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Benchmarking cell type annotation methods for 10x Xenium spatial transcriptomics data
No full textBACKGROUND: Imaging-based spatial transcriptomics technologies allow us to explore spatial gene expression profiles at the cellular level. Cell type annotation of imaging-based spatial data is challenging due to the small gene panel, but it is a crucial step for downstream analyses. Many good reference-based cell type annotation tools have been developed for single-cell RNA sequencing and sequencing-based spatial transcriptomics data. However, the performance of the reference-based cell type annotation tools on imaging-based spatial transcriptomics data has not been well studied yet. RESULTS: We compared performance of five reference-based methods (SingleR, Azimuth, RCTD, scPred and scmapCell) with the marker-gene-based manual annotation method on an imaging-based Xenium data of human breast cancer. A practical workflow has been demonstrated for preparing a high-quality single-cell RNA reference, evaluating the accuracy, and estimating the running time for reference-based cell type annotation tools. CONCLUSIONS: SingleR was the best performing reference-based cell type annotation tool for the Xenium platform, being fast, accurate and easy to use, with results closely matching those of manual annotation
Identifying Metabolomic Mediators of the Physical Activity and Colorectal Cancer Relationship
No full textBACKGROUND: Current evidence suggests higher physical activity (PA) levels are associated with a reduced risk of colorectal cancer. However, the mediating role of the circulating metabolome in this relationship remains unclear. METHODS: Targeted metabolomics data from 6,055 participants in the European Prospective Investigation into Cancer and Nutrition cohort were used to identify metabolites associated with PA and derive a metabolomic signature of PA levels. PA levels were estimated using the validated Cambridge PA index based on baseline questionnaires. Mediation analyses were conducted in a nested case-control study (1,585 cases, 1,585 controls) to examine whether individual metabolites and the metabolomic signature mediated the PA-colorectal cancer association. RESULTS: PA was inversely associated with colorectal cancer risk (OR per category change: 0.90, 95% confidence interval, 0.83-0.97; P value = 0.009). PA levels were associated with 24 circulating metabolites after FDR correction, with the strongest associations observed for phosphatidylcholine acyl-alkyl (PC ae) C34:3 (FDR-adjusted P value = 1.18 × 10-10) and lysophosphatidylcholine acyl C18:2 (FDR-adjusted P value = 1.35 × 10-6). PC ae C34:3 partially mediated the PA-colorectal cancer association (natural indirect effect: 0.991, 95% confidence interval, 0.982-0.999; P value = 0.04), explaining 7.4% of the association. No mediation effects were observed for the remaining metabolites or the overall PA metabolite signature. CONCLUSIONS: PC ae C34:3 mediates part of the PA-colorectal cancer inverse association, but further studies with improved PA measures and extended metabolomic panels are needed. IMPACT: These findings provide insights into PA-related biological mechanisms influencing colorectal cancer risk and suggest potential targets for cancer prevention interventions
The Association Between Anesthetist Leadership Styles and Their Resilience: A Single-Center Study.
No full textPURPOSE: To explore the association between the leadership styles and resilience of anesthetists in leadership roles. METHODOLOGY: This prospective study of all anesthetists in leadership roles within a university teaching hospital in Melbourne, Australia, employed three validated, anonymous questionnaires (Multifactor Leadership Questionnaire, Authentic Leadership Questionnaire, and the Resilience Scale). Questionnaire data were summarized using descriptive statistics and presented as counts and proportions. Spearman's rank correlation was used to evaluate quantitative continuous variables to identify linear relationships. RESULTS: Of the 14 anesthetists in leadership roles, 14 completed all three questionnaires (response rate 100%). Ten participants (71.5%) displayed behaviors consistent with transformational leadership. Three participants (21.4%) displayed behaviors typically associated with transactional leadership, and one (7.1%) exhibited characteristics consistent with passive-avoidant leadership. Anesthetists with transformational leadership styles exhibited significantly higher resilience scores than those with transactional or passive-avoidant leadership styles. Those with transformational leadership qualities also had increased job satisfaction overall. CONCLUSION: Anesthetists who exhibit transformational and authentic leadership are likely to be more resilient than those with transactional or passive-avoidant leadership styles. Higher levels of resilience were also associated with greater role effectiveness and experiencing greater levels of job satisfaction
Improving the management of hyponatraemia due to the Syndrome of Inappropriate Antidiuresis
No full text© 2025 Annabelle Margaret WarrenHyponatraemia is the most common electrolyte disorder, and can cause significant morbidity and mortality. The most frequent cause of hypotonic hyponatraemia is the syndrome of inappropriate antidiuresis (SIAD) mediated by non-osmotic release of arginine vasopressin (AVP) which acts on renal vasopressin 2 (V2) receptors to promote water retention.
In the absence of severe symptoms requiring urgent intervention, fluid restriction is widely endorsed as first line treatment for SIAD in current guidelines. When fluid restriction is unsuccessful, which occurs in around half of cases, second line management options include the aquaretic V2 receptor antagonist tolvaptan, or agents promoting osmotic diuresis such as urea, dietary protein supplementation, or sodium-glucose co-transporter 2 inhibitors (SGLT2i).
Current guidelines are largely based on expert opinion with few high-quality trials. Controversy exists regarding the role of tolvaptan, as a significant risk of rapid sodium rise, known as ‘overcorrection’, has been observed in clinical practice, leading some to recommend against its use.
I conducted an open-label single-centre randomised clinical trial in hospitalised patients with moderate-profound hyponatraemia comparing two treatments: Tolvaptan and Fluid Restriction. The aim was to compare their efficacy and safety, with a pre-specified protocol for dextrose 5% intervention if sodium correction targets were exceeded. Participants were randomised to Tolvaptan 7.5mg oral daily or FR below 1000ml/day for 3 days, with daily titration according to plasma sodium response.
We enrolled 54 hospitalised patients with a plasma sodium of 115-130mmol/L (mean 124mmol/L) meeting criteria for SIAD.
Plasma sodium concentrations increased more in the Tolvaptan group, compared to Fluid Restriction, over 3 days (p.overall less than 0.001). The mean adjusted difference in plasma sodium between groups at Days 2, 3 and 4 was 3.2 (95%CI 1.6-4.7), 3.5 (95%CI 1.9-5.2), and 2.5mmol/L (95%CI 0.8-4.2), respectively. Five tolvaptan recipients (19%) required dextrose 5% to treat rapid sodium rise. With this intervention, no patient had a sodium rise above 10mmol/L at 24 hours. Despite the faster rise in plasma sodium with tolvaptan, there was no difference in length of stay or symptoms, compared to the Fluid Restriction group.
In addition, hyponatraemia has been reported to occur more frequently with higher ambient temperatures, though the underlying mechanisms are not well understood. Global temperatures are rising due to climate change, which may impact the incidence of hyponatraemia worldwide. We conducted a systematic review that identified 34 studies exploring this relationship, of which 30 reported a significant association between heat and abnormal plasma sodium.
We also conducted an observational study at my institution of hyponatraemia presentations linked to local temperature data over the past 10 years. Over this period, 45 718 low plasma sodium results were identified from 26 557 unique patients. Plasma sodium concentrations in January (Australian Summer) were 0.55mmol/L lower (95% CI 0.36 to 0.77, p less than 0.001) compared to September (Australian early Spring). Women had lower sodium concentrations compared to men, as did patients older than 80 years when compared to those younger than 65 years. Hospital admissions with hyponatraemia were more frequent during summer months. Profound hyponatraemia admissions (plasma sodium below 125 mmol/L) were more frequent following a heatwave, compared to without (7.6% vs 6.5%, p=0.04).
This study demonstrated that plasma sodium concentrations are lower and profound hyponatraemia-related hospital admissions higher when ambient temperatures are warmer.
Overall, while our randomised trial showed that tolvaptan was more effective at raising plasma sodium, there was no difference in other clinically meaningful outcomes. Fluid restriction should remain first line in most cases due to the lower burden of monitoring and cost. Ours is the first prospectively-validated protocol to detect and prevent tolvaptan-related overcorrection, which suggests it can be used safely and effectively in patients with moderate-profound hyponatraemia if indicated. We advocate for inclusion of this protocol for tolvaptan use in future hyponatraemia guidelines.
The connection between heat and hyponatraemia suggests that hyponatraemia is a climate associated health issue. As temperatures rise with climate change, hyponatraemia presentations may become even more frequent. Local public health advice for water consumption during heatwaves should consider this risk, and prompt action to limit climate change is required to mitigate this risk
Drug repurposing candidates for amyotrophic lateral sclerosis using common and rare genetic variants
No full textAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which novel disease modifying therapies are urgently needed. Given the increasing bottlenecks in drug discovery pipelines, repurposing existing drugs for ALS may represent a path to expedite translation and improve disease outcomes. However, ALS is a heterogeneous disease for which the aetiology remains poorly characterized, complicating efforts to effectively repurpose drugs. We propose that the polygenic architecture of ALS genetic liability, which ranges from ultra-rare, high-impact variation to common frequency loci of small-individual effect, could be leveraged to prioritize drug repurposing candidates which are more generalizable to the ALS clinical population. Here, we utilize common and rare frequency ALS genetic risk with a novel approach to uncover therapeutic classes that may be prospective repurposing opportunities in ALS. The common variant-led analyses integrated both positional-based and functional gene-based tests on SNP-genotype data from a genome-wide association study of ALS and implicated mitogen-activated protein kinase signalling related downregulation through B-Raf inhibitors as a prospective target for repurposing. The rare variant-led approaches leveraged rare variant burden testing of exonic variation on whole genome-sequencing data from a subset of the common variant genome-wide association study cohort and prioritized B-vitamin related candidates, such as cobalamin and niacin. Clinical characterization of these putative repurposing opportunities revealed genetic support to existing biology for which related compounds are actively proceeding through ALS clinical studies. Moreover, leveraging transcriptomic data from ALS derived cell lines carrying a selection of pathogenic variants in genes that cause familial forms of ALS (C9orf72, SOD1, FUS and TARDBP) suggested that the action of B-Raf inhibitors may be of particular relevance to C9orf72 carriers, whilst the signal for B-vitamin signalling related targets was strongest in SOD1 carriers. In summary, we demonstrate the importance of considering the therapeutic actionability of both common and rare-variant mediated risk for ALS given the immense biological heterogeneity of this disorder. Future pre-clinical and clinical studies are now warranted to further characterize the tractability of these prioritized compounds
Internet addiction and its association with quality of life in college students: a network perspective
No full textBackground: Internet addiction (IA), especially in young people, has gained increasing attention in recent years. This study examined the prevalence of IA and its associated factors, relationship with quality of life (QoL) and network structure among college students. Methods: A cross-sectional study was conducted between September and December 2023 in China. Internet addiction symptoms were assessed using the Internet Addiction Test (IAT). Univariate and multivariate analyses were performed to explore the correlates of IA. The relationship between IA and QoL was examined using analysis of covariance (ANCOVA). The Expected Influence (EI) centrality index was used in the network model to characterize the structure of IA symptoms. Results: A total of 6,514 college students were included. The prevalence of IA was 27.9% [95% confidence interval (CI): 26.8%-29.0%]. A binary logistic regression analysis indicated that living in urban areas (OR=1.135, P=0.032), being in senior grade (OR=1.396, P=0.017), and having current drinking (OR=1.431, P(1, 6514) = 128.167, P < 0.001). The most central (influential) symptoms were “Academic efficiency declines” (IAT8, EI value=1.10), “Request an extension for longer time” (IAT16, EI value=1.10) and “Neglect chores to spend more time online” (IAT2, EI value=1.00) in the network model of IA symptoms. The symptom “Form new relationships with online users” (IAT4) had the strongest direct positive relationship with QoL, while “Sleep loss” (IAT14) and “Prefer the excitement online to the time with others” (IAT3) had the strongest direct negative relationship with QoL. Conclusion: Internet addiction was common among Chinese college students. Interventions targeting the most central symptoms and those closely associated with QoL should be developed to address IA in college students and improve the QoL of those with IA in this population
Artificial Intelligence for Assisting Glaucomatous Optic Neuropathy Detection in Primary Care Settings
No full text© 2025 Catherine JanGlaucoma is the leading cause of irreversible blindness worldwide, yet in Australia, over 60% of glaucoma cases go undetected, representing a critical public health and economic problem. Glaucoma severely and profoundly affects visual function and quality of life. People with glaucoma have slower reading and mobility, fall more frequently, and are at higher risk of motor vehicle accidents. Although there is no cure for glaucoma, early detection and timely treatment can halt or delay vision loss and significantly improve prognosis. As such, glaucoma represents an ideal candidate for early detection interventions.
Recent research has shown that, of the undiagnosed cases, 66% exhibited Cup-to-Disc Ratios (CDR) indicative of glaucomatous optic neuropathy (GON) (>0.7), yet these findings were not appropriately recorded by clinicians. Notably, of those with CDR >0.7, 65% had consulted an optometrist, and 48% had seen an ophthalmologist within the past year. This highlights a critical gap in the detection of GON, suggesting that accurate diagnosis remains a considerable challenge even among trained eye care professionals.
Artificial Intelligence (AI) has shown substantial promise in providing accurate, consistent, and efficient assessments of the optic disc and retinal nerve fibre layer, making it a potential game-changer in glaucoma detection and screening. However, for AI tools to be successfully integrated into a country’s healthcare system, it is essential to first evaluate the current practice patterns of glaucoma detection within the local context. Given that AI is a recent innovation, key gaps exist in the existing body of knowledge:
1. To date, there is no published evidence evaluating the accuracy or inter-practitioner variability of optometrists in detecting glaucoma in Australia.
2. No external validation studies of AI for glaucoma detection have been conducted using data from different ethnicity, either within Australia or internationally.
3. There is no published research on how AI assistance affects clinician accuracy, consistency, or speed in detecting glaucoma in Australia or abroad.
4. No real-world clinical trials have evaluated the challenges, feasibility and acceptability of AI tools for glaucoma detection in primary care settings or other healthcare settings, either in Australia or internationally.
5. There is no available evidence on the cost-effectiveness of AI-assisted glaucoma screening in Australia or internationally, representing a critical gap for policymakers considering adoption of such technologies in national eye health programs.
To address these gaps, my PhD research aims to investigate current glaucoma care practices, with a particular focus on primary eye care, to develop and validate AI systems for glaucoma detection, and to evaluate the role of AI in facilitating accurate, reliable, efficient, feasible, and cost-effective glaucoma detection.
Chapter 1 of this thesis reports undiagnosed glaucoma is a significant public health problem, the role of optometrist and family doctor or general practitioner (GP) in glaucoma management, and AI’s potential to reduce this burden. Chapter 2 found that optometrists have played an increasingly important role in glaucoma detection and management in Australia over the past 15 years. While most optometrists employ appropriate diagnostic procedures, significant variability exists in the detection of GON from fundus photo grading among both optometrists and ophthalmologists. AI algorithms were found to achieve comparable diagnostic accuracy to Australian optometrists (Chapter 3), while AI assistance (combined clinician expertise plus AI) significantly improved clinician accuracy, consistency, and speed in identifying referable glaucoma cases using retinal photographs (Chapter 4). Additionally, through world’s first prospective clinical trial, I evaluated the real-world performance and barriers to AI adoption for glaucoma screening, and that patient acceptance of AI tools was high, indicating their potential for widespread adoption (Chapter 5). Most GPs expressed willingness to integrate AI into their clinical practice, provided that logistical challenges, such as workflow integration, could be addressed (Chapter 5). Furthermore, AI-assisted population screening for glaucoma has shown to be both cost-saving and cost-effective in the Australian healthcare context (Chapter 6).
Collectively, the novel findings reported in this thesis provide insights into the steps required to integrate AI technology into the healthcare system, particularly for glaucoma detection in primary care settings. This research outlines a robust evidence-based framework that can inform policymakers, clinicians, and technology developers on the implementation of AI tools to address gaps in glaucoma detection, ultimately improving early diagnosis and reducing the burden of irreversible blindness
Recovery trajectories after major abdominal surgery: A retrospective pooled cohort study
No full textBACKGROUND: Recovery from major surgery can be difficult to predict given the many factors involved in treating disease and restoring preoperative function. Postoperative recovery metrics such as length of stay, complications, and mortality are typically described. However, large data quantities for patient-reported recovery are scarce. In this retrospective study, we aimed to describe the multidimensional recovery trajectory of patients undergoing major abdominal surgery 4-8 weeks after surgery and explore factors related to incomplete overall recovery. METHODS: We retrospectively analysed pooled cohort data of adults undergoing elective major abdominal surgery between 2018 and 2024 across three tertiary-level hospitals. Recovery was measured at postoperative days 1, 3, 7, 14, weeks 4-8, and 3 months using the Postoperative Quality of Recovery Scale (PostopQRS). Physiological, nociceptive, emotive, activities of daily living (ADL), and cognitive domains were assessed, with recovery defined as a return to, or improvement of, preoperative baseline levels. Overall recovery was defined as recovery in all domains. Length of stay was assessed for patients who recovered overall, or did not recover, at postoperative weeks 4-8. RESULTS: Six hundred and fifty-three patients were included, with mean (SD) age of 57.8 (14.4) years. Of these, 36% were aged ≥65 years and 58% were male. The incidence of overall recovery at postoperative week 4-8 was 42%. Domain-level recovery at postoperative weeks 4-8 was 63% for nociception, 81% for emotion, 82% for ADLs, and 83% for cognition. Patients failing to achieve overall recovery at weeks 4-8 had longer mean (SD) lengths of stay compared to those who recovered (11.3 (10.3) vs. 7.3 (7.1) days, p < .001). CONCLUSIONS: The incidence of overall recovery at postoperative week 4-8 was 42%. Patients with incomplete overall recovery had longer lengths of stay. Multidimensional strategies to improve the recovery trajectory warrant further investigation. EDITORIAL COMMENT: Major surgical procedures are often followed by a lengthy and difficult recovery period. Traditional measures such as mortality and complications are usually analysed, but this 653-patient study investigated patient-reported recovery scores after major abdominal surgery. Novel findings include that only 42% of patients have recovered fully in all recovery domains at weeks 4-8, and these patients also had longer hospital stays. Preoperative risk factors were analysed for associations with recovery trajectories
Longitudinal assessment of female carriers of choroideremia using multimodal retinal imaging
No full textBACKGROUND/AIMS: Female choroideremia carriers present with a spectrum of disease severity. Unlike in men, the rate of disease progression has not been well characterised in carriers. This longitudinal study aimed to determine the rate of retinal degeneration in choroideremia carriers, using multimodal imaging and microperimetry. METHODS: Choroideremia carriers previously seen at Oxford Eye Hospital (United Kingdom) between 2012 and 2017 returned for testing between 2015 and 2023, providing up to 11 years' follow-up data. Participants had optical coherence tomography, fundus-tracked microperimetry and fundus autofluorescence (FAF) imaging performed. RESULTS: Thirty-four eyes of 17 choroideremia carriers were examined using multimodal imaging. Median age was 44 (range: 15-73) years at baseline and median follow-up duration was 7 (range: 1-11) years. At baseline, phenotype was classified as fine (n=5 eyes), coarse (n=13 eyes), geographic (n=12 eyes) or male pattern (n=4 eyes). Thirteen patients showed no change in phenotype classification, four showed slight changes associated with choroideremia-related retinal degeneration. Despite this, carriers with severe retinal phenotypes had a statistically significant decline in average retinal sensitivity (-0.7 dB and -0.8 dB per year, respectively, p<0.001), area of geographic loss defined by FAF (+2.5 mm2 and +3.7 mm2 per year, respectively, p<0.001) and thinning of the photoreceptor complex (up to -2.8 microns and -10.3 microns per year, p<0.001). CONCLUSION: Choroideremia carriers, particularly those with severe retinal phenotypes, exhibit progressive retinal degeneration, as evident by multimodal imaging biomarkers and functional testing. Clinicians should not rely on retinal severity classification alone to assess disease progression
Molecular characterisation of cerebellar ataxia caused by a pentanucleotide repeat expansion in RFC1
No full text© 2025 Kayli Christine DaviesPathogenic repeat expansions (RE) are an important disease mechanism that underlie a diverse group of more than 60 neurogenetic disorders of major clinical significance including Huntington disease, fragile X syndrome, and hereditary cerebellar ataxias. Collectively, RE disorders are the most common genetic conditions seen by neurologists. In recent years many new pathogenic RE have been identified, including in 2019 the identification of a biallelic intronic pentanucleotide AAGGG RE in RFC1. This was shown to cause cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and was also identified as a major cause of late-onset ataxia. Subsequent studies have demonstrated that homozygous pathogenic RE in RFC1 underlies >20% of idiopathic late-onset ataxia, making RFC1 one of the most common genetic causes of ataxia. Despite its frequency, clinical diagnostic testing is not yet available in Australia and is offered by few commercial service providers internationally. The limited test availability is in part due to significant heterogeneity present at the RFC1 locus and the lack of understanding of this complexity in both the general population and affected individuals. Furthermore, the pathogenic mechanisms underlying RFC1-mediated ataxia are yet to be elucidated.
The hypothesis of this project is that the molecular and functional characterisation of RFC1-mediated cerebellar ataxia using advanced genomic technologies and iPSC models will lead to mechanistic insights into the RFC1 RE. The primary research aims are
1. to characterise the population variation in RFC1 repeat composition and structure and compare with the repeat in individuals with CANVAS/RFC1-related disease and other adult-onset ataxias; and
2. to generate iPSC and neuronal models from individuals with CANVAS to investigate the pathogenic mechanisms underlying RFC1 RE.
The first part of this study focused on comprehensively characterising the heterogeneity of the RFC1 repeat in an Australian cohort of 232 individuals with adult-onset ataxia and 269 healthy controls. Biallelic pathogenic RFC1 variants were identified in 79/232 (34.1%) affected individuals, with 74/79 (93.7%) carrying biallelic AAGGG RE. Alternate pathogenic alleles were identified in five individuals, including three compound heterozygous individuals with complex alleles that were resolved by targeted long-read sequencing. One of the five individuals was compound heterozygous for an AAGGG RE and a multi-exon RFC1 deletion, the first reported case of CANVAS caused by a pathogenic RE and a copy number variant. Genetic analysis of the control cohort revealed that the carrier frequency of the pathogenic AAGGG RE was approximately 1 in 16, highlighting the potential for pseudodominant inheritance and the likelihood that RFC1-related disease is underdiagnosed. This analysis also demonstrated the significant RFC1 repeat heterogeneity, identifying 16 distinct motifs and complex repeat structures.
In the second part of this study, iPSC lines from three individuals with CANVAS carrying biallelic AAGGG RE and matching isogenic lines with heterozygous deletion of an AAGGG RE were generated from fibroblasts using a simultaneous reprogramming and CRISPR/Cas9 gene editing approach. The AAGGG RE was confirmed to be present at the correct zygosity in iPSCs and remained stable over continuous passaging. Consistent with prior studies of patient-derived tissues, no difference in RFC1 RNA expression or protein steady-state levels was observed between CANVAS and control iPSCs, suggesting this is an appropriate model for investigating RFC1-related disease pathomechanisms. Transcriptomic analysis of iPSC-derived neurons (iNeurons) generated via lentiviral-based overexpression of neurogenin-2 identified dysregulated pathways and genes in CANVAS iNeurons, including REC8, FAM135B, MEG3, and SLITRK2 providing novel insights into the pathogenesis of CANVAS.
In conclusion, this thesis advances the understanding of the complexity and heterogeneity of the RFC1 repeat and provides valuable insights into the frequency of pathogenic RFC1 RE alleles and the pathomechanisms underlying RFC1-related disease