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Abstract Macitentan is a dual endothelin receptor antagonist (ERA) approved for treating pulmonary arterial hypertension (PAH). SOPRANO evaluated the efficacy and safety of macitentan versus placebo in pulmonary hypertension (PH) patients after left ventricular assist device (LVAD) implantation. SOPRANO was a phase 2, multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group study. Patients with an LVAD implanted within the prior 90 days who had persistent PH (i.e., mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure [PAWP] ≤18 mmHg, and pulmonary vascular resistance [PVR] >3 Wood units [WU]) were randomized (1:1) to macitentan 10 mg or placebo once daily for 12 weeks. The primary endpoint was change in PVR. Secondary endpoints included change in right‐heart catheterization hemodynamic variables, N‐terminal prohormone of brain natriuretic peptide levels, World Health Organization functional class, and safety/tolerability. Fifty‐seven patients were randomized to macitentan (n = 28) or placebo (n = 29). A statistically significant reduction in PVR from baseline to Week 12 was observed with macitentan versus placebo (placebo‐corrected geometric mean ratio, 0.74; 95% confidence interval, 0.58–0.94; p = .0158). No statistically significant differences were observed in secondary endpoints. In a post‐hoc analysis, 66.7% of patients receiving macitentan achieved PVR

A recent trend in hydroinformatics has been the growing number of data, models, and cyber tools, which are web accessible, each aiming to improve common research tasks in hydrology through web technologies. Coupling web-based models and tools holds great promise for an integrated environment that can facilitate community participation, collaboration, and scientific replication. There are many examples of server-side, hydroinformatics resource coupling, where a common standard serves as an interface. Yet, there are few, if any, examples of client-side resource coupling, particularly cases where a common specification is employed. Toward this end, we implemented the basic model interface (BMI) specification in the JavaScript programing language, the most widely used programing language on the web. By using BMI, we coupled two client-side hydrological applications (HydroLang and HLM-Web) to perform rainfall–runoff simulations of historical events with rainfall data and a client-side hydrological model as a case study demonstration. Through this process, we present how a common and often tedious task – the coupling of two independent web resources – can be made easier through the adoption of a common standard. Furthermore, applying the standard has facilitated a step toward the possibility of client-side ‘Model as a Service’ for hydrological models. HIGHLIGHTS We present the basic model interface (BMI) specification for the JavaScript programming language.; We present a comprehensive example of how BMI may be used as a common standard to couple client-side, hydroinformatics web resources.; For developers, BMI for JavaScript simplifies the effort needed to implement an Application Programing Interface for their resource.; For users, BMI for JavaScript accelerates learning and working with a new resource.;

Computational hydrological models and simulations are fundamental pieces of the workflow of contemporary hydroscience research, education, and professional engineering activities. In support of hydrological modelling efforts, web-enabled tools for data processing, storage, computation, and visualization have proliferated. Most of these efforts rely on server resources for computation and data tasks and client-side resources for visualization. However, continued advancements of in-browser, client-side compute performance present an opportunity to further leverage client-side resources. Towards this end, we present an operational rainfall-runoff model and simulation engine running entirely on the client side using the JavaScript programming language. To demonstrate potential uses, we also present an easy-to-use in-browser interface designed for hydroscience education. Although the use case presented here is self-contained, the core technologies can extend to leverage multi-core processing on single machines and parallelization capabilities of multiple clients or JavaScript-enabled servers. These possibilities suggest that client-side hydrological simulation can play a central role in a dynamic, interconnected ecosystem of web-ready hydrological tools. HIGHLIGHTS We present the Hillslope Link Model (HLM)-Web, a simulation engine for rainfall-runoff modelling in JavaScript.; The simulation engine runs full-scale, physically based rainfall-runoff models.; All computations are performed on the client side within the browser.; HLM-Web is demonstrated with a use case for hydroscience education.; The use case facilitates hydrological education and research ‘sandboxing’.;

Sensors and control technologies are being deployed at unprecedented levels in both urban and rural water environments. Because sensor networks and control allow for higher-resolution monitoring and decision making in both time and space, greater discretization of control will allow for an unprecedented precision of impacts, both positive and negative. Likewise, humans will continue to cede direct decision-making powers to decision-support technologies, e.g. data algorithms. Systems will have ever-greater potential to effect human lives, and yet, humans will be distanced from decisions. Combined these trends challenge water resources management decision-support tools to incorporate the concepts of ethical and normative expectations. Toward this aim, we propose the Water Ethics Web Engine (WE)2, an integrated and generalized web framework to incorporate voting-based ethical and normative preferences into water resources decision support. We demonstrate this framework with a ‘proof-of-concept’ use case where decision models are learned and deployed to respond to flooding scenarios. Findings indicate that the framework can capture group ‘wisdom’ within learned models to use in decision making. The methodology and ‘proof-of-concept’ system presented here are a step toward building a framework to engage people with algorithmic decision making in cases where ethical preferences are considered. We share our framework and its cyber components openly with the research community. HIGHLIGHTS Water Ethics Web Engine (WE)2 is a web framework to incorporate voting-based ethical preferences into water resources decision support.; We share (WE)2 openly at our project repository: https://github.com/uihilab/waterethicswebengine.; A proof-of-concept use case is presented where decision models are learned and deployed with flooding scenarios.; Results indicate that the framework can capture group ‘wisdom’ in learned models.;

BackgroundHeart failure remains a leading cause of mortality and a major driver of health care utilization. Despite numerous medical advances in heart failure, associated hospitalizations continue to increase, owing largely to suboptimal outpatient management. Remote patient monitoring (RPM) aims to further address this current need in heart failure care by providing data to clinical teams to act pre-emptively to address clinical decompensation. However, to date, RPM approaches using noninvasive home-based patient sensors have failed to demonstrate clinical efficacy. ObjectiveThe Novel Data Collection and Analytics Tools for Remote Patient Monitoring in Heart Failure (Nov-RPM-HF) Trial aims to address current noninvasive RPM limitations. Nov-RPM-HF will evaluate a clinician co-designed RPM platform using emerging data collection and presentation tools for heart failure management. These tools include a ballistocardiograph to monitor nocturnal patient biometrics, clinical alerts for abnormal biometrics, and longitudinal data presentation for clinician review. MethodsNov-RPM-HF is a 100-patient single-center prospective trial, evaluating patients over 6 months. The outcomes will include patient adherence to data collection, patient/clinician-perceived utility of the RPM platform, medication changes including the titration of guideline-directed medical therapy to target doses, heart failure symptoms/performance status, and unplanned heart failure hospitalizations or emergency department visits. ResultsThis prospective trial began enrollment in March 2020 and anticipates enrollment completion by June 2022, with trial completion by December 2022. ConclusionsThis trial protocol aims to provide a systematic framework for the evaluation of heart failure RPM strategies, which are currently heavily used but seldom robustly studied. The trial results will help to inform the role of noninvasive RPM as a viable clinical management strategy in heart failure care. International Registered Report Identifier (IRRID)DERR1-10.2196/32873

The challenge of distinguishing genetic drift from selection remains a central focus of population genetics. Time-sampled data may provide a powerful tool for distinguishing these processes, and we here propose approximate Bayesian, maximum likelihood, and analytical methods for the inference of demography and selection from time course data. Utilizing these novel statistical and computational tools, we evaluate whole-genome datasets of an influenza A H1N1 strain in the presence and absence of oseltamivir (an inhibitor of neuraminidase) collected at thirteen time points. Results reveal a striking consistency amongst the three estimation procedures developed, showing strongly increased selection pressure in the presence of drug treatment. Importantly, these approaches re-identify the known oseltamivir resistance site, successfully validating the approaches used. Enticingly, a number of previously unknown variants have also been identified as being positively selected. Results are interpreted in the light of Fisher's Geometric Model, allowing for a quantification of the increased distance to optimum exerted by the presence of drug, and theoretical predictions regarding the distribution of beneficial fitness effects of contending mutations are empirically tested. Further, given the fit to expectations of the Geometric Model, results suggest the ability to predict certain aspects of viral evolution in response to changing host environments and novel selective pressures.

The present paper describes an exercise model that produces a voluntary hindlimb weight-lifting response. Each rat was operantly conditioned to enter a vertical tube, insert its head into a weighted ring (either 70 g or 700 g), lift the ring until its nose interrupted an infrared detector, and then lower the ring. Load cells measured the external force generated, and displacement transducers measured the vertical displacement of the ring during each lifting and lowering movement. The apparatus and training procedures were computer automated. Peak force, velocity, work, and power were calculated for each movement. Rats in both groups easily acquired the task after 12-15 training sessions, on average, conducted 5 days/wk. Once rats were trained, the lifting patterns were quite stable during several more weeks of posttraining exercise; however, the lighter 70-g load gave rise to more variable performances across rats. Results demonstrate the utility of quantitating the biomechanics of volitional movements and suggest that the present model can establish and maintain controlled repetitive movements necessary for studies of adaptation and/or injury in muscles, tendon, and bone.

The purpose of this study was to determine whether a marked decrease in red cell mass with a normal blood volume (normovolemic anemia) would compromise osseous repair in experimental mandibular bone grafts. In adult male dogs, osseous defects in the mandibular body were restored with combined allogeneic and autologous bone grafts. In the experimental group, the red cell mass was depleted by a mean 55% of the baseline value and the resulting anemia maintained for eight weeks by serial phlebotomies. In the control group phlebotomy was not performed. Osseous repair was evaluated by quantitative sequential radionuclide imaging, subjective and quantitative determinations of graft stability, and histologic examination. Results demonstrated no significant difference in bone graft repairs between the anemic and control animals by any of the evaluation methods over the eight-week period of study (P greater than 0.05).

The limitations of autologous vascularized grafts include morbidity at the donor site and the increased surgical time associated with graft retrieval. To overcome these limitations, freeze-dried allogeneic and fresh autologous vascularized rib grafts were compared in 6-cm mid-radial defects of dogs. There was no statistically significant difference between the two graft systems when postoperative radiographs, in vivo intraarterial angiograms, and histologic evaluation of vessel patency were compared. However, clinical assessment of graft stability favored the autologous grafts, and force deflection tests revealed that the freeze-dried grafts had only 64% of the graft strength of the fresh autologous grafts at the end of the experiment at 26 weeks.

A technique for securing skin grafts for vestibuloplasty with the Fibrin Adhesive System is described. This technique proved to be less time-consuming than the standard technique and provided secure, immobile stabilization of the skin grafts without hematoma formation.

This study compared the ability of fresh autogenous and freeze-dried allogenic split-thickness skin grafts to maintain vestibular depth following vestibuloplasty. Both graft systems resulted in covering of the alveolar ridge by firmly attached tissue, which would be expected to enhance prosthetic stability. The appearance of the fresh autogenous grafts was consistent with that of mature skin grafts, whereas the freeze-dried grafts had the appearance of alveolar mucosa. Vestibular depth stabilized at six weeks with both graft systems, and at six months there was no significant difference (P less than 0.05) between the freeze-dried and fresh grafts with respect to their ability to maintain vestibular depth.