The effect of foot orientation modifications on knee joint biomechanics during different activities

Introduction Foot position during daily activities can influence the magnitude and rate of knee joint loading [1]. Over time, increased loading can cause cumulative damage to the articulating surfaces of the knee joint, especially in people with existing knee osteoarthritis [2]. Knee joint loading is difficult to measure in vivo as the majority of knee loading is distributed on the medial compartment of the knee joint, therefore, knee adduction moment (KAM) is commonly used as a surrogate measure for knee joint loading [3].   Foot orientation is believed to have an impact on knee loading during daily activities such as walking and standing from a chair, altering the direction of the ground reaction force vector to reduce the adduction moment arm, relative to the knee joint [4]. However, limited studies have systematically explored the effect of foot orientation on KAM in activities other than walking, which is crucial for improving functional mobility and quality of life in this population beyond the lab. Therefore, this study aims to evaluate the effect of different foot orientations (toe-in, parallel and toe-out) on knee loading across several daily activities (walking, sit-to-stand, and stair climbing).   Methods Twenty-nine participants (56 ± 5 years, 170 ± 8 cm, 74 ± 14 kg) performed over-ground walking, stair climbing and sit-to-stand movements at their preferred constant speed under three foot conditions, 10° toe-in, 10° toe-out, neutral (0°). Participants performed walking and sit-to-stand on overground force plates, and stair climbing on a portable force plate embedded within the stairs. Each condition within each activity was repeated until five successful trials were obtained.   Three-dimensional kinematic (200 Hz) and kinetic data (1000 Hz) were recorded to obtain knee joint moments and foot progression angles. Foot progression angle was identified using the frontal angle of foot (defined as a 6DOF rigid body) to the global coordinate system (QTM). KAM was computed using inverse dynamics (Visual 3D) and normalised to body mass. Mean within-participant values were calculated for statistical analysis, with repeated measures ANOVA and Bonferroni post-hoc analysis used to compare the KAMs of three foot orientations across all activities.   Results KAMs during toe-in foot position were significantly lower than those under neutral foot position during walking (P = 0.011), stair climbing and sit-to-stand (P &lt; 0.001), while the KAMs during neutral foot position were significantly lower than those in toe-out foot position across all activities (P &lt; 0.001) (Fig 1). Figure 1: Median and interquartile, peak KAM for toe-out, toe-in and neutral foot position conditions during walking, stair climbing and sit-to-stand.   Discussion All results showed a significant decrease in peak KAM during the toe-in foot position condition compared to toe-out and neutral foot positions, which is consistent with previous gait studies. The results of this study indicate that toe-in gait can reduce knee joint loading not only during walking, but also in stair climbing and sit-to-stand activities.   The results of this study will be of help in gait retraining programme in clinics and rehabilitation aimed at minimising knee loading and joint pain to slow the progression of the disease. They may provide a range of clinical guidance for injury prevention in a healthy older population under the common contexts  of stair climbing and sit-to-stand, taking the technique outside the lab. Future studies should explore the effectiveness of altered foot orientation modifications on knee loading and pain reduction, in a patient population such as knee osteoarthritis.   References 1.   Valenzuela et al, J Sports Sci. Med, 15:50-56, 2016. 2.   Lynn et al, Clin Biomech, 23: 779-786, 2008. 3.   Manal et al, Osteoarthr. Cartil, 23:1107-1111, 2015. 4.   Rutherford et al, Osteoarthr. Cartil, 16:883-889, 2008.   Acknowledgements This project was funded by China Scholarship Council.</p

Quantification of the distribution of macromolecules in vascular tissue

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1998.Includes bibliographical references (leaves 67-71).by Wade K. Wan.M.S

Adaptive format conversion information as enhancement data for scalable video coding

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2002.Includes bibliographical references (p. 143-145).Scalable coding techniques can be used to efficiently provide multicast video service and involve transmitting a single independently coded base layer and one or more dependently coded enhancement layers. Clients can decode the base layer bitstream and none, some or all of the enhancement layer bitstreams to obtain video quality commensurate with their available resources. In many scalable coding algorithms, residual coding information is the only type of data that is coded in the enhancement layers. However, since the transmitter has access to the original sequence, it can adaptively select different format conversion methods for different regions in an intelligent manner. This adaptive format conversion information can then be transmitted as enhancement data to assist processing at the decoder. The use of adaptive format conversion has not been studied in detail and this thesis examines when and how it can be used for scalable video compression. A new scalable codec is developed in this thesis that can utilize adaptive format conversion information and/or residual coding information as enhancement data. This codec was used in various simulations to investigate different aspects of adaptive format conversion such as the effect of the base layer, a comparison of adaptive format conversion and residual coding, and the use of both adaptive format conversion and residual coding.(cont.) The experimental results show adaptive format conversion can provide video scalability at low enhancement bitrates not possible with residual coding and also assist residual coding at higher enhancement layer bitrates. This thesis also discusses the application of adaptive format conversion to the migration path for digital television. Adaptive format conversion is well-suited to the unique problems of the migration path and can provide initial video scalability as well as assist a future migration path.by Wade K. Wan.Ph.D

TIES 2.0: A dual-topology open source relative binding free energy builder with web portal

Relative binding free energy (RBFE) calculations are widely used to aid the process of drug discovery. TIES, Thermodynamic Integration with Enhanced Sampling, is a dual-topology approach to RBFE calculations with support for NAMD and OpenMM molecular dynamics engines. The software has been thoroughly validated on publicly available datasets. Here we describe the open source software along with a web portal (https://ccs-ties.org) that enables users to perform such calculations correctly and rapidly

Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

Although researchers have been working tirelessly since the COVID-19 outbreak, so far only three drugs – remdesivir, ronapreve and molnupiravir – have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposing of existing drugs for the ongoing disease is an attractive proposition. In a recent study, a high-throughput X-ray crystallographic screen was performed for a selection of drugs which have been approved or are in clinical trials. Thirty-seven compounds have been identified from drug libraries all of which bind to the SARS-CoV-2 main protease (3CLpro). In the current study, we use molecular dynamics simulation and an ensemble-based free energy approach, namely, enhanced sampling of molecular dynamics with approximation of continuum solvent (ESMACS), to investigate a subset of the aforementioned compounds. The drugs studied here are highly diverse, interacting with different binding sites and/or subsites of 3CLpro. The predicted free energies are compared with experimental results wherever they are available and they are found to be in excellent agreement. Our study also provides detailed energetic insights into the nature of the associated drug–protein binding, in turn shedding light on the design and discovery of potential drugs

Ensemble-Based Approaches Ensure Reliability and Reproducibility

It is increasingly widely recognized that ensemble-based approaches are required to achieve reliability, accuracy, and precision in molecular dynamics calculations. The purpose of the present article is to address a frequently raised question: what is the optimal way to perform ensemble simulation to calculate quantities of interest

Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision, and Reproducibility

The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat a myriad of diseases. In this work, we examine the computation of alchemical relative binding free energies with an eye for assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2, and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2, and NAMD3 alpha. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between them of 0.50 kcal/mol. The correlation between packages is very good, with the lowest Spearman's, Pearson's and Kendall's tau correlation coefficients being 0.92, 0.91, and 0.76, respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging