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The role of hypoxia in idiopathic pulmonary fibrosis
Get PDFIdiopathic pulmonary fibrosis (IPF) is a devastating condition of unknown cause that results in progressive, irreversible scarring of the lung. Resultant lung function decline is currently poorly controlled by antifibrotic therapies. The mechanisms driving pathology remain poorly understood. Current evidence suggests that repetitive epithelial injury, in genetically susceptible individuals, escalates to an aberrant wound healing response. Positive feedback potentiates fibroblast ECM secretion. Lung resident macrophages are implicated as the link between injury and fibroblast activation, as key orchestrators of normal wound healing.
Various genetic and environmental factors likely contribute to disease progression. Evidence indicates that some patients’ lung tissue contains areas of hypoxia. Nocturnal hypoxemia correlates with worse outcomes in IPF patients, suggesting a pathological role for hypoxia in IPF. Accordingly, hypoxia drives fibrotic changes in human stromal cells in vitro.
This thesis hypothesises that hypoxia can cause and/or potentiate profibrotic effects in the IPF lung, altering alveolar macrophage (AM) phenotype and function and causing multi-cellular effects in precision cut lung slices (PCLS). This hypothesis is assessed in using cells and PCLS derived from human lung tissue.
A 48-hour 1% oxygen hypoxic exposure was validated in AMs, to assess phenotypic and functional effects. After demonstrating HIF1α induced transcriptional responses, key mediators implicated in AM contribution to fibrosis were assessed, detecting increased matrix metalloproteinase (MMP)-7 secretion and a trend towards increased MMP-1 secretion. Additionally, hypoxia impaired AM efferocytosis of apoptotic neutrophils, but not phagocytosis of heat-killed Streptococcus pneumoniae. No changes in pro-efferocytic (CD163 and CD260) or anti-efferocytic (SIRPα) receptor levels corresponded to this difference.
As efferocytosis introduces more complex cargo than phagocytosis, differences in metabolic demand were a possible distinguishing factor. The role of HIF1α was assessed, given its role in glycolytic shift in hypoxia. Artificial HIF1α stabilisation did not alter efferocytosis, however trends indicate it increased phagocytosis. This distinction suggests that HIF1α activation has distinct effects on the two processes. Further work is required to delineate this difference.
AMs underutilise glycolysis due to adaptation to the lung environment. Therefore, glycolysis was assessed by measuring lactate release in hypoxia with and without lipopolysaccharide (LPS) stimulation. Lactate secretion was increased in hypoxia, although LPS and hypoxia did not have additive effects. This preliminary data on AM glycolytic capacity in hypoxia provides the rationale for real-time analysis of AM metabolism in hypoxia and during efferocytosis.
A 48-hour 1% oxygen challenge was also validated in PCLS, to assess whether profibrotic effects extended beyond effects on human monocultures. HIF1α signalling was again activated and fibrotic markers collagen I and α smooth muscle actin were assessed. Although no changes could be detected at the RNA level, collagen I protein was increased by hypoxia after 48 hours. There was no additive effect of a previously published profibrotic cocktail on changes induced by hypoxia. Future work should explore these findings using spatial techniques to discern cellular contributions.
Overall, this data shows that AMs may contribute to the profibrotic effects of hypoxia, as hypoxia causes increased release of damaging MMP enzymes and reduces efferocytic capacity. Additionally, a human PCLS model supports previous literature describing increased collagen secretion in hypoxia
Topologically close-packed phase development during solution heat treatment of rhenium containing single crystal nickel-based superalloys
Get PDFSuperalloys, aptly named for their high-temperature performance, are at the forefront of materials technology for applications such as turbine blades in jet engines for both power and propulsion. Their complex chemistry, comprising often over a dozen elements, unique production methods, such as single-crystal casting, on top of their manufacturing complexity, with preformed cooling channels and coatings enable these materials to function in extreme circumstances.
However, their ever-growing complexity creates equally complex problems that are ever more unique to the alloys and harder to separate from all the different processes involved in the manufacture and operation.
Of these, topologically close-packed phases, or TCP phases, stand out as they are poorly understood in both why and how they form. It is known they are typically enriched in refractory elements, the same elements that provide the alloy with its superior high-temperature properties. However, the growing complexity of these alloys now see TCP phases occurring not just in-service conditions, but during manufacturing, in the as-cast state, heat-treatments and the focus of this work; the solution heat-treatment stage. The occurrence of these phases during solutioning is particularly problematic, as this stage is intentionally included to homogenise the alloy into a single phase, not introduce additional detrimental phases in a heterogeneous manner.
This work seeks to review past work on the study of nickel-based superalloys, in particular high refractory content alloys prone to TCP phase precipitation. As well as other works carried out to understand the occurrence of TCP phases. Through the casting of single-crystal alloys containing varying levels of Re; CMSX4, CMSX10K and CMSX10N, where Re is an element strongly associated with TCP phase precipitation, experiments
are carried out on the standard solutioning regime of these alloys to better understand the microstructural evolution during the solutioning process.
Through these experimental results, supported with modelling experiments primarily carried out using ThermoCalc software, efforts are undertaken to better the understanding of when; if at all, which TCP phases occur during the solutioning process. Calculation of volume fractions present, where in the microstructure they occur and expansion of the understanding of their initial formation, and why in some cases they appear to eventually redissolve or never form in the first place. The aspiration of this work is to inform future alloy development of the risk certain aspects such as composition and processing contribute to TCP phase precipitation during manufacturing and how, if at all, it can be avoided or minimised.
Through the experiments and analysis undertaken during this thesis, it has been shown that TCP phases; namel
The association between severe mental illness and cardiovascular disease: systematic review and retrospective cohort studies using routinely collected electronic primary care data
Get PDFCompared with the general population, people with severe mental illness (SMI), such as schizophrenia and bipolar disorder (BD) have shorter life expectancy, dying up to 20 years earlier. Death rates are two to three times higher than those without SMI and the mortality gap has not reduced in recent decades. Much of the premature mortality is due to preventable causes, with cardiovascular disease (CVD) being the most common cause of death in those with SMI.
This thesis aims to summarise the evidence on the relationship between SMI and CVD, describe changes over time, explore the factors associated with highest CVD risk and quantify their relative importance.
Methods
Three different methodologies were used to assess the association between BD, schizophrenia, and CVD. A large-scale systematic review of SMI and CVD-related mortality and incidence; matched and unmatched cohort studies, which explored the effects of SMI on all-cause mortality, post-CVD case-fatality and CVD incidence; and a mediation analysis, which explored the effect of four mediators (smoking, diabetes mellitus (DM), obesity and blood pressure) on the causal pathway between SMI and CVD.
Results
The systematic review found that CVD-related mortality was elevated for those with SMI compared with the general population. Meta-analyses showed that pooled standardised mortality ratios were 1.96, 95% confidence interval (CI): 1.61-2.39 and 1.65, 95% CI: 1.53-1.77 for schizophrenia and BD, respectively. Deaths from individual CVD diagnoses of coronary heart disease (CHD), cerebrovascular accident (CVA) and heart failure (HF) were also high for people with SMI compared with the general population. There was a consistent association between SMI and increased incidence of CVA, CVD events and HF, and between BD and CHD. However, most pooled estimates showed no evidence of difference in CHD incidence between those with schizophrenia and the general population. Excess risk of CVD-related mortality appeared higher in the 1990s and 2000s compared with earlier decades and relative risk of CVD incidence appeared highest during 2000-2004. Risk of bias was high for most included studies, with only 12 incidence studies judged to be at low risk of bias.
The cohort studies found the risk of all-cause mortality was two to three times higher for people with SMI compared with the general population. Relative risk of death after CVD diagnosis for those with SMI was also around two-fold higher than the general population. Hazard ratios (HRs) adjusted for confounders were 1.67, 95% CI 1.42-1.96 and 1.97, 95% CI: 1.75-2.21 for BD and schizophrenia, respectively. Excess risks of CVD incidence, however, were more modest: HR=1.21, 95% CI: 1.15-1.29 and HR=1.12, 95% CI: 1.07-1.17 for BD and schizophrenia, respectively. There was no consistent evidence of changes in mortality over time, although some increases in relative risk of CVD incidence found during the period 2005-2014 in the matched study disappeared after 2015. In the unmatched study, there was no evidence of temporal changes when adjusted for all measured confounders.
Mediation analysis found that smoking was an important mediator of the association between SMI and CVD incidence, mediating 34.5% and 53.5% of the excess risk for BD and schizophrenia, respectively. DM also had a substantial effect. However, obesity and hypertension had no significant mediating effect, after accounting for smoking and DM.
Conclusions
This research highlights health disparities for people with SMI compared with the general population and the evidence that they are not improving over time suggests that current interventions are not effective. Development of smoking cessation and physical health monitoring interventions and investigation of differential access to treatments are important recommendations to improve the cardiovascular health of people with SMI
Determining the optimal method of triage for the UK major incident setting
Get PDFMajor incidents are characterised by a mismatch between the immediate needs of patients and the resources available to treat them. In the UK, man-made major incidents comprising blast and penetrating trauma have occurred with increasing frequency in recent years and continue to constitute the greatest threat to national security (Chapter 1). Triage tools have a crucial role in ensuring that finite healthcare resources are allocated to maximise overall survival. Existing tools have largely been developed based on expert opinion and implemented without formal validation. A major challenge in furthering the science of major incident management is the lack of consensus and standardisation of end-points which best define Priority 1 (P1) status and other triage categories. In this thesis, the literature surrounding major incident triage was reviewed and modern, evidencebased definitions of triage categories were validated amongst adults and children from the UK national trauma registry (Chapters 1 and 2). This system developed by Lerner et al defined P1 patients as those requiring any one of eight time-critical life-saving surgical and major resuscitative interventions, directly reflecting patient resource requirements, and correlates well with casualty distribution within UK regionalised systems of trauma care. Hence it is recommended that Lerner’s criteria should become the gold standard in reporting triage tool performance in future UK major incidents. These intervention-based triage category definitions were compared with the triage category assignments of ten existing international triage tools. This comparative analysis demonstrated that the current UK national triage tool, the NARU Triage Sieve, is poorly sensitive in identifying P1 patients who require time-critical, life-saving interventions, and was surpassed in sensitivity by several tools, the best of which was the UK military’s BCD Triage Sieve (Chapter 2, publication number 1). Similarly, in children from the national trauma registry, the current UK tools, the Paediatric Triage Sieve and JumpSTART, demonstrated suboptimal performance and were substantially outperformed by several tools, with the BCD Triage Sieve again demonstrating the greatest sensitivity (Chapter 2, publication number 2). This has directly informed national policy, resulting in the removal of previous existing tools and a recommendation for the NHS Major Incident Triage Tool (MITT), the civilian adaptation of the BCD Triage Sieve, to become a single tool for NHS first responders to apply to all adults and children in future UK major incidents. Subsequently, using tree-based machine learning methodology, a novel primary triage tool, Quick Triage, as well as a secondary triage tool that is applicable via a portable device, have been developed (Chapter 3). Both tools outperform the BCD Triage Sieve amongst TARN patients, with reduced associated over-triage rates. The app-based secondary triage tool has withstood external validation amongst injured patients from the UK military’s Joint Theatre Trauma Registry (JTTR); however, a paucity of pre-hospital data precluded external validation of Quick Triage amongst JTTR patients, necessitating further work. Quick Triage has balanced, favourable performance amongst adults, children and elders with blunt and penetrating trauma from the UK national trauma registry, with lower over-triage rates than the NHS MITT (Chapter 4). This offers the possibility of a single tool for use amongst patients of all ages by all NHS and non-NHS first responders, allowing complete interchangeability, simplification of the prehospital triage process and likely more rapid and accurate triage of major incident casualties in future UK and international major incidents
Zinc as a potential therapy for Burkitt’s lymphoma
Get PDFBurkitts lymphoma (BL) is a form of non-Hodgkin lymphoma (NHL) that arises from germinal center B cells. BL is characterized by translocations of the C-MYC oncogene to immunoglobulin light and heavy chain loci resulting in its constitutive deregulated expression. BL shows a rapid and aggressive growth pattern. There are three different forms of BL; sporadic BL (sBL), immunodeficiency-associated BL and endemic BL (eBL) which accounts for ~50% of all paediatric cancers in Sub-Saharan Africa. Due to financial restrictions, treatment and supportive care options are limited resulting in poorer outcomes in low - middle income countries (LMICs). Thus, there is a need to develop new affordable effective low toxicity treatments for eBL.
Prior to this study, a panel of BL cell lines were tested against an in-house custom drug repurposing library developed in our lab (FMC Library) that contains ~100 approved and commonly used drug. This screen identified the nutritional supplement zinc acetate as an effective anti-BL candidate. Dose response studies showed that all BL cell lines tested had little/no response to zinc at 50 μM whereas 100 μM zinc killed all BL cell lines. In contrast, 100 μM zinc acetate induced no killing against a panel of non-BL cell lines including acute myeloid leukaemia (AML) which is a non BL cell tumour, diffuse large B cell lymphoma (DLBCL) which represent a B cell lymphoma that arise from germinal centre B cells and BV infected lymphoblastoid cell lines (LCL) as a control cells. The latter were used as karyotypically normal B cell controls. Cell death in BL cells was associated with positive flow cytometry staining for propidium iodide and annexin V and activation of caspase 3 and 9 (western blotting) indicating cell death by apoptosis.
The proto-oncogene C-MYC is mutated or deregulated in >50% of cancers. In BL, deregulated expression occurs as a consequence of translocation of C-MYC on chromosome 8q24 to either the immunoglobulin heavy chain enhancer region on 14q32 (85% of cases) or the immunoglobulin kappa light chain or lambda loci on 2p12 or 22q11, respectively (15% of cases). Thus, the effect of zinc on C-MYC protein levels were studied. Western blot analysis showed that 100 μM zinc was able to reduce C-MYC protein levels rapidly and sustainably in BL cell lines whereas no change in C-MYC protein levels was observed in non-BL cell lines. Zinc-induced reduction of C-MYC protein levels was time-dependent, reducing by approximately 20% after 6 hours with little/no protein detectable after 24 hours.
C-MYC protein levels were not reduced following treatment with 50 μM zinc. Quantitative real time PCR (qRT-PCR) also showed a rapid reduction in C-MYC mRNA levels in BL cell lines after 6 hours exposure to 100 μM but not upon exposure to 50μM. Again, no reduction in C-MYC mRNA levels was seen in non-BL cell lines. Translocations of other genes to the immunoglobulin loci occur in other forms of NHL. The DLBCL cell line SU-DHL-4 has a t(14;18) translocation resulting in deregulated expression of the protooncogene BCL2. Western blotting showed no decrease in BCL-2 protein levels in SU-DHL-4 in response to either 100 μM or 50 μM zinc acetate after 6 or 24 hours indicating a selectivity of zinc action against C-MYC protein in BL cells.
To further investigate the role of altered C-MYC expression in zinc-mediated killing of BL cells, the eBL cell lines Raji and Namalwa were stably transfected with C-MYC using a piggyBac transposon system that allows gene expression under a constitutively active promoter. However, overexpression of C-MYC from an alternative promoter did not rescue BL cells from killing by 100μM zinc. Although western blotting showed that C-MYC protein levels were protected after 6 hours, protein reduction and loss of viability was again observed after 24 hours indicating that loss of C-MYC is important in zinc-mediated killing of BL cells. In a second approach to rescue C-MYC expression, the proteasome inhibitor Bortezomib was used to inhibit C-MYC protein degradation via the ubiquitin-proteasome system (UPS). Whilst increases were observed in overall ubiquitinated proteins indicating bortezomib was working, western blotting and flow cytometry showed no rescue of C-MYC protein levels. Furthermore, bortezomib did not rescue cells from zinc-mediated killing after 24 hours.
In conclusion, findings from this study have identified that 100 mM zinc is effective at killing BL cell lines selectively, and that this killing is associated with activation of apoptotic markers. Treatment with zinc resulted in a rapid and sustained reduction in C-MYC mRNA and protein levels that could not be rescued through constitutive overexpression or the use of proteasome inhibitors. Given that zinc deficiency is common in sub-Saharan Africa and that zinc supplementation is safely used to treat diarrhoeal episodes in children, the studies proposed here indicate that zinc may safely be used as an adjunctive therapy to target C-MYC in BL
White matter really matters in cerebral small vessel disease: role of hypoxia signalling in oligodendrocyte precursor cells and its crosstalk with endothelial cells
Get PDFCerebral small vessel disease (cSVD) is a vascular risk factor associated disorder characterised by white matter lesions. These lesions are associated with cerebral hypoperfusion and increased blood-brain barrier (BBB) permeability. The cellular and molecular mechanisms underlying small vessel dysfunction and loss of white matter integrity remains largely unknown. In that context both endothelial cells (ECs) and oligodendroglia are key players, as ECs have a critical role in cerebral perfusion and BBB permeability and oligodendrocytes and oligodendrocyte precursor cells (OPCs) are responsible for myelination in the brain. Although EC dysfunction could affect oligodendrocytes and OPCs and lead to white matter damage, the role of their interplay is poorly studied in context of cSVD.
In this thesis, we identified Wnt7a as a potential modulator of EC-OPC interaction in a systematic literature search (Chapter 2). We studied the effects of Wnt7a and β-catenin signalling on endothelial barrier integrity in vitro, demonstrating its impact on the expression of tight junction proteins (Chapter 3). Our transcriptomic analysis revealed the role of Wnt7a in regulating a signalling pathway of importance for OPCs. We showed that Wnt7a suppressed Cxcl12 in ECs but had no influence on Cxcl12 receptor Cxcr4 in OPCs (Chapter 4). Finally, we demonstrated that cerebral hypoperfusion in mice leads to hypoxia in OPCs and an increased BBB permeability. In vitro experiments with OPCs exposed to hypoxia resulted in upregulation of Vegfa, rather than Wnt7a, via Hif1a and Epas1 signalling. We also showed in a retrospective human study that higher VEGFA plasma levels were associated with increased BBB permeability in normal appearing white matter of cSVD patients (Chapter 5).
Taken together, our findings support (a) a role for Wnt7a in regulating BBB integrity and OPC migration and (b) an early role for OPC-derived VEGFA in hypoxia contributing to BBB impairment and possibly white matter lesion development in cSVD patients
A study to assess the reproducibility of facial expressions used in the Sunnybrook facial grading scale using 4D motion capture technology
Get PDFAIM:
The aim of this study was to assess the reproducibility of facial expressions used in the Sunnybrook scale using 4D motion capture technology. This was determined by how well the participants could perform six facial expressions at a 6-month interval (T and T).
STUDY DESIGN:
Prospective longitudinal cohort study.
MATERIALS AND METHODS:
Twenty healthy participants (10 male & 10 female) meeting the inclusion criteria, were invited to voluntarily participate in the study. They were imaged performing the six facial expressions stated in the Sunnybrook scale (eyebrow lift, eye closed gentle, maximum smile, snarl, lower teeth show and lip pucker) at T and T (6 months later). All facial expressions were carried out from repose and the volunteers were imaged using a 4D facial motion capture system on both occasions. Upto 8 landmarks were digitally placed on the images, depending on the facial expression, which were then automatically tracked throughout the recording.
The Euclidian distance of each landmark, between T and T, for each facial expression were analysed to determine the magnitude of displacement of the landmarks and determine their reproducibility over the two time points. In addition, for each facial expression the mean absolute displacement of each landmark, in the x, y and z direction between T and Twas determined. A threshold of 2mm was set as being clinically significant different.
RESULTS:
Based on the Euclidian distances, the results of this study showed four of the six facial expressions i.e., snarl, pucker, maximum smile, and eyebrow lift were reproducible. The other two expressions, eye closed gentle and lower teeth show, had differences in Euclidian distance which were statistically significantly different between the two-time intervals.
On further assessment of the x, y and z directions the eyes closed gentle expression was associated with the least reproducibility error, with all distances being statistically significantly less than 2.0mm (p>0.05). None of the six facial expressions had mean absolute differences statistically significantly greater than 2.0mm. The greatest errors in reproducibility were seen with lip pucker were in some directions the upper 95% confidence interval limit exceeded 3.0mm.
CONCLUSIONS:
Four of the facial expressions showed acceptable reproducibility over a 6-month interval, snarl, eyes closed gentle, maximum smile, and eyebrow lift. Lip pucker and lower teeth show were the least reproducible in the x, y and z directions, with the majority of the landmarks being clinically significantly greater than the 2.0mm threshold. The clinical impact of the study is that any changes in facial movement, because of an intervention, need to be greater than 3.0mm to be a true change and not a result of decreased reproduciblity of the facial expression over time
Design and development of -titanium alloys using iron ass a low cost -stabiliser
No full textTwo key imperatives of 21st Century aviation are an improvement in fuel consumption of turbine jet engines and thus a reduction in environmental impact. It has been widely reported that improvements can be made in both thermal and propulsive efficiency of the gas turbine. One pathway to achieving this objective is to utilise materials capable of operating in a higher temperature regime in the hottest sections of the engine, leading to improvements in efficiency. To replace the incumbent nickel-based superalloys will require development of a cost-effective, competitor material which can exceed the balance of properties in one or more domain. The bcc--Ti phase offers significant density improvements over high temperature alloys based on Ni, Fe or Co and therefore substantial weight savings, while for structural applications the high specific strength of titanium alloys is well documented. These are the core reasons for the use of titanium alloys operating in higher temperature regimes. In addition to being a low-cost -Ti stabiliser, alloying with Fe can also promote formation of a ’-TiFe superlattice structure as the strengthening precipitate. This is an attractive concept as it offers scope to develop a microstructure based on a disordered-bcc matrix with a high phase fraction of a coherent, ordered-bcc second phase.
Chapter 1 presents an overview of the incumbent superalloys utilised in turbine jet engines, in addition to selected commercial titanium alloys and their composition – microstructure – property relationships. The benefits of a bcc -Ti alloy are then discussed comparatively and strategies to impart strength, ductility and oxidation resistance are outlined. Consideration is given to the influence of the metastable -phase which forms from the -Ti phase and its impact on the mechanical response of the alloys.
An experimental investigation of phase equilibria in the dual -Ti + ’-TiFe phase field of the base Ti-Fe system is presented in Chapter 2. This binary experimental investigation was crucial as the literature review highlighted key uncertainties in this system. A key finding from this work was the minor oxygen levels required to stabilise the -Ti phase in the supposed dual -Ti + ’-TiFe phase field at near eutectoid temperatures.
In Chapter 3 the evolution of the metastable -phase was studied in Ti-Fe alloys as a function of bulk composition and temperature. This work revealed that for Ti-Fe alloys in the range 14-22Fe (at%) neither the athermal- nor the isothermal- can form, instead retaining the parent -matrix and nano-scale domains of distorted- phase on quenching from a high temperature. This was an important finding as it indicates the phase separation associated with the isothermal -phase does not contribute to the inherent brittle nature of the high solute content alloys.
A notable challenge in development of -Ti alloys based on the Ti-Fe system is designing for oxidation resistance. In Chapter 4 a diffusion couple approach was utilised to rapidly assess the effects of Al and Cr additions to the binary Ti-Fe system with a focus on composition – microstructure – property relationships. The microstructural gradient was evaluated to identify a dual -Ti + ’-TiFe microstructure and this was coupled with an oxidation investigation of the entire composition space bounded by the diffusion couple. This work enabled identification of a suitable composition range to manufacture discrete bulk alloys for onward investigation
Haunted and held: a Christian theology of place
Get PDFThis is a thesis about place. More specifically, it is a Christian theology of place. My argument is not simple, but it is straightforward – place is a discursive structure of intelligibility or apprehension in the Holy Spirit that enables creatures to go-on in the world. To gloss Jeff Malpas, place is that on which our subjectivity is founded, it is the ‘somewhere’ that is necessarily entailed in every assertion of relationship. Places hold us in some sort of relationship of intelligibility with other creaturely bodies and as Pope Francis has so eloquently put it, “the history of our friendship with God is always linked to particular places.” But precisely because place holds us in relationships that are produced and sustained through communicative exchanges, place also haunts us. Indeed, as Michel de Certeau remarks, “Haunted places are the only ones people can live in.” While places hold the potential for our intimate joining with one another in discourses of mutual recognition, places are also haunted by miscommunications, misrecognitions, and misinterpretations that point to histories that might have been other and hoped for futures that have not arrived. Contemporary theologies of place, while helpful, have been afflicted by a ‘colonial hole’ through an inattention to the role Christian theologies of place have played in the harms of colonialism. This thesis offers a critical reading against this tradition of Christian place theologies and provides a reparative and pastoral theology of place to aid in the ongoing work of reconciliation
How do teachers conceptualise motivation for behaviour and how do they apply this to their practice?
Get PDFMotivation as a construct is used to explain factors that influence and drive behaviours. Understanding of motivation for behaviour has grown considerably and it is now recognised as a complex multi-dimensional construct. Despite this, critics argue that UK government education policy remains focused on a behaviourist approach. Pupil behaviour is an ongoing concern in education. The behaviour of concern has been labelled as ‘disruptive behaviour’ and is recognised as impacting upon pupil and teacher outcomes, including contributing to pupil aggression (Greer-Chase et al., 2002) and teacher stress (Hastings & Bham, 2003). School behaviour policies have been found to mainly focus on rewards and sanctions as a classroom behaviour management (CBM) strategy (Ellis & Tod, 2018). Research indicates that teachers’ beliefs impact upon their choice of CBM and teacher beliefs have been shown to affect pupil outcomes. This research is limited and mostly based on populations from the United States. The present study uses a thematic analysis grounded in a critical realist approach to explore four teachers’ experiences and perceptions of pupil motivation and how this relates to their practice. The study found that participants’ conceptualisation of motivation for pupil behaviour was like that found in the motivation literature. This included Pupil Factors, Complex Family Backgrounds, and External Factors all being identified as causal mechanisms for pupil behaviour. Intrinsic Value, as a Pupil Factor was hypothesised to be a superior type of motivation and this influenced most participants’ CBM choices, which were identified as relational in their approach. An Ethos of Teacher Responsibility and Teacher Values enabled participants to utilise relational approaches to motivating behaviours with the pupils they worked with. Strengths and limitations are discussed. Four areas for future research are suggested. This study can aid the integration of teacher beliefs into educational policy and practice in relation to pupil behaviour
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