The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Endothelin-A receptor antagonists (ETRAs) and phosphodiesterase-type 5 inhibitors are approved monotherapies for the treatment of pulmonary arterial hypertension; combining agents from these two drug classes could be beneficial. * There is a significant pharmacokinetic (PK) interaction between the ETRA bosentan and the phosphodiesterase-type 5 inhibitor sildenafil. * This study assessed whether the ETRA sitaxentan similarly impacts the PK of sildenafil. WHAT THIS STUDY ADDS: * This study demonstrates that sitaxentan has little effect on sildenafil PK and pharmacodynamics and that no dose adjustment of either agent is required upon co-administration of sildenafil with sitaxentan. AIMS: This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers. METHODS: Healthy subjects (18-60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period. RESULTS: Sildenafil exposure was slightly higher [AUC(infinity) geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (E(max)+) and maximum negative (E(max)-) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8-7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study. CONCLUSION: The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan

Deep learning cardiac motion analysis for human survival prediction

Motion analysis is used in computer vision to understand the behaviour of moving objects in sequences of images. Optimising the interpretation of dynamic biological systems requires accurate and precise motion tracking as well as efficient representations of high-dimensional motion trajectories so that these can be used for prediction tasks. Here we use image sequences of the heart, acquired using cardiac magnetic resonance imaging, to create time-resolved three-dimensional segmentations using a fully convolutional network trained on anatomical shape priors. This dense motion model formed the input to a supervised denoising autoencoder (4Dsurvival), which is a hybrid network consisting of an autoencoder that learns a task-specific latent code representation trained on observed outcome data, yielding a latent representation optimised for survival prediction. To handle right-censored survival outcomes, our network used a Cox partial likelihood loss function. In a study of 302 patients the predictive accuracy (quantified by Harrell's C-index) was significantly higher (p < .0001) for our model C=0.73 (95$\%$ CI: 0.68 - 0.78) than the human benchmark of C=0.59 (95$\%$ CI: 0.53 - 0.65). This work demonstrates how a complex computer vision task using high-dimensional medical image data can efficiently predict human survival

Variability in prey field structure drives inter-annual differences in prey encounter by a marine predator, the little penguin

This study was funded by Australian Research Council Linkage Grants (grant nos. LP110200603 and LP160100162), with contributions from the Taronga Conservation Society Australia.Understanding how marine predators encounter prey across patchy landscapes remains challenging due to difficulties in measuring the three-dimensional structure of pelagic prey fields at scales relevant to animal movement. We measured at-sea behaviour of a central-place forager, the little penguin (Eudyptula minor), over 5 years (2015–2019) using GPS and dive loggers. We made contemporaneous measurements of the prey field within the penguins' foraging range via boat-based acoustic surveys. We developed a prey encounter index by comparing estimates of acoustic prey density encountered along actual penguin tracks to those encountered along simulated penguin tracks with the same characteristics as real tracks but that moved randomly through the prey field. In most years, penguin tracks encountered prey better than simulated random movements greater than 99% of the time, and penguin dive depths matched peaks in the vertical distribution of prey. However, when prey was unusually sparse and/or deep, penguins had worse than random prey encounter indices, exhibited dives that mismatched depth of maximum prey density, and females had abnormally low body mass (5.3% lower than average). Reductions in prey encounters owing to decreases in the density or accessibility of prey may ultimately lead to reduced fitness and population declines in central-place foraging marine predators.Publisher PDFPeer reviewe

Coastal seascape variability in the intensifying East Australian Current Southern Extension

Funding: This study was funded by Australian Research Council Linkage Grants (LP110200603 awarded to RH, DS and Iain Field, and LP160100162 awarded to IJ, Martina Doublin, MC, GC, DS, Iain Suthers and RH) with contributions from the Taronga Conservation Society Australia, NSW National Parks and the Australian Antarctic Division.Coastal pelagic ecosystems are highly variable in space and time, with environmental conditions and the distribution of biomass being driven by complex processes operating at multiple scales. The emergent properties of these processes and their interactive effects result in complex and dynamic environmental mosaics referred to as “seascapes”. Mechanisms that link large-scale oceanographic processes and ecological variability in coastal environments remain poorly understood, despite their importance for predicting how ecosystems will respond to climate change. Here we assessed seascape variability along the path of the rapidly intensifying East Australian Current (EAC) Southern Extension in southeast Australia, a hotspot of ocean warming and ecosystem tropicalisation. Using satellite and in situ measures of temperature, salinity and current velocity coupled with contemporaneous measurements of pelagic biomass distribution from nine boat-based active acoustic surveys in five consecutive years, we investigated relationships between the physical environment and the distribution of pelagic biomass (zooplankton and fish) at multiple timescales. Survey periods were characterised by high variability in oceanographic conditions, with variation in coastal conditions influenced by meso-to-large scale processes occurring offshore, including the position and strength of eddies. Intra-annual variability was often of a similar or greater magnitude to inter-annual variability, suggesting highly dynamic conditions with important variation occurring at scales of days to weeks. Two seascape categories were identified being characterised by (A) warmer, less saline water and (B) cooler, more saline water, with the former indicating greater influence of the EAC on coastal processes. Warmer waters were also associated with fewer, deeper and less dense biological aggregations. As the EAC continues to warm and penetrate further south, it is likely that this will have substantial effects on biological activity in coastal pelagic ecosystems, including a potential reduction in the accessibility of prey aggregations to surface-feeding predators and to fisheries. These results highlight the import role of offshore oceanographic processes in driving coastal seascape variability and biological activity in a region undergoing rapid oceanic warming and ecological change.Publisher PDFPeer reviewe

The Last Hurrah (and The Long Haul): co-creation of theatre as climate change education

Meaningful action on climate change requires affective engagement with the human impacts of the problem. The Last Hurrah (and The Long Haul) project was developed using theatrical storytelling as a tool to provoke thought and empathy about the lived experience of climate change. Over a period of three years, a company of Acting students and their lecturer worked with faculty and students from a Geography department to explore climate change stories and the physical and human geographies that shape their impacts. This paper reflects on the process, highlighting opportunities and challenges for Geographers to become involved in interdisciplinary teaching and creative engagement as part of a more holistic approach to wicked problems, and explores the impact of the learning experience with the students involved. We conclude that storytelling is profoundly suited to overcoming the psychological barriers that can stand in the way of appreciating and empathising with the implications for everyday life of an altered climate system. Recommendations are made for future interdisciplinary education projects using creative arts to address global challenges

Use of responder threshold criteria to evaluate the response to treatment in the phase III CHEST-1 study

BackgroundIn the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase - Stimulator Trial 1 (CHEST-1) study, riociguat improved 6-minute walking distance (6MWD) vs placebo in patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. In this study, the proportion of patients who achieved responder thresholds that correlate with improved outcome in patients with pulmonary arterial hypertension was determined at baseline and at the end of CHEST-1.MethodsPatients received placebo or riociguat individually adjusted up to 2.5 mg 3 times a day for 16 weeks. Response criteria were defined as follows: 6MWD increase ≥40 m, 6MWD ≥380 m, cardiac index ≥2.5 liters/min/m2, pulmonary vascular resistance <500 dyn∙sec∙cm−5, mixed venous oxygen saturation ≥65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg.ResultsRiociguat increased the proportion of patients with 6MWD ≥380 m, World Health Organization functional class I/II, and pulmonary vascular resistance <500 dyn∙sec∙cm−5 from 37%, 34%, and 25% at baseline to 58%, 57%, and 50% at Week 16, whereas there was little change in placebo-treated patients (6MWD ≥380 m, 43% vs 44%; World Health Organization functional class I/II, 29% vs 38%; pulmonary vascular resistance <500 dyn∙sec∙cm−5, 27% vs 26%). Similar changes were observed for thresholds for cardiac index, mixed venous oxygen saturation, N-terminal pro-brain natriuretic peptide, and right atrial pressure.ConclusionsIn this exploratory analysis, riociguat increased the proportion of patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy achieving criteria defining a positive response to therapy

Heteroepitaxial growth of ferromagnetic MnSb(0001) films on Ge/Si(111) virtual substrates

Molecular beam epitaxial growth of ferromagnetic MnSb(0001) has been achieved on high quality, fully relaxed Ge(111)/Si(111) virtual substrates grown by reduced pressure chemical vapor deposition. The epilayers were characterized using reflection high energy electron diffraction, synchrotron hard X-ray diffraction, X-ray photoemission spectroscopy, and magnetometry. The surface reconstructions, magnetic properties, crystalline quality, and strain relaxation behavior of the MnSb films are similar to those of MnSb grown on GaAs(111). In contrast to GaAs substrates, segregation of substrate atoms through the MnSb film does not occur, and alternative polymorphs of MnSb are absent