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Evidence regarding whether imaging can be used effectively to select patients for endovascular thrombectomy (EVT) is scarce. We aimed to investigate the association between baseline imaging features and safety and efficacy of EVT in acute ischaemic stroke caused by anterior large-vessel occlusion. In this meta-analysis of individual patient-level data, the HERMES collaboration identified in PubMed seven randomised trials in endovascular stroke that compared EVT with standard medical therapy, published between Jan 1, 2010, and Oct 31, 2017. Only trials that required vessel imaging to identify patients with proximal anterior circulation ischaemic stroke and that used predominantly stent retrievers or second-generation neurothrombectomy devices in the EVT group were included. Risk of bias was assessed with the Cochrane handbook methodology. Central investigators, masked to clinical information other than stroke side, categorised baseline imaging features of ischaemic change with the Alberta Stroke Program Early CT Score (ASPECTS) or according to involvement of more than 33% of middle cerebral artery territory, and by thrombus volume, hyperdensity, and collateral status. The primary endpoint was neurological functional disability scored on the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included symptomatic intracranial haemorrhage, parenchymal haematoma type 2 within 5 days of randomisation, and mortality within 90 days. For the primary analysis, we used mixed-methods ordinal logistic regression adjusted for age, sex, National Institutes of Health Stroke Scale score at admission, intravenous alteplase, and time from onset to randomisation, and we used interaction terms to test whether imaging categorisation at baseline modifies the association between treatment and outcome. This meta-analysis was prospectively designed by the HERMES executive committee but has not been registered. Among 1764 pooled patients, 871 were allocated to the EVT group and 893 to the control group. Risk of bias was low except in the THRACE study, which used unblinded assessment of outcomes 90 days after randomisation and MRI predominantly as the primary baseline imaging tool. The overall treatment effect favoured EVT (adjusted common odds ratio [cOR] for a shift towards better outcome on the mRS 2·00, 95% CI 1·69–2·38; p<0·0001). EVT achieved better outcomes at 90 days than standard medical therapy alone across a broad range of baseline imaging categories. Mortality at 90 days (14·7% vs 17·3%, p=0·15), symptomatic intracranial haemorrhage (3·8% vs 3·5%, p=0·90), and parenchymal haematoma type 2 (5·6% vs 4·8%, p=0·52) did not differ between the EVT and control groups. No treatment effect modification by baseline imaging features was noted for mortality at 90 days and parenchymal haematoma type 2. Among patients with ASPECTS 0–4, symptomatic intracranial haemorrhage was seen in ten (19%) of 52 patients in the EVT group versus three (5%) of 66 patients in the control group (adjusted cOR 3·94, 95% CI 0·94–16·49; pinteraction=0·025), and among patients with more than 33% involvement of middle cerebral artery territory, symptomatic intracranial haemorrhage was observed in 15 (14%) of 108 patients in the EVT group versus four (4%) of 113 patients in the control group (4·17, 1·30–13·44, pinteraction=0·012). EVT achieves better outcomes at 90 days than standard medical therapy across a broad range of baseline imaging categories, including infarcts affecting more than 33% of middle cerebral artery territory or ASPECTS less than 6, although in these patients the risk of symptomatic intracranial haemorrhage was higher in the EVT group than the control group. This analysis provides preliminary evidence for potential use of EVT in patients with large infarcts at baseline. Medtronic.

Snake venom is comprised of a combination of different proteins and peptides with a wide range of molecular weights and different disposition processes inherent to each compound. This causes venom to have a complex exposure profile. Our study investigates 1) how each molecular weight fraction (toxin) of venom contributes to the overall time course of the snake venom, and 2) the ability to determine toxin profiles based on the profile of the overall venom only. We undertook an in silico simulation and modelling study. Sixteen variations of venom, comprising of two to nine toxins with different molecular weights were investigated. The pharmacokinetic parameters (i.e., clearance,  C L , and volume of distribution,  V ) of each toxin were generated based on a log-linear relationship with molecular weight. The concentration–time data of each toxin were simulated for 100 virtual patients using MATLAB and the total concentration–time data of each toxin were modelled using NONMEM. We found that the data of sixteen mixtures were best described by either two- or three-compartment models, despite the venom being made up of more than three different toxins. This suggests that it is generally not possible to determine individual toxin profiles based on measurements of total venom concentrations only.

We develop numerically stable and accurate stochastic simulation approaches for solving dynamic economic models. First, instead of standard least‐squares approximation methods, we examine a variety of alternatives, including least‐squares methods using singular value decomposition and Tikhonov regularization, least‐absolute deviations methods, and principal component regression method, all of which are numerically stable and can handle ill‐conditioned problems. Second, instead of conventional Monte Carlo integration, we use accurate quadrature and monomial integration. We test our generalized stochastic simulation algorithm (GSSA) in three applications: the standard representative–agent neoclassical growth model, a model with rare disasters, and a multicountry model with hundreds of state variables. GSSA is simple to program, and MATLAB codes are provided.

Water is an essential natural resource that is being impacted by climate change. Thus, knowledge of future water availability conditions around the globe becomes necessary. Based on that, this study aimed to simulate future climate scenarios and evaluate the impact on water balance in southern Brazil. Daily data of rainfall and air temperature (maximum and minimum) were used. The meteorological data were collected in 28 locations over 30 years (1980-2009). For the data simulation, we used the climate data stochastic generator PGECLIMA_R. It was considered two scenarios of the fifth report of the Intergovernmental Panel on Climate Change (IPCC) and a scenario with the historical data trend. The water balance estimates were performed for the current data and the simulated data, through the methodology of Thornthwaite and Mather (1955). The moisture indexes were spatialized by the kriging method. These indexes were chosen as the parameters to represent the water conditions in different situations. The region assessed presented a high variability in water availability among locations; however, it did not present high water deficiency values, even with climate change. Overall, it was observed a reduction of moisture index in most sites and in all scenarios assessed, especially in the northern region when compared to the other regions. The second scenario of the IPCC (the worst situation) promoting higher reductions and dry conditions for the 2099 year. The impacts of climate change on water availability, identified in this study, can affect the general society, therefore, they must be considered in the planning and management of water resources, especially in the regional context

This paper introduces time-continuous numerical schemes to simulate stochastic differential equations (SDEs) arising in mathematical finance, population dynamics, chemical kinetics, epidemiology, biophysics, and polymeric fluids. These schemes are obtained by spatially discretizing the Kolmogorov equation associated with the SDE in such a way that the resulting semi-discrete equation generates a Markov jump process that can be realized exactly using a Monte Carlo method. In this construction the jump size of the approximation can be bounded uniformly in space, which often guarantees that the schemes are numerically stable for both finite and long time simulation of SDEs. By directly analyzing the infinitesimal generator of the approximation, we prove that the approximation has a sharp stochastic Lyapunov function when applied to an SDE with a drift field that is locally Lipschitz continuous and weakly dissipative. We use this stochastic Lyapunov function to extend a local semimartingale representation of the approximation. This extension makes it possible to quantify the computational cost of the approximation. Using a stochastic representation of the global error, we show that the approximation is (weakly) accurate in representing finite and infinite-time expected values, with an order of accuracy identical to the order of accuracy of the infinitesimal generator of the approximation. The proofs are carried out in the context of both fixed and variable spatial step sizes. Theoretical and numerical studies confirm these statements, and provide evidence that these schemes have several advantages over standard methods based on time-discretization. In particular, they are accurate, eliminate nonphysical moves in simulating SDEs with boundaries (or confined domains), prevent exploding trajectories from occurring when simulating stiff SDEs, and solve first exit problems without time-interpolation errors.

This paper introduces AlphaSimR, an R package for stochastic simulations of plant and animal breeding programs. AlphaSimR is a highly flexible software package able to simulate a wide range of plant and animal breeding programs for diploid and autopolyploid species. AlphaSimR is ideal for testing the overall strategy and detailed design of breeding programs. AlphaSimR utilizes a scripting approach to building simulations that is particularly well suited for modeling highly complex breeding programs, such as commercial breeding programs. The primary benefit of this scripting approach is that it frees users from preset breeding program designs and allows them to model nearly any breeding program design. This paper lists the main features of AlphaSimR and provides a brief example simulation to show how to use the software.

We establish general conditions under which Markov chains produced by the Hamiltonian Monte Carlo method will and will not be geometrically ergodic. We consider implementations with both position-independent and position-dependent integration times. In the former case, we find that the conditions for geometric ergodicity are essentially a gradient of the log-density which asymptotically points towards the centre of the space and grows no faster than linearly. In an idealised scenario in which the integration time is allowed to change in different regions of the space, we show that geometric ergodicity can be recovered for a much broader class of tail behaviours, leading to some guidelines for the choice of this free parameter in practice.

 Stochastic models are commonly employed in the system and synthetic biology to study the effects of stochastic fluctuations emanating from reactions involving species with low copy-numbers. Many important models feature complex dynamics, involving a state-space explosion, stiffness, and multimodality, that complicate the quantitative analysis needed to understand their stochastic behavior. Direct numerical analysis of such models is typically not feasible and generating many simulation runs that adequately approximate the model's dynamics may take a prohibitively long time.  We propose a new memoization technique that leverages a population-based abstraction and combines previously generated parts of simulations, called segments, to generate new simulations more efficiently while preserving the original system's dynamics and its diversity. Our algorithm adapts online to identify the most important abstract states and thus utilizes the available memory efficiently.  We demonstrate that in combination with a novel fully automatic and adaptive hybrid simulation scheme, we can speed up the generation of trajectories significantly and correctly predict the transient behavior of complex stochastic systems.

Abstract Bayesian inference plays an important role in phylogenetics, evolutionary biology, and in many other branches of science. It provides a principled framework for dealing with uncertainty and quantifying how it changes in the light of new evidence. For many complex models and inference problems, however, only approximate quantitative answers are obtainable. Approximate Bayesian computation (ABC) refers to a family of algorithms for approximate inference that makes a minimal set of assumptions by only requiring that sampling from a model is possible. We explain here the fundamentals of ABC, review the classical algorithms, and highlight recent developments. [ABC; approximate Bayesian computation; Bayesian inference; likelihood-free inference; phylogenetics; simulator-based models; stochastic simulation models; tree-based models.]