Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Influence of Housing Material and Geometry on Thermal Stability of Threaded Spindle Bearing Assembly

The accuracy of guiding a spindle is greatly influenced by the thermal load of the bearing. Increased thermal load implies deformation of the bearing parts which is directly reflected in the work quality of the machine system. For this reason, the aim of this paper is to analyse the influence of the material and the geometry of the housing on the temperature field of the threaded spindle bearing assembly, which was realised by "radially mounting" of axial angular contact ball bearing ZKLN. This paper represents a new approach for thermal analysis of the special bearings, type ZKLN which are not involved in the relevant standards for the determination of the reference speed. At the same time the value of this paper finds itself in finding of the guideline at engineering practice which is very important at early design phase of the systems with threaded spindle. The analysis was carried out using experimental and numerical methods. Combination of the mentioned methods gave result which was used to define appropriate guideline regarding influence of housing material and geometry on thermal stability of the ZKLN bearing

OTPADNE EMULZIJE MASTI I ULJA IZ TEHNOLOŠKOG PROCESA OBRADE METALA KAO ZAGAĐUJUĆE MATERIJE ŽIVOTNE SREDINE

The exploitation of industrial waste oils and fats, along with the influence of physical, thermal, chemical and biological factors, is the reason for their transformation and formation of waste emulsions that pose a potential risk of environmental pollution. This paper provides an overview of reference technological processes which are considered as the sources of environmental pollutants. In addition, this study presents the qualitative and quantitative characteristics of aqueous emulsions of waste fats and oils from metal processing and thus proposes a system for treatment that would minimize the risk of environmental pollution. Eksploatacijom industrijskih masti i ulja, usled delovanja fizičkih, termičkih, hemijskih i bioloških faktora, dolazi do njihove transformacije i stvaranja otpadnih emulzija koje predstavljaju potencijalni rizik zagađenja životne sredine. U radu su dati referentni tehnološki procesi koji predstavljaju izvore ovih zagađujućih materija, a zatim je dat prikaz kvalitativno-kvantitativnih karakteristika otpadnih vodenih emulzija masti i ulja iz procesa obrade metala, kao i predlog sistema prečišćavanja, kojim se rizik zagađenja životne sredine svodi na minimum

Ways towards city development and new technologies

Cities are challenged with constant changes. Unpredictability is a product of multilevel changes implying new thinking of city development and place making process. New thinking is related to theory of decision making, according to which we have to develop plenty ways of city development to be in a position for travelling along and across the ways. Therefore, we need new technologies to generate and evaluate the ways, so we can be proactive in city development and place making. The paper will discuss pros and cons of using new technologies in the process assuming that the technology per se is not an instrument for place making. Research thesis is that integration between new technologies, interdisciplinary and social knowledge is necessary to generate and evaluate appropriate ways. In line with this, the ways should be agreed in various social arenas, lining on new technologies as a support for data gathering, producing new information for discussion and clarification, using different diagrams, graphs, charts, reports and thematic maps for analysis of city’s places and generating consensual ways for improving them or create new ones. Therefore, the aim of the paper is to discuss the role of new technologies in city development and place making in regards to decision making and place making theory. The paper will result in a form of conceptual model for using new technologies in city and place development. The method will use comparative analysis of decision making and place making theory as well as students’ case studies that are result of ten years work at the subject “The Future of the City”