Development of upright, multimodal, respiratory MRI

Respiratory diseases can have a severe impact on people's quality of life and life expectancy. To investigate these diseases, CT and spirometry are the current "gold standards" used by clinicians. In tandem, CT and spirometry, offer high resolution images and lung function information. However, CT exposes the patient to ionising radiation, making multiple investigations undesirable. The results of pulmonary function tests, such as spirometry, are also variable and depend on the effort levels of the patient. In addition, the information provided from most pulmonary function tests is a global measure; abnormal values may only occur when a large region of the lung is affected. These issues mean that, using current measures, it can be difficult to diagnose respiratory diseases and track their progression to see if a particular treatment is being effective. In tissues other than the lungs, proton MRI can offer highly detailed structural, as well as functional information. However, proton MRI is difficult to perform in the lungs due to their low proton density. In order to maximise the information obtainable from respiratory MRI, other techniques need to be employed . Implementing hyperpolarised xenon-129 MRI, fluorine MRI and proton diaphragm imaging are the major focuses of this thesis. The other problem with most conventional MRI for respiratory imaging is that it is performed supine. Lung function is reduced when supine, as opposed to seated or standing. This causes two problems. Firstly, patients with severe lung disease may struggle to lie down for extended periods of time; arguably these are the people who it is most useful to scan. Secondly, most people spend the majority of their lives upright, therefore images acquired upright should be of greater relevance for clinicians. At Nottingham, the 0.5T Paramed MROpen Upright scanner is the first of its kind to offer proton and multinuclear imaging. This scanner allows for imaging in a variety of orientations. The open design of the scanner also makes it particularly suited to paediatric imaging. Children as young as three have sat comfortably inside the scanner, on a parent or guardian's lap, without need for sedation. In this thesis, the optimum conditions for polarising xenon-129 in a batch mode system are investigated. Higher rates of polarisation build-up were observed at higher temperatures. Vastly higher temperatures were also observed inside the cell (particularly in the first few cm after the laser strikes the cell), than the oven during runaway. Higher polarisations of xenon-129 were found in gas mixes with lower concentrations of xenon-129 (leaner mixes). However, the largest bulk magnetisation was found with a balance of xenon-129 and nitrogen. For a given Rb vapour density replacing nitrogen with helium-4 appeared to have little effect on the polarisation build-up rate of xenon-129. The polarisation build-up rate was also seen to be highly variable in a cell with a bead of Rb, using the same external conditions. After "spreading" the Rb bead, by vaporising it and forcing it to condense on the walls of the cell, the build-up rate became more consistent. Before the Paramed MRI scanner was built, hyperpolarised xenon-129 imaging at Nottingham was performed using a 1.5T GE scanner. The original Rapid birdcage xenon-129 coil, was not fit for purpose; larger volunteers couldn't be imaged. The testing of a new coil from Clinical MR Solutions L.L.C. is detailed; with the aim of investigating if it was fit for use. In QTAR mode, an inconsistent signal was seen throughout the lungs, making it unsuitable. In QUAD T/R mode, initial tests were encouraging. On the Paramed, a sequence has been developed to image a single slice in <0.5s. This allows for the movement of the diaphragm to be characterised throughout the breathing cycle and to track repeating lung density changes. In addition, a stock Paramed sequence was altered so the duration of the scan was reduced from an average of 35s to 21s; the acquired resolution was maintained at 160x128x7. This meant the sequence could be acquired within a breath hold; allowing the diaphragm morphology at full expiration and inspiration to be characterised. Compressed sensing has also been implemented on the upright. A sequence has been developed, at a resolution of 256x200x22 and undersampling by a factor of 3, to acquire an image in 22.6s. By undersampling a resolution of 256x160x10 by a factor of 4.82 an image can be acquired in 5.1s. With both, the diaphragm can be accurately characterised. The shorter duration sequence is tailored for patients with more severe lung disease, who can't hold their breath for as long. The intention is to apply compressed sensing to hyperpolarised imaging in the future. Using a small surface xenon-129 test coil on the Paramed scanner, a 3D GRE sequence has been developed, which can resolve detail of <3mm in <20s. Also using xenon-129 a flip angle calibration and dissolved phase spectroscopy have been performed. A calibration for an SAR monitoring system has been produced, to allow for in vivo imaging using the test coil once the system has been built. Proton on a hydrofluorocarbon gas has also been imaged, illustrating it should be possible to image fluorine using the Paramed. MRI has excellent potential to be used clinically to diagnose and track the progression of respiratory disease. By imaging in an upright orientation, fewer patients will be excluded from being scanned using the techniques developed and the images should be of greater diagnostic use for clinicians. By using techniques such as hyperpolarisation, the lower field strength of the upright scanner than a conventional scanner can be counteracted

Modelling spatiotemporal dynamics of cerebral blood flow using multiple-timepoint arterial spin labelling MRI

Introduction: Cerebral blood flow (CBF) is an important physiological parameter that can be quantified non-invasively using arterial spin labelling (ASL) imaging. Although most ASL studies are based on single-timepoint strategies, multi-timepoint approaches (multiple-PLD) in combination with appropriate model fitting strategies may be beneficial not only to improve CBF quantification but also to retrieve other physiological information of interest. Methods: In this work, we tested several kinetic models for the fitting of multiple-PLD pCASL data in a group of 10 healthy subjects. In particular, we extended the standard kinetic model by incorporating dispersion effects and the macrovascular contribution and assessed their individual and combined effect on CBF quantification. These assessments were performed using two pseudo-continuous ASL (pCASL) datasets acquired in the same subjects but during two conditions mimicking different CBF dynamics: normocapnia and hypercapnia (achieved through a CO2 stimulus). Results: All kinetic models quantified and highlighted the different CBF spatiotemporal dynamics between the two conditions. Hypercapnia led to an increase in CBF whilst decreasing arterial transit time (ATT) and arterial blood volume (aBV). When comparing the different kinetic models, the incorporation of dispersion effects yielded a significant decrease in CBF (∼10–22%) and ATT (∼17–26%), whilst aBV (∼44–74%) increased, and this was observed in both conditions. The extended model that includes dispersion effects and the macrovascular component has been shown to provide the best fit to both datasets. Conclusion: Our results support the use of extended models that include the macrovascular component and dispersion effects when modelling multiple-PLD pCASL data

Evaluations of land cover risk factors for canine leptospirosis: 94 cases (2002–2009)

Associations of land cover/land use variables and the presence of dogs in urban vs. rural address locations were evaluated retrospectively as potential risk factors for canine leptospirosis in Kansas and Nebraska using Geographic Information Systems (GIS). The sample included 94 dogs positive for leptospirosis predominantly based on a positive polymerase chain reaction test for leptospires in urine, isolation of leptospires on urine culture, a single reciprocal serum titer of 12,800 or greater, or a four-fold rise in reciprocal serum titers over a 2–4 weeks period; and 185 dogs negative for leptospirosis based on a negative polymerase chain reaction test and reciprocal serum titers less than 400. Land cover features from 2001 National Land Cover Dataset and 2001 Kansas Gap Analysis Program datasets around geocoded addresses of case/control locations were extracted using 2500 m buffers, and the presence of dogs’ address locations within urban vs. rural areas were estimated in GIS. Multivariate logistic models were used to determine the risk of different land cover variables and address locations to dogs. Medium intensity urban areas (OR = 1.805, 95% C.I. = 1.396, 2.334), urban areas in general (OR = 2.021, 95% C.I. = 1.360, 3.003), and having urban address locations (OR = 3.732, 95% C.I. = 1.935, 7.196 entire study region), were significant risk factors for canine leptospirosis. Dogs regardless of age, sex and breed that live in urban areas are at higher risk of leptospirosis and vaccination should be considered

The 'Short Course Oncology Treatment' (SCOT) trial

6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment. Methods: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862

Rapid cerebrovascular reactivity mapping: Enabling vascular reactivity information to be routinely acquired

Cerebrovascular reactivity mapping (CVR), using magnetic resonance imaging (MRI) and carbon dioxide as a stimulus, provides useful information on how cerebral blood vessels react under stress. This information has proven to be useful in the study of vascular disorders, dementia and healthy ageing. However, clinical adoption of this form of CVR mapping has been hindered by relatively long scan durations of 7–12 min. By replacing the conventional block presentation of carbon dioxide enriched air with a sinusoidally modulated stimulus, the aim of this study was to investigate whether more clinically acceptable scan durations are possible. Firstly, the conventional block protocol was compared with a sinusoidal protocol of the same duration of 7 min. Estimates of the magnitude of the CVR signal (CVR magnitude) were found to be in good agreement between the stimulus protocols, but estimates of the relative timing of the CVR response (CVR phase) were not. Secondly, data from the sinusoidal protocol was reanalysed using decreasing amounts of data in the range 1–6 min. The CVR magnitude was found to tolerate this reduction in scan duration better than CVR phase. However, these analyses indicate that scan durations in the range of 3–5 min produce robust data

Modelling spatiotemporal dynamics of cerebral blood flow using multiple-timepoint arterial spin labelling MRI

Introduction: Cerebral blood flow (CBF) is an important physiological parameter that can be quantified non-invasively using arterial spin labelling (ASL) imaging. Although most ASL studies are based on single-timepoint strategies, multi-timepoint approaches (multiple-PLD) in combination with appropriate model fitting strategies may be beneficial not only to improve CBF quantification but also to retrieve other physiological information of interest. Methods: In this work, we tested several kinetic models for the fitting of multiple-PLD pCASL data in a group of 10 healthy subjects. In particular, we extended the standard kinetic model by incorporating dispersion effects and the macrovascular contribution and assessed their individual and combined effect on CBF quantification. These assessments were performed using two pseudo-continuous ASL (pCASL) datasets acquired in the same subjects but during two conditions mimicking different CBF dynamics: normocapnia and hypercapnia (achieved through a CO2 stimulus). Results: All kinetic models quantified and highlighted the different CBF spatiotemporal dynamics between the two conditions. Hypercapnia led to an increase in CBF whilst decreasing arterial transit time (ATT) and arterial blood volume (aBV). When comparing the different kinetic models, the incorporation of dispersion effects yielded a significant decrease in CBF (∼10–22%) and ATT (∼17–26%), whilst aBV (∼44–74%) increased, and this was observed in both conditions. The extended model that includes dispersion effects and the macrovascular component has been shown to provide the best fit to both datasets. Conclusion: Our results support the use of extended models that include the macrovascular component and dispersion effects when modelling multiple-PLD pCASL data

Cricket, migration and diasporic communities

Ever since different communities began processes of global migration, sport has been an integral feature in how we conceptualise and experience the notion of being part of a diaspora. Sport provides diasporic communities with a powerful means for creating transnational ties, but also shapes ideas of their ethnic and racial identities. In spite of this, theories of diaspora have been applied sparingly to sporting discourses. Due mainly to its central role in spreading dominant white racial narratives within the British Empire, and the various ways different ethnic groups have ‘played’ with the meanings and associations of the sport in the (post-)colonial period, cricket is an interesting focus for academic research. Despite W.G. Grace’s claim that cricket advances civilisation by promoting a common bond, binding together peoples of vastly different backgrounds, to this day cricket operates strict symbolic boundaries; defining those who do, and equally, do not belong. C.L.R. James’ now famous metaphor of looking ‘beyond the boundary’ captures the belief that, to fully understand the significance of cricket, and the sport’s roles in changing and shaping society, one must consider the wider social and political contexts within which the game is played. The collection of papers in this special issue does just that. Cricket acts as the point of departure in each, but the way in which ideas of power, representation and inequality are ‘played out’ is unique in each