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High-sensitivity free light chain detection for minimal residual disease analysis in multiple myeloma
Get PDFPurpose: To overcome the various limitations of bone marrow-based minimal residual disease (MRD) measurement in patients with multiple myeloma (MM), the clinical Immunology service (CIS) at the University of Birmingham has developed a non-invasive, serum-based technique named hsFLC, which is capable of MRD detection via high-sensitive measurement of serum free light chains (FLCs). We compared MRD results from hsFLC analysis with those produced using multi-parameter flow cytometry (MFC). We also assessed the potential application of hsFLC for the diagnosis and monitoring of non-secretory (NS) and low-level FLC secretory MM patients.
Methods: The hsFLC assay combines isoelectric focussing with immunoblotting, and uses highly- specific mouse monoclonal antibodies targeted to FLCs. A total of 110 MM patient samples from the national Myeloma X & XI trials who had all undergone autologous stem cell transplants, were retrospectively analysed by hsFLC for the presence of MRD. From the selected patients, 54 had m-proteins with involved Kappa FLCs and 56 had involved Lambda FLCs at diagnosis. The original MRD results by MFC were available for 80 of these patients. A total of 29 MM patients clinically classified as NS from the national myeloma IX and XI clinical trials were also analysed by hsFLC for the presence of monoclonal FLCs. A small analysis of light-chain only MM (LCMM) and oligo-secretory MM (OSMM) patients was also conducted using hsFLC.
Results: Monoclonal FLCs were detected by hsFLC in all of the primary diagnostic samples tested, including the NSMM, LCMM and OSMM patients. MRD was detected in around double the number of post-transplant patients as those that were MRD-positive by MFC. Retrospective analysis of disease relapsed patients by hsFLC, demonstrated monoclonal FLCs several months before conventional methods detected any disease.
Conclusions: The hsFLC assay is a highly-sensitive and non-invasive alternative to bone marrow-based techniques for the systemic measurement of disease in almost all MM patients
“You’ve gotta be a man and be strong”: fathers’ experiences of perinatal loss in the Pakistani community
Get PDFThe literature review includes a meta-analysis of the prevalence rates of Postnatal Depression (PND) in Black ethnic groups compared to White ethnic groups. A systematic search found 27 articles up to April 2023, reporting prevalence rate data. The prevalence rate of PND was 15% in Black ethnic groups. The relative risk of PND in Black ethnic groups compared to White ethnic groups was higher at 1.29. The measure used for PND, country of recruitment and ethnic subtype are significant factors in these estimations. There appears to be no difference in prevalence rate of PND between Black ethnic groups and the global population. However, further research is needed to determine the suitability of PND measures alongside increased research with more Black ethnic subgroups.
The empirical paper is a qualitative Interpretative Phenomenological Analysis study exploring Pakistani father’s experiences of perinatal loss. Five men who had experienced perinatal loss took part in semi-structured interviews. Three Group Experiential Themes were identified – ‘A rollercoaster of emotions: from shock and distress to having hope’, ‘The hidden experience of baby loss as a Muslim man’, and ‘The felt stigma of baby loss in the Muslim community’. Findings suggest that perinatal loss results in ever-changing emotions for men. Perinatal loss was perceived as taboo, and the men wanted to be viewed as strong, meaning their emotional responses were often masked. Further research is necessary to consider how different experiences of perinatal loss (e.g. time since loss) may influence how men interpret their experiences of loss
Social and non-social reasoning in relation to autism and autistic traits
Get PDFFour experiments examined reasoning and decision-making tendencies across social and non-social domains in relation to autism and autistic traits in adults. Experiments were created to measure forced-choice judgments and written justifications in a comparison paradigm of social and non-social scenario-based domains. Three experiments used a scenario-based task to measure moral reasoning, while one experiment focused specifically on causal reasoning with a task following a common cause network structure.
Dual Process Theories propose a distinction between two types of information processing: intuition and deliberation. Intuition represents a quicker and more automatic process, while deliberation represents a slower and more effortful process. Following this notion, the Dual Process Theory of Autism suggests a tendency of greater deliberation and less intuition in decision-making and reasoning among autistic people and those with high autistic traits. To test this hypothesis across domains to see whether these tendencies are domain-specific or domain-general, three experiments (Experiment 1, 2, and 4) recruited participants from the general population and measured their levels of autistic traits. One experiment (Experiment 3) recruited autistic and well-matched non-autistic participants for a between group comparison.
Experiment 1 found a relationship between higher autistic traits and a greater reliance on deliberation for forced-choice moral judgments within the social domain, and not the non-social domain. However, Experiment 2, using a modified version of the same task, did not reveal such a relationship, which was supported with participants’ written justifications. Experiment 3 used the first version of the same task and found no meaningful differences between autistic and matched non-autistic people in their moral judgments. Experiment 3 revealed subjective yet not objective differences between groups in their reasoning and decision-making, suggesting a subjective preference for and performance in reduced intuition among autistic people. Finally, Experiment 4 revealed no substantial differences in levels of autistic traits between participants, clustered as decisive and indecisive reasoners, based on their reasoning tendencies. Consistently, across all experiments, a distinction between social and non-social domains in terms of reasoning and decision-making was found.
Taken together, this thesis suggests that there is strong evidence for a distinction between social and non-social domains in reasoning and decision-making. However, this thesis does not provide strong evidence for a greater deliberation and less intuition associated with a diagnosis of autism or high autistic traits. Nevertheless, mismatch between subjective and objective reasoning and decision-making among autistic people might suggest meta-cognitive differences to non-autistic people, rather than a difference in reasoning and decision-making
The immune response to SARS-CoV-2infection in tissue: A multi-omic spatial investigation
Get PDFThe SARS-CoV-2 virus primarily infects the lung and can induce a localised and systemic immune response, which in some patients, can be fatal. The virus can also infect other non-respiratory tissues such as the placenta. SARS-CoV-2 infection in the placenta is associated with fetal compromise and intra-uterine death. Whilst much work has been done to describe the systemic immune response to SARS-CoV-2 infection, little has been done to describe the immune response in primary tissue. Adopting a multi-modal, spatial profiling approach on fixed tissue specimens from post- mortem and pathology archives, I describe the characteristics of the immune response in COVID-19 lung tissue and COVID-19 placentitis. Multi-modal approaches contributing towards this deep phenotypic characterisation included bulk and spatial transcriptomics, multiplex immunohistochemistry, single-plex immunohistochemistry and RNAscope, enabling robust cross-validation.
Lung tissues from 8 post mortem COVID-19 patients were analysed and compared to diseased and normal controls. On histological assessment, the lungs of COVID-19 patients invariably showed diffuse alveolar damage, with varying degrees of fibrosis, vasculitis, thrombosis and secondary infection. SARS-CoV-2 virus was predominantly detected in early-stage disease within the epithelium and a small proportion of macrophages. Macrophages were the predominant immune cells, with less numerous infiltrations of granulocytes and lymphocytes. The immediate virus microenvironment was enriched for immune evasive PDL1 expressing macrophages and deplete of lymphocytes. Whilst virus was apparently cleared in later stage disease, the immune infiltrate appeared to increase. Collagens were upregulated in the interstitium of COVID-19 lungs, in particular collagen VI. Serum pro-collagen VI was measured in the serum of a cohort of living patients with variable severity COVID-19. Increased serum pro-collagen VI was associated with severe disease and poor outcome.
Placentas from 13 SARS-CoV-2 positive mothers histologically showed chronic histiocytic intervillositis (CHI) and massive peri-villous fibrin deposition (MPVFD) in most cases, with a small subset showing chronic villitis. Trophoblastic SARS-CoV-2 infection and intra-uterine death was exclusively associated with CHI/MPVFD. Trophoblastic SARS-CoV-2 infection, compared to diseased and normal controls, was associated with prominent M1 macrophage infiltration and enrichment for CD4+ T-cells and B-cells. Macrophages showed CXCL10 expression which is associated with immune cell recruitment and fibrin deposition. The immediate immune microenvironment showed enrichment for CD4+ T-cells and PDL1 expressing macrophages. Interferon responses were transcriptomically blunted in viral rich regions of the placenta. A subset of placentas from SARS-CoV-2 infected with CHI morphology showed no evidence of virus, which may represent viral clearance akin to lung infection.
In summary, both diseases are characterised by florid localised immune responses with prominent innate and adaptive immune cell infiltrates and marked alterations in tissue architecture. There are competing antiviral and immune evasive responses present in both infected tissue, which ultimately lead to the observed pathological changes. The changes observed in lung and placenta can be used to infer novel prognosticators and treatments. Specifically, the elevated collagen VI signature observed in post-mortem lung translates into a novel serum-based prognosticator for mortality in hospitalised COVID-19 patients. Furthermore, the observed upregulation of CXCL10 in macrophages in COVID-19 placentitis could represent a novel therapeutic target.
Overall, the study demonstrates how spatial profiling techniques can be harnessed to understand complex phenomena in fixed archival tissue, inferring data of clinical relevance
Mitigating the impact of COVID-19 in the United Kingdom through data to safeguard patients with cancer and an immunogenomic analysis of colorectal cancer
Get PDFAn immunogenomic analysis of colorectal cancer:
Anti-tumour immune responses in colorectal cancer (CRC) have been defined in the context of immune cell infiltration and checkpoint regulation. However, functional immunogenomic changes and interplay with other features of CRC biology have not been fully described. I performed transcriptomic immune expression profiling in CRC primary tumours, pre-CRT treatment rectal cancers, local lymph node metastases and adjacent normal tissue, and secondary liver metastases and lung metastases. This included developing a pipeline analysing the Cancer Immunity Cycle and cancer antigen presentation characterised using validated gene sets, with immune expression profiles subsequently compared to other CRC features. I observed enrichment of functional immune gene sets defining immune cell infiltration into tumours and cancer cell killing in microsatellite instability and right-sided CRC tumours. Cancer antigen presentation signatures were highly expressed in rectal cancers with good CRT responses and expression within lymph nodes associated with early-stage CRC tumour proliferation and aggressiveness, corresponding with clinical outcomes. Higher tumour-infiltrating lymphocyte expression, driven by increased MHC Class II antigen presentation and cDC1 dendritic cell expression activity, was observed in CRC lung metastases. Better understanding immune functionality underlying anti-tumour responses is important for identifying CRC patients with increased risk of CRC tumour recurrence/metastasis and may elucidate novel targets for immunotherapy.
Mitigating the impact of COVID-19 in the UK through data to safeguard patients with cancer:
Individuals with a cancer diagnosis were reported to have poor clinical outcomes associated with COVID-19. following infection. However, cancer is a heterogeneous group of diseases and studies assessing individual risk, and benefits of COVID-19 vaccines, had not previously been performed using population-level data. I evaluated COVID-19 disease phenotype in patients with cancer compared to the general population and within cancer subgroups in 2020 and over the course of the pandemic, assessing the effects of cancer features and demographics, and determining the efficacy of vaccines from SARS-CoV-2 antigen and antibody testing data. An acute COVID-19 disease phenotype was observed in patients with cancer in 2020 but became less severe over the course of the pandemic. COVID-19 vaccines provided effective protection against infections, severe disease, and COVID-related mortality for many patients with cancer. However, individuals with cancer show lower levels of vaccine protection and more rapid waning, reduced post-vaccine antibody responses, and remain at higher risk of COVID-19 hospitalisation and death compared to the general population. Individuals with haematological malignancies had the lowest level of vaccine protection and poorest post-COVID-19 outcomes. The overall impact of COVID-19 is heterogeneous but individuals with cancer still require protection from being exposed to COVID-19
Foundations of digital circuits: denotational, operational, and algebraic semantics with applications to graph rewriting
Get PDFThis thesis details the culmination of a project to define a fully compositional theory of synchronous sequential circuits built from primitive components, motivated by applying techniques successfully used in programming languages to hardware.
The first part of the thesis defines the syntactic foundations required to create sequential circuit morphisms, and then builds three different semantic theories on top of this: denotational, operational and algebraic. We characterise the denotational semantics of sequential circuits as certain causal stream functions, as well as providing a link to existing circuit methodologies by mapping between circuit morphisms, stream functions and Mealy machines. The operational semantics is defined as a strategy for applying some global transformations followed by local reductions in order to demonstrate how a circuit processes a value, leading to a notion of observational equivalence. The algebraic semantics consists of equations for bringing circuits into a pseudo-normal form, and then encoding between different state sets. This part of the thesis concludes with a discussion of some novel applications, such as those for using partial evaluation for digital circuits.
While mathematically rigorous, the categorical string diagram formalism is not suited for reasoning computationally. The second part of this thesis details an extension of existing work on string diagram rewriting with hypergraphs so that it is compatible with the traced comonoid structure present in the category of digital circuits. We identify the properties that characterise cospans of hypergraphs corresponding to traced comonoid terms, and demonstrate how to identify rewriting contexts valid for rewriting modulo traced comonoid structure. We apply the graph rewriting framework to fixed point operators as well as the operational semantics from the first part, and present a new hardware description language based on these theoretical developments
Oliver O’Donovan’s moral theology, world order, and the practice of ecological restoration: a theological phenomenology of ecological restoration
Get PDFThe United Nations has named the decade of 2021-2030 “The UN Decade of Ecosystem Restoration”. According to the UN scientists, this decade represents the last chance to avoid catastrophic climate change. There has never been a more perspicuous time for theologians to address the issue of ecological restoration. The problem is a fundamental question about who we are as modern humans, what constitutes a world, and the relation to temporality. In other words, the answer is deeply theological. In this thesis, I argue that thinking about restoration requires a theological phenomenological exploration of self, world, and time. I examine Oliver O’Donovan phenomenological ethics series, Ethics as Theology, as an applied ethic for understanding the relationship between Creator, creature, and ecological restoration. I propose that O’Donovan’s theological phenomenology approach to ethics allows for a ground-up look at the practice of restoration, from a dirt under the fingernail perspective. My approach is multi-faceted, arguing that restoration must address various concerns—a shared world, subjectivity, and temporal limits. I present theological phenomenological ethics as a countervailing method to the anxiety inducing neoliberalism by appealing to the moods of faith, hope, and love. Highlighting these relationships is intended to elucidate for Christians how they might think about ecological restoration and degraded ecosystems. To illuminate these issues, I critique current restoration practices that I argue are antithetical to a Christian ethic—specifically those associated with neoliberalism
Experimental and numerical study of Triply Periodic Minimal Surface structures
Get PDF3D printing is an emerging additive manufacturing technology that has revolutionised the development of new materials and structures across various industries. Its ability to produce complex shapes with ease has notably contributed to many fields. Among these innovations, Triply Periodic Minimal Surface (TPMS) structures stand out as a novel type of porous structures, characterised by their particular features such as high specific strength and stiffness. These structures, resembling forms found in biological systems, have become a focal point in materials research over the last decade.
In the last few years, civil engineering practitioners started exploring applying TPMSs in their field. Previous studies on TPMS, however, have largely focused on small-scale material properties, limiting their direct applicability in civil engineering contexts. The structural properties of large-scale TPMS structures, including their static and dynamic characteristics, remain largely undefined. This gap signifies a crucial need for further exploration of large-scale TPMS structures, especially for applications in civil engineering, like railway engineering.
This thesis investigates the suitability of TPMS structures for civil engineering (specifically railways), undertaking a series of static and dynamic studies. The research begins by establishing simplified models of several TPMSs and proceeds to design corresponding solid models. Several TPMS structures have been 3D printed to create large-scale samples for compressive testing. Based on these tests, Finite Element Method (FEM) models of individual unit cells are developed and validated, allowing for the generation of complex structures and their subsequent numerical analysis.
To examine the effect of unit arrangement on the mechanical and cracking behaviours of specific TPMS structures, the Discrete Element Method (DEM) has been employed. This approach utilises the compressive test data of individual units to validate the DEM models. The study then numerically simulates various TPMS configurations, performing a mesoscopic analysis of their behaviour.
To assess the dynamic properties of these structures, multiple TPMS units have been 3D printed and subjected to impact hammer tests. This testing analyses the frequency, dynamic stiffness, and damping characteristics of the structures. A combined DEM and FEM approach conceptualises the TPMS structure as a support layer in railway applications, examining its mechanical performance under sleeper displacement. Finally, the thesis explores the applicability of concrete TPMS structures by modelling concrete TPMS structures under combined compressive and torsional loads via DEM
Invariant Gibbs measures for dispersive partial differential equations
Get PDFThis thesis focuses on the construction of Gibbs measures, their invariance under the flows of Hamiltonian partial differential equations, and their application in understanding macroscopic properties of these partial differential equations. The presentation of these focuses will be carried out through the example of Gibbs measure for the fractional nonlinear Schr\"odinger equations posed on the torus.
In Chapter 2, we consider the Cauchy problem for the cubic nonlinear fractional Schr\"odinger equation (FNLS) on the circle, considering initial data distributed via the Gibbs measure. By reformulating the local theory via the random averaging operator theory from Deng-Nahmod-Yue [34, 35], we construct global strong solutions with the flow property for FNLS on the support of the Gibbs measure in the full dispersive range, thus addressing a question proposed by Sun-Tzvetkov [105]. Additionally, we prove the invariance of the Gibbs measure and the sharpness of the result. This chapter mainly comes from [70].
In Chapter 3, we study the Gibbs measures for the focusing mass-critical fractional nonlinear Schr\"odinger equation on the torus . We identify the critical nonlinearity and optimal mass threshold for normalisablity and non-normalisability of the Gibbs measures for the fractional nonlinear Schr\"odinger equation on the multi-dimensional torus, which extends the works of Lebowitz-Rose-Speer [68], Bourgain [2], and Oh-Sosoe-Tolomeo [85] on the nonlinear Schr\"odinger equations on one-dimensional torus . To achieve this purpose, we prove an almost sharp fractional Gagliardo-Nirenberg-Sobolev inequality on the multi-dimensional torus. This chapter is from [69]
Speed freaks: acceleration & accelerationism from the mid-century to now
Get PDFThroughout this thesis I examine accelerationism in select works from the mid-century through to the contemporary moment. I characterise accelerationism as a litany of affirmative responses to experiences of “acceleration”, the idea that forms of technological and social change, as well as the pace of life, are increasing. Contemporary studies of acceleration tend to focus on its negative aspects by expressing critical concern for its deleterious consequences on individuals and institutions. Accelerationists take a different view. Existing on the inverse, mirror-side, of ambivalence, accelerationists either accept or embrace the consequences of acceleration. In doing so, they perform a political gesture, one which both observes and hopes to overcome a stasis that they associate with a given political status quo.
As political gestures go, it is my view that accelerationism is an uneasy one. The idea is obtuse, often favouring complicity with the harms of frenetic change over other forms of political resistance. This often makes the perspectives of its adherents questionable and, at times, even outright reactionary. Yet, accelerationism is a position that has persisted and that continues to manifest alongside acceleration at varying levels of intensity. It is my contention in this thesis that it was palpable in the works of advocates for mass and consumer culture in the fifties, in visual arts that championed change in the sixties, and in the digital “revolutionaries” of the nineties. It also remains detectable today in proponents of spaceflight and automation. This continued insistence of accelerationism throughout the twentieth century, and into the twenty-first make probing it a necessity. Working at the intersection between art and literature, throughout this thesis I analyse examples of accelerationist responses to experiences of acceleration in order to both clarify what accelerationism is, and critique it. In doing so, I produce the first sustained study that analyses and synthesizes the accelerationist currents of the Independent Group, Eduardo Paolozzi, and J.G. Ballard, while furthering studies of contemporary accelerationism and the outputs of the Cybernetic Culture Research Unit. This research will be of interest to audiences hoping to gain greater insight into the conflicted political terrain that is accelerationism, and for those more generally interested in cultural responses to acceleration
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