Species-specific differences in the inhibition of 11β-hydroxysteroid dehydrogenase 2 by itraconazole and posaconazole

11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) converts active 11β-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids. Disruption of 11β-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypokalemia, hypernatremia and hypertension. Recently, the azole antifungals itraconazole and posaconazole were identified to potently inhibit human 11β-HSD2, and several case studies described patients with acquired AME. To begin to understand why this adverse drug effect was missed during preclinical investigations, the inhibitory potential of itraconazole, its main metabolite hydroxyitraconazole (OHI) and posaconazole against 11β-HSD2 from human and three commonly used experimental animals was assessed. Whilst human 11β-HSD2 was potently inhibited by all three compounds (IC; 50; values in the nanomolar range), the rat enzyme was moderately inhibited (1.5- to 6-fold higher IC; 50; values compared to human), and mouse and zebrafish 11β-HSD2 were very weakly inhibited (IC; 50; values above 7 μM). Sequence alignment and application of newly generated homology models for human and mouse 11β-HSD2 revealed significant differences in the C-terminal region and the substrate binding pocket. Exchange of the C-terminus and substitution of residues Leu170,Ile172 in mouse 11β-HSD2 by the corresponding residues His170,Glu172 of the human enzyme resulted in a gain of sensitivity to itraconazole and posaconazole, resembling human 11β-HSD2. The results provide an explanation for the observed species-specific 11β-HSD2 inhibition by the studied azole antifungals. The obtained structure-activity relationship information should facilitate future assessments of 11β-HSD2 inhibitors and aid choosing adequate animal models for efficacy and safety studies

Aplicación del Láser Escáner Terrestre (TLS) a la modelización de estructuras: precisión, exactitud y diseño de la adquisición de datos en casos reales

Terrestrial laser scanner is employed in a wide range of engineering applications, because of the specifications of TLS units and the good precision reached. This paper presents the application of TLS to structures and walls modeling. It analyzes the factors that influence final accuracy: cloud registration, target type and the effect of scanning angle and distance. A field test was performed with calibrated panels, obtaining real precision and accuracy values for the most common distance ranges in engineering. We propose and validate the usage of pattern graphs relating precision and accuracy versus distance and scanning angle for field survey design. The application of pattern graph in the design of field scan surveys for dam movement control is also presented. Recommendations are made for the application of TLS technique to large structures.<br><br>El láser escáner terrestre se emplea en numerosas aplicaciones de Ingeniería, debido a las prestaciones de los equipos y a las precisiones alcanzadas. Se presenta la aplicación del TLS a la modelización de estructuras y paramentos verticales. Se analizan los factores que influyen en la precisión final: registro de nubes, tipo de dianas y el efecto del ángulo y distancia de escaneo. Se realizó una prueba de campo con testigos calibrados, obteniendo valores reales de precisión y exactitud para los rangos de distancia más usuales en Ingeniería. Se propone y valida el empleo de gráficos patrón que relacionan las variables precisión y exactitud con los factores distancia y ángulo de escaneo para el diseño de trabajos de campo. Se expone su aplicación al diseño de los escaneos para el control de movimientos de una presa. Se realizan recomendaciones para la aplicación de la técnica TLS a grandes estructuras

Racial Disparities in Emergency General Surgery: Do Differences in Outcomes Persist Among Universally Insured Military Patients?

Research Objective: Described as one of the most serious health problems affecting the nation, racial disparities are estimated to account for \u3e83,000 deaths, \u3e$57 billion per year. They have been identified in multiple surgical settings, including differences in outcomes by race among emergency general surgery(EGS) patients. As many minority patients are uninsured, increasing access to care is thought to be a viable solution to mitigate inequities. The objectives of this study were to determine whether racial disparities in 30/90/180day outcomes exist within a universally-insured population of military/civilian-dependent EGS patients and whether differences in outcomes differentially persist in care received at military-vs-civilian hospitals and among sponsors who are enlisted-service members-vs-officers. It also considered longer-term outcomes of care. Study Design: Risk-adjusted survival analyses using Cox proportional-hazards models assessed race-based differences in mortality, major morbidity, and readmission from index-hospital admission (discharge for readmission) through 30/90/180days. Models accounted for hospital clustering and possible biases associated with missing race (reweighted-estimating equations). Sub-analyses considered effects restricted to operative interventions, stratified by 24 EGS-diagnostic categories defined by the American Association for the Surgery of Trauma(AAST), and effect modification related to rank (SES-proxy: officers-vs-enlisted-sponsors) and military-vs-civilian-hospital care. Population Studied: Five years of national TRICARE Prime/Prime-plus data, which provides insurance to active/reserve/retired members of the US Armed Services and dependents, were queried for adults (≥18y) with primary EGS conditions, defined by the AAST. Patients who did not have an index admission between 01/01/2006-01/07/2010 (minimum 180days follow-up) or who were not continuously enrolled in TRICARE for 180days were excluded. Non-surviving patients were retained while they survived. Principal Findings: A total of 101,011 patients were included: 73.5% White, 14.5% Black, 4.4% Asian, 7.7% other. Risk-adjusted analyses reported equivalent-or-better mortality and readmission outcomes among minority patients at 30/90/180days—even when restricted to civilian hospitals where studies suggest that EGS disparities are found. Readmissions within military hospitals were lower among minority patients. Major morbidity was higher among Black versus White patients (HR[95%CI]): 30day-1.23[1.13-1.35], 90day-1.18[1.09-1.28], 180day-1.15[1.07-1.24]—a finding driven by appendiceal disorders (HR:1.69-1.70). No other diagnostic category-based HR was significant. When considered by rank, significant effects were isolated to enlisted-service members. However, given the relatively small number of patients who were (dependents of) officers, it is difficult to determine whether rank-based findings are a result of social determinants or influenced by the limited number of minority patients. Conclusions: The first of its kind to examine racial disparities in longer-term outcomes of EGS care, this longitudinal analysis of military patients demonstrated apparent mitigation of racial disparities within a universally-insured health system when compared to the overall US health system. Efforts to explain findings based on consideration of care provided in military-vs-civilian hospitals, among specific EGS-diagnostic categories, and based on sponsor rank revealed modification of the association between race and outcomes to some extent for all three. Implications for Policy or Practice: The contrast between results for universally-insured military/civilian-dependent patients and reported disparities among all US civilian patients merits consideration. The data speak to the importance of insurance-coverage in the development of disparities interventions nationwide and will help to inform policy within the DoD

A review of the use of terrestrial laser scanning application for change detection and deformation monitoring of structures

Change detection and deformation monitoring is an active area of research within the field of engineering surveying as well as overlapping areas such as structural and civil engineering. The application of Terrestrial Laser Scanning (TLS) techniques for change detection and deformation monitoring of concrete structures has increased over the years as illustrated in the past studies. This paper presents a review of literature on TLS application in the monitoring of structures and discusses registration and georeferencing of TLS point cloud data as a critical issue in the process chain of accurate deformation analysis. Past TLS research work has shown some trends in addressing issues such as accurate registration and georeferencing of the scans and the need of a stable reference frame, TLS error modelling and reduction, point cloud processing techniques for deformation analysis, scanner calibration issues and assessing the potential of TLS in detecting sub-centimetre and millimetre deformations. However, several issues are still open to investigation as far as TLS is concerned in change detection and deformation monitoring studies such as rigorous and efficient workflow methodology of point cloud processing for change detection and deformation analysis, incorporation of measurement geometry in deformation measurements of high-rise structures, design of data acquisition and quality assessment for precise measurements and modelling the environmental effects on the performance of laser scanning. Even though some studies have attempted to address these issues, some gaps exist as information is still limited. Some methods reviewed in the case studies have been applied in landslide monitoring and they seem promising to be applied in engineering surveying to monitor structures. Hence the proposal of a three-stage process model for deformation analysis is presented. Furthermore, with technological advancements new TLS instruments with better accuracy are being developed necessitating more research for precise measurements in the monitoring of structures

Experimental study of negative photoconductivity in n-PbTe(Ga) epitaxial films

We report on low-temperature photoconductivity (PC) in n-PbTe(Ga) epitaxial films prepared by the hot-wall technique on -BaF_2 substrates. Variation of the substrate temperature allowed us to change the resistivity of the films from 10^8 down to 10_{-2} Ohm x cm at 4.2 K. The resistivity reduction is associated with a slight excess of Ga concentration, disturbing the Fermi level pinning within the energy gap of n-PbTe(Ga). PC has been measured under continuous and pulse illumination in the temperature range 4.2-300 K. For films of low resistivity, the photoresponse is composed of negative and positive parts. Recombination processes for both effects are characterized by nonexponential kinetics depending on the illumination pulse duration and intensity. Analysis of the PC transient proves that the negative photoconductivity cannot be explained in terms of nonequilibrium charge carriers spatial separation of due to band modulation. Experimental results are interpreted assuming the mixed valence of Ga in lead telluride and the formation of centers with a negative correlation energy. Specifics of the PC process is determined by the energy levels attributed to donor Ga III, acceptor Ga I, and neutral Ga II states with respect to the crystal surrounding. The energy level corresponding to the metastable state Ga II is supposed to occur above the conduction band bottom, providing fast recombination rates for the negative PC. The superposition of negative and positive PC is considered to be dependent on the ratio of the densities of states corresponding to the donor and acceptor impurity centers.Comment: 7 pages, 4 figure

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