Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder

<p>Abstract</p> <p>Background</p> <p>Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine.</p> <p>Methods</p> <p>Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models.</p> <p>Results</p> <p>The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively.</p> <p>Conclusions</p> <p>A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials.</p> <p>Trial Registration</p> <p>The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).</p

How much power does your server consume? Estimating wall socket power using RAPL measurements

Full system electricity intake from the wall socket is important for understanding and budgeting the power consumption of large scale data centers. Measuring full system power, however, requires extra instrumentation with external physical devices, which is not only cumbersome, but also expensive and time consuming. To tackle this problem, in this paper, we propose to model wall socket power from processor package power obtained from the running average power limit (RAPL) interface, which is available on the latest Intel processors. Our experimental results demonstrate a strong correlation between RAPL package power and wall socket power consumption. Based on the observations, we propose an empirical power model to predict the full system power. We verify the model using multiple synthetic benchmarks (Stress-ng, STREAM), high energy physics benchmark (ParFullCMS), and non-trivial application benchmarks (Parsec). Experimental results show that the prediction model achieves good accuracy, which is maximum 5.6Â % error rate

Capsid Mutated Adeno-Associated Virus Delivered to the Anterior Chamber Results in Efficient Transduction of Trabecular Meshwork in Mouse and Rat.

Adeno associated virus (AAV) is well known for its ability to deliver transgenes to retina and to mediate improvements in animal models and patients with inherited retinal disease. Although the field is less advanced, there is growing interest in AAV's ability to target cells of the anterior segment. The purpose of our study was to fully articulate a reliable and reproducible method for injecting the anterior chamber (AC) of mice and rats and to investigate the transduction profiles of AAV2- and AAV8-based capsid mutants containing self-complementary (sc) genomes in the anterior segment of the eye.AC injections were performed in C57BL/6 mice and Sprague Dawley rats. The cornea was punctured anterior of the iridocorneal angle. To seal the puncture site and to prevent reflux an air bubble was created in the AC. scAAVs expressing GFP were injected and transduction was evaluated by immunohistochemistry. Both parent serotype and capsid modifications affected expression. scAAV2- based vectors mediated efficient GFP-signal in the corneal endothelium, ciliary non-pigmented epithelium (NPE), iris and chamber angle including trabecular meshwork, with scAAV2(Y444F) and scAAV2(triple) being the most efficient.This is the first study to semi quantitatively evaluate transduction of anterior segment tissues following injection of capsid-mutated AAV vectors. scAAV2- based vectors transduced corneal endothelium, ciliary NPE, iris and trabecular meshwork more effectively than scAAV8-based vectors. Mutagenesis of surface-exposed tyrosine residues greatly enhanced transduction efficiency of scAAV2 in these tissues. The number of Y-F mutations was not directly proportional to transduction efficiency, however, suggesting that proteosomal avoidance alone may not be sufficient. These results are applicable to the development of targeted, gene-based strategies to investigate pathological processes of the anterior segment and may be applied toward the development of gene-based therapies for glaucoma and acquired or inherited corneal anomalies

Localization of the GFP signal in the anterior section of eyes injected with similar titers of scAAVs.

<p>The transduction efficiency (grading:-,-/+, +, ++) is based on the intensity and distribution of the GFP signal in tissues of the anterior section. Unless otherwise noted (see asterisks) the term cornea represents GFP-expression in the corneal endothelium.</p><p>* One out of five showed GFP-positivity in the corneal stroma in addition to the corneal endothelium.</p><p>** One out of five showed GFP-positivity in the corneal stroma.</p><p>Localization of the GFP signal in the anterior section of eyes injected with similar titers of scAAVs.</p

Corneas of scAAV2(triple)- and scAAV8(Y733F)- injected animals.

<p>GFP expression was detected in (A) scAAV(triple) and (B) scAAV8(Y733F)- injected mouse as well as in (C) scAAV2(triple)- and (D) scAAV8(Y733F)- injected rat corneas. Arrows indicate GFP- positive keratinocytes.</p

GFP expression in scAAV-injected rat eyes.

<p>In A-D, representative sections of the region around the chamber angle are shown. The small inserts illustrate the cornea, the iris and the NPE. Nuclei are stained with DAPI. Arrows indicate GFP signals in the cornea, the iris, the chamber angle and/or the NPE. Arrowheads mark the region of the TM.</p