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

Investigations of High Precision Terrestrial Laser Scanning with Emphasis on the Development of a Robust Close-Range 3D-Laser Scanning System

In recent years, numerous measurement systems and techniques have become available on the market for three-dimensional (3D) surveying of objects. Largely due to the increasing need of 3D-data, fast area-wide 3D-measurement methods are in high demand. In the world of surveying and the field of engineering geodesy, terrestrial laser scanning has been established as a newer measurement method for fast, area-wide 3D-surveying. Terrestrial laser scanners measure distances and angles to objects without any contact. The actual geometry information of the scanned object has to be derived from a resulting 3D-point cloud in post-processing. After the initial hype of terrestrial laser scanning, a slight disillusionment set in. Projects were not profitable or failed due to insufficient knowledge about laser scanning technology and its specifics. In addition, the hardware and software products available on the market often do not meet the requirements of specific applications. Thus, the selection of convenient applications for a particular terrestrial laser scanning system, the sensitivity in terms of environmental conditions, or the extensive post-processing of laser scanning data are just a few of the difficulties in using laser scanning technology. As a result, terrestrial laser scanning is rarely used for projects in engineering geodesy. Even though terrestrial laser scanning offers great potential, new fields of application have yet to be investigated. This thesis originated from a project addressing the development of a qualified measurement system based on terrestrial laser scanning for the surveying of underground utility caverns in the field of water and sewage engineering. There was no convenient measurement system available on the market when the project started in 2005. There are three main objectives of this thesis: the development of a cost-efficient robust close-range 3D-laser scanning system largely for surveying underground utility caverns, the calibrations and investigations of terrestrial laser scanners with focus on the newly developed measurement system, and the development of new fields of application for terrestrial laser scanning. Moreover, this thesis contributes to the area of terrestrial laser scanning by offering better knowledge on its integration into engineering geodesy. For the hardware development, the 2D-laser scanner SICK LMS200-30106 by Sick AG was selected and implemented as a distance measurement unit measuring distances and angles. This unit is well known and established in industrial applications and in the field of robotics. In addition, all components that were used for the close-range 3D-laser scanning system were selected according to predefined requirements. These requirements were strongly related to the application of the measurement of underground utility caverns. Furthermore, this thesis shows that an appropriate calibration of the close-range 3D-laser scanning system – the distance measurement unit specifically – allows its application in the field of engineering geodesy. Thus, appropriate calibration routines were developed, and intensive additional investigations of the measurement systems enabled the verification of the measurement accuracy and performance. The close-range terrestrial 3D-laser scanner ZLS07 resulted from the development of a 3Dmeasurement system based on the terrestrial laser scanning technology. The ZLS07 is a robust and reliable measurement system that fulfils the requirements focused on surveying of underground utility caverns. Its specific limitations lie in the measurement range, accuracy, and angular resolution. However, the ZLS07 has been successfully established as a new measurement instrument at the surveying department of the city of Zurich. In addition to the hardware developments, an approach for automatic geometry modelling from 3D-point clouds was developed, tested, and discussed for post-processing 3D-point clouds of underground utility caverns. Furthermore, the ZLS07 was successfully used in other applications, such as the damage detection of an incinerator or the reverse engineering of technical constructions. In den letzen Jahren sind verschiedene neue Messsysteme und Messtechniken für die dreidimensionale (3D) Vermessung von Objekten auf dem Markt erschienen. Schnelle und flächendeckende Messmethoden sind wegen der stark steigenden Nachfrage nach 3D-Daten gesucht. Im Bereich der Vermessung und im Speziellen in der Ingenieurvermessung hat sich terrestrisches Laserscanning als eine neue Messmethode im Bereich der 3D-Vermessung etabliert. Terrestrische Laserscanner messen berührungslos Winkel und Distanzen. Das Resultat eines solchen Scans ist eine so genannte 3D-Punktwolke. Die gesuchten geometrischen Informationen des gescannten Objektes werden anschliessend im Post-Processing aus der 3DPunktwolke abgeleitet. Terrestrisches Laserscanning erfuhr zu Beginn des neuen Jahrtausends kurz nach dessen Einführung im Bereich der Ingenieurvermessung einen grossen Aufschwung. Eine erste Ernüchterung liess jedoch nicht lange auf sich warten. Projekte blieben erfolglos oder misslangen wegen ungenügender Kenntnis über die Besonderheiten der neuen Messmethode. Zudem wurden häufig für terrestrisches Laserscanning ungeeignete Projekte durchgeführt. Ebenso wurde die aufwändige Auswertung der 3D-Punktwolken unterschätzt. Daher wird terrestrisches Laserscanning heutzutage eher selten für Projekte in der Ingenieurvermessung eingesetzt. Ausserdem können die auf dem Markt erhältlichen Hardware- und Software-Produkte die an ein Projekt geforderten Spezifikationen oft nicht erfüllen. Die vorgelegte Arbeit entstand aus einem Projekt zur Entwicklung eines geeigneten Messsystems basierend auf der Laserscanning-Technologie zur Ausmessung von Schachtkammern im Bereich des Wasser- und Abwasser-Ingenieurwesens. Drei Ziele werden mit dieser Arbeit speziell verfolgt: 1. die Entwicklung eines robusten terrestrischen Laserscanners für den Nahbereich zur Aufnahme von Schachtkammern; 2. die Kalibrierung und Untersuchung von terrestrischen Laserscannern im Allgemeinen und des neu entwickelten Laserscanners im spezifischen; 3. die Erschliessung von neuen Einsatzgebieten für terrestrisches Laserscanning im Bereich der Ingenieurvermessung. Zusätzlich soll diese Arbeit einen Beitrag zum besseren Verständnis der Laserscanning-Technologie und deren Integration in das Gebiet der Vermessung leisten. Als Distanzmesssensor für das neue Messsystem wurde der Profilscanner SICK LMS200-30106 von der Firma Sick AG ausgewählt. Dieser Sensor ist aus den Bereichen der Robotik und der industriellen Anwendungen (u.a. Sicherheitssysteme) bekannt. Anhand eines Anforderungskatalogs an das neue Messsystem wurden die Komponenten ausgewählt. Die Anforderungen sind fokussiert auf den Einsatz zur Vermessung von Schachtkammern. Weiter zeigt diese Arbeit, dass eine geeignete Kalibrierung der eingesetzten Komponenten und des gesamten Messsystems Anwendungen im Bereich der Ingenieurvermessung ermöglicht. Passende Kalibrierroutinen wurden dazu entwickelt. Intensive zusätzliche Untersuchungen des entwickelten Messsystems erlauben Aussagen zur Messgenauigkeit und Leistungsfähigkeit. Der terrestrische Laserscanner ZLS07 ist das Resultat der Entwicklung eines neuen Messsystems basierend auf der Laserscanning-Technologie. Der ZLS07 ist ein robuster und zuverlässiger terrestrischer Laserscanner, welcher die Anforderungen für die Aufnahme von Schachtkammern erfüllt. Die Grenzen des Laserscanners liegen in den Bereichen der maximalen Messdistanz, der Messgenauigkeit und der Winkelauflösung. Zusätzlich zu den Entwicklungen der Hardware wurde ein Ansatz zur automatisierten Auswertung von 3D-Punktwolken von Schachtkammern entwickelt und getestet. Der ZLS07 wird heutzutage erfolgreich bei der Vermessungsabteilung der Stadt Zürich eingesetzt. Neben der Aufnahme von Schachtkammern wurde der ZLS07 beispielsweise auch erfolgreich für die Bestimmung von Schadstellen in einem Verbrennofen oder für die Aufnahme von technischen Bauwerken eingesetzt

Lead Chalcogenide on Silicon Infrared Focal Plane Arrays for Thermal Imaging(Review Paper)

"Narrow gap IV-VI [lead chalcogenides like Pbl-xSnxSe and PbTe] layers grown epitaxially on silicon( III) substrates by molecular beam epitaxy exhibit high quality despite the large lattice and thermal expansion mismatch. A CaF2 buffer layer is employed for compatibility. Due to easy glide of misfit dislocations in the IV- VI layers, thei1rtal strains relax even at cryogenic. temperatures and after many temperature cyclings. The high permittivities of the IV- VI layers effectively shield the electric fields from charged defects. Higher quality devices are obtained from lower quality material, at variance to narrow gap 11- VI and 111- V compounds. Material characterisation and sensor array properties have been reviewed. Schottky barrier or p-n+ sensor arrays have been delineated using standard photolithography. At low temperatures, the sensitivities are limited by defects, mainly dislocations, and the device performance is predicted by the dislocation density. At higher temperatures, the ultimate theoretical sensitivity is obtained with Schottky barrier devices despite large mismatch and with only 3 µm thickness of the layers. First chara'cterisations of a 96 x 128 array on a silicon substrate containing the read-out circuits show that the concept is functional and gives high yield

Mid-Infrared Tunable Resonant Cavity Enhanced Detectors

Mid-infrared detectors that are sensitive only in a tunable narrow spectral band are presented. They are based on the Resonant Cavity Enhanced Detector (RCED) principle and employing a thin active region using IV-VI narrow gap semiconductor layers. A Fabry-Pérot cavity is formed by two mirrors. The active layer is grown onto one mirror, while the second mirror can be displaced. This changes the cavity length thus shifting the resonances where the detector is sensitive. Using electrostatically actuated MEMS micromirrors, a very compact tunable detector system has been fabricated. Mirror movements of more than 3 μm at 30V are obtained. With these mirrors, detectors with a wavelength tuning range of about 0.7 μm have been realized. Single detectors can be used in mid-infrared micro spectrometers, while a detector arrangement in an array makes it possible to realize Adaptive Focal Plane Arrays (AFPA)

Mid-Infrared Tunable Resonant Cavity Enhanced Detectors

sensor