Medicine (St Vincent's) - Research Publications
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ItemHow effective are family-based and institutional nutrition interventions in improving children's diet and health? A systematic review(BMC, 2017-10-17)BACKGROUND: Effective strategies to improve dietary intake in young children are a priority to reduce the high prevalence of chronic non-communicable diseases in adulthood. This study aimed to assess the impact of family-based and school/preschool nutrition programs on the health of children aged 12 or younger, including the sustainability of these impacts and the relevance to socio-economic inequalities. METHODS: A systematic review of literature published from 1980 to December 2014 was undertaken. Randomised controlled trials involving families with children aged up to 12 years in high income countries were included. The primary outcomes were dietary intake and health status. Results were presented in a narrative synthesis due to the heterogeneity of the interventions and outcomes. RESULTS: The systematic search and assessment identified 39 eligible studies. 82% of these studies were set in school/preschools. Only one school study assessed the impact of involving parents systematically. The family-based programs which provided simple positive dietary advice to parents and regular follow-up reduced fat intake significantly. School and family-based studies, if designed and implemented well, increased F&V intake, particularly fruit. Effective school-based programs have incorporated role-models including peers, teachers and heroic figures, rewards and increased access to healthy foods. School nutrition programs in disadvantaged communities were as effective as programs in other communities. CONCLUSIONS: Family and school nutrition programs can improve dietary intake, however evidence of the long-term sustainability of these impacts is limited. The modest overall impact of even these successful programs suggest complementary nutrition interventions are needed to build a supportive environment for healthy eating generally.
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ItemSugar-sweetened beverage (SSB) consumption, correlates and interventions among Australian Aboriginal and Torres Strait Islander communities: a scoping review(BMJ PUBLISHING GROUP, 2019-06)OBJECTIVES: Sugar-sweetened beverage (SSB) consumption in Australian Aboriginal and Torres Strait Islander people is reported to be disproportionally high compared with the general Australian population. This review aimed to scope the literature documenting SSB consumption and interventions to reduce SSB consumption among Australian Aboriginal and Torres Strait Islander people. Findings will inform strategies to address SSB consumption in Aboriginal and Torres Strait Islander communities. METHODS: PubMed, SCOPUS, CINAHL, Informit, Joanna Briggs Institute EBP, Mura databases and grey literature were searched for articles published between January 1980 and June 2018. Studies were included if providing data specific to an Australian Aboriginal and/or Torres Strait Islander population's SSB consumption or an intervention that focused on reducing SSB consumption in this population. DESIGN: Systematic scoping review. RESULTS: 59 articles were included (1846 screened). While reported SSB consumption was high, there were age-related and community-related differences observed in some studies. Most studies were conducted in remote or rural settings. Implementation of nutrition interventions that included an SSB component has built progressively in remote communities since the 1980s with a growing focus on community-driven, culturally sensitive approaches. More recent studies have focused exclusively on SSB consumption. Key SSB-related intervention elements included incentivising healthier options; reducing availability of less-healthy options; nutrition education; multifaceted or policy implementation (store nutrition or government policy). CONCLUSIONS: There was a relatively large number of studies reporting data on SSB consumption and/or sales, predominantly from remote and rural settings. During analysis it was subjectively clear that the more impactful studies were those which were community driven or involved extensive community consultation and collaboration. Extracting additional SSB-specific consumption data from an existing nationally representative survey of Aboriginal and Torres Strait Islander people could provide detailed information for demographic subgroups and benchmarks for future interventions. It is recommended that a consistent, culturally appropriate, set of consumption measures be developed.
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ItemJAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018-06-01)Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
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ItemPeripheral neuropathy in the hands of people with diabetes mellitus(ELSEVIER IRELAND LTD, 2016-09)AIMS: Peripheral sensorimotor neuropathy is a recognised complication of diabetes mellitus however little attention has been given to its development in the hands. The aim of this study was to determine the prevalence of sensory impairment in the hands of participants with diabetes, the agreement between two measurement tools for assessing sensation and the association between hand sensibility, age, glycaemic control and end-organ damage. METHODS: A total of 162 participants were recruited and divided into two cohorts based on a diagnosis of diabetes. Participants were tested for the presence of hand neuropathy using Semmes-Weinstein monofilaments and the AsTex™. Medical records of participants with diabetes were accessed retrospectively to determine glycaemic control and diabetes complications. RESULTS: A highly statistically significant association was found between neuropathy and diabetes status (P<0.001) on monofilament testing. The prevalence of neuropathy was 64% compared to ∼10% amongst participants without diabetes. Age, male gender and diabetic retinopathy were associated with neuropathy. The AsTex™ identified participants with diminished protective sensation on monofilament testing. CONCLUSIONS: This study demonstrates a relationship between diabetes and upper limb neuropathy. Age, male gender and retinopathy were associated with diminished hand sensation. The AsTex™ may have a role as a screening tool for identifying clinically significant hand neuropathy.
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ItemIL-23 costimulates antigen-specific MAIT cell activation and enables vaccination against bacterial infection(AMER ASSOC ADVANCEMENT SCIENCE, 2019-11-01)Mucosal-associated invariant T (MAIT) cells are activated in a TCR-dependent manner by antigens derived from the riboflavin synthesis pathway, including 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), bound to MHC-related protein-1 (MR1). However, MAIT cell activation in vivo has not been studied in detail. Here, we have found and characterized additional molecular signals required for optimal activation and expansion of MAIT cells after pulmonary Legionella or Salmonella infection in mice. We show that either bone marrow–derived APCs or non–bone marrow–derived cells can activate MAIT cells in vivo, depending on the pathogen. Optimal MAIT cell activation in vivo requires signaling through the inducible T cell costimulator (ICOS), which is highly expressed on MAIT cells. Subsequent expansion and maintenance of MAIT-17/1-type responses are dependent on IL-23. Vaccination with IL-23 plus 5-OP-RU augments MAIT cell–mediated control of pulmonary Legionella infection. These findings reveal cellular and molecular targets for manipulating MAIT cell function under physiological conditions.
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ItemEvidence-Practice Gaps in Postdischarge Initiation With Oral Anticoagulants in Patients With Atrial Fibrillation.(Ovid Technologies (Wolters Kluwer Health), 2019-12-17)Background Oral anticoagulant (OAC) therapy reduces the risk of stroke in people with atrial fibrillation (AF), and is considered best practice; however, there is little Australian evidence around the uptake of OACs in this population. Methods and Results We used linked hospital admissions, pharmaceutical dispensing claims, medical services, and mortality data for people in Australia's 2 most populous states (July 2010 to June 2015). Among OAC-naïve people hospitalized with AF, we estimated initiation of OAC therapy within 30 days of discharge, and persistence with therapy in the first year. We analyzed both outcomes using multivariable Cox regression. In 71 184 people with AF (median age 78 years, 49% female), 22.7% initiated OAC therapy. Initiation was lowest in July to December 2011 (17.0%) and highest in July to December 2014 (30.1%) after subsidy of the direct OACs. In adjusted analyses, initiation was most likely in people with a CHA2DS2-VA score ≥7 (versus 0) (hazard ratio=6.25, 95% CI 5.08-7.69), and a history of venous thromboembolism (hazard ratio=2.65, 95% CI 2.49-2.83). Of the people who initiated OAC therapy, 39.9% discontinued within 1 year; a lower risk of discontinuation was associated with a CHA2DS2-VA score ≥7 (versus 0) (hazard ratio=0.22, 95% CI 0.14-0.35), or initiation on a direct OAC (versus warfarin) (hazard ratio=0.55, 95% CI 0.50-0.60). Conclusions We found that OAC therapy was severely underutilized in people hospitalized with AF, even among high-risk individuals. Reasons for this underuse, whether patient, prescriber, or hospital related, should be identified and addressed to reduce stroke-related morbidity and mortality in people with AF.
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ItemNo Preview AvailableStreamlined genetic education is effective in preparing women newly diagnosed with breast cancer for decision making about treatment-focused genetic testing: a randomized controlled noninferiority trial(NATURE PUBLISHING GROUP, 2017-04)PURPOSE: Increasingly, women newly diagnosed with breast cancer are being offered treatment-focused genetic testing (TFGT). As the demand for TFGT increases, streamlined methods of genetic education are needed. METHODS: In this noninferiority trial, women aged <50 years with either a strong family history (FH+) or other features suggestive of a germ-line mutation (FH-) were randomized before definitive breast cancer surgery to receive TFGT education either as brief written materials (intervention group (IG)) or during a genetic counseling session at a familial cancer clinic (usual-care group (UCG)). Women completed self-report questionnaires at four time points over 12 months. RESULTS: A total of 135 women were included in the analysis, all of whom opted for TFGT. Decisional conflict about TFGT choice (primary outcome) was not inferior in the IG compared with the UCG (noninferiority margin of -10; mean difference = 2.45; 95% confidence interval -2.87-7.76; P = 0.36). Costs per woman counseled in the IG were significantly lower (AUD$89) compared with the UCG (AUD$173; t(115) = 6.02; P < 0.001). CONCLUSION: A streamlined model of educating women newly diagnosed with breast cancer about TFGT seems to be a cost-effective way of delivering education while ensuring that women feel informed and supported in their decision making, thus freeing resources for other women to access TFGT.Genet Med 19 4, 448-456.
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ItemThe DEAD-Box RNA Helicase DDX3 Interacts with NF-κB Subunit p65 and Suppresses p65-Mediated Transcription.(Public Library of Science (PLoS), 2016)RNA helicase family members exhibit diverse cellular functions, including in transcription, pre-mRNA processing, RNA decay, ribosome biogenesis, RNA export and translation. The RNA helicase DEAD-box family member DDX3 has been characterized as a tumour-associated factor and a transcriptional co-activator/regulator. Here, we demonstrate that DDX3 interacts with the nuclear factor (NF)-κB subunit p65 and suppresses NF-κB (p65/p50)-mediated transcriptional activity. The downregulation of DDX3 by RNA interference induces the upregulation of NF-κB (p65/p50)-mediated transcription. The regulation of NF-κB (p65/p50)-mediated transcriptional activity was further confirmed by the expression levels of its downstream cytokines, such as IL-6 and IL-8. Moreover, the binding of the ATP-dependent RNA helicase domain of DDX3 to the N-terminal Rel homology domain (RHD) of p65 is involved in the inhibition of NF-κB-regulated gene transcription. In summary, the results suggest that DDX3 functions to suppress the transcriptional activity of the NF-κB subunit p65.
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ItemHigh Intensity Interval Training Increases Natural Killer Cell Number and Function in Obese Breast Cancer-challenged Mice and Obese Women.(Korean Society of Cancer Prevention, 2017-12)High intensity interval training (HIIT) boosts natural killer (NK) cell number and activity in normal weight breast cancer patients; however, whether this occurs in obese individuals is not well established. The goal of this study was to determine whether HIIT effectively boosts NK cells as a therapeutic strategy against breast cancer in an obese mouse model and in overweight/obese women. Diet induced female C57Bl/6 obese mice were assigned to undergo HIIT for four weeks or remain sedentary. Female participants were subjected to a six weeks HIIT protocol. HIIT mice acclimatized to treadmill running were subsequently injected with 5 × 105 polyoma middle T (MT) breast cancer cells intravenously. NK cell number and activation were monitored using flow cytometry, and tumor burden or lipid content evaluated from histological lung and liver tissues, respectively. In both mice and humans, circulating NK cell number and activation (CD3-NK1.1+CD27+ and CD3-CD56+, respectively) markedly increased immediately after HIIT. HIIT obese mice had reduced lung tumor burden compared to controls following MT challenge, and had diminished hepatic lipid deposition despite minimal body weight loss. Our findings demonstrate that HIIT can benefit obese individuals by enhancing NK cell number and activity, reducing tumor burden, and enhancing metabolic health.