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Prospective observational study to assess the performance accuracy of clinical decision rules in children presenting to emergency departments with possible cervical spine injuries: The Study of Neck Injuries in Children (SONIC)
No full textINTRODUCTION: Paediatric cervical spine injury (CSI) is uncommon but can have devastating consequences. Many children, however, present to emergency departments (EDs) for the assessment of possible CSI. While imaging can be used to determine the presence of injuries, these tests are not without risks and costs, including exposure to radiation and associated life-time cancer risks. Clinical decision rules (CDRs) to guide imaging decisions exist, although two of the existing rules, the National Emergency X-Radiography Low Risk Criteria and the Canadian C-Spine Rule (CCR), focus on adults and a newly developed paediatric rule from the Pediatric Emergency Care Applied Research Network (PECARN) is yet to be externally validated. This study aims to externally validate these three CDRs in children. METHODS AND ANALYSIS: This is a multicentre prospective observational study of children younger than 16 years presenting with possible CSI following blunt trauma to 1 of 14 EDs across Australia, New Zealand and Singapore. Data will be collected on presenting features (history, injury mechanism, physical examination findings) and management (diagnostic imaging, admission, interventions, outcomes). The performance accuracy (sensitivity, specificity, negative and positive predictive values) of three existing CDRs in identifying children with study-defined CSIs and the specific CDR defined outcomes will be determined, along with multiple secondary outcomes including CSI epidemiology, investigations and management of possible CSI. ETHICS AND DISSEMINATION: Ethics approval for the study was received from the Royal Children's Hospital Melbourne Human Research Ethics Committee in Australia (HREC/69436/RCHM-2020) with additional approvals from the New Zealand Human and Disability Ethics Committee and the SingHealth Centralised Institutional Review Board. Findings will be disseminated through peer-reviewed publications and future management guidelines. TRIAL REGISTRATION NUMBER: Registration with the Australian New Zealand Clinical Trials Registry prior to the commencement of participant recruitment (ACTRN12621001050842). 50% of expected patients have been enrolled to date
Leaky gut in systemic inflammation: exploring the link between gastrointestinal disorders and age-related diseases
No full textGlobal average life expectancy has steadily increased over the last several decades and is projected to reach ~ 77 years by 2050. As it stands, the number of people > 60 years currently outnumbers children younger than 5 years, and by 2050, it is anticipated that the global population of people aged > 60 years will double, surpassing 2.1 billion. This demographic shift in our population is expected to have substantial consequences on health services globally due to the disease burden associated with aging. Osteoarthritis, chronic obstructive pulmonary disease, diabetes, cardiovascular disease, and cognitive decline associated with dementia are among the most common age-related diseases and contribute significantly to morbidity and mortality in the aged population. Many of these age-related diseases have been linked to chronic low-grade systemic inflammation which often accompanies aging. Gastrointestinal barrier dysfunction, also known as "leaky gut," has been shown to contribute to systemic inflammation in several diseases including inflammatory bowel disease and irritable bowel syndrome, but its role in the development and/or progression of chronic low-grade systemic inflammation during aging is unclear. This review outlines current literature on the leaky gut in aging, how leaky gut might contribute to systemic inflammation, and the links between gastrointestinal inflammatory diseases and common age-related diseases to provide insight into a potential relationship between the intestinal barrier and inflammation
Fibroblast hierarchy dynamics during mammary gland morphogenesis and tumorigenesis
No full textFibroblasts form a major component of the stroma in normal mammary tissue and breast tumors. Here, we have applied longitudinal single-cell transcriptome profiling of >45,000 fibroblasts in the mouse mammary gland across five different developmental stages and during oncogenesis. In the normal gland, diverse stromal populations were resolved, including lobular-like fibroblasts, committed preadipocytes and adipogenesis-regulatory, as well as cycling fibroblasts in puberty and pregnancy. These specialized cell types appear to emerge from CD34high mesenchymal progenitor cells, accompanied by elevated Hedgehog signaling. During late tumorigenesis, heterogeneous cancer-associated fibroblasts (CAFs) were identified in mouse models of breast cancer, including a population of CD34- myofibroblastic CAFs (myCAFs) that were transcriptionally and phenotypically similar to senescent CAFs. Moreover, Wnt9a was demonstrated to be a regulator of senescence in CD34- myCAFs. These findings reflect a diverse and hierarchically organized stromal compartment in the normal mammary gland that provides a framework to better understand fibroblasts in normal and cancerous states
Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2
No full textPURPOSE: It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers. METHODS: Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression. RESULTS: Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively). CONCLUSION: Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual
Relationship between time-varying achieved HbA 1c and risk of coronary artery disease events among common haptoglobin phenotype groups with type 2 diabetes: The ADVANCE study
No full textIntroduction This study sought to determine whether the association between attaining specific glycated hemoglobin (HbA 1c) targets (<7.0% (<53 mmol/mol) and ≥8.0% (≥64 mmol/mol) compared with 7.0%-7.9%) over time and risk of incident coronary artery disease (CAD) was dependent on haptoglobin (Hp) phenotype in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. Research design and methods Prospectively collected HbA 1c data from the ADVANCE biomarker case-cohort study, updated at 6 months and every 12 months thereafter over a median of 5.0 (IQR 4.5-5.3) years, were analyzed in relation to incident CAD in the Hp2-2 (n=1323) and non-Hp2-2 (n=2069) phenotypes separately using weighted multivariable-adjusted Cox regression models. Additional a priori stratifications by sex, race, previous cardiovascular disease (CVD), and type 2 diabetes duration were performed. Results Mean HbA 1c was similar in each phenotype group throughout the study. Compared with HbA 1c of 7.0%-7.9%, HbA 1c <7.0% was not associated with CAD risk for any phenotype group or subgroup. HbA 1c ≥8.0% compared with 7.0%-7.9% over time was associated with higher CAD risk for the Hp2-2 phenotype only (HR 1.53, 95% CI 1.01 to 2.32; no significant association in the non-Hp2-2 type: 1.26, 0.89 to 1.77, p-interaction=0.71); this was pronounced when those with previous CVD at baseline were excluded (Hp2-2: 2.80, 1.41 to 5.53, p-interaction=0.03). Compared with HbA 1c of <8.0%, having HbA 1c ≥8.0% was associated with a 59% higher CAD risk among participants with the Hp2-2 phenotype (1.59, 1.12 to 2.26) and a 39% higher CAD risk among participants without the Hp2-2 phenotype (1.39, 1.03 to 1.88, p-interaction=0.97). Conclusions The present ADVANCE analysis suggests that not having HbA 1c ≥8.0%, rather than achieving HbA 1c <7.0%, was found to be particularly important for CAD prevention among people with type 2 diabetes and the common Hp2-2 phenotype. While the subgroup analyses were likely underpowered, their inclusion is hypothesis generating and can be used in future meta-analyses to improve power and generalizability
Within-host modeling of primaquine-induced hemolysis in hemizygote glucose-6-phosphate dehydrogenase deficient healthy volunteers
No full textPrimaquine is the only widely available drug to prevent relapses of Plasmodium vivax malaria. Primaquine is underused because of concerns over oxidant hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency. A pharmacometric trial showed that ascending-dose radical cure primaquine regimens causing ‘slow burn’ hemolysis were safe in G6PD-deficient Thai and Burmese male volunteers. We developed and calibrated a within-host model of primaquine hemolysis in G6PD deficiency, using detailed serial hemoglobin and reticulocyte count data from 23 hemizygote deficient volunteers given ascending-dose primaquine (1,523 individual measurements over 656 unique time points). We estimate that primaquine doses of ~0.75 mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian G6PD variants. We predict that 5 mg/kg primaquine total dose can be administered safely to G6PD-deficient individuals over 14 days with expected hemoglobin drops of 18 to 43% (2.7 to 6.5 g/dL drop from a baseline of 15 g/dL)
Optimisation of high containment in vivo infectious disease studies and animal welfare outcomes
No full text© 2025 Rachel Louise LaytonThe use of in vitro and ex vivo methods can achieve some scientific objectives, but the complexities of physiology and immune responses means that animal studies are still required for infectious disease research. For serious zoonotic or exotic diseases, animal studies are conducted in purpose-built high biocontainment facilities, using restrictive personal protective equipment and strict animal management procedures. This can present challenges to animal welfare, by limiting the implementation of best-practice approaches.
In this thesis, novel methods of sample and data collection were developed to reduce reliance on manual and chemical restraint for improved pig welfare in high biocontainment disease studies. A novel positive reinforcement training (PRT) regimen was developed and assessed in both individually and group housed pigs, in addition to vascular access ports (VAPs) for conscious blood collection. PetPace collar monitors and VetChip implantable devices were also assessed for the regular and automatic measurement of pulse rate, heart rate variability and respiratory rate. Group-housed pigs responded more rapidly to training than individually housed pigs and were trained for conscious sample collections within 7 days without requiring sling restraint. VAPs facilitated consistent and voluntary blood collections, with pigs displaying few negative and increasingly positive behaviours, low salivary corticosterone, and reduced physiological disruption compared to anaesthetised pigs. PetPace collar monitors required modification for safe use in pigs, resulting in in successful data collection. VetChips collected accurate data, but mid-scapular placement was sub-optimal. In addition, the welfare of pigs recovering from anaesthesia, with and without the use of a low dose of atipamezole for partial anaesthetic antagonism, was assessed. Pigs administered atipamezole displayed reduced recovery times and improved thermoregulation, but increased adverse behaviours. This led to overall poorer welfare outcomes for pigs administered low-dose atipamezole during recovery from anaesthesia.
Based on these results, welfare and disease outcomes were compared in pigs sampled either whilst conscious using PRT and VAPs, or anaesthetised, in studies of highly pathogenic African swine fever (ASF). ASF disease onset occurred significantly later in anaesthetised pigs compared to VAP sampled pigs, and lameness with haemorrhage, tissue necrosis and ASF-infected macrophage infiltration and apoptosis was observed only in anaesthetised pigs. Tissue surrounding the VAP sites also displayed ASF-infected macrophage infiltration and apoptosis, but no haemorrhage or tissue necrosis was evident. Mean pulse rate and HRV decreased, and data variability increased, in pigs after ASF challenge. These changes were detected by multiple daily readings collected via PetPace collar monitors, but not by single daily point in-time readings. Abnormal readings of all parameters occurred both during and prior to clinical disease, leading to the development of a non-artificial intelligence (AI) algorithm. This algorithm detected healthy pigs (99.998% accuracy) and pigs infected with ASF (100% accuracy), and successfully predicted ASF disease onset in 67% of pigs.
This thesis was successful in developing novel methods of pig management in high biocontainment, resulting in reduced manual and chemical restraint and enhanced pig welfare. When applied to ASF disease studies, welfare outcomes were improved and confounding variables were reduced, leading to optimised welfare and scientific outcomes
Global impoverishment of natural vegetation revealed by dark diversity
No full textAnthropogenic biodiversity decline threatens the functioning of ecosystems and the many benefits they provide to humanity1. As well as causing species losses in directly affected locations, human influence might also reduce biodiversity in relatively unmodified vegetation if far-reaching anthropogenic effects trigger local extinctions and hinder recolonization. Here we show that local plant diversity is globally negatively related to the level of anthropogenic activity in the surrounding region. Impoverishment of natural vegetation was evident only when we considered community completeness: the proportion of all suitable species in the region that are present at a site. To estimate community completeness, we compared the number of recorded species with the dark diversity-ecologically suitable species that are absent from a site but present in the surrounding region2. In the sampled regions with a minimal human footprint index, an average of 35% of suitable plant species were present locally, compared with less than 20% in highly affected regions. Besides having the potential to uncover overlooked threats to biodiversity, dark diversity also provides guidance for nature conservation. Species in the dark diversity remain regionally present, and their local populations might be restored through measures that improve connectivity between natural vegetation fragments and reduce threats to population persistence
Downregulation of type I interferon signalling pathway by urate in primary human PBMCs
No full textType I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-β were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-β did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections
Proteomics and Machine Learning–Based Approach to Decipher Subcellular Proteome of Mouse Heart
No full textProtein compartmentalization to distinctive subcellular niches is critical for cardiac function and homeostasis. Here, we employed a rapid and robust workflow based on differential centrifugal-based fractionation with mass spectrometry–based proteomics and bioinformatic analyses for systemic mapping of the subcellular proteome of mouse heart. Using supervised machine learning of 450 hallmark protein markers from 16 subcellular niches, we further refined the subcellular information of 2083 proteins with high confidence. Our data validation focused on specific subcellular niches such as mitochondria, cell surface, cardiac dyad, myofibril, and nuclear, unfolding dominant subcellular localization of proteins in their native environment of mouse heart. We further provide targeted nuclear enrichment and co-immunoprecipitation–based proteomic validation from the heart of nuclear-localizing protein networks. This study provides novel insights into the molecular landscape of different subcellular niches of the heart and serves as a draft map for heart subcellular proteome