Doing What we Know we Should: Engaged scholarship and community development

In Australia, engaged scholarship oriented towards community development objectives has yet to be recognised in funding regimes as being inherently beneficial in terms of scholarly excellence and university rankings. While the civic role of universities is acknowledged by individual universities, higher education management and at the Federal policy level, they are most often framed as funding problems related to ‘community service’ rather than as research opportunities which can raise the university’s profile by providing the basis for excellent research outputs and community enrichment. Community engagement has become a familiar term in the Australian higher education lexicon in recent years but there is still little institutional infrastructure that directly embodies the principles and sentiment of community engagement evident in current Australian universities. In this paper, the inaugural Director and Research Manager of the University of Queensland’s Community Service and Research Centre reflect on their five years leading a Centre that was/has been privileged to enjoy significant institutional support and the lessons learnt in forging into unknown territories. The reflections focus on the Centre’s seminal project, the Goodna Service Integration Project

Identification and pathogenicity of a natural reassortant between a very virulent serotype 1 infectious bursal disease virus (IBDV) and a serotype 2 IBDV

AbstractInfectious bursal disease virus (IBDV) causes an economically important, immunosuppressive disease in chickens. There are two serotypes of the virus that contain a bi-segmented double-stranded RNA genome. In December 2008, the first very virulent (vv)IBDV was identified in California, USA and in 2009 we isolated reassortant viruses in two different locations. Genome segment A of these reassortants was typical of vvIBDV serotype 1 but genome segment B was most similar to IBDV serotype 2. The CA-K785 reassortant caused 20% mortality in chickens but no morbidity or mortality in commercial turkey poults despite being infectious. There have been previous reports of natural reassortants between vvIBDV and other serotype 1 strains, but a natural reassortant between IBDV serotypes 1 and 2 has not been described. The apparent reassorting of California vvIBDV with an endemic serotype 2 virus indicates a common host and suggests vvIBDV may have entered California earlier than originally thought

Aberration in DNA Methylation in B-Cell Lymphomas Has a Complex Origin and Increases with Disease Severity

Despite mounting evidence that epigenetic abnormalities play a key role in cancer biology, their contributions to the malignant phenotype remain poorly understood. Here we studied genome-wide DNA methylation in normal B-cell populations and subtypes of B-cell non-Hodgkin lymphoma: follicular lymphoma and diffuse large B-cell lymphomas. These lymphomas display striking and progressive intra-tumor heterogeneity and also inter-patient heterogeneity in their cytosine methylation patterns. Epigenetic heterogeneity is initiated in normal germinal center B-cells, increases markedly with disease aggressiveness, and is associated with unfavorable clinical outcome. Moreover, patterns of abnormal methylation vary depending upon chromosomal regions, gene density and the status of neighboring genes. DNA methylation abnormalities arise via two distinct processes: i) lymphomagenic transcriptional regulators perturb promoter DNA methylation in a target gene-specific manner, and ii) aberrant epigenetic states tend to spread to neighboring promoters in the absence of CTCF insulator binding sites

Single cell transcriptome analysis reveals disease-defining T cell subsets in the tumor microenvironment of classic Hodgkin lymphoma

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. SIGNIFICANCE: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints

Networks and social capital: a relational approach to primary healthcare reform

Collaboration among health care providers and across systems is proposed as a strategy to improve health care delivery the world over. Over the past two decades, health care providers have been encouraged to work in partnership and build interdisciplinary teams. More recently, the notion of networks has entered this discourse but the lack of consensus and understanding about what is meant by adopting a network approach in health services limits its use. Also crucial to this discussion is the work of distinguishing the nature and extent of the impact of social relationships – generally referred to as social capital. In this paper, we review the rationale for collaboration in health care systems; provide an overview and synthesis of key concepts; dispel some common misconceptions of networks; and apply the theory to an example of primary healthcare network reform in Alberta (Canada). Our central thesis is that a relational approach to systems change, one based on a synthesis of network theory and social capital can provide the fodation for a multi-focal approach to primary healthcare reform. Action strategies are recommended to move from an awareness of 'networks' to fully translating knowledge from existing theory to guide planning and practice innovations. Decision-makers are encouraged to consider a multi-focal approach that effectively incorporates a network and social capital approach in planning and evaluating primary healthcare reform

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Genotoxicity of chewing tobacco samples

The intra-oral use of tobacco-containing mixtures plays an important aetiological role in the occurrence of oral cancers. In vitro genotoxicity assays may provide means for the rapid evaluation of factors contributing to or modulating this form of tobacco carcinogenesis. An essential requirement for an effective test system is the capability to detect the genotoxic effects of a variety of tobacco mixtures which are expected to differ in chemical composition. Freshly prepared aqueous extracts of four tobacco mixtures, locally available snuff and "chewing" tobacco, Khaini tobacco (India) and nass (Uzbekistan, USSR), were assayed for genotoxic activity in three different test systems: chromosome aberrations in Chinese hamster ovary cells, micronuclei in Chinese hamster ovary cells and unscheduled DNA synthesis in human fibroblasts. A DNA repair inhibition test was included as a complement to the unscheduled DNA synthesis assay. All four tobacco extracts were found to contain direct acting agents capable of inducing chromosome aberrations and micronuclei formation in Chinese hamster ovary cells. Catalase was found to suppress the clastogenic activity of the chewing and Khaini tobaccos, implicating H₂O₂-mediated production of chromosome damage. The genotoxic activities of snuff and nass did not appear to be dependent on the generation of H₂O₂. Only the chewing tobacco initiated unscheduled DNA synthesis in human fibroblasts. All tobacco extracts reduced the levels of UV initiated unscheduled DNA synthesis, indicating the extracts exerted an inhibitory effect on DNA repair. The failure of the snuff, Khaini tobacco and nass to induce a demonstrable unscheduled DNA synthesis was interpreted to be a consequence of this inhibition. On the basis of these results it was concluded that the chromosome aberration and micronucleus tests in Chinese hamster ovary cells, but not the unscheduled DNA synthesis, appear to be suitable as test systems for the study of factors influencing oral tobacco carcinogenicity.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Phylogenetic Relationships among Virulent Newcastle Disease Virus Isolates from the 2002-2003 Outbreak in California and Other Recent Outbreaks in North America

Isolates from the 2002-2003 virulent Newcastle disease virus (v-NDV) outbreak in southern California, Nevada, Arizona, and Texas in the United States were compared to each other along with recent v-NDV isolates from Mexico and Central America and reference avian paramyxovirus type 1 strains. Nucleotide sequencing and phylogenetic analyses were conducted on a 1,195-base genomic segment composing the 3′ region of the matrix (M) protein gene and a 5′ portion of the fusion (F) protein gene including the M-F intergenic region. This encompasses coding sequences for the nuclear localization signal of the M protein and the F protein cleavage activation site. A dibasic amino acid motif was present at the predicted F protein cleavage activation site in all v-NDVs, including the California 2002-2003, Arizona, Nevada, Texas, Mexico, and Central America isolates. Phylogenetic analyses demonstrated that the California 2002-2003, Arizona, Nevada, and Texas viruses were most closely related to isolates from Mexico and Central America. An isolate from Texas obtained during 2003 appeared to represent a separate introduction of v-NDV into the United States, as this virus was even more closely related to the Mexico 2000 isolates than the California, Arizona, and Nevada viruses. The close phylogenetic relationship between the recent 2002-2003 U.S. v-NDV isolates and those viruses from countries geographically close to the United States warrants continued surveillance of commercial and noncommercial poultry for early detection of highly virulent NDV