Effectiveness of BNT162b2 COVID-19 primary series vaccination in children aged 5-17 years in the United States: a cohort study.

BACKGROUND: COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study's objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. METHODS: This cohort study identified children aged 5-17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. RESULTS: There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36-40%]) and hospital/ED-diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56-65%]). VE estimates were lowest among children 5-11 years and during the Omicron-variant era. CONCLUSIONS: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED-diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. REGISTRATION: The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).

Multi-modal cross-linguistic perception of fricatives in clear speech.

Research shows that acoustic modifications in clearly enunciated fricative consonants (relative to the plain, conversational productions) facilitate auditory fricative perception, particularly for auditorily salient sibilant fricatives and for native perception. However, clear-speech effects on visual fricative perception have received less attention. A comparison of auditory and visual (facial) clear-fricative perception is particularly interesting since sibilant fricatives in English are more auditorily salient while non-sibilants are more visually salient. This study thus examines clear-speech effects on multi-modal perception of English sibilant and non-sibilant fricatives. Native English perceivers and non-native (Mandarin, Korean) perceivers with different fricative inventories in their native languages (L1s) identified clear and conversational fricative-vowel syllables in audio-only, visual-only, and audio-visual (AV) modes. The results reveal an overall positive clear-speech effect when visual information is involved. Considering the factor of AV saliency, clear speech benefits sibilants more in the auditory domain and non-sibilants more in the visual domain. With respect to language background, non-native (Mandarin and Korean) perceivers benefit from visual as well as auditory information, even for fricatives non-existent in their respective L1s, but the patterns of clear-speech gains are affected by the relative AV weighting and "nativeness" of the fricatives. These findings are discussed in terms of how saliency-enhancing and category-distinctive cues of speech sounds are adopted in AV perception to improve intelligibility.

Expanding transplant outcomes research opportunities through the use of a common data model.

The volume of solid organ transplant in the United States is increasing, providing improved quality of life and survival for patients with organ failure. The growth of transplant requires a systematized management of transplant outcomes assessment, especially with the movement toward value-based care. However, there are several challenges to analyzing outcomes in the current registry-based, transplant reporting system: (1) longitudinal data points are difficult to capture in outcomes models; (2) data elements are restricted to those that already exist in the registry data; and (3) there is a delay in the release of outcomes report. In this article, we propose an informatics approach to solve these problems by using a "common data model" to integrate disparate data sources, data elements, and temporal data points. Adopting such a framework can enable multicenter outcomes analyses among transplant centers, nationally and internationally.

Cost-effectiveness of 10-Year Risk Thresholds for Initiation of Statin Therapy for Primary Prevention of Cardiovascular Disease.

IMPORTANCE: The American College of Cardiology and the American Heart Association (ACC/AHA) cholesterol treatment guidelines have wide-scale implications for treating adults without history of atherosclerotic cardiovascular disease (ASCVD) with statins. OBJECTIVE: To estimate the cost-effectiveness of various 10-year ASCVD risk thresholds that could be used in the ACC/AHA cholesterol treatment guidelines. DESIGN, SETTING, AND PARTICIPANTS: Microsimulation model, including lifetime time horizon, US societal perspective, 3% discount rate for costs, and health outcomes. In the model, hypothetical individuals from a representative US population aged 40 to 75 years received statin treatment, experienced ASCVD events, and died from ASCVD-related or non-ASCVD-related causes based on ASCVD natural history and statin treatment parameters. Data sources for model parameters included National Health and Nutrition Examination Surveys, large clinical trials and meta-analyses for statin benefits and treatment, and other published sources. MAIN OUTCOMES AND MEASURES: Estimated ASCVD events prevented and incremental costs per quality-adjusted life-year (QALY) gained. RESULTS: In the base-case scenario, the current ASCVD threshold of 7.5% or higher, which was estimated to be associated with 48% of adults treated with statins, had an incremental cost-effectiveness ratio (ICER) of $37,000/QALY compared with a 10% or higher threshold. More lenient ASCVD thresholds of 4.0% or higher (61% of adults treated) and 3.0% or higher (67% of adults treated) had ICERs of $81,000/QALY and $140,000/QALY, respectively. Shifting from a 7.5% or higher ASCVD risk threshold to a 3.0% or higher ASCVD risk threshold was estimated to be associated with an additional 161,560 cardiovascular disease events averted. Cost-effectiveness results were sensitive to changes in the disutility associated with taking a pill daily, statin price, and the risk of statin-induced diabetes. In probabilistic sensitivity analysis, there was a higher than 93% chance that the optimal ASCVD threshold was 5.0% or lower using a cost-effectiveness threshold of $100,000/QALY. CONCLUSIONS AND RELEVANCE: In this microsimulation model of US adults aged 45 to 75 years [corrected], the current 10-year ASCVD risk threshold (≥7.5% risk threshold) used in the ACC/AHA cholesterol treatment guidelines has an acceptable cost-effectiveness profile (ICER, $37,000/QALY), but more lenient ASCVD thresholds would be optimal using cost-effectiveness thresholds of $100,000/QALY (≥4.0% risk threshold) or $150,000/QALY (≥3.0% risk threshold). The optimal ASCVD threshold was sensitive to patient preferences for taking a pill daily, changes to statin price, and the risk of statin-induced diabetes.

Assessment of potential adverse events following the 2022-2023 seasonal influenza vaccines among U.S. adults aged 65 years and older.

BACKGROUND: While safety of influenza vaccines is well-established, some studies have suggested potential associations between influenza vaccines and certain adverse events (AEs). This study examined the safety of the 2022-2023 influenza vaccines among U.S. adults ≥ 65 years. METHODS: A self-controlled case series compared incidence rates of anaphylaxis, encephalitis/encephalomyelitis, Guillain-Barré Syndrome (GBS), and transverse myelitis following 2022-2023 seasonal influenza vaccinations (i.e., any, high-dose or adjuvanted) in risk and control intervals among Medicare beneficiaries ≥ 65 years. We used conditional Poisson regression to estimate incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) adjusted for event-dependent observation time and seasonality. Analyses also accounted for uncertainty from outcome misclassification where feasible. For AEs with any statistically significant associations, we stratified results by concomitant vaccination status. RESULTS: Among 12.7 million vaccine recipients, we observed 76 anaphylaxis, 276 encephalitis/encephalomyelitis, 134 GBS and 75 transverse myelitis cases. Only rates of anaphylaxis were elevated in risk compared to control intervals. With all adjustments, an elevated, but non-statistically significant, anaphylaxis rate was observed following any (IRR: 2.40, 95% CI: 0.96-6.03), high-dose (IRR: 2.31, 95% CI: 0.67-7.91), and adjuvanted (IRR: 3.28, 95% CI: 0.71-15.08) influenza vaccination; anaphylaxis IRRs were 2.54 (95% CI: 0.49-13.05) and 1.64 (95% CI: 0.38-7.05) for persons with and without concomitant vaccination, respectively. CONCLUSIONS: Rates of encephalitis/encephalomyelitis, GBS, or transverse myelitis were not elevated following 2022-2023 seasonal influenza vaccinations among U.S. adults ≥ 65 years. There was an increased rate of anaphylaxis following influenza vaccination that may have been influenced by concomitant vaccination.

Effectiveness of monovalent COVID-19 booster/additional vaccine doses in the United States.

Background: Monovalent booster/additional doses of COVID-19 vaccines were first authorized in August 2021 in the United States. We evaluated the real-world effectiveness of receipt of a monovalent booster/additional dose of COVID-19 vaccine compared with receiving a primary vaccine series without a booster/additional dose. Methods: Cohorts of individuals receiving a COVID-19 booster/additional dose after receipt of a complete primary vaccine series were identified in 2 administrative insurance claims databases (Optum, CVS Health) supplemented with state immunization information system data between August 2021 and March 2022. Individuals with a complete primary series but without a booster/additional dose were one-to-one matched to boosted individuals on calendar date, geography, and clinical factors. COVID-19 diagnoses were identified in any medical setting, or specifically in hospitals/emergency departments (EDs). Propensity score-weighted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated with Cox proportional hazards models; vaccine effectiveness (VE) was estimated as 1 minus the HR by vaccine brand overall and within subgroups of variant-specific eras, immunocompromised status, and homologous/heterologous booster status. Results: Across both data sources, we identified 752,165 matched pairs for BNT162b2, 410,501 for mRNA-1273, and 11,398 for JNJ-7836735. For any medically diagnosed COVID-19, meta-analyzed VE estimates for BNT162b2, mRNA-1273, and JNJ-7836735, respectively, were: BNT162b2, 54% (95% CI, 53%-56%); mRNA-1273, 58% (95% CI, 56%-59%); JNJ-7836735, 34% (95% CI, 23%-44%). For hospital/ED-diagnosed COVID-19, VE estimates ranged from 70% to 76%. VE was generally lower during the Omicron era than the Delta era and for immunocompromised individuals. There was little difference observed by homologous or heterologous booster status. Conclusion: The original, monovalent booster/additional doses were reasonably effective in real-world use among the populations for which they were indicated during the study period. Additional studies may be informative in the future as new variants emerge and new vaccines become available.Registration: The study protocol was publicly posted on the BEST Initiative website (https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf).

An interactive fitness-for-use data completeness tool to assess activity tracker data.

OBJECTIVE: To design and evaluate an interactive data quality (DQ) characterization tool focused on fitness-for-use completeness measures to support researchers' assessment of a dataset. MATERIALS AND METHODS: Design requirements were identified through a conceptual framework on DQ, literature review, and interviews. The prototype of the tool was developed based on the requirements gathered and was further refined by domain experts. The Fitness-for-Use Tool was evaluated through a within-subjects controlled experiment comparing it with a baseline tool that provides information on missing data based on intrinsic DQ measures. The tools were evaluated on task performance and perceived usability. RESULTS: The Fitness-for-Use Tool allows users to define data completeness by customizing the measures and its thresholds to fit their research task and provides a data summary based on the customized definition. Using the Fitness-for-Use Tool, study participants were able to accurately complete fitness-for-use assessment in less time than when using the Intrinsic DQ Tool. The study participants perceived that the Fitness-for-Use Tool was more useful in determining the fitness-for-use of a dataset than the Intrinsic DQ Tool. DISCUSSION: Incorporating fitness-for-use measures in a DQ characterization tool could provide data summary that meets researchers needs. The design features identified in this study has potential to be applied to other biomedical data types. CONCLUSION: A tool that summarizes a dataset in terms of fitness-for-use dimensions and measures specific to a research question supports dataset assessment better than a tool that only presents information on intrinsic DQ measures.

Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype.

Injectable hydrogels may be pre-formed through dynamic crosslinks, allowing for injection and subsequent retention in the tissue by shear-thinning and self-healing processes, respectively. These properties enable the site-specific delivery of encapsulated therapeutics; yet, the sustained release of small-molecule drugs and their cell-targeted delivery remains challenging due to their rapid diffusive release and non-specific cellular biodistribution. Herein, we develop an injectable hydrogel system composed of a macrophage-targeted nanoparticle (cyclodextrin nanoparticles, CDNPs) crosslinked by adamantane-modified hyaluronic acid (Ad-HA). The polymer-nanoparticle hydrogel uniquely leverages cyclodextrin's interaction with small molecule drugs to create a spatially discrete drug reservoir and with adamantane to yield dynamic, injectable hydrogels. Through an innovative two-step drug screening approach and examination of 45 immunomodulatory drugs with subsequent in-depth transcriptional profiling of both murine and human macrophages, we identify celastrol as a potent inhibitor of pro-inflammatory (M1-like) behavior that furthermore promotes a reparatory (M2-like) phenotype. Celastrol encapsulation within the polymer-nanoparticle hydrogels permitted shear-thinning injection and sustained release of drug-laden nanoparticles that targeted macrophages to modulate cell behavior for greater than two weeks in vitro. The modular hydrogel system is a promising approach to locally modulate cell-specific phenotype in a range of applications for immunoregenerative medicine.

Identifying Data Quality Dimensions for Person-Generated Wearable Device Data: Multi-Method Study.

BACKGROUND: There is a growing interest in using person-generated wearable device data for biomedical research, but there are also concerns regarding the quality of data such as missing or incorrect data. This emphasizes the importance of assessing data quality before conducting research. In order to perform data quality assessments, it is essential to define what data quality means for person-generated wearable device data by identifying the data quality dimensions. OBJECTIVE: This study aims to identify data quality dimensions for person-generated wearable device data for research purposes. METHODS: This study was conducted in 3 phases: literature review, survey, and focus group discussion. The literature review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline to identify factors affecting data quality and its associated data quality challenges. In addition, we conducted a survey to confirm and complement results from the literature review and to understand researchers' perceptions on data quality dimensions that were previously identified as dimensions for the secondary use of electronic health record (EHR) data. We sent the survey to researchers with experience in analyzing wearable device data. Focus group discussion sessions were conducted with domain experts to derive data quality dimensions for person-generated wearable device data. On the basis of the results from the literature review and survey, a facilitator proposed potential data quality dimensions relevant to person-generated wearable device data, and the domain experts accepted or rejected the suggested dimensions. RESULTS: In total, 19 studies were included in the literature review, and 3 major themes emerged: device- and technical-related, user-related, and data governance-related factors. The associated data quality problems were incomplete data, incorrect data, and heterogeneous data. A total of 20 respondents answered the survey. The major data quality challenges faced by researchers were completeness, accuracy, and plausibility. The importance ratings on data quality dimensions in an existing framework showed that the dimensions for secondary use of EHR data are applicable to person-generated wearable device data. There were 3 focus group sessions with domain experts in data quality and wearable device research. The experts concluded that intrinsic data quality features, such as conformance, completeness, and plausibility, and contextual and fitness-for-use data quality features, such as completeness (breadth and density) and temporal data granularity, are important data quality dimensions for assessing person-generated wearable device data for research purposes. CONCLUSIONS: In this study, intrinsic and contextual and fitness-for-use data quality dimensions for person-generated wearable device data were identified. The dimensions were adapted from data quality terminologies and frameworks for the secondary use of EHR data with a few modifications. Further research on how data quality can be assessed with respect to each dimension is needed.

Factors Affecting the Quality of Person-Generated Wearable Device Data and Associated Challenges: Rapid Systematic Review.

BACKGROUND: There is increasing interest in reusing person-generated wearable device data for research purposes, which raises concerns about data quality. However, the amount of literature on data quality challenges, specifically those for person-generated wearable device data, is sparse. OBJECTIVE: This study aims to systematically review the literature on factors affecting the quality of person-generated wearable device data and their associated intrinsic data quality challenges for research. METHODS: The literature was searched in the PubMed, Association for Computing Machinery, Institute of Electrical and Electronics Engineers, and Google Scholar databases by using search terms related to wearable devices and data quality. By using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, studies were reviewed to identify factors affecting the quality of wearable device data. Studies were eligible if they included content on the data quality of wearable devices, such as fitness trackers and sleep monitors. Both research-grade and consumer-grade wearable devices were included in the review. Relevant content was annotated and iteratively categorized into semantically similar factors until a consensus was reached. If any data quality challenges were mentioned in the study, those contents were extracted and categorized as well. RESULTS: A total of 19 papers were included in this review. We identified three high-level factors that affect data quality-device- and technical-related factors, user-related factors, and data governance-related factors. Device- and technical-related factors include problems with hardware, software, and the connectivity of the device; user-related factors include device nonwear and user error; and data governance-related factors include a lack of standardization. The identified factors can potentially lead to intrinsic data quality challenges, such as incomplete, incorrect, and heterogeneous data. Although missing and incorrect data are widely known data quality challenges for wearable devices, the heterogeneity of data is another aspect of data quality that should be considered for wearable devices. Heterogeneity in wearable device data exists at three levels: heterogeneity in data generated by a single person using a single device (within-person heterogeneity); heterogeneity in data generated by multiple people who use the same brand, model, and version of a device (between-person heterogeneity); and heterogeneity in data generated from multiple people using different devices (between-person heterogeneity), which would apply especially to data collected under a bring-your-own-device policy. CONCLUSIONS: Our study identifies potential intrinsic data quality challenges that could occur when analyzing wearable device data for research and three major contributing factors for these challenges. As poor data quality can compromise the reliability and accuracy of research results, further investigation is needed on how to address the data quality challenges of wearable devices.

Content Coverage Evaluation of the OMOP Vocabulary on the Transplant Domain Focusing on Concepts Relevant for Kidney Transplant Outcomes Analysis.

BACKGROUND: Improving outcomes of transplant recipients within and across transplant centers is important with the increasing number of organ transplantations being performed. The current practice is to analyze the outcomes based on patient level data submitted to the United Network for Organ Sharing (UNOS). Augmenting the UNOS data with other sources such as the electronic health record will enrich the outcomes analysis, for which a common data model (CDM) can be a helpful tool for transforming heterogeneous source data into a uniform format. OBJECTIVES: In this study, we evaluated the feasibility of representing concepts from the UNOS transplant registry forms with the Observational Medical Outcomes Partnership (OMOP) CDM vocabulary to understand the content coverage of OMOP vocabulary on transplant-specific concepts. METHODS: Two annotators manually mapped a total of 3,571 unique concepts extracted from the UNOS registry forms to concepts in the OMOP vocabulary. Concept mappings were evaluated by (1) examining the agreement among the initial two annotators and (2) investigating the number of UNOS concepts not mapped to a concept in the OMOP vocabulary and then classifying them. A subset of mappings was validated by clinicians. RESULTS: There was a substantial agreement between annotators with a kappa score of 0.71. We found that 55.5% of UNOS concepts could not be represented with OMOP standard concepts. The majority of unmapped UNOS concepts were categorized into transplant, measurement, condition, and procedure concepts. CONCLUSION: We identified categories of unmapped concepts and found that some transplant-specific concepts do not exist in the OMOP vocabulary. We suggest that adding these missing concepts to OMOP would facilitate further research in the transplant domain.

Validation of a Cardiovascular Disease Policy Microsimulation Model Using Both Survival and Receiver Operating Characteristic Curves.

BACKGROUND: Despite some advances, cardiovascular disease (CVD) remains the leading cause of death and healthcare costs in the United States. We therefore developed a comprehensive CVD policy simulation model that identifies cost-effective approaches for reducing CVD burden. This paper aims to: 1) describe our model in detail; and 2) perform model validation analyses. METHODS: The model simulates 1,000,000 adults (ages 35 to 80 years) using a variety of CVD-related epidemiological data, including previously calibrated Framingham-based risk scores for coronary heart disease and stroke. We validated our microsimulation model using recent National Health and Nutrition Examination Survey (NHANES) data, with baseline values collected in 1999-2000 and cause-specific mortality follow-up through 2011. Model-based (simulated) results were compared to observed all-cause and CVD-specific mortality data (from NHANES) for the same starting population using survival curves and, in a method not typically used for disease model validation, receiver operating characteristic (ROC) curves. RESULTS: Observed 10-year all-cause mortality in NHANES v. the simulation model was 11.2% (95% CI, 10.3% to 12.2%) v. 10.9%; corresponding results for CVD mortality were 2.2% (1.8% to 2.7%) v. 2.6%. Areas under the ROC curves for model-predicted 10-year all-cause and CVD mortality risks were 0.83 (0.81 to 0.85) and 0.84 (0.81 to 0.88), respectively; corresponding results for 5-year risks were 0.80 (0.77 to 0.83) and 0.81 (0.75 to 0.87), respectively. LIMITATIONS: The model is limited by the uncertainties in the data used to estimate its input parameters. Additionally, our validation analyses did not include non-fatal CVD outcomes due to NHANES data limitations. CONCLUSIONS: The simulation model performed well in matching to observed nationally representative longitudinal mortality data. ROC curve analysis, which has been traditionally used for risk prediction models, can also be used to assess discrimination for disease simulation models.

Management of infected urethral diverticulum with urethral dilation.

BACKGROUND: Urethral diverticula are rare but underdiagnosed entities that may cause a variety of urinary and pelvic symptoms in women. Management can be very challenging, especially in cases of chronic infection. CASE: A 69-year-old gravida 4, para 2 woman with a history of type 2 diabetes and hypothyroidism presented with long history of a painful midline 3-cm suburethral cystic mass, recurrent urinary tract infections, dysuria, dyspareunia, and incomplete voiding. The diagnosis was consistent with an infected urethral diverticulum unresponsive to multiple courses of oral antibiotics. Given the patient's comorbidities and the persistence of infection of the diverticulum, conservative treatment with urethral dilation was performed before surgical treatment. Urethral dilation successfully alleviated the patient's symptoms; the surgical treatment was not ultimately required, and the patient continues to be completely asymptomatic well over 17 months later. CONCLUSIONS: We present a unique case of infected urethral diverticulum, which was conservatively treated with dilatation and resulted in resolution of all symptoms, and there is no need for further surgical management.

Increasing Prescription Length Could Cut Cardiovascular Disease Burden And Produce Savings In South Africa.

South Africa's rates of statin use are among the world's lowest, despite statins' demonstrated effectiveness for people with a high blood cholesterol level or history of cardiovascular disease. Almost 5 percent of the country's total mortality has been attributed to high cholesterol levels, fueled in part by low levels of statin adherence. Drawing upon experience elsewhere, we used a microsimulation model of cardiovascular disease to investigate the health and economic impacts of increasing prescription length from the standard thirty days to either sixty or ninety days, for South African adults on a stable statin regimen. Increasing prescription length to sixty or ninety days could save 1,694 or 2,553 lives per million adults, respectively. In addition, annual per patient costs related to cardiovascular disease would decrease by $152.41 and $210.29, respectively. Savings would largely accrue to patients in the form of time savings and reduced transportation costs, as a result of less frequent trips to the pharmacy. Increasing statin prescription length would both save resources and improve health outcomes in South Africa.

Changes in the soluble mucosal immune environment during genital herpes outbreaks.

BACKGROUND: Genital tract secretions provide variable inhibitory activity against herpes simplex virus (HSV) ex vivo. We hypothesize that the anti-HSV activity may prevent the spread of virus from the more commonly affected sites, such as the external genitalia, to the upper genital tract. METHODS: The antimicrobial activity of cervicovaginal lavage (CVL) and concentrations of mucosal immune mediators were measured in 10 HIV-seronegative women with an active external herpetic lesion and compared with 10 HIV-seronegative women who were HSV-1 and HSV-2 seronegative. Samples were obtained at the time of a symptomatic external lesion (day 0), after 1 week of oral acyclovir (day 7), and 1 week after completing treatment (day 14). Controls were evaluated at parallel intervals. RESULTS: The anti-HSV activity was higher in CVL obtained from cases compared to controls at presentation (day 0) (54.3% vs. 28%), fell to similar levels on day 7, and then rebounded on day 14 (69% vs. 25%). The anti-HSV activity correlated positively and significantly with the concentrations of several inflammatory proteins; the concentrations of these proteins tended to be higher in cases compared with controls and followed a similar temporal pattern. CONCLUSIONS: Increases in inflammatory immune mediators and anti-HSV activity were detected in CVL at the time of clinical outbreaks and after completion of a short course of acyclovir. These mucosal responses may protect against HSV spread but could facilitate HIV infection and contribute to the clinical observation that, independent of clinical lesions, HSV-2 is a risk factor for HIV acquisition.

A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel.

BACKGROUND: Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition. METHODS: 30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood. RESULTS: A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators. CONCLUSIONS: Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00594373.

Female genital tract secretions inhibit herpes simplex virus infection: correlation with soluble mucosal immune mediators and impact of hormonal contraception.

PROBLEM: Female genital tract secretions inhibit herpes simplex virus (HSV) infection, however, the intra- and inter-subject variability, contribution of specific mediators, and impact of reproductive hormones have not been defined. METHOD: of study Cervicovaginal lavage (CVL) (n = 89) obtained from nine cyclers and seven women on hormonal contraception (HC), who completed between three and eight weekly visits, were examined for anti-herpes simplex virus activity and concentrations of mediators. RESULTS: The CVL inhibited HSV infection by a mean value of approximately 57% during the follicular or luteal phase, but only by 36% in hormonal contraceptive users. Human neutrophil peptides 1-3 (HNP1-3) (P = 0.03), IL-8 (P = 0.003), lactoferrin (P = 0.005), lysozyme (P = 0.003), IgA (P = 0.002), and IgG (P = 0.02) correlated with antiviral activity. Intra-subject and inter-subject variability was observed, suggesting that factors other than hormones contribute to innate defense. CONCLUSION: Endogenous antimicrobial activity may provide a biomarker of healthy mucosal immunity and may be reduced in the setting of HC. However, larger prospective studies are needed.

Postcoital bioavailability and antiviral activity of 0.5% PRO 2000 gel: implications for future microbicide clinical trials.

BACKGROUND: The pharmacokinetics and pharmacodynamics of vaginal microbicides are typically assessed among sexually abstinent women. However, the physical act of sex may modulate gel distribution, and preclinical studies demonstrate seminal plasma interferes with the antiviral activity of several microbicides. This study compared the biological activity and concentration of PRO 2000 in cervicovaginal lavage (CVL) collected in the absence or following coitus. METHODS: CVL samples were collected from ten heterosexual couples at baseline, after sex, after a single dose of 0.5% PRO 2000 gel and sex, and after gel application without sex. The impact of CVL on HIV-1 infection of TZM-bl cells and HSV-2 infection of CaSki cells was monitored by luciferase and plaque assay, respectively. PRO 2000 concentrations were measured by fluorescence. RESULTS: CVL collected after PRO 2000 application significantly inhibited HIV-1 and HSV-2 (p = 0.01). However, the antiviral activity was reduced following sex and no significant protective effect was observed in postcoital CVL obtained in the presence compared to the absence of PRO 2000 for HIV (p = 0.45) or HSV-2 (p = 0.56). Less PRO 2000 was recovered in postcoital CVL, which, in conjunction with interference by seminal plasma, may have contributed to lower antiviral activity. CONCLUSIONS: Postcoital responses to PRO 2000 differ from precoital measures and the results obtained may provide insights into the clinical trial findings in which there was no significant protection against HIV-1 or HSV-2. Postcoital studies should be incorporated into clinical studies before embarking on large-scale efficacy trials.