Pandemic ethics: the case for risky research

There is too much that we do not know about COVID-19. The longer we take to find it out, the more lives will be lost. In this paper, we will defend a principle of risk parity: if it is permissible to expose some members of society (e.g. health workers or the economically vulnerable) to a certain level of ex ante risk in order to minimize overall harm from the virus, then it is permissible to expose fully informed volunteers to a comparable level of risk in the context of promising research into the virus. We apply this principle to three examples of risky research: skipping animal trials for promising treatments, human challenge trials to speed up vaccine development, and low-dose controlled infection or “variolation.” We conclude that if volunteers, fully informed about the risks, are willing to help fight the pandemic by aiding promising research, there are strong moral reasons to gratefully accept their help. To refuse it would implicitly subject others to still graver risks

Report from ionospheric science

The general strategy to advance knowledge of the ionospheric component of the solar terrestrial system should consist of a three pronged attack on the problem. Ionospheric models should be refined by utilization of existing and new data bases. The data generated in the future should emphasize spatial and temporal gradients and their relation to other events in the solar terrestrial system. In parallel with the improvement in modeling, it will be necessary to initiate a program of advanced instrument development. In particular, emphasis should be placed on the area of improved imaging techniques. The third general activity to be supported should be active experiments related to a better understanding of the basic physics of interactions occurring in the ionospheric environment. These strategies are briefly discussed

Opioid-induced constipation in intensive care patients: relief in sight?

Constipation is the most common gastrointestinal complication associated with opioid therapy in chronic pain patients, and also frequently occurs in sedated intensive care unit patients. Conventional therapy may not provide sufficient relief from constipation, which can be severe enough to limit opioid use or the dose. In a recent study on terminally ill patients suffering from laxative-resistant opioid-induced constipation, Thomas and colleagues demonstrated subcutaneous methylnaltrexone to rapidly induce defecation. This appealing result might also have favourable prospects for intensive care patients, as their outcome is often codetermined by recovery of bowel functioning

Heparinase selectively sheds heparan sulphate from the endothelial glycocalyx

A healthy vascular endothelium is coated by the endothelial glycocalyx. Its main constituents are transmembrane syndecans and bound heparan sulphates. This structure maintains the physiological endothelial permeability barrier and prevents leukocyte and platelet adhesion, thereby mitigating inflammation and tissue oedema. Heparinase, a bacteria] analogue to heparanase, is known to attack the glycocalyx. However, the exact extent and specificity of degradation is unresolved. We show by electron microscopy, immunohistological staining and quantitative measurements of the constituent parts, that heparinase selectively sheds heparan sulphate from the glycocalyx, but not the synclecans

Perspectives in Microvascular Fluid Handling: Does the Distribution of Coagulation Factors in Human Myocardium Comply with Plasma Extravasation in Venular Coronary Segments?

Background: Heterogeneity of vascular permeability has been suggested for the coronary system. Whereas arteriolar and capillary segments are tight, plasma proteins pass readily into the interstitial space at venular sites. Fittingly, lymphatic fluid is able to coagulate. However, heart tissue contains high concentrations of tissue factor, presumably enabling bleeding to be stopped immediately in this vital organ. The distribution of pro- and anti-coagulatively active factors in human heart tissue has now been determined in relation to the types of microvessels. Methods and Results: Samples of healthy explanted hearts and dilated cardiomyopathic hearts were immunohistochemically stained. Albumin was found throughout the interstitial space. Tissue factor was packed tightly around arterioles and capillaries, whereas the tissue surrounding venules and small veins was practically free of this starter of coagulation. Thrombomodulin was present at the luminal surface of all vessel segments and especially at venular endothelial cell junctions. Its product, the anticoagulant protein C, appeared only at discrete extravascular sites, mainly next to capillaries. These distribution patterns were basically identical in the healthy and diseased hearts, suggesting a general principle. Conclusions: Venular extravasation of plasma proteins probably would not bring prothrombin into intimate contact with tissue factor, avoiding interstitial coagulation in the absence of injury. Generation of activated protein C via thrombomodulin is favored in the vicinity of venular gaps, should thrombin occur inside coronary vessels. This regionalization of distribution supports the proposed physiological heterogeneity of the vascular barrier and complies with the passage of plasma proteins into the lymphatic system of the heart. Copyright (C) 2010 S. Karger AG, Base

When and Where to Step: Terrain-Aware Real-Time Footstep Location and Timing Optimization for Bipedal Robots

Online footstep planning is essential for bipedal walking robots, allowing them to walk in the presence of disturbances and sensory noise. Most of the literature on the topic has focused on optimizing the footstep placement while keeping the step timing constant. In this work, we introduce a footstep planner capable of optimizing footstep placement and step time online. The proposed planner, consisting of an Interior Point Optimizer (IPOPT) and an optimizer based on Augmented Lagrangian (AL) method with analytical gradient descent, solves the full dynamics of the Linear Inverted Pendulum (LIP) model in real time to optimize for footstep location as well as step timing at the rate of 200~Hz. We show that such asynchronous real-time optimization with the AL method (ARTO-AL) provides the required robustness and speed for successful online footstep planning. Furthermore, ARTO-AL can be extended to plan footsteps in 3D, allowing terrain-aware footstep planning on uneven terrains. Compared to an algorithm with no footstep time adaptation, our proposed ARTO-AL demonstrates increased stability in simulated walking experiments as it can resist pushes on flat ground and on a $10^{\circ}$ ramp up to 120 N and 100 N respectively. For the video, see https://youtu.be/ABdnvPqCUu4. For code, see https://github.com/WangKeAlchemist/ARTO-AL/tree/master.Comment: 32 pages, 15 figures. Submitted to Robotics and Autonomous System

Small-volume resuscitation with hyperoncotic albumin: a systematic review of randomized clinical trials

Background Small-volume resuscitation can rapidly correct hypovolemia. Hyperoncotic albumin solutions, long in clinical use, are suitable for small-volume resuscitation; however, their clinical benefits remain uncertain. Methods Randomized clinical trials comparing hyperoncotic albumin with a control regimen for volume expansion were sought by multiple methods, including computer searches of bibliographic databases, perusal of reference lists, and manual searching. Major findings were qualitatively summarized. In addition, a quantitative meta-analysis was performed on available survival data. Results In all, 25 randomized clinical trials with a total of 1,485 patients were included. In surgery, hyperoncotic albumin preserved renal function and reduced intestinal edema compared with control fluids. In trauma and sepsis, cardiac index and oxygenation were higher after administration of hydroxyethyl starch than hyperoncotic albumin. Improved treatment response and renal function, shorter hospital stay and lower costs of care were reported in patients with liver disease receiving hyperoncotic albumin. Edema and morbidity were decreased in high-risk neonates after hyperoncotic albumin administration. Disability was reduced by therapy with hyperoncotic albumin in brain injury. There was no evidence of deleterious effects attributable to hyperoncotic albumin. Survival was unaffected by hyperoncotic albumin (pooled relative risk, 0.95; 95% confidence interval 0.78 to 1.17). Conclusion In some clinical indications, randomized trial evidence has suggested certain benefits of hyperoncotic albumin such as reductions in morbidity, renal impairment and edema. However, further clinical trials are needed, particularly in surgery, trauma and sepsis

The agronomic performance and nutritional content of oat and barley varieties grown in a northern maritime environment depends on variety and growing conditions

Funding for this research came from the Scottish Government's Rural and Environment Science and Analytical Services Division (RESAS) through their support for this Strategic Partnership project. We are also grateful to Ingvar Andersson at Lantmännen SW Seed AB for supplying seed of the Scandinavian varieties for the trials each year and to the seed merchant William Shearer (Kirkwall) for importing it. We are indebted to Grietje Holtrop from Biomathematics and Statistics Scotland for her help with statistical analysis. Andy Beer (The Royal Zoological Society, Edinburgh) performed all NIRS analysis and Gill Campbell (Rowett Institute of Nutrition and Health) performed the mineral content analysis. The Centre for Sustainable Cropping platform is supported through Scottish Government Underpinning Capacity funding. The Agronomy Institute acknowledges support from the Northern Periphery and Arctic Programme's Northern Cereals project in preparing this publication.Peer reviewedPostprin

Input estimation for drug discovery using optimal control and Markov chain Monte Carlo approaches

Input estimation is employed in cases where it is desirable to recover the form of an input function which cannot be directly observed and for which there is no model for the generating process. In pharmacokinetic and pharmacodynamic modelling, input estimation in linear systems (deconvolution) is well established, while the nonlinear case is largely unexplored. In this paper, a rigorous definition of the input-estimation problem is given, and the choices involved in terms of modelling assumptions and estimation algorithms are discussed. In particular, the paper covers Maximum a Posteriori estimates using techniques from optimal control theory, and full Bayesian estimation using Markov Chain Monte Carlo (MCMC) approaches. These techniques are implemented using the optimisation software CasADi, and applied to two example problems: one where the oral absorption rate and bioavailability of the drug eflornithine are estimated using pharmacokinetic data from rats, and one where energy intake is estimated from body-mass measurements of mice exposed to monoclonal antibodies targeting the fibroblast growth factor receptor (FGFR) 1c. The results from the analysis are used to highlight the strengths and weaknesses of the methods used when applied to sparsely sampled data. The presented methods for optimal control are fast and robust, and can be recommended for use in drug discovery. The MCMC-based methods can have long running times and require more expertise from the user. The rigorous definition together with the illustrative examples and suggestions for software serve as a highly promising starting point for application of input-estimation methods to problems in drug discovery

Input estimation for extended-release formulations exemplified with exenatide

Estimating the in vivo absorption profile of a drug is essential when developing extended-release medications. Such estimates can be obtained by measuring plasma concentrations over time and inferring the absorption from a model of the drug’s pharmacokinetics. Of particular interest is to predict the bioavailability—the fraction of the drug that is absorbed and enters the systemic circulation. This paper presents a framework for addressing this class of estimation problems and gives advice on the choice of method. In parametric methods, a model is constructed for the absorption process, which can be difficult when the absorption has a complicated profile. Here, we place emphasis on non-parametric methods that avoid making strong assumptions about the absorption. A modern estimation method that can address very general input-estimation problems has previously been presented. In this method, the absorption profile is modeled as a stochastic process, which is estimated using Markov chain Monte Carlo techniques. The applicability of this method for extended-release formulation development is evaluated by analyzing a dataset of Bydureon, an injectable extended-release suspension formulation of exenatide, a GLP-1 receptor agonist for treating diabetes. This drug is known to have non-linear pharmacokinetics. Its plasma concentration profile exhibits multiple peaks, something that can make parametric modeling challenging, but poses no major difficulties for non-parametric methods. The method is also validated on synthetic data, exploring the effects of sampling and noise on the accuracy of the estimates