Rozprawy doktorskie na temat „Musculoskeletal development”

The drastic rise in the worldÂ’s population coupled to an ever increasing aging population poses a considerable challenge to the orthopaedic community to maintain healthy activity levels. The field of Tissue Engineering and Regenerative Medicine aims to tackle these challenges by implementing more biomimetic strategies to improve upon current treatments. The success of new therapeutic developments in musculoskeletal tissue engineering relies on our ability to study and understand the complex biological interactions between cells, materials, and native tissues so that we may subsequently guide neotissue formation. This thesis is focused on the development of novel, welldefined, and reproducible in-vitro tissue culture models to explore, characterise, and control cellular behaviour and differentiation for osteochondral regeneration. In particular, these models utilised combinations of polymeric biomaterials, differentiated osteoblasts, human periosteal stem cells, and physico-chemical cell signalling cues. In a commercial venture with PolyNovo Ltd (Melbourne, Australia), a novel two-component injectable polymer platform was synthesized and evaluated for uses as a biomaterial construct in orthopaedic applications. The second aspect of this thesis focuses on the harvest, isolation, expansion, and extensive characterisation of human periosteal cells in-vitro. The periosteum is a bi-layered membrane that covers the outside of cortical bone and has been recently identified as a potential stem cell source; with the ability to form osteogenic, chondrogenic, adipogenic, and myogenic tissue types. To detail the heterogeneous cellular features and behaviours of human periosteal cells in-vitro, cells were isolated from surgical explants, expanding in monolayer in the absence of differentiation supplements, and characterised for changes in morphology, growth rate, cell-cycle, gene expression, and phenotype. Additionally, enrichment techniques were designed to preferentially isolate distinct progenitor cell types identified in periosteal cell cultures. Most interestingly, a novel cell-sorting platform utilising droplet microfluidic approaches, was developed and evaluated for its ability to identify and separate periosteal progenitor cells. In the third part of this thesis, a 3-dimensional agarose culture model was created to control and monitor lineage specific human periosteal cell differentiation in various biomechanical and biochemical environments. The work presented herein further demonstrates the potential of human periosteal cells for osteochondral repair and more importantly provides critical information regarding human periosteal cell expansion, phenotype, and differentiation.

Despite the frequency of musculoskeletal (MSK) complaints in childhood, doctors involved in the care of children report low self-confidence in their paediatric musculoskeletal (pMSK) clinical skills and show poor performance. This is hardly surprising considering the little pMSK teaching delivered within UK medical schools and the perception that this is poorly done compared with other clinical skills within child health. This lack of pMSK education is likely to be significant when considering the delayed diagnosis and access to specialist care that affects many children with pMSK disease. As any doctor could be involved in the care of children from the point of graduation, clinical skills and knowledge needs to be introduced at undergraduate level. Although efforts have been made to improve adult MSK education, this does not take into account the principles of child health and differences between adults and children. There is therefore a need to identify and agree on core pMSK educational content to be taught within the UK undergraduate curriculum. This should follow the principles of outcome-based education as practised in UK medical schools. This study has identified the content for a pMSK undergraduate curriculum. Focus groups and interviews were held with medical students, and key stakeholders within pMSK medicine and child health. Participants proposed content for pMSK teaching and identified the barriers within the current teaching environment. Expert consensus was then achieved on curriculum content using a Delphi process followed by a Nominal Group Technique. The final pMSK curriculum comprised learning outcomes (n=47), core presentations (n=8) and core conditions (n=14). These should inform the rest of the curriculum content and could be included in undergraduate child health teaching at all UK medical schools. It is hoped that by delivering this curriculum, all graduating doctors will then be equipped with the appropriate clinical skills and knowledge to assess all children with pMSK presentations, and will ultimately improve patient care. Further work is need on implementation and evaluation of this curriculum.

Bio-inspired musculoskeletal bipedal robots with tendon driven series elastic actuation including biarticular structures have the potential to outperform rigidly actuated robots. But the design, the control and the tuning of these bio-inspired robots are more complex than for their rigidly actuated counterparts. In this thesis new approaches to solving the problems arising from the bio-inspired design of robots are proposed and evaluated using a prototype series of musculoskeletal bipedal robots developed in the BioBiped project. This includes a systematic approach to tuning of hardware and software parameters in a hardware-in-the-loop optimization process with increased efficiency through the use of expert knowledge.

Musculoskeletal complaints are the most common reason for patients to visit a physician, yet competency in musculoskeletal medicine is invariably reported as a deficiency in medical education in the USA. Sports medicine clinical rotations improve both medical students' and residents' musculoskeletal knowledge. Despite the importance of this knowledge, a standardized sports medicine curriculum in emergency medicine (EM) does not exist. Hence, we developed a novel sports medicine rotation for EM residents to improve their musculoskeletal educational experience and to improve their knowledge in musculoskeletal medicine by teaching the evaluation and management of many common musculoskeletal disorders and injuries that are encountered in the emergency department. The University of Arizona has two distinct EM residency programs, South Campus (SC) and University Campus (UC). The UC curriculum includes a traditional 4-week orthopedic rotation, which consistently rated poorly on evaluations by residents. Therefore, with the initiation of a new EM residency at SC, we replaced the standard orthopedic rotation with a novel sports medicine rotation for EM interns. This rotation includes attendance at sports medicine clinics with primary care and orthopedic sports medicine physicians, involvement in sport event coverage, assigned reading materials, didactic experiences, and an on-call schedule to assist with reductions in the emergency department. We analyzed postrotation surveys completed by residents, postrotation evaluations of the residents completed by primary care sports medicine faculty and orthopedic chief residents, as well as the total number of dislocation reductions performed by each graduating resident at both programs over the last 5 years. While all residents in both programs exceeded the ten dislocation reductions required for graduation, residents on the sports medicine rotation had a statistically significant higher rate of satisfaction of their educational experience when compared to the traditional orthopedics rotation. All SC residents successfully completed their sports medicine rotation, had completed postrotation evaluations by attending physicians, and had no duty hour violations while on sports medicine. In our experience, a sports medicine rotation is an effective alternative to the traditional orthopedics rotation for EM residents.

The musculoskeletal system supports the internal structures of the body and consists of bones, ligaments, muscles and tendons. This system forms during early embryonic development, a process where many components today are unknown. In order to get a better understanding for those developmental steps, fluorescent in situ hybridisation has been performed on five genes. All five genes represent different transcription factors. These genes were selected based on the assumption that they could be important for the formation of the musculoskeletal system. After in situ hybridisation was performed, embryos were stained by immunohistochemistry to get a reference signal in the cartilage to enable easier interpretation of the expression pattern. In this study four of the selected transcription factors, Scleraxis a, Scleraxis b, Mohawk a and Mohawk b turned out to be expressed close to points where muscles are attached to the cartilage elements in the zebrafish head. Therefore, these genes are good candidates for future functional studies of muscle attachment development.

This thesis investigates the mechanics behind Achilles tendinopathies and their respective treatments using a musculoskeletal modelling approach. Specifically, the eccentric heel-drop exercise used to treat Achilles tendinosis and orthotic heel wedges used to treat Achilles tendonitis were investigated, as the mechanics which drive tendon healing are not currently understood, but are believed to work by directly altering the mechanical loading of the Achilles tendon. An inverse dynamics model of the lower limb including the hip, knee ankle and MTP joints was developed to include a musculoskeletal foot and ankle model. An existing muscle geometry dataset was used, but a new algorithm to account for soft tissue and bony constraints at the ankle to ensure physiological musculo-tendon paths around the foot and ankle was developed. Optical motion, forceplate and instrumented pressure insole data was used to derive independent 3D ground reaction vectors necessary for the data inputs for each of the two foot segments modelled. In addition to the moments of the hip and knee, foot and ankle muscle forces and ankle joint reaction forces were also estimated. A cohort of 19 healthy individuals performed the eccentric heel-drop exercise used to treat Achilles tendinosis and walked on a level and up and down an inclined (10°) surface barefoot and in running shoes with and without prefabricated orthotic heel wedges used to treat Achilles tendonitis. Clinical questions regarding changes in lower limb mechanics due to variants of the eccentric heel-drop exercise and orthotic heel wedges were considered as well as model sensitivity to foot models and sources of centre of pressure (CoP) data. CoP data source and number of foot segments modelled did not consistently change the model outputs, with greater or worse similarity between sources depending on the specific phase of stance considered. An example of this are the reduced knee and hip extension moments and increased ankle dorsiflexion moments at heel-strike, but consistent peak ankle joint reaction and Achilles tendon forces due to different CoP inputs. Across all walking conditions, heel wedges were found to have minimal impact on Achilles tendon force, but had a significant impact on knee moments and secondary plantarflexors such as Tibialis Posterior and the toe flexor muscles. The ability of heel wedges to reduce Achilles tendon load during walking was not supported by this thesis. Key observations regarding the eccentric heel-drop exercise were the reductions in peak Achilles tendon force achieved when performing the exercise in running shoes compared to barefoot and with a flexed compared to extended knee. Given the increased difficulty in performing the flexed knee exercise, this questioned the efficacy of the flexed knee version of the task and possible changes to the rehabilitation protocol, incorporating the effect of shoes on peak Achilles tendon force were suggested.

Adolescent growth provides a unique opportunity for the growing body to adapt to external stimuli. A positive association between site-specific mechanical loading and increases in regional bone mineral content (BMC) during adolescence is established. Mechanical loads associated with middle-distance running expose the skeleton to a combination of compressive ground reaction forces and muscular contraction. Previous studies concerning musculoskeletal health in active adolescents are largely limited to planar, two-dimensional measures of bone mineral status, using Dual X-ray Absorptiometry (DXA). Intrinsic bone material properties are accurately measured using DXA. However, the interaction between bone material and structural properties that reflects the mechanical integrity of bone require a combination of imaging modalities. Magnetic Resonance Imaging (MRI) provides a three-dimensional geometric and biomechanical assessment of bone. When MRI is integrated with DXA technology, an effective non-invasive method of assessing in vivo bone strength is achieved. The impact of high training volumes on musculoskeletal development of male and female adolescent athletes engaged in repetitive, high magnitude mechanical loading has not been investigated. Specifically, differences in total body and regional bone mineral, bone and muscle geometry, bone biomechanical indices and bone strength at differentially-loaded skeletal sites have not been compared between adolescent middle-distance runners and age- and gender-matched non-athletic controls. Objectives: (i) to investigate the effects of intense sports participation involving mechanical loading patterns on bone mineral, bone and muscle geometry, biomechanical indices and estimated regional bone strength between elite adolescent male and female middle-distance runners and age- and gender-matched controls (ii) to examine factors predictive of total body BMC, distal tibial bone geometry, distal tibial bone strength, and Hip Strength Analysis (HSA)- derived indicators of bone strength at the femoral neck. Methods: Four groups of 20 adolescents were comprised of male (mean (SD) age 16.8 ± 0.6 yr, physical activity 14.1 ± 5.7 hr.wk-1) and female (age 16 ± 1.7 yr, physical activity 8.9 ± 2.1 hr.wk-1) middle-distance runners, and male (16.4 ± 0.7 yr, physical activity 2.2 ± 0.7 hr.wk-1) and female (age 16 ± 1.8 yr, physical activity 2.0 ± 0.07 hr.wk-1) controls. Total body and regional BMC were calculated using DXA. Distal tibial bone and muscle cross-sectional areas (CSA) were assessed using MRI. To calculate distal tibial bone strength index (BSI), a region of interest representing 10% of the mid distal tibia was analysed for DXA-derived bone mineral and was combined with bone geometry and biomechanical properties from MRI assessments. Calculations for femoral neck strength were acquired from DXA-derived HSA software. Results: No differences were found between male athletes and controls for unadjusted BMC at total body or regional sites. After covarying for fat mass (kg), male athletes displayed greater BMC at the lumbar spine (p = 0.001), dominant proximal femur (p = 0.001) and dominant leg (p = 0.03) than male controls. No differences were found in distal tibial bone geometry, bone strength at the distal tibia or HSA-derived indicators of bone strength at the femoral neck between male athletes and controls. Lean tissue mass and fat mass were the strongest predictors of total body BMC (R2 = 0.71), total muscle CSA explained 43.5% of variance in BSI at the distal tibia, and femur length and neck of femur CSA explained 33.4% of variance at the femoral neck. In females, athletes displayed greater unadjusted BMC at the proximal femur (+3.9 ±1.4 g, p = 0.01), dominant femoral neck (+0.5 ± 0.12 g, p = 0.01) and dominant tibia (+4.1 ± 2.1 g, p = 0.05) than female controls. After covarying for fat mass (kg), female athletes displayed greater (p = 0.001) total body, dominant proximal femur and dominant leg BMC than female controls. Female athletes also showed greater distal tibial cortical CSA (+30.9 ± 9.5 mm2, p = 0.003), total muscle (+240.2 ± 86.4 mm2, p = 0.03) and extensor muscle (+46.9 ±19.5 mm2, p = 0.02) CSA, smaller medullary cavity (-32.3 ± 14.7 mm2, p = 0.03) CSA and greater BSI at the distal tibia (+28037 ± 8214.7 g/cm3.mm4, p = 0.002) than female controls. Lean tissue mass and fat mass were the strongest predictors of total body BMC (R2 = 65), hours of physical weekly activity and total muscle CSA explained 58.3% of the variance of distal tibial BSI, and neck of femur CSA accounted for 64.6% of the variance in a marker of femoral neck HSA. Conclusion: High training loads are associated with positive musculoskeletal outcomes in adolescent middle-distance runners compared to non-athletic controls. Exposure to similar high training loads may advantage female adolescent athletes, more than male adolescent athletes compared with less active peers in bone strength at the distal tibia.

Musculoskeletal knee conditions present a growing burden for community based rehabilitation. Outcome measures profile current health status, detect change and evaluate response to interventions. There is, however, an abundance of outcome measures but no recommendation on which to use or what data to collect, leading to widespread variation in practice. The purpose of this study was to identify those outcome measures with robust scientific evidence for adults undergoing conservative treatment of musculoskeletal knee conditions and establish, through consensus with clinicians, researchers and patients, which are acceptable and feasible for use in community based settings. An investigation of current clinical practice in NHS Scotland profiled data collection and outcome measure use in community rehabilitation. Evidenced based, validated patient vignettes were developed to establish the scope of the study. The literature reporting and testing the clinimetric properties of outcome measures was systematically reviewed and the OMERACT filters of 'truth' and 'discrimination' applied to the data for each outcome measure by an expert panel. Those measures meeting predefined quality thresholds were presented to a national Consensus Development Conference where delegates voted on their acceptability and feasibility, followed by wider public consultation. None of the 37 outcome measures identified had been fully tested or were fully supported with sufficient quality and breadth of evidence for all components of the OMERACT filter, only ten met the preset criteria for 'truth' and 'discrimination' . Five were presented to Conference and two (Lysholm and WOMAC) were subsequently recommended for use in clinical practice. Barriers to implementation included time, administration and cost. This thesis reports on a study to recommend a core set of outcome measures that could facilitate standardisation of data collection and demonstrate effectiveness of interventions for adults with musculoskeletal conditions of the knee. It captures thoughts and concerns of clinicians on the introduction of a minimum core set of outcome measures.

Background and need: Burn injuries are a major cause of hospital admission in low-income countries such as Zimbabwe and often lead to secondary complications such as disfigurements, contractures, and scar formations. The study aimed to establish “Guidelines for Rehabilitation of Musculoskeletal Impairments and Functional Limitations for Zimbabwe for Patients with Burns” based on the best evidence available. There were three good candidates for use as the source guideline, but ultimately, the Agency for Clinical Innovation (ACI) of New South Wales in Australia guidelines1 was chosen. The contextualisation of these guidelines for the Zimbabwean situation was informed by the outcomes of five sub-studies. A summary of the methodologies applied and the key results follow. Methods and Results: The Epidemiology of Burns in Zimbabwe: The characteristics of patients with burns in Zimbabwe was established through a retrospective record review (descriptive review) to characterise patients admitted with burns to the two central hospitals in Harare over fifteen months. The sample consisted of 926 admission records and 435 full patient folders were retrieved and analysed. Unfortunately, 425 full folders of children were missing and 85 folders of adults. There was a clear difference in presentation between children and adults, with children constituting over threequarters of all admissions, but with less severe injuries. Post-discharge follow-up: Access to rehabilitation and impact on Health-Related Quality of Life (HRQoL): The second study investigated the utilisation of post-discharge care, regarding referral after discharge and home programme. This was a study with a small sample, 14 adult and 23 child respondents. Despite referrals having been made to local rehabilitation departments, there was practically no further post-discharge contact with rehabilitation and only a single person received post-discharge rehabilitation. Both Health-Related Quality of Life (HRQoL) instruments used by the adult respondents indicated less impact on physical domains of functioning with the greatest impact in pain and emotional well-being. In the absence of trained counsellors, rehabilitation therapists might need to step into this role. Systematic review: The broad objective of this review was to systematically evaluate the effectiveness, safety and applicability to low-income countries of therapeutic exercises utilised by physiotherapists to improve function in patients with burns. The review, which included 19 papers, established that exercises (either resistance or aerobic), are effective and generally have a positive effect on muscle strength and aerobic capacity. However, there was a risk of bias in many of the papers and the evidence is not of high quality. As most of the research enrolled paediatric patients older than seven years and no adverse effects were reported, it can be concluded that resistance exercise is safe for this group of patients. However, as most children admitted with burns are younger than seven years, exercise needs to be carefully monitored in this group as safety and efficacy have not been proven for younger children. iii The results from this support the use of aerobic and resistance as an important component of a burn rehabilitation program as they have shown to improve muscle strength aerobic capacity and functional status even after hospital discharge, especially in patients with severe burns. Documentation of the current rehabilitation practice: This phase documented clinical interventions used to treat musculoskeletal problems by observation of seven rehabilitation workers (not only physiotherapists), based in the five central hospitals, one provincial and one district hospital. The treatments of five adults and five paediatric patients were observed at each hospital, a total of 70 treatments in all. The most significant finding was that the management of patients with burns was offered by a single rehabilitation worker a Physiotherapists (PT), Occupational Therapists (OT) or Rehabilitation Technician (RT), working in Burns' Units without any specialised training or additional courses. The management of burns across all hospitals was similar, and information saturation was reached with the planned number of observations. Passive and active movements were used almost universally, and the patients received a ward programme, which included positioning. Sitting and standing were included in some patients and patients were monitored for any adverse effects. A major weakness observed was the lack of baseline assessment or treatment progress during treatment. No compression bandages were applied and no scar tissue massage was done. Identification and adaptation of the suitable guidelines: Following a literature search and examination of different guidelines by two independent reviewers, the Agency for Clinical Innovation of New South Wales, Australia1 was chosen as a candidate for amendment. The guidelines were amended based on the results of the previous studies and subjected to a Delphi process with four to six Zimbabwean rehabilitation therapists who were experienced in the field of burn management. A credible set of guidelines for Zimbabwe for the rehabilitation of musculoskeletal impairments and functional limitations was thus produced. Conclusion: The current study adds to the body of knowledge through the development of guidelines for the physiotherapy rehabilitation of musculoskeletal impairments and functional limitations for patients with burns in low- and middle-income countries. The thesis has provided an evidence-based framework for patients, rehabilitation workers and policymakers to inform the provision of effective management of patients with burns. The Zimbabwe Guidelines should be regarded as a first attempt rather than the final version and hopefully will be subjected to further review as they are tried out in practice.

Background: Attitudes and beliefs that healthcare practitioners (HCPs) hold about musculoskeletal (MSK) pain influence their clinical behaviour. The Pain Attitudes and Beliefs Scale (PABS), originally developed for low back pain (LBP), is the most widely used and tested measure of HCPs’ attitudes and beliefs, however further development and testing is indicated. Poor performance of its biopsychosocial orientation scale is attributed to inadequate conceptualisation of the orientation. Aims: To develop a new biopsychosocial orientation scale for the PABS and adapt the original LBP specific version as a measure of HCPs' attitudes and beliefs about common MSK pain. Methods: The research was conducted in six stages. Firstly, a scoping review identified constructs used to quantify HCPs’ attitudes towards common MSK pain. Stage two used a concept mapping methodology to develop a new conceptual framework for biopsychosocial clinical orientation to common MSK pain. This framework was used to generate candidate items for redevelopment of the biopsychosocial scale (stage three) and then included in a national survey of physiotherapists, GPs and chiropractors (stage four) to collect data for initial development and testing (stage five and six). Methods: The research was conducted in six stages. Firstly, a scoping review identified constructs used to quantify HCPs’ attitudes towards common MSK pain. Stage two used a concept mapping methodology to develop a new conceptual framework for biopsychosocial clinical orientation to common MSK pain. This framework was used to generate candidate items for redevelopment of the biopsychosocial scale (stage three) and then included in a national survey of physiotherapists, GPs and chiropractors (stage four) to collect data for initial development and testing (stage five and six). Conclusion: The new version of the PABS (the PABS-MSK) is the most comprehensively developed measure of HCPs’ attitudes and beliefs concerning MSK pain to date. The biomedical scale is robust and while both scales require further validation, the research provides a solid conceptual grounding for further amendments of the measure. The conceptual framework provides a contemporary comprehensive understanding of the biopsychosocial clinical approach to MSK pain.

Blood flow Restriction Training [BfRT] involves the intentional and temporary reduction of blood flow through a limb to induce short periods of mild limb ischaemia, often during periods of low-intensity exercise. A systematic review into the use of BfRT to attenuate losses to lower-limb muscle strength and size during periods of injury-related impaired weight bearing revealed wide variations in the equipment, methodology and outcomes described. No evidence specifically investigated the acute physiological effect of BfRT during un-resisted, or ‘no-load’ rehabilitation exercises. This doctoral research project aimed to address these issues, by developing externally-valid BfRT methodologies utilising relatively inexpensive BfR equipment, and determining the acute physiological effects of combining BfRT with ‘no-load’ lower-limb exercise. Phase I recruited sixty-one healthy participants across 3 subgroups; 21 males, 19 females and 21 elite male rugby players. Short periods of lower-limb blood flow restriction [BfR] were applied to participants at 40, 60, 80, 100 or 120mmHg via a thigh blood-pressure cuff. Ultrasound imaging was used to quantify the degree of popliteal arterial blood-flow remaining [%PBfR] at each cuff pressure. Subgroups were statistically different to each other across nine physical characteristics (p ≤ 0.05). %PBfR decreased as cuff pressure increased (p < 0.0001), but with no between-subgroup differences (p = 0.122). Only weak bivariate correlations existed between physical characteristics and %PBfR across tested cuff pressures. A polynomial equation was created to indicate %PBfR based only upon the amount of thigh-cuff pressure applied. Phase II recruited sixteen participants (n=9 male, n=7 female) who undertook four un-resisted, seated, unilateral knee extension exercise sessions with 0, 40, 60 or 80mmHg of continuous thigh-cuff pressure applied. A near-infra red spectroscopy [NIRS] device measured tissue oxygen saturation [SmO2] of the vastus lateralis muscle before and during exercise sessions. Compared to 0mmHg, greater cuff pressures resulted in greater drops in vastus lateralis SmO2 during exercise sessions (p < 0.05). Bivariate correlations existed between physical characteristics and the mean magnitude of change in SmO2 during BfRT sessions, including Body Mass Index (Pearson r = 0.791, p < 0.001). Phase III recruited three injured professional rugby players to undertake lower-limb BfRT 4-5 times per week over periods of 4 to 12 weeks. BfRT sessions were as per Phase II, but delivered at higher cuff pressures (100 and 120mmHg). No adverse events or pain occurred during any BfRT session. NIRS data indicated that greater cuff pressure resulted in greater drops in vastus lateralis SmO2 during exercise sessions. Thigh girth (recorded via tape measurement) was maintained longitudinally in all players. MRI evidence suggested that BfRT did not hinder healing from a tibial and femoral osseous stress injury. This doctoral project has expanded the evidence base available to healthcare professionals wishing to use BfRT during lower-limb injury rehabilitation. In particular, findings support the use of relatively inexpensive blood-pressure cuffs as a method of delivering BfRT, and in the ability of BfR to amplify the acute, local metabolic demand of an un-resisted ‘no-load’ exercise suitable for use in rehabilitation.

Thesis: Ph. D. in Aerospace Systems Engineering, Massachusetts Institute of Technology, Department of Aeronautics and Astronautics, 2019
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 163-179).
Prolonged exposure of a vertebrate musculoskeletal system to the microgravity environment of space leads to a reduction in bone mineral density, muscle mass, strength and endurance. Such deconditioning may impede critical astronaut activities and presents an increased injury risk during flight and when exposed to increased gravity like that of Earth or Mars. Exercise countermeasures are used extensively on the International Space Station to mitigate musculoskeletal deconditioning during long duration spaceflight missions. Despite vigorous exercise protocols, bone loss and muscle atrophy are often observed even when countermeasures are in effect. As a first step in understanding the mechanisms of injury and how on-orbit exercise countermeasures compare to those on the ground, an accurate load sensing system is needed to collect ground reaction force data in reduced gravity.
To date, no means of continuous, high resolution biomechanical force data collection and analysis has been realized for on-orbit exercise. Such a capability may advance the efficiency of these systems in mitigating the incidence of bone and muscle loss and injury risk by quantifying loading intensity and distribution during exercise in microgravity, thus allowing for cause-effect tracking of ISS exercise regimes and biomechanics. By measuring these forces and moments on the exercise device and correlating them with the post-flight fitness of crewmembers, the efficacy of various exercise devices may be assessed. More importantly, opportunities for improvement, including optimized loading protocols and lightweight exercise device designs will become apparent.
The overall goal of this research effort is to improve the understanding of astronaut joint loading during resistive exercise in a microgravity environment through the use of rigorous quantitative dynamic analysis, simulation and experimentation. This is accomplished with the development and evaluation of a novel, self-contained load sensing system. The sensor assembly augments existing countermeasures and measures loads imparted by the crew during exercise. Data collected with this system is used to parameterize a unique musculoskeletal model which is then used to evaluate associated joint reaction forces generated during exercise. The effects of varying body posture and load application points on joint loading were investigated and recommendations for enhancing on-orbit exercise protocols that mitigate both injury and deconditioning are discussed.
By validating the sensor and modeling joint loading during on-orbit exercise as described herein, a unique contribution is made in expanding NASA's capability to continuously record and quantify crew loading during exercise on ISS. Data obtained through the system is used to characterize joint loading, inform and optimize exercise protocols to mitigate musculoskeletal deconditioning and may aid in the design of improved, lightweight exercise equipment for use during long-duration spaceflight, including future missions to Mars.
"This research effort was supported by a NASA Phase I Small Business Innovation Research (SBIR) contract awarded to Aurora Flight Sciences Corporation with MIT as subcontractor. The contract period of performance spanned from June 2014 through August 2016. Contract number: 2012-11 NNX14CS55C"--Page 6
by Roedolph Adriaan Opperman.
Ph. D. in Aerospace Systems Engineering
Ph.D.inAerospaceSystemsEngineering Massachusetts Institute of Technology, Department of Aeronautics and Astronautics

Background. The surgical treatment of dysfunctional hips is a severe condition for the patient and a costly therapy for the public health. Hip resurfacing techniques seem to hold the promise of various advantages over traditional THR, with particular attention to young and active patients. Although the lesson provided in the past by many branches of engineering is that success in designing competitive products can be achieved only by predicting the possible scenario of failure, to date the understanding of the implant quality is poorly pre-clinically addressed. Thus revision is the only delayed and reliable end point for assessment. The aim of the present work was to model the musculoskeletal system so as to develop a protocol for predicting failure of hip resurfacing prosthesis. Methods. Preliminary studies validated the technique for the generation of subject specific finite element (FE) models of long bones from Computed Thomography data. The proposed protocol consisted in the numerical analysis of the prosthesis biomechanics by deterministic and statistic studies so as to assess the risk of biomechanical failure on the different operative conditions the implant might face in a population of interest during various activities of daily living. Physiological conditions were defined including the variability of the anatomy, bone densitometry, surgery uncertainties and published boundary conditions at the hip. The protocol was tested by analysing a successful design on the market and a new prototype of a resurfacing prosthesis. Results. The intrinsic accuracy of models on bone stress predictions (RMSE < 10%) was aligned to the current state of the art in this field. The accuracy of prediction on the bone-prosthesis contact mechanics was also excellent (< 0.001 mm). The sensitivity of models prediction to uncertainties on modelling parameter was found below 8.4%. The analysis of the successful design resulted in a very good agreement with published retrospective studies. The geometry optimisation of the new prototype lead to a final design with a low risk of failure. The statistical analysis confirmed the minimal risk of the optimised design over the entire population of interest. The performances of the optimised design showed a significant improvement with respect to the first prototype (+35%). Limitations. On the authors opinion the major limitation of this study is on boundary conditions. The muscular forces and the hip joint reaction were derived from the few data available in the literature, which can be considered significant but hardly representative of the entire variability of boundary conditions the implant might face over the patients population. This moved the focus of the research on modelling the musculoskeletal system; the ongoing activity is to develop subject-specific musculoskeletal models of the lower limb from medical images. Conclusions. The developed protocol was able to accurately predict known clinical outcomes when applied to a well-established device and, to support the design optimisation phase providing important information on critical characteristics of the patients when applied to a new prosthesis. The presented approach does have a relevant generality that would allow the extension of the protocol to a large set of orthopaedic scenarios with minor changes. Hence, a failure mode analysis criterion can be considered a suitable tool in developing new orthopaedic devices.

Background. The surgical treatment of dysfunctional hips is a severe condition for the patient and a costly therapy for the public health. Hip resurfacing techniques seem to hold the promise of various advantages over traditional THR, with particular attention to young and active patients. Although the lesson provided in the past by many branches of engineering is that success in designing competitive products can be achieved only by predicting the possible scenario of failure, to date the understanding of the implant quality is poorly pre-clinically addressed. Thus revision is the only delayed and reliable end point for assessment. The aim of the present work was to model the musculoskeletal system so as to develop a protocol for predicting failure of hip resurfacing prosthesis. Methods. Preliminary studies validated the technique for the generation of subject specific finite element (FE) models of long bones from Computed Thomography data. The proposed protocol consisted in the numerical analysis of the prosthesis biomechanics by deterministic and statistic studies so as to assess the risk of biomechanical failure on the different operative conditions the implant might face in a population of interest during various activities of daily living. Physiological conditions were defined including the variability of the anatomy, bone densitometry, surgery uncertainties and published boundary conditions at the hip. The protocol was tested by analysing a successful design on the market and a new prototype of a resurfacing prosthesis. Results. The intrinsic accuracy of models on bone stress predictions (RMSE < 10%) was aligned to the current state of the art in this field. The accuracy of prediction on the bone-prosthesis contact mechanics was also excellent (< 0.001 mm). The sensitivity of models prediction to uncertainties on modelling parameter was found below 8.4%. The analysis of the successful design resulted in a very good agreement with published retrospective studies. The geometry optimisation of the new prototype lead to a final design with a low risk of failure. The statistical analysis confirmed the minimal risk of the optimised design over the entire population of interest. The performances of the optimised design showed a significant improvement with respect to the first prototype (+35%). Limitations. On the authors opinion the major limitation of this study is on boundary conditions. The muscular forces and the hip joint reaction were derived from the few data available in the literature, which can be considered significant but hardly representative of the entire variability of boundary conditions the implant might face over the patients population. This moved the focus of the research on modelling the musculoskeletal system; the ongoing activity is to develop subject-specific musculoskeletal models of the lower limb from medical images. Conclusions. The developed protocol was able to accurately predict known clinical outcomes when applied to a well-established device and, to support the design optimisation phase providing important information on critical characteristics of the patients when applied to a new prosthesis. The presented approach does have a relevant generality that would allow the extension of the protocol to a large set of orthopaedic scenarios with minor changes. Hence, a failure mode analysis criterion can be considered a suitable tool in developing new orthopaedic devices.

Philosophiae Doctor - PhD
Occupational health (OH) in physiotherapy is well known for addressing workrelated musculoskeletal disorders (WRMDs), which are high in number according to the available statistics (Fingerhut, Concha, Punnet, Steenland, & Driscoll, 2014). The introduction of the Bachelor of Science in Physiotherapy degree in Kenya in 2010 created a good platform for the development and review of occupational health content in the curriculum

Computational models of the human musculoskeletal system allow researchers to investigate human biomechanics without the need for invasive methods or expensive experiments. These models can be combined with standard motion capture technology to simulate individual’s movement patterns. With relatively little data processing, the model’s joint kinematics can be calculated along with joint kinetics, thus characterising an individual’s generalised joint coordinates (i.e., joint motion) and external joint loads. Without and with the incorporation of electromyograms (EMG) acquired during these tasks, further methods can be employed to estimate muscle forces and subsequently joint contact loading (Lloyd and Besier, 2003; Pandy and Andriacchi, 2010; Pizzolato et al., 2015; Sartori et al., 2012a; Sasaki and Neptune, 2010; Saxby et al., 2016b; Sritharan et al., 2012; Winby et al., 2009). Indeed, substantial research has focused on developing methods for estimating the magnitude of the joint contact loading within the tibiofemoral joint (TFJ) during a range of locomotion tasks (Fregly et al., 2012; Gerus et al., 2013; Kim et al., 2009). Understanding typical TFJ contact loading is crucial, as the magnitude of joint contact loading has been associated with the development and progression of TFJ osteoarthritis (Andriacchi and Mundermann, 2006). Tibiofemoral joint contact loading is primarily caused by muscles, which act to compress the joint (Sasaki, 2010). Although net and grouped muscle contributions to TFJ contact loading has previously been investigated during walking gait (Pandy and Andriacchi, 2010; Sasaki and Neptune, 2010; Saxby et al., 2016b; Sritharan et al., 2012; Winby et al., 2009), other locomotion tasks such as running and sidestep cutting, herein referred to as sidestepping remain largely unexplored. Along with the loading magnitude, other loading parameters may play a vital role influencing joint health, such as the region of loading in combination with the distribution of loading (Chaudhari et al., 2008) Models previously used to estimate the magnitude of joint contact loading have typically been linearly scaled versions of a generic musculoskeletal model, e.g., “gait2392” (Delp et al., 2007) or TLEM 2.0 (Carbone et al., 2015). These models use generic bone geometries which may not reflect each individual’s anatomy, even after linear scaling (Kainz et al., 2017a). As such, these models may be inappropriate tools to accurately estimate TFJ contact loading magnitudes, as bone geometry influence muscle tendon unit (MTU) force estimates and contact mechanics (Demers et al., 2014; Gerus et al., 2013; Lerner et al., 2015). Furthermore, these models may be inappropriate for the estimation of the region of loading within the TFJ, as this feature is highly dependent on joint anatomy (Lerner et al., 2015). Additionally, limitations within these linear scaled generic models, particularly the TFJ kinematic models, further hamper their utility for investigating regional loading within the TFJ (Demers et al., 2014). If regional loading is to be investigated, computational models that accurately represent subject-specific three-dimensional (3D) bone and joint geometry, 6 degree of freedom (DOF) joint kinematics, and feasible MTU pathways, lengths, and moment arms are required. The overarching aim of this thesis was to investigate features related to TFJ contact loading. Specifically, estimate individual muscle contributions to medial and lateral TFJ contact loading during walking, running, and sidestepping. Second, develop a framework that automatically creates and tunes highly detailed subject-specific computational musculoskeletal models that can be used to investigate various feature of TFJ loading. To investigate individual muscle contributions to TFJ contact loading during various dynamic locomotion tasks, 54 healthy individuals were recruited as part of an ongoing project. Each participant underwent a standard motion capture gait analysis session, wherein whole body and segment motions were captured using 3D motion capture. Ground reaction forces were acquired via in-ground force plates and muscle activation patterns acquired via surface EMG. Motion capture data were used within the free and open-source musculoskeletal modelling platform OpenSim (Delp et al., 2007) to estimate model joint kinematics and kinetics. Using established calibrated EMG-informed neuromusculoskeletal modelling methods (Hoang et al., 2018; Pizzolato et al., 2015; Saxby et al., 2016b), muscle forces and subsequently muscle contributions to TFJ contact loading (Winby et al., 2009) were estimated. Results for walking, running, and sidestepping showed during weight acceptance, the vastus medialis and vastus lateralis muscles dominated contribution to medial and lateral TFJ contact loading respectively. During mid-stance and push-off, the contribution to medial and lateral TFJ contact loading was dominated by the medial and lateral gastrocnemii muscles respectively for all three tasks. Although there were similarities in which muscles dominated medial and lateral TFJ contact loading, differences were shown in the magnitude of relative muscle contributions between locomotion tasks. These differences were driven by different kinematic (Novacheck, 1995), kinetic (Novacheck, 1995), muscle activations (Besier et al., 2003a), and stabilisation requirements present in each tasks. Specific differences were, quadriceps contribution to medial and lateral TFJ contact loading were higher during running compared to walking, while gastrocnemii contribution to medial and lateral TFJ contact loading were higher during walking compared to running. Comparing running and sidestepping, contribution of selected muscles to medial TFJ contact loading were higher during sidestepping, while selected muscle contributions to lateral TFJ contact loading were higher in running. Muscles which dominate the contribution to TFJ contact loading, also provide a majority a TFJ stabilisation during these tasks. Results may provide valuable information for rehabilitation following orthopaedic surgeries to restore TFJ stability and prevent future injuries. To further address the overarching aims of this thesis, highly detailed subject-specific musculoskeletal models were required and thus developed. Subject-specific musculoskeletal models may contain joints and MTU pathways that are both physically and physiologically infeasible. First, the articulating bones of joints may interpenetrate, and similarly MTUs can penetrate bone surfaces. Second, joint kinematics can have discontinuities and may not follow the patterns of previously reported cadaveric studies. Likewise, MTU pathways, if inappropriately defined, can create MTU lengths and moment arms (MTU kinematics) that exhibit discontinuities and do not follow patterns of previously published cadaveric data. This thesis created subject-specific musculoskeletal models that addressed these shortcomings along with shortcomings of previous modelling methods. To evaluate the framework developed to create detailed subject-specific musculoskeletal models, a set of 6 individuals from an on-going study were used. These subjects spanned age (21 – 32 years), height (160.5 – 185 cm), and mass (45 – 89 kg) ranges, and were composed of three females and three males. Each subject underwent a standard gait analysis session as well as a comprehensive magnetic resonance imaging (MRI) protocol enabling detailed visualisation of their bones, muscles, cartilages, and other articular structures (i.e., ligaments). The framework developed within this thesis was built atop a pre-existing open-source framework, the Musculoskeletal Atlas Project (MAP) Client (Zhang et al., 2014), written in Python (Python Software Foundation. Python Language Reference, version 2.7. Available at http://www.python.org). The MAP Client was used in combination with manually segmented MRIs to well reconstruct subject-specific bone geometry using direct image segmentation and pre-developed MAP Client statistical shape models (SSMs). Bone geometries were then used to customise a generic OpenSim model (Delp et al., 2007) with subject-specific bone geometries and other personalised features (i.e., joint positions , MTU origin and insertions, and MTU via points). This generated model represents the standard model produced via the MAP Client pathway; however a number of further developments were required. Required improvements ranged from simple inclusions, such as adding customised marker sets, patellae, and patellofemoral joints (PFJs). More complex additions involved the definition of 6 DOF TFJ and PFJ kinematics, MTU origins, insertions and pathways. Six DOF (1 independent and 5 coupled) subject-specific TFJ and PFJ mechanisms were built from segmented MRIs. These mechanisms were then automatically tuned to be physically and physiologically feasible using previously published methods (Brito da Luz et al., 2017), which were incorporated into the MAP Client framework. The MTU pathways, i.e., origins, insertions and wrapping surfaces, were defined using the MAP Client mean SSMs and subject-specific MAP Client-generated bone reconstructions, which were automatically tuned to be physically and physiologically feasible (discussed in detail later). In the present study, MTU origins and insertions were defined using an atlas-based method (Zhang et al., 2015). The MTU origins and insertions were positioned on the MAP Client mean SSMs in the same anatomical regions (i.e., node point) as the atlas and could be queried using node indices. Node indices were used to define subject-specific MTU origin and insertions on the subject-specific MAP Client-generated bone models. The MTU wrapping surfaces were defined in a two-step process: (i) placement and fitting of wrapping surfaces, and (ii) optimisation of the wrapping surfaces’ geometrical dimensions and positions. Initial selection and placement of wrapping surfaces was done manually based on anatomical regions and landmarks defined as bone mesh elements and nodes indices on the MAP Client mean SSM bones. Following this manual identification, using individual’s subject-specific bones, wrapping surfaces were automatically positioned using bone elements and nodes identified through the MAP Client using custom written Python (Python Software Foundation. Python Language Reference, version 2.7. Available at http://www.python.org) software. Wrapping surface dimensions were based on analytical shapes automatically fit to anatomical regions of subject-specific MAP Client-generated bones using custom written Python software. Once wrapping surfaces were placed, their positions, orientations, and dimensions were automatically optimised with the aim of producing MTU pathways that were physically and physiologically feasible. “Physically feasible” MTU pathways (i) did not penetrate bones, and (ii) did not produce non-sensible wrapping scenarios, such as completing a circumferential loop of a wrapping cylinder. “Physiological feasible” MTU lengths and moment arms (i) closely follow the pattern of measurements taken from cadavers, available in literature, and (ii) are free of discontinuities. The developed framework created and tuned subject-specific rigid body musculoskeletal models that largely produced the desired outcomes while overcoming limitations with previous modelling methods. With respect to the definition of physically feasible MTU pathways, the inclusion of MTU wrapping surfaces fit to each subject’s anatomy largely reduced the number of bone MTU penetrations. However, prior to tuning, including MTU wrapping surfaces fit to each subject’s anatomy were detrimental to many MTU kinematic metrics (i.e., MTU kinematic smoothness, and pattern similarity to literature data). The designed optimisation routine, to tune MTU wrapping surfaces provided further improvements to MTU pathways, and more importantly improved MTU kinematic smoothness and pattern similarity with literature data. Improvements to both MTU pathways and kinematics was present in models which contained simplified (MAP Client standard) as well as subject-specific 6 DOF TFJ and PFJ kinematic mechanisms. The fact that improvements were shown in both models, regardless of the joint model, provided further confidence in the MTU wrapping surface optimisation process that was developed. Additionally, the fact that improvements were only shown once tuned, provided further evidence that the tuning of subject-specific musculoskeletal models is a necessary step in the developed framework. The optimised subject-specific musculoskeletal models containing simplified joint models, compared to subject-specific joint models, performed more consistently and often produced favourable MTU kinematics and pathways. Models with simplified joint models often exhibited fewer bone MTU penetrations, smoother MTU kinematics, and kinematics which more closely matched the pattern of previously reported cadaveric data. The less consistent results seen in models with subject-specific joint kinematics may be due to greater inter-subject variability within estimated kinematics for both the TFJ and PFJ. Further improvements to both the developed MTU wrapping surface optimisation framework and joint kinematic models may produce more consistent results for models with subject-specific joint kinematic models. Although not implemented within this thesis, the models produced using this proposed framework can be used to investigated the regional loading of the TFJ during a range of locomotion and other dynamic tasks. The framework presented here represents a large advancement of the field of subject-specific computational modelling. Along with addressing a number of short comings of previous models, the methods presented in this thesis are predominately automated which reduces the time and cost burdens which are typically associated with building subject-specific models. These time and cost burdens are related to the collection and segmentation of full lower limb MRI. Additionally, all developed methods utilise free and open-source software, facilitating the sharing and wider adoption of these subejct specific methods and models. Improvments to these developed models and methods facilitate their use in both academic research as well as a number of clinical and medical applications. The highly automated and tuned framework reduces both the time and knowledge burden on the user, providing further advantages to these methods.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School Allied Health Sciences
Griffith Health
Full Text

Pre-clinical studies are a necessary step in the process of material and drug testing. For this, high-throughput monolayer cell cultures are conducted followed by in vivo animal experiments. However, animal use is ethically questionable and in many cases yields misleading results. In vitro three dimensional (3D) tissue engineered (TE) structures have been shown to better represent in vivo tissue morphology and biochemical pathways than monolayer cultures and are less ethically questionable than animal models. Therefore, an in vitro biomimetic musculoskeletal junction (MSKjct) is required as a more relevant pre-clinical testbed. This thesis describes the steps taken to co-culture 3D TE skeletal muscle and bone models as a material testbed and towards an in vitro MSKjct.

The Kinaesthetics care conception is a nursing approach for patient handling which aims to prevent work-related complaints and diseases. The evidence about the influence of Kinaesthetics on musculoskeletal disorders among persons who handle patients is unclear to date. The purposes of the scoping review are to gain insight into the current state of research regarding the clinical effectiveness of Kinaesthetics (in terms of perceived exertion and musculoskeletal complaints) among persons who handle patients and to identify potential research gaps. A scoping review was conducted. The search strategy comprised a systematic search in electronic databases (MEDLINE, EMBASE, AMED, CINAHL), a hand search, a fast forward search (Web of Science) and a Google scholar-search. The review process was carried out independently by two reviewers. Methodological quality was assessed for all studies using three methodological main categories (reporting quality, internal validity, external validity). Thirteen studies with different study designs were included. Seven studies investigated musculoskeletal complaints and nine studies the perceived exertion of nursing staff. Most studies were of very low methodology. Most studies reported a decrease of musculoskeletal complaints and perceived exertion due to Kinaesthetics. In conclusion, there is only little evidence of very low quality about the effectiveness of Kinaesthetics. Out of the studies it could be assumed that Kinaesthetics may decrease the patient handling related perceived exertion and musculoskeletal pain of persons who handle patients. But an overestimation of these results is likely, due to inadequate methodology of included studies. As a result, no clear recommendations about the effectiveness of the Kinaesthetics care conception can be made yet. Since a research gap was shown, further high quality intervention studies are necessary for clarifying the effectiveness of Kinaesthetics.

The Kinaesthetics care conception is a nursing approach for patient handling which aims to prevent work-related complaints and diseases. The evidence about the influence of Kinaesthetics on musculoskeletal disorders among persons who handle patients is unclear to date. The purposes of the scoping review are to gain insight into the current state of research regarding the clinical effectiveness of Kinaesthetics (in terms of perceived exertion and musculoskeletal complaints) among persons who handle patients and to identify potential research gaps. A scoping review was conducted. The search strategy comprised a systematic search in electronic databases (MEDLINE, EMBASE, AMED, CINAHL), a hand search, a fast forward search (Web of Science) and a Google scholar-search. The review process was carried out independently by two reviewers. Methodological quality was assessed for all studies using three methodological main categories (reporting quality, internal validity, external validity). Thirteen studies with different study designs were included. Seven studies investigated musculoskeletal complaints and nine studies the perceived exertion of nursing staff. Most studies were of very low methodology. Most studies reported a decrease of musculoskeletal complaints and perceived exertion due to Kinaesthetics. In conclusion, there is only little evidence of very low quality about the effectiveness of Kinaesthetics. Out of the studies it could be assumed that Kinaesthetics may decrease the patient handling related perceived exertion and musculoskeletal pain of persons who handle patients. But an overestimation of these results is likely, due to inadequate methodology of included studies. As a result, no clear recommendations about the effectiveness of the Kinaesthetics care conception can be made yet. Since a research gap was shown, further high quality intervention studies are necessary for clarifying the effectiveness of Kinaesthetics.

This thesis deals with clinical pain intervention research from a behavioural medicine perspective. The general aim was to develop and evaluate an individually tailored treatment protocol focused on pain management in everyday life in people who experience persistent musculoskeletal pain. Another aim was to develop and incorporate an idiographic outcome measure for behavioural goal assessment in the formal evaluation of the clinical significance of treatment outcomes.

The studies were conducted in a primary health care setting demonstrating a contribution from physical therapists in the field of behavioural medicine. Two separate samples of patients with musculoskeletal pain with a duration exceeding one month, n = 197 (Study I, descriptive and correlational design), and n = 97/82 (Study III/IV, randomized group-study) were included. In addition, four women were recruited for a series of experimental single-case studies (Study II).

The treatment protocol that was individually tailored to each participant’s behavioural treatment goals and assumed determinants of pain-related disability was more effective in reducing pain-related disability, pain intensity, fear-avoidance, and in increasing pain control when compared to an intervention including physical exercises. The individually tailored treatment was generally more beneficial for resumption of everyday life activity, increasing satisfaction, fulfilling pre-treatment expectations, and in preparing individuals for self-management of pain. The Patient Goal Priority Questionnaire that was elaborated over the course of the project can be used to a) identify and assess behavioural treatment goals, b) elaborate individual functional behavioural analyses relevant for everyday life functioning, and c) determine the clinical significance of treatment outcomes – that is, whether interventions produce outcomes of relevance for each individual’s everyday life. The inclusion of idiographic outcome measures in clinical pain intervention research is necessary and improves the ecological validity of the evaluation of clinical significance.

Ankle sprains are one of the most common type of sports injury. They occur most frequently when the foot is in a supine or inverted position. Recovery from an ankle sprain can take from one and up to 26 weeks depending on the severity of the injury. During that period the individual will be unable to participate in any meaningful sports activity and as such it is important to be able to prevent the occurrence of such injuries. Prevention of ankle sprain injuries would require a better understanding of the risk factors of this injury. Several studies attempted to assess such risk actors by inducing foot inversion or supination however the platforms used in these studies were shown to be limited. Hence the main aim of this project is to develop a system that can be used to assess the effect of sudden foot and ankle inversion/supination on the musculoskeletal system of dynamic subjects (e.g. walking, running, jumping, etc.). For this purpose a three degrees of freedom (DOF) rotating platform has been designed, manufactured and installed in the Institute of Motion Analysis and Research (IMAR) Sports Laboratory. The platform rotates around 3 different axes allowing inversion or supination of the foot and ankle of dynamic subjects. The degree of rotation around each axis can easily be set by the researcher/operator. A strain gauge was used to detect foot strike to the platform. As a safety measure laser emitter/receivers check that the entire foot is on the footplate before the platform rotates. Optical encoders provide essential feedback of rotation angles, speed and acceleration. The necessary software and user interface for controlling the platform were also written and tested. The platform was synchronised with a bilateral four-channel EMG (electromyography) system and a 12 camera Vicon® MX-13 system thus allowing measurement of muscle activity and kinematic data during the supination of the foot. A set of software modules were written to allow automated management and processing of the data generated by the new system. The new system was then implemented in a study to validate it and to assess the role of shoes in ankle sprains. In this study, subjects would walk in three different foot conditions: barefoot, and with two different types of sports shoes, along the walkway of the Sports Laboratory where the platform was fitted. When a subject steps on the embedded platform, it rotates causing the subject's foot to supinate. At the same time, the EMG data from the peroneus longus, tibialis anterior, and lateral gastrocnemius muscles are recorded, along with the kinematics of the subject's whole body. The obtained results demonstrated the validity of the newly developed system. Data from the validation study also revealed increased muscle activity following induced foot supination in shod conditions compared to barefoot. Muscle activity of the rotating platform step was found to be significantly higher than the steps before and after. The platform rotation was also found to have an observable effect on body kinematics. The newly developed system is hoped to help provide a better understanding of the risk factors of ankle sprain injury and how to prevent this injury. The system can be used to help improve the design of current footwear and identify which footwear provides better protection against ankle sprain injury. The system can also be used to assess the effectiveness of different ankle injury rehabilitation schemes and different training programs that aim to reduce ankle sprain injuries. The new system can be utilised to identify individuals who are at risk of sustaining an ankle sprain injury. The system can also be utilised in studies outside the scope of ankle sprain injuries.

Tre skelett från en kyrkogård daterad till Gotlands sen-vikingatid till tidig medeltid har analyserats avseende aktivitetsspår. Metoden som användes innebar observation av muskelutvecklingen tillsammans med förändringar i entesiterna som är fästen för muskler och ligament. Hittills har forskningen ägnat sig åt att studera dessa förändringar på ett kvantitativt sätt, genom att tilldela poäng till de olika förändringarna enligt hur utvecklade de är och sedan skapa en statistik. Men dessa metoder har fortfarande många begränsningar, eftersom det är väldigt få av dessa entesiter som har studerats. Syftet med studien har varit att undersöka vilka muskler var utvecklade och utröna hur dessa rörde sig tillsammans för att återskapa ett rörelsemönster som kan hjälpa att skapa en teori om vilka aktiviteter individerna sysslade med (arbetsuppgifter, fritidssysslor, m.m.). Analysen har gjorts med hjälp av litteratur om aktivitetsspår, paleopatologi, fysioterapi och med referensmaterialet från Osteologilaboratoriet vid Uppsala Universitet, Campus Gotland.

As cartilage tissue has limited repair capacities, tissue engineering has emerged as a promising alternative for cartilage repair. The scaffold is a primary component of the tissue engineering design, yet little information exists regarding the effects of polymer and scaffold properties on tissue growth. In this study, we have developed a novel scaffold, PLG microspheres, for use in cartilage tissue engineering, which has the capacity for alterations in polymer and scaffold. We examined the effects of molecular weight, hydrophobic capping, delivery of Mg(OH)2, microsphere size, and controlled release of IGF-I. Our findings demonstrated that polymer parameters distinctively affect tissue and matrix output. Specifically, micro spheres with high molecular weight polymer produced tissue with high GAG content and tissue mass in vivo and in vitro, while micro spheres with capped polymer induced steady tissue and matrix accumulation, but may have precluded cell attachment. Release of buffer to the growing cartilage had negative effects on tissue formation in vivo and in vitro. Additionally, increasing microsphere diameter generated more samples with center of necrotic tissue. The presence of microspheres induced greater cartilage mass and matrix content than cartilage from cells alone. Delivery of IGF-I induced a dose-dependent effect on matrix and tissue production in vivo, with the highest effective load of IGF-I (0.3%) generating the most matrix and tissue accumulation. In contrast, the in vitro IGF-I dose-dependent effect induced on matrix and tissue production peaked at a dose of 0.02% IGF-I, with higher doses generating less tissue and matrix. Taken together, changes in polymer or scaffold composition and release of growth factor can be optimized to form cartilage with enhanced tissue parameters. Moreover, these results demonstrate a novel scaffold with potential to support cartilage regeneration and provide simultaneous drug delivery.

Introduction: Statements of commitment to change are commonly used to evaluate continuing medical education. However, this approach is new to evaluating the continuing professional development (CPD) of other health care practitioners such as audiology, speech-language therapy, occupational therapy, and physiotherapy in low- and middle-income countries. This study explored the use of Personal Commitment (to change) Statements (PCSs) as an evaluation tool of continuing education for health professionals in low- and middle-income countries, and its impact on the integration of new knowledge and skills with previous knowledge and clinical practice. Methods: PCSs were used in a case study conducted at a 1-day interprofessional CPD event held for health practitioners in South Africa. A qualitative thematic analysis was made of these PCSs, and results were synthesized into main themes. Results: Thirty-two participants turned in a PCS at the end of the CPD event with a total of 71 text statements. Three main domains were identified: (1) applying new knowledge in practice (61.97%); (2) increasing training-related content knowledge (21.12%); and (3) sharing information, skill, and resources (16.9%). Discussion: This study demonstrated that personal commitment statements can be used to describe the outcomes of CPD events for audiologists, speech-language, occupational, and physiotherapists. Participants engaged in reflection generated by the personal commitment statement, which contained no guiding statements, yet elicited responses showing that participants were more aware of the assessment tools and how they could use them in practice. Further study is warranted into the process and the role of follow-up regarding health practitioners' commitment to change in clinical practice.

This thesis is the culmination of a series of studies designed to improve the management of musculoskeletal (MSK) injury in an infantry training centre (ITC Catterick, UK). The overall aim of this thesis is to develop and evaluate a management strategy for MSK injury during Combat Infantryman’s Courses (CIC) training. Included is an epidemiological study of MSK injuries in the British Army (Study1), a risk factor model for MTSS (Study 2) and two randomised controlled trials (RCTs) in which the effects of prevention (Study 3) and rehabilitation interventions (Study 4) were examined. The aim of Study 1 was to quantify incidence, type and impact of the MSK injuries during military CIC training (26 weeks). Over a two year period (April 2006 -March 2008), 6608 British infantry CIC trainees completed an informed consent form to take part in this study. A prospective epidemiological study was conducted. Data for the injuries were reported according to: onset, anatomical location, diagnosis and regiment-specific incidence, week and months, impact and occupational outcome. It was clearly demonstrated that MSK injuries are a substantial burden to the British Army. Injury rate was 48.65% and overuse injury was significantly higher than acute and recurrence. Most overuse injuries occurred in the lower limb (82.34%) and were more frequent (p <0.01) in the first phase of training (Weeks 0-13). One third of the recruits (33%) were discharged prior to completion of training. A further 15% (n=991) were removed from training for further rehabilitation. Rehabilitation time ranged from 21 to 168 days and 12% of total training time was lost due to injury (equivalent to 155,403 days of training). Owing to its high severity index, medial tibial stress syndrome (MTSS) is argued to be the most impactful of these injuries despite only being second most frequent. Implications for practice and research (Study 1): MSK injuries are a significant burden to the British Army and strategies to improve prevention and treatment need to be explored. An initial focus on MTSS is warranted. In order to develop interventions for Studies 3 and 4 it is necessary to identify those risk factors for developing MTSS. The aim of Study 2 was to determine prospectively whether gait biomechanics and/or lifestyle factors can identify those at risk of developing MTSS. Again, British Infantry male recruits (n = 468) were selected for the study. Based on a review of the literature of known risk factors for MSK injury, plantar pressure variables, lifestyle factors comprising smoking habits and aerobic fitness as measured by a 1.5 mile timed-run were collected on the first day of training. A logistic regression model for membership of the MTSS and non-MTSS groups showed that an imbalance in foot pressure (heel rotation = pressure on the medial heel minus pressure on the lateral heel) was the primary risk factor for MTSS. Low aerobic fitness and smoking habit were also important, but were additive risk factors for MTSS. The logistic regression model combining all three risk factors was capable of predicting 96.9% of the non-injured group and 67.5% of the MTSS group with an overall accuracy of 87.7%. Implications for practice and research (Study 2): Foot pronation, as measure by heel rotation, is a primary risk factor for MTSS. Previous studies have shown that gait retraining can change risk factors for injury. The aim of Study 3 was to examine the effectiveness of gait retraining on reducing risk factors associated with MTSS and on reducing the incidence of MTSS during the subsequent 26 week training period. British Infantry recruits (n = 450) volunteered for the study and baseline plantar pressure variables were recorded on the first day of training. Based on the findings of Study 2, those with abnormal foot pronation at baseline (n = 134, age 20.1 ± 2.03 years; height 167 ±1.4 cm; body mass 67 ± 2.4 kg) were randomly allocated to an intervention (n = 83) or control group (n = 83). The intervention group undertook a gait retraining program which included targeted exercises three times a week and biofeedback on risk factors once per week. Both groups continued with the CIC training concurrently. Injury diagnoses over the 26 week training regimen were made by physicians who were blinded to the study. Post-measures of plantar pressure were recorded at 26 weeks. There was a significant reduction in the pronation (p <0.001) and overall difference survival function between MTSS and non-MTSS (Log rank test X2 = 6.12, p = 0.013). The absolute risk reduction was 60% in the intervention group. Implications for practice and research (Study 3): Gait retraining can reduce risk factors and incidence of MTSS injury. Based on such positive findings for the prevention of MTSS in Study 3, it was hypothesised that gait retraining may also have potential for the rehabilitation of MTSS. The aim of Study 4 was to examine the effectiveness of a gait retraining on plantar pressure variables, pain intensity and time spent in rehabilitation due to MTSS. Recruits diagnosed with MTSS but not responding to current treatment were eligible for this study (n = 66, age 20.85 ± 2.03 years; height 167 ±1.4 cm; body mass 67 ± 2.4 kg). The participants were randomly allocated to an intervention (n = 32) or control group (n = 34). In order to overcome the debilitating pain suffered by MTSS patients during exercise, the intervention group received a corticosteroid injection prior to the gait retraining programme. The control group continued with the current rehabilitation programme. There were significant improvements in terms of time to reach peak heel rotation (p<0.001), pain intensity (p<0.001) and positive occupational outcome in the intervention group (p<0.019). Implications for practice and research (Study 4): A combined corticosteroid-exercise intervention is beneficial in normalising plantar pressure, reducing rehabilitation times, pain intensity and occupational outcome of MTSS.

Avian leukosis virus (ALV)-induced osteopetrosis is a proliferative disorder of the bone affecting the growth and differentiation of osteoblasts. Osteopetrosis is a polyclonal disease in which cells of the bone contain, on average, multiple viral DNA copies. Osteopetrotic bone is also characterized by the accumulation of unintegrated viral DNA, suggesting an atypical life cycle of the virus in the infected osteoblasts. To better understand virus-host interactions in the induction of osteopetrosis by ALVs, infected chick osteoblast cultures and osteopetrotic bone were examined for aspects of the virus life cycle and effects of infection on osteoblast function. Levels of infection and virus expression were compared in cultured osteoblasts and osteopetrotic bone. Osteopetrotic bone contained higher levels of viral DNA and correspondingly higher levels of viral proteins than infected osteoblast cultures, suggesting a higher viral load in the diseased bone. A significant level of mature Gag protein was present in the bone, suggesting the accumulation of mature virus particles in the diseased bone. It is possible that the accumulation of virus could facilitate the high levels of infection observed in the diseased bone. The mechanism by which unintegrated viral DNA persisted in osteopetrotic bone was investigated by examining the susceptibility of infected osteoblasts to superinfection. The results indicated that, in culture, infected osteoblasts were able to establish interference to superinfection. This suggests that the persistence of unintegrated viral DNA in osteopetrotic bone may not result from the continuing infection of productively infected osteoblasts. The effect of virus infection on osteoblast function was examined in the diseased bone and in osteoblast cultures. In infected chickens, osteoblast activity, as evidenced by the expression of osteoblast phenotypic markers, was increased only in chickens developing severe osteopetrosis. In culture, virus infection had no apparent effect on either the proliferation or differentiation of osteoblasts. This indicates that infection was itself not sufficient to perturb osteoblast function. Furthermore, it suggested that additional components of the bone may be required for ALV infection to induce the abnormal activity of osteoblasts observed in osteopetrosis.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Introdução: Na sociedade moderna, a prática regular de exercícios físicos é considerada não só por seu valor profiláctico, mas também como um tipo de intervenção com potencial para atenuar diferentes sintomas relacionados a várias doenças. Diante de tal plano de fundo, a prática de esportes tem ganho cada vez mais espaço, sendo uma das manifestações mais importantes de exercício físico entre crianças e adolescentes. Se por um lado, a prática regular de esportes entre jovens pode afetar positivamente a sua saúde e qualidade de vida, por outro lado, a prática esportiva (principalmente aquela objetivando alto rendimento) expõe cada vez mais crianças e adolescentes a um aumento no risco em lesões musculares. Objetivos: Analisar o impacto da prática esportiva sobre a ocorrência de sintomas musculoesqueléticos (dor, formigamento ou dormência) ao longo de 12 meses de seguimento entre adolescentes de ambos os sexos, bem como, identificar a relação de sintomas musculoesqueléticos com variáveis ligadas ao crescimento humano e inflamação entre adolescentes. Métodos: Este longitudinal com doze meses de seguimento envolvendo adolescentes com idade entre 12 e 16 anos de ambos os sexos. Amostra mínima para a realização do estudo foi estimada em 231 sujeitos. Os adolescentes serão agrupados segundo o envolvimento em diferentes modalidades esportivas (natação, futebol de campo, basquetebol, voleibol, karatê, judô e kung-fu) e grupos controle. Sintomas musculoesqueléticos serão avaliados por questionário previamente validado, ao passo que estimativas de composição corporal serão feitas por aparelho de densitometria óssea. Maturação biológica será estimada por medidas antropométricas. Resultados: Nos últimos 12 meses, o segmento corporal que os adolescentes mais relataram sintomas musculoesqueléticos foi no joelho (28,5%), enquanto o joelho permaneceu como o segmento corporal mais relatado com sintomas musculoesqueléticos na última semana antes da entrevista. Após dividir a amostra em grupos de participação esportiva, houve associação entre a participação esportiva e os sintomas musculoesqueléticos nos últimos 12 meses em quadris/coxas e joelhos. Da mesma forma, houve associação entre a participação esportiva e os sintomas musculoesqueléticos na última semana e em pés. Conclusão: os adolescentes que participaram de esportes de impacto e artes marciais tiveram maior ocorrência de sintomas musculoesqueléticos do que aqueles que não praticaram, principalmente em membros inferiores.
Introduction: In modern society, regular physical exercise is considered not only because of its prophylactic value, but also as a type of intervention with the potential to attenuate different symptoms related to various diseases. Faced with such background, the practice of sports has gained more and more space, being one of the most important manifestations of physical exercise among children and adolescents. On the one hand, the regular practice of sports among young people can positively affect their health and quality of life, on the other hand, sports practice (especially those aiming at high income) increasingly exposes children and adolescents to an increase in risk in muscle injuries. Objective: To analyze the impact of sports participation on the occurrence of musculoskeletal symptoms (pain, tingling or numbness) during 12 months of follow-up among adolescents of both sexes, as well as to identify the relation of musculoskeletal symptoms with variables related to human growth and inflammation among adolescents. Methods: This was a 12-month longitudinal follow-up involving adolescents aged 12 to 16 years of both sexes. Minimum sample for the study was estimated in 231 subjects. The adolescents will be grouped according to the involvement in different sports modalities (swimming, field soccer, basketball, volleyball, karate, judo and kung-fu) and control groups. Musculoskeletal symptoms will be assessed by a previously validated questionnaire, while body composition estimates will be made by bone densitometry apparatus. Biological maturation will be estimated by anthropometric measurements. Results: In the last 12 months, the body segment that adolescents most reported musculoskeletal symptoms was in the knee (28.5%), while the knee remained the most reported body segment with musculoskeletal symptoms in the last week before the interview. After dividing the sample into sports participation groups, there was an association between sports participation and musculoskeletal symptoms in the last 12 months on hips / thighs and knees. Likewise, there was an association between sports participation and musculoskeletal symptoms in the last week and in feet. Conclusion: adolescents who participated in sports impact and martial arts had a higher occurrence of musculoskeletal symptoms than those who did not practice, especially in lower limbs.
FAPESP: 2016/20354-0; 2017/18056-3

Rigid-body-musculoskeletal models are becoming commonly used to study human motion, particularly of people with some form of neuromusculoskeletal condition. However, these musculoskeletal models are typically generic, having simplified anatomical and kinematic representations, with coarse-meshed bone geometries, and body-segment inertial parameters (BSIP) obtained from a limited number of adult-male cadavers. Furthermore, these models have hip joints that articulate around an estimated hip-joint centre (HJC), two-dimensional-sagittal-plane tibiofemoral (TFJ) and patellofemoral joints (PFJ) models at the knee, and hinges for the talocrural (TCJ) and subtalar (STJ) joints in the ankle and foot. Each person’s model has bone dimensions, BSIPs and joint kinematics that are linearly scaled from the generic models using scale-factors obtained from three-dimensional (3D) positions of motion capture (3DMOCAP) markers or from magnetic resonance images (MRI). However, bone dimensions might not be properly adjusted with linear scaling, which will affect the position and orientation of joint centres and axis, the location of the segments’ centre of mass and moments of inertia, the position of musculotendon length, origins and insertions as well as bone geometry e.g. femur neck-length. Finally, muscle forces, joint angles, moments and internal joint loads of gait estimated using these scaled-generic models have been shown to be inaccurate, probably due to the aforementioned imprecise bone geometries and simplified joint models.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Allied Health
Griffith Health
Full Text

Most of the load-bearing demand placed on the human body is transduced by skeletal tissue, and the capacity of the skeleton to articulate in various opposing directions is essential for body movement and locomotion. Consequently, cartilage and bone defects due to trauma, disease, and developmental abnormalities result in disabling pain and immobility for millions of people worldwide. A novel way of promoting cartilage and bone regeneration is through the incorporation of either primary cells or multipotent progenitor cells in a three-dimensional (3D) biomaterial scaffold, and/or the addition of exogenous growth and differentiation factors. The first part of this study reports a protocol for using freshly isolated mature chondrocytes seeded in a 3D hydrogel biomaterial scaffold, developed to explore mechanotransduction of engineered cartilage constructs cultured in a designed bioreactor. The bioreactor was designed to allow the application of physiological mechanical forces (compression and fluid flow), as well as a non-invasive/non-destructive method for analyzing regenerating tissue in real time through ultrasound transducers and a computerized monitoring system. In the second part of this study, an engineered immortalized osteoprecursor cell line, designated OPC1 (osteoblastic precursor cell line 1), was used as a culture model system for exploring the effects of exogenous growth and differentiation factors, mainly vitamin D, on early bone development. OPC1 was previously designed to provide a consistent reproducible culture system for direct comparisons of engineered bone constructs, evaluating bone development and cell/biomaterial interactions, and for investigating putative bone differentiating factors. One of the objectives of this research effort was to explore tissue development and regeneration by culturing OPC1 in the presence of vitamin D metabolites vitaD3 and 1,25OH2D3, while assaying the concomitant biological response. Results indicate that OPC1 is capable of metabolizing the parental metabolite vitaD3, and thus 25OHD3, to the active vitamin D form 1,25OH2D3. The metabolism of vita3 resulted in an anti-proliferative and pro-differentiative influence on OPC-1. These results support the hypothesis that extra-endocrine synthesis of 1,25OH2D3 functions in a tissue specific manner to regulate growth and differentiation, in addition to the classic calcimic actions of the vitamin D endocrine pathway. Understanding the influence of vitamin D on bone development will have significant implications on healthy aging, including the susceptibility to skeletal disorders involved in development and aging, such as osteoarthritis (OA) and osteoporosis.

Aim:  The overall aim of this thesis was to explore the development of a video-supported interactive learning model for movement awareness among nursing students. Methods:  Study I was a cross-sectional survey regarding prevalence and impact of musculoskeletal symptoms (MSS) among nursing students. In the remaining three studies a learning model was developed and explored; II - the inter-personal interaction (qualitative content analysis), III - the students’ experiences of using the learning model (phenomenological hermeneutics), IV - the students’ learning processes (hermeneutic approach). Results: 143 of the 224 respondents in study I reported MSS during the previous 12 months and of those 91 reported impact on physical daily life activities. The odds ratio for reporting MSS study year 3 was 4.7 (95% CI: 2.1 – 10.7). Study II shows that the students’ movement awareness and self-analysis developed when encountering their own movement through video feedback. Studies III and IV show that the facilitator’s reflective and responsive approach appears to be essential in creating interaction and a permitting learning atmosphere. The students became emotionally and cognitively challenged and personally engaged, were motivated to change by discovering details in their movements and gained a greater understanding of the relationship between their own movements and current or risk for future MSS. They also experienced emotional, cognitive and bodily confusion, which was interpreted as a necessary step in the changing process. Conclusion: MSS among nursing students appears to be a problem and education regarding ergonomic movements and principles is suggested to be emphasized in the nursing curriculum. The video-supported learning model enabled encountering and discovering one’s own body and movement in different ways, which facilitated reflection and motivation for change, which was supported by the facilitator’s reflective approach. The learning model, which could contribute to multifactorial ergonomic interventions, could also support movement awareness and learning in practical learning situations within education and rehabilitation. Further research needs to study the model in different contexts and in relation to MSS prevention.

The purpose of this thesis is to explore the subject of industrial exoskeleton in accord-ance to the applicability of the technology preventing musculoskeletal disorders within the automotive industry. The modern technology of exoskeletons has a limited field of research and knowledge and is in need to be studied to provide organisations with proper findings for understanding the applicability of the technology. In the auto-motive industry musculoskeletal disorders (MSDs) is one of the most common disor-ders among employees and industries work constantly to decrease and prevent MSDs within their work environments. By conducting literature reviews, the status of exo-skeleton research and development concluded that academic research mostly focuses on technological development of exoskeletons, and not laboratory and/or field testing of currently available industrial exoskeletons. However, through database and website searches, twenty-four available industrial exoskeletons were identified which could be applicable within the automotive industry. Through literature and a case illustration, a number of potential causes for MSDs within the automotive industry were identified and a framework was developed in order to match appropriate available industrial ex-oskeleton to be used in potentially preventing common MSDs. The discussion of the thesis highlights the benefits and challenges of implementing an industrial exoskele-ton within an industry. Proper research on the currently available industrial exoskele-tons is lacking and creates questions of reliability for the technology. However, devel-opment of industrial exoskeletons have shown to focus on prevention of the most common causes of MSDs within industries in their design and development, making the applicability of industrial exoskeletons highly possible.

Muscle performance is partially a consequence of its recent contractile history. Postactivation potentiation (PAP) can occur after muscle contractions and leads to enhanced neuromuscular performance. The purpose of this dissertation was to explain the relationship between muscle factors (twitch potentiation, TP) and neural factors (reflex potentiation, RP) contributing to overall PAP following a non-fatiguing volitional muscle contraction. The tibial nerves of fifteen resistance trained volunteers (eleven men, four women) were stimulated intermittently at supramaximal (Mmax) and submaximal (Hmax) intensities for 20 minutes on separate days under three conditions: rest (Control); after a after a 10 second maximum voluntary isometric contraction (MVIC) of the plantarflexors; and after a low frequency fatigue protocol prior to the MVIC. Plantarflexion isometric torque and rate of force development (RFD), and soleus and gastrocnemius EMG Hmax/Mmax ratios, were analyzed. Both experimental conditions resulted in TP at 10 seconds post-MVIC compared to the control condition. The two experimental conditions were not different for any measure. Torque and RFD at Hmax (overall PAP) were highest at 3 and 4.5 minutes post MVIC, respectively, but were not significantly different from the control condition. EMG values generally were insignificantly increased in the experimental conditions versus the control condition. Mmax torque and RFD significantly contributed to Hmax torque and RFD at 20 seconds, Hmax peak, and 20 minute post-MVIC time points. The soleus significantly contributed to Hmax torque at 20 seconds and 20 minutes post-MVIC, and Hmax RFD at 20 seconds, 4.5 minutes, and 20 minutes post-MVIC. The results of this study suggest that both muscle and neural factors play a significant role in overall PAP, and that neural factors may play a more meaningful role in RFD potentiation than torque potentiation.

Background summary. Leg pain is a common complaint in relation to low back pain (LBP), present in up to 65% of all patients with LBP. Radiating leg pain is an important predictor for chronicity of LBP and an indicator of the severity of the disorder. Consequently patients with back and leg pain account for a disproportionate amount of the costs of medical care and disability compensation caused by LBP. As many structures in the lower quarter are capable of evoking a similar pattern of pain, the primary pathology causing low back related leg pain is often difficult to differentiate resulting in inappropriate investigations and treatment.A number of published classification systems for LBP based on symptom response and pathoanatomy incorporate radiating leg pain. While these systems may be suitable and successful for LBP, this approach may be insufficient for the more complex pain conditions related to nerve injury. Failure to correctly classify subjects into homogenous subgroups could be one reason why randomized controlled trials often report conflicting results for conservative treatment of patients with sciatica. Mechanism based classification of patients is crucial in that it not only provides a better understanding of the presenting complaint, but also directs treatments which interact with specific neurophysiologic pain mechanisms. Therefore we developed a new classification system for low back related leg pain on the basis of pathomechanisms extending the ideas originally proposed by Elvey and Hall, with four distinct subgroups. These hierarchical categories are: Neuropathic Sensitization (NS) comprising major features of neuropathic pain with sensory sensitization; Denervation (D) arising from significant axonal compromise without major features of neuropathic pain; Peripheral Nerve Sensitization (PNS) arising from nerve trunk inflammation without clinical evidence of significant denervation; and Musculoskeletal (M) referred from non-neural structures such as the disc or facet joints.Objective. The objective of the research project was to investigate aspects of validity of the classification system: Inter-rater reliability, concurrent validity, and predictive validity.Methods. As there is no gold standard against which the classification system can be tested, three studies were undertaken to investigate inter-rater reliability, concurrent validity and predictive validity. Inter-rater reliability was tested consecutively by six blinded experienced clinicians in a subset of 40 patients. Concurrent validity was investigated by implementing a comprehensive quantitative sensory test (QST) protocol as a criterion measure within a cross-sectional cohort design. The aim was to explore whether sensory profiles of the different diagnostic groups would correlate with the putative pathomechanisms in each group. To investigate predictive validity we conducted a longitudinal cohort study to explore whether treatment response differs between diagnostic groups. Outcome measures were pain intensity, degree of disability and patient global perceived change as well as QST parameters related to small nerve fibre function and pain sensitivity.Results. Seventy-seven patients with unilateral low back related leg pain and 18 healthy age and sex matched controls were included. The proportion of patients in each classification were 26% in Group NS, 36% in Group D, 12% in Group PNS and 26% in Group M. Interrater reliability was good (percentage agreement = 80; κ = 0.72; 95% CI = 0.57 to 0.86). QST revealed signs of pain hypersensitivity in Group NS compared to a healthy control group. Significant sensory deficits occurred only in Group D and were most pronounced over the affected foot. QST parameters in Groups PNS and M were not significantly different to healthy controls. The longitudinal cohort study showed that the proportion of patients responding to treatment was greater in PNS (55.6%) than the other three groups (NS 10%; D 14.3 % and M 10%; Fishers exact test p=0.031). The mean magnitude of improvement was greater in Group PNS in all outcome measures compared to the other groups (p ≤ 0.052). Additionally, Group PNS showed a greater improvement pre to post treatment of C fibre function, decreased sensitivity to cold pain and decreasedtemporal summation compared to the other groups (all p<0.05). In contrast, GroupNS exhibited loss of C fibre function and increased pressure pain sensitivityfollowing treatment (all p<0.05).Discussion. Patients with low back related leg pain could be reliably classified into four groups by experienced musculoskeletal physiotherapists using a new classification system. Reliability is an essential requirement for any classification system to be valid. Significant differences in QST thresholds were found in groups NS and D when comparing them to a group of healthy controls, indicating that in these two groups sensory dysfunctions were most pronounced. These dysfunctions match findings from the clinical examination: Sensory deficits in Group D and pain hypersensitivity in Group NS. These findings support concurrent validity. The findings of the longitudinal study indicate that the new classification system identifies a subgroup of patients (PNS) more likely to respond to neural mobilisation intervention. This result contributes to the evidence for predictive validity of the classification system and supports the concept that correct categorization of subjects will improve treatment outcomes.Conclusion. The findings of our research project support validity of the new classification system and its use as a reliable and feasible tool to improve diagnosis and treatment outcome in patients with low back related leg pain.

Chromosomal alterations involving the RUNXI or CBFB genes are specifically and recurrently associated with human acute myeloid leukemia (AML). One such chromosomal alteration, a pericentric inversion of chromosome 16, is present in the majority of cases of the AML subtype M4Eo. This inversion joins CBFB with the smooth muscle myosin gene MYH11 creating the fusion CBFB-MYH11. Knock-in studies in the mouse have demonstrated that expression of the protein product of the Cbfb-MYH11fusion, Cbfβ-SMMHC, predisposes mice to AML and that chemical mutagenesis both accelerates and increases the penetrance of the disease (Castilla et al., 1999). However, the mechanism of transformation and the associated collaborating genetic events remain to be resolved. As detailed in Chapter 2, we used retroviral insertional mutagenesis (RIM) to identify mutations in Cbfb-MYH11 chimeric mice that contribute to AML. The genetic screen identified 54 independent candidate cooperating genes including 6 common insertion sites: Plag1, Plagl2, Runx2, H2T23, Pstpip2, and Dok1. Focusing on the 2 members of the Plag family of transcription factors, Chapter 3 presents experiments demonstrating that Plag1 and Plagl2 independently cooperate with Cbfβ-SMMHC in vivo to efficiently trigger leukemia with short latency in the mouse. In addition, Plag1 and PLAGL2 increased proliferation and in vitro cell renewal in Cbfβ-SMMHC hematopoietic progenitors. Furthemore, PLAG1 and PLAGL2 expression was increased in 20% of human AML samples suggesting that PLAG1 and PLAGL2 may also contribute to human AML. Interestingly, PLAGL2was preferentially increased in samples with chromosome 16 inversion, t(8;21), and t(15;17). To define the mechanism by which PLAGL2 contributes to leukemogenesis, Chapter 4 presents studies assessing the role of the Mp1 signaling cascade as a Plagl2 downstream pathway in leukemia development. Using microarray analysis we discovered that PLAGL2 induces the expression of Mp1 transcript in primary bone marrow cells that express Cbfβ-SMMHC and that this induction is maintained in leukemogenesis. We have also performed luciferase assays to confirm that the Mp1 proximal promoter can be directly bound and activated by PLAGL2. Furthermore, we demonstrate increased Mp1 expression leads to hypersensitivity to the Mp1 ligand thrombopoietin (TPO) in PLAGL2/Cbfβ-SMMHC leukemic cells. To test the functional relevance in leukemia formation, we performed a bone-marrow transplantation assay and demonstrate that overexpression of Mp1 is indeed sufficient to cooperate with Cbfβ-SMMHC in leukemia induction. This data reveals that PLAGL2 cooperates with Cbfβ-SMMHC at least in part by inducing the expression of the cytokine receptor Mp1. Thus, we have identified the Mp1 signal transduction pathway as a novel target for therapeutic intervention in AML.

Skeletal muscle differentiation requires synergy between tissue-specific transcription factors, chromatin remodeling enzymes and the general transcription machinery. Here we demonstrate that two distinct protein arginine methyltransferases are required to complete the differentiation program. Prmt5 is a type II methyltransferase, symmetrically dimethylates histones H3 and H4 and has been shown to play a role in transcriptional repression. An additional member of the Prmt family, Carm1 is a type I methyltransferase, and asymmetrically methylates histone H3 and its substrate proteins. MyoD regulates the activation of the early class of skeletal muscle genes, which includes myogenin. Prmt5 was bound to and dimethylates H3R8 at the myogenin promoter in a differentiation-dependent fashion. When proteins levels of Prmt5 were reduced by antisense, disappearance of H3R8 dimethylation and Prmt5 binding was observed. Furthermore, binding of Brg1 to regulatory sequences of the myogenin promoter was abolished. All subsequent events relying on Brg1 function, such as chromatin remodeling and stable binding by muscle specific transcription factors such as MyoD, were eliminated. Robust association of Prmt5 and dimethylation of H3R8 at myogenin promoter sequences was observed in mouse satellite cells, the precursors of mature myofibers. Prmt5 binding and histone modification were observed to a lesser degree in mature myofibers. Therefore, these results indicate that Prmt5 is required for dimethylating histone at the myogenin locus during skeletal muscle differentiation in order to facilitate the binding of Brg1, the ATPase subunit of the chromatin remodeling complex SWI/SNF. Further exploration of the role of Prmt5 during the activation of the late class of muscle genes revealed that though Prmt5 is associated with and dimethylates histones at the regulatory elements of late muscle genes in tissue and in culture, it was dispensable for late gene activation. Previous reports had indicated that Carm1 was involved during late gene activation. We observed that Carm1 was bound to and responsible for dimethylating histones at late muscle gene promoters in tissue and in culture. In contrast to Prmt5, a complete knockout of Carm1 resulted in abrogation of late muscle gene activation. Furthermore, loss of Carm1 binding and dimethylated histones resulted in a disappearance of Brg1 binding and chromatin remodeling at late muscle gene loci. Time course chromatin immunoprecipitations revealed that Carm1 binding and histone dimethylation occurred concurrently with the onset of late gene activation. In vitro binding assays revealed that an interaction between Carm1, myogenin and Mef2D exists. These results demonstrate that Carm1 is recruited to the regulatory sequences of late muscle genes via its interaction with either myogenin or Mef2D and is responsible for dimethylates histones in order to facilitate the binding of Brg1. Therefore, these results indicate that during skeletal muscle differentiation, distinct roles exist for these Prmts such that Prmt5 is required for activation of early genes while Carm1 is essential for late gene induction.

The overall goal of the thesis was to investigate the nature of the healthy human self and the process of achieving health. This was undertaken by reviewing established self-theory and presenting a summary of each theory and its position with regard to self-composition, self-agency and the nature of the healthy self. An inclusive self-theory was then developed, congruent with reviewed literature, which positioned spirituality as the essential core of self. From the foundational Spiritual Theory of Self and the findings of the first study in this thesis, the Health Change Process Theory was developed to explain and predict how people achieve sustainable health. Three subsequent studies resulted in the construction and testing of a quantitative measure which enabled scientific investigation of the nature of the healthy self and the process of achieving health. Method The methodology of the four studies in this thesis was based on the instrumental approach which posits that, while there are procedural differences between qualitative and quantitative methodologies, philosophically speaking, there is no fundamental difference as they are both equally applicable and valuable. Consequently, the methodology judged to be the most appropriate instrument to investigate each study's topic of inquiry was chosen rather than allegiance to either qualitative or quantitative methodology. The first study was qualitative, as it investigated the definition of health and the process by which it was achieved from the perspective of 30 people with chronic musculoskeletal impairments. The findings from this study provided the theoretical basis for the three subsequent questionnaire development and validation studies. The second study used qualitative methodology with 59 participants to identify participant-generated items used in a new quantitative holistic health questionnaire and then employed quantitative methods to perform preliminary tests of the reliability and validity of this measure. The third study used quantitative methods with 233 participants to evaluate more robustly the reliability, content and concurrent validity of the original developmental measure and another, behaviourally-orientated assessment instrument, which used the identical item content but re-framed in the past tense. The fourth study employed qualitative and quantitative methods with 205 participants to evaluate the clinical validity of the scale found to possess reliability and validity in the previous investigation. Results The critical review of self-theory concluded with the development of the Spiritual Theory of Self. The initial study supported this theory as a robust explanation and predictor of the determinants of a healthy self. Furthermore, the findings of this study and a review of relevant literature concluded with the development of a Health Change Process Theory, which was based on the Spiritual Theory of Self. The Health Change Process Theory explains and predicts the process by which a healthy self develops. The subsequent questionnaire development and validation studies sought to provide a quantitative holistic assessment tool, congruent with the Health Change Process Theory, and found the 28-item QE Health Scale (QEHS) to be a reliable and valid measure of holistic health. These results also demonstrated that the Health Change Process Theory and the underpinning Spiritual Theory of Self were robust. With regard to clinical application, the QEHS was found to aid assessment, therapeutic intervention, a client-centred holistic approach to healthcare and evidenced-based practice. The Patient Profile, derived from QEHS responses, provided a tool that enabled theory to be applied to practice by identifying the key indicator personal attributes determining holistic health status. Conclusion The research results demonstrated that the Spiritual Theory of Self and the Health Change Process Theory provide valid explanations of the constructs that enable people with musculoskeletal disorders to remain otherwise healthy with such conditions. Furthermore, the relationship between the findings and established self-theories suggest that the Spiritual Theory of Self and the Health Change Process Theory may advance knowledge of the predictors and interventions that enable all people to undertake a health-enhancing process of change when confronted with adversity. The QEHS and associated Patient Profile were found to be reliable and valid tools that facilitated assessment and enhancement of the holistic health status for people with musculoskeletal impairments. These tools identified barriers to achievement of holistic health, predicted by the Health Change Process Theory; facilitated the therapeutic process through a focus on issues meaningful to those receiving healthcare; aided treatment decision making; and enabled quantitative evidence-based evaluation of the efficacy of interventions. Moreover, the overall results have advanced psychological knowledge with implications for all fields of psychology involved in the study of people. The evidence of the research undertaken provides a basis for promoting knowledge and research of chronic healthcare delivery and a spiritually based conception of self and health. The QEHS and associated theories provide a tool and basis for investigations where people are experiencing traumatic, irreversible crises. However, the initial aims of further research should be to refine the QEHS and the associated Patient Profile to enable the use of theory and the QEHS across a diverse range of research populations and to investigate the applicability of these to facilitate the maintenance or achievement of a healthy self.