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Development and validation of diagnostic and prognostic prediction tools for dental caries in young children through prospective and cross-sectional observational studies: a protocol
No full textINTRODUCTION: Dental caries is the most common oral disease worldwide, affecting up to 90% of children globally. It can lead to pain, infection and impaired quality of life. Early prevention is a key strategy for reducing the prevalence of dental caries in young children. Valid and reliable diagnostic or prognostic tools that enable accurate individualised prediction of current or future dental caries are essential for facilitating personalised caries prevention and early intervention. However, no efficacious tools currently exist in early childhood-the optimal period for disease prevention. We aim to develop and validate diagnostic and prognostic prediction tools for dental caries in young children, using a combination of environmental, physical, behavioural and biological early life data. METHODS AND ANALYSIS: Data sources include two prospective studies, with a total sample size of approximately 600 children. These cohorts have collected detailed demographic, antenatal, perinatal and postnatal data from medical records and parent-completed questionnaires and biological samples including a dental plaque swab. Candidate predictor variables will include sociodemographic characteristics, health history, behavioural and microbiological characteristics. The outcome variable will be the presence, incidence or severity of dental caries diagnosed using the International Caries Detection and Assessment System. Statistical and machine learning approaches will be used for selection of predictor variables and model development. Internal validation will be conducted using resampling methods (i.e., bootstrapping) and nested cross-validation. Model performance will be evaluated using standard performance metrics such as accuracy, discrimination and calibration. Where feasible, external validation will be performed in an independent cohort. Model development and reporting will be guided by the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) statement and the Prediction model Risk Of Bias Assessment Tool (PROBAST) guidelines. ETHICS AND DISSEMINATION: This study has ethical and governance approval from The Royal Children's Hospital Melbourne Human Research Ethics Committee (HREC/111803/RCHM-2024). Results of this study will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: Infant2Child: ACTRN12622000205730-pre-results; MisBair: NCT01906853-post results
Differential PARP inhibitor responses in BRCA1-deficient and resistant cells in competitive co-culture
No full textSynthetic lethality describes a genetic relationship where the loss of two genes results in cell death, but the loss of one of those genes does not. Drugs used for precision oncology can exploit synthetic lethal relationships; the best described are PARP inhibitors which preferentially kill BRCA1-deficient tumours preferentially over BRCA1-proficient cells. New synthetic lethal targets are often discovered using genetic screens, such as CRISPR knockout screens. Here, we present a competitive co-culture assay that can be used to analyse drugs or gene knockouts with synthetic lethal effects. We generated new BRCA1 isogenic cell line pairs from both a triple-negative breast cancer cell line (SUM149) and adapted pre-existing noncancerous BRCA1 isogenic pair (RPE). Each cell line of the isogenic pair was transformed with its own fluorescent reporter. The two-coloured cell lines of the isogenic pair were then grown together in the same vessel to create a more competitive environment compared to when grown separately. We used four PARP inhibitors to validate the ability to detect synthetic lethality in BRCA1-deficient cancer cells. The readout of the assay was performed by counting the fluorescently coloured cells after drug treatment using flow cytometry. We observed preferential targeting of BRCA1-deficient cells, by PARPi, at relative concentrations that broadly reflect clinical dosing. Further we reveal subtle differences between PARPi resistant lines compared to BRCA1-proficient cells. Here, we demonstrate the validation and potential use of the competitive assay, which could be extended to validating novel genetic relationships and adapted for live cell imaging
Effects of a closed-loop mindfulness-based program for reducing stress in family caregivers of people with dementia: a study protocol of a randomized controlled trial
No full textBACKGROUND: Mindfulness-based interventions (MBIs) have shown promise in reducing stress among family caregivers (FCs) of people with dementia (PWD). However, the long-term stress-relieving effects of traditional MBIs are often limited by challenges in maintaining regular practice, leading to issues with adherence and attrition. To address these limitations, this study protocol aims to test a novel closed-loop mindfulness-based program, integrated with a mobile application (Mind & Care App), to facilitate sustained mindfulness practice by providing quantifiable practice feedback and adaptive practice durations based on attentional capacity. METHODS: This is a three-arm randomized controlled trial involving 189 FCs of PWD. Participants will be randomly assigned to one of three groups: (1) the closed-loop mindfulness-based program, (2) a traditional mindfulness program, or (3) a control group receiving brief education on dementia care. The closed-loop mindfulness program will consist of three weekly face-to-face training sessions (90 minutes each) and daily guided self-practice using the Mind & Care App over an 8-week period. Evaluations will occur at baseline, post-intervention, and at a 6-month follow-up. The primary outcome will be perceived stress, while secondary outcomes will include depressive symptoms, peace of mind, caregiving burden, dyadic relationship quality, dispositional mindfulness, heart rate variability, and the care recipients' neuropsychiatric symptoms. A process evaluation will examine whether dispositional mindfulness mediates the relationship between mobile app usage and stress reduction. A cost-effectiveness analysis will evaluate between-group differences in intervention costs relative to work productivity and activity impairment with caregiving activities. Focus group interviews will be conducted to explore the strengths, limitations, and therapeutic components of the intervention from the perspective of FCs. DISCUSSION: This study will contribute to the understanding of how integrating quantifiable feedback and adaptive practice durations into mindfulness programs can enhance long-term mindfulness practice. By empowering FCs of PWD with mindfulness skills to manage the long-term challenges of caregiving, this intervention can improve caregiver well-being and caregiving outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06880822. Registered on March 2025
Regulation of actin cytoskeletal dynamics in T cell development and function
No full textT cell development and function depend on precise remodeling of the actin cytoskeleton, which regulates migration, cell division, immunological synapse formation, and signal transduction. Regulators of actin include nucleators (Arp2/3, Formins) and binding proteins (coronins, cofilin, myosin) that orchestrate cytoskeletal dynamics to ensure efficient antigen recognition and signaling, while Rho GTPases (Rac1, Cdc42, RhoA) link extracellular cues to actin rearrangements, influencing both conventional T cell activation and function. Dysregulated actin dynamics contribute to immunodeficiencies and autoimmunity, and thus understanding how the actin cytoskeleton is regulated in T cells has important implications
The relative importance of key life domains for people with disability: findings from a cross-sectional survey of NDIS participants in Australia
No full textPURPOSE: This study investigates the relative importance for people with disability of key life domains and whether this differs between young people (15-24) and adults (25 and over). METHODS: A cross-sectional survey was conducted from 20 October to 31 December 2022 with National Disability Insurance Scheme (NDIS) participants asked to rank eight domains: Choice & control, Daily living, Relationships, Home, Health & wellbeing, Lifelong learning, Work, Social, Community and Civic participation. Based on a random utility framework, the data were analysed based on a ranked-ordered logit model to estimate preference shares for the order of preferences across domains. Analyses were conducted separately for the young and adult cohorts. Sensitivity analyses were conducted by relaxing the equal importance of NDIS domains in the ranking exercise based on related life domain importance rating information, which was also collected in the survey. RESULTS: Our sample consisted of 1140 NDIS participants. While the majority ranked the domains as equally important, answers from the rating module suggested otherwise. Adjustments for these differences lead to similar results with both age cohorts ranking Health & Wellbeing, Home and Daily living as the most important domains. These were followed by Relationships, Choice & control, Social, Community & Civic participation, Lifelong learning, and Work for younger people. For older people the importance order between the Choice & control and Relationships was switched. CONCLUSION: Our results revealed similarity between what younger and older people perceive as important and despite often receiving a fair share of policy attention, work was seen, on average, as the least important life domain
Understanding mechanistic relationships between IgG titers and Fc effector functions: a computational framework to assess polyfunctionality
No full textIntroduction: Recent vaccine and infectious disease studies have highlighted the importance of antibodies that activate cellular Fc functions, including antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), which are mediated by different Fc gamma Receptors (FcγRs). Activation of these functions requires complex overlapping interactions between IgG antibodies, FcγRs, and antigens that can be challenging to deconvolve experimentally. Methods: Here we created an ordinary differential equation model that simultaneously predicted FcγRIIIa immune complexes upstream of ADCC and FcγRIIa immune complexes upstream of ADCP as a function of antigen, IgG, and FcγR concentration and binding properties. We then used the model to dissect mechanisms driving immune complex formation. Results: Model results suggested that the maximum formation of immune complexes would not occur at highest total IgG titers. Instead, higher IgG titers have the potential to decrease FcγRIIIa (ADCC) and/or FcγRIIa (ADCP) immune complexes, due to competition between antibody subclasses for antigen and FcγR binding. We used the model to simulate vaccine boosts of IgG1 or IgG3 in 105 participants from an HIV vaccine trial, and found that boosting IgG1 and IgG3 in combination was not predicted to result in significant changes in either FcγRIIIa (ADCC) or FcγRIIa (ADCP) immune complexes. Surprisingly, simulated boosting of IgG3 alone had the potential to significantly decrease ADCP (p<0.00001), though it would increase ADCC responses. We also illustrated how the model could be used to assess how variability in viral load, FcγR expression, FcγR polymorphisms, and IgG titers across different tissue compartments can lead to differences in FcγRIIIa and FcγRIIa complexes. Discussion: Altogether, these results illustrate how a computational framework provides new quantitative insights into activation of Fc effector functions that could be used to guide future rational design of therapeutic and prophylactic interventions
Exploring the association between Cultural and Linguistic Diversity (CALD) on treatment and outcomes in pancreatic cancer: an analysis of PURPLE real-world registry data from an Australian population
No full textBackground: Culturally and/or linguistically diverse (CALD) patients have unique health needs and may face multiple barriers when accessing healthcare. This study explored the association between of CALD status on treatment received and outcomes for patients with pancreatic cancer. Methods: Data were extracted from the multi-site PURPLE Pancreatic cancer Translational Registry between January 2016 and April 2023. Registry data was supplemented by country of birth and preferred language data from linkage with hospital administrative datasets. CALD status was defined by being born overseas in a non-main English-speaking country and/or having a preferred language other than English. Descriptive statistics were used to analyse demographic data. Survival analysis was conducted using Kaplan-Meier estimates to generate survival curves, with comparisons assessed via the log-rank test. Moreover, univariable and multivariable Cox proportional hazards regression were employed. Results: Of 1796 patients with pancreatic cancer enrolled at seven participating institutions, 1451 (80.8%) had their CALD status determined; with 661 (46%) identified as CALD. The CALD population were older (median age 72 vs. 68 years; P 1: 20 vs. 13%, P = 0.004) and a greater number of comorbidities (Charlson Comorbidity Index > 3: 55 vs. 43%, P < 0.001). The use of neoadjuvant therapy in resectable/borderline resectable disease was similar. However, fewer CALD patients proceeded to curative-intent surgery following neoadjuvant therapy (30% vs. 51%, P = 0.041). In the metastatic setting, a higher proportion of CALD patients were offered best supportive care (50% vs. 41%; P = 0.021). Overall, there were no significant differences identified in the progression-free, recurrence-free or overall survival for CALD patients with pancreatic cancer across all stages of disease. Conclusions: CALD status was associated with multiple adverse prognostic factors (age, PS, comorbidities), which likely impacted differences in treatment received and challenges analysis of the independent impact of CALD status on outcomes. Notably, however, there were no striking differences by CALD status in treatment delivered or survival outcomes
Piezo-Electro-Catalytic Hydrogen Production via Piezoelectric Fluoropolymers
No full textProducing future fuels, such as green hydrogen, using less external energy input is a key factor in making such fuels truly environmentally friendly. In addition, the requirement of reducing the amount of catalyst used per mass of fuel produced is key for resource stability, particularly for platinum group metals which dominate such catalysis fields. Herein, a proof‐of‐principle approach is demonstrated to achieve both targets through piezo‐electro‐catalysis from chemically stable, flexible, fluoropolymers. Highly polarized MXene‐poly(vinylidene‐difluoride)‐co‐(trifluoro‐ethylene) interfaces, with an embedded platinum mesh electrode, are shown to decrease the onset overpotential of the mesh by 200 mV, thus lowering the overall energy and Pt required to produce a given mass of hydrogen. The simple approach used herein can be applied to other, advanced catalysts, to boost performance and efficiency
Experimental and analytical investigation of a novel adhesive-free timber-steel composite using Eucalyptus globulus hardwood
No full textThe objective of this study is to investigate the structural behaviour of a novel adhesive-free timber-steel composite (AFTSC) system as a high-performance floor panel for sustainable mid- and high-rise construction. Local plantation Eucalyptus globulus timber boards and laser cut mild-steel were used to fabricate the test specimens. Four-point bending tests were carried out to experimentally record the force, displacement, and failure mechanism of the panels. An analytical model informed by material grading tests was generated and compared against the experimental results. The novel AFTSC panels maintained near full composite action past 40 % of ultimate load and consistently exhibited substantial ductile behaviour. In addition, the effective ultimate bending capacity of the timber components was found to increase by up to 20 % when included in the AFTSC panels. This demonstrates the high-performance credentials of the novel AFTSC system along with the potential to valorise plantation hardwoods such as Eucalyptus globulus
Osteoarthritis year in review 2025: Epidemiology and therapy
No full textAIM: To summarise key epidemiological and therapeutic research on osteoarthritis (OA) published between April 2024 and March 2025. METHODS: A narrative review was conducted using the MEDLINE database, focusing on English-language studies involving human participants published between April 1, 2024 and March 31, 2025. Eligible studies included observational longitudinal studies, systematic reviews, meta-analyses, and phase II-IV randomised controlled trials (RCTs) examining OA treatment and epidemiology. A total of 1920 studies were screened by 3 authors, resulting in 133 studies considered for potential inclusion. Ultimately, 41 studies were selected. Inclusion was based on perceived importance and relevance to identifying risk factors or advancing OA treatment. RESULTS: The global burden of OA continues to rise, with a notable increase in early-onset OA, driven in part by obesity and joint injuries. Epidemiologically, body composition-characterised by high fat mass and low lean mass-emerged as a critical factor influencing OA severity and physical function. Furthermore, the presence of other chronic conditions significantly impacts OA progression and outcomes, and influences management choice, increasing the risk of patients receiving low-value care. Therapeutic interventions for OA, including intra-articular injections (e.g., corticosteroids, hyaluronic acid, stem cells) and pharmacological therapies (e.g., metformin, methotrexate), continue to show limited efficacy. Semaglutide, which targets obesity, demonstrated substantial weight and pain reductions in individuals with knee OA and obesity, suggesting a potential disease-modifying effect through weight loss. CONCLUSION: The past year's research highlights the complexity of OA and the limited effectiveness of current interventions. While therapies targeting obesity hold promise, further research is needed to confirm their role in disease modification. Personalised treatment approaches that integrate metabolic, biomechanical, and psychosocial factors may be crucial for advancing OA care management