The diagnostic use of metabolomics for the identification of secondary infections in critical coronavirus disease 2019

Background: Critically ill patients with coronavirus disease 2019 are at high risk of developing secondary infections, which pose a challenge to identify clinically. Empirical antibiotic usage in this group is therefore high. Identification of novel biomarkers of secondary infections would minimise unnecessary antibiotic usage while ensuring that patients with secondary infections receive appropriate antibiotics as early as possible. This project aimed to investigate whether metabolomics could produce a panel of biomarkers capable of distinguishing critically ill coronavirus disease 2019 patients with and without secondary infections. Methods: Blood samples were collected from patients in critical care with coronavirus disease 2019, along with a group of healthy volunteer controls. Using high performance liquid chromatography-mass spectrometry, metabolites which showed significant differences in abundance between patients with and without secondary infections were identified. A panel of metabolites capable of distinguishing Gram positive and negative infections was also explored. Results: A total of 105 patients were recruited to the study, of whom 40 developed a secondary infection during the trial period. The metabolites creatine and 2-hydroxyisovalerylcarnitine were significantly increased in patients with secondary infections, while S-methyl-L-cysteine was significantly reduced. This metabolite panel demonstrated good diagnostic performance with an AUROC of 0.83. The panel of metabolites distinguishing Gram positive and negative infections consisted of betaine, N(6)-methyllysine and four phosphatidylcholines. This panel performed with high accuracy, with an AUROC of 0.88. Conclusion: Metabolomic profiling may be used to identify biomarkers of secondary infections in critically ill coronavirus disease 2019 patients. Investigation of biomarkers for secondary infections in other critical illnesses should be explored

Understanding the role of genetic testing in parental adjustment to their child’s developmental and epileptic encephalopathy or treatment-resistant epilepsy diagnosis

Abstract available at each chapter

The application of the Delphi methodology in intervention development for social withdrawal and Hikikomori

Abstract available at each chapter

Micro-optics: From wormholes to medical applications

Lying within the overarching boundaries of micro-optics, this thesis begins by exploring two different “pixelated” approaches to medical spectacles. The first was aimed as a treatment alternative to surgical corrections for torsional diplopia (double vision due to a relative eyeball rotation around the back-to-front axis). To do this, the spectacles were designed to approximately rotate the view seen through them. In the very basic design consisting of simple wedges (each of which we call a pixel), the component does not actually perform imaging leading to a reduced visual acuity of about 6/420. This was worse than desired, which is why the latter half of the chapter was designated to implementing methods that may improve the visual acuity, consisting of a pupil restriction and a new approach we call derivative control. Using this, the visual acuity was improved to a value of about 6/35, but at the cost of added complexity and bulkiness. The second spectacle pair was designed to help with uncorrected refractive errors by permitting patients to adjust the focusing power of the spectacles through simply rotating two cylindrical lens spirals relative to one another. The combination yields an equivalent Fresnel lens, which is the reason we call these adaptive Fresnel lenses. These were simulated in the ray optical limit, yielding an expected feasible variable range of ±2 diopters. Several configurations were explored where the distances and spiral types were varied, with ray trace simulations confirming the expected view through the adaptive lens. The other half of the text is dedicated to an extension of the previously published ideal lens cloak. The cloaking principles were explored, yielding conditions for which a light ray within the cloak must remain within the cloak and hence travel in a closed ray trajectory. These were used in the theoretical creation of a novel “extreme omnidirectional ideal lens cloak” which hides an object within from all viewing directions. Furthermore, attractor-like properties were found within the cloak, trapping some light rays entering from the outside. These properties were also found in a more realizable cloak we call the “shifty cloak”, which suggests significant similarities between the two cloaks. The shifty cloak was used to construct a Janus device and an optical wormhole, the latter of which was adversely affected by the attractor properties

Gendered power dynamics and the development of Mammisi Temples in Ptolemaic Egypt: reading Cleopatra VII in context

Despite the large body of research dedicated to the reign of Cleopatra VII in Egypt, little of it relies on evidence from Egypt during her reign as its primary source material. What little is referenced is often read out of context and used to prop up themes established by foreign authorship without consideration of potential conflict of interests held by the authors of these texts, or ethnocentric beliefs about Egypt and the Ptolemaic Period as a whole, which may alter both ancient and modern authors’ ability to interpret the information that is being discussed. For this study, I developed an intersectional approach to understanding gendered power dynamics as they developed in Egypt during the Ptolemaic period, their correlation with Cleopatra VII’s reign and method of rulership. This new approach focuses on establishing patterns in religious iconography sourced from Ptolemaic Mammisi Temples and utilizes new analytical tools to allow for a more dynamic discussion of themes of legitimacy, power, and gender which would in turn affect the politico-religious landscape during Cleopatra VII’s reign

Investigating the innate immune barriers that constrain the transmission of coronaviruses

Since the turn of the century, the emergence of three highly pathogenic coronaviruses highlights the importance of understanding coronavirus-host interactions. If sufficient cellular factors are available for a virus to complete its life cycle, genome-encoded post-entry blocks to replication may determine whether virus replication is successful. One such barrier is the interferon response, a signalling pathway upregulating hundreds of interferon-stimulated genes (ISGs), many of which encode proteins with specific and potent antiviral activity. The presence and timing of a functional interferon response is important in controlling coronavirus infection. Thus, identifying ISGs with antiviral activity can provide insights into genetic risk factors associated with coronavirus disease severity and the barriers to coronavirus zoonosis. To identify ISGs that inhibit unmodified coronaviruses, I optimised an arrayed ISG expression screening protocol that utilises immunostaining of the dsRNA replication intermediate and quantification of virus infection by plate-based image cytometry. I screened the endemic coronavirus HCoV-OC43 against multiple ISG libraries encoded into lentiviral vectors, including three published species libraries (human, macaque, bovine) and two newly generated libraries (mouse, bat). This revealed ISGs with known and novel antiviral activity against coronaviruses, including 2’-5’-oligoadenylate synthetase 2 (OAS2). OAS proteins classically activate RNase L via the synthesis of 2’-5’-oligoadenylates, resulting in the degradation of cellular and viral RNA. Alternative splicing generates two OAS2 isoforms, p69 and p71, exhibiting differential antiviral activity. I show that the p69 isoform restricts HCoV-OC43,while the p71 isoform restricts the unrelated picornavirus Cardiovirus A (EMCV) via different mechanisms. The OAS gene family thus enhances antiviral breadth in the host genome by both gene duplication and alternative splicing. This research has provided insights into how coronaviruses interact with the innate immune system

An investigation into the influence of the systemic inflammatory response on treatment response to neoadjuvant chemoradiotherapy in rectal cancer

An abnormal systemic inflammatory response is associated with adverse short and long term outcomes in cancer. Systemic inflammation can be a surrogate maker of the interaction between host immune response and tumour. Systemic inflammation can influence treatment response to chemoradiotherapy. At present there is no reliable biomarker of response to chemoradiotherapy in rectal cancer. This thesis examines the influence of the systemic inflammatory response on treatment response to neoadjuvant chemoradiotherapy in rectal cancer. A dataset of patients receiving neoadjuvant long course chemoradiotherapy (CRT) for non metastatic disease followed by potentially curative resection for rectal cancer was compiled from two prospectively databases of patients treated at Glasgow Royal Infirmary from 2008-2014 and the wider West of Scotland between 2014-2016. Blood results and clinic-pathological data for these patients were collected from electronic patient records to create a comprehensive dataset. Biomarkers of systemic inflammation included: differential blood count; neutrophil to lymphocyte ratio (NLR); haemoglobin; C reactive protein; albumin; and modified Glasgow Prognostic Score(mGPS). Treatment response to chemoradiotherapy was quantified with tumour regression grade, pathological complete response and the neoadjuvant rectal score. I observed white cell count (WCC), NLR and mGPS were not associated with treatment response. Lower haemoglobin and elevated CEA were associated with poorer tumour response. There was no association with changes in WCC, NLR, CRP and tumour response. I observed the development of lymphopenia during treatment but no association with tumour response. I observed baseline anaemia was associated with poorer tumour response and an association between anaemia and systemic inflammation. A significant proportion of my time was in the recruitment and coordination of sample collection for a novel pilot study for the feasibility of protocolised blood and tumour sampling during neoadjuvant therapy. I have not demonstrated an association between serum markers of systemic inflammation and treatment response. I have demonstrated anaemia is a marker of poor response and the association between anaemia and systemic inflammation. This highlights the difficulty in measurements of the systemic inflammatory response from routine blood tests and the importance of more detailed study of markers of systemic inflammatory response which are being done in research settings rather than routine clinical practice. This would help identify reliable biomarkers of treatment response to neoadjuvant chemotherapy and organ preservation strategies

Human behavior-driven robotics and security

Abstract not currently available

A new measurement of the neutron electric form factor with the Super Bigbite Spectrometer apparatus

Protons and neutrons, collectively known as nucleons, make up the nuclei at the core of atoms which form our world. The nucleon has been under intensive study for over 100 years, and yet we still do not fully understand the internal dynamics which govern properties like its spin or its mass - which contributes to almost all of the visible mass in the universe. These dynamics are governed by quantum chromodynamics (QCD), the predictions of which are experimentally tested at high energy accelerator facilities such as Jefferson Lab. The GEN-II experiment (E12-09 016) is one such experiment. GEN-II is part of the Super Bigbite Spectrometer (SBS) experimental form factor programme taking place in Hall A at Jefferson Lab, which aims to make precision measurements of the nucleon electromagnetic form factors (EMFFs) at record high values of squared four-momentum transfer Q2 . EMFFs describe the electric and magnetic moment distributions within the nucleon. They can be measured through elastic electron scattering off the nucleon, and describe the recoil response of the target nucleon at a given energy scale. GEN-II is a double polarised semi-exclusive beam target asymmetry (BTA) experiment, seeking to measure the electric form factor of the neutron, GnE, at three new values of squared four-momentum transfer Q2 = 2.92,6.74 and 9.82 GeV². The latter two points being at record high Q2 . The form factor is determined through measuring the BTA of quasielastic scattering of a neutron from a polarised nuclear target. The experiment utilised the CEBAF accelerator to produce longitudinally polarised electrons up to ∼85% polarisation, which were scattered off neutrons within a novel polarised helium-3 (³He) target. This new polarised ³He target was employed by building on the technology of its precursors which existed in similar preceding experiments. This target was designed to operate at the high luminosities typical of Hall A, and reached a record breaking combination of polarisation and beam intensity known as figure of merit, three times larger than those predecessors. The SBS collaboration designed and constructed two brand new high acceptance spectrometers for these experiments, an electron arm named Bigbite (BB) and a hadron arm named Super Bigbite. Both spectrometers featured a large acceptance EM dipole magnet, and complementary detector systems. The electron arm contained gaseous electron multipliers (GEMs) which were used for high precision tracking of the scattered electrons, a heavy gas cherenkov (GRINCH) which was used for PID between electrons and pions, a plastic scintillator timing hodoscope to provide high resolution timing of the start of events, and a pair of EM calorimeters (BBCal) which provided energy measurements of detected particles, and provided the experimental trigger. The hadron arm also contained a system of GEMs which will be utilised for future SBS experiments, and a hadron calorimeter designed to provide position, timing and energy measurements of the recoiling nucleon. The calibration of all detector subsystems, beam and target data is discussed, with a focus on novel timing calibrations to the hodoscope and hadron calorimeter. An analysis of selecting quasielastic events and suppressing background contributions from a number of sources which contaminate the final event sample is given. The largest irreducible backgrounds are found to be from misidentified protons, timing accidentals and inelastic events. The physical asymmetry is measured and used to extract a value for the form factor ratio GnE/GnM. High precision Q2 data for GnM is used to then extract GnE. This work finds at Q2 = 2.92 GeV2 that GnE = 0.0129+0.0019 −0.0020. This result is in statistical agreement with existing fits to world data, and predictions from the constituent quark model and Dyson–Schwinger equations, in this region of Q2

Spatial variability of meander characteristics in an avulsing distributive fluvial system

Previous studies of meandering fluvial systems have mainly focused on meanders at a localised ‘reach’ scale within a river system, without consideration of the spatial context. As such, much of the research has focused on exhumed meander deposits instead of active meanders. More research is therefore required on the spatial variability of meander deposits across a single system or sedimentary basin. Recent research has found meandering fluvial systems to be a dominant planform type in modern-day sedimentary basins; meander deposits are consequently assumed to be more dominant than originally perceived in the fluvial rock record. Distributive fluvial systems (DFSs) have also been shown to dominate sedimentation patterns in modern-day aggradational sedimentary basins and therefore warrant further study due to their abundance. Due to the prevalence of meandering systems and distributive fluvial systems in modern-day sedimentary basins, this study aims to fill a critical literature gap with regards to the spatial and temporal variability of meander characteristics across a modern-day distributive fluvial system (i.e., from apex to toe of a DFS). This study uses satellite imagery of Brazil, acquired through Google Earth Engine and analysed in ArcGIS software, to conduct a spatial analysis of the meandering Taquari DFS. The Taquari DFS is a well-documented, dominantly meandering system, which provides a good spatial context for the study of meander characteristics across the DFS. Spatial changes in: channel width, channel belt width, meander deposit dimensions and sinuosity are quantified on the Taquari DFS to explore downstream changes in meander characteristics within this system. Polygons are created in ArcGIS using the available satellite imagery, which allows for detailed measurements of meander dimensions downstream. This study also explores the temporal changes in channel width, channel belt width, meander deposit dimensions, and sinuosity on the Taquari DFS since the initiation of the large Caronal avulsion (initiation between 1996 to 1997) by comparing meander dimensions pre-avulsion and during-avulsion. The Caronal avulsion is ongoing and continues to divert flow from the parent channel to the avulsed channel. Using the oldest and most modern satellite imagery available from 1985 and 2022, respectively, fluvial dimensions are compared between pre-avulsion (1985) and during-avulsion (2022) imagery, to understand the impact of the avulsion on the parent channel (active channel) and its associated channel belt and meander deposits. On the modern Taquari DFS (2022), active variables (i.e., active channel width, active channel belt width, and active meander deposit dimensions) show a decrease in dimensions downstream, with a significant decrease in dimensions downstream of the avulsion point (where flow is diverted to the avulsed channel). Pre avulsion variables were also identified on the 2022 satellite imagery including pre avulsion channel belt width and abandoned meander deposit dimensions. Pre-avulsion channel belt width displays weak downstream trends and abandoned meander deposit dimensions display no downstream trends. Important differences in downstream trends were identified between active and abandoned meander deposit dimensions along the Taquari DFS. The active meander deposits are larger in size than the abandoned meander deposits upstream of the Caronal avulsion point and the abandoned meander deposits are larger than active meander deposits downstream of the avulsion point. The active meander deposits also show clear changes in size and shape downstream as they change from larger, more rounded deposits, to much smaller crescent-shaped deposits. The abandoned deposits however, display a range of shapes and sizes downstream and show no clear decrease in size, especially between medial and distal DFS zones. The decrease in active meander dimensions (active channel width, active channel belt width, and active meander deposit dimensions) is due to a decrease in discharge downstream as a result of typical DFS bifurcation processes in addition to the diversion of flow from the parent channel to the avulsed channel. Active meander deposit size and shape change downstream as sediment load, and therefore deposition, decrease as discharge decreases. The weak downstream trends displayed by the channel belt relate to confinement in the upper DFS where channel belt migration capacity is limited. The lack of downstream trends displayed by the abandoned meander deposits is due to the range of conditions under which these deposits were formed over time. This research has important implications for the understanding of avulsing rivers due to the significant decrease in width of the parent channel and the size of active deposit dimensions downstream, which influence the redistribution of water and sediment resources within modern DFS. In addition, this research creates an important database on the spatial variability of meander deposit dimensions on a modern DFS which can contribute to the understanding of sandstone-body reservoir dimensions which is important for resource exploration or hydrocarbon storage