Application of Bayesian statistics to support approval of intravenous belimumab in children with systemic lupus erythematosus in the United States.

ObjectiveDue to the rarity of childhood-onset systemic lupus erythematosus (cSLE), the pediatric study (NCT01649765) conducted to support approval of intravenous (IV) belimumab in that population could not be designed with adequate power for efficacy to make statistical inferences based solely on the pediatric data. Bayesian analyses have been proposed to implement more flexible pediatric extrapolation approaches in similar situations. Here we discuss a post-hoc Bayesian analysis the FDA employed which borrowed information from the phase 3 IV belimumab studies in adults to supplement the efficacy information collected in the pediatric population.

Bayesian Hierarchical Models for Subgroup Analysis.

In conventional subgroup analyses, subgroup treatment effects are estimated using data from each subgroup separately without considering data from other subgroups in the same study. The subgroup treatment effects estimated this way may be heterogenous with high variability due to small sample sizes in some subgroups and much different from the treatment effect in the overall population. A Bayesian hierarchical model (BHM) can be used to derive more precise, and less heterogenous estimates of subgroup treatment effects that are closer to the treatment effect in the overall population.

Perspectives on informative Bayesian methods in pediatrics.

Bayesian methods have been proposed as a natural fit for pediatric extrapolation, as they allow the incorporation of relevant external data to reduce the required sample size and hence trial burden for the pediatric patient population. In this paper we will discuss our experience and perspectives with these methods in pediatric trials. We will present some of the background and thinking underlying pediatric extrapolation and discuss the use of Bayesian methods within this context.

Bayesian Methods in Human Drug and Biological Products Development in CDER and CBER.

The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) have been leaders in protecting and promoting the U.

Bayesian adaptive design for pediatric clinical trials incorporating a community of prior beliefs.

Background: Pediatric population presents several barriers for clinical trial design and analysis, including ethical constraints on the sample size and slow accrual rate. Bayesian adaptive design methods could be considered to address these challenges in pediatric clinical trials.

Methods: We developed an innovative Bayesian adaptive design method and demonstrated the approach as a re-design of a published phase III pediatric trial.

Applying the Noninferiority Paradigm to Assess Exposure-Response Similarity and Dose Between Pediatric and Adult Patients.

The use of extrapolation of efficacy in pediatric drug development programs is possible when disease progression and treatment response are similar in adult and pediatric populations. Historically, the exposure-response (E-R) similarity was assessed by visual inspection of 2 E-R curves to support pediatric extrapolation. The aim of this study was to develop a quantitative framework to describe the E-R relationship and the difference in E-R between pediatric and adult patients based on accumulated experience in pediatric drug development programs.

An Empirical Comparison of Statistical Methods for Missing Data in Randomized, Double-Blind, Placebo-Controlled, Phase 3 Clinical Trials for Chronic Pain and Lipid-Lowering Products.

Background: Missing data are uncollected data but meaningful for the statistical analysis due to clinical relevancy of the data for properly specified estimands in clinical trials. Meanwhile the efforts to prevent or minimize missing data are commonly applied in clinical trials, in practice, missing data still occurs. Choosing a statistical method for imputation that deals with missing data targeting specified estimands provides the more reliable estimates of treatment effects.

The histopathologic features of autoimmune progesterone dermatitis.

Background: The histologic features of autoimmune progesterone dermatitis (APD) are generally non-specific and have been described only in brief case reports. We present a case of APD and review the literature with a focus on the histologic findings described.

Methods: A review of the English literature on APD was performed using PubMed and MEDLINE.

Titania-hydroxypropyl cellulose thin films for the detection of peroxide vapors.

Titania nanoparticles in a hydroxypropyl cellulose matrix produced using a sol-gel method were utilized to prepare films on polycarbonate slides and coatings on cellulose papers. The exposure of these materials to hydrogen peroxide gas leads to the development of an intense yellow color. By using an inexpensive web camera and a tungsten lamp to measure the reflected light, first-order behavior in the color change was observed when exposed to peroxide vapor of less than 50 ppm.

Primary prevention of pediatric lead exposure requires new approaches to transfusion screening.

Objective: To facilitate further assessment of transfusion-associated lead exposure by designing a procedure to test packed red blood cells (pRBCs) prepared for transfusion.

Study Design: The relationship between pRBCs and whole blood lead concentration was investigated in 27 samples using a modified clinical assay. Lead concentrations were measured in 100 pRBC units.

Rootstock-regulated gene expression patterns associated with fire blight resistance in apple.

Background: Desirable apple varieties are clonally propagated by grafting vegetative scions onto rootstocks. Rootstocks influence many phenotypic traits of the scion, including resistance to pathogens such as Erwinia amylovora, which causes fire blight, the most serious bacterial disease of apple. The purpose of the present study was to quantify rootstock-mediated differences in scion fire blight susceptibility and to identify transcripts in the scion whose expression levels correlated with this response.

Use of Gibberellic Acid for Management of Bunch Rot on Chardonnay and Vignoles Grape.

Harvest bunch rot of wine grape, caused primarily by Botrytis cinerea, is a perennial problem limiting the productivity of eastern vineyards, especially on cultivars with compact clusters. The aim of the present study was to evaluate the effectiveness of gibberellic acid (GA) sprays at reducing the compactness of Chardonnay and Vignoles clusters and minimizing bunch rot. Applications of GA reduced the number of berries per centimeter and the incidence and severity of bunch rots in Vignoles and, to a lesser extent, in Chardonnay over three consecutive years; however, the magnitude of GA effects often depended on the timing and rate of application.

Diversity and biogeography of sooty blotch and flyspeck fungi on apple in the eastern and midwestern United States.

Sooty blotch and flyspeck (SBFS) fungi on apple fruit were sampled from nine orchards in four midwestern U.S. states during 2000 and 30 orchards in 10 eastern U.

Relationship Between Cluster Compactness and Bunch Rot in Vignoles Grapes.

The impact of cluster compactness and debris retention on harvest bunch rot of Vitis interspecific hybrid 'Vignoles' was investigated between 2001 and 2005 near Lake Erie, in Pennsylvania. Cluster compactness was characterized subjectively based on the OIV code 204 standard and objectively by determining the number of berries per centimeter of rachis. In 2001, 2002, and 2004, the median number of berries per centimeter for loose clusters was 6.

Direct measurement of free copper in serum or plasma ultrafiltrate.

Copper is an essential element and, under conditions of overload, a toxicant. A dramatic example of copper toxicity is Wilson disease (WD), a treatable but often fatal condition that is difficult to diagnose and monitor. A method for direct measurement of free copper concentrations in serum or plasma ultrafiltrate by inductively coupled mass spectrometry was developed and validated to assist with diagnosis and monitoring WD.

Dual regulation of interleukin-8 production in human oral epithelial cells upon stimulation with gingipains from Porphyromonas gingivalis.

Cysteine proteinases from Porphyromonas gingivalis, or gingipains, are considered to be key virulence factors of the bacterium in relation to periodontal diseases. Incubation of human oral epithelial cells with lysine-specific gingipain (Kgp) and high-molecular-mass arginine-specific gingipain (HRgpA) resulted in a decrease in the production of interleukin (IL)-8, but not in the production of other pro-inflammatory cytokines. In contrast, arginine-specific gingipain 2 (RgpB) increased IL-8 production.

Does the importance of the C-terminal residues in the maturation of RgpB from Porphyromonas gingivalis reveal a novel mechanism for protein export in a subgroup of Gram-Negative bacteria?

The mature 507-residue RgpB protein belongs to an important class of extracellular outer membrane-associated proteases, the gingipains, from the oral pathogen Porphyromonas gingivalis that has been shown to play a central role in the virulence of the organism. The C termini of these gingipains along with other outer membrane proteins from the organism share homologous sequences and have been suggested to function in attachment of these proteins to the outer membrane. In this report, we have created a series of truncated and site-directed mutants of the C terminus from a representative member of this class, the RgpB protease, to investigate its role in the maturation of these proteins.

Gingipains from Porphyromonas gingivalis W83 synergistically disrupt endothelial cell adhesion and can induce caspase-independent apoptosis.

We have shown previously that gingipains from Porphyromonas gingivalis W83 can induce cell detachment, cell adhesion molecule (CAM) cleavage, and apoptosis in endothelial cells; however, the specific roles of the individual gingipains are unclear. Using purified gingipains, we determined that each of the gingipains can cleave CAMs to varying degrees with differing kinetics. Kgp and HRgpA work together to quickly detach endothelial cells.

Investigations into sigmaB-modulated regulatory pathways governing extracellular virulence determinant production in Staphylococcus aureus.

The commonly used Staphylococcus aureus laboratory strain 8325-4 bears a naturally occurring 11-bp deletion in the sigmaB-regulating phosphatase rsbU. We have previously published a report (M. J.

Interaction of a novel form of Pseudomonas aeruginosa alkaline protease (aeruginolysin) with interleukin-6 and interleukin-8.

Pseudomonas aeruginosa secretes several proteases considered as important virulence factors. In this report we present data indicating that two key proinflammatory cytokines, interleukin-6 (IL-6) and IL-8, are substrates for pseudolysin (elastase) and aeruginolysin (alkaline protease). While IL-6 was totally digested by both proteases, a long form of IL-8 (IL-8-77) was first rapidly processed into a 72-residue form with enhanced chemokine activity, then very slowly degraded.

Selective inhibition of Porphyromonas gingivalis growth by a factor Xa inhibitor, DX-9065a.

Background: Porphyromonas gingivalis is a causative bacterium of adult periodontitis. However, there is no drug specific for P. gingivalis and for its virulence factor.