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Clonal haematopoiesis and inflammation in patients with heart failure
Get PDFBackground:
The prevalence of heart failure (HF) continues to grow. Its incidence rises substantially with age and the mean age of patients at HF diagnosis is almost 77 years. HF with preserved ejection fraction (HFpEF) now accounts for over half of cases and has an even closer relationship to ageing than does HF with reduced ejection fraction (HFrEF). Unlike HFrEF, limited evidence-based therapies currently exist for the treatment of patients with HFpEF which is more commonly associated with multi-morbidity, myocardial stiffening and coronary macro- andmicro-vascular endothelial dysfunction.
Both HFrEF and HFpEF are associated with systemic inflammation. However, inflammation appears to be more important in the pathophysiology of HFpEF than HFrEF. High circulating levels of inflammatory markers have been consistently associated with worse outcomes in patients with both types of HF.
Clonal haematopoiesis of indeterminate potential (CHIP) reflects the accumulation of specific somatic genetic abnormalities with a variant allele frequency (VAF) ≥2% in haematopoietic stem cells with age. The consequence of this is the accumulation of mutant leukocytes that confer an increased risk of subsequent haematologic malignancy. Most carriers will never develop leukaemia and the progression rate is approximately 0.5% per year. Despite the low risk of progression to haematologically important diagnoses, all-comers with CHIP have a 40% higher mortality than those without CHIP. This excess is a reflection of cardiovascular (CV)events, including fatal, and non-fatal MI, percutaneous coronary intervention and fatal stroke (ischaemic and haemorrhagic). Importantly, however, the presence of CHIP also confers a substantially increased risk for CV disease independent of traditional risk factors and recently the presence of mutations with a VAF<2% has been associated with worse CV outcomes.
CHIP was initially found to be associated with an increased risk of coronary artery disease (CAD). Subsequently it has been associated with a wide range of CV disease including HF and cardiac arrhythmias. The presence of CHIP has also been associated with an increased risk of adverse CV outcomes including death and subsequent hospitalisation. The commonly detected CHIP mutations play a central role in the regulation of inflammation, and the inflammatory and pro-atherogenic effects of CHIP have become a major recent focus for research.
To date, studies have mostly retrospectively examined the prevalence of CHIP in patients with HF and there is limited information on the presence of CHIP and its association with circulating cardiac and inflammatory biomarkers. There is also limited information on the roles and associations of specific circulating inflammatory biomarkers on adverse CV outcomes. Furthermore, there is also little information on whether standard HF therapies reduce levels of inflammation.
Aim:
The main aim of this study was to investigate the prevalence of CHIP in an unselected cohort of patients with HF and to understand the clinical and HF characteristics of patients with CHIP while obtaining mechanistic data to inform therapeutic strategies for the treatment of HF, in particular, examining its association with inflammation.
To further obtain mechanistic data to inform future trials of anti-inflammatory therapy in both stable and decompensated HF, the role of inflammation was comprehensively investigated in different HF cohorts. In particular, interleukin-6 (IL-6) and relative lymphocyte count (RLC) were examined. In addition, I examined whether treatment with sacubitril/valsartan reduced levels of inflammation in stable patients with HFpEF and HFrEF.
Methods:
I performed a prospective observational study of 96 patient (48 patients with HFpEF and 48 patients with HFrEF) admitted to NHS Greater Glasgow and Clyde Hospitals with decompensated HF over a one-year period. All patients recruited had their deoxyribonucleic acid (DNA) analysed for the presence of CHIP driver mutations and serum/plasma was analysed to examine levels of circulating cardiac and inflammatory biomarkers at the time of HF decompensation. Participants recruited to the study had detailed demographic and clinical data collected and they had an echocardiogram (echo) and electrocardiogram (ECG) performed at baseline.
In addition, to performing the prospective observational study, I also examined three large datasets of outpatients with decompensated HF. Two were large clinical trial datasets (PARADIGM-HF and PARAGON HF) and one was a large observational HF study (Microvolt T wave alternans). I specifically investigated the role of circulating levels of IL-6 and RLC in patients with HFrEF and HFpEF, and their association with adverse CV outcomes including death and subsequent HF hospitalisation. I also examined whether treatment with sacubitril/valsartan reduced circulating levels of inflammation over time.
Results:
Of the 96 patients recruited to the prospective observational study, the average age of patients was 72 years. As expected, patients with HFpEF were older (74 years) than those with HFrEF (70 years). CHIP driver mutations with a VAF≥2% were detected in 5 patients with HFrEF (10%) and 8 patients with HFpEF (17%). CHIP driver mutations with VAF≥1% were detected in 25 patients with HFrEF (52%) and 21 patients with HFpEF (44%). There was an age-dependent increase in the prevalence of CHIP, and the total number of mutations was higher in older patients in both HF groups. The most common mutation identified in both HFpEF and HFrEF was in deoxyribonucleic acid methyltransferase 3 alpha (DNMT3A). Patients with CHIP were older than patients without CHIP. Baseline haematological parameters (WBC, neutrophiles and lymphocytes), CV disease and CV therapies were similar between the groups. Furthermore, there was no difference in circulating levels of relative lymphocyte count (RLC) or neutrophil lymphocyte ratio (NLR) according to CHIP status. The presence of CHIP was not associated with levels of N-terminal prohormone of brain natriuretic peptide (NTproBNP). The presence of CHIP was associated with higher levels of novel biomarkers of inflammation. Specifically, concentrations of interleukin-1 beta (IL-1b), interleukin-18 (IL-18) and transforming growth factor-beta 2 (TGF-b2) were higher in those with, compared to those without, CHIP. In HFpEF, the presence of CHIP was associated with elevated levels of IL-1b and upstream and downstream makers of nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome activity. In HFrEF, the presence of CHIP was associated with elevated levels of IL-18 and TGF-b2. Surprisingly, the
presence of CHIP was not associated with higher levels of circulating IL-6, another
downstream marker of NLRP3 inflammasome activity.
IL-6 while not elevated in my CHIP cohort, is an important pro-inflammatory cytokine which appears to play an important role in CV disease. Therefore, I went on to examine levels of IL-6 in the observational study (Microvolt T wave alternans) dataset. Levels of IL-6 were high in patients with both decompensated HFpEF and HFrEF. Higher levels of IL-6 were associated with increased age in both groups. Higher levels of IL-6 were associated with an increased risk of all-cause mortality and CV death in HFrEF. Whereas higher levels of IL-6 were associatedwith an increased risk of all-cause mortality, CV death and 1st HF hospitalisation in patients with HFpEF. In HFrEF and HFpEF groups, IL-6 remained an independent predictor of events even after adjustment for established independent predictors or risk including BNP. This potentially suggests in my CHIP cohort that we saw a false negative due to small size and this warrants further investigation.
Levels of IL-6 are not routinely measured in clinical practice, and standard clinical haematological parameters such as RLC and NLR have found to be important in CV disease. In PARADIGM-HF and PARAGON-HF the distribution of RLC was similar in ambulatory patients with chronic HFrEF and HFpEF. Lower RLC was due to a higher total leukocyte (and neutrophil) count, as well as lower lymphocyte count. In each of HFrEF and HFpEF, lower RLC was associated with a similar higher risk of HF hospitalization and death (CV and all-cause). A 10% decrease in RLC was associated with a 17% higher risk of the primary composite end point in both the HFpEF and HFrEF. Importantly, treatment with sacubitril/valsartan appeared to attenuated reduction in RLC suggesting that HF therapies have an impact on circulating levels of inflammation over time.
Conclusion:
CHIP is common in patients with both HFpEF and HFrEF. CHIP appears to be associated with elevated levels of inflammatory biomarkers associated with the NLRP3 inflammasome. In patients with recently decompensated HFrEF and HFpEF, circulating levels of IL-6 were particularly high and correlated with worse CV events even after adjustment for established independent predictors of risk including BNP. Considering the findings of my thesis, further research into CHIP and its role as a marker and mediator of inflammation in patients with CVdisease is warranted. Further research is also necessary to determine if novel anti-inflammatory therapies might be beneficial for patients with HF and whether these may be personalised based on CHIP status and inflammatory biomarker profiles
The invention of the self in female travel writings: Isabella Bird, Alexandra David-Néel and Isabelle Eberhardt
Get PDFThe British writer Isabella Bird, the French writer and orientalist Alexandra David-Néel and the Swiss journalist and writer Isabelle Eberhardt all had travel in common. They wandered throughout the 19th and 20th centuries, a period when women were more associated with the home and therefore with immobility. These writers show how nomadism allows them to redefine themselves.
First of all, we will see that the reinvention of identity is done through a departure for elsewhere. Indeed, travelling to a new country (Japan, India, Tibet, Algeria) will offer the three writers the access to new practices, but these practices reflect the complexity of the relationship between the West and the East. That being said, Isabella Bird, Alexandra David Néel and Isabelle Eberhardt, thanks to an intellectual nomadism, break down the West-East binary opposition by questioning it. Indeed, they learn new languages (Arabic and Tibetan), they understand the culture of a different country, they participate in all kinds of local practices, and they even convert to a new religion: Buddhism for Alexandra David-Néel and Sufism for Eberhardt. In other words, they become the other, or rather they become other and show that identity is a process in constant movement.
The three women also challenge the opposition between women and men, shaking up the codes associated with their gender by travelling through spaces considered masculine, dressing as men, existing in the public and intellectual spheres. Isabella Bird was the first woman member of the Royal Geographical Society, Alexandra David-Néel travelled alone for 14 years and became the first European woman to enter Lhasa (a forbidden city at the time), and Isabelle Eberhardt lived her nomadic life under a male and Muslim identity .
But identity is also defined by the narrative. Indeed, we will see that their travel writings contribute to the reinvention of the self and even have a therapeutic effect. Whether through travel writings, fiction or letters: writing permits the performative to exist. Indeed, for Isabella Bird, Alexandra David-Néel and Isabelle Eberhardt, the reinvention of the self is found in the balance between the narrative and the performative, with a need to fix memories, to be one’s own witness to the evolution of the self while existing in the predominantly male public space
Controlling nanomaterial properties with the angular momentum of light
Get PDFThe properties of nanomaterials can be tailored through structural and geometrical design, chemical functionalization, strain engineering and other techniques. However,many existing methods for property control are either irreversible or depend on complexphysical set-ups, limiting their practicality and broader technological implementation. This thesis addresses that challenge by developing a non-contact, all-optical approach that leverages the orbital angular momentum carried by Laguerre-Gaussian beams.
The method is investigated for two different applications. In the first instance, the focus is given to orbital angular momentum transfer from Laguerre-Gaussian beams to two dimensional (2D) materials. A theoretical framework for calculating optical forces and torques in dielectric media is presented and angular momentum beams are implemented into a numerical simulation software to predict their effects on the 2D materials. Building on this, a novel, non-contact experimental method is developed to induce wrinkling in two common examples of 2D materials, monolayer graphene and WS2, using the optical torques of Laguerre-Gaussian beams. The out-of-plane deformations and property changes are characterized using various experimental techniques, including electrical conductance measurements, Raman spectroscopy, atomic force microscopy and photoluminescence. The method is reversible and spatially-selective and only limited by sample heterogeneity and monolayer-substrate interactions.
In the second instance, the application of optical angular momentum is extended to chiral sensing. The dynamic control of the optical activity of chiral shuriken meta-materials is demonstrated through numerical simulations and experimental dichroism measurements under varying beam focusing conditions. Together, this thesis highlights the potential of angular momentum beams as a versatile tool for controlling nanomaterial properties with high spatial precision
Scots emigrants to East Jersey, 1682-1702: motivations and outcomes
Get PDFBetween 1683 and 1685 several hundred Scots emigrated to East New Jersey, home to the Native American Lenape and earlier Dutch and English settlers. While Insh in his Scottish Colonial Schemes (1922) deemed this venture a success, it has been overshadowed by the later failure of the Darien expedition. It deserves attention, seeking greater understanding of the emigrants, their motivations, and the nature of ‘success’: what did this mean, and for whom?
This study delves into the backgrounds of the emigrants and what became of them in the period of settlement up to 1702 when New Jersey became a royal province. It adopts a prosopographical approach, based on a project database drawing on underused sources in Scotland and New Jersey. This captured details of 603 emigrants plus those of a wider range of people, including their kin in Scotland, influential supporters, absentee investors and emigration agents.
The research highlights an unusual mix of emigrants, brought together at a time of social strife and economic uncertainty. They came from discordant religious-cum-political groups (Royalists and religious moderates, Quakers and Covenanters), and included transported prisoners as well as free emigrants and indentured servants.
The dissertation provides fresh perspectives on the main protagonists and lesser-known figures, informed by a model of influences on decisions to emigrate. Distinctive features relating to their motivations include the influence of leaders, the closeness of kinship groups and business networks, religious affinity, and economic aspirations varying by social status.
Some free emigrants thrived, establishing farms and estates and doing well as merchants. Several played a substantial role in the governance of the province. Amongst indentured servants and Covenanter prisoners there were conspicuous examples of economic and social mobility. Others got by or struggled, and there is no record of over 40% after their arrival. Evidence suggests that in this period there were constructive relationships with
the Lenape, and few enslaved people were owned or employed by Scots.
The database can facilitate future prosopographical research, e.g., on longer term outcomes for emigrant families and on the activities and networks of Scottish East Coast merchants, including how family members established themselves in transatlantic trade based beyond Scotland
Attitude control and design of satellites with flexible structures using Inverse Simulation
Get PDFEnsuring the stable and accurate pointing of a satellite’s instrumentation is the task of the attitude control system, a problem made substantially more complex by the influence of flexible structural dynamics often exhibited by satellites. The inclusion of flexible structures is necessitated by the desire to maximise the satellite’s functionality while ensuring its mass and form factor are conducive to being launched into orbit. Commonly, satellites will make use of lightweight and flexible, deployable appendages to facilitate the mounting of additional instrumentation, larger antennas, and extra solar panels. In addition, the construction of larger flexible space structures, using advancing orbital assembly and manufacturing technologies, opens the door to complex missions such as space stations, space telescopes, large solar sail spacecraft, orbital solar reflectors, and space-based solar power satellites. While the variety of applications for flexible space structures may be wide, each will require stable and accurate attitude control of the satellite platform.
A range of attitude control methodologies for satellites with flexible structures has been studied previously, each attempting to achieve good tracking performance by imitating the satellite’s inverse dynamic behaviour. Many of these approaches are based on analytical techniques, requiring the control solution to be derived from a mathematical model that approximates the satellite’s dynamics. This thesis proposes that, if a sufficiently accurate mathematical model is available, then an alternative, highly-computational, numerical approach known as Inverse Simulation could instead be employed. Having already been demonstrated as a viable control methodology in several fields of research, such as planetary rovers and helicopters, this thesis will investigate the application of the generalised integral Inverse Simulation algorithm for attitude control of satellites with flexible structures.
As part of the thesis, several mathematical models for the Inverse Simulation numerical process to solve are derived. This includes models that assume only rigid body behaviour, those that consider the flexible dynamics of deployable appendages, and finally a modular model for large flexible space structures. These models also account for the dynamics of various actuator types, some of which may have an impact on the stability and performance of the integral Inverse Simulation algorithm.
The attitude reorientation manoeuvres used to drive the Inverse Simulation solution are provided using a mixture of polynomials, spherical interpolation, and splines. Before implementation as a control technique, the effect of each of the Inverse Simulation’s hyperparameters is studied to optimise the accuracy and computational efficiency of the algorithm. Additionally, issues of numerical stability specific to the application of satellites with flexible structures are identified and addressed.
It is found that the integral Inverse Simulation algorithm does provide a more flexible, practical, and accurate method for solving the inverse attitude dynamics of a satellite with flexible structures than alternative analytical techniques. The generality of the numerical process allows for a ready-to-go control solution, provided a suitable up-to-date model is available. The control methodology is however highly sensitive to model uncertainty and requires significant computational power to compute, somewhat limiting its practical use. Additional online parameter estimation and improved computational efficiency of the algorithm will therefore be required if the control approach is to be realistically used.
Inverse Simulation is also employed to improve attitude path planning, evaluating the performance of prospective paths to minimise excitation of the flexible structural dynamics. One of the most common applications of Inverse Simulation within the literature, as a conceptual design tool, is also demonstrated for satellites with flexible structures. It is shown that Inverse Simulation allows for the performance of different actuator configurations for large space structures to be assessed, informing designs that minimise structural deformation during slew manoeuvres. A final contribution of the thesis is the development of a faster integral Inverse Simulation algorithm based on Broyden’s method, improving performance particularly when a large number of inputs/actuators are in use
On the economic preferences towards household recycling in China: the role of social norm nudges and long-term life goals
Get PDFThis thesis examines the relationship between pro-environmental behaviour—specifically household waste recycling—and the impact of intervention policies and long-term personal goals. It investigates whether factors beyond the traditional neoclassical choice model, including external influences such as social norms and internal factors such as personal values, affect individuals' willingness to participate in community recycling programmes and their willingness to pay (WTP) for recycling.
Using a choice experiment (CE) approach, individual-level data was collected from residents in three Chinese cities: Zhengzhou and Shijiazhuang, which currently implement advocative policies, and Shanghai, where recycling is mandatory. The study first investigates whether differing local policy frameworks influence stated preferences (SP) for household recycling and evaluates how effective nudges are in enhancing recycling participation. Specifically, it examines the compatibility and consistency of nudges—such as descriptive social norm communication—with existing local recycling policies. A randomised experiment was designed, varying two dimensions of social norms: the proportion of residents reportedly participating in recycling and their geographical proximity. Results show that mandatory policies significantly outperform advocative approaches in promoting recycling participation. Social norms generally enhance recycling efforts; however, excessively high normative expectations can reduce motivation. Additionally, residents from cities with advocative policies demonstrated greater responsiveness to social norms than those under mandatory policies. The influence of social norms was also found to vary according to individuals' current recycling behaviours, being stronger among those who were initially less engaged.
The second aim of this thesis is to evaluate whether the integration of goal theories can enhance the Theory of Planned Behaviour (TPB) framework in the context of recycling. It examines whether life goals impact recycling preferences directly or indirectly through attitudes, perceived behavioural control, and subjective norms. Employing a Hybrid Mixed Logit (HMXL) model, the study investigates the relationships among TPB components, life goals (categorised as hedonic, gain-oriented, and normative), demographic factors, and recycling decisions. Findings indicate a strong relationship between positive recycling preferences and the TPB latent variable, suggesting that individuals with more favourable attitudes, greater perceived control, and subjective social norm demonstrate increased engagement in recycling. Moreover, specific recycling and disposal preferences are linked to normative life goals, underscoring that individuals driven by altruistic motivations prioritise effective waste management. Structural equation modelling confirms that normative life goals indirectly influence recycling decisions by strengthening key TPB elements
Exploring evolutionary dynamics of influenza viruses through the lens of equine influenza
Get PDFThough many vaccines exist to confer protection from Influenza A viruses, they remain viruses of great concern in both mammalian and avian species. Influenza A viruses circulate in many wild, domestic and human species; often with the potential to transmit between these populations. Emergence in these other populations can lead to widespread transmission and/or severe pathology and indeed has occurred multiple times over just the last century.
As obligate pathogens, influenza viruses are only able to evolve during infection of hosts, as it is the only setting in which they can replicate. However, in addition to the local environment (i.e. the infected host) influenza viruses must also adapt to transmission between hosts.
Differences between hosts can be minimal but may be as dramatic as alternative tissue tropism or even host species. This work aims to study how influenza viruses evolve both within infected hosts and across transmission events, and the interaction between these two,
sometimes competing, ecological niches that viruses must adapt to. Integral to the continued success of influenza viruses is the ability to circumvent the host immune system. Host adaptive immunity places strong selective pressures upon viral populations. Transmission experiments were carried out in which mixed populations of horses (either vaccinated or unvaccinated) were sequentially exposed to one another to create a five-step chain of transmission. The first experiment mixed naive individuals with horses that had received a multivalent vaccine, the second mixed naive horses with hosts that had received a univalent vaccine. Horses were nasally-swabbed daily in order to collect shed virus particles which could then be quantified and deep-sequenced.
137 qPCR values and 53 sequences of viral populations were collected. Differences in viral load, consensus genomes and lowfrequency mutations were observed across transmission chains and between vaccinated and unvaccinated hosts. Unvaccinated horses shed more virus than their vaccinated counterparts, though this difference was much greater when comparing naive hosts to those that received a multivalent vaccine. Conversely, genomic diversity at the consensus level appeared highest in hosts that received the monovalent vaccine - suggesting strong selective pressures that mutations are attempting to overcome. This genetic diversity however was not reflected in sub-consensus reads, where lessened selective pressures allowed for greater diversification of viruses replicating in unvaccinated hosts
Investigating the effect of PDE4D PROTACs in a cellular model of Parkinson’s disease
No full textAbstract not currently available
From emblem to album: transhistorical comparisons of text/image interplay in cover art and renaissance emblems
Get PDFDrawing upon a transhistorical perspective that has, over the past two decades, gained traction in visual culture and text/image scholarship (Daly, Mödersheim, Rypson, Van Dongen, and Grove), this thesis considers text/image interplay as exhibited in album cover art and Renaissance emblems (and emblematic manifestations) by drawing comparisons in form and function. Rather than provide an account of each form’s historical evolution in its multifarious cultural contexts, this study uses album covers and emblems as part of wider transhistorical comparisons of recurring communicative procedures in Western visual culture.
Chapter 1 begins by briefly addressing questions of definition with respect to the terms ‘emblem’ and ‘emblematic’, and then moves to explore what the existing literature has offered as a theorisation of emblematic text/image interaction. The second section of the chapter looks at the work previously carried out by text/image scholars who have also made transhistorical comparisons between the Emblematic Age and our modern text/image culture. These studies show that current-day emblematic parallels are discovered in symbolic advertising, tattoo art, American paperback covers, contemporary art, and bande dessinée. As such, Chapter 2 builds on this work by introducing album cover art to the critical discussion; an exploration of its design origins from a text/image perspective, a survey of existing scholarly approaches, and finally an ‘emblematic reading’ of cover art’s visual/verbal characteristics opens up new comparative dimensions. To draw a formal parallel between album covers and emblems, a set of threefold criteria is proposed and applied to a case in point.
The conclusions drawn in Chapter 2 are then applied to Chapters 3-5, which feature close analytical readings of text/image interplay in three examples of album cover art, spanning 1940–1970. By way of the criteria of visual topoi, bi-medial structure, and interactive hybridity, emblematic counterparts to these album covers are discovered and analysed. The overriding conclusion of this study is that through close analysis of selected cultural objects, we can identify analogous communicative tendencies involving the interaction of text and image across disparate historical periods and contexts in Western culture. To that end, this thesis asserts that album covers and emblems can further advance Grove’s notion of parallel mentalities with respect to the Renaissance period and our modern age
Advancing the concept of Democratic Public Ownership
Get PDFThis thesis examines and refines the concept of Democratic Public Ownership, which has emerged in both theory and practice in recent years as neoliberalism continues to mutate and falter. While increasingly referenced and discussed in academic, policy, and movement settings, Democratic Public Ownership currently lacks conceptual clarity, coherence, and distinctiveness, and could benefit from heightened scrutiny and development. This thesis reviews the modern literature on Democratic Public Ownership, investigating its connections to, and impact on, political economic shifts and theorizing since the turn of the 21st century (such as the global remunicipalization movement); identifies and analyzes numerous relevant historical and contemporary theories, experiments, and prototypes ranging from the early days of the industrial revolution to the Great Financial Crisis of the late 2000s; locates the concept of Democratic Public Ownership historically and ideologically as part of the broader effort to advance and implement systemically transformative visions of economic democracy, especially as it relates to moving beyond historical and contemporary versions of capitalism; and presents a refined and coherent concept consisting of a novel definition, numerous revised and new principles, and a suggested theory of change. This thesis significantly advances the literature and discourse on Democratic Public Ownership, economic democracy, and democratic participation in the economy more broadly, opening new research directions and serving as an important theoretical steppingstone
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