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Early mucosal responses following a randomised controlled human inhaled infection with attenuated Mycobacterium bovis BCG
No full textThe development of an effective vaccine against Mycobacterium tuberculosis is hampered by an incomplete understanding of immunoprotective mechanisms. We utilise an aerosol human challenge model using attenuated Mycobacterium bovis BCG, in BCG-naïve UK adults. The primary endpoint of this study (NCT03912207) was to characterise the early immune responses induced by aerosol BCG infection, the secondary endpoint was to identify immune markers associated with in-vitro protection. Blinded volunteers were randomised to inhale 1 × 107 CFU aerosolised BCG or 0.9% saline (20:6); and sequentially allocated to bronchoscopy at day 2 or 7 post-inhalation (10 BCG, 3 saline each timepoint). In the bronchoalveolar lavage post-aerosol BCG infection, there was an increase in frequency of eosinophils, neutrophils, NK cells and Donor-Unrestricted T cells at day 7, and the frequency of antigen presenting cells decreased at day 7 compared with day 2. The frequency of interferon-gamma+ BCG-specific CD4+ T cells increased in the BAL and peaked in the blood at day 7 post-BCG infection compared to day 2. BAL cells at day 2 and day 7 upregulated gene pathways related to phagocytosis, MHC-II antigen loading, T cell activation and proliferation. BCG's lack of key virulence factors and its failure to induce granulomas, may mean the observed immune responses do not fully recapitulate Mycobacterium tuberculosis infection. However, human infection models can provide unique insights into early immune mechanisms, informing vaccine design for complex pathogens
A randomized pilot and feasibility trial of live and recorded music interventions for management of delirium symptoms in acute geriatric patients
No full textBackground: Delirium is an acute shift in attention and arousal, usually triggered by acute illness or surgery in older dementia patients. Prognosis is poor, and pharmacological options are limited; non-pharmacological interventions and music show promise. Methods: This randomised pilot and feasibility trial tested feasibility, acceptability, fidelity, and safety of music interventions (MIs) for delirium patients and assessed preliminary effectiveness and suitability of the selected effect outcomes. Participants from an acute geriatric ward were randomised to Preferred Recorded Music (PRM) and Preferred Live Music (PLM), delivered for 30 min over three consecutive days. Feasibility outcomes included recruitment rate, retention, adherence, deviations, and treatment fidelity. Clinical outcomes were trajectory of delirium symptoms (arousal, attention, cognition), delirium duration, hospital stay length, and medication intake. Post-intervention and between groups changes in delirium symptoms were compared using mixed linear regression models for the repeated measurements. Mann-Whitney test and Fishers exact test were used for length of stay and medication use, respectively. Results: 26 participants (PLM = 14; PRM = 12), median age 87, most with hypoactive delirium were recruited at a rate of three participants per month. Retention rates for PLM and PRM were 64% and 33% respectively and adherence to PLM and PRM intervention protocols were 83% and 58%, respectively. Total adherence to the assessment protocols was 44%. PLM was delivered as intended, (treatment fidelity 93%), and PRM did not satisfy treatment fidelity (83%). All delirium symptoms except arousal improved on day 3 compared to baseline, with statistically significant improvement in attention. No conclusive pre-post or between-group differences were detected for any outcomes; confidence intervals were wide. Conclusions: Feasibility of recruitment, interventions and assessments was indicated, and greater acceptability, safety and fidelity of the PLM intervention compared with the PRM. Adoption of external assessors is warranted in future trials, to mitigate slow recruitment and low adherence. Wide confidence intervals for most measures and comparisons indicate that the possible effect of the MIs on delirium cannot be excluded. The trial was registered at Clinical Trials, ID: NCT05398211, on 31/05/2022
Deficiency of the palmitoyl acyltransferase ZDHHC7 modulates depression-like behaviour in female mice after a mild chronic stress paradigm
No full textChronic stress (CS) is a debilitating condition that negatively affects body and brain. In mice, CS effects range from changes in behaviour and brain microstructure down to the level of gene expression. These effects are partly mediated by sex and sex steroid hormones, which in turn are affected by the palmitoyl acyltransferase ZDHHC7. ZDHHC7 might modulate also the response to CS via palmitoylation of sex steroid hormone receptors and other proteins critical for neuronal structure and functions. Therefore, we aimed to investigate the role of ZDHHC7 in response to CS on different system levels in a mouse model of Zdhhc7-deficiency. Female and male Zdhhc7-knockout (KO) and -wildtype (WT) mice underwent a four-week-mild CS paradigm or non-stress control (C) condition. After C or CS, behaviours, hippocampal microstructures (via MRI-based diffusion tensor imaging) and brain gene expression profiles (via mRNA-seq transcriptomics) were investigated. Analyses focused on effects of genotype (KO vs. WT) or condition (C vs. CS) separately in both sexes. Our results revealed significant effects particularly in females. Female KOs displayed increased locomotion and reduced depression-like behaviour after CS (KO vs. WT, C vs. CS: pall < 0.05). Hippocampal fibres were reduced in female KOs after C (KO vs. WT: pall < 0.05) but in female WTs after CS (C vs. CS: pall < 0.05). Furthermore, female KOs showed increased cortistatin expression after CS (C vs. CS: mRNAseq and qPCR pall < 0.05). In sum, Zdhhc7-deficiency reduced depression-like behaviours, prevented hippocampal fibre reduction and upregulated cortistatin after CS. It seemed to be related to a sex-specific stress response and may reveal genetic factors of CS-resilience in female mice
The Das Kapital II, Archive, 2025
No full textThe show creates space for relational worlds featuring films by multicultural, First Peoples, LGBTQI+ artists that encompass how we scan and perceive digital cultures, with a vision for tangible and modest recuperation in the time of ecocide, with a strong commitment to diversity & inclusion. Moving image stories and practices of becoming-with in times that remain at stake, in precarious times, in which the world is not finished, and the sky has not fallen yet. [1]
[1] Haraway, Donna J. Staying with the Trouble: Making Kin in the Chthulucene, Duke University Press, 2016. P55
Heritage Council Regulatory Committee: Former Sunshine Technical College (H2458)
No full textThe Brimbank City Council is the responsible authority for the area in which the Former Sunshine Technical College is located and made the nomination for inclusion of the Place in the Heritage Register. The Brimbank City Council was represented at the hearing by Mr Greg Tobin, Principal, Harwood Andrews Lawyers. The Brimbank City Council called two expert witnesses during the hearing: Mr Jim Gard’ner, Director GJM Heritage, and Dr Deborah Towns OAM, Senior Research Fellow, Faculty of Business and Economics, University of Melbourne
Long lived liver-resident memory T cells of biased specificities for abundant sporozoite antigens drive malaria protection by radiation-attenuated sporozoite vaccination
No full textVaccination with radiation-attenuated sporozoites (RAS) can provide highly effective protection against malaria in both humans and mice. To extend understanding of malaria immunity and inform the development of future vaccines, we studied the protective response elicited by this vaccine in C57BL/6 mice. We reveal that successive doses of Plasmodium berghei RAS favour the generation of liver CD8+ tissue-resident memory T cells (TRM cells) over circulating memory cells and markedly enhance their longevity. Importantly, RAS immunisation strongly skews the composition of the liver CD8+ TRM compartment towards cells specific for abundant sporozoite antigens, such as thrombospondin-related adhesive protein (TRAP) and circumsporozoite protein (CSP), which become major mediators of protection. The increased prevalence of sporozoite specificities is associated with limited intrahepatic attenuated parasite development and inhibition of naïve T cell responses to all parasite antigens, whether previously encountered or not, in previously vaccinated mice. This leads to the exclusive expansion of effector T cells formed upon initial immunisation, ultimately reducing the diversity of the liver TRM pool later established. However, stronger responses to less abundant epitopes can be achieved with higher initial doses of RAS. These findings provide novel insights into the mechanisms governing malaria immunity induced by attenuated sporozoite vaccination and highlight the susceptibility of this vaccine to limitations imposed by strain-specific immunity associated with the abundant, yet highly variable sporozoite antigens CSP and TRAP
Decentring Ethics: AI Art as Method [Introduction]
No full textThis book was developed both on Wurundjeri and Bidjigal country in the place we now call Australia, and across many online networks around the world. Australia’s economy is dependent on mining. For decades, mining corporations have ravaged Indigenous land and ancestral sites in the name of mineral resource extraction and profit (Povinelli 2016; Puutu Kunti Kurrama People and Pinikura People 2020). We want to open the book by acknowledging this context as a deeply conflicted and yet generative position from which to start discussion of AI ethics. In doing so, we acknowledge the traditional owners of lands on which we work and live, and the important community of First Nations scholars who are leading debates in Indigenous AI internationally
Bivalent mRNA booster vaccination recalls cellular and antibody immunity against antigenically divergent SARS-CoV-2 spike antigens
No full textThe ongoing rollout of SARS-CoV-2 vaccines lags behind rapid viral evolution. Updated vaccine immunogens elicit neutralising antibodies against the component strain. However, protection against future SARS-CoV-2 variants is unclear. Here, we sought to understand factors underpinning serological breadth following bivalent BA.1 vaccination. Booster vaccination of 33 individuals elicited robust and durable antibody responses against component vaccine antigens and elevated frequencies of spike-specific CD4 and CD8 T cells. Immunisation predominantly drove recall of cross-reactive memory B cells which also recognised XBB.1.5 spike, with significantly enhanced neutralisation titres against XBB virus seen within 91% of participants. Multivariate regression indicated that both baseline neutralising titres and spike-specific CD4 T cell frequencies were strong predictors of ancestral, BA.1 and XBB neutralisation post-immunisation. These data highlight that updated SARS-CoV-2 vaccines recall cross-reactive memory that maintains recognition of antigenically evolved viral variants and suggests T cell help and prior antibody titres underpin robust vaccine-induced neutralising activity
Automated deep learning-based assessment of tumour-infiltrating lymphocyte density determines prognosis in colorectal cancer
No full textBACKGROUND: The presence of tumour-infiltrating lymphocytes (TILs) is a well-established prognostic biomarker across multiple cancer types, with higher TIL counts being associated with lower recurrence rates and improved patient survival. We aimed to examine whether an automated intraepithelial TIL (iTIL) assessment could stratify patients by risk, with the ability to generalise across independent patient cohorts, using routine H&E slides of colorectal cancer (CRC). To our knowledge, no other existing fully automated iTIL system has demonstrated this capability. METHODS: An automated method employing deep neural networks was developed to enumerate iTILs in H&E slides of CRC. The method was applied to a Stage III discovery cohort (n = 353) to identify an optimal threshold of 17 iTILs per-mm2 tumour for stratifying relapse-free survival. Using this threshold, patients from two independent Stage II-III validation cohorts (n = 1070, n = 885) were classified as "TIL-High" or "TIL-Low". RESULTS: Significant stratification was observed in terms of overall survival for a combined validation cohort univariate (HR 1.67, 95%CI 1.39-2.00; p < 0.001) and multivariate (HR 1.37, 95%CI 1.13-1.66; p = 0.001) analysis. Our iTIL classifier was an independent prognostic factor within proficient DNA mismatch repair (pMMR) Stage II CRC cases with clinical high-risk features. Of these, those classified as TIL-High had outcomes similar to pMMR clinical low risk cases, and those classified TIL-Low had significantly poorer outcomes (univariate HR 2.38, 95%CI 1.57-3.61; p < 0.001, multivariate HR 2.17, 95%CI 1.42-3.33; p < 0.001). CONCLUSIONS: Our deep learning method is the first fully automated system to stratify patient outcome by analysing TILs in H&E slides of CRC, that has shown generalisation capabilities across multiple independent cohorts
Multiprobe cosmology from the abundance of SPT clusters and des galaxy clustering and weak lensing
No full textCosmic shear, galaxy clustering, and the abundance of massive halos each probe the large-scale structure of the Universe in complementary ways. We present cosmological constraints from the joint analysis of the three probes, building on the latest analyses of the lensing-informed abundance of clusters identified by the South Pole Telescope (SPT) and of the auto- and cross-correlation of galaxy position and weak lensing measurements (3 ×2pt) in the Dark Energy Survey (DES). We consider the cosmological correlation between the different tracers and we account for the systematic uncertainties that are shared between the large-scale lensing correlation functions and the small-scale lensing-based cluster mass calibration. Marginalized over the remaining Λ cold dark matter (ΛCDM) parameters (including the sum of neutrino masses) and 52 astrophysical modeling parameters, we measure Ωm =0.300 ±0.017 and 8 =0.797 ±0.026. Compared to constraints from Planck primary cosmic microwave background (CMB) anisotropies, our constraints are only 15% wider with a probability to exceed of 0.22 (1.2) for the two-parameter difference. We further obtain 8 ≡8(Ωm/0.3)0.5 =0.796 ±0.013 which is lower than the Planck measurement at the 1.6 level. The combined SPT cluster, DES 3 ×2pt, and Planck datasets mildly prefer a nonzero positive neutrino mass, with a 95% upper limit ∑ <0.25 eV on the sum of neutrino masses. Assuming a CDM model, we constrain the dark energy equation of state parameter =−1.15+0.23−0.17 and when combining with Planck primary CMB anisotropies, we recover =−1.20+0.15−0.09, a 1.7 difference with a cosmological constant. The precision of our results highlights the benefits of multiwavelength multiprobe cosmology and our analysis paves the way for upcoming joint analyses of next-generation datasets