Delivering Load-Modifying Gait Retraining Interventions via Telehealth in People With Medial Knee Osteoarthritis: A Pilot Randomized Placebo-Controlled Clinical Trial.

We aimed to investigate the effects of delivering 3 gait retraining interventions (toe-in, toe-out, and placebo gait) on proxy measures of medial knee load (early- and late-stance peak knee adduction moment [KAM], KAM impulse, and varus thrust) in people with knee osteoarthritis, using a hybrid model of face-to-face and telehealth-delivered sessions over 5 months. This was an originally planned 3-arm randomized placebo-controlled clinical trial. However, during the 2021 COVID-19 outbreak and lockdown in Sydney, Australia, the study became a pilot randomized controlled trial with the remainder of interventions delivered via telehealth. Nine individuals with symptomatic medial knee osteoarthritis were allocated to receive either a toe-in, toe-out, or posture re-education (placebo) gait retraining intervention. Primary outcomes of early- and late-stance peak KAM, KAM impulse, and varus thrust were assessed at baseline and follow-up. Eight participants returned for their follow-up gait assessment. Participants in both active intervention groups (toe-in and toe-out) achieved foot progression angle changes at follow-up. Overall, knee biomechanics in the placebo group did not change at follow-up. It is possible to achieve biomechanical changes in individuals with medial knee osteoarthritis when delivering gait retraining interventions via a hybrid model of face-to-face and telehealth.

The Biomechanics Research and Innovation Challenge: Development, Implementation, Uptake, and Reflections on the Inaugural Program.

Biomechanics as a discipline is ideally placed to increase awareness and participation of girls and women in science, technology, engineering, and mathematics. A nationwide Biomechanics and Research Innovation Challenge (BRInC) centered on mentoring and role modeling was developed to engage high school girls (mentees) and early-mid-career women (mentors) in the field of biomechanics through the completion of a 100-day research and/or innovation project. This manuscript describes the development, implementation, and uptake of the inaugural BRInC program and synthesizes the research and innovation projects undertaken, providing a framework for adoption of this program within the global biomechanics community. Eighty-seven high school girls in years 9 and 10 (age range: 14-16 y) were mentored in teams (n = 17) by women in biomechanics (n = 24). Using a design thinking approach, teams generated solutions to biomechanics-based problem(s)/research question(s). Eight key reflections on program strengths, as well as areas for improvement and planned changes for future iterations of the BRInC program, are outlined. These key reflections highlight the innovation, impact, and scalability of the program; the importance of a program framework and effective communication tools; and implementation of strategies to sustain the program as well as the importance of diversity and building a sense of community.

Toe-in and toe-out gait retraining interventions to reduce proxy measures of medial knee joint load in people with medial knee osteoarthritis: Protocol for a randomised placebo-controlled trial.

OBJECTIVE: Our primary aim is to determine the effect of a six-week toe-in, toe-out and active placebo gait retraining program on proxy measures of medial knee joint load and varus thrust in people with medial knee osteoarthritis. Our secondary aim is to determine the intervention effects on patient reported outcomes and physical function and determine if changes are maintained at three-months follow-up. METHODS: We will conduct a three-arm randomised placebo-controlled trial. Ninety participants with medial knee osteoarthritis will be randomised and stratified via varus thrust status (presence/absence) to: toe-in, toe-out or placebo gait retraining (an intervention that does not change proxy measures of medial knee joint load). The intervention involves weekly clinician-supervised sessions with biofeedback, knee osteoarthritis education, motor learning and behaviour change principles, and daily gait retraining practice. Primary outcomes are proxy measures of medial knee joint load: knee adduction moment (early- and late-stance peaks and impulse), and varus thrust (presence/absence). Secondary outcomes include pain, physical function, medication and health care utilisation, quality of life, work ability, treatment blinding, intervention credibility and other biomechanical outcomes. Assessment timepoints are at baseline, six weeks (post intensive training), and three-months following the six-week intervention. CONCLUSION: Our trial will determine whether toe-in or toe-out gait retraining is most effective at reducing proxy measures of medial knee joint load and varus thrust in people with medial knee osteoarthritis. This study will also evaluate if toe-in or toe-out gait retraining interventions are superior at improving pain, physical function and quality of life compared to placebo. CLINICAL TRIAL REGISTRATION: This clinical trial protocol is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000414819).

Relationship Between Knee Biomechanics and Pain in People With Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Our primary aim was to determine the cross-sectional relationship between knee biomechanics during gait and pain in people with medial knee osteoarthritis. Our secondary aim was to evaluate differences in knee biomechanics between symptomatic and asymptomatic participants with medial knee osteoarthritis. METHODS: Four online databases were searched from inception to July 2021. Eligible studies included people with medial/nonspecific knee osteoarthritis and a reported relationship between knee biomechanics during gait and pain or biomechanics of symptomatic and asymptomatic participants. Two reviewers independently extracted data and evaluated risk of bias. Random-effects meta-analyses were performed when three or more studies reported the same biomechanical variable for pooling (knee adduction moment [KAM], KAM impulse, varus thrust, and peak knee flexion moment [KFM]). RESULTS: Forty studies were included. Methodological quality ranged from 4 to 9/10. Forty-seven unique biomechanical variables were reported. For the KAM, there was no correlation with pain for peak values pooled (early stance and overall) (r = 0.00, 95% confidence interval [95% CI]: -0.12, 0.11, k = 16), a small negative correlation for early stance peak alone (r = -0.09, 95% CI -0.18, -0.002, k = 12), and a medium positive correlation for the overall peak during stance (r = 0.30, 95% CI 0.17, 0.42, k = 4). Metaregression identified that body mass index moderated the peak KAM-pain relationship (P < 0.001). KAM impulse had a small positive correlation with pain (r = 0.23, 95% CI 0.04, 0.40, k = 5), and people with varus thrust had 3.84 greater odds of reporting pain compared with people without (95% CI 1.72, 8.53, k = 3). Meta-analyses for the peak KFM and pain correlation and secondary aim were nonsignificant. CONCLUSION: Some knee gait biomechanics were associated with pain in this cohort. Longitudinal studies are required to determine causality.

The suitability of high throughput automated patch clamp for physiological applications.

Although automated patch clamp (APC) devices have been around for many years and have become an integral part of many aspects of drug discovery, high throughput instruments with gigaohm seal data quality are relatively new. Experiments where a large number of compounds are screened against ion channels are ideally suited to high throughput APC, particularly when the amount of compound available is low. Here we evaluate different APC approaches using a variety of ion channels and screening settings. We have performed a screen of 1920 compounds on GluN1/GluN2A NMDA receptors for negative allosteric modulation using both the SyncroPatch 384 and FLIPR. Additionally, we tested the effect of 36 arthropod venoms on NaV 1.9 using a single 384-well plate on the SyncroPatch 384. As an example for mutant screening, a range of acid-sensing ion channel variants were tested and the success rate increased through fluorescence-activated cell sorting (FACS) prior to APC experiments. Gigaohm seal data quality makes the 384-format accessible to recording of primary and stem cell-derived cells on the SyncroPatch 384. We show recordings in voltage and current clamp modes of stem cell-derived cardiomyocytes. In addition, the option of intracellular solution exchange enabled investigations into the effects of intracellular Ca2+ and cAMP on TRPC5 and HCN2 currents, respectively. Together, these data highlight the broad applicability and versatility of APC platforms and also outlines some limitations of the approach. KEY POINTS: High throughput automated patch clamp (APC) can be used for a variety of applications involving ion channels. Lower false positive rates were achieved using automated patch clamp versus a fluorometric imaging plate reader (FLIPR) in a high throughput compound screen against NMDA receptors.  Genetic variants and mutations can be screened on a single 384-well plate to reduce variability of experimental parameters. Intracellular solution can be perfused to investigate effects of ions and second messenger systems without the need for excised patches. Primary cells and stem cell-derived cells can be used on high throughput APC with reasonable success rates for cell capture, voltage clamp measurements and action potential recordings in current clamp mode.

The effect of footwear and foot orthoses on transverse plane knee motion during running - A pilot study.

OBJECTIVES: This study aimed to determine the immediate effects of footwear and foot orthoses on transverse plane rotation of the knee joint during the stance phase of jogging gait. DESIGN: An experimental, within subjects, repeated measures design. METHODS: Three-dimensional knee kinematics were estimated in the transverse plane by surface-mounted markers as 14 asymptomatic participants ran in four randomised conditions; neutral shoe, neutral shoe with customised orthoses, neutral shoe with prefabricated orthoses, and a stability shoe. Peak internal/external rotation joint angles and ranges of motion (ROM) during loading response, midstance and propulsion were determined. Immediate subjective comfort was also recorded for each condition using a 100 mm visual analogue scale. RESULTS: Significant main effects of condition were observed for all outcomes except transverse plane knee ROM during loading response (p < 0.05). All significant differences occurred between the stability shoe and another condition, with less knee internal rotation in the stability shoe (mean differences ranged between 1.7° and 6.1°) (p < 0.05). The neutral shoe with prefabricated orthoses was reported as more uncomfortable than all other testing conditions. CONCLUSIONS: The stability shoe reduced peak knee internal rotation throughout stance phase of jogging more than any other condition. Importantly, it was subjectively as comfortable as the other conditions. These results identify the ability for footwear alone to induce immediate proximal kinematic effects. The use of the kinematic theory behind foot orthoses therapy is also questioned.

Control and measurement of plasma pH in equilibrium dialysis: influence on drug plasma protein binding.

Past publications have highlighted the influence of postdialysis plasma pH on the measured fraction unbound in plasma (fup). There is disparity in the industry as to which of two main methods is more suitable for controlling postdialysis plasma pH: the use of either a stronger buffer or a CO(2) atmosphere for the incubation. In the current study, it has been found that 10% CO(2) could be too high for the buffering capacities of both 100 mM sodium phosphate (pH 7.40 decreased to pH 6.90 after a 6-h incubation) and plasma (decreased below pH 7.40 after a 6-h incubation). To provide appropriate control over the postdialysis plasma pH, for a range of species, it is proposed that a standard phosphate buffer strength (100 mM) and pH (7.40) in combination with a 5% CO(2) atmosphere be used for equilibrium dialysis. Furthermore, statistically significant differences in fup values obtained with a pH difference of less than 0.32 pH unit have been demonstrated. An acceptance range for postdialysis plasma pH in routine in vitro fup screening assays of pH 7.40 ± 0.10 is recommended.

The effects of PM10 particles and oxidative stress on macrophages and lung epithelial cells: modulating effects of calcium-signaling antagonists.

We have previously examined the ability of air pollution particles (PM(10)) to promote release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) from human peripheral blood mononuclear cells and demonstrated a role for calcium as a signaling molecule in this process. We have now studied the ability of oxidative stress induced by a synthetic oxidant tert-butyl hydroperoxide (tBHP) to induce TNF-alpha production via calcium signaling in the mouse macrophage cell line (J774). The oxidant tBHP significantly increased intracellular calcium and the release of TNF-alpha in J774 cells, an effect that was reduced to control levels by inhibition of calcium signaling with verapamil, BAPTA-AM, and W-7. This study also investigated interactions between PM(10)-treated macrophages and epithelial cells by using conditioned medium (CM) from PM(10)-treated mononuclear cells to stimulate the release of the neutrophil chemoattractant chemokine IL-8 from A549 lung epithelial cells. TNF-alpha protein release was demonstrated in human mononuclear cells after PM(10) treatment, an effect that was inhibited by calcium antagonists. Treatment of A549 cells with monocyte/PM(10) CM produced increased IL-8 release that was reduced with CM from monocyte/PM(10)/calcium antagonist treatments. The expression of ICAM-1 was increased after incubation with CM from monocyte/PM(10) treatment, and this increase was prevented by treatment with CM from monocyte/PM(10)/calcium antagonist. These data demonstrate a link between oxidative stress, calcium, and inflammatory mediator production in macrophages and lung epithelial cells.