Introduction Diagnosis of periprosthetic joint infection (PJI) can be challenging and discrimination between septic and aseptic loosening might be difficult due to the high rate of false negative bacterial culture results particularly when patients have been on long-term antibiotics. Quantitative polymerase chain reaction (qPCR) seems to be a promising technique with higher sensitivity than conventional microbiological methods in the diagnosis of PJI in such cases. However, this technique has proved to have a lower specificity due to, at least in part, detection of DNA from dead bacteria. Propidium monoazide (PMA), a DNA binding reagent, can inhibit the DNA from membrane-compromised cells from being amplified during the PCR. In this study, we have tested the performance of qPCR of clinical samples with and without prior treatment with PMA as a diagnostic tool for PJI diagnosis and compared to the conventional microbiological culture. Methods 208 periprosthetic tissues and/or explanted prosthesis samples were collected from 62 revision episodes from 60 patients undergoing revision arthroplasties due to either PJI or non-infective causes. Tissues were homogenized, and prostheses were sonicated. Homogenates and sonicates were used for aerobic and anaerobic cultures, qPCR, and PMA-qPCR. Our PCR assay included genus-specific primers for staphylococci and enterococci and species-specific primers for Propionibacterium acnes being the commonest PJI causative organisms. Sample analysis was performed blindly without referral to patients’ clinical data which was reviewed later. Results Among the 62 revision episodes, 15 satisfied the Musculoskeletal Infection Society (MSIS) criteria for diagnosing PJI and 46 did not. One patient who was indeterminate as not satisfying the MSIS criteria but with a high clinical suspicion was included in the PJI group for a more conservative data analysis. Two PJI episodes caused by organisms outside our qPCR panel were excluded. Sensitivity of culture, qPCR, and PMA-qPCR were 63%, 71%, and 79% respectively. Their specificities were 96%, 72%, and 89% respectively. Conclusion PMA-qPCR (viability PCR) has the potential to improve the diagnosis of PJI as it increases not only the specificity but also the sensitivity of qPCR with a higher overall accuracy. It could be used as a viability marker to confirm eradication of infection prior to reimplantation in the two-stage treatment protocol of PJI or in post-septic arthritis patients before considering arthroplasty.

This thesis focusses on chronic pain, pain sensitivity, depression, and anxiety in people with knee osteoarthritis (OA). The thesis includes details of three interrelated sub-studies: Study 1: An investigation into the associations between pain pressure thresholds (PPTs) and self-reported pain, depression, anxiety, and gender in knee OA; Study 2: An investigation into the inter-rater reliability of pressure algometry Quantitative Sensory Testing (QST); and Study 3: Rasch analysis of the State-Trait Anxiety Inventory short form (STAI-SF). Previous research into self-reported pain and pain sensitivity assessed via QST in knee OA suggests that there are significant associations between these factors and depression and anxiety. However, few studies have investigated the relationships between pain sensitivity and mood in people with knee OA, as the majority of these studies are very medical in their focus. Gender differences in some QST studies have also been found, with women often presenting with lower pain thresholds than men. However, this finding has not been consistent, and appears to vary across different samples. For Study 1, 77 people with a diagnosis of knee OA completed self-report measures of current pain level, depression, and anxiety. PPTs at four body sites were then measured for each participant using QST. Correlations showed that female gender, higher pain rating, and higher levels of depression and anxiety, were associated with lower PPTs. Parallel multiple regression models found that self-reported pain rating, depression, anxiety, and gender explained between 13 and 18% of the variance in PPTs (for each individual body site). For Study 2, 20 healthy participants underwent the QST procedure used in Study 1 to measure their PPTs at four body sites. The QST was administered by the two testers who administered the QST in Study 1, in order to investigate inter-rater reliability. Acceptable inter-class coefficients were found for each body site PPT, suggesting that lack of inter-rater reliability was not a weakness of Study 1. For Study 3, 246 people with a diagnosis of knee OA completed the STAI-SF. In order to evaluate the measurement properties of the STAI-SF with this client group, Rasch analysis was undertaken. The study examined the fit between the data collected from the STAI-SF and the Rasch model, in order to investigate whether it meets the psychometric requirements of interval-level measurement. An acceptable fit to the Rasch model was found, although the measure showed evidence of mistargetting. The main conclusions of this thesis research were that, for people with knee OA, depression, anxiety, gender, and pain rating are related to PPTs and explain some of the variance in PPTs. The utility of the STAI-SF with people with knee OA was also queried. The key implication of this research is that it is important for the appropriateness of assessment tools used in knee OA for mood and pain (in research and/or clinical practice) to be more critically considered than they are in most current literature. This would help ensure that the data collected is more meaningful and helpful in guiding interventions for this client group.

Introduction: Knee osteoarthritis (KOA) is a common complex disorder. Although previously believed to be degenerative, KOA is in fact a regenerative condition, compensating against insults sustained at the joint. However, a failure of this compensatory repair process, especially in the presence of constitutional and local joint factors, increases the risk of KOA and inevitably leads to joint-failure (Dieppe and Lohmander, 2005, Arden and Nevitt, 2006, Sandell, 2012). Diagnosis of KOA may be made via clinical presentation, imaging, or using clinical algorithms, which may be a combination both in addition to biochemical diagnostic tests (Brandt et al., 2003). Knee pain (KP) is the most common symptom, and in the general population its prevalence is 25% (Peat et al., 2001a). Patients may also experience early morning stiffness of the joint and reduced function. Physician-observed signs include crepitus, restricted movement, and bony and soft tissue swellings (Abhishek and Doherty, 2013). Although considered the gold standard to diagnose KOA, plain film radiography is not without its limitations (Wick et al., 2012). Clinicians, however, favour radiography because it can easily discern two key features of the condition: joint space narrowing (JSN), a surrogate of cartilage loss, and the formation of osteophytes on the joint margin (Roemer et al., 2014). Assessment of radiographs is most commonly undertaken using Kellgren-Lawrence (KL) grade verbal descriptors (Altman et al., 1986a). The prevalence of radiographic KOA (RKOA) may be higher than KP, but there is a discordance between people reporting symptoms and those with structural change (RKOA) (Peat et al., 2001a, Bedson and Croft, 2008). A plethora of constitutional risk factors and joint-specific biomechanical factors increase the risk of KOA, including joint injury and occupation (Suri et al., 2012, Silverwood et al., 2015). One such occupation, which has a greater risk of injury are professional footballers (Drawer and Fuller, 2002) and knee injuries account for 17% of all footballing injuries (Ekstrand et al., 2011). Football is one of the most common team sports worldwide, with over 265 million people worldwide play the game (FIFA, 2007a), and of these, 110,000 are male professional footballers (FIFA, 2007b). Although perceived that that footballers are at great risk of long-term consequences such as KOA, due to their high risk of injury, the current evidence supporting this is limited (Kuijt et al., 2012, Tran et al., 2016). The previous studies observing KOA in footballers are difficult to generalise to the wider football population. This is for a number of reasons, including recruitment of inadequate sample, absence of inappropriate control groups, and differing case definitions, all resulting in a large variation in prevalence of KOA. Thus, there exists a need for a comprehensive study to determine the true prevalence and risk of KOA in retired professional footballers compared to the general population. Aims: (1) To determine the prevalence and risk of KOA (measured as KP, RKOA and requirement for total knee replacement (TKR)) in retired professional footballers compared to the general population; (2) To determine the specific factors (constitutional, biomechanical and football-specific) that are associated with an increased risk of each of these outcomes (KP, RKOA and TKR) within footballers. Methods: The Nottingham University Hospitals NHS Trust and the Nottingham Research Ethics Committee (Refs 14/EM/0045; 14/EM/0015) approved this study, which was registered on the clinicaltrials.gov portal (NCT02098044; NCT02098070). This study design involved carrying out two cross-sectional studies. The Football Study involved distributing 4775 postal questionnaire surveys to retired professional footballers via multiple sources, including football clubs, their former players’ associations and the Professional Footballers Association (PFA). The Knee Pain and Related Health in the Community Study (KPIC) involved distributing 40,500 postal questionnaires, via 12 general practice surgeries, to both men and women in the East Midlands general population. However, only men formed the control group for this study. The inclusion criteria for both the footballers and control participants was the same: men aged 40 and older. The questionnaires, developed based on previously literature, were similar to capture detailed information about KP, undergoing a TKR and putative risk factors for KOA, including knee injuries, surgery and alignment. The questionnaires also gathered information regarding demographics, medical and occupational history, general health and current medication. Following this, footballers and controls who consented had radiographic assessments of both their knees, including weight-bearing semi-flexed posterior-anterior (PA) view using the Rosen template (Rosenberg et al., 1988) and a seated 30° flexion skyline view. A single observer (GSF) scored all the radiographs as a single mixed batch using HIPAX Dicom software. In addition to the KL grades, the Nottingham Line Drawing Atlas (NLDA) was used (Nagaosa et al., 2000) (Wilkinson et al., 2005), which scored composite joint space narrowing (JSN), composite osteophyte, and a combined global score for each knee. Primary outcomes observed were current KP, RKOA (measured using the NLDA) and TKR. Secondary outcomes observed were ever having KP (chronic), physician-diagnosed KOA, RKOA (measured using KL grades) and radiographic CC. Power calculations determined the sample size for the questionnaire survey and the radiographic survey. Categorical variables presented as frequency and percent and compared using a chi-squared test. Continuous variables presented as mean and standard deviation and compared using a t-test. The risk of KOA (measured for each outcome independently) in footballers compared to the controls was determined using a generalised linear model (GLM) with a Poisson distribution, and adjusted for known risk factors (including age, body mass index (BMI) and previous knee injury). The specific risk factors within footballers associated with outcomes of KOA (namely KP, RKOA and TKR) were determined using multivariate logistic regression. Results: 1207 footballers (response rate of 25.3%) and 4085 control men responded to the Football and KPIC studies respectively, which was far lower than studies previously conducted in both populations. Following this, 470 footballers and 500 men consented to undergoing radiographic assessment of their knees. For participants who returned the questionnaire (footballers and controls), characteristics were compared between those who underwent a knee radiograph and those who did not. Age and sustaining a knee injury were the main factors significantly difference in both. Footballers were significantly older (3.9 years) than the controls, but were gender-matched (males-only) and had a similar BMI. Footballers had a significantly greater number of injuries (64.5% v. 23.3%) compared to the controls. They also had significantly more body pain (74.7% v. 69.8%) and therefore took more pain-relief medication (61.9% v. 28.5%). However, footballers suffered from far fewer comorbidities compared to the controls (29.4% v. 45.7%). Footballers had a far greater prevalence of both primary and secondary outcomes. The prevalence of KP was almost twice as great in footballers (52.2%) compared to the controls (26.9%) and this increased prevalence was regardless of age. The peak prevalence of KP also occurred at least ten years earlier in footballers compared to the controls. Although the prevalence of physician-diagnosed KOA was much lower than the prevalence of KP in footballers (28.3%), it was more than double that of the controls (12.2%). Additionally, footballers (11.1%) had almost three times greater prevalence of TKR compared to the controls. Risk factors significantly associated with footballers who had undergone a TKR, included age [OR 1.09, 95% CI 1.07-1.11], being obese [OR 1.77, 95% CI 1.00-3.12] and having gout [OR 3.11, 95% CI 1.96-4.70]. Sustaining a significant knee injury [OR 3.11, 95% CI 1.94-4.99] and receiving an intra-articular knee injection [OR 2.56, 95% CI 1.76-3.73] were also significant risk factors for footballers who underwent a TKR. However, those footballers with a longer duration of playing the game [OR 0.95, 95% CI 0.92-0.98] had a reduced risk of TKR. / Conclusion: These findings show footballers have a greater risk of KOA compared to the general population, reporting up to three times higher prevalence of various outcomes (KP, RKOA, physician-diagnosed KOA and TKR). The age-prevalence of all outcomes of KOA, are greater in footballers compared to the controls. The high prevalence of injuries significantly account the risk of KOA in footballers compared to the controls (even following adjustment of other risk factors). Within footballers, knee injuries, together with subsequent investigations (specifically exploratory and interventional arthroscopy) and management (specifically intra-articular knee injections), were strongly associated with risk of KOA (KP, RKOA and TKR independently). Football’s governing bodies need to set out and implement strategies to reduce or even prevent the risk of serious injury (thus reducing the risk of subsequent investigation). This will reduce the risk of long-term consequences, such as KOA. However, whether the Industrial Injuries Advisory Council considers the risk of KOA in footballers an industrial compensable disease remains a question.

Acute low back pain: A randomised, controlled, prospective trial of ketoprofen and McKenzie physiotherapy within three weeks of onset. Aims: (1) To establish whether McKenzie physiotherapy is beneficial compared with a non steroidal anti inflammatory drug in the treatment of acute low back pain. (2) To investigate the mode of action of McKenzie lumbar spine treatment. Method: Patients with acute back pain of less than three weeks standing aged between 18 and 55 years were admitted to the trial. On attending clinic the patient underwent interview and examination by a doctor. Those patients without evidence of nerve root entrapment; underlying pathological lesion or psychological abnormality (illness behaviour) completed formal psychometric testing and social enquiry. The St Thomas back disability questionnaire was used throughout the study and was the principle outcome measure. Patients underwent randomisation into study and control groups. They both had information leaflets; and a supply of back disability questionnaires with stamped addressed envelopes to return to the study office at weekly intervals. Both groups were seen again on the seventh week after the onset of the back pain. Study Group Patients were assessed by one of two research physiotherapists and underwent a treatment regimen according to the McKenzie principles. Control Group Patients were given a 28 day course of non steroidal anti inflammatory drug. At follow up clinic repeated clinical examination and questioning recorded the following outcomes: disability; analog pain score; return to work; patient's appraisal of change in condition and personal responsibility for pain control. Further postal follow up occurred at six months and one year. Initial psychological factors explained much of the disability seen seven weeks after the onset of back pain. An analysis of covariance employing psychological information showed that physiotherapy was significantly more effective in reducing disability at the seventh week only when the 8.5% of patients who the physiotherapists were unable to diagnose on their first assessment were excluded from analysis. The physiotherapy patients were away from work significantly longer than the patients who had drug treatment. At six months and one year a tendency to less frequent attacks in the physiotherapy group was not significant owing to the power of the study. Physiotherapy patients became significantly more responsible for their pain than the drug patients when assessed by means of a pain locus of control questionnaire. This finding persisted at a year after onset.

Objectives: o To determine the prevalence of knee pain in the population aged ≥45 years. o To determine the benefit or otherwise of regular home exercise and telephone contact in reducing the burden of knee pain in the community. o To determine the economic burden of knee pain from a societal perspective. o To determine the cost-effectiveness and cost-utility of the compared interventions. Design: An initial postal questionnaire regarding knee pain was sent to 9296 individuals aged ≥45 years registered with two large general practices in Nottingham. This was followed by a two-year, single-blind, randomised factorial trial. Treatment arms included: exercise therapy, telephone social support, a placebo health food product and no intervention. Economic data were collected prospectively alongside the trial. Analysis was conducted on an intent-to-treat basis. Primary outcome: Self-reported knee pain at 24 months. This was assessed using the Western Ontario MacMaster's Universities Osteoarthritis Index (WOMAC) - a knee specific questionnaire. Results: The postal questionnaire was returned by 65% of the study population. The prevalence of self-reported knee pain in the community in those aged ≥45 years was 32% (35% in females and 28% in males). Costs incurred during the 6-month period prior to randomisation showed medical costs for the treatment of knee pain to be 7% of total medical costs and 11% of primary care costs. Annual societal costs were estimated to be £48 per person. The intervention study demonstrated that a simple, home-exercise programme could reduce self-reported knee pain, knee stiffness and knee related physical disability after 24 months (p=<0.001, 0.01 and <0.001 respectively). Effect sizes were modest, but improvements were incremental to normal care. The number needed to treat (NNT) in order to achieve a ≥ 50% reduction in pain at 24 months for individuals allocated to the exercise programme was between 8 and 13. Neither telephone contact nor the placebo dolomite tablet contributed significantly to the observed reduction in pain. The cost per person of delivering the two-year exercise programme was £ 113. Analysis of GP records revealed no change in medical costs during the trial. Cost-effectiveness analysis suggested hat the cost per unit change on the WOMAC pain scale was £ 108. The cost-effectiveness of achieving a ≥ 50% reduction in pain in a single individual (based on NNT figures) was £1,012. Conclusion: Knee pain is common in the general UK population aged ≥45 years and incurs an estimated cost of £218 to £350 million per annum (excluding indirect costs) in 1996 prices. The burden of knee pain could be reduced by the implementation of a cost-effective primary care-based exercise programme, although such improvements are likely to be modest.

An experimental model of a contaminated open fracture has been developed in rabbits, using a reproducible midshaft fracture of the tibia. This model has been used to: 1) Test the hypothesis that stable fixation of an open fracture will reduce its susceptibility to infection. 2) Assess the effect of antibiotics on infection rate, with particular reference to the delay in administering the initial dose. The pattern of fracture healing was initially determined for stable and unstable fixation, without inoculation with bacteria. Fractures fixed with a dynamic compression plate ("stable" group) healed by primary bone union, while fractures stabilised with a loose-fitting intramedullary rod ("unstable" group) healed by external callus formation. Forty- one rabbits were used in the definitive study of the effect of stability. All fractures were inoculated with Staphylococcus aureus in a standard concentration. There were twenty rabbits in the stable group (compression plate) and osteomyelitis developed in seven (35%). Of the twenty- one rabbits in the unstable group (loose- fitting intramedullary rod), fifteen (71%) became infected. This difference in infection rate is statistically significant (p<0.02). The "rod- fixed fracture" model had the highest infection rate and was therefore used to study the effect of antibiotics. Fifty-one rabbits were used; a single intramuscular injection of cephradine was given to each animal at varying times in relation to inoculation with bacteria. Although the maximal reduction in infection rate was observed when the antibiotic was given before inoculation with bacteria, a 40% decrease in the infection rate was still seen when the antibiotic was given after bacterial inoculation. This effect persisted even if the initial dose of antibiotic was delayed four hours after inoculation. These findings support the concept of stabilisation of open fractures in man; and suggest that appropriate systemic antibiotics should be routinely used in the management of open fractures in man, even if the treatment is delayed up to four hours after injury.

Idiopathic scoliosis (lS) is a structural lateral curvature of the spine with rotation for which no cause is established. Surgical treatment for scoliosis focuses on the spine and achieves only partial correction of spine and trunk deformity. This correction deteriorates with time. Some pathomechanisms of deteriorating body shape are suggested from sequential anthropometry. The correction and prevention of future deterioration in body shape are the aims of any scoliosis treatment. Application of knowledge of pathomechanisms to treatment may improve outcome. Section 1: Infantile and juvenile idiopathic scoliosis: long-term follow-up and effects of Luque trolley instrumentation and anterior release and convex epiphysiodesis. Patients with infantile (IIS) and juvenile idiopathic scoliosis (JIS) are evaluated by radiological examination before surgery and at intervals after surgery. The patients are also reviewed clinically at longest follow-up by surface and ultrasound methods. Appropriate non-parametric and parametric tests and multivariate analysis are used to evaluate results. Factors important in curve progression are identified and new strategies for treatment suggested. Section 2: Adolescent Idiopathic Scoliosis: 2 year follow-up and effects of each of posterior and anterior instrumentation with the Universal Spine System. Patients with adolescent idiopathic scoliosis (AIS) are evaluated before surgery and at intervals after surgery. Data from surface, anthropometry, questionnaire and plain radiography are considered. Statistical analyses were performed using parametric and nonparametric tests where appropriate. Attention is directed at factors that determine rib-hump progression post-operatively. Aims of studies: The aims of these studies are to quantitate the change in surface and skeletal morphology after surgery and after follow-up, to infer pathogenesis and pathomechanisms for each of infantile and adolescent idiopathic scoliosis, to consider new strategies for the treatment of IS and to quantify the subjective experience of scoliosis and surgery and compare with established objective measurements of scoliosis deformity.

Hypothesis A modified brace position would help to prevent injury to some aircraft passengers in the event of an impact accident. Aim of Experiments To evaluate a modified crash brace position. Materials and Methods 1. Impact Testing Impact testing was performed at the RAF Institute of Aviation Medicine, Farnborough. Aircraft seats, mounted on a sled, were propelled down a track at an acceleration of 16G. A 50% Hybrid III dummy was used as the experimental model. Four dummy positions were investigated: upper torso either braced forwards or sitting upright and lower legs placed either forwards or rearwards. The impact pulses used were based upon guidelines defined in Aerospace Standard AS8049 which relates to the dynamic testing of aircraft seats. Transducers located in the head, lumbar spine and lower limbs of the dummy recorded the forces to which each body segment was exposed during the impact. These forces were compared for each brace position. 2. Computer Simulation A mathematical model was developed to simulate occupants kinematics during an impact aircraft accident. This was based upon MADYMO -a crash victim simulation computer programme for biomechanical research and optimization of designs for impact injury prevention. Results Impact testing revealed that the risk of a head injury as defined by the Head Injury Criterion was greater in the upright position than in the braced forwards position (p < 0.00 1). The risk of injury to the lower limbs was dependant in part to their flailing behaviour. Flailing did not occur when the dummy was placed in a braced legs back position. Computer simulation revealed that lower limb injury may result from the feet becoming entrapped under the luggage retaining spar of the seat ahead. Conclusion A modified brace position would involve passengers sitting with their upper torso inclined forwards so that their head rested against the structure in front if possible. Legs would be positioned with the feet resting on the floor in a position slightly behind the knee. This position differs from those previously recommended in that the feet are positioned behind the knee. This study suggests that such a position would reduce the potential for head and lower limb injury in some passengers given that only a single seat type and single size of occupant have been evaluated. Standardisation to such a position would improve passenger understanding and uptake. Such a recommendation should not obscure the fact that an occupant seated in a forward facing aircraft seat, restrained only by a lap belt is exposed to considerable forces during an impact accident. Such forces are capable of producing, injuries in the femur, pelvis and lumbar spine.

Pronation of the foot is proposed as a possible aetiological factor in hallux valgus. Root type foot orthoses have been shown to restrict foot pronation and therefore have been used to treat hallux valgus. A controlled prospective 3 year trial tested the value of a Root foot orthosis in the treatment of juvenile hallux valgus. Six thousand nine year old Kettering children were screened for hallux valgus using goniometric and clinical examination. A clinical diagnosis of hallux valgus was made in 150 children and confirmed using radiography in 122 cases. Pes planus was as common in children with hallux valgus as children with no hallux valgus. The biomechanical examination of hallux valgus children revealed that a plantarflexed first metatarsal was the only consistent biomechanical abnormality. The sagittal plane position of the first metatarsal did not however relate to the degree of metatarsus primus varus which is apparent in the unaffected feet of children with unilateral hallux valgus prior to the development of hallux valgus in both feet. The 122 children with hallux valgus were randomised into a non-treatment control group and a treatment group where Root foot orthoses were worn for three years. Compliance and fit of the orthoses were checked every 4 to 6 months. At the end of the 3 year period, 96 children underwent a second weight bearing radiograph of both feet. The same observer measured the intermetatarsal and hallux valgus angle on all radiographs. The hallux valgus had deteriorated significantly in both the control and treatment group. Though not statistically significant, the deterioration was slightly more marked in the treatment group. A Root foot orthosis prescribed to restrict foot pronation will not significantly alter the progression of juvenile hallux valgus. This may indicate that pronation of the foot is not an important aetiological factor in juvenile hallux valgus.

Impact biomechanics of the pelvis and lower limbs in occupants involved in an aircraft accident have been investigated using a variety of techniques. These techniques have been used to: 1) Explore whether the position adopted by the occupant of the plane at the time of impact had implications for the pelvic and lower limb injuries sustained. 2) Test and assess the relevance of hypothesised injury mechanisms for the pelvis and lower limbs, described in the automobile industry to that of an impact aircraft accident. Clinical data has been derived from a cohort-of accident victims on board Boeing 737-400, G-OBME, when it crashed-on the M1 motorway on the 8 January, 1989. Experimental impact testing has been carried out using anthropomorphic test devices and a deceleration sled test facility. Further investigation of the impact biomechanics has utilised new techniques of impact occupant modelling with the aid of computer simulations. The results have indicated that in areas of the aircraft where seating and restraint mechanisms remained intact and fuselage disruption was minimal, severe lower limb and pelvic injuries were sustained by the occupants. These injuries may have been sustained in the absence of significant secondary impacts of the lower limbs with the seat in front. Further experiments have indicated that the position adopted by the occupants, and in particular the placement of the lower limbs on the floor can affect the trajectories of the limbs in their flail behaviour. In addition it is apparent that the knee-femur-pelvis mechanism of lower limb injury recognised by the automobile industry may not have been an important mechanism in this aviation situation. These findings have implications for the design of occupant safety systems if pelvic and lower limb injuries are to be reduced in future aircraft accidents.