obtained questionnaire information. HPV VLPs for types 16, 18, 33, 45 and 52 were produced using a baculovirus expression system. These highly purified VLPs were used in a polymer-based ELISA test. Cases with biopsy-confirmed CIN (CIN I, n = 237; CIN II, n = 56; CIN III, n = 48) and controls (n = 351) with normal Pap smears were tested for HPV DNA by PCR and serologic response to multiple oncogenic HPV VLPs. 258/341 (76%) of cases and 230/351 (65.5%) of control patients had any type of HPV VLP antibody (OR = 1.63, 95% CI 1.16-2.30). More cases were seropositive than controls for each individual HPV type (p < 0.001 for HPV types 16, 18, 33 and 45; p = 0.06 for HPV 52). Reactivity to an increasing number of different HPV type-specific VLPs are associated with high-grade CIN independent of HPV DNA status. HPV VLP assays may be useful as an adjunct to HPV DNA testing in a subset of patients that needs to be defined by further studies.

Background An ecological correlation between invasive cervical cancer incidence and burden of soil-transmitted helminths (STH) is hypothesized to explain the excess in detectable human papillomavirus (HPV) infection in Latin America, via a global T-helper type 2 (Th2)-biased mucosal immune response secondary to STH infection. Methods The association between current STH infection and HPV prevalence was compared in regions of Peru where STH is or is not endemic. Adjusted prevalence ratios (PRs) with robust variance were estimated as an effect measure of STH infection on HPV prevalence in each study site. Soluble immune marker profiles in STH-infected and STH-uninfected women were compared using Spearman rank correlation with the Sidak correction. Results Among women in the helminth-endemic region of the Peruvian Amazon, those with STH infection women had a 60% higher prevalence of HPV, compared with those without STH infection (PR, 1.6; 95% confidence interval, 1.0-2.7). Non-STH parasitic/protozoal infections in the non-STH-endemic population of Peru were not associated with HPV prevalence. In Iquitos, A Th2 immune profile was observed in cervical fluid from helminth-infected women but not helminth-uninfected women. Conclusions A proportion of the increased HPV prevalence at older ages observed in Latin America may be due to a population-level difference in the efficiency of immunological control of HPV across the lifespan due to endemic STH infection.

Background Herpes zoster ophthalmicus (HZO), caused by reactivation of varicella-zoster virus in or around the eye, can be severe and often results in care-seeking that may be less discretionary than for uncomplicated herpes zoster (HZ). We compared the vaccine effectiveness (VE) of live zoster vaccine against HZO with the VE against HZ overall. Methods Kaiser Permanente Northern California (KPNC) members enter the ongoing cohort study when age-eligible for zoster vaccine starting in 2007. Incident HZ was defined as a new diagnosis of HZ with an antiviral prescription or a positive varicella viral test. Among those, an HZO case was defined as having an HZO diagnosis during an ophthalmology visit within 30 days of the initial HZ diagnosis. VE by age at vaccination and time since vaccination was estimated using Cox regression adjusted for age, race, sex and time-varying measures of healthcare use, comorbidities and immunocompromise status. Average VE over the first 5 years following vaccination was calculated as a weighted average of annual VE estimates. Results During 2007–2014, ~1.3 million individuals ≥50 years of age entered the study population and 29% were vaccinated. Among 48,889 incident HZ cases, 2,858 (6%) had HZO, 87% of whom were unvaccinated. For all ages combined, VE against HZO was 72% (95% CI, 64%-79%) in year 1, similar to 68% (95% CI, 65%-70%) against HZ. VE fell in years 2, 3, 4, and 5 to 47%, 45%, 42% and 27% for HZO and to 47%, 39%, 41% and 37% for HZ. For age groups 60 – 69 and 70 – 79, where we have the most data, initial VE and waning were similar for HZO and HZ. Numbers of HZO cases for 50–59 year olds were too small to evaluate at this time. Average VE against HZO over the first 5 years following vaccination was 52% (95% CI, 42%–60%) for ages 60–69, 51% (95% CI, 39%–61%) for ages 70-79, and 39% (95% CI, 14%-57%) for ages 80+; similarly, 5-year average VE against HZ was 49%, 46%, and 44% for these 3 age groups. Conclusion VE against HZO was similar to VE against HZ regardless of age at vaccination or time since vaccination. Effectiveness of live zoster vaccine in preventing HZO was highest in year one with subsequent waning. Disclosures E. Earley, Merck & Co.: Research Contractor, Salary; M. Marks, Merck and Co. Inc.: Employee, Restricted Stock and Salary; P. Saddier, Merck & Co., Inc.: Employee, Salary; N. P. Klein, GSK: Investigator, Grant recipient; sanofi pasteur: Investigator, Grant recipient; Merck & Co.: Investigator, Grant recipient; MedImmune: Investigator, Grant recipient; Protein Science: Investigator, Grant recipient Pfizer: Investigator, Grant recipient

Approximately 8 million people have Trypanosoma cruzi infection, and nearly 30% will manifest Chagas cardiomyopathy (CC). Identification of reliable early indicators of CC risk would enable prioritization of treatment to those with the highest probability of future disease. Serum markers and electrocardiogram (EKG) changes were measured in 68 T. cruzi-infected individuals in various stages of cardiac disease and 17 individuals without T. cruzi infection or cardiac disease. T. cruzi-infected individuals were assigned to stage A (normal EKG/chest x-ray [CXR]), B (abnormal EKG/normal CXR), or C (abnormal EKG/cardiac structural changes). Ten serum markers were measured using enzyme-linked immunosorbent assay (ELISA)/Luminex, and QRS scores were calculated. Higher concentrations of transforming growth factor-β1 (TGFβ1), and TGFβ2 were associated with stage B compared with stage A. Matrix Metalloproteinase 2 (MMP2), Tissue Inhibitors of MMP 1, QRS score, and Brain Natriuretic Protein rose progressively with increasing CC severity. Elevated levels of several markers of cardiac damage and inflammation are seen in early CC and warrant additional evaluation in longitudinal studies.

Background Vector-borne transmission of Trypanosoma cruzi is seen exclusively in the Americas where an estimated 8 million people are infected with the parasite. Significant research in southern Peru has been conducted to understand T. cruzi infection and vector control, however, much less is known about the burden of infection and epidemiology in northern Peru. Methodology A cross-sectional study was conducted to estimate the seroprevalence of T. cruzi infection in humans (n=611) and domestic animals [dogs (n=106) and guinea pigs (n=206)] in communities of Cutervo Province, Peru. Sampling and diagnostic strategies differed according to species. An entomological household study (n=208) was conducted to identify the triatomine burden and species composition, as well as the prevalence of T. cruzi in vectors. Electrocardiograms (EKG) were performed on a subset of participants (n=90 T. cruzi infected participants and 170 age and sex-matched controls). The seroprevalence of T. cruzi among humans, dogs, and guinea pigs was 14.9% (95% CI: 12.2 – 18.0%), 19.8% (95% CI: 12.7- 28.7%) and 3.3% (95% CI: 1.4 – 6.9%) respectively. In one community, the prevalence of T. cruzi infection was 17.2% (95% CI: 9.6 - 24.7%) among participants < 15 years, suggesting recent transmission. Increasing age, positive triatomines in a participant's house, and ownership of a T. cruzi positive guinea pig were independent correlates of T. cruzi infection. Only one species of triatomine was found, Panstrongylus lignarius, formerly P. herreri. Approximately forty percent (39.9%, 95% CI: 33.2 - 46.9%) of surveyed households were infested with this vector and 14.9% (95% CI: 10.4 - 20.5%) had at least one triatomine positive for T. cruzi. The cardiac abnormality of right bundle branch block was rare, but only identified in seropositive individuals. Conclusions Our research documents a substantial prevalence of T. cruzi infection in Cutervo and highlights a need for greater attention and vector control efforts in northern Peru., Author Summary Chagas disease causes significant morbidity and mortality throughout Central and South America. The epidemiology and control of this disease is subject to unique regional particularities, including the behavior and ecology of the local insect vector species. Significant resources have been allocated towards research and control efforts in southern Peru, yet very little is known about the prevalence and epidemiology of Trypanosoma cruzi in northern Peru. Our study highlights significant T. cruzi infection in northern Peru and is one of the first to document substantial transmission by the insect Panstrongylus lignarius. Our results illustrate major gaps in knowledge and the need for public health interventions targeted at Chagas disease in the region of Cutervo Province of northern Peru.

Background Twenty to thirty percent of persons with Trypanosoma cruzi infection eventually develop cardiomyopathy. If an early indicator were to be identified and validated in longitudinal studies, this could enable treatment to be prioritized for those at highest risk. We evaluated cardiac and extracellular matrix remodeling markers across cardiac stages in T. cruzi infected (Tc+) and uninfected (Tc−) individuals. Methods Participants were recruited in a public hospital in Santa Cruz, Bolivia and assigned cardiac severity stages by electrocardiogram and echocardiogram. BNP, NTproBNP, CKMB, troponin I, MMP-2, MMP-9, TIMP-1, TIMP-2, TGFb1, and TGFb2 were measured in specimens from 265 individuals using multiplex bead systems. Biomarker levels were compared between Tc+ and Tc− groups, and across cardiac stages. Receivers operating characteristic (ROC) curves were created; for markers with area under curve>0.60, logistic regression was performed. Results Analyses stratified by cardiac stage showed no significant differences in biomarker levels by Tc infection status. Among Tc+ individuals, those with cardiac insufficiency had higher levels of BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 than those with normal ejection fraction and left ventricular diameter. No individual marker distinguished between the two earliest Tc+ stages, but in ROC-based analyses, MMP-2/MMP-9 ratio was significantly higher in those with than those without ECG abnormalities. Conclusions BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 levels rose with increasing severity stage but did not distinguish between Chagas cardiomyopathy and other cardiomyopathies. Among Tc+ individuals without cardiac insufficiency, only the MMP-2/MMP-9 ratio differed between those with and without ECG changes., Author Summary In Chagas disease, a parasitic disease found primarily in Central and South America, individuals are chronically infected with the parasite Trypanosoma cruzi. A few decades after initial infection, 20–30% of infected individuals will develop cardiac disease. If we were able to predict which individuals would progress to cardiac disease, treatment in these low resource areas could be targeted to those at highest risk. The ideal transition point to identify those at risk would be as individuals progress from a normal electrocardiogram to an abnormal electrocardiogram, the first step in the progression of cardiac disease. Previous studies have suggested a group of serum biomarkers able to differentiate between these stages of disease. However, our larger and more comprehensive study finds that none of the ten cardiac and remodeling biomarkers we tested are able to distinguish between healthy individuals and those with the earliest evidence of cardiac disease. We did find cardiac biomarkers to be elevated in those with severe cardiac disease as expected in both T. cruzi infected and uninfected individuals.