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Importance of infarct topography in determination of stroke mechanism and recurrence risk: a post-hoc analysis of the dabigatran acute treatment of stroke trial
No full textObjective To evaluate the relationship between infarct pattern, inferred stroke mechanism and risk of recurrence in patients with ischaemic stroke. The question is clinically relevant to optimise secondary stroke prevention investigations and treatment. Design We conducted a retrospective analysis of the dabigatran treatment of acute stroke II (DATAS II) trial (ClinicalTrials.gove NCT NCT02295826), in which patients underwent diffusion-weighted imaging (DWI) at baseline and 30 days after randomisation to one of two antithrombotic therapies. Patients were classified as embolic, isolated small subcortical infarcts or transient ischaemic attack TIA (no infarct) at baseline and day 30. Stroke mechanism was determined by traditional and modified (based on DWI lesion findings) Trial of Org 10 172 in Acute Stroke Treatment (TOAST) criteria (DWI-TOAST). Setting Multicentre (6) tertiary acute stroke treatment hospitals. Participants 305 adults with minor ischaemic stroke (National Institutes of Health Stroke Scale (NIHSS) score≤9). Results Of 305 patients, 148 had embolic pattern infarcts, 93 were isolated small subcortical infarcts and 64 had no infarct on baseline MRI (TIA). In the absence of DWI, TOAST classification indicated the mechanism was cryptogenic in 147 patients (48.2%), and small-vessel occlusion in 127 (41.6%). Using, DWI-TOAST, the number of cryptogenic strokes decreased to 123 (40.3%), and the number of small-vessel occlusion strokes increased to 151 (49.5%). Recurrent infarcts were seen in 13% of patients with an MRI-defined embolic infarct pattern and cryptogenic mechanism on DWI-TOAST. The relative risk of recurrent infarction in patients with undetermined aetiology was increased compared with other categories (standardised coefficient=1.0 (0.1, 1.9), p=0.029). The topography of recurrent infarcts was most often embolic (60.9%), but in 39.1% an isolated small subcortical infarct was seen. Conclusions Definitive identification of infarct topography with DWI has a significant impact on infarct mechanism classification. The variable relationship between baseline infarct patterns, clinical presentation and recurrent infarct distribution is a challenge to both the lacunar and embolic stroke of uncertain source (ESUS) concepts. Irrespective of aetiological classification, patients with MRI-defined cryptogenic embolic pattern infarcts are at high risk for recurrent events. Trial registration number Linked to the DATAS II trial. ClinicalTrials.gov ID NCT02295826
Microbial biogeochemical cycles within deep-sea sponges
No full textSponges (Porifera) have symbiotic relations with diverse microbial communities that contribute to their nutrition through both autotrophic and heterotrophic processes. Whilst shallow-water sponges are well-studied, the mechanisms that underpin this symbiosis in the deep-sea remain unknown.
To identify the autotrophic potential of microorganisms using sequencing-based approaches, I first developed curated hidden-Markov models for key carbon fixation enzymes. I applied these models to 52,515 metagenome assembled genomes spanning the archaeal and bacterial tree of life and identified the genomic potential for autotrophy in 104 different genomes previously thought to be strictly heterotrophic.
To define the microbiome of deep-sea sponges, I collected 72 sponge samples from the South Atlantic. Using amplicon sequencing of the 16S rRNA gene, I highlight the dominance of autotrophic ammonia-oxidising archaea from the family Nitrosopumilaceae, which constitute 25–98% of the microbial communities in different sponges. Each sponge species harbors 1–2 dominant Nitrosopumilaceae phylotypes, suggesting vertical symbiont transmission.
To characterise the metabolic interactions in deep-sea sponges, I analysed, via metagenomics, the microbiome of Aphrocallistes beatrix, which only contains one autotrophic archaeon and one heterotrophic bacterium. Metatranscriptomics showed high expression of genes involved in ammonia oxidation and carbon fixation in the archaeon, while the bacterium functions as a scavenger. The microbiome also contains a novel virus, which likely has role on controlling vitamin B12 flux and organic carbon exchanges within the holobiont.
Finally, I analysed the complex microbiome of Calyx sp. based on 142 metagenome-assembled genomes. Metatranscriptomic analysis suggests hydrocarbon degradation likely involves syntrophic interactions among different organisms. Members of the taxa Chloroflexota, Latescibacterota and Poribacteria appear to be the most active carbohydrate-degraders. Ex-situ heavy isotope labelling showed that microbial autotrophy was stimulated by ammonia addition and could fix the equivalent of 20% of the sponge biomass annually.
Overall, I provide genomic, transcriptomic and experimental evidence that deep-sea sponges rely both on ammonia-oxidising symbionts and heterotrophic interactions to supplement their nutritional requirements
Effects of Electron-Electron Interactions in Two Dimensional Systems and Their Response to External Electric and Magnetic Fields
No full textThis thesis presents a study of the effects of electron-electron interactions in two dimensional (2D) mesoscopic devices, particularly their response to external electric and magnetic fields.
Firstly, I consider the viscous electron fluid in 2D. I propose a method by which the viscous signal may be increased by an order of magnitude to be on par with the ohmic signal by controlling the electron flow with a micromagnet superlattice. The modulated magnetic field generates wiggling flow, which generates vorticity away from the boundaries and significantly enhances viscous dissipation compared to all previous experiments. This opens a new way to study electron hydrodynamics. I present the theory for this new method and the related experimental set up in both a 2D GaAs quantum well and in monolayer graphene.
Next, I study excitons in 2D transition metal dichalcogenides (TMDs) in magnetic fields. Usually, to analyse experimental data the perturbative formula for diamagnetic shift is used. I show that Rydberg s-wave excitons are outside the perturbative regime at experimentally achievable magnetic fields. I develop the theory of excitons in 2D TMD in arbitrary magnetic field, reanalyse experimental data and arrive at a different set of parameters compared to the perturbative method. I also propose a method to probe the dark p-wave states by using an in-plane electric field to mix s- and p-wave states. This will reveal rich physics of the p-wave excitons and allow the calculation of particle-hole asymmetry.
Finally, I investigate the effect of charge carrier induced screening of the Coulomb interaction on the band gap in 2D TMD and biased bilayer graphene (BLG). Experiments in TMD show a reduction of the gap in the metal compared to the insulator. Charge carriers may be introduced by electrostatic gating or finite temperature. I develop the theory of charge carrier induced band gap reduction in 2D based on the Feynman diagrammatic technique. I first apply this theory to TMD and then to biased BLG. In both cases I predict a significant decrease in band gap at low charge carrier density. The effect is the same for gate induced or thermally excited charges
Macromolecular Structure Prediction to Guide Studies of RNA Virus Proteins
No full textRNA viruses pose significant global health threats, yet the development of effective therapeutics is hampered by limited structural information for many viral proteins and the challenge of drug resistance. This thesis demonstrates how computational structural prediction, particularly AlphaFold2, can guide experimental structural biology approaches to characterise novel viral proteins and inform structure-based drug design. Four viral protein systems were investigated: the Ebola virus L polymerase, two proteins (ThVP RNA-dependent RNA polymerase and ThVC capsid) from a putative archaeal RNA virus, and the HIV capsid protein. AlphaFold2 models were generated for the Ebola L protein and ThV proteins to guide construct design and experimental strategies. Expression of the Ebola L protein was successfully achieved and validated through mass spectrometry and Western blot analysis. For the ThV proteins, expression was confirmed using mass photometry and single-particle cryo-EM, leading to successful structure determination of ThVC trimer at 2.85 Å and ThVP at 4.00 Å resolution - representing the first experimental structures for proteins from this archaeal virus family. Functional characterisation revealed that ThVP retained polymerase activity but lacked thermostability, while ThVC appeared to form assemblies (likely artificial) and exhibited thermostability. For the HIV capsid protein, which had a previously solved structure, lenacapavir analogues synthesised by collaborators were tested, with one analogue successfully forming a complex that was crystallised and resolved at 1.74 Å resolution via X-ray crystallography. These findings demonstrate that AlphaFold2 predictions can effectively guide experimental design for challenging viral protein targets, enabling successful structural characterisation of previously uncharacterised proteins, while known structural information can be leveraged for therapeutic compound development
Hard Hats and Glass Ceilings: Women's Experiences in the Construction Industry in Developed Western Nations
No full textContributing to the growing body of research, this systematic literature review (SLR) aims to investigate barriers faced by women in construction across developed Western nations, including Australia, New Zealand, North America, and the United Kingdom. While numerous studies have identified barriers such as gender discrimination, workplace culture, and career progression issues, these findings are often disconnected, leading to a lack of holistic understanding. This fragmentation results in inefficient policy efforts, wasted resources, missed opportunities to implement best practices, and limited comparative insights, all hindering the development of targeted, evidence-based solutions. To address these challenges, this study bridges a critical gap by conducting an SLR that consolidates and synthesizes existing research on the barriers that women face in construction across these developed nations. A systematic literature search found 63 journal articles that explore the barriers faced by women in Western countries. Four major barriers - workplace environment and culture, career development and opportunities, work-life balance and support, and policies and institutional factors with a number of subbarriers - emerged from the review. The findings of this research lay the foundation for organizations to inform their strategies for mitigating talent deficit and to assist governments in developing effective policies around women inclusion and retention in construction. The findings of this study present a comparative analysis of the barriers faced by women across different Western countries, revealing both common challenges and region-specific differences. This cross-regional comparison is a key contribution of our research, offering valuable insights into the unique and shared obstacles that hinder women's participation in the construction industry
Test-retest reliability and measurement error of the numerical rating scale and visual analogue scale in people with low back pain
No full textThe 0–10 numerical rating scale (NRS) and 0–100 visual analogue scale (VAS) are commonly used to assess pain intensity in low back pain (LBP) trials, but their measurement properties remain unclear. AIMS: We aimed to determine the reliability and measurement error of the NRS and VAS in non-specific LBP. We used a test-retest design with online questionnaire administration. Adults proficient in English with acute (3 months) non-specific LBP were recruited. Pain intensities were recorded using the NRS and VAS at baseline, as well as 20 min and 24 h after baseline. Intraclass correlation coefficients (ICC), standard error of measurement (SEM), and smallest detectable change (SDC) were estimated for acute and chronic LBP over two recall periods: 24 h and 7 days. A total of 733 began the survey; 298 (100 acute, 198 chronic) and 165 (62 acute, 103 chronic) completed 20-minute and 24-hour follow-ups respectively. Reliability was good to excellent (ICC 0.75 to 0.94) for the NRS and moderate to good (ICC 0.68 to 0.89) for the VAS across both intervals and for both LBP types. The SDC was 1.6 to 2.8 of 10 for the NRS and 20.9 to 36.5 of 100 for the VAS. Our results suggest the reliability of the NRS and VAS is acceptable in people with low back pain, however their measurement errors are higher than generally accepted minimal important change scores, which needs to be considered when interpreting trial results and measuring pain in clinical practice. Perspective: This study examines the reliability and measurement error of two commonly used pain scales in people with low back pain. The findings suggest that small changes in pain intensity scores should be interpreted cautiously and add to growing evidence on the challenges of measuring fluctuating pain
Accelerating Shortest Path Counting on Road Networks
No full textCounting the number of shortest paths between two query vertices on road networks has a wide range of applications and has recently drawn significant research attention. The state-of-the-art solution builds a tree-based index using the concept of tree decomposition. However, its performance deteriorates when the tree decomposition results in an unbalanced tree and may not perform well when the query vertices are close to each other. This thesis aims to accelerate shortest path counting queries on road networks. We introduce a new indexing scheme that combines hub labeling with a balanced tree hierarchy. This approach significantly reduces the number of visited labels compared to the state-of-the-art solution. Furthermore, we introduce several optimizations to enhance the efficiency of index construction and minimize its size. Extensive experiments conducted on 12 real-world road networks demonstrate that our method achieves up to 4.1 times higher query efficiency and reduces the index size by a factor of 2.5 compared to the state-of-the-art solution
Breaking the Cycle: Innovation, Imaginaries, and the Birth of Digital Contraception
No full textFrom tracking apps and wearables to ‘smart’ condoms, hormonal profiling, and implantable microchips, novel digital contraceptive technologies offer a potential ‘solution’ to unintended pregnancy, limited pharmaceutical innovation, and enduring user dissatisfaction of pharmaceutical contraceptives. While a promising glimpse of hope for a landscape long overdue for change, the transformation of pregnancy prevention from a pharmaceutical drug to a direct-to-consumer digital technology brings about novel risks regarding efficacy, safety, security, and accountability. Indeed, the very ‘novelty’ of these technologies and their ‘transformative’ potential is debatable given the similarity of tracking apps to ‘old’ fertility awareness-based methods and their position within the broader context of retrogressing reproductive rights. In this thesis, I examine the emerging field of digital contraceptive technologies in Australia and internationally. Drawing on sociology, science and technology studies, and critical digital health studies, I use a sociomaterially-informed conceptual framework of sociotechnical imaginaries to trace the co-production of society and technoscience through the dynamics of emergence, stabilisation, and destabilisation. I present findings from two interrelated studies. Study 1 was an exploratory, online technographic analysis that mapped the sociotechnical imaginary of digital contraceptive technologies and identified case study technologies through public-facing media sourced using Google Search. Study 2 involved 46 young Australians, as potential users, who were invited to respond to, and intervene in, the imaginary through creative qualitative workshops. In analysing the findings from both studies together, I aimed to understand how the sociotechnical imaginary of digital contraceptive technologies is made to matter and made sense of. In doing so, I uncovered key points of convergence and divergence between user wants and needs, and what digital contraceptives appear to offer.
This thesis is an empirically situated, theoretically informed, and methodologically innovative approach to the emerging landscape of digital contraceptive technologies. I argue that digital contraceptives do little to ‘break the cycle’ and ‘transform’ contraceptive care for the benefit of users. In response, I surface alternative participant-led imaginaries for contraception that gesture towards collective social change rather than a simple ‘tech fix’
Virtual reality obstacle avoidance training can be enhanced by physical feedback via perturbations: A proof-of-concept study
No full textBackground: Fall injuries resulting from trips are a major health concern. Virtual reality (VR) offers an effective way of training obstacle avoidance while walking due to its ability to provide safe and meaningful real-time feedback during rehabilitation. This proof-of-concept study examined the benefit of providing physical feedback during obstacle avoidance gait training using VR. Methods: Twenty-six young adults walked on an instrumented treadmill while wearing a head-mounted display in two 8-min conditions. Virtual obstacles to be avoided were presented in a VR-only condition and a VR + Perturbation (VR + P) condition where additional rapid belt acceleration simulated tripping on an obstacle. Results: A lower obstacle collision rate, greater step length and height of the leading foot over the obstacles were found in the VR + P condition compared to the VR-only condition (p < 0.05). Step height of the trailing foot over the obstacles significantly decreased over time during the VR-only condition (p < 0.01) but not during the VR + P condition. The margin of stability significantly improved over time during the VR + P condition only (p < 0.01). Conclusions: Immediate physical feedback via treadmill belt acceleration can improve obstacle avoidance performance in a virtual environment. Future research is required to examine the generalizability of this finding to other populations and real-world falls
The association between circulating SIGLEC6 and preeclampsia: observational studies of seven cohorts
No full textBackground: Preeclampsia is a serious complication of pregnancy. Methods: We did an observational study using seven tissue bank/cohorts to examine the association between circulating SIGLEC6 and preeclampsia. We included samples from participants with preterm disease (delivering −9). SIGLEC6 levels correlated with disease severity: compared to preeclampsia without severe features, SIGLEC6 was raised 1.5–2.5-fold with eclampsia, or preeclampsia with life-threatening complications. There was a stepwise increase in SIGLEC6 with increasing numbers of maternal complications, accentuated when expressed as a SIGLEC6/PlGF ratio (10.7-fold rise with ≥3 maternal complications, versus no complications). Circulating SIGLEC6 concentrations were significantly increased among those later diagnosed with preeclampsia in samples collected at 36 weeks (n = 1032; Australia), 26–34 weeks (n = 235; UK), 28 (n = 283; Australia), and 20 weeks' gestation (n = 1945; New Zealand). Interpretation: SIGLEC6 is elevated with preeclampsia and levels correlate with disease severity. Funding: National Health and Medical Research Council (#1065854) and the Norman Beischer Medical Research Foundation. Additional sources of funding for the biobank from South Africa was received from the Swedish Medical Society, Märta Lundqvist Foundation, Swedish Foundation for International Cooperation in Research and Higher Education, Jane and Dan Olssons Foundation, Mercy Perinatal (Australia), the Swedish Research Council (Vetenskaps-rådet), Sweden, and the Center for Clinical Research Dalarna, Sweden. The MAViS study (UK) was funded through National Institute Health Research (NIHR-CS-011-020). MUMS was funded by a St George and Sutherland Medical Research Foundation of Australia grant. Salary or scholarship support was received from: Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) Taylor Hammond Scholarship to TM; National Health and Medical Research Council Fellowships to ST (#2017897) and DMK (#2008017); Australian Research Council Future Fellowships to TKL (FT230100125) and NJH (FT210100193), Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation Fellowship and a National Heart Foundation Future Leader Fellowship (#105663) to FZM