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Clinical, molecular and microbial characterisation of the eosinophilic endotype of bronchiectasis: data from the EMBARC-BRIDGE study
Get PDFObjectives: Eosinophilic bronchiectasis is defined by a blood eosinophil count (BEC) ≥300 cells/µL, but blood eosinophils imperfectly reflect airway eosinophilic inflammation. Here, we investigated the relationship between eosinophilic airway inflammation, blood eosinophils and clinical severity in bronchiectasis and explored the phenotype associated with eosinophilic bronchiectasis. Methods: Sputum from 180 patients with stable CT-confirmed bronchiectasis was utilised to investigate airway levels of eosinophil proteins (eosinophil peroxidase (EPX), eosinophil derived-neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein (MBP) and Galectin-10 (Gal-10)) using a novel stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. To profile eosinophilic bronchiectasis, a nested analysis of patients with BEC 0.35 kUA/L, 24.5% vs 3.8%) in eosinophilic bronchiectasis. Sputum inflammatory biomarkers and clinical parameters did not differ between groups. Conclusions: LC-MS/MS can detect eosinophilic inflammation within bronchiectasis sputum. Weak associations between elevated airway eosinophil proteins, bronchiectasis severity and P. aeruginosa infection were observed. Direct measurement of eosinophilic airway inflammation provides additional information in addition to BECs. Eosinophilic bronchiectasis associated with P. aeruginosa infection and Aspergillus sensitisation
Diagnostic accuracy of symmetric dimethylarginine for chronic kidney disease in cats and dogs: a systematic review
Get PDFBackgroundChronic kidney disease is common in cats and dogs. The diagnosis previously relied upon serum creatinine; however, symmetric dimethylarginine (SDMA) may identify chronic kidney disease (CKD) earlier. A recent evidence summary questioned the superiority of SDMA in cats. Another study raised concerns over the specificity of SDMA in dogs.MethodsElectronic databases and grey literature were systematically searched for all relevant studies up to October 2024. Studies were included based on prespecified criteria by two independent reviewers. Studies were assessed for risk of bias and applicability concerns.ResultsEleven studies were included: five in cats (481 animals) and six in dogs (460 animals). There was marked heterogeneity in the design, population and tests used. Nine studies were at high risk of bias, and nine had high applicability concerns. There was marked variation in sensitivity and specificity. Heterogeneity and risk of bias present precluded meta-analysis. Sources of heterogeneity were explored.LimitationsGrey literature searching, data extraction and risk of bias assessment lacked independent duplication.ConclusionSignificant uncertainty remains regarding the diagnostic accuracy of SDMA in CKD in cats and dogs. Well-designed diagnostic accuracy trials in clinically relevant populations with optimised reference standards and thresholds are needed. The use of SDMA may increase the risk of misdiagnosis and overdiagnosis of CKD
Transsaccadic working memory in healthy ageing and neurodegenerative disease
Get PDFThe brain continuously integrates rapidly changing visual input across eye movements to maintain stable perception, yet the precise mechanisms underpinning dynamic working memory and how these break down in brain diseases remain unclear. We developed a novel eye-tracking paradigm and computational models to investigate how spatial and colour information are updated across saccades in the human brain. Our findings reveal that saccades selectively impair spatial but not colour memory. Computational modelling identified that spatial representations are maintained in a dual eye-centred frame of reference which is actively updated by a noisy memory of saccades but is vulnerable to interference. Using this model, we found that specific mechanistic failures in initial encoding and memory decay, rather than the saccadic updating process itself, account for spatial working memory deficits in Alzheimer’s and Parkinson’s disease. These results provide a mechanistic understanding of how dynamic spatial memory operates in health and its disruption in neurodegenerative disorders
The future of fundamental science led by generative closed-loop artificial intelligence
Get PDFArtificial intelligence is approaching the point at which it can complete the scientific cycle, from hypothesis generation to experimental design and validation, within a closed loop that requires little human intervention. Yet, the loop is not fully autonomous: humans still curate data, set hyperparameters, adjudicate interpretability, and decide what counts as a satisfactory explanation. As models scale, they begin to explore regions of hypothesis and solution space that are inaccessible to human reasoning because they are too intricate or alien to our intuitions. Scientists may soon rely on AI strategies they do not fully understand, trusting goals and empirical payoffs rather than derivations. This prospect forces a choice about how much control to relinquish to accelerate discovery while keeping outputs human relevant. The answer cannot be a blanket policy to deploy LLMs or any single paradigm everywhere. It demands principled matching of methods to domains, hybrid causal and neurosymbolic scaffolds around generative models, and governance that preserves plurality and counters recursive bias. Otherwise, recursive training and uncritical reuse risk model collapse in AI and an epistemic collapse in science, as statistical inertia amplifies flaws and narrows the investigation. We argue for graded autonomy in AI-conducted science: systems that can close the loop at machine speed, while remaining anchored to human priorities, verifiable mechanisms, and domain-appropriate forms of understanding
Beyond mental disorders: The role of child maltreatment in childhood suicidal behaviour
Get PDFSuicide is one of the leading causes of death in children aged 14 years and under in Australia, and child maltreatment is consistently identified as an antecedent. Despite this, not enough is known about the pathways from child maltreatment to suicidal behaviour, hampering prevention efforts. In this perspective, we examine the association between (1) various types of childhood maltreatment, and (2) the presence of mental disorders, and subsequent suicidal behaviours in children aged 14 years and under. We present a conceptual model of childhood suicidal behaviours which incorporates both direct and indirect mechanisms by which maltreatment (and other risk factors) exert an influence. Bodily intrusive maltreatment, especially sexual and physical abuse, significantly increases the risk of suicidal behaviours in childhood. Other forms of maltreatment, such as neglect and emotional abuse, may also contribute. While the presence of a mental disorder is another prominent risk factor for suicidal behaviours in adolescents and adults, there is less evidence of this association in childhood. Efforts to prevent child maltreatment can support suicide prevention efforts in children and other age groups. In addition, screening for suicidal behaviours and targeted interventions should be prioritised for populations at increased risk, particularly children with a history of maltreatment and their families
Uncertainties of enhanced rock weathering for climate-change mitigation
Get PDFEnhanced rock weathering (ERW) on agricultural soils is under consideration as a long-term carbon dioxide removal (CDR) strategy. In this Perspective, we evaluate uncertainties related to ERW around feedstock availability, plant–soil system impacts, CDR efficiency along the land–ocean continuum and socio-economic considerations. The composition of (ultra)mafic rocks places constraints on the availability of suitable feedstock when considering their potential for CDR and toxic element contents. For ERW application at scale, dedicated mining for suitable feedstock seems unavoidable. ERW can positively and negatively affect soil structure, hydrology, and overall carbon and nutrient cycles, and so optimal ERW will require site-specific assessment of effective CDR and mitigation of potential negative impacts. Additionally, the fate of weathering products along the land–ocean continuum in rivers remains poorly constrained, which is a challenge for verifying successful CDR. The socio-economic effects and constraints of ERW regarding financing and risk responsibility are also uncertain. Ultimately, large-scale ERW deployment seems limited by substantial challenges throughout its application, from its initial set-up to final CDR. Future research prioritizing site-specific assessments, long-term monitoring along the land–ocean continuum, and system modelling to constrain uncertainties and address socio-economic factors is needed to ensure that ERW deployment is effective, equitable, and sustainable
Sex-difference in stroke outcome in young people in relation to haemoglobin level
No full textIntroduction: Worse stroke outcome in women than men is partly explained by differences in age, aetiology and pre-morbid disability, but lower haemoglobin (Hb) could also contribute, particularly at younger ages. We therefore aimed to explore whether lower Hb levels might correlate with stroke outcome in younger women.
Methods: In a population-based cohort (Oxford Vascular study) we studied all patients aged ≤55 years with a stroke between 1st April 2002 and 31st March 2023 and face-to-face follow up at one-month. We used ordinal multi-regression models to assess one-month post-stroke modified Rankin Scale score (mRS), and the change from pre-morbid status (ΔmRS), in relation to Hb levels (continuous and by WHO definition of anaemia) and sex, with adjustment for age, vascular comorbidities, pre-morbid mRS and medications.
Results: Among 348 patients (mean/SD age = 45.4/8.01; 149 female, 42.8%) anaemia was associated with a higher post-stroke mRS (adjusted OR=3.18, 95%CI =1.66-6.06, p<0.001) and greater ΔmRS (adjusted OR=2.72, 1.39-5.30, p=0.003). These trends were consistent in both women and men analysed separately and in those with ischaemic stroke only. Women had higher one-month mRS compared with men (adjusted OR=1.58,1.05-2.38, p=0.03), but further adjustment for the sex difference in Hb (mean/SD Hb: 13.12/1.64 g/dl in women vs 15.13/1.36 in men, p<0.001) removed the effect of sex (fully adjusted OR=1.07, 0.65-1.74, p=0.80). The higher ΔmRS in women (adjusted OR=1.57, 1.04-2.38, p=0.03) also diminished after adjustment for Hb (fully adjusted OR=1.04; 0.64-1.70, p=0.87).
Conclusion: Low Hb levels are associated with a poor outcome after stroke and could be a clinically important determinant of the sex-difference in stroke outcome at younger ages. If confirmed, these findings further justify correction of iron-deficient anaemia at the population level and in situations where stroke risk is increased
A Rational Optimization Approach for the Development of a Multiplexed Lateral Flow Immunoassay: Detection of Nonepithelial Ovarian Cancer Markers in Human Serum
Get PDFWith the rise of non‐communicable diseases, lateral flow immunoassays (LFIAs) are well‐positioned to address the demand for disease monitoring. We present the use of peroxidase‐mimicking platinum nanozyme conjugates targeting three ovarian germ cell tumor markers (alpha‐fetoprotein (AFP), human chorionic gonadotropin (HCG), and cancer antigen 125 (CA125)) in LFIA. A “design of experiments” (DoE) approach was used to optimize antibody–nanozyme conjugation, superseding conventional “one‐factor‐at‐a‐time” optimization strategies, which neglect factor‐to‐factor interactions obscuring identification of optimal conditions. Crucial to disease monitoring, assays must demonstrate limits of detection (LoD) within clinically defined ranges and produce quantitative readouts. We address limitations of typical LoD calculations, which assume homoscedastic variance across marker concentrations, presenting an alternative model and applying it to assess LFIA performance, subsequently demonstrating clinically relevant LoDs in human serum. To robustly derive marker concentrations from LFIA readouts, the model was coupled with the resolution molecular concentration and, using patient samples, validated against laboratory gold standard values. AFP and HCG assays align well with gold standard measurements, with sensitivities of 87.5% and 100%, and specificities of 98.3% and 100%, respectively. This work outlines a development pipeline of a patient sample validated semiquantitative LFIA, utilizing DoE for streamlined optimization and improving modeling approaches to quantify performance in a manner representative of assay function
Fully automated volumetry of ventricular subregions on computed tomography using object detection and semantic segmentation
Get PDFBackgroundOur goal was to develop and validate machine learning models that are capable of fully automatic identification and segmentation of frontal, temporal, and posterior horns, the body of the lateral ventricle, the third and fourth ventricle, as well as the atrium on either side.MethodsPatients shunted for hydrocephalus were included. Data from two centers was used for development/external validation, respectively. Manual labelling of ventricular subregions on computed tomography (CT) was performed. First, an object detection algorithm (YOLOv5) was trained. This allowed for precise cropping of the subregions that could then be used as input for a 2D U-Net. For comparison, a nnU-Net was also trained. Precision, recall, mean average precision 50 and 50-95 (mAP50; mAP50-95) were used as performance metrics for the YOLO algorithm. Dice score, Jaccard score, and 95th percentile Hausdorff distance assessed performance for the U-Net.Results80 CTs from patients at our center were included, as well as 50 from a second center. The mean age was 68.59 ± 15.89 and 75.94 ± 4.17 for the first and second centers, and 43 (52.5%) and 30 (60%) were male. MAP 50, mAP50-95 was 0.728, 0.453 for internal and 0.274, 0.124 for external validation across all classes. Best mean Dice scores were 0.92 ± 0.1 and 0.90 ± 0.05 for the body of the left lateral ventricle.ConclusionsAutomatic segmentation and volumetry of ventricles including their subregions was feasible with high precision on computed tomography, potentially helping the clinical evaluation of even subtle changes in ventricular volume
Between Word and Spirit: A Methodological Consideration of Human Rights Genealogies
Get PDFIn English Public Theology, Joan O’Donovan retrieves a robust account of the public foundation undergirding the English Reformation's rich scriptural tradition. From this vantage point, O’Donovan unfurls both a sweeping diagnosis and a scathing critique of the modern liberal natural rights tradition. However, what remains unclear is to what extent O’Donovan's historical narration succeeds, especially in contrast to alternative historical accounts that trace a central role for inherent human rights within the broader Christian scriptural tradition. This article poses two questions. First, how should these competing histories be evaluated? Second, must a theological account of rights solely rest upon scriptural grounds? I argue that theological interpretations of human rights history need not capitulate to rational or historical reductions, or even a certain Christological reduction wherein the value of rights-talk is made to hinge on either its secular or scriptural genealogy. This article begins with a methodological consideration of O’Donovan's ‘Christological’ interpretation of church tradition. Then, as a counterexample, I will examine Wolterstorff's intentionally ‘loose’ coordination between his philosophical and scriptural grounds for inherent rights. Lastly, I will suggest that Hans Joas’s affirmative genealogy of human rights provides a helpful methodological supplement to Wolterstorff's scriptural reasoning