Objectives/Goals: Osteosarcoma (OS) is the most common primary bone malignancy in humans and dogs. >40% of children and >90% of dogs succumb to metastatic disease. We hypothesize MYC overexpression in metastatic canine and human OS contributes to an immunosuppressive tumor environment by driving tumor-associated macrophage influx and T lymphocyte exclusion. Methods/Study Population: To characterize the role of oncogenic MYC signaling in the canine metastatic tumor immune microenvironment (TIME), 42 archived FFPE lung metastatic canine OS samples were evaluated for MYC copy number variation (CNV), mRNA, and protein expression via ddPCR, nanostring analysis, and immunohistochemistry (IHC). Seven samples also underwent GeoMX spatial profiling to more specifically evaluate T cell and macrophage transcriptional profiles based on MYC status. To determine the role of MYC target modulation as a potential therapeutic option, canine and human OS cell lines were treated with a novel MYC inhibitor (MYCi975) and assessed for effects on survival, proliferation, and cytokine profiles. Results/Anticipated Results: We demonstrate that copy number gains are not a key driver of MYC hyperactivity in canine metastatic OS. However, stratification based on MYC protein expression demonstrates that “MYC-high” tumors are associated with downregulation of cytotoxic effector T-cell associated transcripts and upregulation of tumor-associated macrophage (TAM) and extracellular matrix remodeling transcripts. We also report that MYCi975 treatment of canine and human OS cell lines results in significant inhibition of OS cell survival and proliferation at concentrations that are pharmacologically achievable in mice. Furthermore, we demonstrate MYC inhibition by MYCi975 is associated with reduced pro-inflammatory cytokine secretion in OS cell culture models. Discussion/Significance of Impact: While MYC overactivity in metastatic canine OS may not be genomically driven, other mechanisms that lead to increased MYC protein expression are associated with transcriptomic profiles supportive of local immunosuppression. Pharmacologic targeting of MYC may serve as a strategy to bolster immunotherapeutic options in metastatic OS treatment.

In August 2019, public health surveillance systems in Scotland and England identified seven, geographically dispersed cases infected with the same strain (defined as isolates that fell within the same five single nucleotide polymorphism single linage cluster) of Shiga toxin-producing Escherichia coli O157:H7. Epidemiological analysis of enhanced surveillance questionnaire data identified handling raw beef and shopping from the same national retailer (retailer A) as the common exposure. Concurrently, a microbiological survey of minced beef at retail identified the same strain in a sample of minced beef sold by retailer A, providing microbiological evidence of the link. Between September and November 2019, a further four primary and two secondary cases infected with the same strain were identified; two cases developed haemolytic uraemic syndrome. None of the four primary cases reported consumption of beef from retailer A and the transmission route of these subsequent cases was not identified, although all four primary cases visited the same petting farm. Generally, outbreaks of STEC O157:H7 in the UK appear to be distinct, short-lived events; however, on-going transmission linked to contaminated food, animals or environmental exposures and person-to-person contact do occur. Although outbreaks of STEC caused by contaminated fresh produce are increasingly common, undercooked meat products remain a risk of infection.

Primary care practitioners (PCPs) do not routinely promote dementia risk reduction. The purpose of this study was to map the published literature on the views of PCPs about dementia risk reduction, in order to identify implementation constructs and strategies crucial to the development of an implementation intervention to support dementia risk reduction in primary care. We undertook a scoping review of the PCPs’ views about promoting brain health for reducing dementia risk. We searched MEDLINE, PsycINFO, CINAHL, and Embase for English-language articles published between 1995 and December 2017. We then applied the Consolidated Framework for Implementation Research (CFIR) and matched Expert Recommendations for Implementing Change to the scoping review findings in order to develop a preliminary implementation model. Eight articles reported views of PCPs about dementia prevention. Study findings were mapped to 5 of the 39 CFIR constructs: (i) knowledge and beliefs about dementia risk reduction, (ii) evidence strength and quality, (iii) relative priority, (iv) available resources, and (v) external policy and incentives. The findings suggest implementation strategies to consider in our preliminary model include (i) educational meetings, (ii) identifying and preparing champions, (iii) conducting local consensus discussions, (iv) altering incentive structures, and (v) capturing and sharing local knowledge. There have been few studies about the views of PCPs about dementia risk reduction. Implementation in the primary care setting is fundamental to early identification of risk and supporting preventive practices, but it needs to focus on more than just education for PCPs. We need more up-to-date and in-depth data on the views of PCPs about dementia risk reduction and context-specific analyses of implementation needs. Further research into effective primary care interventions to reduce dementia risk is expected to support implementation efforts.

Despite aspirations to be a world-class national curriculum, the Australian Curriculum (AC) has been criticised as ‘manifestly deficient’ (Australian Government Department of Education and Training, 2014 p. 5) as an inclusive curriculum, failing to meet the needs of all students with disabilities (SWD) and their teachers. There is a need for research into the daily attempts of educators to navigate the tension between a ‘top-down’ system-wide curriculum and a ‘bottom-up’ regard for individual student needs, with a view to informing both policy and practice. This article is the first of two research papers in which we report the findings from a national online Research in Special Education (RISE) Australian Curriculum Survey of special educators in special schools, classes, and units regarding their experience using the AC to plan for and teach SWD. Survey results indicated (a) inconsistent use of the AC as the primary basis for developing learning objectives and designing learning experiences, (b) infrequent use of the achievement standards to support assessment and reporting, and (c) considerable supplementation of the AC from other resources when educating SWD. Overall, participants expressed a lack of confidence in translating the AC framework into a meaningful curriculum for SWD. Implications for policy, practice, and future research are discussed.

Mutations in Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) and Cyclin-Dependent Kinase 4 (CDK4) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 (BAP1) has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families; however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based sample of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations in CDKN2A, including some with novel missense mutations (p.R22W, p.G35R and p.I49F). BAP1 missense variants occurred in 0.63% of cases but no CDK4 variants were observed in the sample. This is the first estimate of the contribution of BAP1 and CDK4 to a population-based sample of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence.

Excavations undertaken at Quarrington, near Sleaford, Lincolnshire, revealed part of an Early and Middle Saxon settlement with associated fields or enclosures. Several timber buildings were identified, both round and rectangular, and there was evidence of ferrous and non-ferrous metalworking at the site. Finds included a large and regionally significant pottery assemblage, showing that Quarrington had an extensive trading network and obtained pottery from Lincolnshire and Leicestershire in the Early Saxon period. Pottery from the Northamptonshire area dominated the assemblage in the Middle Saxon period, with a smaller component from Lincolnshire and a limited quantity from Ipswich. Spatial variations in the Saxon ceramic assemblage suggest that the focus of settlement shifted towards the west or north west in the Middle Saxon period.

Few rural sites of Early and Middle Saxon date have produced sufficient faunal material to permit an analysis of changes during the fifth to eighth centuries until now; the large bone assemblage from Quarrington indicates changes in diet and the husbandry of domestic animals through time, with sheep becoming more important as pig diminished. Alterations to the slaughter profiles of cattle and sheep were also evident and may indicate changes from subsistence to surplus production. An apparently isolated Neolithic cremation and a post-medieval stone building were also revealed.