A phase II dose-ranging study of mirabegron in patients with overactive bladder

Introduction and hypothesis Mirabegron is a potent and selective β3-adrenoceptor agonist that may represent an alternative treatment option in place of antimuscarinics for patients with overactive bladder. Methods Patients completed a single-blinded, 2-week placebo run-in period followed by 12 weeks of randomized (n=928) double-blinded treatment with mirabegron oral controlled absorption system (OCAS) 25, 50, 100, or 200 mg once-daily (QD), placebo or tolterodine extended release (ER) 4 mg QD. The primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes/24 h. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes/24 h; severity of urgency; nocturia; and quality of life measures. Safety parameters included vital signs, adverse events, laboratory tests, electrocardiogram measurements and post-void residual volume. Results Mirabegron 25, 50, 100, and 200 mg resulted in dosedependent reductions (improvements) from baseline to end-oftreatment in micturition frequency of 1.9, 2.1, 2.1, and 2.2 micturitions/24 h respectively, versus 1.4 micturitions/24 h with placebo (p≤0.05 for the mirabegron 50-, 100-, and 200-mg comparisons). There was a statistically significant improvement with mirabegron compared with placebo for most secondary endpoints including quality of life variables. While there was a significant (p<0.05) increase from baseline in pulse rate in the mirabegron 100-mg and 200-mg groups, this was not associated with an increased incidence of cardiovascular adverse events. Conclusions The favorable efficacy and tolerability of mirabegron in this phase II dose-finding study has led to its successful advancement into a phase III clinical development program

A Search for High-Frequency Coronal Brightness Variations in the 21 August 2017 Total Solar Eclipse

We report on a search for short-period intensity variations in the green-line FeXIV 530.3 nm emission from the solar corona during the 21 August 2017 total eclipse viewed from Idaho in the United States. Our experiment was performed with a much more sensitive detection system, and with better spatial resolution, than on previous occasions (1999 and 2001 eclipses), allowing fine details of quiet coronal loops and an active-region loop system to be seen. A guided 200-mm-aperture Schmidt-Cassegrain telescope was used with a state-of-the-art CCD camera having 16-bit intensity discrimination and a field-of-view 0.43 degree x 0.43 degree that encompassed approximately one third of the visible corona. The camera pixel size was 1.55 arcseconds, while the seeing during the eclipse enabled features of approx. 2 arcseconds (1450 km on the Sun) to be resolved. A total of 429 images were recorded during a 122.9 second portion of the totality at a frame rate of 3.49 images per second. In the analysis, we searched particularly for short-period intensity oscillations and travelling waves, since theory predicts fast-mode magneto-hydrodynamic (MHD) waves with short periods may be important in quiet coronal and active-region heating. Allowing first for various instrumental and photometric effects, we used a wavelet technique to search for periodicities in some 404 000 pixels in the frequency range 0.5-1.6 Hz (periods: 2 second to 0.6 second). We also searched for travelling waves along some 65 coronal structures. However, we found no statistically significant evidence in either. This negative result considerably refines the limit that we obtained from our previous analyses, and it indicates that future searches for short-period coronal waves may be better directed towards Doppler shifts as well as intensity oscillations

A quick approach for rheological evaluation of warm asphalt binders using response surface method

This paper describes a quick approach for quantification of the effects of a chemical warm named Rediset, and its interactions with temperature and aging on the rheological properties of asphalt binders using Response Sur-face Method. The central composite method was applied to design experimental programs for three test temperature conditions, namely; very high temperature (120–180 °C), high temperature (46–82 °C), and intermediate temperature (19–31 °C). Rotational viscosity, G*/sin δ and G*sin δ were selected as parameters to assess the effects of the chemical warm additive on the rheological properties of asphalt binders for different aging conditions. Evaluation of the effects of this additive on the transformed value of G*/sin δ at high temperatures indicates that additive content has significant effect on Ln(G*/sin δ). The results for intermediate temperatures show that this additive has a positive effect on G*sin δ of asphalt binders

Foresight Study of Road Pavement Technologies

The objectives of this paper are foresight study of the anticipated needs and requirements as well as identification of development directions of materials and technologies for use in road construction in the time perspective of approximately 30 years. In order to address this goal, Delphi forecasting method was utilized in the Polish-nationwide study with 150 invited experts. Paper presents results of research project dealing with development of directions of road pavement technologies with regards to the environmental aspects. As a result of the analyses, it was concluded that binding materials with improved viscoelastic range (often with modifications) would continue to play a leading role. Furthermore, according to the experts, the technologies that enable to monitor the state of road pavement in a continuous manner will be used to a greater range. Introduction of sensors into the pavement network will lead to the construction of "smart" roads while the spread of nanomaterial technologies in road construction will improve the durability and reliability of road pavement construction.Joanicjusz Nazark

The Baltic Journal of Road and Bridge Engineering

Construction of modern and durable asphalt and cement pavements requires high quality materials and suitable technologies that take into account sustainability concerns which are related to the environmental protection, mitigation and compensation for road construction effects on surface water and groundwater, soil, air, wildlife, landscape, vibration and noise. The objectives of this paper are to identify possible development directions of materials and technologies in road construction in the time perspective of approximately 30 years. In order to achieve that goal a nationwide Delphi survey with 150 invited experts was deployed. The study concluded that binding materials with improved viscoelastic range – and often with specific modifications – would continue to play a leading role. Furthermore, technologies that enable monitoring the state of road pavement condition in a continuous manner would be used to a greater range. Introduction of sensors into the pavement network would lead to the construction of “smart” roads while spreading of nanomaterial technology would improve the durability and reliability of road pavement construction.Łukasz NazarkoGeneralna Dyrekcja Dróg Krajowych i Autostra

ПЕРИОПЕРАЦИОННАЯ ХИМИОТЕРАПИЯ ПРИ ИНВАЗИВНОМ РАКЕ МОЧЕВОГО ПУЗЫРЯ: СОВРЕМЕННЫЕ ПРЕДСТАВЛЕНИЯ И ОБОСНОВАНИЕ НЕОБХОДИМОСТИ ПОИСКА АЛЬТЕРНАТИВНЫХ МЕТОДОВ ЛЕЧЕНИЯ. ИССЛЕДОВАНИЕ MAGNOLIA

The paper gives an overview of peri-operative chemotherapy in patients with muscle-invasive bladder cancer (MIBC) as insufficient option, demonstrates a clinical need for the development of more efficacious and safe treatment and introduces a MAGNOLIA study proposed by the European Association of Urology Research Fund in a concept of MIBC immunotherapy. The MAGNOLIA trial conducted in 56 research centers of 10 countries assesses whether adjuvant immunotherapy with recMAGE-A3+AS15 vaccine is safe and effective and improves outcome of patients with MAGE-A3 positive MIBC after cystectomy. 60 of 273 patients have been enrolled. The trial has to be continued to elaborate a general peri-operative treatment strategy for MIBC.Представлены данные II фазы рандомизированного исследования MAGNOLIA, проводившегося в 56 исследовательских центрах в 10 странах. Целью исследования MAGNOLIA является изучение эффективности и безопасности применения вакцины (recMAGEA3+ AS15) у больных инвазивным раком мочевого пузыря (ИРМП). В исследовании приняли участие 342 пациента. На основании полученных данных сделан вывод: периоперационная химиотерапия не может быть рекомендована во всех случаях выявления ИРМП и требуется продолжение исследования для выработки общей стратегии химиотерапевтического воздействия при ИРМП

Variants in the <em>DDX6-CXCR5</em> autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

\ua9 2025 The Author(s). Objectives: Sj\uf6gren\u27s disease (SjD) and systemic lupus erythematosus (SLE) share genetic risk at the DDX6-CXCR5 locus (11q23.3). Identifying and functionally characterising shared SNPs spanning this locus can provide new insights into common genetic mechanisms of autoimmunity. Methods: Transdisease meta-analyses, fine-mapping, and bioinformatic analyses prioritised shared likely functional single nucleotide polymorphisms (SNPs) for allele-specific and cell type–specific functional interrogation using electromobility shift, luciferase reporter, and quantitative chromatin conformation capture assays and clustered regularly interspaced short palindromic repeat (CRISPR) gene regulation. Results: Five shared SNPs were identified as likely functional in primary human immune cells, salivary gland and kidney tissues: rs57494551, rs4936443, rs4938572, rs7117261, and rs4938573. All 5 SNPs exhibited cell type-specific and allele-specific effects on nuclear protein binding affinity and enhancer/promoter regulatory activity in immune, salivary gland epithelial, and kidney epithelial cell models. Mapping of chromatin–chromatin interactions revealed a chromatin regulatory network that expanded beyond DDX6 and CXCR5 to include PHLDB1, lnc-PHLDB1-1, BCL9L, TRAPPC4, among others. Coalescence of functional assays and multiomic data analyses indicated that these SNPs likely modulate the activity of 3 regulatory regions: intronic rs57494551 regulatory region, intergenic SNP haplotype (rs4938572, rs4936443, and rs7117261) regulatory region, and rs4938573 regulatory region upstream of the CXCR5 promoter. Conclusions: Shared genetic susceptibly at the DDX6-CXCR5 locus in SjD and SLE likely alters common mechanisms of autoimmunity, including interferon signalling (DDX6), autophagy (TRAPPC4), and lymphocytic infiltration of disease-target tissues (CXCR5). Further, using multiomic data from patients with SjD, combined with bioinformatic and in vitro functional studies, can provide mechanistic insights into how genetic risk influences the biological pathways that drive complex autoimmunity