Predicting surgical outcomes for paediatric spinal deformity patients using subject specific finite element models

INTRODUCTION Adolescent idiopathic scoliosis (AIS) is a spinal deformity, which may require surgical correction by attaching rods to the patient’s spine using screws inserted into the vertebrae. Complication rates for deformity correction surgery are unacceptably high. Determining an achievable correction without overloading the adjacent spinal tissues or implants requires an understanding of the mechanical interaction between these components. Our novel patient specific modelling software creates individualized finite element models (FEM) representing the thoracolumbar spine and ribcage of scoliosis patients. We have recently applied the model to investigate the influence of increasing magnitudes of surgically applied corrective force on predicted deformity correction...

Ratcheting and wear behavior of Australian rail steel: Experimental investigation of material properties and sampling method

To The ratcheting behavior of high-strength rail steel (Australian Standard AS1085.1) is studied in this work for the purpose of predicting wear and damage to the rail surface. Historically, researchers have used circular test coupons obtained from the rail head to conduct cyclic load tests, but according to hardness profile data, considerable variation exists across the rail head section. For example, the induction-hardened rail (AS1085.1) shows high hardness (400-430 HV100) up to four-millimeters into the rail head’s surface, but then drops considerably beyond that. Given that cyclic test coupons five millimeters in diameter at the gauge area are usually taken from the rail sample, there is a high probability that the original surface properties of the rail do not apply across the entire test coupon and, therefore, data representing only average material properties are obtained. In the literature, disks (47 mm in diameter) for a twin-disk rolling contact test machine have been obtained directly from the rail sample and used to validate rolling contact fatigue wear models. The question arises: How accurate are such predictions? In this research paper, the effect of rail sampling position on the ratcheting behavior of AS1085.1 rail steel was investigated using rectangular shaped specimens. Uniaxial stress-controlled tests were conducted with samples obtained at four different depths to observe the ratcheting behaviour of each. Micro-hardness measurements of the test coupons were carried out to obtain a constitutive relationship to predict the effect of depth on the ratcheting behaviour of the rail material. This work ultimately assists the selection of valid material parameters for constitutive models in the study of rail surface ratcheting.

The role of environmental factors in the spatial distribution of Japanese encephalitis in mainland China

Japanese encephalitis (JE) is the most common cause of viral encephalitis and an important public health concern in the Asia-Pacific region, particularly in China where 50% of global cases are notified. To explore the association between environmental factors and human JE cases and identify the high risk areas for JE transmission in China, we used annual notified data on JE cases at the center of administrative township and environmental variables with a pixel resolution of 1 km×1 km from 2005 to 2011 to construct models using ecological niche modeling (ENM) approaches based on maximum entropy. These models were then validated by overlaying reported human JE case localities from 2006 to 2012 onto each prediction map. ENMs had good discriminatory ability with the area under the curve (AUC) of the receiver operating curve (ROC) of 0.82-0.91, and low extrinsic omission rate of 5.44-7.42%. Resulting maps showed JE being presented extensively throughout southwestern and central China, with local spatial variations in probability influenced by minimum temperatures, human population density, mean temperatures, and elevation, with contribution of 17.94%-38.37%, 15.47%-21.82%, 3.86%-21.22%, and 12.05%-16.02%, respectively. Approximately 60% of JE cases occurred in predicted high risk areas, which covered less than 6% of areas in mainland China. Our findings will help inform optimal geographical allocation of the limited resources available for JE prevention and control in China, find hidden high-risk areas, and increase the effectiveness of public health interventions against JE transmission.

Adjustable stiffness, external fixator for the rat femur osteotomy and segmental bone defect models

The mechanical environment around the healing of broken bone is very important as it determines the way the fracture will heal. Over the past decade there has been great clinical interest in improving bone healing by altering the mechanical environment through the fixation stability around the lesion. One constraint of preclinical animal research in this area is the lack of experimental control over the local mechanical environment within a large segmental defect as well as osteotomies as they heal. In this paper we report on the design and use of an external fixator to study the healing of large segmental bone defects or osteotomies. This device not only allows for controlled axial stiffness on the bone lesion as it heals, but it also enables the change of stiffness during the healing process in vivo. The conducted experiments have shown that the fixators were able to maintain a 5 mm femoral defect gap in rats in vivo during unrestricted cage activity for at least 8 weeks. Likewise, we observed no distortion or infections, including pin infections during the entire healing period. These results demonstrate that our newly developed external fixator was able to achieve reproducible and standardized stabilization, and the alteration of the mechanical environment of in vivo rat large bone defects and various size osteotomies. This confirms that the external fixation device is well suited for preclinical research investigations using a rat model in the field of bone regeneration and repair.

Fractional diffusion models of cardiac electrical propagation: Role of structural heterogeneity in dispersion of repolarization

Impulse propagation in biological tissues is known to be modulated by structural heterogeneity. In cardiac muscle, improved understanding on how this heterogeneity influences electrical spread is key to advancing our interpretation of dispersion of repolarization. We propose fractional diffusion models as a novel mathematical description of structurally heterogeneous excitable media, as a means of representing the modulation of the total electric field by the secondary electrical sources associated with tissue inhomogeneities. Our results, analysed against in vivo human recordings and experimental data of different animal species, indicate that structural heterogeneity underlies relevant characteristics of cardiac electrical propagation at tissue level. These include conduction effects on action potential (AP) morphology, the shortening of AP duration along the activation pathway and the progressive modulation by premature beats of spatial patterns of dispersion of repolarization. The proposed approach may also have important implications in other research fields involving excitable complex media.

Mimicking breast cancer-induced bone metastasis in vivo: Current transplantation models and advanced humanized strategies

Bone metastasis is a complication that occurs in 80 % of women with advanced breast cancer. Despite the prevalence of bone metastatic disease, the avenues for its clinical management are still restricted to palliative treatment options. In fact, the underlying mechanisms of breast cancer osteotropism have not yet been fully elucidated due to a lack of suitable in vivo models that are able to recapitulate the human disease. In this work, we review the current transplantation-based models to investigate breast cancer-induced bone metastasis and delineate the strengths and limitations of the use of different grafting techniques, tissue sources, and hosts. We further show that humanized xenograft models incorporating human cells or tissue grafts at the primary tumor site or the metastatic site mimic more closely the human disease. Tissue-engineered constructs are emerging as a reproducible alternative to recapitulate functional humanized tissues in these murine models. The development of advanced humanized animal models may provide better platforms to investigate the mutual interactions between human cancer cells and their microenvironment and ultimately improve the translation of preclinical drug trials to the clinic.

Population of computational rabbit-specific ventricular action potential models for investigating sources of variability in cellular repolarisation

Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration) and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K(+), inward rectifying K(+), L-type Ca(2+), and Na(+)/K(+) pump currents) in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al.) at multiple cycle lengths (400, 600, 1,000 ms) was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in experimentally observed intercellular variability of rabbit ventricular action potential repolarisation.

Mixture models of nucleotide sequence evolution that account for heterogeneity in the substitution process across sites and across lineages

Molecular phylogenetic studies of homologous sequences of nucleotides often assume that the underlying evolutionary process was globally stationary, reversible, and homogeneous (SRH), and that a model of evolution with one or more site-specific and time-reversible rate matrices (e.g., the GTR rate matrix) is enough to accurately model the evolution of data over the whole tree. However, an increasing body of data suggests that evolution under these conditions is an exception, rather than the norm. To address this issue, several non-SRH models of molecular evolution have been proposed, but they either ignore heterogeneity in the substitution process across sites (HAS) or assume it can be modeled accurately using the distribution. As an alternative to these models of evolution, we introduce a family of mixture models that approximate HAS without the assumption of an underlying predefined statistical distribution. This family of mixture models is combined with non-SRH models of evolution that account for heterogeneity in the substitution process across lineages (HAL). We also present two algorithms for searching model space and identifying an optimal model of evolution that is less likely to over- or underparameterize the data. The performance of the two new algorithms was evaluated using alignments of nucleotides with 10 000 sites simulated under complex non-SRH conditions on a 25-tipped tree. The algorithms were found to be very successful, identifying the correct HAL model with a 75% success rate (the average success rate for assigning rate matrices to the tree's 48 edges was 99.25%) and, for the correct HAL model, identifying the correct HAS model with a 98% success rate. Finally, parameter estimates obtained under the correct HAL-HAS model were found to be accurate and precise. The merits of our new algorithms were illustrated with an analysis of 42 337 second codon sites extracted from a concatenation of 106 alignments of orthologous genes encoded by the nuclear genomes of Saccharomyces cerevisiae, S. paradoxus, S. mikatae, S. kudriavzevii, S. castellii, S. kluyveri, S. bayanus, and Candida albicans. Our results show that second codon sites in the ancestral genome of these species contained 49.1% invariable sites, 39.6% variable sites belonging to one rate category (V1), and 11.3% variable sites belonging to a second rate category (V2). The ancestral nucleotide content was found to differ markedly across these three sets of sites, and the evolutionary processes operating at the variable sites were found to be non-SRH and best modeled by a combination of eight edge-specific rate matrices (four for V1 and four for V2). The number of substitutions per site at the variable sites also differed markedly, with sites belonging to V1 evolving slower than those belonging to V2 along the lineages separating the seven species of Saccharomyces. Finally, sites belonging to V1 appeared to have ceased evolving along the lineages separating S. cerevisiae, S. paradoxus, S. mikatae, S. kudriavzevii, and S. bayanus, implying that they might have become so selectively constrained that they could be considered invariable sites in these species.

The root locus method: application to linear stability analysis and design of cooperative car-following models

A global framework for linear stability analyses of traffic models, based on the dispersion relation root locus method, is presented and is applied taking the example of a broad class of car-following (CF) models. This approach is able to analyse all aspects of the dynamics: long waves and short wave behaviours, phase velocities and stability features. The methodology is applied to investigate the potential benefits of connected vehicles, i.e. V2V communication enabling a vehicle to send and receive information to and from surrounding vehicles. We choose to focus on the design of the coefficients of cooperation which weights the information from downstream vehicles. The coefficients tuning is performed and different ways of implementing an efficient cooperative strategy are discussed. Hence, this paper brings design methods in order to obtain robust stability of traffic models, with application on cooperative CF models

Predictive models for water sources with high susceptibility for bromine-containing disinfection by-product formation: Implications for water treatment

This study examines a matrix of synthetic water samples designed to include conditions that favour brominated disinfection by-product (Br-DBP) formation, in order to provide predictive models suitable for high Br-DBP forming waters such as salinity-impacted waters. Br-DBPs are known to be more toxic than their chlorinated analogues, in general, and their formation may be favoured by routine water treatment practices such as coagulation/flocculation under specific conditions; therefore, circumstances surrounding their formation must be understood. The chosen factors were bromide concentration, mineral alkalinity, bromide to dissolved organic carbon (Br/DOC) ratio and Suwannee River natural organic matter concentration. The relationships between these parameters and DBP formation were evaluated by response surface modelling of data generated using a face-centred central composite experimental design. Predictive models for ten brominated and/or chlorinated DBPs are presented, as well as models for total trihalomethanes (tTHMs) and total dihaloacetonitriles (tDHANs), and bromide substitution factors for the THMs and DHANs classes. The relationships described revealed that increasing alkalinity and increasing Br/DOC ratio were associated with increasing bromination of THMs and DHANs, suggesting that DOC lowering treatment methods that do not also remove bromide such as enhanced coagulation may create optimal conditions for Br-DBP formation in waters in which bromide is present.

Estimates on the coverage of parameter space using populations of models

In this paper we provide estimates for the coverage of parameter space when using Latin Hypercube Sampling, which forms the basis of building so-called populations of models. The estimates are obtained using combinatorial counting arguments to determine how many trials, k, are needed in order to obtain specified parameter space coverage for a given value of the discretisation size n. In the case of two dimensions, we show that if the ratio (Ø) of trials to discretisation size is greater than 1, then as n becomes moderately large the fractional coverage behaves as 1-exp-ø. We compare these estimates with simulation results obtained from an implementation of Latin Hypercube Sampling using MATLAB.

Comparing multilevel and Bayesian spatial random effects survival models to assess geographical inequalities in colorectal cancer survival: a case study

Background Multilevel and spatial models are being increasingly used to obtain substantive information on area-level inequalities in cancer survival. Multilevel models assume independent geographical areas, whereas spatial models explicitly incorporate geographical correlation, often via a conditional autoregressive prior. However the relative merits of these methods for large population-based studies have not been explored. Using a case-study approach, we report on the implications of using multilevel and spatial survival models to study geographical inequalities in all-cause survival. Methods Multilevel discrete-time and Bayesian spatial survival models were used to study geographical inequalities in all-cause survival for a population-based colorectal cancer cohort of 22,727 cases aged 20–84 years diagnosed during 1997–2007 from Queensland, Australia. Results Both approaches were viable on this large dataset, and produced similar estimates of the fixed effects. After adding area-level covariates, the between-area variability in survival using multilevel discrete-time models was no longer significant. Spatial inequalities in survival were also markedly reduced after adjusting for aggregated area-level covariates. Only the multilevel approach however, provided an estimation of the contribution of geographical variation to the total variation in survival between individual patients. Conclusions With little difference observed between the two approaches in the estimation of fixed effects, multilevel models should be favored if there is a clear hierarchical data structure and measuring the independent impact of individual- and area-level effects on survival differences is of primary interest. Bayesian spatial analyses may be preferred if spatial correlation between areas is important and if the priority is to assess small-area variations in survival and map spatial patterns. Both approaches can be readily fitted to geographically enabled survival data from international settings

Optimizing the quantum dot: Plasmon interaction in a nano gap waveguide

Spontaneous emission (SE) of a Quantum emitter depends mainly on the transmission strength between the upper and lower energy levels as well as the Local Density of States (LDOS)[1]. When a QD is placed in near a plasmon waveguide, LDOS of the QD is increased due to addition of the non-radiative decay and a plasmonic decay channel to free space emission[2-4]. The slow velocity and dramatic concentration of the electric field of the plasmon can capture majority of the SE into guided plasmon mode (Гpl ). This paper focused on studying the effect of waveguide height on the efficiency of coupling QD decay into plasmon mode using a numerical model based on finite elemental method (FEM). Symmetric gap waveguide considered in this paper support single mode and QD as a dipole emitter. 2D simulation models are done to find normalized Гpl and 3D models are used to find probability of SE decaying into plasmon mode ( β) including all three decay channels. It is found out that changing gap height can increase QD-plasmon coupling, by up to a factor of 5 and optimally placed QD up to a factor of 8. To make the paper more realistic we briefly studied the effect of sharpness of the waveguide edge on SE emission into guided plasmon mode. Preliminary nano gap waveguide fabrication and testing are already underway. Authors expect to compare the theoretical results with experimental outcomes in the future

Optimal management of the critically Ill: Anaesthesia, monitoring, data capture, and point-of-care technological practices in ovine models of critical care

Animal models of critical illness are vital in biomedical research. They provide possibilities for the investigation of pathophysiological processes that may not otherwise be possible in humans. In order to be clinically applicable, the model should simulate the critical care situation realistically, including anaesthesia, monitoring, sampling, utilising appropriate personnel skill mix, and therapeutic interventions. There are limited data documenting the constitution of ideal technologically advanced large animal critical care practices and all the processes of the animal model. In this paper, we describe the procedure of animal preparation, anaesthesia induction and maintenance, physiologic monitoring, data capture, point-of-care technology, and animal aftercare that has been successfully used to study several novel ovine models of critical illness. The relevant investigations are on respiratory failure due to smoke inhalation, transfusion related acute lung injury, endotoxin-induced proteogenomic alterations, haemorrhagic shock, septic shock, brain death, cerebral microcirculation, and artificial heart studies. We have demonstrated the functionality of monitoring practices during anaesthesia required to provide a platform for undertaking systematic investigations in complex ovine models of critical illness.

Post-transcriptional regulation in the nucleus and cytoplasm: study of mean time to threshold (MTT) and narrow escape problem

Messenger RNAs (mRNAs) can be repressed and degraded by small non-coding RNA molecules. In this paper, we formulate a coarsegrained Markov-chain description of the post-transcriptional regulation of mRNAs by either small interfering RNAs (siRNAs) or microRNAs (miRNAs). We calculate the probability of an mRNA escaping from its domain before it is repressed by siRNAs/miRNAs via cal- culation of the mean time to threshold: when the number of bound siRNAs/miRNAs exceeds a certain threshold value, the mRNA is irreversibly repressed. In some cases,the analysis can be reduced to counting certain paths in a reduced Markov model. We obtain explicit expressions when the small RNA bind irreversibly to the mRNA and we also discuss the reversible binding case. We apply our models to the study of RNA interference in the nucleus, examining the probability of mRNAs escaping via small nuclear pores before being degraded by siRNAs. Using the same modelling framework, we further investigate the effect of small, decoy RNAs (decoys) on the process of post-transcriptional regulation, by studying regulation of the tumor suppressor gene, PTEN : decoys are able to block binding sites on PTEN mRNAs, thereby educing the number of sites available to siRNAs/miRNAs and helping to protect it from repression. We calculate the probability of a cytoplasmic PTEN mRNA translocating to the endoplasmic reticulum before being repressed by miRNAs. We support our results with stochastic simulations