This PhD project developed the femoral 3-in-1 nerve block to provide safe, effective regional analgesia to the 60,000 patients admitted annually to UK hospitals with a fractured neck of femur. The hospital mortality for patients with a fractured hip in a large UK study was 14.3% with cardiac aetiologies predominating in the first 2 days (Bottle & Aylin 2006). In contrast to the marked improvements in mortality for elective surgery, the overall mortality from emergency surgery and in particular surgery for fractured neck of femur patients has remained unchanged (Roberts & Goldacre 2003). Development of the femoral 3-in-1 nerve block for fractured neck of femur patients will provide analgesia but may also improve outcome. A relationship between effective pain analgesia and improved cardiac morbidity and reduced mortality in patients with a fractured neck of femur was demonstrated by Matot et al using epidural analgesia in 2001 but this is not the current clinical standard in the UK (Matot et al. 2003). The femoral 3-in-1 nerve block (also called the fascia iliacus block or anterior psoas compartment block) offered a viable solution to provide analgesia to patients with a fractured neck of femur prior to surgical fixation. The femoral 3-in-1 nerve block is technically undemanding and requires a minimum of extra training and resources. In contrast to epidural analgesia which requires extensive training of practitioners and continuous cardio-respiratory monitoring of patients and an increased level of nursing care, ultrasound guided nerve blocks have been associated with an increased success rate, need less local anaesthetic and have shorter onset times than traditional techniques (Marhofer et al. 1997;Marhofer et al. 1998). Ultrasound guidance may increase the nerve block success rate and lower complication rates but it is associated with the extra cost of the ultrasound machine, disposables and staff training. In contrast, needle guidance using loss of resistance for a femoral 3-in-1 block is technically simple and cheap but is potentially inaccurate and, as a result, may be less effective. Anaesthetists currently utilise the femoral 3-in-1 nerve block to provide effective pain after surgical fixation of the femur but these techniques use large doses of local anaesthetic. Further information on dosing based on efficacy and duration of action will allow a reduction in dose and hence an improvement in safety of the femoral 3-in-1 nerve block. The information needed to develop the femoral 3-in-1 nerve block to provide analgesia for patients with a fractured neck of femur was provided by undertaking one prospective observer-blinded muticentre randomised controlled study, a clinical trial of an investigational medicinal product and a cadaveric dissection study. A multicentre randomised controlled study compared the efficacy of using ultrasound, nerve stimulator and loss of resistance techniques to guide the needle for a femoral 3-in-1 nerve block in elective primary total hip arthroplasty patients. This initial study recruited patients scheduled for a similar operation to fracture neck of femur patients (elective primary total hip arthroplasty) as it was impossible to recruit and assess a large number (>100) elderly, frail emergency patients. The use of the nerve stimulator is the current gold standard for elective femoral 3-in-1 nerve blocks but if used on patients with a fractured neck of femur it will cause unnecessary discomfort in a limb with an unfixed fracture. In order to determine the comparative efficacy of ultrasound, nerve stimulator and loss of resistance techniques, we performed femoral 3-in-1 nerve blocks on 180 patients scheduled for elective primary total hip arthroplasty. The efficacy of these three techniques was measured by assessing femoral nerve sensory and motor response at 30 minutes after the femoral 3-in-1 nerve block. The use of ultrasound and nerve stimulator (US+NS) for the femoral 3-in-1 femoral nerve block for elective total hip replacement was statistically significantly more effective than loss of resistance (LOR-59.5%, US+NS-80.3%, p=0.0159 (p≤0.025)) with a number needed to treat of 5. There was no statistically significant difference in the effectiveness of using the nerve stimulator(NS) and ultrasound(US) to guide the insertion of a femoral 3-in-1 nerve block (NS-77.5, US-83.1%, p=0.527 (p≤0.025)). Since the use of nerve stimulator would result in significant unnecessary discomfort in patients with an unfixed fracture it was concluded that ultrasound was the optimal technique to guide femoral 3-in-1 nerve blocks for analgesia in patients with a fractured neck of femur. The dosing and safety of the femoral 3-in-1 nerve block was determined in patients with a fractured neck of femur. Levobupivacaine dosing was estimated by a Dixon’s up/down sequential methodology. Femoral 3-in-1 nerve blocks were performed and the concentration of levobupivacaine was increased or decreased (using a fixed volume) for an ineffective or effective nerve block respectively, as a result the concentration tended towards the EC50 (effective concentration in 50% of patients). The EC50 and the EC95 (effective concentration in 95% of patients) for 30 ml of levobupivacaine was estimated using a binary probit regression model; in which the probability of an effective nerve block was modelled against the concentration of levobupivacaine. The second part of this clinical trial assessed the pharmacokinetics (to ensure that serum levels were within the safe range) and pharmacodynamics (to assess duration of analgesia). The estimated EC95 concentration of levobupivacaine for the femoral 3-in-1 nerve block was 30mls of 0.036% with 95% confidence interval of 0.0332% to 0.0383%. The EC95 concentration of levobupivacaine gave a mean duration of analgesia of 166 minutes with a standard error of the mean of 35 minutes and peak median plasma level of 52 ng/ml 30 minutes after the femoral 3-in-1 nerve block. The measured plasma levobupivacaine concentrations were below the threshold (2100ng/ml) associated with toxicity. The clinical anatomy of the femoral 3-in-1 nerve block was determined by dissection. We investigated the distribution of 30 ml of black 10% latex injected lateral to the femoral nerve under the fascia iliacus membrane in two unembalmed adult cadavers. In all four dissections the lateral cutaneous and femoral nerves were stained at the inguinal ligament and the latex travelled distally in the adductor canal into the popliteal fossa to stain the sciatic nerve and its terminal branches.

Pulmonary hypertension (PH), a disease state affecting the pulmonary circulation, was first recognised in the 1950s. Obliteration of pulmonary capillary beds and vasoconstriction lead to elevated pulmonary vascular resistance (PVR) and increased right ventricular afterload. The direct consequence is impaired cardiac output (CO) response to exercise, resulting in progressive exercise limitation, and ultimately premature death from right heart failure. Despite the considerable expansion in pulmonary vasodilatory therapy in recent years, PH remains an incurable disease associated with high morbidity and mortality. Exercise CO is an important outcome measure in PH as it is directly linked to the consequences of disease. Cardiac output is conventionally measured at right heart catheterisation (RHC). The invasive nature of this procedure does not permit serial measurements to be made readily during follow-up to assess disease progression or treatment response. As a result, six-minute walk distance (6MWD), a simple measure of submaximal exercise capacity, has been used as a surrogate of exercise CO and the primary end-point in most randomised controlled trials of pulmonary vasodilatory agents to date. However, there are recognised limitations to the ability of 6MWD to predict outcome, and this necessitates the development of alternative outcome measures which are non-invasive, reproducible and responsive to change. Measurement of CO using the inert gas rebreathing method (IGR) may be such an alternative to 6MWD. It is a direct measure of right heart function and hence disease-specific. It can be combined with submaximal constant-load exercise to provide an objective assessment independent of patient effort. This form of exercise would also allow isotime comparison of metabolic variables which were shown to be more sensitive than variables measured at peak exercise in demonstrating improved exercise capacity from therapeutic interventions in chronic obstructive pulmonary disease (COPD). Another potential alternative outcome measure is end-tidal carbon dioxide partial pressure (PETCO2). It is a marker of ventilatory inefficiency and was shown to correlate with disease severity in PH. Accurate prognostication is central to PH management as it would inform treatment planning and patient counselling. Different strategies could be adopted to optimise the performance of existing prognostic factors. The predictive value of 6MWD may be improved by using % predicted 6MWD which adjusts for age, gender and anthropometric factors, and hence would give a more accurate representation of disease severity. A composite scoring system, combining key prognostic variables, would be more discriminatory than individual variables in predicting survival. Such prognostic equations have been derived from contemporary PH cohorts in France and the United States. Validation data published so far support their predictive value, but these equations may not perform as well in the United Kingdom (UK) as a locally derived risk score, due to differences in patient demographics and healthcare systems. The aims of this thesis were to investigate the use of novel non-invasive exercise variables and prognostic algorithms as outcome measures in PH. 1. The first two studies evaluate the ability of IGR haemodynamic measurements and isotime metabolic variables during submaximal constant-load exercise, and PETCO2 during the six-minute walk test (6MWT) to predict treatment response. 2. The last two studies explore the prognostic value of % predicted 6MWD and a novel UK-based composite risk score. The reproducibility and clinical correlates of IGR pulmonary blood flow (PBF) and stroke volume (SV) were determined. Changes in IGR PBF and SV and isotime metabolic variables, at rest and during submaximal constant-load exercise, were assessed after three months of new or modified disease-targeted therapy in patients with precapillary PH. IGR measurements were found to have good intersession reproducibility and correlate with conventional outcome measures including World Health Organisation functional class (WHO FC), 6MWD, N-terminal pro-brain natriuretic peptide (NT-proBNP) and Cambridge Pulmonary Hypertension Outcome Review (CAMHPOR) score. Resting and submaximal exercise IGR PBF and SV were able to detect treatment response, and may be more sensitive than 6MWD in detecting the effects of therapy in fitter patients. In comparison, isotime metabolic variables were less useful in detecting a treatment effect. The metabolic response during the 6MWT was determined and changes in PETCO2 were assessed after 3 months of new or modified disease-targeted therapy. Therapy-induced changes in the nadir of PETCO2 (PETCO2 nadir) correlated with changes in 6MWD, but resting, end-of-walk or PETCO2 nadir did not improve significantly at follow-up. Post-hoc analysis demonstrated that the study was under-powered to detect a change in PETCO2 with therapy. The prognostic performance of % predicted 6MWD, calculated using four different published reference equations, was compared with that of absolute 6MWD, at baseline and on treatment. Despite adjusting for physiological inter-subject variance, % predicted 6MWD is not superior to absolute 6MWD in predicting all-cause mortality. This may be related to limitations of existing reference equations or the use of all-cause rather than disease-specific mortality as the end-point. Baseline mortality predictors were identified from a Scottish cohort of incident and treatment-naive PH patients, and used to derive a simple scoring system for survival prediction over time. When validated in an independent UK PH cohort, the Scottish Composite Score (SCS) was predictive of survival and able to provide further risk stratification in WHO FC III patients. It may perform better in UK populations than other published equations derived from PH cohorts in France and the United States. In conclusion, IGR haemodynamic measurements may be useful as alternative outcome measures to 6MWD, and the SCS shows promise as the first UK-based composite risk score in PH. Further studies in larger cohorts are warranted to confirm their clinical utility.

This study presents three single case investigations of sentence processing disorders in aphasia. Assessment of the subjects was guided by models of normal sentence production and comprehension, and involved several new tests which were developed to investigate particular aspects of processing. The assessment phase generated hypotheses about where the processing system was breaking down for each patient. Although all three subjects showed disordered verb retrieval and use, different processing impairments were identified. The first subject had a deficit in the connections between verbs' semantic and phonological representations. The second subject had a hypothesised deficit in the early message level processes. The third subject had a semantic verb deficit which particularly impaired access to verbs' thematic information. Therapies were developed in the light of these hypotheses. Post therapy evaluation showed that all subjects made significant gains, although the nature and extent of their gains varied. These treatment responses are interpreted against the presumed cognitive models. The concluding discussion addresses a number of theoretical questions about the nature of the language processing system and how therapy may influence the workings of that system. Possible future directions for research are proposed.

The aims of this work were to assess the effects of different stimulus parameters on chromatic sensitivity, with particular emphasis on the effect of retinal illumination, and to investigate aspects of suprathreshold visual performance under mesopic conditions. All investigations were performed using visual psychophysical techniques. Chromatic thresholds were obtained using dynamic luminance contrast noise to isolate responses to colour signals. The effects of stimulus size and spatial distribution were examined in normal trichromats, dichromats and subjects with acquired colour vision deficiency. The chromatic sensitivity of normal trichromats was investigated with reduction in light level. Measurements were also performed to assess the possible involvement of rods in chromatic processing at threshold. Suprathreshold performance in the mesopic range was assessed in terms of the relative contributions of colour and luminance contrast to a measure of stimulus conspicuity and to visual search time. The conspicuity of a stimulus defined by colour and luminance contrast was defined as the value of achromatic contrast of a similar stimulus with an equal perceived conspicuity. An empirical model was developed from an extensive data set of conspicuity matches, to enable prediction of conspicuity for a wide range of coloured stimuli. Visual search performance for both achromatic and coloured stimuli was investigated under mesopic conditions, and results for the coloured stimuli were compared to the measure of stimulus conspiculty combined with an achromatic search time calibration. The results revealed that chromatic sensitivity is dependent on stimulus size, spatial distribution, eccentricity of presentation and level of illumination. These factors are suggested to reflect changes in cone performance and the relative cone contributions to the postreceptoral chromatic channels. Chromatic sensitivity was found to be independent of rod activity in the mesopic range, suggesting separate processing of rod signals and threshold colour signals under mesopic conditions. Measurements of stimulus conspicuity under mesopic conditions revealed individual variations in response to both luminance contrast and chromatic signals indicative of individual differences in gain control of postreceptoral mechanisms. Conspicuity was successfully modelled as a function of photopic contrast, scotopic contrast, chromatic difference to the background and the level of illumination. The nonlinear relationship between search time and luminance contrast was found to change with reduction in light level, reflecting increased contrast thresholds and diminishing effectiveness of unit physical contrast. Mesopic visual search was also found to depend on the photopic contrast, scotopic contrast and chromatic content of the stimulus, but with an apparent greater emphasis on scotopic contrast and reduced emphasis on colour compared to the measure of stimulus conspicuity. Conspicuity was successfully used to predict visual search times, and was found to be an improved indicator of search performance than either photopic or scotopic contrast.

A number of industries involved with coloured products were surveyed to assess the role of visual colour judgement in the processes and determine the industrial handicap of defective colour vision. The colour vision testing policies of the individual companies were investigated and an attempt was made to discover the industrial mistakes which could be attributed to defective colour vision. Visits were made to selected Industries to supplement information obtained from a postal survey. Discussions with Employment Medical Advisers and Industrial Medical Officers proved to be valuable. A field trial to determine the performance of paper colour matchers at standard colour vision tests was undertaken. A number of industrial jobs involving colour judgement were simulated in the laboratory. One hundred colour defective observers and a group of colour normals took part in the tasks, and an analysis of their performance is presented. In particular, comparisons are drawn between performance at these tasks and scores on standard colour vision tests. An enquiry into the colour vision tests used in school medical examinations was made and the career guidance given to colour defective children throughout England and Wales was studied. A list of occupations, jobs and careers which are likely to cause difficulty to the colour defective are presented. Finally recommendations concerning colour vision testing in industry are given.

This study aims to redesign and measure patient satisfaction and treatment of the patient flow process. Based on ontology, it will redesign the core patient flow processes with the simultaneous introduction of a patient-oriented model that will conceptualise and implement this ontological framework. A gap regarding scientific, patient-oriented, measurable frameworks has been discovered and demonstrates the need for a new healthcare management framework. As the need for this new framework is identified, this study aims at fulfilling the following objectives:  A novel redesign of core transactions of the patient flow process, based on ontology, and its supporting patient-oriented information system, from being healthcare oriented to being patient oriented.  Implement this study’s conceptualisation (patient-oriented flow) in a novel beyond any doubt, way through the function of the supporting information system as well as its measures used for the ontological process redesign.  Improve efficiency in the healthcare system through competent management of institutional resources by providing a fertile framework for strategic cooperation among patients and healthcare providers.  Assist in the development and maintenance of measurable activity-based driven results that improve patient quality value added services, turning everyday healthcare acts into healthcare facts relevant to this study’s concept. Concluding, scientific contributions of this study include the discovery and redesign of the contemporary both conceptual and structural gaps in the patient flow process and the introduction of a measurable scientific, not practical, redesign through the enterprise ontology methodology. Finally, the implementation of a novel patient-oriented framework (OS), based on universal characteristics, that results to effective GP appointment, proper diagnosis and referral, economically traceable and structurally measurable, both qualitative and quantitative, hospital inflow-outflow as well as patient awareness and patient relations management.

Tendon disorders - tendinopathies - are the primary reason form musculoskeletal consultation in primary care in the UK and the US. The molecular pathophysiology of tendinopathy remains difficult to interpret while inflammation and its role in tendinopathy have been historically ignored due to its absence in human surgical specimens. This thesis explores the role of inflammation in human tendinopathy and dissects potential molecular pathways involved in its initiation and perpetuation. Firstly I characterize inflammatory cell subtypes within a model of human tendinopathy highlighting a distinct inflammatory infiltrate particularly of mast cells and macrophages. Hypoxia and hypoxic cell death have been a long considered aetiology of tendon degeneration. In this thesis I demonstrate that hypoxia related proteins are present in early tendinopathy biopsies and thereafter in mechanistic studies demonstrate that hypoxia regulates inflammatory and apoptotic mediators in tendon cells associated with a significant shift in collagen matrix synthesis. The cytokines, interleukins 17 and 33 are emerging inflammatory mediators known to play key roles in fibroblast biology. I explored the cellular sources of IL- 17A in human tendinopathy with experiments revealing the majority of IL17A colocalised to mast cells. Moreover IL-17A induced proinflammatory cytokines and apoptosis in vitro and again resulted in a significant switch in collagen extracellular matrix production. IL 33 is a new member of the IL-1 superfamily that signals through the ST2 receptor. Herein I demonstrate that IL-33 expression is up regulated in human tendinopathic biopsies whilst rhIL-33 promotes proinflammatory cytokine release and significantly shifts matrix production toward a collagen III phenotype. WT mice undergoing a tendon injury model showed significant up regulation of IL-33 and ST2 while ST2-/- mice exhibit a reduced collagen response and biomechanical tendon strength at early time points post injury Addition of rh-IL33 increased type III collagen production and reduced the biomechanical strength of WT tendons. Furthermore mechanistic investigations has highlighted a key role for the microRNA 29 family in the modulation of collagen regulation in tendinopathy but also in controlling IL-33 induced changes as a direct target of sST2. Based on these experiments I propose IL-33 as an important and influential alarmin in early tendon injury and tendinopathy, which may be influential in the balance between reparation and degeneration in tendon disease.

In the last two decades an abundance of contact lens materials with unknown surface properties have been introduced as well as new contact lens design. Recent studies have identified the importance of physical and chemical interactions between materials and liquids. The purpose of this experimental research work was to investigate the relationship between a contact lens surface and a liquid. The wettability and hydrophilicity of both soft and rigid contact lens surfaces were determined using two novel techniques and an established method. The two novel techniques were the un-separated adherent quid/laser method and the adherent liquid/ maximum force method whereas the established technique involved monitoring the receding wetting angle and interface are a diameter of a sessile drop. Contact lens surface preparation and the method of removing a liquid from hydrated surfaces were found to be important variables when determining wettability or hydrophilicity. Experiments showed that the use of surface tension to remove liquid from hydrated surfaces significantly improved the reproducibility of subsequent measurements. Variation of the sessile drop wetting angle and interface area diameter with evaporation time demonstrated different values for different contact lenses. The clinical consequence of monitoring the receding values would be; if a material to spread tear break up time occurs the dry patches will be advanced on PMMA, rather than Paraperm contact lens. Surface hydrophilicity, if defined in terms of the maximum adherent force, describes the ability of a lens surface to attract a liquid, whereas wettability may be defined as the ability of a liquid to spread on a contact lens surface. The wettability and hydrophilicity, therefore, are two different issues. When a wetting angle is 01, or close to 0" the surface is described as wettable. Results demonstrated that Equalens had a greater surface wettability and hydrophilicity than the PMMA for pre-wear, but the post-wear hydrophilicity for PMMA was greater than Equalens. The use of each measurement method, therefore, resulted in a value that is intrinsically related to measurement method and definition. The clinical consequenceo f the valuesi s to help practitioners prescribea lens material either on wettability or hydrophilicity values. In contact lens practice, a lens surface is required to maintain a stable tear film and produce a long tear film break up time. A combination of hydrophilicty and wetting angle values can help to determine the requirement of wettability and hydrophilicity in the contact lens industry and also in practice. It can be concluded that no single test can fully describe the surface properties of contact lens surface materials, but it is proposed that information and results from a series of tests provides the most useful clinical description.

Anopheles gambiae s.l. species are reported as the most important vectors due to their ability to spread and exploit both temporary and man-made breeding sites. These factors combined with their capacity to transmit malaria, make them wide-open subject for researchers to find alternative different methods to control malaria disease. Historically, there were many attempts to limit or eradicate malaria disease by controlling the mosquitoes. The control methods varied between using insecticide-treated bed nets and indoor residual spraying, in addition to other methods that based on sterile insect technique (SIT) or genetic modification techniques. However, the success of any attempts to eliminate malaria depends on our understanding of the genetic diversity of the vectors in field. In this regard, two distinct sibling species Anopheles coluzzii and Anopheles gambiae s.s. were defined in An. gambiae complex based on single nucleotide polymorphisms intergenic spacer (IGS) near the centromere of the X chromosome. These species were found to mate assortatively even within mixed swarms. Moreover, genetic differences between them were limit to three regions that were 2L, 3L and X chromosome near the centromere regions. Several studies tried to explain the sympatric speciation process between the An. gambiae s.l. sibling species based on these islands of speciation and their role in assortative mating behaviour, but no full explanation was concluded so far. Therefore, two objectives were taken into consideration in this thesis. The first was genetic objective that aims to identify the islands of speciation that more likely responsible for assortative mating. The second was behavioural objective that aims to identify the mechanisms of assortative mating using recombinant and parental strains. These studies were important step for trying to explain the speciation process within An. gambiae s.l. species that in turn important for malaria control strategies.

No description available.