pSSAlib: The partial-propensity stochastic chemical network simulator.

Chemical reaction networks are ubiquitous in biology, and their dynamics is fundamentally stochastic. Here, we present the software library pSSAlib, which provides a complete and concise implementation of the most efficient partial-propensity methods for simulating exact stochastic chemical kinetics. pSSAlib can import models encoded in Systems Biology Markup Language, supports time delays in chemical reactions, and stochastic spatiotemporal reaction-diffusion systems. It also provides tools for statistical analysis of simulation results and supports multiple output formats. It has previously been used for studies of biochemical reaction pathways and to benchmark other stochastic simulation methods. Here, we describe pSSAlib in detail and apply it to a new model of the endocytic pathway in eukaryotic cells, leading to the discovery of a stochastic counterpart of the cut-out switch motif underlying early-to-late endosome conversion. pSSAlib is provided as a stand-alone command-line tool and as a developer API. We also provide a plug-in for the SBMLToolbox. The open-source code and pre-packaged installers are freely available from http://mosaic.mpi-cbg.de.

Observer reliability of CT angiography in the assessment of acute ischaemic stroke: data from the Third International Stroke Trial.

INTRODUCTION: CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke. METHODS: We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with various degrees of arterial obstruction in different intracranial locations on CTA. To assess inter-observer reliability, seven members of the IST-3 expert image reading panel (>5 years experience reading CTA) and seven radiology trainees (<2 years experience) rated all 15 scans independently and blind to clinical data for: presence (versus absence) of any intracranial arterial abnormality (stenosis or occlusion), severity of arterial abnormality using relevant scales (IST-3 angiography score, Thrombolysis in Cerebral Infarction (TICI) score, Clot Burden Score), collateral supply and visibility of a perfusion defect on CTA source images (CTA-SI). Intra-observer reliability was assessed using independently repeated expert panel scan ratings. We assessed observer agreement with Krippendorff's-alpha (K-alpha). RESULTS: Among experienced observers, inter-observer agreement was substantial for the identification of any angiographic abnormality (K-alpha = 0.70) and with an angiography assessment scale (K-alpha = 0.60-0.66). There was less agreement for grades of collateral supply (K-alpha = 0.56) or for identification of a perfusion defect on CTA-SI (K-alpha = 0.32). Radiology trainees performed as well as expert readers when additional training was undertaken (neuroradiology specialist trainees). Intra-observer agreement among experts provided similar results (K-alpha = 0.33-0.72). CONCLUSION: For most imaging characteristics assessed, CTA has moderate to substantial observer agreement in acute ischaemic stroke. Experienced readers and those with specialist training perform best.

Global parameter identification of stochastic reaction networks from single trajectories.

We consider the problem of inferring the unknown parameters of a stochastic biochemical network model from a single measured time-course of the concentration of some of the involved species. Such measurements are available, e.g., from live-cell fluorescence microscopy in image-based systems biology. In addition, fluctuation time-courses from, e.g., fluorescence correlation spectroscopy (FCS) provide additional information about the system dynamics that can be used to more robustly infer parameters than when considering only mean concentrations. Estimating model parameters from a single experimental trajectory enables single-cell measurements and quantification of cell-cell variability. We propose a novel combination of an adaptive Monte Carlo sampler, called Gaussian Adaptation (GaA), and efficient exact stochastic simulation algorithms (SSA) that allows parameter identification from single stochastic trajectories. We benchmark the proposed method on a linear and a non-linear reaction network at steady state and during transient phases. In addition, we demonstrate that the present method also provides an ellipsoidal volume estimate of the viable part of parameter space and is able to estimate the physical volume of the compartment in which the observed reactions take place.

Implantation of Large Diameter (5.5-6 mm) Derivo Embolization Devices for the Treatment of Cerebral Aneurysms.

BACKGROUND: The efficacy of flow diverters is dependent upon robust wall apposition in the parent artery. Usage in large caliber cerebral vessels has therefore been limited as few implants with diameters > 5 mm exist. We present our initial experience in treating cerebral aneurysms using the 5.5 mm and 6 mm diameter implants of the Derivo embolization device (DED). METHODS: Our prospectively maintained institutional database was reviewed to identify patients in whom a > 5 mm DED was implanted between November 2016 and February 2021. The primary efficacy outcome was complete or near-complete aneurysm occlusion at 6 months (O'Kelly-Marotta, OKM, C-D, adapted for magnetic resonance angiography). Safety outcomes included 30-day major morbidity defined as modified Rankin Score (mRS) 3-5, mortality, serious adverse events and procedural complications. RESULTS: A total of 21 large diameter DEDs were deployed in 18 patients (age 59.5 ± 14.1 years), harboring 19 unruptured aneurysms. Of the aneurysms 14 (73.7%) were saccular in morphology (sac diameter 10.9 ± 5.5 mm, neck diameter 6.8 ± 3.1 mm), 3 (15.8%) aneurysms were dissecting, 1 (5.3%) iatrogenic pseudoaneurysm and 1 (5.3%) fusiform. Aneurysm locations were: ICA (internal carotid artery) (n = 17); (7 cavernous, 4 paraophthalmic, 2 paraclinoid, 1 petrous, 2 communicating, 1 cervical); vertebrobasilar (n = 2). Adjunct stenting to optimize proximal wall apposition was undertaken in 5 (27.8%) patients. At 6 months 75% of patients followed-up met the primary efficacy endpoint (OKM C-D). There were no serious adverse events, 30-day major morbidity (mRS 3-5) or mortality. CONCLUSION: Implantation of large diameter (5.5 mm and 6 mm) DEDs into capacious cerebral vessels to treat a range of complex aneurysms is safe and technically feasible but may require adjunct stenting to optimize proximal wall apposition. Short-term efficacy of this device subset is comparable to previous DED and other flow diverter studies. Long-term follow-up and comparative studies are required for further assessment.

A partial-propensity formulation of the stochastic simulation algorithm for chemical reaction networks with delays.

Several real-world systems, such as gene expression networks in biological cells, contain coupled chemical reactions with a time delay between reaction initiation and completion. The non-Markovian kinetics of such reaction networks can be exactly simulated using the delay stochastic simulation algorithm (dSSA). The computational cost of dSSA scales with the total number of reactions in the network. We reduce this cost to scale at most with the smaller number of species by using the concept of partial reaction propensities. The resulting delay partial-propensity direct method (dPDM) is an exact dSSA formulation for well-stirred systems of coupled chemical reactions with delays. We detail dPDM and present a theoretical analysis of its computational cost. Furthermore, we demonstrate the implications of the theoretical cost analysis in two prototypical benchmark applications. The dPDM formulation is shown to be particularly efficient for strongly coupled reaction networks, where the number of reactions is much larger than the number of species.

Exact on-lattice stochastic reaction-diffusion simulations using partial-propensity methods.

Stochastic reaction-diffusion systems frequently exhibit behavior that is not predicted by deterministic simulation models. Stochastic simulation methods, however, are computationally expensive. We present a more efficient stochastic reaction-diffusion simulation algorithm that samples realizations from the exact solution of the reaction-diffusion master equation. The present algorithm, called partial-propensity stochastic reaction-diffusion (PSRD) method, uses an on-lattice discretization of the reaction-diffusion system and relies on partial-propensity methods for computational efficiency. We describe the algorithm in detail, provide a theoretical analysis of its computational cost, and demonstrate its computational performance in benchmarks. We then illustrate the application of PSRD to two- and three-dimensional pattern-forming Gray-Scott systems, highlighting the role of intrinsic noise in these systems.

Submitral Aneurysm Presenting as Pulsating Epigastric Mass-Diagnostic and Surgical Considerations.

Submitral aneurysm (SMA) is a rare anomaly that typically occurs adjacent to the posterior leaflet of the mitral valve. We report the case of a ten-year-old female child presenting with SMA with anteroinferior extension, differing from the more typical posterior and lateral extension. Successful surgical management is described.

Virtual reality-guided left ventricular assist device implantation in pediatric patient: Valuable presurgical tool.

Virtual reality (VR) is increasingly used for presurgical planning and teaching during surgery. However, VR aided presurgical planning toolbox for left ventricular assist device (LVAD) implantation is not widely available. We investigated the use of a VR environment with wearable headsets and touch controllers in simulating an implant in an 11-year-old boy. The technology played a significant role in the optimal positioning of the LVAD.

A partial-propensity variant of the composition-rejection stochastic simulation algorithm for chemical reaction networks.

We present the partial-propensity stochastic simulation algorithm with composition-rejection sampling (PSSA-CR). It is an exact formulation of the stochastic simulation algorithm (SSA) for well-stirred systems of coupled chemical reactions. The new formulation is a partial-propensity variant [R. Ramaswamy, N. Gonzalez-Segredo, and I. F. Sbalzarini, J. Chem. Phys. 130, 244104 (2009)] of the composition- rejection SSA [A. Slepoy, A. P. Thompson, and S. J. Plimpton, J. Chem. Phys. 128, 205101 (2008)]. The computational cost of this new formulation is bounded by a constant for weakly coupled reaction networks, and it increases at most linearly with the number of chemical species for strongly coupled reaction networks. PSSA-CR thus combines the advantages of partial-propensity methods and the composition-rejection SSA, providing favorable scaling of the computational cost for all classes of reaction networks.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism.

In our previous study on individuals with autism spectrum disorder (ASD) (Sokhadze et al., Appl Psychophysiol Biofeedback 34:37-51, 2009a) we reported abnormalities in the attention-orienting frontal event-related potentials (ERP) and the sustained-attention centro-parietal ERPs in a visual oddball experiment. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. In the present study we examine the effects of low-frequency, repetitive Transcranial Magnetic Stimulation (rTMS) on novelty processing as well as behavior and social functioning in 13 individuals with ASD. Our hypothesis was that low-frequency rTMS application to dorsolateral prefrontal cortex (DLFPC) would result in an alteration of the cortical excitatory/inhibitory balance through the activation of inhibitory GABAergic double bouquet interneurons. We expected to find post-TMS differences in amplitude and latency of early and late ERP components. The results of our current study validate the use of low-frequency rTMS as a modulatory tool that altered the disrupted ratio of cortical excitation to inhibition in autism. After rTMS the parieto-occipital P50 amplitude decreased to novel distracters but not to targets; also the amplitude and latency to targets increased for the frontal P50 while decreasing to non-target stimuli. Low-frequency rTMS minimized early cortical responses to irrelevant stimuli and increased responses to relevant stimuli. Improved selectivity in early cortical responses lead to better stimulus differentiation at later-stage responses as was made evident by our P3b and P3a component findings. These results indicate a significant change in early, middle-latency and late ERP components at the frontal, centro-parietal, and parieto-occipital regions of interest in response to target and distracter stimuli as a result of rTMS treatment. Overall, our preliminary results show that rTMS may prove to be an important research tool or treatment modality in addressing the stimulus hypersensitivity characteristic of autism spectrum disorders.

A new class of highly efficient exact stochastic simulation algorithms for chemical reaction networks.

We introduce an alternative formulation of the exact stochastic simulation algorithm (SSA) for sampling trajectories of the chemical master equation for a well-stirred system of coupled chemical reactions. Our formulation is based on factored-out, partial reaction propensities. This novel exact SSA, called the partial-propensity direct method (PDM), is highly efficient and has a computational cost that scales at most linearly with the number of chemical species, irrespective of the degree of coupling of the reaction network. In addition, we propose a sorting variant, SPDM, which is especially efficient for multiscale reaction networks.

Activity induces traveling waves, vortices and spatiotemporal chaos in a model actomyosin layer.

Inspired by the actomyosin cortex in biological cells, we investigate the spatiotemporal dynamics of a model describing a contractile active polar fluid sandwiched between two external media. The external media impose frictional forces at the interface with the active fluid. The fluid is driven by a spatially-homogeneous activity measuring the strength of the active stress that is generated by processes consuming a chemical fuel. We observe that as the activity is increased over two orders of magnitude the active polar fluid first shows spontaneous flow transition followed by transition to oscillatory dynamics with traveling waves and traveling vortices in the flow field. In the flow-tumbling regime, the active polar fluid also shows transition to spatiotemporal chaos at sufficiently large activities. These results demonstrate that level of activity alone can be used to tune the operating point of actomyosin layers with qualitatively different spatiotemporal dynamics.

Discreteness-induced concentration inversion in mesoscopic chemical systems.

Molecular discreteness is apparent in small-volume chemical systems, such as biological cells, leading to stochastic kinetics. Here we present a theoretical framework to understand the effects of discreteness on the steady state of a monostable chemical reaction network. We consider independent realizations of the same chemical system in compartments of different volumes. Rate equations ignore molecular discreteness and predict the same average steady-state concentrations in all compartments. However, our theory predicts that the average steady state of the system varies with volume: if a species is more abundant than another for large volumes, then the reverse occurs for volumes below a critical value, leading to a concentration inversion effect. The addition of extrinsic noise increases the size of the critical volume. We theoretically predict the critical volumes and verify, by exact stochastic simulations, that rate equations are qualitatively incorrect in sub-critical volumes.

Intrinsic noise alters the frequency spectrum of mesoscopic oscillatory chemical reaction systems.

Mesoscopic oscillatory reaction systems, for example in cell biology, can exhibit stochastic oscillations in the form of cyclic random walks even if the corresponding macroscopic system does not oscillate. We study how the intrinsic noise from molecular discreteness influences the frequency spectrum of mesoscopic oscillators using as a model system a cascade of coupled Brusselators away from the Hopf bifurcation. The results show that the spectrum of an oscillator depends on the level of noise. In particular, the peak frequency of the oscillator is reduced by increasing noise, and the bandwidth increased. Along a cascade of coupled oscillators, the peak frequency is further reduced with every stage and also the bandwidth is reduced. These effects can help understand the role of noise in chemical oscillators and provide fingerprints for more reliable parameter identification and volume measurement from experimental spectra.

Noise-induced modulation of the relaxation kinetics around a non-equilibrium steady state of non-linear chemical reaction networks.

Stochastic effects from correlated noise non-trivially modulate the kinetics of non-linear chemical reaction networks. This is especially important in systems where reactions are confined to small volumes and reactants are delivered in bursts. We characterise how the two noise sources confinement and burst modulate the relaxation kinetics of a non-linear reaction network around a non-equilibrium steady state. We find that the lifetimes of species change with burst input and confinement. Confinement increases the lifetimes of all species that are involved in any non-linear reaction as a reactant. Burst monotonically increases or decreases lifetimes. Competition between burst-induced and confinement-induced modulation may hence lead to a non-monotonic modulation. We quantify lifetime as the integral of the time autocorrelation function (ACF) of concentration fluctuations around a non-equilibrium steady state of the reaction network. Furthermore, we look at the first and second derivatives of the ACF, each of which is affected in opposite ways by burst and confinement. This allows discriminating between these two noise sources. We analytically derive the ACF from the linear Fokker-Planck approximation of the chemical master equation in order to establish a baseline for the burst-induced modulation at low confinement. Effects of higher confinement are then studied using a partial-propensity stochastic simulation algorithm. The results presented here may help understand the mechanisms that deviate stochastic kinetics from its deterministic counterpart. In addition, they may be instrumental when using fluorescence-lifetime imaging microscopy (FLIM) or fluorescence-correlation spectroscopy (FCS) to measure confinement and burst in systems with known reaction rates, or, alternatively, to correct for the effects of confinement and burst when experimentally measuring reaction rates.

Holding power of variable pitch screws in osteoporotic, osteopenic and normal bone: are all screws created equal?

INTRODUCTION: Biomechanical properties of four different commercially available small fragment cannulated screws (Twin fix (Stryker, Freiburg, Germany), Herbert, (Zimmer, Warsaw, USA), Omnitech (Unimedical, Torino, Italy), Barouk (Depuy, Warsaw, USA)), with variable pitch, used for fracture fixation were compared. MATERIALS AND METHODS: Polyurethane foam blocks of three different densities with mechanical properties similar to osteoporotic, osteopenic and normal bones were used to conduct the tests. Each screw was tested for pushout and pullout holding power after a primary insertion and for pullout after a repeated insertion into the respective foam blocks. RESULTS: The mean pullout and pushout strengths of all screws correlated to the foam density, and were significantly (p<0.001 and <0.001, respectively) better in foam with higher density. The mean pullout strength of each screw was consistently lower after reinsertion into the osteoporotic, osteopenic and normal bone densities by 4-30%, when compared to the index insertion (Fig. 4b). Yet, this difference was not found to be statistically significant (p=0.23). The Barouk screw performed significantly (p<0.0001) better than the other screws in all three different densities of foam for both for pushout and pullout after index insertion as well as for pullout tests after reinsertion. CONCLUSION: The holding power of screws is directly correlated to bone density, thread design and number of threads engaging the bone. Reinsertion through the same hole could reduce the ultimate pullout strength. The surgeon should consider the advantages and disadvantages of each implant, depending on the clinical situation and choose accordingly.

Gout arthropathy following hip arthroplasty: a need for routine aspiration microscopy? A review of the literature and case report.

This article presents the case of a patient with pain associated with a total hip replacement. Following aspiration microscopy, a diagnosis of gout in a total hip replacement was made. Successful treatment was instituted with medical management in the presence of coexisting aseptic loosening. Gout in a total hip replacement is an exceptionally rare diagnosis. The gold standard for diagnosis is not urate level but crystal identification in the synovial fluid. The authors would therefore recommend that as part of a thorough workup for painful prosthetic joint requiring revision, a present or past history of gout is sought and a fluid aspirate should be examined not only for infection but also under polarized light for crystal arthropathy.

Bilateral rotational osteotomies of the proximal tibiae and tibial tuberosity distal transfers for the treatment of congenital lateral dislocations of patellae: a case report and literature review.

Congenital dislocation of patella (CDP) causes varying degree of disability. Patients may present as late walkers with asymmetric gait, habitual or recurrent dislocators or even non-walkers if the condition is bilateral. Patellar instability is often associated with soft tissue or bony pathology. Soft tissue anomalies include lateral soft tissue contractures, shortened quadriceps as well as vastus medialis dysplasia (abnormal origin and insertion). Bony anomalies include shallow trochlear groove and hypoplastic patella or lateral femoral condyle. Soft tissue etiologies result in an imbalance of the dynamic forces acting on the patella while in bony etiologies the static stabilizers to resist lateral dislocation are compromised. External tibial torsion is an additional etiology, often under diagnosed due to the difficulty in measuring the Q angle of dislocated patella. We report a case of bilateral congenital lateral dislocations of the patellae treated with bilateral tibial rotational osteotomies with an 8 year and a 4 year follow up.