Safe system demonstration project in a remote Aboriginal and Torres Strait Islander community

This paper reports on key findings and recommendations of the first known application of a comprehensive Safe System audit in a remote Aboriginal and Torres Strait Islander community; commissioned by the Indigenous Road Safety Working Group with funding from Austroads. The audit was conducted in Bidyadanga WA in collaboration with the Bidyadanga Community Council during June-August 2010, including: review of policy, management and police records; physical observation of roads, speeds and vehicles; and interviews with community members and local stakeholders including regarding road user issues and vehicle access. Bidyadanga was found to have high quality roads and safe speeds within residential areas, with limited need for upgrades and new work; however, several issues were identified on roads to access the nearest town, including a high crash “blackspot” location. Access to safe vehicles was limited. Unlicensed driving, lack of child restraints, drink driving and fatigue were key road user concerns. Needs for across-government improvements in policy and management were identified. Cost effective actions were identified. This project demonstrated that application of the Safe System was feasible in a remote Aboriginal community, while lessons learned can be adapted and applied nationally to improve Aboriginal road safety

He\u27s the number one thing in my world : Application of the precede-proceed model to explore child car seat use in a regional community in new South Wales

We explored the factors influencing the use of age-appropriate car seats in a community with a high proportion of Aboriginal families in regional New South Wales. We conducted a survey and three focus groups with parents of children aged 3-5 years enrolled at three early learning centres on the Australian south-east coast. Survey data were triangulated with qualitative data from focus groups and analysed using the PRECEDE-PROCEED conceptual framework. Of the 133 eligible families, 97 (73%) parents completed the survey including 31% of parents who reported their children were Aboriginal. Use of age-appropriate car seats was reported by 80 (83%) of the participants, and awareness of the child car seat legislation was high (91/97, 94%). Children aged 2-3 years were less likely reported to be restrained in an age-appropriate car seat than were older children aged 4-5 years (60% versus 95%: χ 2 = 19.14, p \u3c 0.001). Focus group participants highlighted how important their child\u27s safety was to them, spoke of the influence grandparents had on their use of child car seats and voiced mixed views on the value of authorised child car seat fitters. Future programs should include access to affordable car seats and target community members as well as parents with clear, consistent messages highlighting the safety benefits of using age-appropriate car seats

Final Report: Evaluation of the AIME Outreach Program

The AIME (Australian Indigenous Mentoring Experience) Program was established in 2005 when 25 students from the University of Sydney volunteered to work with 25 Indigenous children from local high schools. Since 2005 more than 3000 mentors have been recruited to work with 3542 Indigenous school students in New South Wales, Queensland and Victoria. The AIME Program is based on the recruitment of university students as mentors who provide advice and personal support to Indigenous school mentees from years 7 to 12. Its overall goals are to improve retention rates of Indigenous high school students to Year 12 and to encourage the transition of Indigenous students to university

Trauma and violence informed care through decolonising interagency partnerships: A complexity case study of waminda’s model of systemic decolonisation

Through the lens of complexity, we present a nested case study describing a decolonisation approach developed and implemented by Waminda South Coast Women\u27s Health and Welfare Aboriginal Corporation. Using Indigenous research methods, this case study has unfolded across three phases: 1) Yarning interviews with the workforce from four partner health services (n = 24); 2) Yarning circle bringing together key informants from yarning interviews to verify and refine emerging themes (n = 14); 3) Semi-structured interviews with a facilitator of Waminda\u27s Decolonisation Workshop (n = 1) and participants (n = 10). Synthesis of data has been undertaken in stages through collaborative framework and thematic analysis. Three overarching themes and eight sub-themes emerged that centred on enhancing the capabilities of the workforce and strengthening interagency partnerships through a more meaningful connection and shared decolonisation agenda that centres Aboriginal and Torres Strait Islander families and communities. Health and social services are complex systems that function within the context of colonisation. Waminda’s innovative, model of interagency collaboration enhanced workforce capability through shared language and collective learning around colonisation, racism and Whiteness. This process generated individual, organisational and systemic decolonisation to disable power structures through trauma and violence informed approach to practice

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

IntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p<0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID.ConclusionIn conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted

Single-cell multi-omics analysis of the immune response in COVID-19

Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255Funder: University College London, Birkbeck MRC Doctoral Training ProgrammeFunder: The Jikei University School of MedicineFunder: Action Medical Research (GN2779)Funder: NIHR Clinical Lectureship (CL-2017-01-004)Funder: NIHR (ACF-2018-01-004) and the BMA FoundationFunder: Chan Zuckerberg Initiative (grant 2017-174169) and from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194)Funder: UKRI Innovation/Rutherford Fund Fellowship allocated by the MRC and the UK Regenerative Medicine Platform (MR/5005579/1 to M.Z.N.). M.Z.N. and K.B.M. have been funded by the Rosetrees Trust (M944)Funder: Barbour FoundationFunder: ERC Consolidator and EU MRG-Grammar awardsFunder: Versus Arthritis Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017-08-ST2-002)Funder: European Molecular Biology Laboratory (EMBL)Abstract: Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Evaluation of Indigenous teaching and learning at Australian universities: developing research-based exemplars for good practice

This report provides an evaluation of the Australian Learning and Teaching (ALTC) Fellowship. The evaluation has been guided by the evaluation tool developed by Chesterton and Cummings (2007) for the evaluation of projects under the ALTC Grants Scheme. The Fellowship aimed to provide both Indigenous and non-Indigenous teachers with research- based, practical exemplars for teaching Indigenous students and Indigenous curricula effectively. The overall aim of the Fellowship was to improve Indigenous teaching and thereby contribute to improving Indigenous student learning experiences and academic success rates