Development and Validation of Two Optimized Multiplexed Serologic Assays for the 9-Valent Human Papillomavirus Vaccine Types.

Two multiplex immunoassays are routinely used to assess antibody responses in clinical trials of the 9-valent human papillomavirus (9vHPV) vaccine. The HPV6/11/16/18/31/33/45/52/58 competitive Luminex immunoassay (HPV-9 cLIA) and HPV6/11/16/18/31/33/45/52/58 total immunoglobulin G Luminex immunoassay are used for measurements of immunogenicity. Following their initial validation in 2010, both assays were redeveloped, and several parameters were optimized, including the coating concentration of virus-like particles, type of Luminex microspheres, serum sample and reference standard diluent, reference standard starting dilution and titration series, and vendor and concentration of the phycoerythrin-labeled antibodies.

Immunogenicity, Safety, and Tolerability of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Immunocompetent Adults Aged 18-49 Years With or Without Risk Factors for Pneumococcal Disease: A Randomized Phase 3 Trial (PNEU-DAY).

Background: Adults with certain medical and behavioral factors are at increased risk for pneumococcal disease (PD). Sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults in some countries.

Methods: This phase 3 trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults aged 18-49 years with or without predefined risk factors for PD (NCT03547167).

Design of a phase III efficacy, immunogenicity, and safety study of 9-valent human papillomavirus vaccine in prevention of oral persistent infection in men.

Background: Seven high-risk human papillomavirus (HPV) types (16/18/31/33/45/52/58) covered by the 9-valent HPV (9vHPV) vaccine cause >90% of HPV-related head and neck cancers (HNCs). An ongoing clinical trial (NCT04199689) was designed to evaluate 9vHPV vaccine efficacy against HPV oral persistent infection, a surrogate endpoint for HPV-related HNCs.

Methods: In this double-blind, placebo-controlled, international trial, men aged 20-45 years (N = 6000) are randomized 1:1 to receive 9vHPV vaccine or placebo on day 1, month 2, and month 6.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in Vietnamese males and females (9 to 26 years of age): an open-label, phase 3 trial.

This open-label, single-center, Phase 3 study (NCT03546842) assessed the immunogenicity and safety of the nine-valent human papillomavirus (9vHPV; HPV6/11/16/18/31/33/45/52/58) vaccine in Vietnamese males and females, with the aim to support 9vHPV vaccine licensure in Vietnam. Participants aged 9-26 years received three 9vHPV vaccine doses (Day 1, Month 2, Month 6). Serum samples were obtained on Day 1 (pre-vaccination) and at Month 7 (one month post-Dose 3) for the measurement of anti-HPV antibodies.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

Background: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age.

Methods: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age.

Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug-Induced Liver Toxicity.

Inhibition of the bile salt export pump (BSEP) may be associated with clinical drug-induced liver injury, but is poorly predicted by preclinical animal models. Here we present the development of a novel rat model using siRNA knockdown (KD) of Bsep that displayed differentially enhanced hepatotoxicity to 8 Bsep inhibitors and not to 3 Bsep noninhibitors when administered at maximally tolerated doses for 7 days. Bsep KD alone resulted in 3- and 4.

Antibiotic-Induced Elevations of Plasma Bile Acids in Rats Independent of Bsep Inhibition.

Drug-induced liver injury (DILI) is a common toxicity observed in drug development and can lead to withdrawal of approved drugs from the market. To better understand the numerous mechanisms of DILI, recent efforts have focused on transporter inhibition, specifically liver canalicular bile salt export pump (Bsep) as one mechanism of DILI, and on the potential use of plasma bile acids as monitorable mechanism-based biomarkers of Bsep inhibition. To explore alternative mechanisms of bile acid increases in plasma, 6 antibiotic and 2 nonantibiotic drugs unlikely to be Bsep inhibitors were evaluated in rat studies.

On exchangeable multinomial distributions.

We derive an expression for the joint distribution of exchangeable multinomial random variables, which generalizes the multinomial distribution based on independent trials while retaining some of its important properties. Unlike de Finneti's representation theorem for a binary sequence, the exchangeable multinomial distribution derived here does not require that the finite set of random variables under consideration be a subset of an infinite sequence. Using expressions for higher moments and correlations, we show that the covariance matrix for exchangeable multinomial data has a different form from that usually assumed in the literature, and we analyse data from developmental toxicology studies.

Pioglitazone increases whole body insulin sensitivity in obese, insulin-resistant rhesus monkeys.

Hyperinsulinemic-euglycemic clamps are considered the "gold standard" for assessing whole body insulin sensitivity. When used in combination with tracer dilution techniques and physiological insulin concentrations, insulin sensitization can be dissected and attributed to hepatic and peripheral (primarily muscle) effects. Non-human primates (NHPs), such as rhesus monkeys, are the closest pre-clinical species to humans, and thus serve as an ideal model for testing of compound efficacy to support translation to human efficacy.

Treatment comparison in randomized clinical trials with nonignorable missingness: A reverse regression approach.

A common problem in randomized clinical trials is nonignorable missingness, namely that the clinical outcome(s) of interest can be missing in a way that is not fully explained by the observed quantities. This happens when the continued participation of patients depends on the current outcome after adjusting for the observed history. Standard methods for handling nonignorable missingness typically require specification of the response mechanism, which can be difficult in practice.

A mixture of transition models for heterogeneous longitudinal ordinal data: with applications to longitudinal bacterial vaginosis data.

Markov models used to analyze transition patterns in discrete longitudinal data are based on the limiting assumption that individuals follow the common underlying transition process. However, when one is interested in diseases with different disease or severity subtypes, explicitly modeling subpopulation-specific transition patterns may be appropriate. We propose a model which captures heterogeneity in the transition process through a finite mixture model formulation and provides a framework for identifying subpopulations at different risks.

Trajectories of kinematic risky driving among novice teenagers.

Objectives: Elevated gravitational force event rates are associated with the likelihood of a crash or near crash and provide an objective measure of risky driving. The purpose of this research is to examine the patterns over time of kinematic measures of risky driving among novice teenage drivers.

Methods: Driving data were collected from 42 newly licensed teenage drivers during the first 18 months of licensure.

The impact of random-effect misspecification on percentile estimation for longitudinal growth data.

Identifying unusual growth-related measurements or longitudinal patterns in growth is often the focus in fetal and pediatric medicine. For example, the goal of the ongoing National Fetal Growth Study is to develop both cross-sectional and longitudinal reference curves for ultrasound fetal growth measurements that can be used for this purpose. Current methodology for estimating cross-sectional and longitudinal reference curves relies mainly on the linear mixed model.

Candidate measures of whole plant food intake are related to biomarkers of nutrition and health in the US population (National Health and Nutrition Examination Survey 1999-2002).

Indices of overall dietary patterns are used in epidemiologic research to examine the relationship between nutrition and health. The objective of this study was to develop and validate an interpretable summary measure of dietary intake of whole plant foods (WPF; whole grains, vegetables, whole fruit, legumes, nuts, seeds) because of their similar nutritional characteristics and health effects. Six candidate WPF measures were calculated using data from subjects (age ≥ 6 years) participating in the 1999-2000 and 2001-2002 National Health and Nutrition Examination Survey.

Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) gene.

Retinitis pigmentosa (RP), a common group of human retinopathic diseases, is characterized by late-onset night blindness, loss of peripheral vision, and diminished or absent electroretinogram (ERG) responses. Mutations in the photoreceptor-specific gene RP1 account for 5-10% of cases of autosomal dominant RP. We generated a mouse model of the RP1 form of RP by targeted disruption of the mouse ortholog (Rp1) of human RP1.