Quantifying the effects of pediatric obesity on musculoskeletal function and biomechanical loading during walking

2015 Spring.Includes bibliographical references.With the high prevalence of pediatric obesity worldwide, there is a critical need for structured physical activity interventions during childhood. However, obese children exhibit altered walking mechanics that are associated with decreased gait stability, reduced walking performance and an increased prevalence of musculoskeletal pain and pathology. Left unaddressed, the increased pain and orthopedic conditions associated with pediatric obesity may lead to reduced physical activity and a cycle of perpetual weight gain for the child and future adult. To enhance the efficacy of health and weight loss interventions, clinicians could benefit from an improved understanding of how pediatric obesity affects the neuromuscular and musculoskeletal systems during walking, the most common form of daily activity. The mechanisms for the altered gait and associated risks to the developing musculoskeletal system in obese children are not well understood, particularly as they relate to excess adiposity and exercise related fatigue. This void in the literature may be attributed in part to the lack of experimental and computational tools necessary to accurately quantify muscle function and joint loads during walking in obese and healthy-weight adults and children. Therefore, to improve our understanding of the musculoskeletal mechanisms for the altered gait mechanics and orthopedic disorders exhibited by obese children, this dissertation sought to first, establish the proper methods to adequately quantify the necessary biomechanical measures in obese and healthy-weight individuals, and second, determine the effects of obesity and duration on muscle function and tibiofemoral loading during walking in children. The accuracy of muscle and joint contact forces estimated from dynamic musculoskeletal simulations is dependent upon the experimental kinematic data used as inputs. Subcutaneous adipose tissue makes the measurement of representative kinematics from motion analysis particularly challenging in overweight and obese individuals. We developed an obesity-specific kinematic marker set and methodology that accounted for subcutaneous adiposity. Next, we determined how this methodology affected muscle and joint contact forces predicted from musculoskeletal simulations of walking in obese individuals. The marker set methodology had a significant effect on model quantified lower-extremity kinematics, muscle forces, and hip and knee joint contact forces. We demonstrated the need for biomechanists to account for subcutaneous adiposity during kinematic data collection and proposed a feasible solution that likely improves the accuracy of musculoskeletal simulations in overweight and obese people. Understanding orthopedic disorders of biological and prosthetic knee joints requires knowledge of the in-vivo loading environment during activities of daily living. Anthropometric and orthopedic differences between individuals make accurate predictions from generic musculoskeletal models a challenge. We developed a knee mechanism within a full-body OpenSim musculoskeletal model that incorporated subject-specific knee parameters to predict medial and lateral tibiofemoral contact forces. To assess the accuracy of our model, we compared measured to predicted medial and lateral compartment contact forces during walking in an individual with an instrumented knee replacement. We determined the importance of specifying subject-specific tibiofemoral alignment and contact locations and validated a simple approach to measure and specify these parameters on a subject-specific basis using radiography. The biomechanical mechanisms responsible for the altered gait mechanics in obese children are not well understood. We investigated the relationship between adiposity and lower extremity kinematics, muscle force requirements, and individual muscle contributions to whole body dynamics by generating musculoskeletal simulations of walking in a group of children with a range of adiposity. Body fat percentage was correlated with average knee flexion angle during stance and pelvic obliquity range of motion, as well as with relative vasti, gluteus medius and soleus force production. The functional demands and relative force requirements of the hip abductors during walking in pediatric obesity likely contribute to the altered gait mechanics in obese children. The combination of larger magnitude and altered application of tibiofemoral loads during physical activity in obese children is commonly theorized to contribute to their increased risk of orthopedic disorders of the knee, such as growth-plate suppression leading to conditions of malalignment. To evaluate this theory and determine how prolonged activity affects knee loading, we quantified the effects of pediatric obesity and walking duration on medial and lateral tibiofemoral contact forces. We found that obese children have elevated medial compartment magnitudes, loading rates, and load share, which further increased with walking duration. The altered tibiofemoral loading environment during walking in obese children likely contributes to their increased risk of knee pain and pathology. These risks may increase with activity duration. This dissertation provides a foundation for improved understanding of the effects of pediatric obesity on the neuromuscular and musculoskeletal systems during walking. The main research outcomes from this dissertation aim to improve rehabilitation and activity guidelines that minimize the risk of musculoskeletal pain and pathology in obese children, address degenerative gait mechanics, and assist in breaking the cycle of weight gain

Development of a human knee joint finite element model to investigate cartilage stress during walking in obese and normal weight adults

Osteoarthritis (OA) is a degenerative condition characterized by the breakdown and loss of joint articular cartilage. While the cause of OA is not precisely known, obesity is a known risk factor [1]. Particular effort has gone towards understanding the relationship between obesity and knee OA because obesity is more strongly linked to OA at the knee than at any other lower extremity joint [2]. Although the relationship between obesity and knee OA is well established, the mechanism of pathogenesis is less understood. Excess body weight generates greater joint contact forces at the knee. However, obese individuals alter their gait, resulting in increased joint contact forces that are not proportional to body mass [3]. In this study, a partially validated knee joint finite element (FE) model was developed to predict cartilage loading during walking across individuals of varying adiposity. The model was used with kinematic and kinetic gait data to address the following hypotheses: 1) increased loading due to obesity will produce greater cartilage stress compared to the normal weight control; and 2) altered gait kinematics of obese individuals will alter the distribution of stress on the surface of the tibial cartilage

Human knee joint finite element model using a two bundle anterior cruciate ligament: Validation and gait analysis

Anterior cruciate ligament (ACL) deficient individuals are at a much higher risk of developing osteoarthritis (OA) compared to those with intact ACLs, likely due to altered biomechanical loading [1]. Research indicates the ACL is comprised of two “bundles”, the anteromedial (AM) and posterolateral (PL) bundles [2]. Although the function of both bundles is to restrain anterior tibial translation (ATT), each bundle has their own distinct range of knee flexion where they are most effective [3]. Articular cartilage contact stress measurements are difficult to measure in vivo. An alternative approach is to use knee joint finite element models (FEMs) to predict soft tissue stresses and strains throughout the knee. Initial and boundary conditions for these FEMs may be determined from knee joint kinematics estimated from motion analysis experiments. However, there is a lack of knee joint FEMs which include both AM and PL bundles to predict changes to articular cartilage contact pressures resulting from ACL injuries. The purpose of this study is to develop and validate a knee joint FEM using both AM and PL bundles and subsequently perform a gait analysis of varying ACL injuries

VEGFA Upregulates FLJ10540 and Modulates Migration and Invasion of Lung Cancer via PI3K/AKT Pathway

BACKGROUND: Lung adenocarcinoma is the leading cause of cancer-related deaths among both men and women in the world. Despite recent advances in diagnosis and treatment, the mortality rates with an overall 5-year survival of only 15%. This high mortality is probably attributable to early metastasis. Although several well-known markers correlated with poor/metastasis prognosis in lung adenocarcinoma patients by immunohistochemistry was reported, the molecular mechanisms of lung adenocarcinoma development are still not clear. To explore novel molecular markers and their signaling pathways will be crucial for aiding in treatment of lung adenocarcinoma patients. METHODOLOGY/PRINCIPAL FINDINGS: To identify novel lung adenocarcinoma-associated /metastasis genes and to clarify the underlying molecular mechanisms of these targets in lung cancer progression, we created a bioinformatics scheme consisting of integrating three gene expression profile datasets, including pairwise lung adenocarcinoma, secondary metastatic tumors vs. benign tumors, and a series of invasive cell lines. Among the novel targets identified, FLJ10540 was overexpressed in lung cancer tissues and is associated with cell migration and invasion. Furthermore, we employed two co-expression strategies to identify in which pathway FLJ10540 was involved. Lung adenocarcinoma array profiles and tissue microarray IHC staining data showed that FLJ10540 and VEGF-A, as well as FLJ10540 and phospho-AKT exhibit positive correlations, respectively. Stimulation of lung cancer cells with VEGF-A results in an increase in FLJ10540 protein expression and enhances complex formation with PI3K. Treatment with VEGFR2 and PI3K inhibitors affects cell migration and invasion by activating the PI3K/AKT pathway. Moreover, knockdown of FLJ10540 destabilizes formation of the P110-alpha/P85-alpha-(PI3K) complex, further supporting the participation of FLJ10540 in the VEGF-A/PI3K/AKT pathway. CONCLUSIONS/SIGNIFICANCE: This finding set the stage for further testing of FLJ10540 as a new therapeutic target for treating lung cancer and may contribute to the development of new therapeutic strategies that are able to block the PI3K/AKT pathway in lung cancer cells

Explaining why simple liquids are quasi-universal

It has been known for a long time that many simple liquids have surprisingly similar structure as quantified, e.g., by the radial distribution function. A much more recent realization is that the dynamics are also very similar for a number of systems with quite different pair potentials. Systems with such non-trivial similarities are generally referred to as "quasi-universal". From the fact that the exponentially repulsive pair potential has strong virial potential-energy correlations in the low-temperature part of its thermodynamic phase diagram, we here show that a liquid is quasi-universal if its pair potential can be written approximately as a sum of exponential terms with numerically large prefactors. Based on evidence from the literature we moreover conjecture the converse, i.e., that quasi-universality only applies for systems with this property

Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2)

Objective- To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods- This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Results- Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2–7.4, 6.5–7.8, and 6.1–6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. Conclusions- The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma

Effects of ankle exoskeleton assistance and plantar pressure biofeedback on incline walking mechanics and muscle activity in cerebral palsy

Ankle dysfunction affects more than 50 % of people with cerebral palsy, resulting in atypical gait patterns that impede lifelong mobility. Incline walking requires increased lower limb effort and is a promising intervention that targets lower-limb extensor muscles. A concern when prescribing incline walking to people with gait deficits is that this exercise may be too challenging or reinforce unfavorable gait patterns. This study aims to investigate how ankle exoskeleton assistance and plantar pressure biofeedback would affect gait mechanics and muscle activity during incline walking in CP. We recruited twelve children and young adults with CP. Participants walked with ankle assistance alone, biofeedback alone, and the combination while we assessed ankle, knee, and hip mechanics, and plantar flexor and knee extensor activity. Compared to incline walking without assistance or biofeedback, ankle assistance alone reduced the peak biological ankle moment by 12 % (p < 0.001) and peak soleus activity by 8 % (p = 0.013); biofeedback alone increased the biological ankle moment (4 %, p = 0.037) and power (19 %, p = 0.012), and plantar flexor activities by 9 – 27 % (p ≤ 0.026); assistance-plus-biofeedback increased biological ankle and knee power by 34 % and 17 %, respectively (p ≤ 0.05). The results indicate that both ankle exoskeleton assistance and plantar pressure biofeedback can effectively modify lower limb mechanics and muscular effort during incline walking in CP. These techniques may help in establishing personalized gait training interventions by providing the ability to adjust intensity and biomechanical focus over time.12 month embargo; first published 12 January 2024This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Audiovisual biofeedback amplifies plantarflexor adaptation during walking among children with cerebral palsy

Abstract Background Biofeedback is a promising noninvasive strategy to enhance gait training among individuals with cerebral palsy (CP). Commonly, biofeedback systems are designed to guide movement correction using audio, visual, or sensorimotor (i.e., tactile or proprioceptive) cues, each of which has demonstrated measurable success in CP. However, it is currently unclear how the modality of biofeedback may influence user response which has significant implications if systems are to be consistently adopted into clinical care. Methods In this study, we evaluated the extent to which adolescents with CP (7M/1F; 14 [12.5,15.5] years) adapted their gait patterns during treadmill walking (6 min/modality) with audiovisual (AV), sensorimotor (SM), and combined AV + SM biofeedback before and after four acclimation sessions (20 min/session) and at a two-week follow-up. Both biofeedback systems were designed to target plantarflexor activity on the more-affected limb, as these muscles are commonly impaired in CP and impact walking function. SM biofeedback was administered using a resistive ankle exoskeleton and AV biofeedback displayed soleus activity from electromyography recordings during gait. At every visit, we measured the time-course response to each biofeedback modality to understand how the rate and magnitude of gait adaptation differed between modalities and following acclimation. Results Participants significantly increased soleus activity from baseline using AV + SM (42.8% [15.1, 59.6]), AV (28.5% [19.2, 58.5]), and SM (10.3% [3.2, 15.2]) biofeedback, but the rate of soleus adaptation was faster using AV + SM biofeedback than either modality alone. Further, SM-only biofeedback produced small initial increases in plantarflexor activity, but these responses were transient within and across sessions (p > 0.11). Following multi-session acclimation and at the two-week follow-up, responses to AV and AV + SM biofeedback were maintained. Conclusions This study demonstrated that AV biofeedback was critical to increase plantarflexor engagement during walking, but that combining AV and SM modalities further amplified the rate of gait adaptation. Beyond improving our understanding of how individuals may differentially prioritize distinct forms of afferent information, outcomes from this study may inform the design and selection of biofeedback systems for use in clinical care