Doherty Institute - Research Publications
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ItemNo Preview AvailableImprovements in patient care: videoconferencing to improve access to interpreters during clinical consultations for refugee and immigrant patients(CSIRO Publishing, 2015)OBJECTIVE: To demonstrate the suitability of accessing interpreters via videoconference for medical consultations and to assess doctor and patient perceptions of this compared with either on-site or telephone interpreting. METHODS: We assessed the suitability and acceptability of accessing interpreters via videoconference during out-patient clinical consultations in two situations: (i) when the doctor and patient were in a consulting room at a central hospital and the interpreter sat remotely; and (ii) when the doctor, patient and interpreter were each at separate sites (during a telehealth consultation). The main outcome measures were patient and doctor satisfaction, number of problems recorded and acceptability compared with other methods for accessing an interpreter. RESULTS: Ninety-eight per cent of patients were satisfied overall with the use of an interpreter by video. When comparing videoconference interpreting with telephone interpreting, 82% of patients thought having an interpreter via video was better or much better, 15% thought it was the same and 3% considered it worse. Compared with on-site interpreting, 16% found videoconferencing better or much better, 58% considered it the same and 24% considered it worse or much worse. CONCLUSIONS: The present study has demonstrated that accessing an interpreter via videoconference is well accepted and preferred to telephone interpreting by both doctors and patients.
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ItemHeterogeneity in HIV and cellular transcription profiles in cell line models of latent and productive infection: implications for HIV latency(BMC, 2019-11-11)BACKGROUND: HIV-infected cell lines are widely used to study latent HIV infection, which is considered the main barrier to HIV cure. We hypothesized that these cell lines differ from each other and from cells from HIV-infected individuals in the mechanisms underlying latency. RESULTS: To quantify the degree to which HIV expression is inhibited by blocks at different stages of HIV transcription, we employed a recently-described panel of RT-ddPCR assays to measure levels of 7 HIV transcripts ("read-through," initiated, 5' elongated, mid-transcribed/unspliced [Pol], distal-transcribed [Nef], polyadenylated, and multiply-sliced [Tat-Rev]) in bulk populations of latently-infected (U1, ACH-2, J-Lat) and productively-infected (8E5, activated J-Lat) cell lines. To assess single-cell variation and investigate cellular genes associated with HIV transcriptional blocks, we developed a novel multiplex qPCR panel and quantified single cell levels of 7 HIV targets and 89 cellular transcripts in latently- and productively-infected cell lines. The bulk cell HIV transcription profile differed dramatically between cell lines and cells from ART-suppressed individuals. Compared to cells from ART-suppressed individuals, latent cell lines showed lower levels of HIV transcriptional initiation and higher levels of polyadenylation and splicing. ACH-2 and J-Lat cells showed different forms of transcriptional interference, while U1 cells showed a block to elongation. Single-cell studies revealed marked variation between/within cell lines in expression of HIV transcripts, T cell phenotypic markers, antiviral factors, and genes implicated in latency. Expression of multiply-spliced HIV Tat-Rev was associated with expression of cellular genes involved in activation, tissue retention, T cell transcription, and apoptosis/survival. CONCLUSIONS: HIV-infected cell lines differ from each other and from cells from ART-treated individuals in the mechanisms governing latent HIV infection. These differences in viral and cellular gene expression must be considered when gauging the suitability of a given cell line for future research on HIV. At the same time, some features were shared across cell lines, such as low expression of antiviral defense genes and a relationship between productive infection and genes involved in survival. These features may contribute to HIV latency or persistence in vivo, and deserve further study using novel single cell assays such as those described in this manuscript.
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ItemTissue memory CD4+T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection(PUBLIC LIBRARY SCIENCE, 2020-04)The primary reservoir for HIV is within memory CD4+ T cells residing within tissues, yet the features that make some of these cells more susceptible than others to infection by HIV is not well understood. Recent studies demonstrated that CCR5-tropic HIV-1 efficiently enters tissue-derived memory CD4+ T cells expressing CD127, the alpha chain of the IL7 receptor, but rarely completes the replication cycle. We now demonstrate that the inability of HIV to replicate in these CD127-expressing cells is not due to post-entry restriction by SAMHD1. Rather, relative to other memory T cell subsets, these cells are highly prone to undergoing latent infection with HIV, as revealed by the high levels of integrated HIV DNA in these cells. Host gene expression profiling revealed that CD127-expressing memory CD4+ T cells are phenotypically distinct from other tissue memory CD4+ T cells, and are defined by a quiescent state with diminished NFκB, NFAT, and Ox40 signaling. However, latently-infected CD127+ cells harbored unspliced HIV transcripts and stimulation of these cells with anti-CD3/CD28 reversed latency. These findings identify a novel subset of memory CD4+ T cells found in tissue and not in blood that are preferentially targeted for latent infection by HIV, and may serve as an important reservoir to target for HIV eradication efforts.
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ItemPhenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir(ELIFE SCIENCES PUBLICATIONS LTD, 2020-09-29)The latent reservoir is a major barrier to HIV cure. As latently infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that, contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. By selecting 8-10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies on HIV persistence.
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ItemDelays in Patient Presentation and Diagnosis for Buruli Ulcer (Mycobacterium ulcerans Infection) in Victoria, Australia, 2011-2017.(MDPI AG, 2019-07-04)Uncertainty regarding transmission pathways and control measures makes prompt presentation and diagnosis for Buruli ulcer critical. To examine presentation and diagnosis delays in Victoria, Australia, we conducted a retrospective study of 703 cases notified between 2011 and 2017, classified as residing in an endemic (Mornington Peninsula; Bellarine Peninsula; South-east Bayside and Frankston) or non-endemic area. Overall median presentation delay was 30 days (IQR 14-60 days), with no significant change over the study period (p = 0.11). There were significant differences in median presentation delay between areas of residence (p = 0.02), but no significant change over the study period within any area. Overall median diagnosis delay was 10 days (IQR 0-40 days), with no significant change over the study period (p = 0.13). There were significant differences in median diagnosis delay between areas (p < 0.001), but a significant decrease over time only on the Mornington Peninsula (p < 0.001). On multivariable analysis, being aged <15 or >65 years; having non-ulcerative disease; and residing in the Bellarine Peninsula or South-East Bayside (compared to non-endemic areas) were significantly associated with shorter presentation delay. Residing in the Bellarine or Mornington Peninsula and being notified later in the study period were significantly associated with shorter diagnosis delay. To reduce presentation and diagnosis delays, awareness of Buruli ulcer must be raised with the public and medical professionals, particularly those based outside established endemic areas.
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ItemCirculating Vaccine-Derived Poliovirus Type 1 and Outbreak Response - Papua New Guinea, 2018(CENTERS DISEASE CONTROL, 2019-02-08)
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ItemThe emergence and spread of one Coxsackievirus A16 Genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016(NATURE PUBLISHING GROUP, 2018-07-18)
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ItemDeterminants and Gaps in Preventive Care Delivery for Indigenous Australians: A Cross-Sectional Analysis(FRONTIERS MEDIA SA, 2016-03-10)BACKGROUND: Potentially preventable chronic diseases are the greatest contributor to the health gap between Aboriginal and Torres Strait Islander peoples and non--Indigenous Australians. Preventive care is important for earlier detection and control of chronic disease, and a number of recent policy initiatives have aimed to enhance delivery of preventive care. We examined documented delivery of recommended preventive services for Indigenous peoples across Australia and investigated the influence of health center and client level factors on adherence to best practice guidelines. METHODS: Clinical audit data from 2012 to 2014 for 3,623 well adult clients (aged 15-54) of 101 health centers from four Australian states and territories were analyzed to determine adherence to delivery of 26 recommended preventive services classified into five different modes of care on the basis of the way in which they are delivered (e.g., basic measurement; laboratory tests and imaging; assessment and brief interventions, eye, ear, and oral checks; follow-up of abnormal findings). Summary statistics were used to describe the delivery of each service item across jurisdictions. Multilevel regression models were used to quantify the variation in service delivery attributable to health center and client level factors and to identify factors associated with higher quality care. RESULTS: Delivery of recommended preventive care varied widely between service items, with good delivery of most basic measurements but poor follow-up of abnormal findings. Health center characteristics were associated with most variation. Higher quality care was associated with Northern Territory location, urban services, and smaller service population size. Client factors associated with higher quality care included age between 25 and 34 years, female sex, and more regular attendance. CONCLUSION: Wide variation in documented preventive care delivery, poor follow-up of abnormal findings, and system factors that influence quality of care should be addressed through continuous quality improvement approaches that engage stakeholders at multiple levels (including, for example, access to care in the community, appropriate decision support for practitioners, and financial incentives and context appropriate guidelines).
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ItemWinding back Wnt signalling: potential therapeutic targets for treating gastric cancers(WILEY, 2017-12)UNLABELLED: Gastric cancer persists as a frequent and deadly disease that claims over 700 000 lives annually. Gastric cancer is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal cancers, making it therapeutically challenging. As such, and largely attributed to late-stage diagnosis, gastric cancer patients show only partial response to standard chemo and targeted molecular therapies, highlighting an urgent need to develop new targeted therapies for this disease. Wnt signalling has a well-documented history in the genesis of many cancers and is, therefore, an attractive therapeutic target. As such, drug discovery has focused on developing inhibitors that target multiple nodes of the Wnt signalling cascade, some of which have progressed to clinical trials. The collective efforts of patient genomic profiling has uncovered genetic lesions to multiple components of the Wnt pathway in gastric cancer patients, which strongly suggest that Wnt-targeted therapies could offer therapeutic benefits for gastric cancer patients. These data have been supported by studies in mouse models of gastric cancer, which identify Wnt signalling as a driver of gastric tumourigenesis. Here, we review the current literature regarding Wnt signalling in gastric cancer and highlight the suitability of each class of Wnt inhibitor as a potential treatment for gastric cancer patients, in relation to the type of Wnt deregulation observed. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.