A physiology-based inverse dynamic analysis of human gait using sequential convex programming: a comparative study.

This paper presents an enhanced version of the previously proposed physiological inverse approach (PIA) to calculate musculotendon (MT) forces and evaluates the proposed methodology in a comparative study. PIA combines an inverse dynamic analysis with an optimisation approach that imposes muscle physiology and optimises performance over the entire motion. To solve the resulting large-scale, nonlinear optimisation problem, we neglected muscle fibre contraction speed and an approximate quadratic optimisation problem (PIA-QP) was formulated. Conversely, the enhanced version of PIA proposed in this paper takes into account muscle fibre contraction speed. The optimisation problem is solved using a sequential convex programing procedure (PIA-SCP). The comparative study includes PIA-SCP, PIA-QP and two commonly used approaches from the literature: static optimisation (SO) and computed muscle control (CMC). SO and CMC make simplifying assumptions to limit the computational time. Both methods minimise an instantaneous performance criterion. Furthermore, SO does not impose muscle physiology. All methods are applied to a gait cycle of six control subjects. The relative root mean square error averaged over all subjects, ε(RMS), between the joint torques simulated from the optimised activations and the joint torques obtained from the inverse dynamic analysis was about twice as large for SO (ε(RMS) = 86) as compared with CMC (ε(RMS) = 39) and PIA-SCP (ε(RMS) = 50). ε(RMS) was at least twice as large for PIA-QP (ε(RMS) = 197) than for all other methods. As compared with CMC, muscle activation patterns predicted by PIA-SCP better agree with experimental electromyography (EMG). This study shows that imposing muscle physiology as well as globally optimising performance is important to accurately calculate MT forces underlying gait.

Functional knee axis based on isokinetic dynamometry data: Comparison of two methods, MRI validation, and effect on knee joint kinematics.

This paper compares geometry-based knee axes of rotation (transepicondylar axis and geometric center axis) and motion-based functional knee axes of rotation (fAoR). Two algorithms are evaluated to calculate fAoRs: Gamage and Lasenby's sphere fitting algorithm (GL) and Ehrig et al.'s axis transformation algorithm (SARA). Calculations are based on 3D motion data acquired during isokinetic dynamometry. AoRs are validated with the equivalent axis based on static MR-images. We quantified the difference in orientation between two knee axes of rotation as the angle between the projection of the axes in the transversal and frontal planes, and the difference in location as the distance between the intersection points of the axes with the sagittal plane. Maximum differences between fAoRs resulting from GL and SARA were 5.7° and 15.4mm, respectively. Maximum differences between fAoRs resulting from GL or SARA and the equivalent axis were 5.4°/11.5mm and 8.6°/12.8mm, respectively. Differences between geometry-based axes and EA are larger than differences between fAoR and EA both in orientation (maximum 10.6°).and location (maximum 20.8mm). Knee joint angle trajectories and the corresponding accelerations for the different knee axes of rotation were estimated using Kalman smoothing. For the joint angles, the maximum RMS difference with the MRI-based equivalent axis, which was used as a reference, was 3°. For the knee joint accelerations, the maximum RMS difference with the equivalent axis was 20°/s(2). Functional knee axes of rotation describe knee motion better than geometry-based axes. GL performs better than SARA for calculations based on experimental dynamometry.

Sensitivity of dynamic simulations of gait and dynamometer experiments to hill muscle model parameters of knee flexors and extensors.

We assessed and compared sensitivities of dynamic simulations to musculotendon (MT) parameters for gait and dynamometer experiments. Our aim with this comparison was to investigate whether dynamometer experiments could provide information about MT-parameters that are important to reliably study MT-function during gait. This would mean that dynamometer experiments could be used to estimate these parameters. Muscle contribution to the joint torque (MT-torque) rather than relative MT-force primarily affects the resulting gait pattern and torque measured by the dynamometer. In contrast to recent studies, therefore, we assessed the sensitivity of the MT-torque, rather than the sensitivity of the relative MT-force. Based on sensitivity of the MT-torque to a parameter perturbation, MT-parameters of the knee flexors and extensors were classified in three categories: low, medium, and high. For gait, classification was based on the average sensitivity during a gait cycle. For isometric and isokinetic dynamometer experiments, classification was based on the highest sensitivity found in the experiments. The calculated muscle contributions to the knee torque during gait and dynamometer experiments had a high sensitivity to only a limited number of MT-parameters of the knee flexors and extensors, suggesting that not all MT-parameters need to be estimated. In general, the highest sensitivity was found for tendon slack length. However, for some muscles the sensitivity to the optimal fibre length or the maximal isometric muscle force was also high or medium. The classification of the individual MT-parameters for gait and dynamometer experiments was largely similar. We therefore conclude that dynamometer experiments provide information about MT-parameters important to reliably study MT-function during gait, so that subject-specific estimates of MT-parameters could be made based on dynamometer experiments.

A physiology based inverse dynamic analysis of human gait: potential and perspectives.

One approach to compute the musculotendon forces that underlie human motion is to combine an inverse dynamic analysis with a static optimisation procedure. Although computationally efficient, this classical inverse approach fails to incorporate constraints imposed by muscle physiology. The present paper reports on a physiological inverse approach (PIA) that combines an inverse dynamic analysis with a dynamic optimisation procedure. This allows the incorporation of a full description of muscle activation and contraction dynamics, without loss of computational efficiency. A comparison of muscle excitations and MT-forces predicted by the classical and the PIA is presented for normal and pathological gait. Inclusion of muscle physiology primarily affects the rate of active muscle force build-up and decay and allows the estimation of passive muscle force. Consequently, it influences the onset and cessation of the predicted muscle excitations as well as the level of co-contraction.

Kalman smoothing improves the estimation of joint kinematics and kinetics in marker-based human gait analysis.

We developed a Kalman smoothing algorithm to improve estimates of joint kinematics from measured marker trajectories during motion analysis. Kalman smoothing estimates are based on complete marker trajectories. This is an improvement over other techniques, such as the global optimisation method (GOM), Kalman filtering, and local marker estimation (LME), where the estimate at each time instant is only based on part of the marker trajectories. We applied GOM, Kalman filtering, LME, and Kalman smoothing to marker trajectories from both simulated and experimental gait motion, to estimate the joint kinematics of a ten segment biomechanical model, with 21 degrees of freedom. Three simulated marker trajectories were studied: without errors, with instrumental errors, and with soft tissue artefacts (STA). Two modelling errors were studied: increased thigh length and hip centre dislocation. We calculated estimation errors from the known joint kinematics in the simulation study. Compared with other techniques, Kalman smoothing reduced the estimation errors for the joint positions, by more than 50% for the simulated marker trajectories without errors and with instrumental errors. Compared with GOM, Kalman smoothing reduced the estimation errors for the joint moments by more than 35%. Compared with Kalman filtering and LME, Kalman smoothing reduced the estimation errors for the joint accelerations by at least 50%. Our simulation results show that the use of Kalman smoothing substantially improves the estimates of joint kinematics and kinetics compared with previously proposed techniques (GOM, Kalman filtering, and LME) for both simulated, with and without modelling errors, and experimentally measured gait motion.

KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.

BACKGROUND: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX). PATIENTS AND METHODS: We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression. RESULTS: OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size >9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)]. CONCLUSIONS: KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.

A semi-active milling procedure in view of preparing implantation beds in robot-assisted orthopaedic surgery.

Bone cutting in total joint reconstructions requires a high accuracy to obtain a well-functioning and long-lasting prosthesis. Hence robot assistance can be useful to increase the precision of the surgical actions. A drawback of current robot systems is that they autonomously machine the bone, in that way ignoring the surgeon's experience and introducing a safety risk. This paper presents a semi-active milling procedure to overcome that drawback. In this procedure the surgeon controls robot motion by exerting forces on a force-controlled lever that is attached to the robot end effector. Meanwhile the robot constrains tool motion to the planned motion and generates a tool feed determined by the feed force that the surgeon executes. As a case study the presented milling procedure has been implemented on a laboratory set-up for robot-assisted preparation of the acetabulum in total hip arthroplasty. Two machining methods have been considered. In the first method the surgeon determines both milling trajectory and feed by the forces that he/she executes on the force-controlled lever. In the second method the cavity is machined contour by contour, and the surgeon only provides the feed. Machining experiments have shown that the first method results in large surface irregularities and is not useful. The second method, however, results in accurate cavity preparation and has therefore potential to be implemented in future robot systems.

Machining and accuracy studies for a tibial knee implant using a force-controlled robot.

Total knee arthroplasty requires accurate preparation of the bone surfaces to maximize bone implant contact area in cementless surgery and to obtain proper joint kinematics and ligament balancing. Robots can make the cuts with the necessary high precision. The purpose of this article is threefold: to propose an alternative method for intraoperative registration using an intramedullary rod and an alternative method for force control using the hybrid force-velocity control scheme; to demonstrate that the accuracy and the surface flatness of the cuts machined by a robot are better than in a conventional operation; and to monitor the machining process and to try to derive some information about the local bone quality from it. The results of the laboratory study are promising: the surface flatness of the tibial plateau, calculated using a least squares method, is 0.1-0.2 mm, which is significantly better than in conventional surgery; and the high angular accuracy of the robot allows the bone cuts to be located precisely. Further, an exponential relation between milling forces and local bone density was established, so measurements of the milling forces can provide the surgeon with on-line information about the local bone quality.

Determination of oxybutinin chloride in pharmaceuticals by reversed-phase ion-pair liquid chromatography with two counter-ions in the eluent.

A reliable stability-indicating method using reversed-phase ion-pair high-performance liquid chromatography for the determination of the anticholinergic drug oxybutinin chloride in pharmaceuticals is reported. Sample extraction is easy and fairly rapid and recovery and precision of the method are excellent. Due to the simultaneous use of an organic amine and of an alkanesulphonate in the mobile phase, good selectivity towards related (quaternary ammonium) anticholinergic drugs was obtained.

Determination of S-carboxymethylcysteine in serum by reversed-phase ion-pair liquid chromatography with column switching following pre-column derivatization with o-phthalaldehyde.

A method is described for the determination of S-(carboxymethyl)-L-cysteine in serum. After addition of S-(carboxyethyl)-L-cysteine as internal standard, both compounds are extracted into methanol, converted into fluorescent derivatives with o-phthalaldehyde and quantitatively determined by reversed-phase high-performance liquid chromatography. Chromatography of unwanted amino acid derivatives is avoided by column switching, thereby shortening analysis time and increasing column lifetime. The technique was applied in a study of the bioavailability of S-(carboxymethyl)-L-cysteine after oral administration to humans. The concentration-response curve was linear from 2 to 16 micrograms/ml; mean serum concentrations are reported.

Polar contributions of the stationary phase to the reversed-phase ion-pair high-performance liquid chromatographic separation of quaternary ammonium drugs.

The chromatographic reproducibility of a methodology, developed for the separation and determination of quaternary ammonium drugs by reversed-phase ion-pair column liquid chromatography, was studied. The results in terms of retention dependence on the residual silanol content of the octadecyl stationary phase and column aging were compared with those obtained with conventional separation techniques. By on-column silylation with N-trimethylsilylimidazole, it was demonstrated that eluents containing both amines and alkanesulphonates, beside a higher resolving power, provide reproducible separations which are far less dependent on the residual and generated silanol groups compared to those obtained with eluents containing only an organic amine.

Reversed-phase ion-pair liquid chromatography of some quaternary ammonium drugs.

The resolving power of a reversed-phase liquid chromatographic method that makes use of a mobile phase system with two counter-ions of opposite charge (N,N-dimethyloctylamine and sodium octanesulphonate) for the separation of quaternary ammonium drugs, is compared with that obtained using more traditional ion-pairing systems. Efficient, selective and well-resolved separations could only be obtained by the combined effects of the eluent modifiers.

Simultaneous effects of amines and alkylsulphonates in reversed-phase ion-pair liquid chromatography--application to the separation of 2-imidazoline drugs.

The reversed-phase liquid chromatographic separation of several pharmaceutically important 2-imidazoline derivatives using eluents containing both amines and alkylsulphonates, is described. The addition of N, N-dimethyloctylamine and sodium octanesulphonate to an acidic aqueous methanolic eluent, resulted in an eluent with much higher separation power than mobile phases containing only one modifier. The combined effect of the amine and of the alkylsulphonate enabled baseline (or nearbaseline) separations of all the 2-imidazolines studied. The use of such eluents is described in terms of efficiency, selectivity, peak symmetry and separation time and the mechanism of retention is discussed. Some separation examples are given to demonstrate the applicability of the developed technique in the quality control of these drugs in pharmaceuticals.

Separation and determination of isopropamide iodide in pharmaceutical formulations by reversed-phase ion-pair high-performance liquid chromatography.

A stability-indicating determination for isopropamide iodide, an anticholinergic quaternary ammonium drug, in several pharmaceutical dosage forms by reversed-phase ion-pair liquid chromatography is reported. The use of eluents containing both an amine as well as an alkylsulphonate proved to be very efficient for separating and determining quaternary ammonium drugs and related other basic drugs: adequate selectivity, excellent peak shape and good reproducibility (coefficient of variation, 1-2%) were obtained in a short analysis time.