Development and Validation of Two Screening Assays for the Hepatitis C Virus NS3 Q80K Polymorphism Associated with Reduced Response to Combination Treatment Regimens Containing Simeprevir.

Persons with hepatitis C virus (HCV) genotype 1a (GT1a) infections harboring a baseline Q80K polymorphism in nonstructural protein 3 (NS3) have a reduced virologic response to simeprevir in combination with pegylated interferon-alfa and ribavirin. We aimed to develop, validate, and freely disseminate an NS3 clinical sequencing assay to detect the Q80K polymorphism and potentially other HCV NS3 drug resistance mutations. HCV RNA was extracted from frozen plasma using a NucliSENS easyMAG automated nucleic acid extractor, amplified by nested reverse transcription-PCR, and sequenced using Sanger and/or next-generation (MiSeq) methods. Sanger chromatograms were analyzed using in-house software (RECall), and nucleotide mixtures were called automatically. MiSeq reads were iteratively mapped to the H77 reference genome, and consensus NS3 sequences were generated with nucleotides present at >20% called as mixtures. The accuracy, precision, and sensitivity for detecting the Q80K polymorphism were assessed in 70 samples previously sequenced by an external laboratory. A comparison of the sequences generated by the Sanger and MiSeq methods with those determined by an external lab revealed >98.5% nucleotide sequence concordance and zero discordant calls of the Q80K polymorphism. The results were both highly repeatable and reproducible (>99.7% nucleotide concordance and 100% Q80K concordance). The limits of detection (>2 and ∼5 log10 IU/ml for the Sanger and MiSeq assays, respectively) are sufficiently low to allow genotyping in nearly all chronically infected treatment-naive persons. No systematic bias in the under- or overamplification of minority variants was observed. Coinfection with other viruses (e.g., HIV and hepatitis B virus [HBV]) did not affect the assay results. The two independent HCV NS3 sequencing assays with the automated analysis procedures described here are useful tools to screen for the Q80K polymorphism and other HCV protease inhibitor drug resistance mutations.

Modelling and simulation of porcine liver tissue indentation using finite element method and uniaxial stress-strain data.

We hypothesize that both compression and elongation stress-strain data should be considered for modeling and simulation of soft tissue indentation. Uniaxial stress-strain data were obtained from in vitro loading experiments of porcine liver tissue. An axisymmetric finite element model was used to simulate liver tissue indentation with tissue material represented by hyperelastic models. The material parameters were derived from uniaxial stress-strain data of compressions, elongations, and combined compression and elongation of porcine liver samples. in vitro indentation tests were used to validate the finite element simulation. Stress-strain data from the simulation with material parameters derived from the combined compression and elongation data match the experimental data best. This is due to its better ability in modeling 3D deformation since the behavior of biological soft tissue under indentation is affected by both its compressive and tensile characteristics. The combined logarithmic and polynomial model is somewhat better than the 5-constant Mooney-Rivlin model as the constitutive model for this indentation simulation.

Liver tissue characterization from uniaxial stress-strain data using probabilistic and inverse finite element methods.

Biological soft tissue is highly inhomogeneous with scattered stress-strain curves. Assuming that the instantaneous strain at a specific stress varies according to a normal distribution, a nondeterministic approach is proposed to model the scattered stress-strain relationship of the tissue samples under compression. Material parameters of the liver tissue modeled using Mooney-Rivlin hyperelastic constitutive equation were represented by a statistical function with normal distribution. Mean and standard deviation of the material parameters were determined using inverse finite element method and inverse mean-value first-order second-moment (IMVFOSM) method respectively. This method was verified using computer simulation based on direct Monte-Carlo (MC) method. The simulated cumulative distribution function (CDF) corresponded well with that of the experimental stress-strain data. The resultant nondeterministic material parameters were able to model the stress-strain curves from other separately conducted liver tissue compression tests. Stress-strain data from these new tests could be predicted using the nondeterministic material parameters.

Accurate two-dimensional cardiac strain calculation using adaptive windowed Fourier transform and Gabor wavelet transform.

PURPOSE: Cardiac strain calculated from tagged magnetic resonance (MR) images provides clinicians information about abnormalities of heart-wall motion in patients. It is important to develop an accurate method to determine the cardiac strain efficiently. An adaptive windowed harmonic phase (AWHARP) method is proposed for cardiac strain calculation. MATERIALS AND METHODS: AWHARP is based on adaptive windowed Fourier transform (AWFT) and 2D Gabor wavelet transform (2D-GWT). The AWFT provides a spatially varying representation of the signal spectra, which allows the harmonic phase (HARP) image to be extracted with high accuracy. Instantaneous spatial frequencies are calculated using 2D-GWT, and the widths of the adaptive windows are then determined according to the instantaneous spatial frequencies for multi-resolution analysis of phase extraction. The proposed method was studied using simulated images and patients' MR images. Both single tagged images (SPAMM) and subtracted tagged images (CSPAMM) were generated using our simulation method, and their results calculated using AWHARP and HARP methods were compared. Normal and pathological tagged MR images were also processed to evaluate the performance of our method. RESULTS: Our experimental results show that the accuracies of phase and strain images calculated using the AWHARP method are higher than that calculated using the HARP method especially for large tag line deformation. The improvement in accuracies can be up to 3.2 strain (E1) and 17.3 calculation from MR images reveals that the cardiac strain in the end-systolic state is significantly reduced for patients with hypertrophic cardiomyopathy (HCM) compared to that of healthy subjects. CONCLUSION: The proposed AWHARP is an accurate and efficient method for cardiac strain estimation from MR images. This new algorithm can help clinicians to detect left ventricle dysfunctions and myocardial diseases with accurate cardiac strain analysis.

A bioabsorbable microclip for laryngeal microsurgery: design and evaluation.

Epithelial flaps created during laryngeal microsurgery require apposition to facilitate proper healing. Current technologies are restricted by minimal access of the surgical site, posing various limitations in application. In this paper, we propose a novel magnesium-based bioabsorbable microclip, discuss our design considerations and evaluate the microclip's feasibility as a miniature wound closure device. Ex vivo experiments demonstrate that the microclip fastens securely to the vocal fold, while in vivo studies show bioabsorbability and a lack of adverse side effects, suggesting that the microclips are viable as implantable devices.

A multiscale model for bioimpedance dispersion of liver tissue.

Radio-frequency ablation (RFA) has been used in liver surgery to minimize blood loss during tissue division. However, the current RFA tissue division method lacks an effective way of determining the stoppage of blood flow. There is limitation on the current state-of-the-art laser Doppler flow sensor due to its small sensing area. A new technique was proposed to use bioimpedance for blood flow sensing. This paper discusses a new geometrical multiscale model of the liver bioimpedance incorporating blood flow impedance. This model establishes correlation between the physical tissue structure and bioimpedance measurement. The basic Debye structure within a multilevel framework is used in the model to account for bioimpedance dispersion. This dispersion is often explained by the Cole-Cole model that includes a constant phase element without physical explanation. Our model is able to account for reduced blood flow in its output with changes in permittivity in gamma dispersion that is mainly due to the polarization of water molecules. This study demonstrates the potential of a multiscale model in determining the stoppage of blood flow during surgery.

A semi-automatic approach to the segmentation of liver parenchyma from 3D CT images with Extreme Learning Machine.

This paper presents a semi-automatic approach to segmentation of liver parenchyma from 3D computed tomography (CT) images. Specifically, liver segmentation is formalized as a pattern recognition problem, where a given voxel is to be assigned a correct label - either in a liver or a non-liver class. Each voxel is associated with a feature vector that describes image textures. Based on the generated features, an Extreme Learning Machine (ELM) classifier is employed to perform the voxel classification. Since preliminary voxel segmentation tends to be less accurate at the boundary, and there are other non-liver tissue voxels with similar texture characteristics as liver parenchyma, morphological smoothing and 3D level set refinement are applied to enhance the accuracy of segmentation. Our approach is validated on a set of CT data. The experiment shows that the proposed approach with ELM has the reasonably good performance for liver parenchyma segmentation. It demonstrates a comparable result in accuracy of classification but with a much faster training and classification speed compared with support vector machine (SVM).

Motion tracking and strain map computation for quasi-static magnetic resonance elastography.

This paper presents a new imaging method for quasi-static magnetic resonance elastography (MRE). Tagged magnetic resonance (MR) imaging of human lower leg was acquired with probe indentation using a MR-compatible actuation system. Indentation force was recorded for soft tissue elasticity reconstruction. Motion tracking and strain map of human lower leg are calculated using a harmonic phase (HARP)-based method. Simulated tagged MR images were constructed and analyzed to validate the HARP-based method. Our results show that the proposed imaging method can be used to generate accurate motion distribution and strain maps of the targeted soft tissue.

Physiological analysis on oscillatory behavior of glucose-insulin regulation by model with delays.

In artificial pancreas, glucose level measurement and insulin infusion are often implemented in the subcutaneous tissues. Understanding the dynamics of glucose and insulin in the subcutaneous tissues is important in the regulation of blood glucose level. We propose a new two-compartmental model of glucose-insulin interaction with two explicit delays that can study the interaction of glucose in different organs and the oscillatory behavior of the glucose-insulin system. The glucose and insulin space are split into plasma compartment and interstitial fluids compartment, respectively. The four m parameters of insulin dynamics and the two delays are analyzed for their influence on the glucose-insulin regulatory system. The ranges of the six parameters are estimated for sustaining the oscillation of glucose and insulin, and ranges for different subjects are discussed based on simulation results. The effect of these parameters on the oscillatory system is related to diseases and irregular blood glucose level. The lag between glucose and insulin in the two compartments has provided an insight on the distribution and metabolism of glucose and insulin in quick- and slow-equilibrating organs and tissues. We have reported in this paper, a model that can effectively deal with concentration of glucose and insulin in the interstitial compartment. This is important for the development of artificial pancreas.

Design of a mechanical larynx with agarose as a soft tissue substitute for vocal fold applications.

Mechanical and computational models consisting of flow channels with convergent and oscillating constrictions have been applied to study the dynamics of human vocal fold vibration. To the best of our knowledge, no mechanical model has been studied using a material substitute with similar physical properties to the human vocal fold for surgical experimentation. In this study, we design and develop a mechanical larynx with agarose as a vocal fold substitute, and assess its suitability for surgical experimentation. Agarose is selected as a substitute for the vocal fold as it exhibits similar nonlinear hyperelastic characteristics to biological soft tissue. Through uniaxial compression and extension tests, we determined that agarose of 0.375% concentration most closely resembles the vocal fold mucosa and ligament of a 20-year old male for small tensile strain with an R(2) value of 0.9634 and root mean square error of 344.05±39.84 Pa. Incisions of 10 mm lengthwise and 3 mm in depth were created parallel to the medial edge on the superior surface of agar phantom. These were subjected to vibrations of 80, 130, and 180 Hz, at constant amplitude of 0.9 mm over a period of 10 min each in the mechanical larynx model. Lateral expansion of the incision was observed to be most significant for the lower frequency of 80 Hz. This model serves as a basis for future assessments of wound closure techniques during microsurgery to the vocal fold.

Fast segmentation of bone in CT images using 3D adaptive thresholding.

Fast bone segmentation is often important in computer-aided medical systems. Thresholding-based techniques have been widely used to identify the object of interest (bone) against dark backgrounds. However, the darker areas that are often present in bone tissue may adversely affect the results obtained using existing thresholding-based segmentation methods. We propose an automatic, fast, robust and accurate method for the segmentation of bone using 3D adaptive thresholding. An initial segmentation is first performed to partition the image into bone and non-bone classes, followed by an iterative process of 3D correlation to update voxel classification. This iterative process significantly improves the thresholding performance. A post-processing step of 3D region growing is used to extract the required bone region. The proposed algorithm can achieve sub-voxel accuracy very rapidly. In our experiments, the segmentation of a CT image set required on average less than 10s per slice. This execution time can be further reduced by optimizing the iterative convergence process.

A biomechanical model for real-time simulation of PMMA injection with haptics.

We have developed a computationally efficient rheological model to simulate polymethylmethacrylate (PMMA) injection into cancellous bone during percutaneous vertebroplasty. The model employs the Hagen-Poiseuille law to predict pressure drop across a delivery cannula with viscoelastic changes of curing PMMA modeled via a time and shear-rate-dependent power law. The power law was derived based on dynamic rheological testing of curing PMMA samples. In conjunction with a branching-pipe geometrical model that is reconstructed from micro-computed tomography scans of cancellous bone for estimating pressure changes during PMMA flow in bone, the method provides a fast estimation of overall injection pressure, and, hence, the reaction force during manual PMMA injection.

Bone material properties and fracture analysis: needle insertion for spinal surgery.

The effectiveness of percutaneous needle-based therapy and biopsy is demonstrated in a wide variety of medical problems including spinal disorders. Combined with osteoporosis, spinal disorders are increasingly prevalent as our society ages. However, the final position of the needle depends on a complex interplay of material properties of the bone and/or pathology, as well as the shape and material of the needle, and the insertion dynamics. This paper is a survey of the literature in the area of bone material properties and needle/bone interaction in the context of needle placement. It describes research findings on bone material properties and fractures using micro-CT imaging, and integrative imaging. This review paper also discusses the feasibility of using computational methods to predict fracture by simulating needle placement on any patient-specific model with both geometrical and mechanical properties approximating those of the patient's anatomy.

Heterogeneous meshing and biomechanical modeling of human spine.

We aim to develop a patient-specific biomechanical model of human spine for the purpose of surgical training and planning. In this paper, we describe the development of a finite-element model of the spine from the VHD Male Data. The finite-element spine model comprises volumetric elements suitable for deformation and other finite-element analysis using ABAQUS. The mesh generation solution accepts segmented radiological slices as input, and outputs three-dimensional (3D) volumetric finite element meshes that are ABAQUS compliant. The proposed mesh generation method first uses a grid plane to divide the contours of the anatomical boundaries and its inclusions into discrete meshes. A grid frame is then built to connect the grid planes between any two adjacent planes using a novel scheme. The meshes produced consist of brick elements in the interior of the contours and with tetrahedral and wedge elements at the boundaries. The nodal points are classified according to their materials and hence, elements can be assigned different properties. The resultant spine model comprises a detailed model of the 7 cervical vertebrae, 12 thoracic vertebrae, 5 lumbar vertebrae, and S1. Each of the vertebrae and intervertebral disc has between 1200 and 6000 elements, and approximately 1200 elements, respectively. The accuracy of the resultant VHD finite element spine model was good based on visual comparison of volume-rendered images of the original CT data, and has been used in a computational analysis involving needle insertion and static deformation. We also compared the mesh generated using our method against two automatically generated models; one consists of purely tetrahedral elements and the other hexahedral elements.

Tactile VR for hand-eye coordination in simulated PTCA.

Percutaneous transluminal coronary angioplasty (PTCA) is a minimally invasive image-guided technique for treatment of coronary diseases. PTCA procedure requires physicians to have good skills of hand-eye coordination in performing the operation. Training of PTCA thus very much emphasizes skill building for hand-eye coordination. We have been developing virtual reality (VR) technology for medical simulation. In this paper, we will address the issue of VR-based simulation for the enhancement of hand-eye coordination for PTCA operation. Starting from the characterization of PTCA procedure, we examine what roles VR can play in training of PTCA physicians. We then describe a computerized PTCA training system we have developed which is composed of a tactile interface and a visual interface. The system is designed in such a way that real PTCA devices (including catheters and guide-wires) can be used to mimic the requirements of the CathLab. The backend computational engine supporting the real-time and realistic PTCA simulation is also presented.

Computational biomechanical modelling of the lumbar spine using marching-cubes surface smoothened finite element voxel meshing.

There is a need for the development of finite element (FE) models based on medical datasets, such as magnetic resonance imaging and computerized tomography in computation biomechanics. Direct conversion of graphic voxels to FE elements is a commonly used method for the generation of FE models. However, conventional voxel-based methods tend to produce models with jagged surfaces. This is a consequence of the inherent characteristics of voxel elements; such a model is unable to capture the geometries of anatomical structures satisfactorily. We have developed a robust technique for the automatic generation of voxel-based patient-specific FE models. Our approach features a novel tetrahedronization scheme that incorporates marching-cubes surface smoothing together with a smooth-distortion factor (SDF). The models conform to the actual geometries of anatomical structures of a lumbar spine segment (L3). The resultant finite element analysis (FEA) at the surfaces is more accurate compared to the use of conventional voxel-based generated FE models. In general, models produced by our method were superior compared to that obtained using the commercial software ScanFE.

Performance analysis of a new semiorthogonal spline wavelet compression algorithm for tonal medical images.

Lossy image compression is thought to be a necessity as radiology moves toward a filmless environment. Compression algorithms based on the discrete cosine transform (DCT) are limited due to the infinite support of the cosine basis function. Wavelets, basis functions that have compact or nearly compact support, are mathematically better suited for decorrelating medical image data. A lossy compression algorithm based on semiorthogonal cubic spline wavelets has been implemented and tested on six different image modalities (magnetic resonance, x-ray computed tomography, single photon emission tomography, digital fluoroscopy, computed radiography, and ultrasound). The fidelity of the reconstructed wavelet images was compared to images compressed with a DCT algorithm for compression ratios of up to 40:1. The wavelet algorithm was found to have generally lower average error metrics and higher peak-signal-to-noise ratios than the DCT algorithm.

Introduction to wavelet-based compression of medical images.

Medical image compression can significantly enhance the performance of picture archiving and communication systems and may be considered an enabling technology for telemedicine. The wavelet transform is a powerful mathematical tool with many unique qualities that are useful for image compression and processing applications. Although wavelet concepts can be traced back to 1910, the mathematics of wavelets have only recently been formalized. By exploiting spatial and spectral information redundancy in images, wavelet-based methods offer significantly better results for compressing medical images than do compression algorithms based on Fourier methods, such as the discrete cosine transform used by the Joint Photographic Experts Group. Furthermore, wavelet-based compression does not suffer from blocking artifacts, and the restored image quality is generally superior at higher compression rates.