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Trajectory of plasma lipidome associated with the risk of late-onset Alzheimer's disease: a longitudinal cohort study
No full textBACKGROUND: Comprehensive lipidomic studies have demonstrated strong cross-sectional associations between the blood lipidome and late-onset Alzheimer's disease (AD) dementia and its risk factors, yet the longitudinal relationship between lipidome changes and AD progression remains unclear. METHODS: We employed longitudinal lipidomic profiling on 4730 plasma samples from 1517 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate the temporal evolution of lipidomes among diagnostic groups. At baseline (n = 1393), participants were classified as stable diagnosis status including stable AD (n = 243), stable cognitive normal (CN; n = 337), and stable mild cognitive impairment (MCI; n = 413), or converters (AD converters: n = 329; MCI converters: n = 71). We developed a dementia risk classification model to stratify the non-converting MCI group into dementia-like and non-dementia-like MCI based on their baseline lipidomic profiles, aiming to identify early metabolic signatures predictive of dementia progression. FINDINGS: Longitudinal analysis identified significant associations between the change in ether lipid species (including alkylphosphatidylcholine, alkenylphosphatidylcholine, lysoalkylphosphatidylcholine, and lysoalkenylphosphatidylcholine) and AD dementia conversion. Specifically, AD dementia converters show a 3-4.8% reduction in these ether lipid species compared to the non-converting CN and MCI groups, suggesting metabolic dysregulation as a key feature of AD progression. Further, The Dementia Risk Model effectively distinguished MCI from AD dementia converters (AUC = 0.70; 95% CI: 0.66-0.74). Within the MCI group, the model identified a high-risk subgroup with a twofold higher likelihood of conversion to AD dementia compared to the low-risk group. External validation in the ASPREE cohort confirmed its predictive utility, with the Dementia Risk Score discriminating incident dementia from cognitively normal individuals (C-index = 0.75, 95% CI: 0.73-0.78), improving prediction by 2% over the combination of traditional risk factors and APOE genetic risk factor. Additionally, the Dementia Risk Score was significantly associated with reduced temporal lobar fludeoxyglucose uptake (β = -0.286, p = 1.34 × 10-4), higher amyloid PET levels (β = 0.308, p = 4.03 × 10-4), and elevated p-tau levels (β = 0.167, p = 2.37 × 10-2), reinforcing its pathophysiological relevance in tracking neurodegeneration, amyloid burden, and tau pathology. INTERPRETATION: These findings highlight lipidomic profiling as a potential blood-based biomarker for identifying individuals at high risk of AD progression, offering a scalable, non-invasive approach for early detection, risk stratification, and targeted interventions in AD. FUNDING: The National Health and Medical Research Council of Australia (#1101320 and #1157607); NHMRC Investigator grant (#GNT1197190); Victorian Government's Operational Infrastructure Support Program; National Heart Foundation of Australia, Future Leader Fellowship (#102604), and National Health and Medical Research Council Investigator Grant (#2026325); Investigator grant (#2009965) from the National Health and Medical Research Council of Australia; a National Health and Medical Research Council of Australia Senior Research Fellowship (#1042095); National Institutes of Health grants: P30AG010133, P30AG072976, R01AG019771, R01AG057739, U19AG024904, R01LM013463, R01AG068193, T32AG071444, U01AG068057, U01AG072177, U19AG074879, R01AG069901, R01AG046171, RF1AG051550, RF1AG057452; National Institutes of Health/National Institute on Aging grants RF1AG058942, RF1AG059093, U01AG061359, U19AG063744, and R01AG081322, NIH/NLM R01LM012535; FNIH: DAOU16AMPA
Development of a digital therapeutic alliance scale (MM-DTA) in the context of fully automated mental health apps
No full textTherapeutic alliance (TA) refers to the relationship between a therapist and a client in face-to-face therapy and is an essential ingredient in successful psychological therapy outcomes. With the availability of fully automated apps, the question arises as to whether there is an analogous notion of a digital therapeutic alliance (DTA), and whether and how it plays a role in usage and outcomes of digital health interventions. Recent work has demonstrated that the DTA comprises five dimensions. Through a two-phase process, we have developed a preliminary scale to quantitatively capture this conceptualisation. Phase 1 described the process of scale development and involved three steps: item generation; content validity establishment; and face validity establishment. Phase 2 was a pilot test of the scale in two studies: a cross-sectional survey of mindfulness apps (sample size, n = 542), and a 30-day study with an evidence-based mental health app (sample size, n = 58). Reliability was assessed using internal consistency and intra-class correlation. We also explored convergent, predictive, and discriminant validity. Following the two phases, we developed a 39-item DTA scale that is reliable and demonstrates good face, content and convergent validity. This new DTA scale, grounded in people's experiences of using mental health apps, provides a valuable tool for evaluating mental health apps. HighlightsOur new 39-item scale, MM-DTA, is grounded in people's experiences of using mental health apps.MM-DTA is reliable and demonstrates good face, content, and convergent validity.MM-DTA can be used to evaluate mental health apps and explore mechanisms of change in digital health interventionsit is important to continue to evaluate the MM-DTA in relation to a range of different mental health apps and with different populations of app users. Our new 39-item scale, MM-DTA, is grounded in people's experiences of using mental health apps. MM-DTA is reliable and demonstrates good face, content, and convergent validity. MM-DTA can be used to evaluate mental health apps and explore mechanisms of change in digital health interventions it is important to continue to evaluate the MM-DTA in relation to a range of different mental health apps and with different populations of app users
JWST, ALMA, and Keck Spectroscopic Constraints on the UV Luminosity Functions at z ∼ 7-14: Clumpiness and Compactness of the Brightest Galaxies in the Early Universe
No full textAbstract
We present the number densities and physical properties of the bright galaxies spectroscopically confirmed at z ∼ 7–14. Our sample is composed of 60 galaxies at z
spec ∼ 7–14, including recently confirmed galaxies at z
spec = 12.34–14.18 with JWST, as well as new confirmations at z
spec = 6.583–7.643 with −24 < M
UV < −21 mag using ALMA and Keck. Our JWST/NIRSpec observations have also revealed that very bright galaxy candidates at z ∼ 10–13 identified from ground-based telescope images before JWST are passive galaxies at z ∼ 3–4, emphasizing the necessity of strict screening and spectroscopy in the selection of the brightest galaxies at z > 10. The UV luminosity functions derived from these spectroscopic results are consistent with a double power-law function, showing tensions with theoretical models at the bright end. To understand the origin of the overabundance of bright galaxies, we investigate their morphologies using JWST/NIRCam high-resolution images obtained in various surveys, including PRIMER and COSMOS-Web. We find that ∼70% of the bright galaxies at z ∼ 7 exhibit clumpy morphologies with multiple subcomponents, suggesting merger-induced starburst activity, which is consistent with SED fitting results showing bursty star formation histories. At z ≳ 10, bright galaxies are classified into two types of galaxies: extended ones with weak high-ionization emission lines, and compact ones with strong high-ionization lines including N
iv]
λ1486, indicating that at least two different processes (e.g., merger-induced starburst and compact star formation/AGN) are shaping the physical properties of the brightest galaxies at z ≳ 10 and are responsible for their overabundance
A biomechanical investigation of periprosthetic fracture risk in individuals with transfemoral amputation using osseointegrated implants
No full text© 2025 E Hong TiewOver the past few decades, bone-anchored prostheses (BAPs) have been introduced as an alternative to traditional socket prostheses to restore mobility and quality of life to individuals with lower-limb amputation. Unlike socket prostheses, which rely on custom fittings that cover the residual limb, BAPs work by directly attaching the external prosthetic limb to a metal implant – known as an osseointegrated implant – that is surgically anchored to the residual bone. This direct connection effectively addresses the challenges faced by socket prosthesis users, such as skin ulcers, dermal irritation, and poor socket fit, and provides additional benefits, such as improved biomechanical leverage, enhanced proprioceptive feedback, and increased mobility. However, one of the challenges facing BAP users is the high risk of bone fracture, particularly in individuals with transfemoral amputation with an estimated risk of 6.3%. Past research has sought to determine the fracture risks associated with BAPs during activities of daily living using finite element (FE) analyses. However, due to the multitude of loading combinations that may cause femoral fracture, the fracture risk of BAP users during activities of daily living remains poorly understood. The wide range of femur-implant parametric combinations such as femur length, implant length, and implant diameter adds complexity to this already challenging issue. As a result, conservative approaches have been used to guide clinical and engineering decisions, limiting the full functional potential and active lifestyle that BAPs could enable for individuals with limb loss.
The objective of this thesis was to enhance the understanding of femoral fracture risk in BAPs for individuals with transfemoral amputation by investigating femurs fitted with press fit osseointegrated implants during various activities of daily living across a wide range of femur implant construct combinations. A specimen-specific FE modelling methodology was first validated by comparing the FE predicted against experimentally measured strains of implanted femurs under load. Cadaveric femurs fitted with osseointegrated implants were mechanically loaded in a uniaxial test machine and the strain responses at various regions of interest were recorded using strain rosettes. Following the collection of strain data in the experiments, 3D geometric models of the intact femurs were created using computed tomography (CT) images and meshed, generating FE models of the implanted femurs. Heterogeneous material properties were then assigned to the FE models using five density elasticity relationships found in literature, and the boundary conditions in the experiments were replicated. The FE models were run, and the strain responses at the registered strain rosette locations were extracted. The FE predicted and strain rosette measured strains were then fitted to linear regression models, and the regression metrics were calculated and compared. The FE model that best predicted the experimental strains was then used to evaluate the fracture risk of the implanted femurs during five routine low-impact activities of daily living: level walking, ascending stairs, descending stairs, ascending inclines, and descending inclines. Factor of safety (FOS) was used as a quantifiable measure. The results reveal that ascending inclines posed the highest fracture risk out of the five activities investigated. Compared to level walking, ambulating stairs had a similar fracture risk while ambulating inclines had a higher fracture risk. These results demonstrate that femoral fracture risk in BAPs is activity dependent, with certain activities imposing higher mechanical demands on the bone implant construct. The results provide new insights on activity-specific fracture risk in BAPs and highlight the importance of incorporating a wider range of activities in future investigations to provide a more comprehensive outcome measure.
Next, to systematically investigate the effects of femur length, implant length, and implant diameter on the fracture strength of the femurs fitted with a press-fit osseointegrated implant, FE models of various femur-implant combinations were created using the validated FE modelling methodology in the previous chapter. The results from the FE models were analysed, and a six-dimensional (6D) failure envelope method was employed to estimate the fracture strength of the implanted femurs. The individual and interaction effects of the femur and implant parameters were assessed using a linear mixed effects model, specifically investigating the interactions between femur length and implant length, with specimen included as a random effect. An analysis of variance (ANOVA) with Type III Satterthwaite’s approximation on the mixed effects model was then conducted to determine the overall significance of each fixed effect in the mixed effects model. Post-hoc pairwise comparisons of estimated marginal means were also performed to determine significant changes in fracture strength within significant factors and across all significant factor combinations. Results demonstrate that implant length alone was a significant predictor of fracture strength, with long implants significantly reducing the fracture strength of the implanted femurs. The results also revealed significant interaction effects between femur length and implant length, with long femurs significantly mitigating the effects of long implants. Notably, short implants were found to be insensitive to femoral length changes, suggesting the broad applicability of short implants in engineering and clinical contexts. By quantitatively characterising these relationships, this work addresses a key gap in understanding how femur and implant geometry interact to influence fracture strength, providing evidence to support more informed implant selection and surgical planning. In terms of the optimal femur-implant combination, medium length femurs with short implants recorded the highest mean fracture strength, approximately 1.8 times that of the short femurs with long implants – the femur-implant combination with the lowest mean fracture strength. These findings highlight the importance of appropriate implant selection and the potential difference it makes in improving patient outcomes. To further contextualise the findings, FE models representing the optimal and weakest femur implant combinations were utilised to re-evaluate the fracture risk of the implanted femurs across the five routine activities of daily living. Interestingly, results revealed that there was no difference in the fracture risk between the optimal and weakest femur-implant combination during level walking and stairs ambulation. Fracture risk between the two femur implant combinations during incline ambulation, on the other hand, varied considerably. These results suggest that overall increase in fracture strength do not necessarily translate uniformly across all loading directions, emphasising the directional dependence of femoral loading in BAPs and the need to consider activity-specific loading conditions in future design and surgical planning.
In summary, this thesis investigated the femoral fracture risk in BAPs for individuals with transfemoral amputation. It validated a specimen-specific FE modelling methodology of femurs fitted with an osseointegrated implant and evaluated the fracture risk of BAP users during various activities of daily living. The thesis also investigated the effects of various femur and implant parameters on the fracture strength of the implanted femur, underscoring the importance of surgical planning procedures such as implant selection in mitigating fracture risks. The results of this thesis may guide future implant designs and influence clinical decision making to reduce fracture risks, enhance long-term patient outcomes, and ultimately improve the quality of life for individuals with limb loss
Developing a prototype for federated analysis to enhance privacy and enable trustworthy access to COVID-19 research data
No full textBACKGROUND: The use of federated networks can reduce the risk of disclosure for sensitive datasets by removing the requirement to physically transfer data. Federated networks support federated analytics, a type of privacy-enhancing technology, enabling trustworthy data analysis without the movement of source data. OBJECTIVES: To set out the methodology used by the International COVID-19 Data Alliance (ICODA) and its partners, the Secure Anonymised Information Linkage (SAIL) Databank and Aridhia Informatics in piloting a federated network infrastructure and consequently testing federated analytics using test data provided from an ICODA project, the International Perinatal Outcome in the Pandemic (iPOP) Study. To share the challenges and benefits of using a federated network infrastructure to enable trustworthy analysis of health-related data from multiple countries and sources. RESULTS: This project successfully developed a federated network between the SAIL Databank and the ICODA Workbench and piloted the use of federated analysis using aggregate-level model outputs as test data from the iPOP Study, a one-year, multi-country COVID-19 research project. This integration is a first step in implementing the necessary technical, governance and user experiences for future research studies to build upon, including those using individual-level datasets from multiple data nodes. CONCLUSIONS: Creating federated networks requires extensive investment from a data governance, technology, training, resources, timing and funding perspective. For future initiatives, the establishment of a federated network should be built into medium to long term plans to provide researchers with a secure and robust data analysis platform to perform joint multi-site collaboration. Federated networks can unlock the enormous potential of national and international health datasets through enabling collaborative research that addresses critical public health challenges, whilst maintaining privacy and trustworthiness by preventing direct access to the source data
Climate-sensitive maternal and child health outcomes: A scoping review and policy implications for Kiribati
No full textBackground Kiribati is situated in the central Pacific Ocean with a population of over 119,000 people. It is facing numerous health and other challenges from climate change, with adverse impacts on priority populations including women and children. Limited capacity and data gaps create challenges for responsive approaches to protect the health of priority populations. This scoping review surveys the peer-reviewed literature on several climate-sensitive maternal and child health outcomes, and considers this evidence in the context of Kiribati’s current climate and health policy landscape. Methods A search of PubMed, Web of Science and Scopus was conducted in August 2024 to identify peer-reviewed articles published in English between 2000 and 2024 examining climate-sensitive child and maternal health outcomes in the Pacific and developing countries. The search returned 463 results. Following abstract and full text screening, 34 articles were included in the review. Kiribati’s climate- and health-related policies were also identified and examined. Results Most (91 %) eligible articles have been published since 2010. Diarrheal disease and malnutrition are the commonest outcomes studied, with temperature and rainfall being key climatic factors affecting disease prevalence. Both outcomes are highly relevant for Kiribati. The limited evidence on climate-related maternal and adverse pregnancy outcomes also suggests temperature and rainfall are influential climatic factors. Conclusion There is increasing evidence across developing contexts that climate change adversely impacts maternal and child health outcomes. An opportunity exists to proactively identify and implement targeted interventions for women and children to reduce the prevalence of climate-sensitive maternal and child health outcomes
687. Paternal immune activation via the viral mimic poly i:c leads to epigenetic changes in sperm and results in behavioural, brain and physiological changes in offspring
No full textAbstract
Background
The paternal pre-conception environment has been shown to impact offspring behaviour and physiology in models of stress, diet, infection and other environmental influences. These altered offspring phenotypes implicate the sperm epigenome as the likely signal carrying these heritable changes. Many pre-clinical models demonstrate negative psychiatric and affective offspring behavioural phenotypes resulting from such paternal pre-conception environmental exposures, however underlying mechanisms are not yet resolved.
Aims & Objectives
We aim to assess the impact of the innate immune response, in the absence of the further effects of pathology present during infection, on paternal epigenetic inheritance and subsequently, offspring brain, behaviour and physiological function. We hypothesise that innate immune activation via the administration of the dsRNA viral mimic polyinosinic:polycytidylic acid (poly I:C) leads to sperm epigenome changes that can be passed to offspring, resulting in altered behavioural and brain phenotypes.
Method
8-week-old male C57BL/6J mice were administered a 12mg/kg dose of poly I:C or vehicle control. After four weeks, roughly corresponding to one round of spermatogenesis, mice were mated with age-matched naïve females. Fixed brains from post-natal day 21 pups and 9-weekold adult offspring brains were analysed for neuron and astrocyte immunohistochemistry. A separate cohort was assessed at 9 weeks of ages in a battery of behavioural tests to examine affective, psychiatric and cognitive behaviours. The paternal sperm short non-coding RNA profile was assessed to explore alterations in the epigenome that may carry the signal leading to offspring phenotypic changes.
Results
Paternal administration of poly I:C resulted in reduced time spent in the open arms of the elevated-plus maze, and a male specific reduction and delay in fear conditioning. Offspring additionally showed altered neuropathohistological measures and an elevated innate immune response to a poly I:C challenge. These offspring behaviour, neurological and physiological changes were correlated to an altered paternal sperm epigenome.
Discussion & Conclusions
These results demonstrate that immune activation via poly I:C alters the sperm epigenome, and in offspring, results in anxiety-related behavioural changes, altered brain parameters and a heighted innate immune response. These results could have broad implications for the impact of viral infections on public health
Effects of substrate quality, temperature, and water content on the decomposition of Sphagnum peat
No full textPeatlands, with their high water tables and anoxic conditions, have inherently low organic matter decomposition rates, making them vital carbon reservoirs. We designed a laboratory incubation experiment to investigate the interactive effects of substrate quality, temperature, and water content on the decomposition rate of Sphagnum peat. Fresh and degraded peat was collected from three different depths (0–5, 5–15, and 15–30 cm) of an Australian alpine peatland. The water contents of the peat samples were adjusted to four levels (field-moist or 50 %, 400 %, or 1500 %) and incubated at four temperatures (7, 14, 21, and 28 °C) for 70 days. Overall, fresh peat had ∼ 50 % higher decomposition rate than degraded peat. Both fresh and degraded peat incubated at 7 °C had higher or similar decomposition rates to peat at 14 °C, regardless of water content, likely due to the Sphagnum peat being dominated by psychrophilic microbes that have optimal metabolism at low temperatures. Further, the duration for which peat at 7 °C had a higher decomposition rate than at 14 °C declined as water content declined in the fresh peat and as peat depth increased in degraded peat. These findings indicate that the decomposition rate of fresh peat with a high percentage of labile carbon content is determined by the availability of liquid water required for microbial metabolism, while in degraded peat, substrate availability controls the decomposition rate. Our study provides critical insights into carbon release dynamics in southern hemisphere Sphagnum peatlands, which can inform strategies for managing and conserving these critical carbon reservoirs
Miniaturized multispectral imaging for microfluidic pH sensing
No full textMultispectral lab-on-chip imaging based on complementary metal-oxide semiconductor (CMOS) is an innovative technology that supports portable microfluidic platforms and enables the extraction of spectral information from specimens under multiple wavelengths. Accurate pH sensing is essential across a diverse range of chemical, biological, medical, and environmental applications. In this paper, we presented a new approach for pH sensing using the CMOS-based multispectral lab-on-chip imaging. Using a six-band color filter array that spans the optical spectrum in the visible and near-infrared range and a U-shape PDMS microfluidic channel, images of solutions with specific pH values were captured by a monochrome CMOS image sensor. To predict pH values, we developed a Support Vector Regression (SVR) model, which was trained using captured images of the six bands. Predicted pH values were obtained by the model with an RMSE of 0.364. Our research demonstrates that multispectral lab-on-chip imaging represents a miniature and rapid method to achieve pH sensing with high sensitivity and accuracy
GS-1 blocks entry of herpes viruses and more broadly inhibits enveloped viruses
No full textVaricella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) are significant global health concerns, infecting over 66% of the population. VZV causes varicella (chickenpox) and herpes zoster (shingles), while HSV leads to oral and genital herpes. Current antiviral treatments target viral replication but face limitations, such as the need for early intervention and the development of drug resistance, particularly in immunocompromised patients. Additionally, while shingles vaccines exist, their use is limited by availability, access, awareness, and cost. There is no vaccine for HSV. This study introduces GS-1, a novel formulation of undecylenic acid compounded with L-Arginine, as an entry inhibitor of enveloped viruses. In vitro studies demonstrate the antiviral activity of GS-1 against both VZV and HSV-1, with EC50 values ranging from 26 μg/mL to 62 μg/mL. Additionally, GS-1 displayed antiviral activity against VZV in an ex vivo human skin model, indicating its potential as a topical antiviral agent. The unique mechanism of action of GS-1, which involved binding directly to viral particles and blocking viral entry, was also extended to another enveloped virus, zika virus (ZIKV), a member of the flavivirus family, but had limited ability to block the non-enveloped virus, rotavirus. GS-1 could offer an effective means of controlling viral infections, particularly when used as combination therapy with other antiviral agents. Future studies will focus on confirming these results in a clinical setting