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This thesis contributes to the ongoing debate on the conduct of monetary and fiscal policies near the lower bound on the policy rate. Chapter 1 studies optimal monetary policy in a model with portfolio adjustment costs. Central bank purchases of long-term debt (quantitative easing; 'QE') influence the average portfolio return and hence aggregate demand and inflation. It is optimal to adopt QE rapidly with large scale asset purchases triggered when the policy rate hits the lower bound, consistent with observed policy responses to the Global Financial Crisis. Optimal exit is gradual. Chapter 2 examines the effects of money-financed fiscal transfers at the lower bound. It is assumed that money may earn interest so that money-financed transfers at the lower bound are feasible, while the short-term policy rate is used to stabilize the economy in normal times. A simple financial friction generates a wealth effect on household spending from government liabilities. This encourages households to spend rather than save a transfer from the government. While temporary money-financed transfers to households can stimulate spending and inflation at the lower bound, similar effects could be achieved by bond-financed tax cuts. Chapter 3 explores optimal monetary policy in a model with long-term government debt and 'active' fiscal policy. This means that stabilization of government debt is a binding constraint on monetary policy. Away from the lower bound, policy cannot fully offset the effects of shocks to the natural rate of interest, reducing welfare. At the lower bound, recessionary shocks increase debt and generate the anticipation that in inflation will be higher in future, to stabilize the real value of debt. This mechanism mitigates the effects of recessionary shocks. For sufficiently long debt duration, improved performance at the lower bound may outweigh welfare losses in normal times.

Chronic pain is a multi-faceted condition comprising of pathological, psychological and biological influences. This poses a significant problem to accurate assessment and treatment, with symptomology commonly not matching pathology. It is also unclear why some individuals develop chronic pain, while others appear resilient. Identifying individual differences in pain processing and modulation may be one method to help identify individuals who are susceptible to pain. Consequently, this thesis examined pain, its assessment and management in a clinical setting and individual differences in pain response in a laboratory setting. Study one evaluated pain ratings from hysteroscopy patients, to understand the prevalence of pain. Clinician estimates of pain were used to examine the accuracy of clinical pain assessment and how this related to pain management. Despite being considered a minimally-painful procedure, we found that patients’ pain ratings varied substantially, and were inversely correlated with clinician estimates. Our results indicate that hysteroscopy should not be advertised as a minimally-painful procedure. Advancing pre-surgical assessments to predict individuals at risk of developing pain could have important clinical implications. Individual differences in pain behaviour and response were examined in studies two and three, using resting-state connectivity in healthy controls. Study 2 investigated dispositional mindfulness, alongside sensory and cognitive pain variables. Trait mindfulness was associated with beneficial pain responses. Mindfulness was also associated with higher functional connectivity to the somatosensory cortex, and lower connectivity to the prefrontal cortex, with a precuneus seed. Our results may suggest that trait mindfulness is associated with increased sensory, present-moment focus, facilitating more effective pain management. Study 3 investigated Conditioned Pain Modulation (CPM), which quantifies the efficiency of descending modulation circuitry. Our results indicate that high CPM is associated with increased connectivity between pain modulatory and processing regions. Taken together, this research suggests that clinical assessments may benefit from psychometrics quantifying individual differences in their intrinsic ability to manage pain, to detect patients vulnerable to pain.

Stem cells may offer solutions for many health issues facing the world’s population. Early Biotech-led approaches are supporting novel mesenchymal stem cell (MSC) therapies through biomedical trials. However, their potential benefits are currently curtailed by challenges linked to high cell dose requirements which pose availability and manufacturing challenges, combined to suboptimal delivery methodologies. Whilst systemic delivery may be suitable for many pharmaceuticals, more complex and selective treatments such as emerging cell therapies require smarter targeting strategies on safety and cost/benefit grounds. Several groups are developing targeting strategies to guide stem cells to specific locations and hold them in situ whilst performing a repair. The targeting approach presented here uses superparamagnetic iron oxide microparticles (MPs) loaded within stem cells to facilitate control of the cells using magnets. Magnetic resonance imaging (MRI) can be used to monitor the loaded cells’ contribution to the repair process. Questions remain around MP safety and effects on both delivered cell therapies and the receiving patient. Presented data demonstrates labelling of MSC populations with a commercially available MP called SiMAG in two sizes (500 nm and 1000 nm). Particles were assessed for characteristics which influence their suitability for labelling and were found to have a non-uniform variable structure and size. Labelling was found to be both rapid and effective with low 10 µg/Fe/mL labelling doses able to distinguish cell populations by flow cytometry. Super-resolution microscopy, fluorescent microscopy and transmission electron microscopy were used to determine the location of particles within the cell and were noted to accumulate around the nucleus in large vesicles. Uptake into the cell was found to be influenced by serum with 10% serum resulting in a 75% drop in relative uptake over a 24 hour period. Potential sharing of MP between MSCs was investigated both qualitatively with fluorescent microscopy and quantitatively in a MSC co-culture experiment. No statistically significant sharing of MPs between MSCs could be seen to be taking place between populations. The fate of MPs within MSCs was investigated using pH nanosensors to interrogate the internal cell pH. A novel flow cytometry assay using pH nanosensors and MPs was used to examine the internal pH of large populations of cells. This yielded results which suggest a pH decrease over 4 days from pH 5.5 to 4.7 followed an increase to 5.4 by day 6. This effect is suggested to be caused by a complex pH mediated degradation of MPs followed by increase in pH due to the degraded iron overloading the cell. This degradation was carried out in simulated lysosomal conditions and found to act in a similar way. Macrophages were also used to test degradation and again they were found to reduce the fluorecense of the MPs rapidly over 7 days. The ability of MSCs to tolerate MPs without impacting cell health was probed with a range of assays. The metabolic assay Presto blue demonstrated doses of 10 µg/Fe/mL did not impact the metabolic status of the cell. This was tested with other potential surface chemistries of the same particle design and these were also found to be well tolerated. Membrane intergrity was assessed with flow cytometry for both 500 and 1000 nm SiMAG and was found to have no damaging effects present at 10 µg/Fe/mL. SiMAG 1000 nm was found to have no membrane compromising effect all the way up to 100 µg/Fe/mL. Cell identity was assessed with common MSC markers established by the Dominici position paper and no change to expression was found to occur even with repeated, high dose long-term (14 day) labelling strategies. As particles accumulate round the nucleus, deleterious effects of MP on DNA were tested using the comet assay and visual inspection with no statistically significant increase up to the maximum tested of 100 µg/Fe/mL. Similarly, no effect on cell cycle status was noticed for populations of MSCs. The retention of cell “function” was tested not only following labelling, but following hypothermic storage of cells to simulate shipping to a clinical setting. This was carried out for a range of clinically relevant cell types including mesenchymal stem cells (MSCs), cardiomyocytes (CaM) and ReNeuron neural stem cells (ReN). MSCs were found to freely differentiate to tri-lineage osteogenic, chondrogenic and adipogenic lineages. CXCR4 expression was measured as a marker of MSCs ability to home in on damage and was found to be raised in response to MP presence. CaM were found to resume beating both after hypothermic storage, as well as at high (1000 µg/Fe/mL SiMAG doses). ReN cells were found to be more sensitive to SiMAG with only 10 µg/Fe/mL doses tolerated although successful neural differentiation was still possible. The ability to culture MSCs and label them in a scalable manufacturing scenario was also examined and found to be possible. SiMAG was demonstrated to be a suitable labelling agent both for imaging as well as magnetic manipulation. Precise magnetic manipulation of labelled cells was demonstrated both as an individual cell and as a cell population moving through a simulated tissue gel. Entrapment of labelled cells from a simulated circulatory system was also shown to be possible with close to 100% of cells recruited in the first pass. The fluorophores on SiMAG were not strong enough to be visualised on their own and quantum dots were used to demonstrate successful retention of labelled MSCs in an ex vivo rat model. MRI was however shown to be a suitable method for assessing the location of labelled cell populations at even low cell concentrations ~1x106 and low SiMAG doses of 5 µf/Fe/mL. In conclusion, this study indicates that MPs represent a cell-safe and effective potential tool to better target cells. The key benefit of this cell labelling technology is in the high degree of understanding over the entire labelling process from entry through to degradation. In addition, this labelling technology has been shown to be cell-safe in a large number of cells both for physical health and basic function. Whilst this should be further explored for further, more specific applications, it makes a compelling case for SiMAG as a multi-functional tool for cell manipulation and tracking.

This thesis examines the response of British urban planners to the rise of private motoring in the 1950s, 1960s and 1970s. The examination begins with an exploration of important planning documents and events of the 1950s and 1960s, relating to the issue of rising car ownership. It is followed by an exploration of the response of urban planners to rising car ownership in Leicester and Milton Keynes. This research covers an important stage in the rise of car culture in Britain and an important stage in the evolution of urban planning. From 1950 to 1960, the number of cars on Britain’s roads rose nearly two-and-a-half times to 5.5 million, which was seen as the beginning of mass car ownership. Although this prospect was often welcomed as a sign of affluence, it was also deemed to require a robust response from physical planners to prevent widespread traffic congestion and environmental nuisance. In this thesis I make four arguments. I argue, firstly, that it was in the 1950s and 1960s that a durable framework for approaching questions of urban transport in a motorised Britain was first worked out. Secondly, the prospect of motorisation posed fresh questions about the type of urban society that planning should be employed to support. The planners elected to encourage automobility and consumerism, but were also obliged to give more recognition to the importance of building conservation, urban environmental quality, and public transport. Thirdly, urban planners were directed by a powerful set of economic and social forces to plan in the car’s favour. Fourthly and finally, I argue that the decision to accommodate motorisation helped to provoke a backlash against sweeping redevelopment and top-down planning that altered planners’ relationship with the public, giving rise to a greater appreciation for the value of the existing urban fabric.