Blood Donor Genotyping

Transfusion of blood is one of the oldest and most widely used clinical interventions. In 2020 the World Health Organisation reported that globally 118.5 million blood donations had been collected worldwide. This blood will be used to provide life-saving transfusion support for millions of individuals with a wide range of medical conditions. To ensure the safety of each blood transfusion it is common policy to identify and ensure compatibility between the ABO and RhD antigens of both donor and recipient. Although this policy prevents the majority of adverse haemolytic transfusion reaction’s (HTR), approximately 3% of recipients become sensitised following an immune reaction to a non-self blood group antigen after a single transfusion episode. This proportion can rise dramatically in patients requiring frequent transfusion support, with immunisation rates as high as 60% being reported for some haemoglobinopathy patients. Sensitisation to non-self red blood cell (RBC) antigens confers a lifetime risk of HTRs, which from 2013 through 2017 were responsible for 17% (32 of 185) and 6% (7 of 110) of transfusion-related deaths reported to the US Food and Drug Administration and Serious Hazards of Transfusion UK, respectively. Furthermore, sensitisation can render transfusion-dependent patients non-transfusable and cause haemolytic disease in pregnancy which is potentially life-threatening to the fetus. A more precise blood matching policy will reduce sensitisation rates, however, adoption of this is resisted because of perceived logistical challenges, donor typing costs, and the lack of evidence from large scale clinical trials that reducing sensitisation rates results in health gains. Antibody-based haemagglutination tests are the current gold standard for RBC antigen typing; however, reliable reagents and high-throughput techniques are not available for all clinically relevant antigens. DNA-based tests have been used to overcome these limitations, and a range of in-house and commercial assays have been developed for donor genotyping. However, due to the limited number of antigens typed for and the low throughput capacity of these assays, they have not been widely applied to blood donor typing. Advances in the technologies used for genome-wide genotyping and sequencing have substantially reduced the cost of generating genetic variation data at population scale. Multiple studies have demonstrated that it is possible to extract antigen typing information from the data produced by these technologies, indicating that they could be used to deliver genomics-based precision transfusion medicine to the patient bedside. However, the same studies also highlight a series of challenges that would have to be overcome before these technologies could be safely integrated into the clinical laboratory. In this thesis, I will present the work that has been done to overcome some of the issues surrounding the interpretation of blood cell antigen typing from genomic data and the development of a universal donor genotyping platform which can be used by blood supply organisations worldwide to implement of a policy of precision transfusion medicine

A note on the fibre-optic light-guides in the eye photophores of watasenia scintillans

A brief account is given of the anatomy and fibre-optic-like light-guiding properties of rod-like elements in the eye photophores on the ventral surface of the eyeball of the Japanese firefly squid Watasenia scintillans.These light-guiding elements form a dominant proportion of the volume of the photophore (which is assumed to function in counter-illumination) and are aligned such that light from the bioluminescent core is directed in acone downwards from the eye. A coplanar arrangement of lamellae in the light-guides strongly suggests that the light passing through will be narrowly restricted both in wavelength and polarization. These features are discussedwith regard to other recent findings in this species

VOLCO: a predictive model for 3D printed microarchitecture

Extrusion-based 3D printing is widely used for porous scaffolds in which polymer filaments are extruded in the form of log-pile structures. These structures are typically designed with the assumption that filaments have a continuous cylindrical profile. However, as a filament is extruded, it interacts with previously printed filaments (e.g. on lower 3D printed layers) and its geometry varies from the cylindrical form. No models currently exist that can predict this critical variation, which impacts filament geometry, pore size and mechanical properties. Therefore, expensive time-consuming trial-and-error approaches to scaffold design are currently necessary. Multiphysics models for material extrusion are extremely computationally-demanding and not feasible for the size-scales involved in tissue engineering scaffolds. This paper presents a new computationally-efficient method, called the VOLume COnserving model for 3D printing (VOLCO). The VOLCO model simulates material extrusion during manufacturing and generates a voxelised 3D-geometry-model of the predicted microarchitecture. The extrusion-deposition process is simulated in 3D as a filament that elongates in the direction that the print-head travels. For each simulation step in the model, a set volume of new material is simulated at the end of the filament. When previously 3D printed filaments obstruct the deposition of this new material, it is deposited into the nearest neighbouring voxels according to a minimum distance criterion. This leads to filament spreading and widening, which is studied experimentally to validate the method. Experimental validation demonstrates the ability of the VOLCO to simulate the geometry of 3D printed filaments. In addition, finite element analysis (FEA) simulations utilising 3D-geometry-models generated by VOLCO demonstrate its value and applicability for predicting the mechanical properties of porous scaffolds. The presented method enables scaffold designs to be validated and optimised prior to manufacture. Potential future adaptations of the model and integration into 3D printing software are discussed

A simplified theory of crystallisation induced by polymer chain scissions for biodegradable polyesters

AbstractA simplified theory for the crystallisation of biodegradable polyesters induced by polymer chain scissions during biodegradation is presented following a theory developed by Han and Pan. The original theory is greatly simplified so that it becomes very straightforward to use and the number of material parameters is significantly reduced. Furthermore it is demonstrated that the spherulite structure widely observed in polymers can be taken into account using the theory. The simplified theory is fitted to the experimental data of poly-l-lactic acids (PLLAs) obtained from literature. It is shown that the simplified theory is equally able to fit the data as the original one. It is also shown that the theory can fit degradation data for PLLAs of different initial degrees of crystallinity with spherulite structures

Computer simulation of polymer chain scission in biodegradable polymers

Biodegradable polymers degrade due to the hydrolysis (chain scission) of the polymer chains. Two theories of hydrolysis are that 1) scissions occur randomly at any bond in chains, and 2) scissions occur in the final bond at chain ends. In this study, a simulation tool was developed to simulate both random chain scission and chain end scission. The effect of each type of scission was analysed. Random scissions were found to have over 1000 time’s greater impact on molecular weight reduction than end scissions. For the degradation of poly lactic acid by random scission, it was found that Mn must reduce to <5000 g/mol in order for a polymer to exhibit significant mass loss due to the diffusion of water-soluble short chains. In contrast, end scission was able to produce a significant fraction of water-soluble chains with little or no effect on Mn. The production rate of water-soluble chains was linearly related to end scission but increase in an accelerated manner due to random scission. Molecular weight distributions were fitted to experimental data for the degradation of poly D-lactic acid

Effectiveness of a six-week high-intensity interval training programme on cardiometabolic markers in sedentary males

High-intensity interval training (HIT) has been proposed as an effective, time efficient strategy to elicit similar cardiometabolic health benefits as traditional moderate-intensity endurance training. This is an important consideration as "lack of time" is a common cited barrier to regular physical activity

Effectiveness of short-term heat acclimation on intermittent exercise in thermoneutral and hot environments

It is well-established that repetition of heat stress exposure has been shown to facilitate adaptations to the heat but these protocols have tended to be of a fixed work intensity, continuous exercise, long-term in duration (>7 days) and use hydration. Secondly, there is limited information on the potential use of heat acclimation as a training method for human performance in thermoneutral conditions. Therefore, the aims of this study were to investigate the effectiveness of short-term heat acclimation (STHA) for 5 days, using the controlled hyperthermia technique with dehydration, on intermittent exercise in thermoneutral and hot environments

Elastostatics of star-polygon tile-based architectured planar lattices

We showed a panoptic view of architectured planar lattices based on star-polygon tilings. Four star-polygon-based lattice sub-families were investigated numerically and experimentally. Finite element-based homogenization allowed computation of Poisson's ratio, elastic modulus, shear modulus, and planar bulk modulus. A comprehensive understanding of the range of properties and micromechanical deformation mechanisms was developed. By adjusting the star angle from $0^\circ$ to the uniqueness limit ($120^\circ$ to $150^\circ$), our results showed an over 250-fold range in elastic modulus, over a 10-fold range in density, and a range of $-0.919$ to $+0.988$ for Poisson's ratio. Additively manufactured lattices showed good agreement in properties. The additive manufacturing procedure for each lattice is available on www.fullcontrol.xyz/#/models/1d3528. Three of the four sub-families exhibited in-plane elastic isotropy. One showed high stiffness with auxeticity at low density with a primarily axial deformation mode as opposed to bending deformation for the other three lattices. The range of achievable properties, demonstrated with property maps, proves the extension of the conventional material-property space. Lattice metamaterials with Triangle-Triangle, Kagome, Hexagonal, Square, Truncated Archimedean, Triangular, and Truncated Hexagonal topologies have been studied in the literature individually. We show that all these structures belong to the presented overarching lattices

An atomic finite element model for biodegradable polymers. Part 2. A model for change in Young’s modulus due to polymer chain scission

Atomic simulations were undertaken to analyse the effect of polymer chain scission on amorphous poly(lactide) during degradation. Many experimental studies have analysed mechanical properties degradation but relatively few computation studies have been conducted. Such studies are valuable for supporting the design of bioresorbable medical devices. Hence in this paper, an Effective Cavity Theory for the degradation of Young's modulus was developed. Atomic simulations indicated that a volume of reduced-stiffness polymer may exist around chain scissions. In the Effective Cavity Theory, each chain scission is considered to instantiate an effective cavity. Finite Element Analysis simulations were conducted to model the effect of the cavities on Young's modulus. Since polymer crystallinity affects mechanical properties, the effect of increases in crystallinity during degradation on Young's modulus is also considered. To demonstrate the ability of the Effective Cavity Theory, it was fitted to several sets of experimental data for Young's modulus in the literature