Interpreting sources of variation in clinical gait analysis: a case study

Objective: To illustrate and discuss sources of gait deviations (experimental, genuine and intentional) during a gait analysis and how these deviations inform clinical decision making. Methods A case study of a 24-year old male diagnosed with Alkaptonuria undergoing a routine gait analysis. A 3D motion capture with the Helen-Hayes marker set was used to quantify lower-limb joint kinematics during barefoot walking along a 10 m walkway at a self-selected pace. Additional 2D video data were recorded in the sagittal and frontal plane. The patient reported no aches or pains in any joint and described his lifestyle as active. Results: Temporal-spatial parameters were within normal ranges for his age and sex. Three sources of gait deviations were identified; the posteriorly rotated pelvis was due to an experimental error and marker misplacement, the increased rotation of the pelvis in the horizontal plane was genuine and observed in both 3D gait curves and in 2D video analysis, finally the inconsistency in knee flexion/extension combined with a seemingly innocuous interest in the consequences of abnormal gait suggested an intentional gait deviation. Conclusions: Gait analysis is an important analytical tool in the management of a variety of conditions that negatively impact on movement. Experienced gait analysts have the ability to recognise genuine gait adaptations that forms part of the decision-making process for that patient. However, their role also necessitates the ability to identify and correct for experimental errors and critically evaluate when a deviation may not be genuine

Age related deviation of gait from normality in alkaptonuria.

Alkaptonuria is a rare metabolic disease leading to systemic changes including early and severe arthropathy which affects mobility. Due to unknown reasons, the onset of degenerative changes is delayed to around 30 years of age when both objective and subjective symptoms develop. In order to complement describing the structural changes in alkaptonuria with measures of movement function, clinical gait analysis was added to the list of assessments in 2013. The aim of this study was to describe the deviation of gait from normality as a function of age in patients with alkaptonuria. Three-dimensional movement of reflective markers attached to joints were captured during walking in 39 patients and 10 controls. Subsequent to processing the data to emphasise the shape of marker trajectories, the mean Movement Deviation Profile was generated for all participants. This single number measure gives the deviation of a patient’s gait from a distributed definition of gait normality. Results showed that gait deviation roughly follows a sigmoid profile with minimal increase of gait deviations in a younger patient group and an abrupt large increase around the second half of the 4th decade of life. Larger variations of gait deviations were found in the older group than in the younger group suggesting a complex interaction of multiple factors which determine gait function after symptoms manifest. Continued gait analysis of adults with AKU, extended to younger adults and children with AKU, is expected to complete understanding of both the natural history of alkaptonuria and how interventions can affect movement function

A unified hyperbolic formulation for viscous fluids and elastoplastic solids

We discuss a unified flow theory which in a single system of hyperbolic partial differential equations (PDEs) can describe the two main branches of continuum mechanics, fluid dynamics, and solid dynamics. The fundamental difference from the classical continuum models, such as the Navier-Stokes for example, is that the finite length scale of the continuum particles is not ignored but kept in the model in order to semi-explicitly describe the essence of any flows, that is the process of continuum particles rearrangements. To allow the continuum particle rearrangements, we admit the deformability of particle which is described by the distortion field. The ability of media to flow is characterized by the strain dissipation time which is a characteristic time necessary for a continuum particle to rearrange with one of its neighboring particles. It is shown that the continuum particle length scale is intimately connected with the dissipation time. The governing equations are represented by a system of first order hyperbolic PDEs with source terms modeling the dissipation due to particle rearrangements. Numerical examples justifying the reliability of the proposed approach are demonstrated.Comment: 6 figure

Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis

Objective: Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. Methods: An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. Results: Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10−8 and cg26401028, P = 1.69 × 10−8). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10−7 and P = 1.05 × 10−6, respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204). Conclusion: We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor–related protein 1. Additional replication experiments in independent sample collections are now needed

Stellar Disk Truncations: Where do we stand ?

In the light of several recent developments we revisit the phenomenon of galactic stellar disk truncations. Even 25 years since the first paper on outer breaks in the radial light profiles of spiral galaxies, their origin is still unclear. The two most promising explanations are that these 'outer edges' either trace the maximum angular momentum during the galaxy formation epoch, or are associated with global star formation thresholds. Depending on their true physical nature, these outer edges may represent an improved size characteristic (e.g., as compared to D_25) and might contain fossil evidence imprinted by the galaxy formation and evolutionary history. We will address several observational aspects of disk truncations: their existence, not only in normal HSB galaxies, but also in LSB and even dwarf galaxies; their detailed shape, not sharp cut-offs as thought before, but in fact demarcating the start of a region with a steeper exponential distribution of starlight; their possible association with bars; as well as problems related to the line-of-sight integration for edge-on galaxies (the main targets for truncation searches so far). Taken together, these observations currently favour the star-formation threshold model, but more work is necessary to implement the truncations as adequate parameters characterising galactic disks.Comment: LaTeX, 10 pages, 6 figures, presented at the "Penetrating Bars through Masks of Cosmic Dust" conference in South Africa, proceedings published by Kluwer, and edited by Block, D.L., Freeman, K.C., Puerari, I., & Groess, R; v3 to match published versio

Altered Neural and Behavioral Dynamics in Huntington's Disease: An Entropy Conservation Approach

Background: Huntington’s disease (HD) is an inherited condition that results in neurodegeneration of the striatum, the forebrain structure that processes cortical information for behavioral output. In the R6/2 transgenic mouse model of HD, striatal neurons exhibit aberrant firing patterns that are coupled with reduced flexibility in the motor system. The aim of this study was to test the patterns of unpredictability in brain and behavior in wild-type (WT) and R6/2 mice. Methodology/Principal Findings: Striatal local field potentials (LFP) were recorded from 18 WT and 17 R6/2 mice (aged 8– 11 weeks) while the mice were exploring a plus-shaped maze. We targeted LFP activity for up to 2 s before and 2 s after each choice-point entry. Approximate Entropy (ApEn) was calculated for LFPs and Shannon Entropy was used to measure the probability of arm choice, as well as the likelihood of making consecutive 90-degree turns in the maze. We found that although the total number of choice-point crossings and entropy of arm-choice probability was similar in both groups, R6/2 mice had more predictable behavioral responses (i.e., were less likely to make 90-degree turns and perform them in alternation with running straight down the same arm), while exhibiting more unpredictable striatal activity, as indicated by higher ApEn values. In both WT and R6/2 mice, however, behavioral unpredictability was negatively correlated with LFP ApEn. Conclusions/Significance: HD results in a perseverative exploration of the environment, occurring in concert with mor

Recombination rate and selection strength in HIV intra-patient evolution

The evolutionary dynamics of HIV during the chronic phase of infection is driven by the host immune response and by selective pressures exerted through drug treatment. To understand and model the evolution of HIV quantitatively, the parameters governing genetic diversification and the strength of selection need to be known. While mutation rates can be measured in single replication cycles, the relevant effective recombination rate depends on the probability of coinfection of a cell with more than one virus and can only be inferred from population data. However, most population genetic estimators for recombination rates assume absence of selection and are hence of limited applicability to HIV, since positive and purifying selection are important in HIV evolution. Here, we estimate the rate of recombination and the distribution of selection coefficients from time-resolved sequence data tracking the evolution of HIV within single patients. By examining temporal changes in the genetic composition of the population, we estimate the effective recombination to be r=1.4e-5 recombinations per site and generation. Furthermore, we provide evidence that selection coefficients of at least 15% of the observed non-synonymous polymorphisms exceed 0.8% per generation. These results provide a basis for a more detailed understanding of the evolution of HIV. A particularly interesting case is evolution in response to drug treatment, where recombination can facilitate the rapid acquisition of multiple resistance mutations. With the methods developed here, more precise and more detailed studies will be possible, as soon as data with higher time resolution and greater sample sizes is available.Comment: to appear in PLoS Computational Biolog

The scale of population structure in Arabidopsis thaliana

The population structure of an organism reflects its evolutionary history and influences its evolutionary trajectory. It constrains the combination of genetic diversity and reveals patterns of past gene flow. Understanding it is a prerequisite for detecting genomic regions under selection, predicting the effect of population disturbances, or modeling gene flow. This paper examines the detailed global population structure of Arabidopsis thaliana. Using a set of 5,707 plants collected from around the globe and genotyped at 149 SNPs, we show that while A. thaliana as a species self-fertilizes 97% of the time, there is considerable variation among local groups. This level of outcrossing greatly limits observed heterozygosity but is sufficient to generate considerable local haplotypic diversity. We also find that in its native Eurasian range A. thaliana exhibits continuous isolation by distance at every geographic scale without natural breaks corresponding to classical notions of populations. By contrast, in North America, where it exists as an exotic species, A. thaliana exhibits little or no population structure at a continental scale but local isolation by distance that extends hundreds of km. This suggests a pattern for the development of isolation by distance that can establish itself shortly after an organism fills a new habitat range. It also raises questions about the general applicability of many standard population genetics models. Any model based on discrete clusters of interchangeable individuals will be an uneasy fit to organisms like A. thaliana which exhibit continuous isolation by distance on many scales

Axion-like-particle search with high-intensity lasers

We study ALP-photon-conversion within strong inhomogeneous electromagnetic fields as provided by contemporary high-intensity laser systems. We observe that probe photons traversing the focal spot of a superposition of Gaussian beams of a single high-intensity laser at fundamental and frequency-doubled mode can experience a frequency shift due to their intermittent propagation as axion-like-particles. This process is strongly peaked for resonant masses on the order of the involved laser frequencies. Purely laser-based experiments in optical setups are sensitive to ALPs in the $\mathrm{eV}$ mass range and can thus complement ALP searches at dipole magnets.Comment: 25 pages, 2 figure