Search

Cancer cachexia is an unmet clinical need that affects more than half of patients with cancer. Pro-inflammatory cytokines and adipokines could be involved in the pathogenesis and development of cachexia, but this relationship is not completely understood. This thesis aimed to examine and characterise the role of (adipo)cytokines in cancer cachexia. A systematic review was conducted to evaluate the relationship between cytokines and cachexia in people with incurable cancer (Chapter 2). Interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were considerably elevated in cachectic individuals, and a high degree of methodological heterogeneity was observed. Furthermore, data from the REVOLUTION trial were analysed to determine if adiponectin, leptin, intelectin-1 and resistin can predict the modified Glasgow Prognostic Score (mGPS) and cachexia status (Chapter 3). Although adipokines could not predict any of the outcome variables in this study, leptin was negatively associated with mGPS and cachexia, while a positive relationship was identified between resistin and mGPS. Previous research suggested that intelectin-1 might be involved in cancer cachexia. Given the limited availability of literature, a Bayesian meta-analysis was conducted to evaluate the role of intelectin-1 in cancer and its physiological concentration (Chapter 4). Intelectin-1 levels were substantially higher in patients with gastrointestinal cancer compared to controls. The meta-analysis also estimated that the physiological concentration of intelectin-1 ranges from 193ng/ml to 275ng/ml. Lastly, a cell culture model was designed to evaluate the effect of intelectin-1 on human myotubes (Chapter 5). Increased levels of intelectin-1 diminish insulin-mediated glucose uptake and downregulate the expression of genes involved in myogenesis. To conclude, IL-6 and TNF-α were highly expressed in cancer cachexia. Leptin and resistin could also contribute to the development of this wasting syndrome, but to a lesser extent. Besides these (adipo)cytokines, intelectin-1 is another potential biomarker of cachexia and future research should focus on elucidating its mechanisms of action.

Buoyant plumes are widespread physical phenomena, present across a large range of scales, from the plume generated by a candle to a mantle plume beneath the crust of the Earth, and spanning laminar to fully turbulent flow. In its most basic form, a plume is the vertical transport of heat emanating from a buoyancy source. Despite the ubiquity of plumes and their role in heat and mass transport, many aspects of their dynamics are still not fully understood. In the literature, plumes are often separated into laminar and turbulent regimes and are yet to be combined into a cohesive theory of plume evolution and structure. In this thesis, I perform a theoretical and numerical analysis of pure plumes generated by a localised point source of heat in order to unify these separate theories in a description of a hybrid laminar-turbulent plume. The governing equations for a plume are shown to be dependent on only one dimensionless parameter, the Prandtl number, which is the ratio of kinematic viscosity to thermal diffusivity. Using direct numerical simulations (DNS) combined with scaling analysis, I establish some universal properties of pure plumes. Following the laminar regime, the height at which instability occurs, hereafter referred to as height to instability, for the case Pr = 1, is found. The turbulent regime is described using similarity scalings and a virtual origin (differing from the height to instability) is found, implying that the transition region exists over a nonzero spatial range. Expanding on this work, further DNS are undertaken to derive a unified laminar-turbulent theory of a plume in an unstratified environment emanating from a point source over a range of Prandtl numbers. The height to instability is found to increase sublinearly with Prandtl number and a formula for interpolating the height to instability within the range Pr = 0.1 to 2.0 is fitted to the results. My investigation into developing a unified laminar-turbulent theory of plume rise from a point source is further expanded by introducing a linear stratification to the background. This introduces another length scale to the problem and the relationship between height to instability and maximum rise height is investigated. I performed DNS of plumes across a wide spectrum of Reynolds numbers and developed a simplified theory of low-Re plumes, resulting in excellent agreement with the predictions of the DNS. Interestingly, the results demonstrate a non-monotonic relationship between rise height and Reynolds number, with a global maximum at Reynolds number is approximately 1500. Finally, the unstratified results are applied to the transport (e.g. of pathogens) in the built environment by local sources of heat. A hybrid laminar-turbulent theory of particle transport in rooms is developed using the results of height to instability. Remarkably, a strongly non-monotonic relationship between transport rates of particles and the initial buoyancy flux, with two turning points, is discovered.

This thesis reports on shock interaction experiments at the MAGPIE pulsed power facility. Bow shocks are produced by placing cylindrical obstacles into the supersonic, super- Alfvénic and super-fast-magnetosonic plasma outflow from an inverse wire array z-pinch. The wire array provides a continuous source of plasma for ~ 500 ns with a velocity of ~ 50 km/s which advects a dynamically significant magnetic field of ~ 1.5 - 2.5 T. The geometry of the experiment allows good diagnostic access to the bow shocks and obstacles are fielded in pairs so that neighbouring bow shocks interact. The complex shock structure which emerges is a result of the resistive diffusion length being much larger than the collisional mean free path. Two types of shock are seen. One is characterised by a large shock transition length and very little heating and is a sub-critical resistive dissipative shock. This is observed to form as a single shock across both obstacles. The second are two shocks which form close to the obstacles and are downstream of the resistive dissipative shock. These exhibit substantial heating and have a shorter transition length. We interpret these to be hydrodynamic-like. The experiments are diagnosed with laser interferometry, Faraday rotation imaging, optical Thomson scattering and optical self-emission imaging which provide detailed time and space resolved measurements of the plasma parameters, including inside the resistive dissipative shock transition. An experimental validation of the Faraday rotation imaging diagnostic is presented to evaluate analysis techniques. Experiments with different plasma materials are compared, which demonstrates the dependence of the resistive dissipative shock transition length on the resistive diffusion length. The experimental results are compared with AstroBEAR simulations including new simulation results which include a magnetic field in such systems for the first time. Preliminary results show good agreement with our interpretation of the experiments.

Background: Assessment of healthcare professionals plays a pivotal role in safeguarding patients by ensuring practitioners have been appropriately trained before being permitted onto professional registers. This prevents the public from being treated by those who are not fit to practise healthcare subjects, including dentistry. In the UK, dental schools must provide the General Dental Council (GDC) with evidence that students have attained the necessary educational outcomes and are suitable to join the professional register. The GDC delegates responsibility of choosing appropriate assessment methods to obtain such evidence to the dental schools themselves. As part of their undergraduate assessment repertoire, some UK dental schools have adopted longitudinal assessment methods to measure development and consistency of competent performance in clinical environments. Although these longitudinal methods create a rich database of multiple points of evaluation over the duration of the Bachelor of Dental Surgery (BDS) curriculum, there is currently little evidence to support their use for assessing development of clinical competence. Therefore, there is a need to conduct thorough analyses of longitudinal clinical data using robust statistical methods and create evidence to support their validity for this purpose. Aims: This thesis aims to investigate the content and criterion validity and reliability of longitudinal clinical assessment, which will contribute towards a validity argument on its use in assessing the development of clinical competence among undergraduate dental students. It will also explore how the evidence for validity could be used to enhance assessment within dental education. Research design: A mixed methods approach, with quantitative and qualitative approaches, was adopted to address the study aims. For the quantitative component, statistical escriptions, and group-based trajectory models (GBTMs) tracking individual undergraduate's clinical performance over time were produced from longitudinal clinical assessment (LIFTUPP©) data for three dental student cohort's (2017-19; n=234). Content validity was investigated using LIFTUPP© performance indicator 4 as the threshold for competence. Distinct trajectories were created using a performance indicator 5 as the threshold, which were then used to investigate the concurrent and predictive subtypes of criterion validity. Concurrent validity was investigated by linking and cross-tabulating LIFTUPP© trajectory group memberships with BDS examination performance (mean scores and a "top 20%" performance in each BDS year). Predictive validity was investigated by linking and cross-tabulating undergraduate LIFTUPP© trajectory group memberships with postgraduate clinical performance trajectory group memberships generated from Longitudinal Evaluations of Performance (LEPs). Reliability was calculated using Cronbach's alpha. For the qualitative component of the study, a series of online focus groups with key stakeholders within dental education were conducted. Participants were presented with the results of the quantitative analyses and their opinions on how these data could be used to enhance assessment within dental education were canvassed. Transcripts of the focus group discussions were analysed using thematic analysis to identify themes (i.e., patterns) of interest within the data. Results: LIFTUPP© GBTMs with a threshold performance indicator of 4 resulted in all students following a single trajectory in all three cohorts and showed progressive development of clinical competence over three BDS clinical years, satisfying criteria for content validity. GBTMs with a threshold performance indicator of 5 provided at least two distinct trajectories of student clinical performance. According to the Bayesian information criterion (BIC), models with two distinct trajectories fitted the data best and a "better" performing trajectory was identifiable in each cohort. In the two most recent cohorts, students who were more likely to belong to the "better performing" LIFTUPP© trajectory scored higher (on average) in the undergraduate examinations for each BDS year. This association was not observed for cohort 1. Students allocated to "better performing" LIFTUPP© trajectories were more likely to also be assigned to "better performing" LEP trajectories in all three cohorts. Reliability for the undergraduate examinations was high in all three cohorts (>0.88) and did not change substantially when longitudinal clinical assessment data were included. Comments from focus group participants appeared to provide further support for content validity. However, quantitative results were met with a degree of mistrust that seemed to stem primarily from previous experiences of operational issues associated with the LIFTUPP© assessment process and the absence of contextual data within the quantitative analyses. Conclusions: The upward trend of LIFTUPP© trajectory patterns suggested there is evidence that longitudinal clinical performance data have content validity for the assessment of clinical competence. Associations between better LIFTUPP© performance and better undergraduate examination outcomes and better postgraduate clinical performance in the two most recent cohorts were indicative of criterion validity. The lack of association in cohort 1 may have been due to poorer calibration among assessors following the initial adoption of LIFTUPP© into the BDS curriculum. Evidence for LIFTUPP© data reliability was inconclusive. This uncertainty may have resulted from using probabilities of student trajectory group membership as the metric for longitudinal clinical assessment in the calculation of Cronbach's alpha. Therefore, further investigations on LIFTUPP© data reliability are required. Data processing procedures and suggestions from focus group participants revealed there is a need to improve current assessment practices and data collection to allow other investigations on validity to be pursued and to further increase confidence in the results produced by this study. Some data collection issues encountered in relation to LIFTUPP© and undergraduate examinations have since been resolved, meaning studies involving subsequent student cohorts should seek to incorporate LIFTUPP© communication, management and leadership, and professionalism data as well data from clinical case presentation examinations and one-off clinical competence tests. Overall, the study provides an early contribution towards a validity argument on the use of longitudinal clinical assessment in assessing development of competence in undergraduate dentists and provides a starting point from which consequent studies can be based. The study should now be expanded into different settings, e.g., other dental schools and disciplines (such as medicine, nursing, and veterinary medicine), to confirm and build upon these initial findings.

The purpose of this mixed methods action research was to determine if increased interactive Schoology-based modules could alter learner perceptions concerning the lack of meaningful learning (learner-instructor, learner-learner, learner-content) in the culture unit of instruction in an Advanced Placement Human Geography (APHG) classroom. A series of instructional modules were facilitated through the learning management system (LMS) Schoology to students (n = 16) in APHG at a southeastern U.S. high school. The interactions were designed to enhance interaction based upon the criteria provided by Piaget's (1981) social constructivist theory, specifically Moore and Kearsley's (2011) systems approach and Miyazoe and Anderson's (2010) interactive equivalency theorem. These approaches sought to create meaningful interactions as described in Vygotsky's (1978) zone of proximal development. This study addressed four research questions: (1) What are learners' perceptions of the learner-instructor, learner-learner, and learner-content interactions presented via the Schoology interactive modules in their culture unit of instruction? (2) What barriers are reported by students that hinder meaningful learner-instructor, learner-learner, and learner-content learning while using Schoology? (3) Do students' perceptions change after receiving increased interactive lessons presented through the Schoology interactive modules? (4) To what extent does student learning, as measured by a culture unit assessment, increase or decrease after the LMS driven instructional innovation? As a mixed methods study, quantitative and qualitative information, namely pre- and post surveys, panel group discussions, and interviews, served as the basis of the evaluation. Results indicated significant variances in the pre- and postsurvey as well as significant improvement from the pre- to posttest. Overall, significant differences were found in the general interactivity, learner-instructor, learner-content, and learner-learner subscales. This signifies that the interactivity in the teacher-created modules was interactive. Limitations such as the novelty effect and the non-generalizability of the results exist in the study. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

This thesis examines the manuscript poems of Thomas St Nicholas (bap. 1602, d. 1668). His poetry is examined through the writing of 'scripturalism' in seventeenth-century England. I argue that 'scripturalism' was a literary trend in print and manuscript, prose and verse that shared the same scriptures to convey mutual religious, social and political values. St Nicholas' poetry engages with, as it exemplifies, this paradigm of writing. Chapter One investigates St Nicholas' Civil War prison verse epistle alongside Foxe's Acts and Monuments (1563) and prison narratives of the seventeenth century. His poem was part of a literary culture of prison writing that used shared scenes of suffering to connect present persecutions via a Protestant past. Chapter Two explores St Nicholas' hymn of recovery from sickness. His account of illness shares much with scriptural acts and attitudes widely performed and recorded in the early modern sick-chamber. Chapter Three looks at the psalm paraphrases used in his prison verse. It shows St Nicholas invoking certain psalms that were widely used by other parliamentarian preachers and poets to justify the war as just and righteous. Chapter Four examines St Nicholas' battle hymn composed during the First Anglo-Dutch War (1652-1654). I demonstrate his contribution to a recognised form of parliamentarian victory praise which used battle hymns to trumpet military victories using key scriptural texts and images. Chapter Five explores St Nicholas' poem on the Great Fire of London (1666). By examining other urban fire narratives, a shared Biblicism emerges, whereby pulpiteers and balladeers were more united than divided when moralising these horrific events. This thesis argues that St Nicholas' poetry is evidence of a pervasive literary culture that used the Bible cross-denominationally, and occasionally cross-politically. Scripture provided a common reference for writers like him to describe both everyday and extraordinary occurrences.

Leucine rich repeat kinase 2 (LRRK2) is a 286 kDa protein expressed in a variety of tissues and cell types, including neuronal tissue and innate immune cells. Mutations in LRRK2 have been linked to inflammatory diseases, most notably Crohn’s disease and Parkinson’s disease. Further to this, LRRK2 expression is induced by innate immune stimuli, and can be phosphorylated by Myd88 directed TLR signalling. Functional experiments were performed using macrophages from WT and LRRK2 knockout mice. Many phenotypes and interactions have been described for LRRK2 in a neuronal or in vitro context; therefore experiments in macrophages were specifically designed to investigate these phenotypes and interactions in an innate immune context. LRRK2 interacts with a range of small GTPase proteins called Rabs, which coordinate and carry out vesicular trafficking, including that of innate immune receptors. Further interactions have been shown with clathrin-mediated endocytic machinery and phagocytic machinery; including cytoskeletal components actin and tubulin. Accordingly, the role of LRRK2 in the expression, membrane localisation, and ligand-induced endocytosis of the innate immune receptors such as TLR4 were assayed. TLR4 plays an important role in immune responses to alpha-synuclein, an immunogenic protein aggregate that accumulates as part of Parkinson’s disease pathology, making it a particularly interesting target for this assay. No effect was shown for LRRK2 on TLR4 expression or receptor mediated endocytosis, so attention was focused upon LRRK2 cytoskeletal interactions. An unclear role of LRRK2 has been described in phagocytosis. Application of LRRK2 KO macrophages in a series of systematic phagocytosis assays was used to demonstrate and clarify that there is no role of LRRK2 in the phagocytosis of simple beads, opsonised material, or complex bacterial targets expressing a range of immunogenic molecules such as LPS. A genome wide approach was applied to further investigate the role of LRRK2 in TLR4 mediated signalling, as well as NOD2 mediated signalling. Comparison of LPS responses between WT and LRRK2 KO genotype macrophages identified a role of LRRK2 in modulating transcription of a range of chemokines and chemokine receptors. This indicates a specific role of LRRK2 in regulating chemotaxis in LPS stimulated cells. Knockout of LRRK2 resulted in a complete reversal of the regulation of the expression of EPAC1, a cAMP inducible protein working in parallel with a previously described LRRK2 interacting protein PKA. EPAC1 acts, at least in part, via Ca2+ signalling. Modulation of signalling through pathways such as Ca2+, Wnt and cAMP appear as a theme in results described in this transcriptomic experiment. A parallel metabolomic approach allowed analysis of ceramide levels in resting and innate immune stimulated macrophages. Ceramides are lipid molecules able to activate the NLRP3 inflammasome, as well as modulate alpha-synuclein pathology via ceramide metabolomic products. In contrast to results described in neuronal tissue, LRRK2 has no effect on ceramide levels in resting macrophages, however stimulation of NOD2 via MDP resulted in a dramatic LRRK2 specific increase in ceramide levels. Together, these results indicate a role of LRRK2 in activated innate immune cells.

The hydroxyl radical (OH), along with the closely coupled species the hydroperoxyl radical (HO2), have a profound effect on the concentration and distribution of most trace atmospheric species associated with climate change and poor air quality as they are essential to the daytime oxidizing capacity of the atmosphere. Tropospheric and mesospheric models that only consider gas-phase chemistry often over predict concentrations of HO2 indicating that heterogeneous reactions with aerosols could be a possible sink. In order to investigate the kinetics of such reactions, the HO2 uptake coefficient (γ(HO2), i.e. the probability that HO2 will collide and react within or on the surface of an aerosol) has been measured onto a variety of aerosols applicable to the troposphere, stratosphere and mesosphere using an aerosol flow tube experiment coupled to a highly sensitive HO2 detector, known as Fluorescence Assay by Gas Expansion (FAGE), and a Scanning Mobility Particle Sizer (SMPS). Deliquesced inorganic aerosols containing transition metal ions (TMI) have been shown to react rapidly with HO2. Measurements of γ(HO2) onto deliquesced inorganic aerosols doped with different concentrations of Cu(II), Fe(II), Mn(II), mixtures of Cu(II) and Fe(II) and I- are presented within this work. HO2 uptake onto deliquesced inorganic aerosols doped with transition metal ions may not be as significant as previously thought. The Thornton expression, used in global modelling studies of HO2 uptake, can predict γ(HO2) at a relative humidity (RH) of 65%, however at a RH of 43%, near the efflorescence point ((NH4)2SO4 = 37%), good agreement was only observed at higher concentrations of Cu(II) and Fe(II) (> 0.1 M) possibly indicating that HO2 solubility decreases as HO2 diffuses further into the bulk of the aerosol. It was expected that as deliquesced NaCl aerosols have a higher pH (7) that most HO2 accommodated within the aerosols will dissociated to the more reactive species O2-. This should result in high values of γ(HO2), however γ(HO2) onto Cu(II)-doped NaCl aerosols was measured to be lower than γ(HO2) onto Cu(II)-doped (NH4)2SO4 aerosols with a lower pH, possibly due to the formation of [Cu(Cl)4]2- complexes which are repelled into the bulk of the aerosol by enhanced concentrations of Cl- ions within the interfacial layer. Measurements of γ(HO2) onto Fe(II)-doped NaCl aerosols were relatively high and agreed with predictions made by the Thornton expression. When irradiated with UVA light, γ(HO2) onto Cu(II)-doped (NH4)2SO4 was lowered, however γ(HO2) onto Cu(II)-doped NaCl remained the same. When the effect of irradiating Fe(II)-doped (NH4)2SO4 aerosols on γ(HO2) was investigated, results indicated possible production of OH. Measurements of γ(HO2) onto mixed Cu(II) and Fe(II)-doped (NH4)2SO4 aerosols could not verify the Mao hypothesis that an electron transfer reaction occurs between Cu(I) and Fe(III) resulting in the conversion of HO2 to H2O, rather than H2O2. However, values of γ(HO2) did not simply equal the sum of γ(HO2) onto Cu or Fe-doped aerosols individually, indicating that the presence of both TMI in the aerosol does alter the chemistry of the aerosol in some way. Irradiation of Cu(II) and Fe(II)-doped aerosols resulted in an enhancement of γ(HO2), possibly indicating an alternative mechanism than that proposed by Mao, where HO2 is converted to H2O via a photochemical mechanism. The presence of I- within NaCl aerosols does not result in a change of γ(HO2), however when converted to I2 by reaction with Cu(II) an enhancement of γ(HO2) greater than when doped with Cu(II) alone was observed Measurements of γ(HO2) onto TiO2, a possible candidate aerosol for use within solar-radiation management (SRM) schemes, showed a positive dependence on Relative Humidity (RH) which correlated with the number of monolayers of water adsorbed onto the TiO2 nanoparticle. This dependence suggests a mechanism by which HO2 adsorbs to the surface of the TiO2 particle by forming complexes with water molecules bound to bridging OH groups. The TOMCAT chemical transport model was used by Professor Chipperfield to predict the possible effects of HO2 uptake (using an upper limit of γ(HO2) = 1) onto the surface of TiO2 nanoparticles on the stratospheric concentrations of HO2 and O3. The amount of TiO2 used was chosen to achieve a similar cooling to that following the Mt. Pinatubo eruption, but the model predicted a very small loss of both stratospheric HO2 and O3. Upon illumination of airborne TiO2 nanoparticles with UV light, significant quantities of HO2 was formed within the gas-phase, thought to be the first direct observations of radicals emitted from the surface of airborne particles. The reaction is dependent on the presence of gas-phase O2 and H2O within the system. The production of HO2 was shown to slow down as a function of time irradiated pointing towards a photochemical aging process occurring on the surface of the TiO2 particles. The dependence of HO2 production on O2 and H2O concentrations was determined, which shows a typical Langmuir adsorption saturation curve for O2 suggesting it is the gas-phase reactant in this process. The addition of H2O into the system inhibits the reaction and reduces the adsorption equilibrium coefficient for both species. Reduction of O2 by photogenerated electrons is likely to be the initial step in this process followed by reaction with a proton. Hydrogen extraction from hydroxyl bridging groups (OHbr) groups by O2- could explain the slow down observed in the rate of HO2 production. Production of gas-phase OH radicals was investigated and showed OH was produced only when large concentrations of TiO2 aerosols entered the aerosol flow tube, probably associated with the decomposition of H2O2 formed from reactive uptake. Although the production of HO2 by TiO2 aerosols initially would not be advantageous for its use within SRM schemes, the reaction ceases upon prolonged photocatalytic aging of the aerosol surface. Meteoric smoke particles (MSP) provide the only significant surfaces within the mesosphere for heterogeneous reactions to occur. To investigate whether such reactions could, in some part, be responsible for the ‘HOx Dilemma’ measurements of γ(HO2) onto analogues of MSP, forsterite, olivine and fayalite, were conducted at a RH of 10%. These experiments showed forsterite to have the lowest reactivity with HO2, similar to that of effloresced inorganic aerosols, and olivine and fayalite to have a similar reactivity that was more than an order of magnitude greater than that of forsterite, thus demonstrating that the presence of Fe within the MSP is required for significant reactivity with HO2. Electronic structure calculations, conducted by Professor Plane, predicts that the difference in reactivity is associated mechanistic and energetic differences between the binding of HO2 to Fe and Mg sites, however, the positive dependence of γ(HO2) with RH and similar values of γ(HO2) for olivine and fayalite suggests that OH bridging groups or complexing with water molecules adsorbed to such sites, as with TiO2 nanoparticles, are adsorption sites for HO2. Taking the measurements made in this work and the likely dependence of γ(HO2) on temperature and RH, a value of 0.2 for γ(HO2) was applied by Dr Sandy James in WACCM-CARMA. This modelling study predicted reductions in the HO2 volume mixing ratio of up to 40% in the polar vortex. Impact to HO2 budgets in the mesosphere was found to be dependent on latitude, giving agreement with the presence of MSPs in the polar night.

Positron emission tomography (PET) is a modality with high temporal resolution but long acquisition times. This can result in blurred images due to subject motion. Respiratory motion in particular is an unavoidable source of degradation, which can cause issues with quantification and clinical interpretation. An important characteristic of respiratory motion is its pseudo-cyclic nature, which has previously been exploited to form mathematical models which describe the motion, driven by a small number of parameters. The aim of this project is to use this form of motion modelling to estimate motion using information acquired from both dynamic magnetic resonance (MR) scans and from the acquired PET data itself to correct for the effects of motion. The use of motion models in this way can overcome the high levels of noise which otherwise characterise the estimation problem. First the feasibility of using motion models is investigated using synthetic data consisting of individual PET gates simulated using real motion information. The PET gates are registered using constraints provided by a motion model derived from MR images. A novelty of this approach is that this is the first time PET data have been used to indirectly drive a parameterised motion model. The next part of the project attempts to formalise the motion estimation process by incorporating the reduced-parameter motion model into the PET image reconstruction. An analytical gradient for a single motion parameter that drives the model is derived from the same objective function used to estimate the image. This results in significant noise averaging, providing robustness to the high level of noise typically found in PET data acquired over short time frames. This is shown to improve robustness to noise well enough that the number of gates can be increased and overall motion correction performance improved. Finally, the formulation is extended further to also model photon attenuation effects. This is shown to improve the performance of the algorithm when dealing with synthetic data that includes attenuation.