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Risk factors and survival analysis in high-risk penetrating keratoplasty: a retrospective cohort study in 220 patients
No full textAbstract Background High-risk penetrating keratoplasty (HRPK) is associated with significantly reduced graft survival compared to low-risk cases, with 5-year survival below 35% in developed countries. However, risk factors and outcomes may differ in developing regions where infectious and traumatic indications are more common. This study evaluates the 1- to 5-year graft survival rates and identified independent predictors of graft failure in HRPK from a tertiary center in China. Methods We performed a retrospective cohort study of 220 HRPK adult patients between December 2019 and December 2023, meeting standardized high-risk criteria including corneal neovascularization in two or more quadrants, re-transplantation, active inflammation, or combined procedures. Preoperative, intraoperative, and postoperative data were collected. Graft failure was defined as central corneal opacity of ≥ 4 mm or persistent corneal edema. Multivariable Cox regression analysis identified independent risk factors, and a prediction nomogram was created and validated via bootstrapping. Results Graft survival rates at 1, 3, and 5 years were 82.7%, 46.3%, and 34.7%, respectively. Graft failure occurred in 113 cases (51.36%) over the total follow-up period. Compared to non-failure cases, the failure group had higher rates of re-transplantation (53.1% vs. 38.3%, p = 0.039), peripheral anterior synechiae (63.7% vs. 47.7%, p = 0.024), and 4-quadrant neovascularization (34.5% vs. 17.8%, p = 0.036). Cox proportional hazards regression identified advancing age (HR 1.02 per year, 95% CI 1.01–1.04, p = 0.023), graft diameter ≥ 9 mm (HR 1.74, 95% CI 1.12–2.71, p = 0.02), and 4 quadrants of neovascularization (HR = 2.53, P < 0.01) as independent predictors of failure. Peripheral anterior synechia and re-transplantation were also associated with increased risk. The five-variable predictive nomogram showed moderate predictive performance for 3-year (AUC = 0.715) and 5-year (AUC = 0.770) survival rate, with strong calibration. Subgroup analysis indicated that mycophenolate mofetil was mostly administered to higher-risk patients; however, propensity-matched analysis demonstrated no significant survival advantage (50.0% vs. 50.0% failure rate, p = 0.856). Conclusion This study identified advanced age, a large graft diameter (≥ 9 mm), and 4 quadrants of neovascularization as significant predictors of HRPK failure, with an especially elevated risk during the initial three postoperative years. Risk-based immunosuppressive strategies and close monitoring are essential to improving long-term outcomes in this high-risk population
Sacred Architecture in the (Post-) Secular Age: Dwelling in the Norfolk Churchscape
No full textThe United Kingdom can be said to be on the threshold of a post-Christian age. This poses an obvious and serious question about the fate of the 16,000 parish churches that have for so long played a central role – visually, socially, and philosophically – in our landscapes and communities. Many in the Church of England who view churches chiefly as venues for public worship would, as a result of decreasing attendance figures and increasing fabric maintenance costs, like to see the Church accelerate its divestment of churches. Meanwhile, other actors such as heritage funders tend to view them as historic buildings like any other. Redundant churches are sold, often for secular use, unless they can be vested with the Churches Conservation Trust, and churches at risk are often reordered to create ‘multi-use’ or ‘multi-purpose’ – i.e. secular – spaces, in the hope that this might help fund the fabric. This leaves churches between Scylla and Charybdis; that is, between those concerned primarily with the immaterial, relational aspects of religion and those whose sole focus is on the material.
If we don’t attempt to find a middle ground between purely immaterial religious concerns and purely material heritage concerns, the category of sacred space may disappear altogether. That being so, it seems imperative to ask whether the immediate and more long-term survival of both the material and immaterial dimensions of churches might be better secured if we ask why we might want to preserve these particular edifices – what it is they might do for us that other edifices don’t – and that we also consider the possibility that 21st-century needs may in fact include existential spaces. After all, whether or not we subscribe to any particular religion, we remain existential beings, i.e. self-conscious beings aware of our own mortality, with a built-in capability – and predilection – for posing the metaphysical questions that an awareness of mortality invariably brings. Pursuant to which, statistics about British religiosity reveal that while the majority do not consider themselves religious or harbour any particular denominational beliefs, few call themselves atheists, many are rediscovering the art of pilgrimage, and most pray. Between the demise of organised religion and the continued existential needs of the non-religious lies a serious and thrilling possibility, as yet unexplored, of re-engagement with sacred architecture. I propose that our best chance of saving churches in a post-Christian – but also ostensibly post-secular – age lies in minding the gap bridged by an enduring need for transcendence.
Although phenomenology is a leading approach among both theorists and practitioners in the field of architecture and has of late also made inroads among cultural heritage scholars, it remains oddly neglected among those managing and researching specifically religious heritage. Yet, I am convinced that it takes a phenomenological perspective to bring into focus the true reason for preserving historic churches and that the very lack of these perspectives is putting them at further risk. As the first large-scale phenomenological study of historic churches, this project explores whether we still need sacred spaces in the 21st century and what conceivable role churches could play in the approaching post-Christian era by apprehending and describing in what ways the 659 extant medieval churches of the Norfolk churchscape embody Martin Heidegger’s mythic-poetic concept of ‘dwelling.’ This concept enables a (re)consideration of the proper mode of perceiving and engaging with these churches as things not reducible either to a collection of art-historically notable buildings or as the defunct and costly relics of public worship spaces of a religion on the run. Instead, it grants a possibility for Mystery to prevail beyond religious dogmas, decrees, and denominations and allows for an imaginative retrieval of Norfolk’s churches as thinging, worlding things with the power of mobilising our slumbering disposition to see ourselves as being-in-the-world – in other words, as sacred
Development of Novel Host-Directed and Antibacterial Compounds for Tuberculosis Therapy
No full textTuberculosis (TB) remains a top 10 cause of death globally, with its causative agent Mycobacterium tuberculosis (Mtb) being the single deadliest infectious agent. The immune response is often unable to effectively fight Mtb infection as the bacteria is adept at manipulating and exploiting the immune system for its survival and persistence. Treatment for TB has been relatively unchanged for decades, involving a 6-month course of up to 4 antibiotics under the best of conditions, which is rapidly losing efficacy due to the acceleration in antibiotic resistance emergence. It is therefore imperative to not only develop novel antibiotics, but to also look beyond antibiotic therapy and develop alternative treatment strategies.
One such alternative strategy is host-directed therapy (HDT), an approach aimed at targeting the host to improve the immune response to infection, which is significantly impaired by Mtb. In this thesis, I demonstrate the viability of targeting the host phosphatase PPM1A for TB HDT, and developed a novel small molecule inhibitor (SMIP-30) that is able to boost clearance of Mtb by macrophages. Mechanistically, SMIP-30 enhances autophagy in macrophages, which is the primary mechanism by which the drug promotes Mtb clearance. SMIP-30 also induces selective apoptosis of infected macrophages, leading to increased efferocytosis of apoptotic cells and enhances bacterial clearance through this mechanism as well. SMIP-30 can be used in combination treatments with TB antibiotics to achieve improved bacterial clearance compared to individual drug treatments, both in vitro and in vivo in Mtb-infected mice. Furthermore, SMIP-30 was successfully optimized to generate a derivative compound SMIP-031 with greater PPM1A-inhibition activity and reduced cytotoxicity. Compared to SMIP-30, SMIP-031 is a stronger activator of autophagy and results in enhanced Mtb clearance. These findings establish PPM1A as a druggable target for TB HDT and provides a pipeline for candidate compound design and optimization.
While HDT is an important strategy, antibiotic therapy is still currently the main avenue of treatment, and an approach that combines both HDT with antibiotics would have even better therapeutic potential. For that, novel antibiotic discovery remains a priority. I have also discovered 2 novel benzophenanthridine compounds, BPD-6 and BPD-9, with narrow-spectrum antimycobacterial antibiotic activity. The more therapeutically viable candidate BPD-9 has bacteriostatic activity against Mtb and is able to maintain the bacteria in a non-replicating state, suggesting it may be able to prevent the reactivation of latent TB into active disease. Importantly, BPD-9 remained active against a panel of clinical and drug-resistant Mtb strains and was effective at clearing M. bovis BCG in vivo in infected mice, demonstrating therapeutic potential as a valuable new candidate compound in the development of novel TB antibiotics.
Overall, my findings contribute to both aspects of TB treatment research, demonstrating the importance of and providing drug candidates for an alternative approach like HDT and traditional antibiotic therapy. Further investigations into the mechanisms of action within the cell and molecular targets of these compounds will allow for optimizations that iteratively increase therapeutic potential in order to ultimately develop viable candidates for clinical use
Engineering-Based Finite Element Approach to Appraise Massive Structures Affected by Alkali-Aggregate Reaction
No full textAlkali-aggregate reaction (AAR) is one of the most harmful distress mechanisms affecting the performance of aging concrete structures worldwide. In massive structures (e.g., dams), AAR has led to economic losses and negatively impacted structural safety. Some of the observed detrimental structural implications include loss of equipment alignment, excessive cracking leading to leakage, map cracking, concrete mechanical properties deterioration, introduction of excessive stresses on pre-stressing strands, inability to operate gates, and closure of expansion joints.
Traditional structural design standards and hand-calculations are not able to accurately represent the effects of AAR on the performance of affected concrete structures due to its overall complexity and anisotropic induced expansion. Therefore, finite element (FE) modelling is one of the most reliable alternatives to evaluate AAR's structural implications. Several prediction models have been developed to assess the macroscopic consequences of AAR, ranging from simplified approaches that do not consider the implications of essential parameters to very complex micro-meso models that require extensive fitting. However, a thorough and comprehensive approach able to assess the current damage state (diagnosis) and to predict potential of further damage (prognosis), while (1) accounting for the most important parameters affecting the reaction, (2) accounting for the mechanical properties of deteriorated materials, and (3) not requiring fitting of parameters, is still lacking. In this context, Gorga (2018) proposed a practical, yet accurate engineering-based FE modelling framework for assessing AAR damage and predicting the future behaviour of affected slender structures, such as bridges. It is currently one of the most comprehensive approaches to assess AAR-affected slender structures, as it does not require fitting parameters.
Even so, there is currently no macro-model capable of assessing AAR-affected massive structures (such as dams) that is able to achieve all the previously listed features. Dams are more complex systems for many reasons, including geometry and structural behaviour, unusual rehabilitation techniques (i.e., slot cutting), unique AAR kinetics, and thermal effects. Moreover, the economic impact and safety risks associated with the operation of massive structures are also much larger than those for slender structures, as they are often critical structures. Regarding rehabilitation of AAR-affected massive structures, often the only alternative is slot cutting, which consists of cutting vertical slots on the dam body to release the built-up compressive stresses and reduce permanent displacements. Even though there are several reports in the literature describing successful implementation of this rehabilitation technique, its efficacy remains the subject of ongoing debate among researchers.
In this context, the main goals of the current thesis are: (1) to develop an updated all-encompassing modeling approach to assess AAR-affected concrete structures (with focus on massive structures) based on what had been proposed by Gorga (2018) and (2) to simulate and verify the effectiveness of slot cutting as a rehabilitation technique for AAR-affected massive structures.
The first goal intends to ensure that all relevant phenomena are accounted for while keeping the same overall characteristics of the original approach (engineering-based assessment without the need for fitting). The commercially available software package Abaqus is used as the FE modelling platform. Key features in dam behaviour that are necessary to implement include: (i) updating the simulation to make it a fully integrated thermo-structural-AAR model, (ii) developing a new stress history-dependent creep subroutine, (iii) validating the thermal behaviour of mass concrete, (iv) validating the analysis in prestressed concrete structures, and (v) adopting an updated semi-empirical AAR model that considers the effect of leaching and alkali release from aggregates. All these steps are validated through data from laboratory tests or AAR-affected dams (Paulo Afonso IV and Bemposta dams). The second goal intends to settle the discussion within the engineering community regarding the effectiveness of slot cutting as a rehabilitation technique, clearly defining the mechanisms involved, their effect on the progression of the reaction, the influence of the most important variables on the slot cuts, and identifying in which situations the rehabilitation technique can be beneficial to the serviceability of the structure
Indigenous Policy Research in Canada: Trends in Canadian Public Administration, 1958-2024
No full textSince the 1970s, public administration scholars have increasingly turned to meta-analysis aimed at systematically analyzing the published output of public administration scholarship to understand scope, nature and disciplinary status. Although these reviews have made significant strides towards understanding the study’s interdisciplinarity and heterodoxy, existing research has rarely examined Indigenous policy scholarship, and this research has tended to ask questions investigating what knowledge is produced, which limits attention to questions of how. Against this backdrop, the present study applies a summative analysis approach to Indigenous policy scholarship, and a sociology of knowledge approach to discourse to the case of self-determination. The present study asks two critically interrelated research questions: (1) How does Canadian public administration scholarship engage with the study of Indigenous policy in terms of topic and knowledge utilization? and (2) How is the self-determination discourse constructed within the studies over time? To answer these research questions, the study used qualitative content analysis to analyze, through ATLAS.ti, 47 texts accessed through the Canadian Public Administration issue archive via Wiley Online Library published between 1982 and 2024. Drawing from the 47 texts, the study examines how the Indigenous policy scholarship increasingly engaged with distinct topics and Indigenous-focused literature over time, while published output remained uneven and concentrated. Drawing from the case of self-determination, the study examines how different schemata in scholarly discourse relate to the social construction of knowledge using interpretive scheme analysis to explore meaning structures that organize the discourses of self-determination
Development of a Multilayered Osteochondral Tissue Construct Using 3D Bioprinting
No full textOsteochondral defects can arise from trauma, age-related degenerative changes, or pathological conditions, leading to pain, impaired mobility, and a reduced quality of life. Current clinical treatments have significant limitations, rendering them inadequate for full-thickness osteochondral defects. Although tissue engineering represents a promising strategy for osteochondral tissue regeneration, the complex, depth-dependent architecture of native tissue presents a major challenge to achieve functional repair. Moreover, conventional tissue engineering strategies remain limited in their ability to replicate the structural and functional characteristics of native tissue. Previous studies have explored osteochondral tissue engineering using two-region constructs comprising cartilage and subchondral bone. Nevertheless, despite these efforts, engineering a biologically functional osteochondral tissue construct that closely resembles native tissue remains elusive. The overall objective of this thesis was to engineer a multilayered osteochondral tissue construct, fabricated using 3D printing with region-specific bioinks to mimic the organization of native tissue. To fulfill this objective, the specific aims were to: 1. develop and characterize specific bioinks for the chondral, calcified, and osseous regions of the multilayered osteochondral tissue construct; and 2. fabricate a full-thickness, multilayered osteochondral tissue construct using 3D bioprinting and characterize its physicochemical, mechanical, and biological properties. The chondral- and calcified-region bioinks were formulated using alginate, heparinized alginate, gelatin methacryloyl (GelMA), and methacrylated hyaluronic acid (MeHA), with hydroxyapatite nanopowder (HAnp) incorporated only into the calcified-region bioink. Both bioinks were supplemented with transforming growth factor β1 (TGF β1). Compared with the calcified-region bioink, the osseous-region bioink included fibrinogen instead of MeHA, a lower concentration of GelMA, and a higher concentration of HAnp. This bioink was supplemented with bone morphogenetic protein 2 (BMP 2). The three inks were characterized in terms of rheological properties and printability. All exhibited shear-thinning behavior and demonstrated good printability, while enabling sustained release of TGF β1 and BMP 2 from 3D-printed region-specific scaffolds. Full-thickness, multilayered constructs were fabricated through sequential extrusion-based 3D bioprinting of region-specific bioinks laden with normal human bone marrow-derived mesenchymal stem cells (hBM-MSC). The compressive modulus of the constructs, determined from unconfined compression testing, remained low. Immunohistochemical analysis of constructs cultured for up to 21 days revealed the presence of osteogenic (type I collagen) and chondrogenic (type II collagen) markers in the osseous and chondral regions of the constructs, respectively, as well as a marker of hypertrophic chondrogenic differentiation (type X collagen) in the calcified region. Histochemical analysis further demonstrated increased alkaline phosphatase (ALP) activity in the osseous region, consistent with early osteogenic differentiation. While a reinforcement strategy remains to be implemented, collectively, these findings demonstrate that the multilayered construct, fabricated using regionally-defined bioinks, has significant potential for full-thickness osteochondral tissue regeneration
Integrating Tragedy and Trauma: Thy Word Be Done as a Model of Post-Traumatic Dramaturgy
No full textThis thesis presents an original post-traumatic play, Thy Word Be Done, developed through a research-creation methodology that investigates how theatre can represent experiences of war trauma and pathways of psychological and spiritual recovery. The project draws on diverse Ukrainian documentary sources—including real-time combat video recordings, interviews with injured Ukrainian soldiers, medical professionals, and civilians, as well as contemporary media accounts—to construct a text that interweaves authentic verbatim language with original, poetically crafted writing within a merged dramatic structure.
The fabric of the play draws on four sources: classical tragedy, mystery plays, the hero’s journey, and psychological models of trauma recovery. By placing these structures side by side, the work reflects both the shattering effects of trauma and the possibility for a person to recover and find a new way forward.
This thesis argues that the contemporary post-traumatic play, by integrating classical dramatic narrative models with functional models of trauma recovery, and, for factual authenticity, bringing together voices from the Ukrainian battlefield, rehabilitation, and media, can embody both testimony and transformation, offering audiences a means to witness trauma while also engaging with resilience and hope
Performance of Post-Tensioned Concrete-Filled GFRP Tubes for Wind Turbine Towers in Remote Areas
No full textProviding sustainable energy infrastructure in remote areas of Canada presents significant challenges such as limited access to materials and skilled labour, large distances between neighbouring communities, and maintenance requirements. Wind turbines are a form of decentralized sustainable energy production that are well-suited for remote areas, though conventional tower structures made of steel or concrete are heavy (requiring large foundations), can be difficult to transport, and have relatively short service lives because of deterioration from corrosion and/or fatigue. Glass Fibre Reinforced Polymer (GFRP) tubes are increasingly used for utility poles because they are light in weight and easily connected on-site, thereby reducing transportation costs and emissions while simplifying erection and foundation requirements. Moreover, GFRP materials have a high tensile strength and improved durability to corrosion and fatigue compared to steel and concrete. In other applications (e.g., bridge piers), GFRP tubes have also been used as structural formwork and filled with concrete to produce a composite system with enhanced performance; the concrete adds strength and stiffness while the outer tube confines the concrete core and provides resistance to bending. Hence, concrete-filled FRP tubes (CFFTs) present a promising unexplored solution for wind turbine towers in northern remote areas.
The research presented in this thesis consists of two phases: experimental work and numerical modelling. Three hollow tapered CFFTs with different diameters were constructed and tested to assess their structural performance. Post-tensioned steel tendons were used to increase the stiffness of the tower and reduce the deflection caused by lateral loads. The towers were large scale, with heights of 5.8 m and base diameters between 460 mm and 535 mm and were tested as vertical cantilevers by fixing them to a large reusable foundation block. The outcomes of the experimental tests include: (I) understanding the response of CFFT wind turbine towers under static loads; (II) dynamic properties of prestressed CFFT towers for use as wind turbine towers; and (III) design recommendations and analysis of CFFT wind turbine towers for remote areas. Furthermore, in the second phase of the project, a finite element model was developed and validated using the experimental results to conduct parametric studies. The results confirmed that post-tensioned CFFT towers provide adequate stiffness, strength, and dynamic performance for wind turbine applications in remote areas. Failure mechanisms observed experimentally were well captured by the models, supporting their use in design optimization. The parametric investigations further clarified the (I) effect of different prestress force levels on the lateral load–deflection behaviour, (II) influence of GFRP thickness on structural response, (III) impact of concrete confinement modelling on structural performance, and (IV) effect of different elastic moduli for the GFRP tube on the lateral load–deflection behaviour of the tower. Together, these results improve understanding of the structural behaviour of CFFT wind turbine towers and offer guidance for their practical application in remote northern energy infrastructure
Approaches to Ancestral Pangenomes and Their Phylogenetic Reconstruction
No full textWe investigate the problem of reconstructing ancestral pangenomes from present- day genomic data by modelling structural variation and evolutionary turnover. Our first chapter models ancestral and descendant pangenomes as sets of gene adjacencies, using phylogenetic validation - based on Dollo's law - to filter out recent innovations unlikely to have existed in any ancestor. This approach enables a meaningful reconstruction of ancestral gene order via iterative steinerization, even without optimization. In a second chapter, we complement this framework with a probabilistic tree model in which discrete objects (e.g., genes or features) are transmitted down a hierarchical phylogeny and replaced, respecting Dollo, with a certain probability. We derive theoretical expectations for the retention and overlap of ancestral objects across nodes and assess the accuracy of steinerization-based reconstruction in simulated datasets. Our simulations demonstrate that while theoretical predictions align with observed retention under low replacement rates, random divergence among novel objects introduces noise in deeper or faster-evolving trees. Together, these studies provide some promising approaches to understanding the limits and potential of ancestral reconstruction in a pangenomic landscape
Co-construction de sens autour de la prise en charge pénale des personnes auteures d'infractions à caractère sexuel sur mineur : une analyse des perceptions et représentations professionnelles au sein d'un dispositif pénal hybride
No full textPar ce travail de recherche, nous souhaitons mener une réflexion collective autour de la prise en charge pénale des personnes auteures d'infractions à caractère sexuel sur mineur. A partir des perceptions et représentations de professionnels du droit et de la clinique, et inscrits dans une posture constructiviste articulant phénoménologie et interactionnisme symbolique, nous interrogeons un dispositif que nous qualifions d'hybride, en ce qu'il conjugue logiques pénales et thérapeutiques. Notre analyse explore la manière dont ces discours participent à le façonner, à le légitimer et parfois à le questionner, tout en ouvrant un espace de co-construction de sens