Minerva Elements Records
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ItemOphthalmic Antimicrobial Prescribing in Australian Healthcare Facilities(MDPI, 2022-05-01)The National Antimicrobial Prescribing Survey (NAPS) is a web-based, standardized tool, widely adopted in Australian healthcare facilities to assess the reasons for, the quantity of, and the quality of antimicrobial prescribing. It consists of multiple modules tailored towards the needs of a variety of healthcare facilities. Data regarding ophthalmological antimicrobial use from Hospital NAPS, Surgical NAPS, and Aged Care NAPS were analysed. In Hospital NAPS, the most common reasons for inappropriate prescribing were incorrect dose or frequency and incorrect duration. Prolonged duration was also common in Aged Care prescribing: about one quarter of all antimicrobials had been prescribed for greater than 6 months. All three modules found chloramphenicol to be the most prescribed antimicrobial with a high rate of inappropriate prescribing, usually for conjunctivitis.
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ItemGerms and germlines: how "public" B-cell clones evolve in the gut(WILEY, 2020-05-16)Chen et al. describe how B-cell clones observed in the gut of many different individuals (recurrent or "public" clonotypes) are shaped by the combined influences of common microbial antigens and underlying genomic recombination biases.
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ItemThe ENJOY MAP for HEALTH: Exercise interveNtion outdoor proJect in the cOmmunitY for older people-More Active People for HEALTHier communities: a study protocol(BMC, 2022-05-21)BACKGROUND: Physical activity is important to maintain health in older age, with physical activity in the outdoors providing mental and physical health benefits for all age groups. One way by which older people can engage in physical activity in the outdoors is through using suitable age-friendly outdoor exercise equipment, the Seniors Exercise Park. The ENJOY MAP for HEALTH aims to evaluate the effect of the Seniors Exercise Park installation and associated capacity building activities on park visitation, park-based physical activity by older people and delivery of community physical activity programs. METHOD: This study is a quasi-experimental (natural experiment) with pre and post study design evaluating the effect of age-friendly outdoor spaces with specialised outdoor exercise equipment on older people's physical activity and wellbeing in six Victorian municipalities (local governments/councils). Each council will undergo four stages (site construction and development, promotion and marketing, capacity building and training, evaluation and sustainability). Several activities and methods will be employed from stage one through stage four to evaluate the potential impact of the age-friendly outdoor spaces on physical activity and wellbeing and will comprise the following elements: site observation and equipment utilisation, face to face intercept surveys, development of an online access monitor and community building activities. DISCUSSION: The project is expected to result in a significant change in the physical outdoor environment for the participating councils and communities whereby older people and other community members will be able to engage in safe physical and social activity programs, socialise more and hence improve the overall wellbeing of older people. TRIAL REGISTRATION: This trial is retrospectively registered with the Australian New Zealand Clinical Trials Registry. Trial registration number ACTRN12621000965808 . Date registered 23/07/2021.
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ItemThe first reptilian allergen and major allergen for fish-allergic patients: Crocodile beta-parvalbumin(WILEY, 2022-05-01)BACKGROUND: Clinical cross-reactivity between bony fish, cartilaginous fish, frog, and chicken muscle has previously been demonstrated in fish-allergic patients. In indicative studies, two reports of anaphylaxis following the consumption of crocodile meat and IgE-cross-binding were linked to the major fish allergen parvalbumin (PV). This study investigates IgE-binding proteins in crocodile meat with a focus on PV and their clinical relevance. METHODS: Proteins were extracted from muscle tissue of crocodile, three bony fish, and two cartilaginous fish. A cohort of fish-allergic pediatric patients (n = 77) underwent allergen skin prick testing (SPT) to three fish preparations (n = 77) and crocodile (n = 12). IgE-binding proteins were identified and quantified by SDS-PAGE, mass spectrometric analyses, and immunoblotting using commercial and in-house antibodies, as well as individual and pooled patients' serum. PV isoforms were purified or recombinantly expressed before immunological analyses, including human mast cell degranulation assay. RESULTS: Of the tissues analyzed, PV was most abundant in heated crocodile preparation, triggering an SPT of ≥3 mm in 8 of 12 (67%) fish-allergic patients. Seventy percent (31 of 44) of fish PV-sensitized patients demonstrated IgE-binding to crocodile PV. Crocodile β-PV was the major IgE-binding protein but 20-fold less abundant than α-PV. Cellular reactivity was demonstrated for β-PV and epitopes predicted, explaining frequent IgE-cross-binding of β-PVs. Both PV isoforms are now registered as the first reptile allergens with the WHO/IUIS (β-PV as Cro p 1 and α-PV as Cro p 2). CONCLUSION: Fish-allergic individuals may be at risk of an allergy to crocodile and should seek specialist advice before consuming crocodilian meat.
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ItemCerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study(MDPI, 2022-05-01)BACKGROUND: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer's disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). METHODS: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. RESULTS: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03-2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31-17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. CONCLUSION: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.
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ItemXIAP promotes melanoma growth by inducing tumour neutrophil infiltration.(EMBO, 2022-06-07)Elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti-apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro-inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up-regulation and secretion of chemokines such as IL8, that are responsible for intra-tumour neutrophil accumulation. Alteration of the XIAP-RIPK2-TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer.
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ItemLinking Data From the Australian Stroke Clinical Registry With Ambulance and Emergency Administrative Data in Victoria(SAGE PUBLICATIONS INC, 2022-05-01)Objective: In Australia, approximately 3 in 4 people with acute stroke use an ambulance. Few examples of merging ambulance clinical records, hospital government data, and national registry data for stroke exist. We sought to understand the advantages of using linked datasets for describing the full clinical journey of people with stroke and the possibility of investigating their long-term outcomes based on pre-hospital management of stroke. Method: Patient-level data from the Australian Stroke Clinical Registry (AuSCR) (January 2013-October 2017) were linked with Ambulance Victoria (AV) records and Victorian Emergency Minimum Dataset (VEMD). Probabilistic iterative matching on personal identifiers were used and records merged with a project specific identification number. Results: Of the 7,373 episodes in the AuSCR and 6,001 in the AV dataset; 4,569 (62%) were matched. Unmatched records that were positive for "arrival by ambulance" in the AuSCR and VEMD (no corresponding record in AV) were submitted to AV. AV were able to identify 148/435 additional records related to these episodes. The final cohort included 4,717 records (median age: 73 years, female 42%, ischemic stroke 66%). Conclusion: The results of the data linkage provides greater confidence for use of these data for future research related to pre-hospital management of stroke.
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ItemTankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death(AMER ASSOC ADVANCEMENT SCIENCE, 2022-05-01)Tumor necrosis factor (TNF) is a key component of the innate immune response. Upon binding to its receptor, TNFR1, it promotes production of other cytokines via a membrane-bound complex 1 or induces cell death via a cytosolic complex 2. To understand how TNF-induced cell death is regulated, we performed mass spectrometry of complex 2 and identified tankyrase-1 as a native component that, upon a death stimulus, mediates complex 2 poly-ADP-ribosylation (PARylation). PARylation promotes recruitment of the E3 ligase RNF146, resulting in proteasomal degradation of complex 2, thereby limiting cell death. Expression of the ADP-ribose-binding/hydrolyzing severe acute respiratory syndrome coronavirus 2 macrodomain sensitizes cells to TNF-induced death via abolishing complex 2 PARylation. This suggests that disruption of ADP-ribosylation during an infection can prime a cell to retaliate with an inflammatory cell death.
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ItemTargeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity(BMJ PUBLISHING GROUP, 2022-05-01)BACKGROUND: The success and limitations of current immunotherapies have pushed research toward the development of alternative approaches and the possibility to manipulate other cytotoxic immune cells such as natural killer (NK) cells. Here, we targeted an intracellular inhibiting protein 'cytokine inducible SH2-containing protein' (CISH) in NK cells to evaluate the impact on their functions and antitumor properties. METHODS: To further understand CISH functions in NK cells, we developed a conditional Cish-deficient mouse model in NK cells (Cishfl/flNcr1Ki/+ ). NK cells cytokine expression, signaling and cytotoxicity has been evaluated in vitro. Using intravenous injection of B16F10 melanoma cell line and EO711 triple negative breast cancer cell line, metastasis evaluation was performed. Then, orthotopic implantation of breast tumors was performed and tumor growth was followed using bioluminescence. Infiltration and phenotype of NK cells in the tumor was evaluated. Finally, we targeted CISH in human NK-92 or primary NK cells, using a technology combining the CRISPR(i)-dCas9 tool with a new lentiviral pseudotype. We then tested human NK cells functions. RESULTS: In Cishfl/flNcr1Ki/+ mice, we detected no developmental or homeostatic difference in NK cells. Global gene expression of Cishfl/flNcr1Ki/+ NK cells compared with Cish+/+Ncr1Ki/+ NK cells revealed upregulation of pathways and genes associated with NK cell cycling and activation. We show that CISH does not only regulate interleukin-15 (IL-15) signaling pathways but also natural cytotoxicity receptors (NCR) pathways, triggering CISH protein expression. Primed Cishfl/flNcr1Ki/+ NK cells display increased activation upon NCR stimulation. Cishfl/flNcr1Ki/+ NK cells display lower activation thresholds and Cishfl/flNcr1Ki/+ mice are more resistant to tumor metastasis and to primary breast cancer growth. CISH deletion favors NK cell accumulation to the primary tumor, optimizes NK cell killing properties and decreases TIGIT immune checkpoint receptor expression, limiting NK cell exhaustion. Finally, using CRISPRi, we then targeted CISH in human NK-92 or primary NK cells. In human NK cells, CISH deletion also favors NCR signaling and antitumor functions. CONCLUSION: This study represents a crucial step in the mechanistic understanding and safety of Cish targeting to unleash NK cell antitumor function in solid tumors. Our results validate CISH as an emerging therapeutic target to enhance NK cell immunotherapy.
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ItemSuicide rates amongst individuals from ethnic minority backgrounds: A systematic review and meta-analysis.(Elsevier BV, 2022-05)Background: Existing evidence suggests that some individuals from ethnic minority backgrounds are at increased risk of suicide compared to their majority ethnic counterparts, whereas others are at decreased risk. We aimed to estimate the absolute and relative risk of suicide in individuals from ethnic minority backgrounds globally. Methods: Databases (Medline, Embase, and PsycInfo) were searched for epidemiological studies between 01/01/2000 and 3/07/2020, which provided data on absolute and relative rates of suicide amongst ethnic minority groups. Studies reporting on clinical or specific populations were excluded. Pairs of reviewers independently screened titles, abstracts, and full texts. We used random effects meta-analysis to estimate overall, sex, location, migrant status, and ancestral origin, stratified pooled estimates for absolute and rate ratios. PROSPERO registration: CRD42020197940. Findings: A total of 128 studies were included with 6,026,103 suicide deaths in individuals from an ethnic minority background across 31 countries. Using data from 42 moderate-high quality studies, we estimated a pooled suicide rate of 12·1 per 100,000 (95% CIs 8·4-17·6) in people from ethnic minority backgrounds with a broad range of estimates (1·2-139·7 per 100,000). There was weak statistical evidence from 51 moderate-high quality studies that individuals from ethnic minority groups were more likely to die by suicide (RR 1·3 95% CIs 0·9-1·7) with again a broad range amongst studies (RR 0·2-18·5). In our sub-group analysis we only found evidence of elevated risk for indigenous populations (RR: 2·8 95% CIs 1·9-4·0; pooled rate: 23·2 per 100,000 95% CIs 14·7-36·6). There was very substantial heterogeneity (I2 > 98%) between studies for all pooled estimates. Interpretation: The homogeneous grouping of individuals from ethnic minority backgrounds is inappropriate. To support suicide prevention in marginalised groups, further exploration of important contextual differences in risk is required. It is possible that some ethnic minority groups (for example those from indigenous backgrounds) have higher rates of suicide than majority populations. Funding: No specific funding was provided to conduct this research. DK is funded by Wellcome Trust and Elizabeth Blackwell Institute Bristol. Matthew Spittal is a recipient of an Australian Research Council Future Fellowship (project number FT180100075) funded by the Australian Government. Rebecca Musgrove is funded by the NIHR Greater Manchester Patient Safety Translational Research Centre (PSTRC-2016-003).