The prediction of adverse outcomes following major non-cardiac surgery is complex. Clinical variables and risk factors, functional status, electrocardiography and non-invasive cardiac investigations can all be used to assess and stratify the risk of post-operative cardiac morbidity or mortality. Multiple factors can be combined into bed-side scoring systems. Increasingly, cardiac biomarkers such as b-type natriuretic peptide (BNP) have been shown to predict heart failure and mortality in non-surgical populations. In the studies in this thesis, I have investigated the incidence of peri-operative cardiac morbidity and mortality in patients undergoing major non-cardiac surgery and identified clinical variables that predicted adverse outcomes. I have tested the utility of BNP for prediction of cardiac complications. I have investigated the long-term survival of the patients in the cohort to identify predictors of reduced survival. I have examined the predictive value of the pre-operative 12-lead ECG for adverse outcomes. I have also studied the utility of a commonly used risk scoring system, the revised cardiac risk index (RCRI), for prediction of cardiac events. The study was a prospectively performed observational study of consecutive patients undergoing major surgery. The cohort consisted of patients undergoing aortic surgery (25.8%), lower limb bypass surgery (29.8%), amputation (25.2%) and laparotomy (20.0%). The patients underwent post-operative screening for myocardial infarction; consisting of serial ECG and troponin measurement. The end-points were major adverse cardiac event (MACE), defined as myocardial infarction or cardiac death and all-cause mortality. Long term follow-up was performed following discharge. Three hundred and forty-five patients were recruited to the trial. Forty-six patients (13.3%) suffered a peri-operative MACE and twenty-seven patients (7.8%) died in the post-operative period (six weeks). Independent predictors of peri-operative MACE were pre-operative anaemia, urgent surgery, a history of hypertension and age > 70 years. Pre-operative BNP was significantly higher in patients who subsequently went on to have a peri-operative MACE, compared with those who did not. An elevated BNP was an independent predictor of both MACE and peri-operative mortality on multivariate analysis. A low BNP was highly indicative of an uneventful post-operative period, with a negative predictive value of 96% for MACE and 95% for all-cause mortality. Traditional clinical markers of heart disease, such as past history of ischaemic heart disease, prior myocardial infarction, cerebro-vascular disease or history of cardiac failure provided no predictive utility for either MACE or mortality. The mortality rate at 1 year was 19.1%. The median follow-up period was 953 days (IQR 661-1216 days). Age > 70 years, diabetes, hypertension, renal impairment, a history of left ventricular failure, anaemia and urgent surgery were associated with reduced long-term survival. A BNP concentration of 87.5 pg/ml provided the best combined sensitivity and specificity for prediction of long-term mortality. Patients with an elevated BNP (>87.5 pg/ml) had a significantly reduced survival and BNP >87.5 pg/ml independently predicted reduced survival on Cox regression analysis. Urgent surgery and anaemia were also independent predictors of reduced long-term survival. An abnormal ECG was observed in 41% of patients recruited. An abnormal ECG was associated with an increased peri-operative MACE and mortality rate. Ventricular strain and prolonged QTc (>440ms) were ECG abnormalities that predicted MACE on multivariate analysis. Patients with an abnormal ECG, but no prior cardiac history, represent a high risk group that may benefit from optimisation. The studies in this thesis have identified that BNP, a simple pre-operative blood test, provides valuable information regarding the risk of both peri-operative morbidity and mortality, and long-term survival after major non-cardiac surgery. Improved risk stratification could allow targeted intervention and medical optimisation prior to surgery with the aim of modifying the risk of adverse outcomes.

Bacterial biofilm infections cause significant morbidity in orthopaedic joint replacement. One of the most common bacteria in orthopaedic prosthetic infections is Staphylococcus aureus. Infection causes implant failure due to bacterial adherence and subsequent biofilm production. Nanotopography refers to the topography of a surface at the nanometre level and has major effects on cell behaviour. Studies suggest that surface nanotopography impacts the differential ability of staphylococci species to adhere, and may reduce orthopaedic implant infection rate. This research thesis focuses on bacterial adhesion on nanofabricated materials, and investigates the related metabolic changes and possible interventions. Staphylococcus aureus growth and quantification methods were optimised, with regard to growth media, incubation time and lysozyme incubation time. Both polystyrene and titanium (Ti) nanosurfaces were studied. Adhesion analysis was performed using fluorescence imaging, quantitative PCR, and bacterial percentage coverage. Metabolomic analysis was conducted by substitution with ‘heavy’ labelled glucose into growth medium, thus allowing for bacterial metabolomic analysis and identification of up-regulated, labelled metabolites and pathways. Bacterial growth was optimal using DMEM + supplement media, with adhesion occurring after 1hr bacterial incubation. Optimal lysozyme incubation for bacterial quantification using qPCR was 2hr. These parameters were used for all subsequent experimentation. Surface topography affects cell behaviour, bacterial adhesion and long term implant survival can be affected. This study found reduced bacterial adhesion on the SQ and HEX polystyrene patterns. While not found to be significant, this trend was supported by a lower average percentage bacterial coverage on both the SQ and HEX patterns (P=0.05 and P=0.01, respectively). It may be that the SQ and HEX nanopatterns are the optimal nanopit orientation required to prevent bacteria microcolony formation, keeping the bacteria in small, isolated clusters. In addition, this series of investigations showed an increase in bacterial concentrations on both the 2.5Hr and 3Hr treated Ti nanowire discs when compared to the polished Ti control disc, suggesting nanoroughness increases are associated with elevated bacterial adhesion. This theory was further supported by average percentage coverage, being significantly higher on the 2.5Hr and 3Hr treated discs. If, however, a disordered NC Ti nanopattern, hexagonal in nature, is used bacterial adhesion is significantly reduced when compared to a polished, control surface. The bacterial percentage coverage was also noted to be significantly lower on the NC surfaces, with over a 10-fold reduction when compared to the control surface. It is postulated that this reduction is through similar mechanisms to those described by Ivanova et al, and primarily related to altered surface interactions. Metabolomic analysis demonstrated increased intensity counts for key metabolites (pyruvate, aspartate, alanine and carbamoyl aspartate) involved in bacterial aggregation, proteoglycan and DNA synthesis. These pathways are also known to be important in bacterial biofilm production. Therapeutic targeting of these pathways was found to result in significantly reduced bacterial adhesion. This study shows that by altering nanotopography bacterial adhesion, and therefore, biofilm formation can be affected. Specific nanopatterned surfaces may reduce implant infection associated morbidity and mortality. The identification of metabolic pathways involved in adhesion allows for a targeted approach to biofilm eradication in S. aureus. This is of significant benefit to the patient, the surgeon and the NHS, and may well extend far beyond the realms of orthopaedics.

Congenital heart disease (CHD) is the most common birth defect, causing an important rate of morbidity and mortality. Treatment of CHD requires surgical correction in a significant percentage of cases which exposes patients to cardiac and end organ injury. Cardiac surgical procedures often require the utilisation of cardiopulmonary bypass (CPB), a system that replaces heart and lungs function by diverting circulation into an external circuit. The use of CPB can initiate potent inflammatory responses, in addition a proportion of procedures require a period of aortic cross clamp during which the heart is rendered ischaemic and is exposed to injury. High O2 concentrations are used during cardiac procedures and when circulation is re-established to the heart which had adjusted metabolically to ischaemia, further injury is caused in a process known as ischaemic reperfusion injury (IRI). Several strategies are in place in order to protect the heart during surgery, however injury is still caused, having detrimental effects in patients at short and long term. Remote ischaemic preconditioning (RIPC) is a technique proposed as a potential cardioprotective measure. It consists of exposing a remote tissue bed to brief episodes of ischaemia prior to surgery in order to activate protective pathways that would act during CPB, ischaemia and reperfusion. This study aimed to assess RIPC in paediatric patients requiring CHD surgical correction with a translational approach, integrating clinical outcome, marker analysis, cardiac function parameters and molecular mechanisms within the cardiac tissue. A prospective, single blinded, randomized, controlled trial was conducted applying a RIPC protocol to randomised patients through episodes of limb ischaemia on the day before surgery which was repeated right before the surgery started, after anaesthesia induction. Blood samples were obtained before surgery and at three post-operative time points from venous lines, additional pre and post-bypass blood samples were obtained from the right atrium. Myocardial tissue was resected during the ischaemic period of surgery. Echocardiographic images were obtained before the surgery started after anaesthetic induction and the day after surgery, images were stored for later off line analysis. PICU surveillance data was collected including ventilation parameters, inotrope use, standard laboratory analysis and six hourly blood gas analysis. Pre and post-operative quantitation of markers in blood specimens included cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), inflammatory mediators including interleukins IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α), and the adhesion molecules ICAM-1 and VCAM-1; the renal marker Cystatin C and the cardiovascular markers asymmetric dymethylarginine (ADMA) and symmetric dymethylarginine (SDMA). Nitric oxide (NO) metabolites and cyclic guanosine monophosphate (cGMP) were measured before and after bypass. Myocardial tissue was processed at baseline and after incubation at hyperoxic concentration during four hours in order to mimic surgical conditions. Expression of genes involved in IRI and RIPC pathways was analysed including heat shock proteins (HSPs), toll like receptors (TLRs), transcription factors nuclear factor κ-B (NF- κ-B) and hypoxia inducible factor 1 (HIF-1). The participation of hydrogen sulfide enzymatic genes, apelin and its receptor were explored. There was no significant difference according to group allocation in any of the echocardiographic parameters. There was a tendency for higher cTnI values and inotropic score in control patients post-operatively, however this was not statistically significant. BNP presented no significant difference according to group allocation. Inflammatory parameters tended to be higher in the control group, however only TNF- α was significantly higher. There was no difference in levels of Cystatin C, NO metabolites, cGMP, ADMA or SDMA. RIPC patients required shorter PICU stay, all other clinical and laboratory analysis presented no difference related to the intervention. Gene expression analysis revealed interesting patterns before and after incubation. HSP-60 presented a lower expression at baseline in tissue corresponding to RIPC patients, no other differences were found. This study provided with valuable descriptive information on previously known and newly explored parameters in the study population. Demographic characteristics and the presence of cyanosis before surgery influenced patterns of activity in several parameters, numerous indicators were linked to the degree of injury suffered by the myocardium. RIPC did not reduce markers of cardiac injury or improved echocardiographic parameters and it did not have an effect on end organ function; some effects were seen in inflammatory responses and gene expression analysis. Nevertheless, an important clinical outcome indicator, PICU length of stay was reduced suggesting benefit from the intervention. Larger studies with more statistical power could determine if the tendency of lower injury and inflammatory markers linked to RIPC is real. The present results mostly support findings of larger multicentre trials which have reported no cardiac benefit from RIPC in paediatric cardiac surgery.

Joint replacements are a common treatment of osteoarthritis, rheumatoid arthritis, or fractures of both the hip and knee. The rising number of procedures being performed each year means that there is a need to assess the performance of an implant design in the general population. The majority of computational studies assessing implants do not take into account inter-patient variability and only use a single patient model. More often than not, it is then assumed that the results can be extrapolated to the general population. This thesis describes a method allowing population-based assessment of joint replacements, focussing on the tibial tray component of a total knee replacement. To generate a large population of models for finite element analysis, two statistical models were used. One was of the tibia, capturing both the variability of the morphology and bone quality, and the other was of the internal knee loads during a gait cycle. Assessment of the statistical models showed that they could adequately generate representative tibiae and gait cycle loads. An automated method was then developed to size, position, and implant the tibial tray in the generated population of tibiae in preparation for finite element analysis. The use of a population-based study, a unique approach compared to current studies, was demonstrated using three case studies assessing the performance of the tibial tray. The first case study examined the factors which might increase the risk of failure of the tibial tray and the effect of under sizing the tibial tray on primary stability. Factors such as bone quality and patient weight were seen to increase the risk of failure. It was found that under sizing the tibial tray did not significantly affect the primary stability of the tibial tray. It was also observed that the peak strain occurred during swing phase of the gait cycle, whereas peak micromotion occurred at the beginning of stance phase of the gait. The second case study investigated the effect of tibia resection depth on primary stability of the tibial tray. A more distal resection was found to increase the peak strain and micromotion of the bone-tray interface. The worsening primary stability with a more distal resection, suggest that to obtain optimal primary stability of the tibial tray it is necessary to resect as little bone as possible. The third case study compared three tibial tray designs. It was ound that the trays with pegs or flanges surrounding the stem tended to perform better, reducing the strain and the micromotion at the bone-tray interface. It was noted that the performance of the trays predicted by the analysis was similar to that observed clinically. This shows the potential use of population-based studies to help predict the clinical outcome of joint replacements.

Observations are informatively censored when there is dependence between the time to the event of interest and time to censoring. When considering the time to death of patients on the waiting list for a transplant, particularly a liver transplant, patients that are removed for transplantation are potentially informatively censored, as generally the most ill patients are transplanted. If this censoring is assumed to be non-informative then any inferences may be misleading. The existing methods in the literature that account for informative censoring are applied to data to assess their suitability for the liver transplantation setting. As the amount of dependence between the time to failure and time to censoring variables cannot be identied from the observed data, estimators that give bounds on the marginal survival function for a given range of dependence values are considered. However, the bounds are too wide to be of use in practice. Sensitivity analyses are also reviewed as these allow us to assess how inferences are affected by assuming differing amounts of dependence and whether methods that account for informative censoring are necessary. Of the other methods considered IPCW estimators were found to be the most useful in practice. Sensitivity analyses for parametric models are less computationally intensive than those for Cox models, although they are not suitable for all sets of data. Therefore, we develop a sensitivity analysis for piecewise exponential models that is still quick to apply. These models are exible enough to be suitable for a wide range of baseline hazards. The sensitivity analysis suggests that for the liver transplantation setting the inferences about time to failure are sensitive to informative censoring. A simulation study is carried out that shows that the sensitivity analysis is accurate in many situations, although not when there is a large proportion of censoring in the data set. Finally, a method to calculate the survival benefit of liver transplantation is adapted to make it more suitable for UK data. This method calculates the expected change in post-transplant mortality relative to waiting list mortality. It uses IPCW methods to account for the informative censoring encountered when estimating waiting list mortality to ensure the estimated survival benefit is as accurate as possible.

This thesis explores the appropriateness of suitably trained children's nurses undertaking the pre-operative assessment of children prior to day case and minor surgery. The central focus of the study is a 60 subject hypothesis refining randomised controlled trial (RCT), comparing the pre-operative assessment of children carried out by suitably trained nurses with the assessment carried out by senior house officers (SHO's). Findings demonstrate significantly greater accuracy by nurses in the detection of abnormalities in children's history, when compared with the SHO's. No significant difference is demonstrated between the performance of nurses and SHO's in detecting abnormalities within the physical examination, or in the correct identification of children who have no detectable abnormalities. However, these findings of 'no significant difference' must be substantiated within a larger equivalence trial before assurances can be given that paediatric pre-operative assessment might safely be transferred from SHO's to nurses. Supplementary data explores the perspectives of parents and practitioners with regard to children's nurses undertaking a pre-operative assessment role. The views of parents, gathered via questionnaires, are supportive of the initiative. The views of nurses and SHO's involved in the RCT are similarly supportive, although the conduct of in-depth interviews with the nurses also reveals insights into their perceived vulnerability when carrying out such expanded roles. The views of anaesthetists are less positive, and convey a reluctance to accept nurses carrying out the pre-operative assessment of children. Finally, a national survey explores the views of nurses and SHO's involved in paediatric pre-operative assessment, revealing that nurses attribute significantly greater importance and enjoyment to the pre-operative assessment role when compared with SHO's. This factor may in part explain the greater accuracy demonstrated by nurses in the RCT, but such speculation must be substantiated by further enquiry. This study contributes to the nursing literature in offering what is thought to be the first systematic UK exploration of the role of the paediatric nurse within pre-operative assessment. It is also the first study, as far as the author is aware, to demonstrate significantly greater accuracy in history taking by nurses when compared with doctors, in a paediatric specific UK study. It therefore makes a meaningful contribution to both the paediatric and expanded role evidence bases. It also offers systematically informed hypothesis generation to underpin the ongoing exploration of an expanded nursing role within paediatric pre-operative assessment.

Neurological rehabilitation technologies such as Robot Therapy (RT) and noninvasive brain stimulation (NIBS) can promote motor recovery after stroke. The novelty of this research was to explore the feasibility and the effect of the combination method of NIBS called transcranial Direct Current Stimulation (tDCS) with uni-lateral and three-dimensional RT for the impaired upper limb (UL) in people with sub-acute and chronic stroke. This thesis involved three studies: (a) systematic review with meta-analyses (b) a pilot double-blinded randomised controlled trial with a feasibility component and (c) a reliability study of the measurement of Motor Evoked Potential (MEP) response using Transcranial Magnetic Stimulation in healthy adults. The first study involved a review of seven papers exploring the combination of tDCS with rehabilitation programmes for the UL in stroke. For the second study, stroke participants underwent 18 x one hour sessions of RT (Armeo®) over eight weeks during which they received 20 minutes real tDCS or sham tDCS. Outcome measures were applied at baseline, post-intervention and at three-month follow-up. The qualitative component explored the views and experiences of the participants of RT and NIBS using semi-structured interviews. The third study involved age-matched healthy adults exploring intrarater and test-retest reliability of the TMS assessment. Results of the three studies were the following: Seven papers were reviewed and a small effect size was found favouring real tDCS and rehabilitation programmes for the UL in stroke. 22 participants (12 sub-acute and 10 chronic) completed the pilot RCT. Participants adhered well to the treatment. One participant dropped out of the trial due to painful sensations and skin problems. The sub-acute and chronic groups showed a clinically significant improvement of 15.5% and 8.8% respectively in UL impairments at post-intervention from baseline. There was no difference in the effects of sham and anodal tDCS on UL impairments. Participants found the treatment beneficial and gave suggestions how to improve future research. In summary, the TMS assessment showed excellent reliability for measurement of resting motor threshold but poor to moderate reliability for MEP amplitude. In conclusion, it was indicated that RT may be of benefit in sub-acute and chronic stroke however, adding tDCS may not result in an additive effect on UL impairments and dexterity. The present study provided a power calculation for a larger RCT to be carried out in the future.

No description available.

Considerable progress has been made in understanding implant wear and developing numerical models to predict certain aspects of wear for new orthopaedic devices. However, any model of wear could be improved through a more accurate representation of the biomaterial micromechanics, including time-varying dynamic and inelastic behaviour such as viscous and plastic deformation as well as any history-dependent evolution of its microstructural properties. Under in-vivo conditions, the contact surface of the UHMWPE tibial insert evolves as a result of applied loads and complex multidirectional motions of the femoral component against it. Overt time, severe inelastic deformations and damage mechanisms occur and ultimately lead to wear. This process is accompanied by the release of UHMWPE debris in the surrounding tissues with the direct consequences of triggering an in ammatory response that leads to osteolysis and subsequently periprosthetic implant loosening. In that case a revision surgery is required. Motivated by these facts, the current research effort has been motivated by the need to gain a mechanistic insight into the micromechanical mechanisms associated with wear of UHMWPE in knee arthroplasty. To this end, two main lines of focus have been followed in this work. One line of focus concerns the inelastic mechanisms of deformation such as creep and plasticity since they are critical in altering the contact properties of the articulating surface of UHMWPE components, leading to damage and formation of wear debris. Therefore, the relative contributions of elastic, creep, and plastic deformations on the contact area, and so contact pressure has been investigated through different numerical techniques. Additionally, contact pressure is a critical input parameter of computational wear algorithms, and it is therefore essential to establish the nature of and quantify the interplay between contact pressure, contact area, creep and plastic deformations. What are the consequences of neglecting creep deformations on wear predictions? A first approach to investigate these aspects consisted in conducting a series of physicallybased finite element analyses replicating the mechanical characteristics and operating conditions of an AMTI Knee Simulator. Experimental creep testing on a unicondylar knee replacement system in a physiologically representative context was simulated. In both studies, linear elastic, plastic and time-varying visco-dynamic properties of computational models were benchmarked using literature data to predict contact deformations, pressures and areas. Results indicate that creep deformations have a significant effect on both experimental and simulated contact pressures at the surface of the UHMWPE tibial insert. The use of a purely elastoplastic constitutive model for UHMWPE lead to compressive deformations of the insert which were in general smaller than those predicted by a creep-capturing viscoelastic model. At high compressive loads, inelastic deformation mechanisms dominate the mechanical response of UHMWPE components by altering the surface geometry (i.e. contact area), and therefore the contact pressure. The second line of focus concerns the study of the role of transient and permanent polymer chain realignment during multidirectional sliding, and its potential correlation to wear. The main working hypothesis is that the evolution of the UHMWPE microstructure during multidirectional pin-on-disk (POD) tests can provide information on possible correlations between wear, sliding track characteristics and the mechanics of UHMWPE. Therefore, finite element-based POD tests were used to investigate the effects of motion paths in simulated multidirectional sliding motions on metrics related to the mechanical response of UHMWPE, with particular attention to evolution of molecular chain realignment. For this purpose, the concept of anticoaxiality as a measure of molecular chain realignment (or anisotropy) has been introduced. The concept of anticoaxiality as a measure of molecular chain realignment (or anisotropy) was introduced to quantify the deviation from mechanical isotropy of UHMWPE microstructure. Results from these metrics support the hypothesis that multidirectional sliding as well as long sliding distances produced microstructural changes in UHMWPE, resulting in an enhanced likelihood of material damage, and so wear.

Hip fracture is one of the most common, serious injuries in old people in England, and with a growing older population it is increasingly important to understand the impact of hip fracture from the patient perspective in order to develop relevant and appropriate healthcare services. The aim of this study was to explore the lived experience of hip fracture in older people in England to inform service development. A scoping review of the literature highlighted the lack of current evidence for hip fracture experience in England, with a particular dearth of evidence concerning the lived experience of hip fracture following discharge from hospital. However, the reviewed highlighted some international evidence around the lived experience of hip fracture while in hospital, and during initial rehabilitation. A meta-synthesis of the data was therefore conducted providing a more interpretive approach to analysing this data, and establishing a better understanding of the current literature on hip fracture patient experiences. The gaps in the evidence reported in the current evidence base provided a rationale for a qualitative study. Hip fracture patients were interviewed at their place of residence 12 to 16 weeks after surgery. Interpretative phenomenological analysis methodology was used for 24 interviews, and patient and public involvement was integral to the study. The study reported the impact on self, and the role of biographical disruption in triggering feelings of incompetency and frustration, particularly in those who had been relatively active prior to hip fracture. Participants perceived that others labelled them as ‘old’ and ‘disabled’ as they became less mobile and more dependent on those around them. Macro health care policies limited individualised care practices, and a greater emphasis is needed on discharge planning and continuity of care after discharge home. The study also reported the need for improved information provision and verbal communication throughout the care trajectory, and a key worker to co-ordinate their care to provide realistic expectations, reassurance and support throughout the recovery period is recommended. A model of continuity of care is presented to provide insight for the development of patient centred health care for this population.