Multivariate Techniques in Biomechanical Analysis

This work outlines the theoretical advantages of multivariate methods in biomechanical data, validates the proposed methods and outlines new clinical findings relating to knee osteoarthritis that were made possible by this approach. New techniques were based on existing multivariate approaches, Partial Least Squares (PLS) and Non-negative Matrix Factorization (NMF) and validated using existing data sets. The new techniques developed, PCA-PLS-LDA (Principal Component Analysis – Partial Least Squares – Linear Discriminant Analysis), PCA-PLS-MLR (Principal Component Analysis – Partial Least Squares –Multiple Linear Regression) and Waveform Similarity (based on NMF) were developed to address the challenging characteristics of biomechanical data, variability and correlation. As a result, these new structure-seeking technique revealed new clinical findings. The first new clinical finding relates to the relationship between pain, radiographic severity and mechanics. Simultaneous analysis of pain and radiographic severity outcomes, a first in biomechanics, revealed that the knee adduction moment’s relationship to radiographic features is mediated by pain in subjects with moderate osteoarthritis. The second clinical finding was quantifying the importance of neuromuscular patterns in brace effectiveness for patients with knee osteoarthritis. I found that brace effectiveness was more related to the patient’s unbraced neuromuscular patterns than it was to mechanics, and that these neuromuscular patterns were more complicated than simply increased overall muscle activity, as previously thought.

An Ergonomic Evaluation of a Wrist Brace for Canadian Tree Planters

Tree planting is one of the most physically demanding occupations in Canada and as a result, tree planters are at an elevated risk of injury, specifically at the wrist. Wrist injuries develop on account of the highly repetitive nature of the job, as well as other musculoskeletal risk factors including non-neutral wrist postures and high impact forces sustained at the wrist during shovel-ground impact. As a result, wrist brace use has become common among planters, in an effort to limit deviated wrist postures while also providing enhanced stability at the wrist. The external stability provided by a wrist brace is thought to reduce the muscular effort required to provide stiffness at the wrist during shovel-ground impact. Since these prospective benefits have not been formally investigated, the purpose of this study was to determine the effect of a wrist brace on wrist posture, muscle activity, and joint rotational stiffness about the wrist joint (for two degrees of freedom: flexion/extension and ulnar/radial deviation). We hypothesized that the brace would promote more neutrally aligned wrist angles, and that muscle activity and joint rotational stiffness would also decrease when participants wore the brace. Fourteen tree planters with at least one season of experience were recruited to complete two planting conditions in a laboratory setting: one condition while wearing the brace (with brace, WB) and one condition without the brace (no brace, NB). The results from this study showed that at shovel-ground impact muscle activity trended towards increasing in three muscles when participants wore the brace. Additionally, wrist angles improved about the flexion/extension axis of rotation while increasing in deviation about the ulnar/radial axis of rotation when participants wore the brace. Joint rotational stiffness increased when participants wore the wrist brace. Participants from this study indicated difficulty gripping the shovel due to the bulk of the wrist brace, and this feature is discussed with possible suggestions for future iterations of design. In addition to grip diameter this analysis also prompts the suggestion that hand length and experience should also be considered in the design of tree planting tools, specifically an ergonomic aid such as a wrist brace.

Investigating the Role of PDE4D1/2 in Vascular Smooth Muscle Cell Desensitization

Vascular smooth muscle cell (VSMC) behaviour and phenotypic modulation is critical to vessel repair following damage, and the progression of various cardiovascular diseases. The second messenger cyclic adenosine monophosphosphate (cAMP) plays a key role in VSMC function under the synthetic/activated phenotype, which is typically associated with unhealthy cell behaviour. Consequently, cAMP signaling is often targeted in attempts to impact several pathological diseases, including atherosclerosis, restenosis, and pulmonary arterial hypertension (PAH). The cyclic nucleotide phosphodiesterases (PDEs) catalyze hydrolysis of cAMP to an inactive form, and therefore directly regulate cAMP signaling. The PDE4D family dominates in synthetic VSMCs, and there is considerable interest in determining how distinct PDE4D isoforms affect cell function. Specifically, we are interested in the potential link between short isoforms of PDE4D and VSMC desensitization to pharmacological agents that impact cardiovascular disease via cAMP signaling. This study extends on previous work that assessed the expression of PDE4D splice variants in rat aortic VSMCs following prolonged challenge with cAMP-elevating agents. It was determined that PDE4D1 and PDE4D2 were uniquely expressed in synthetic VSMCs incubated with these agents, and that this upregulation impacted PDE activity and cAMP accumulation in these cells. Here, we report that PDE4D1 and PDE4D2 are markedly upregulated in synthetic human aortic smooth muscle cells (HASMCs) following prolonged challenge with cAMP-elevating agents. Using a combination of RNAi-based and pharmacological approaches, we establish that this upregulation is reflected in levels of cAMP PDE activity, and restricted to the cytosolic sub-cellular compartment. Our results suggest a role for localized PDE4D1 and PDE4D2 activity in regulating cAMP-mediated desensitization in HASMCs, and highlight their therapeutic potential in treating various cardiovascular diseases.