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Learning from models: knowing sages as sages in Confucian philosophy
Get PDFIn the Confucian tradition, sages are moral reference points. They may serve as models against which we measure our own behaviours, and help us imagine how we can improve the quality of our moral lives. This defining feature of Confucian philosophy has persisted though the subsequent development of the tradition to the present. Yet, little has been said about the important epistemological issues that underlie the Confucian modelling process. In order to uphold sages as moral reference points, people need to recognize sages as sages and to deem the ways in which their lives embody virtue as desirable. This paper draws on a form of knowing, namely, knowing-as, to illuminate the process of learning from sages in the Confucian tradition. It will also help us better understand the process of modelling more generally
STatin TReatment for COVID-19 to Optimise NeuroloGical recovERy (STRONGER): study protocol for a randomised, open label clinical trial in patients with persistent neurological symptoms after COVID-19 infection
Get PDFIntroduction Increasing awareness of the high frequency, wide spectrum and disabling nature of symptoms that can persist following COVID-19 infection has prompted the investigation of management strategies. Our study aims to determine the effectiveness of atorvastatin on cognitive function, physical activity, mood, health-related quality of life and features of neurovascular impairment and neuroinflammation in adults with ongoing neurological symptoms after COVID-19 infection. Methods and analysis The STatin TReatment for COVID-19 to Optimise NeuroloGical recovERy study is an ongoing international, investigator-initiated and conducted, multicentre, prospective, randomised, open label, blinded endpoint trial with fixed time points for outcome assessments. A total of 410 participants with long covid neurological symptoms were planned to be randomly assigned to either the intervention group to receive 40 mg atorvastatin for 12 months or to a control group of no treatment, on top of usual care. Ethics and dissemination This study protocol was designed, implemented and reported, in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice, the National Health and Medical Research Council of Australia, the National Statement on Ethical Conduct in Human Research and with the ethical principles laid down in the World Medical Association Declaration of Helsinki. Central ethics committee approval was obtained from Sydney Local Health District Royal Prince Alfred Hospital Ethics (No: X21-0113 and 2021/ETH00777 10) in Australia. Site-specific ethics committee approvals were obtained elsewhere before any local study activities. All participants provided written informed consent. Trial registration number The study protocol is registered at Clinicaltrials.gov (NCT04904536)
Cardiac sodium ion channelopathies: Predicting the likelihood of pathogenicity of SCN5A variants through functional phenotyping
Get PDFCardiac sodium ion channelopathies are inheritable arrhythmia conditions associated with variants in SCN5A, the gene encoding the cardiac sodium ion channel, NaV1.5. Pathogenic variants in SCN5A can lead to Brugada Syndrome (BrS; prevalence 1:2000) and Long QT Syndrome type 3 (LQT3, prevalence 1:20,000), and a range of other less common conditions including sodium channel overlap syndrome. These arrhythmia syndromes are associated with sudden cardiac death, where there are no structural changes in the heart identified during post-mortem evaluation. Deaths due to sodium channelopathies are particularly tormenting for families as victims are typically young and otherwise healthy.
Next generation sequencing has enabled rapid identification of genetic changes and improved familial screening to determine at-risk family members. However, over 80% of rare variants identified, cannot be classified due to lack of sufficient clinical data. This impedes the benefits of genetic tests, such as confirming diagnosis, facilitating therapeutic management and identifying at-risk family members. In 2015, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) published guidelines to facilitate the determination of variant pathogenicity using a range of criteria, including functional data. However, due to the time- and resource-consuming nature of electrophysiology studies, there is limited functional evidence available. Following the development of automated patch clamp platforms, however, there is the opportunity to improve functional characterisation of SCN5A variants and thereby improve clinical classification of variants.
In this PhD thesis, the electrophysiological underpinnings of inherited arrhythmia and the design of functional assays to aid variant classifications are described in Chapter 1. An overview of the methods is described in Chapter 2. The establishment of an SCN5A-BrS functional assay that provides graded functional evidence primarily based on current density Z-scores to aid variant classification is discussed in Chapter 3. Chapter 4 demonstrates the application of the validated SCN5A-BrS assay to a large cohort of rare missense SCN5A variants from the International Brugada Syndrome Genetics Consortium and its utility alongside other ACMG criteria for cohort-scale variant reclassification. In Chapter 5, an SCN5A-LQT3 functional assay is established; the SCN5A-LQT3 assay explores gating parameters disruptive to cardiac repolarisation to offer an aggregated Z-score to determine variant risk. Both SCN5A-BrS and SCN5A-LQT3 assays were validated in accordance with ClinGen Sequence Variant Interpretation framework using a large set of clinically-classified variant controls to provide clinical-grade functional evidence for ACMG variant classification
Mechanomics engineering of stem cell structure and function toward targeted tissue neogenesis for regenerative medicine
Get PDFMechanical cues play ubiquitous roles in biological processes. Together with biochemical cues, mechanical forces (e.g. shear and compression) underpin the emergence of structure-function relationships in tissue development and regeneration. Mechanomics, i.e. stem cells’ emergent, adaptive response to mechanical environment, regulates their structural protein (e.g., extracellular matrix, cytoskeleton) synthesis and degradation, and their dynamic mechanical milieu. Mechanomics approaches to deliver highly controlled mechanical cues and track stem cells spatiotemporal adaptation, are needed to understand how structure-function relationships emerge, which is key to targeting tissue neogenesis and to designing materials and/or devices for regenerative medicine.
C3H/10T/1/2 murine embryonic stem cells were treated with paclitaxel (PAX) or cytochalasin D (cyto D) to perturb their cytoskeleton dynamics and their adaptation was probed under controlled delivery of mechanical cues. Increasing seeding density and laminar flow (0.2 dyn/cm2) were introduced as respective volume- and shape-changing stresses, emulating compression and shear in development. Stem cells were seeded on glass vs. compliant hydrogels (1-100 kPa) for emulating tissue template formation. Micropatterning was employed to dictate single cells geometry for probing cytoskeleton distribution and adaptation to flow.
PAX treatment was associated with cell volume increase and flatter shape in a time- and concentration-dependent manner, concomitant to increase in f-actin alignment, f-actin and microtubule concentration, that corresponded to increase in cell stiffness. Increasing seeding density and compliant substrates exert greater effect than PAX in modulating cytoskeleton concentration increase, whereby multicellular complexes could readily match the stiffness of the compliant substrates. Experimental flow and the computational validation reveal how seeding density influences flow fields around and along cell height. Flow and high seeding density complementarily upregulated msx2, col1a1, and col2a1, the markers for mesenchymal condensation. In contrast, expressions of acan, sp7, and pecam-1 (respective chondrogenic, osteogenic and angiogenic markers), were abrogated either by flow or increasing seeding density. Micropatterned cells exhibit varied f-actin and microtubule distribution relative to the non-adhesive regions, with thicker stress fibers developed along straight and non-adhesive edges, contributing to unique responses to flow and flow profile.
Modulation of stem cells mechanical environment and mapping their adaptation using mechanomics engineering tools enables further understanding of how structure-function relationships emerge in specific tissues. Ultimately, this knowledge could be proactively used to guide stem cells lineage commitment for engineering of healthy and disease tissues and improving regenerative medicine
Trial protocol of an open-label pilot study of oral naltrexone–bupropion combination pharmacotherapy for the treatment of methamphetamine use disorder (the NABU trial)
Get PDFIntroduction Methamphetamine use disorder is a global public health concern with no approved pharmacotherapies for its treatment. One recent randomised controlled trial conducted in the USA examined a combination of bupropion and naltrexone not readily available globally. Here, we report a trial protocol for an oral formulation of combined naltrexone and bupropion. Methods and analysis This single-arm, open-label pilot study will assess the safety and feasibility of oral naltrexone and bupropion (40 mg/450 mg daily in divided doses) in adults with methamphetamine use disorder. Participants (n=20) will be outpatients of a stimulant treatment program at an inner-city hospital in Sydney, Australia. The primary endpoint is Day 84. Participants will attend weekly study visits from Baseline to Week 12 and a follow-up telephone visit at Week 16. All participants will receive treatment as usual, such as psychosocial therapy. Primary outcomes are safety (measured by treatment-emergent adverse events (AEs)/adverse reactions) and feasibility (measured by the time taken to recruit, the proportion of ineligible participants, retention in the study and study medication adherence). Secondary outcomes will assess methamphetamine use, craving and withdrawal; treatment goals and expectations; physical and psychological well-being; depression and anxiety; and treatment satisfaction. Qualitative interviews will assess the acceptability of the intervention and outcome measures. Ethics and dissemination This study received ethics approval from the St Vincent’s Hospital Human Research Ethics Committee (2023/ETH00549). Results will be submitted to peer-reviewed journals and scientific conferences, and a video abstract will be created to ensure that the findings are accessible to participants and people who use methamphetamines
Domestic violence among adult male victims in non-intimate relationships: a text mining study using NSW police narratives
Get PDFBackground setting: Domestic violence (DV) is a major public health problem and a violation of human rights. To date, research on DV has predominantly focused on women as victims and men as perpetrators. Male DV victims particularly in non-intimate relationships have received little attention in the literature. This study represents the first attempt to report on DV among male victims in non-intimate relationships using population-level data. Methods: This is a population-level retrospective observational study using data extracted from a large sample of police-attended narratives in New South Wales (NSW) from 2005 to 2016 using rule-based text mining. Results: From 18,611 DV events involving non-intimate relationships, most of the Persons of Interest (POIs)—individuals suspected or charged with a DV offence—were male (78%) and members of the victims’ family (26.8%, cousins, uncles and aunts). A total of 42 different types of abuse were identified in 74.3% (n = 13,832) events, the most prevalent being physical abuse with assault (unspecified) accounting for half of the cases (53.9%, n = 7462) and punching for more than one third of cases (35.4%). Almost half of DV events (46.3%, n = 8616) recorded injury type to the victim, the most common being cut(s) (43.6%, n = 3754), followed by swelling (19.9%, n = 1716), and bruising (19.5%, n = 1679). A total of 2,903 (15.6%) events had a mental illness mentions for the POIs and 857 (4.6%) for the victims, with 23 different mental illnesses recorded. Schizophrenia and dementia were the most common mental illnesses among POIs (13.6%) and victims (13.0%), respectively. Conclusions: This study provides new insights and empirical evidence on abuse types, perpetrator-victim relationships, victim injuries and mental illness on DV events involving adult male victims in non-intimate relationships. The findings form an important evidence base to trigger further research in the future
Understanding and Defining Regional and Remote Areas: Criteria and Classifications for Australia
Get PDFRegional and Remote solutions is a key thematic area of the Sustainable Communities and Waste (SCaW) Hub, through which place-based, fit-for-purpose technology that address local needs across Australia are explored. Specifically, research in Impact Priority 2 (IP2) is being conducted to find technological recycling solutions for regional and remote communities. These communities face unique challenges when it comes to dealing with waste.
Some common examples include [ ]:
• Limited or no kerbside collection – of the 23% of the LGAs that do not offer any kerbside collection, the majority were in remote and regional communities
• Distance from recycling facilities – due to travel distance, road quality and weather events, transportation to Municipal Recycling Facilities (MRFs) represents a more significant cost factor leading to recoverable waste being sent to landfill
• Limited sorting technology - technical upgrades to facilities are less viable, requiring more labour-intensive sorting and difficulty separating co-mingled, contaminated waste
In general, smaller populations and a lack of viable technology prevent recycling options enabled through economies of scale from being implemented. Instead, regional and remote communities require “economies of purpose” with tailored solutions. In developing frameworks and tools to enable these communities to identify opportunities to shift from linear to circular economies, it has been important to engage with stakeholders from areas with varying degrees of remoteness.
The definitions of regional and remote areas in Australia vary across different levels of government, reflecting diverse criteria and purposes. These definitions are largely shaped by the purpose for which the distinction is required. For example, the purpose could be to capture data, to make policy and investment decisions, to secure funding, or to meet administrative needs
Redefine oral health: a call for inclusivity in the concept of oral health
Get PDFCurrent, globally accepted definitions of oral health emphasize pain-free functionality, expressive capacity, and specific psychosocial dimensions that contribute to self-confidence, well-being, and societal participation. However, these definitions inadvertently exclude diverse lived experiences by framing oral health solely through a lens of “normal” functionality and absence of discomfort, failing to consider the ways in which oral health can be experienced uniquely by different individuals and communities. The narrow focus on “pain-free” oral health excludes valid aspects of sexual expression, which may involve consensual oral activities that some find pleasurable even if associated with discomfort. This manuscript examines the limitations of the WHO and FDI definitions of oral health, critiques their exclusion of minority perspectives, and advocates for a more inclusive, holistic approach. Such an approach recognizes the complex and varied ways oral health intersects with identity, intimacy, and societal norms. Normalizing discussions on oral sexual health are essential to advancing a comprehensive understanding of well-being and reducing stigma around sexual minority experiences. Expanding oral health definitions to accommodate broader conceptions of intimacy and pleasure can enhance public health policy, clinical practice, and education, fostering a comprehensive understanding of well-being that reduces stigma around sexual minority experiences and further marginalization of sexual minorities in accessing inclusive care
Structure-Property Relationships in 2205 Duplex Stainless Steels Manufactured via Laser Powder Bed Fusion
Get PDFDuplex stainless steels (DSSs) possess desirable combinations of mechanical and corrosion properties due to their microstructure of roughly equivalent d-ferrite/austenite fractions. They are used in harsh environments such as marine infrastructures, oil & gas, and paper & pulp industries. Additive manufacturing (AM) techniques such as laser powder bed fusion (LPBF) can be harnessed to fabricate components with greatest complexity. However, as-built DSS parts exhibit highly non-equilibrium microstructures (>98% d-ferrite) with high densities of dislocations and precipitates, worsening ductility. This is generally regarded as a challenge, however, the desirable balanced d-ferrite/austenite microstructure can be recovered after a brief heat treatment, potentially achieving much finer duplex microstructures than in wrought counterparts. A systematic understanding of how LPBF parameters control the microstructural characteristics of the parent d-ferrite and, hence, the transformed austenite product, is currently missing. In addition, a fundamental understanding of the d-ferrite to austenite phase transformation and characteristics of the interfaces formed is currently lacking. The predominantly d-ferritic as-LPBF DSS can be used as a model system to reveal these phase transformation fundamentals. Recently, heat-treated LPBF DSSs have been reported to possess strength higher than wrought counterparts and ductility better than the as-built state. However, the underlying deformation mechanisms remain poorly understood.
The current Thesis initially establishes the process-microstructure-property relationship using electron microscopy and nano-indentation on a series of as-built and heat-treated conditions fabricated with different LPBF parameters. It is shown that, the texture, dislocation density, and residual stress in the d-ferrite all control austenite phase fraction, texture, grain size, and variant selection. The next two Chapters use three-dimensional electron backscatter diffraction to study the phase transformation pathways in two distinct as-solidified microstructures, analysing complex morphologies and interface crystallography that control the properties. Lastly, multi-scale characterization uncovers the multiple strengthening mechanisms during tensile deformation. The findings of this Thesis provide new insights into microstructural engineering via adjusting LPBF parameters and controlling materials performance through manipulating solid-state phase transformation products and interfaces formed. This knowledge is crucial for designing AM parts with reproducible and optimized mechanical properties for wider industrial applications