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A multi-hospital, clinician-initiated bacterial genomics programme to investigate treatment failure in severe Staphylococcus aureus infections
No full textBacterial genomics is increasingly used for infectious diseases surveillance, outbreak detection and prediction of antibiotic resistance. With expanding availability of rapid whole-genome sequencing, bacterial genomics data could become a valuable tool for clinicians managing bacterial infections, driving precision medicine strategies. Here, we present a clinician-driven bacterial genomics framework that applies within-patient evolutionary analysis to identify in real-time microbial genetic changes that have an impact on treatment outcomes of severe Staphylococcus aureus infections, a strategy that is increasingly used in cancer genomics. Our approach uses a combination of bacterial genomics and antibiotic susceptibility testing to identify and track bacterial adaptive mutations that underlie microbiologically documented treatment failure (i.e. ongoing positive cultures [persistent infection] or new positive cultures after initial response [recurrent infection]). We show the potential added value of our approach to clinicians and propose a roadmap for the use of bacterial genomics to advance the management of severe bacterial infections
A Systematic Review of Dental Antibiotic Stewardship Interventions
No full textBACKGROUND: Antimicrobial resistance is a significant threat to global health. Antimicrobial stewardship is reducing inappropriate antimicrobial prescribing to counter it. Dentists prescribe ~10% of all antibiotics worldwide, yet up to 90% of antibiotic prescriptions by dentists are inappropriate. The aim of this systematic review was to update a 2017 review evaluating the effects of antibiotic stewardship interventions in dental settings, using the international consensus on core outcomes for dental antibiotic stewardship. METHODS: Systematic database searches were undertaken in April 2023, of the: Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE via OVID, EMBASE via OVID, Dentistry and Oral Sciences Source, the US National Institutes of Health Trials Register, the World Health Organisation International Clinical Trials Registry Platform and the ISRCTN registry databases. Randomised controlled trials (or non-randomised studies with clearly reported mechanism of group formation and inclusion criteria) of interventions to optimise and/or reduce dental antibiotic prescribing were eligible for inclusion. Two authors independently screened for eligible studies. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, certainty of evidence assessed using GRADE. Meta-analysis was planned whether the results of studies reported similar outcomes, otherwise narrative synthesis was undertaken. RESULTS: Three eligible studies randomising 2148 participants were included. The interventions were combinations of education, audit and feedback and written behaviour change messages, guideline summary, practice visits and patient leaflets. None of the control groups received an intervention. All three included studies measured the quantity of antibiotics prescribed and two measured the appropriateness of prescribing. None measured patient-reported or adverse outcomes. Two included studies were assessed as 'high risk' and one with 'low risk' of bias. There was high-certainty evidence that audit and personalised feedback with individualised behaviour change messages can be effective. Evidence for in-person education was low-certainty. Guideline dissemination alone was ineffective at improving antibiotic prescribing. Due to different outcomes reported, meta-analysis was inappropriate. CONCLUSION: Although various dental antibiotic stewardship interventions have been reported in the literature, only three have been evaluated using a randomised design, of which only one provided high certainty evidence. To strengthen the body of evidence, well-powered, robust, randomised controlled trials are required, with adequate follow-up, reporting the internationally-agreed core outcomes and including a parallel process evaluation is recommended. TRIAL REGISTRATION: PROSPERO (CRD42023411476)
Barriers to cervical cancer screening among refugee women: A systematic review
No full textCervical cancer disproportionately affects vulnerable populations including refugee women. Understanding the barriers to cervical cancer screening uptake in this group is crucial to inform targeted interventions and improve health outcomes. This review aimed to identify barriers hindering their access to cervical cancer screening. Five databases - Ovid MEDLINE, EMBASE, PsycINFO, CINAHL, and SCOPUS - were searched in December 2024. The inclusion criteria included studies - a) targeting healthy refugee women, b) conducted in community or hospital/clinic settings, c) reporting barriers to cervical cancer screening from the women's perspective, and d) published in English. Thematic analysis was performed to identify the barriers. The review followed the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eleven studies, seven from the USA, one from each of the UK, Australia, South Korea and Jordan, were included in this review. Of these, six were qualitative, three were quantitative and two were mixed methods studies. There was a consistent pattern of lack of knowledge about cervical cancer and cancer screening in refugee women. A unique barrier was women's negative experiences in refugee camps. Four interconnected themes emerged including 1) individual level barriers, 2) cultural and religious barriers, 3) social and structural barriers, and 4) healthcare system barriers. Ninety percent of included studies were assessed as medium or high quality. The findings underscore the urgent need for targeted interventions to address the diverse challenges faced by refugee women globally which hinder their access to cervical cancer screening. Strategies should include culturally sensitive awareness campaigns, active engagement of healthcare professionals, and structural reforms within healthcare systems to enhance cervical cancer screening uptake among refugee women
Implementation science research priorities for Universal Health Coverage: methodological lessons from the design and implementation of a multicountry modified Delphi study
No full textDelphi studies are rapidly gaining prominence in global health research. However, researchers' modifications to the Delphi method are often not well-described or justified, limiting opportunities to systematically learn from these studies when the methods are applied to other topics and settings. This paper aims to describe an approach to implementing a modified Delphi study and reflect on the research process in the context of a multicountry study of implementation science research priorities to advance Universal Health Coverage (UHC). We review trends in the use of the modified Delphi method in global health research, outline our three-phased modified Delphi approach, and share reflections on five decision points for implementing the study: (I) identifying and recruiting participants for the expert panel, (II) addressing participant attrition between rounds, (III) justifying the most appropriate cutoff points, (IV) incorporating new items raised by participants in open-ended survey sections, and (V) ensuring maximum variation in perspective in the panel of experts. Insights from this work foster greater understanding of the underlying assumptions for, and interpretation of, 'modified' in modified Delphi studies. This study will encourage critical dialogue about points of methodological contention in Delphi methodology and thus are relevant for scaling the use of modified Delphi studies in public health, including global health research
Plasma proteomics for cognitive decline and dementia—A Southeast Asian cohort study
No full textINTRODUCTION: The prognostic utility of plasma proteomics for cognitive decline and dementia in a Southeast Asian population characterized by high cerebrovascular disease (CeVD) burden is underexplored. METHODS: We examined this in a Singaporean memory clinic cohort of 528 subjects (n = 300, CeVD; n = 167, incident cognitive decline) followed-up for 4 years. RESULTS: Of 1441 plasma proteins surveyed, a 12-protein signature significantly predicted cognitive decline (q-value < .05). Sixteen diverse biological processes were implicated in cognitive decline. Ten proteins independently predicted incident dementia (q-value < .05). A unified prediction model combining plasma proteins with clinical risk factors increased the area under the curve for outcome prediction from 0.62 to 0.85. External validation in the cerebrospinal fluid proteome of an independent Caucasian cohort replicated four of the significantly predictive plasma markers for cognitive decline namely: GFAP, NEFL, AREG, and PPY. DISCUSSION: The prognostic proteins prioritized in our study provide robust signals in two different biological matrices, representing potential mechanistic targets for dementia and cognitive decline. HIGHLIGHTS: A total of 1441 plasma proteins were profiled in a Singaporean memory clinic cohort. We report prognostic plasma protein signatures for cognitive decline and dementia. External validation was performed in the cerebrospinal fluid proteome of a Caucasian cohort. A concordant proteomic signature was identified across both biofluids and cohorts. Further studies are needed to explore the therapeutic implications of these proteins for dementia
MUTATE: a human genetic atlas of multiorgan artificial intelligence endophenotypes using genome-wide association summary statistics
No full textArtificial intelligence (AI) has been increasingly integrated into imaging genetics to provide intermediate phenotypes (i.e. endophenotypes) that bridge the genetics and clinical manifestations of human disease. However, the genetic architecture of these AI endophenotypes remains largely unexplored in the context of human multiorgan system diseases. Using publicly available genome-wide association study summary statistics from the UK Biobank (UKBB), FinnGen, and the Psychiatric Genomics Consortium, we comprehensively depicted the genetic architecture of 2024 multiorgan AI endophenotypes (MAEs). We comparatively assessed the single-nucleotide polymorphism-based heritability, polygenicity, and natural selection signatures of 2024 MAEs using methods commonly used in the field. Genetic correlation and Mendelian randomization analyses reveal both within-organ relationships and cross-organ interconnections. Bi-directional causal relationships were established between chronic human diseases and MAEs across multiple organ systems, including Alzheimer’s disease for the brain, diabetes for the metabolic system, asthma for the pulmonary system, and hypertension for the cardiovascular system. Finally, we derived polygenic risk scores for the 2024 MAEs for individuals not used to calculate MAEs and returned these to the UKBB. Our findings underscore the promise of the MAEs as new instruments to ameliorate overall human health. All results are encapsulated into the MUlTiorgan AI endophenoTypE genetic atlas and are publicly available at https://labs-laboratory.com/mutate
Economic evaluation of personalized <i>vs</i>. standard dosing of 5-fluorouracil in first-line chemotherapy for metastatic colorectal cancer in Australia
No full textAIMS: Using pharmacokinetics (PK)-guided 5-fluorouracil (5-FU) for metastatic colorectal cancer (mCRC) improves overall survival (OS) and decreases toxicity, yet its value for money in the Australian setting is unknown. Our study assesses the cost-effectiveness of PK vs. body surface area (BSA) dosing of 5-FU for patients with mCRC. METHODS: We developed a semi-Markov model with four health states to compare PK-guided dosing within a FOLFOX regimen vs. BSA-guided dosing for mCRC patients from an Australian healthcare system perspective. Transition probabilities were derived from fitted survival models, with utility values obtained directly from published studies. We calculated direct healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), and included both one-way and probabilistic sensitivity analyses. RESULTS: BSA-guided FOLFOX provided 1.291 QALYs at a cost of 32 564. Therefore, PK-guided dosing emerges as the dominant strategy offering both better health outcomes and lower costs. The variables that had the greatest impact on the overall ICER were the adverse event rates in the BSA and PK groups, model time horizon, utility of progression-free survival and PREDICT assay cost. Our univariate and multivariate sensitivity analysis confirmed that the ICER for PK FOLFOX consistently remained below $50 000 per QALY across all tested variables. CONCLUSIONS: PK dose management of 5-FU-based chemotherapy in mCRC patients appears to be a cost-saving strategy in Australia. However, our model estimates are drawn from limited, low-quality evidence. Further evidence from randomized controlled trials (RCTs), directly comparing PK-based to BSA-based dosing across a variety of current regimens, is needed to address our model's uncertainties
Speech and language biomarkers for Parkinson’s disease prediction, early diagnosis and progression
No full textParkinson’s disease (PD), a multifaceted neurodegenerative disorder, can manifest as an array of motor and non-motor symptoms. Among these, speech and language impairments are particularly prevalent, often preceding motor dysfunctions. Emerging research indicates that these impairments may serve as early disease indicators. In this narrative review, we synthesised current findings on the potential of speech and language symptoms in PD identification and progression monitoring. Our review highlights convergent, albeit preliminary, lines of evidence supporting the value of speech-related features in detecting early or prodromal PD, even across language groups, especially with sophisticated analytical techniques. Distinct speech patterns in PD subtypes and other neurological disorders may assist in differential diagnosis and inform targeted management efforts. These features also evolve over the disease course and could effectively be utilised for disease tracking and guide management plan modifications. Advances in digital voice processing allow cost-effective, remote and scalable monitoring for larger populations
Biotechnology driven strategies to improve iron deficiency tolerance and grain nutrition in bread wheat (Triticum aestivum L.)
No full text© 2025 Oscar Oliver Joseph FungAdvances in plant transformation and genome editing have revolutionised the capacity of biotechnology to accelerate crop breeding. Unlike conventional breeding, biotechnology-assisted breeding can circumvent linkage drag and introduce genetic diversity beyond natural gene pools. Biotechnology driven strategies such as genetic modification (GM) and genome editing (GEd) therefore provide breeders with complementary tools to develop innovative varieties that meet stakeholder demands and address emerging global challenges. Bread wheat (Triticum aestivum L.) provides ~20% of global calories and is grown on more land than any other crop. However, GM and GEd has rarely been used to develop new bread wheat varieties to date, partly due to its complex hexaploid genome (2n = 6x = 42) and recalcitrance to tissue culture.
Iron (Fe) deficiency is both a societal and agronomic challenge. Over two billion people are affected by Fe deficiency globally. Rates of Fe deficiency anaemia are often high in regions where wheat provides more than 20% of daily caloric intake. Delivering bioavailable Fe via bread wheat could be one part of a practical strategy to combat Fe deficiency anaemia. Agronomically, alkaline soils reduce Fe availability for plant uptake. Calcareous soils (pH 7.5 – 9) cover 60% of Australia’s south-eastern grain growing regions and severely constrain crop productivity. Improving the Fe deficiency tolerance of bread wheat could increase productivity and reduce reliance on fertiliser inputs in calcareous soils.
Plant Fe deficiency causes leaf chlorosis and stunted growth, while Fe toxicity leads to cellular damage via reactive oxygen species (ROS) production. Ascorbate (vitamin C) acts as a ROS scavenger and can facilitate Fe mobilisation by reducing ferric (Fe3+) to ferrous (Fe2+) iron. Nicotianamine (NA) chelates Fe2+ for intra- and extra-cellular transport and aids in Fe uptake from the soil as a phytosiderophore precursor. Fe homeostasis is tightly regulated by transcription factors (e.g. Iron deficiency-responsive element-binding factor 1 and 2; IDEF1 and IDEF2), E3 ligases (e.g. Hemerythrin motif-containing Really Interesting New Gene and Zinc-finger protein 1 and 2; HRZ1 and HRZ2), and regulatory peptides. Modifying the expression of genes linked to ascorbate or Fe homeostasis presents an opportunity to alter Fe nutrition in the plants.
In this thesis, we explored the use of transgenesis and CRISPR-Cas9 genome editing to improve grain nutrition and abiotic stress tolerance of bread wheat. We characterised the NAS family in the bread wheat genome, comprising of 34 TaNAS genes, and independently overexpressed six native or modified TaNAS genes in bread wheat cv. Fielder. Under field conditions, overexpression of a truncated TaNAS6-D1 homoeolog increased grain Fe, zinc, and NA concentrations by 1.6-, 1.8-, and 3.7-fold, respectively. The GDP-L-galactose phosphorylase (GGP) gene encodes the most rate limiting ascorbate biosynthesis enzyme in plants. Constitutive expression of the Oryza sativa L. GGP (OsGGP) gene in bread wheat cv. Gladius had no discernible effect on grain nutrition or plant growth. We discovered two translationally repressive cis-regulatory sequences, known as upstream Open Reading Frames (uORFs), within the 5’ leader sequences of OsIDEF1 and IDEF2. Dual luciferase assays demonstrated that mutation of the uORFs within the 5’ LS of OsIDEF1, OsIDEF2, and TaIDEF2-A1 derepressed translation of the main ORF. In bread wheat cv. Fielder, CRISPR-Cas9 mutagenesis of the uORFs in TaIDEF2-A1 and TaIDEF2-D1 enhanced chlorophyll content (up to 5-fold) and shoot biomass (up to 1.5-fold) under hydroponic Fe deficient conditions. Transcriptomic analyses implicated the TaIDEF2 homoeologs in ribosomal biogenesis regulation. We further described the generation of four CRISPR-Cas9 populations in bread wheat (cvs. Fielder and. Borlaug 100) targeting either the coding sequences of TaHRZ1 or TaHRZ2 or uORFs within TaGGP1 and TaGGP2. The generation and analysis of transgenic and genome edited bread wheat in this thesis highlights multiple strategies to improve wheat using biotechnology
Rapid synthesis of glycosylated insulins by flow-based peptide synthesis
No full textInsulin is a key life-saving drug for patients with diabetes and is used clinically worldwide. To address the physicochemical challenges of insulin, such as low solubility and aggregation, glycosylated insulins have been chemically synthesized, exhibiting improved stability due to the hydration effect of glycans. In this work, we demonstrated the rapid synthesis of glycosylated insulins (glycoinsulins) using flow-based solid-phase peptide synthesis (SPPS). The insulin A-chain and glycosylated B-chain were synthesized by flow-based SPPS, with each elongation cycle completed in just 3 minutes. Through our investigations, the glycosylation step was successfully performed within 10 minutes under optimized flow-based conditions. Additionally, we examined the incorporation of dipeptide units (isoacyl dipeptide and pseudoproline) under flow conditions and demonstrated efficient peptide elongation by combining flow-based SPPS with these dipeptide units. The synthesized A- and B-chains were subsequently used for the stepwise formation of disulfide bond linkages. The resulting glycoinsulins exhibited comparable binding affinities to insulin receptors. These findings highlight a novel flow-based approach for the rapid synthesis of glycosylated peptide and protein drugs