Melbourne Medical School Collected Works - Research Publications

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    Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF).
    McMurray, JJV ; Anand, IS ; Diaz, R ; Maggioni, AP ; O'Connor, C ; Pfeffer, MA ; Solomon, SD ; Tendera, M ; van Veldhuisen, DJ ; Albizem, M ; Cheng, S ; Scarlata, D ; Swedberg, K ; Young, JB ; RED-HF Committees Investigators, (Wiley, 2013-03)
    AIMS: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. METHODS AND RESULTS: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L. CONCLUSION: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
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    Dendritic cell immunotherapy: clinical outcomes
    Apostolopoulos, V ; Pietersz, GA ; Tsibanis, A ; Tsikkinis, A ; Stojanovska, L ; McKenzie, IFC ; Vassilaros, S (WILEY, 2014-07-01)
    The use of tumour-associated antigens for cancer immunotherapy studies is exacerbated by tolerance to these self-antigens. Tolerance may be broken by using ex vivo monocyte-derived dendritic cells (DCs) pulsed with self-antigens. Targeting tumour-associated antigens directly to DCs in vivo is an alternative and simpler strategy. The identification of cell surface receptors on DCs, and targeting antigens to DC receptors, has become a popular approach for inducing effective immune responses against cancer antigens. Many years ago, we demonstrated that targeting the mannose receptor on macrophages using the carbohydrate mannan to DCs led to appropriate immune responses and tumour protection in animal models. We conducted Phase I, I/II and II, clinical trials demonstrating the effectiveness of oxidised mannan-MUC1 in patients with adenocarcinomas. Here we summarise DC targeting approaches and their efficacy in human clinical trials.
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    Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The delay study
    Strange, G ; Gabbay, E ; Kermeen, F ; Williams, T ; Carrington, M ; Stewart, S ; Keogh, A (SAGE PUBLICATIONS INC, 2013-01-01)
    Survival rates for patients with idiopathic pulmonary arterial hypertension (IPAH) have improved with the introduction of PAH-specific therapies. However, the time between patient-reported onset of symptoms and a definitive diagnosis of IPAH is consistently delayed. We conducted a retrospective, multi-center, descriptive investigation in order to (a) understand what factors contribute to persistent diagnostic delays, and (b) examine the time from initial symptom onset to a definitive diagnosis of IPAH. Between January 2007 and December 2008, we enrolled consecutively diagnosed adults with IPAH from four tertiary referral centers in Australia. Screening of patient records and "one-on-one" interviews were used to determine the time from patient-described initial symptoms to a diagnosis of IPAH, confirmed by right heart catheterization (RHC). Thirty-two participants (69% female) were studied. Mean age at symptom onset was 56 ± 16.4 years and 96% reported exertional dyspnea. Mean time from symptom onset to diagnosis was 47 ± 34 months with patients subsequently aged 60 ± 17.3 years. Patients reported 5.3 ± 3.8 GP visits and 3.0 ± 2.1 specialist reviews before being seen at a pulmonary hypertension (PH) center. Advanced age, number of general practitioner (GP) visits, heart rate, and systolic blood pressure at the time of diagnosis were significantly associated with the observed delay. We found a significant delay of 3.9 years from symptom onset to a diagnosis of IPAH in Australia. Exertional dyspnea is the most common presenting symptom. Current practice within Australia does not appear to have the specific capacity for timely, multi-factorial evaluation of breathlessness and potential IPAH.
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    Women Versus Men with Chronic Atrial Fibrillation: Insights from the Standard Versus Atrial Fibrillation spEcific managemenT studY (SAFETY)
    Ball, J ; Carrington, MJ ; Wood, KA ; Stewart, S ; Ai, X (PUBLIC LIBRARY SCIENCE, 2013-05-29)
    BACKGROUND: Gender-based clinical differences are increasingly being identified as having significant influence on the outcomes of patients with cardiovascular disease (CVD), including atrial fibrillation (AF). OBJECTIVE: To perform detailed clinical phenotyping on a cohort of hospitalised patients with chronic forms of AF to understand if gender-based differences exist in the clinical presentation, thrombo-embolic risk and therapeutic management of high risk patients hospitalised with chronic AF. METHODS: We are undertaking the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY) - a multi-centre, randomised controlled trial of an AF-specific management intervention versus usual care. Extensive baseline profiling of recruited patients was undertaken to identify gender-specific differences for risk delineation. RESULTS: We screened 2,438 patients with AF and recruited 335 into SAFETY. Of these, 48.1% were women who were, on average, 5 years older than their male counterparts. Women and men displayed divergent antecedent profiles, with women having a higher thrombo-embolic risk but being prescribed similar treatment regimens. More women than men presented to hospital with co-morbid thyroid dysfunction, depression, renal impairment and obesity. In contrast, more men presented with coronary artery disease (CAD) and/or chronic obstructive pulmonary disease (COPD). Even when data was age-adjusted, women were more likely to live alone (odds ratio [OR] 2.33; 95% confidence interval [CI] 1.47 to 3.69), have non-tertiary education (OR 2.69; 95% CI 1.61 to 4.48) and be symptomatic (OR 1.93; 95% CI 1.06 to 3.52). CONCLUSION: Health care providers should be cognisant of gender-specific differences in an attempt to individualise and, hence, optimise the management of patients with chronic AF and reduce potential morbidity and mortality.
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    Predictors of Mean Arterial Pressure Morning Rate of Rise and Power Function in Subjects Undergoing Ambulatory Blood Pressure Recording
    Head, GA ; Andrianopoulos, N ; McGrath, BP ; Martin, CA ; Carrington, MJ ; Lukoshkova, EV ; Davern, PJ ; Jennings, GL ; Reid, CM ; Pizzi, C (PUBLIC LIBRARY SCIENCE, 2014-03-25)
    BACKGROUND: We determined clinical predictors of the rate of rise (RoR) in blood pressure in the morning as well as a novel measure of the power of the BP surge (BP(power)) derived from ambulatory blood pressure recordings. METHODS: BP(power) and RoR were calculated from 409 ambulatory blood pressure (ABP) recordings from subjects attending a cardiovascular risk clinic. Anthropometric data, blood biochemistry, and history were recorded. The 409 subjects were 20-82 years old (average 57, SD = 13), 46% male, 9% with hypertension but not on medication and 34% on antihypertensive medication. RESULTS: Average RoR was 11.1 mmHg/hour (SD = 8) and BP(power) was 273 mmHg(2)/hour (SD = 235). Only cholesterol, low density lipoprotein and body mass index (BMI) were associated with higher BP(power) and RoR (P<0.05) from 25 variables assessed. BP(power) was lower in those taking beta-blockers or diuretics. Multivariate analysis identified that only BMI was associated with RoR (4.2% increase/unit BMI, P = 0.020) while cholesterol was the only remaining associated variable with BP(power) (17.5% increase/mmol/L cholesterol, P = 0.047). A follow up of 213 subjects with repeated ABP after an average 1.8 years identified that baseline cholesterol was the only predictor for an increasing RoR and BP(power) (P<0.05). 37 patients who commenced statin subsequently had lower BP(power) whereas 90 age and weight matched controls had similar BP(power) on follow-up. CONCLUSIONS: Cholesterol is an independent predictor of a greater and more rapid rise in morning BP as well as of further increases over several years. Reduction of cholesterol with statin therapy is very effective in reducing the morning blood pressure surge.
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    Plasma lipid profiling in a large population-based cohort
    Weir, JM ; Wong, G ; Barlow, CK ; Greeve, MA ; Kowalczyk, A ; Almasy, L ; Comuzzie, AG ; Mahaney, MC ; Jowett, JBM ; Shaw, J ; Curran, JE ; Blangero, J ; Meikle, PJ (ELSEVIER, 2013-10-01)
    We have performed plasma lipid profiling using liquid chromatography electrospray ionization tandem mass spectrometry on a population cohort of more than 1,000 individuals. From 10 μl of plasma we were able to acquire comparative measures of 312 lipids across 23 lipid classes and subclasses including sphingolipids, phospholipids, glycerolipids, and cholesterol esters (CEs) in 20 min. Using linear and logistic regression, we identified statistically significant associations of lipid classes, subclasses, and individual lipid species with anthropometric and physiological measures. In addition to the expected associations of CEs and triacylglycerol with age, sex, and body mass index (BMI), ceramide was significantly higher in males and was independently associated with age and BMI. Associations were also observed for sphingomyelin with age but this lipid subclass was lower in males. Lysophospholipids were associated with age and higher in males, but showed a strong negative association with BMI. Many of these lipids have previously been associated with chronic diseases including cardiovascular disease and may mediate the interactions of age, sex, and obesity with disease risk.
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    Circulating antibodies against Plasmodium falciparum histidine-rich proteins 2 interfere with antigen detection by rapid diagnostic tests
    Ho, M-F ; Baker, J ; Lee, N ; Luchavez, J ; Ariey, F ; Nhem, S ; Oyibo, W ; Bell, D ; Gonzalez, I ; Chiodini, P ; Gatton, ML ; Cheng, Q ; McCarthy, JS (BMC, 2014-12-06)
    BACKGROUND: Rapid diagnostic tests (RDTs) for detection of Plasmodium falciparum infection that target P. falciparum histidine-rich protein 2 (PfHRP2), a protein that circulates in the blood of patients infected with this species of malaria, are widely used to guide case management. Understanding determinants of PfHRP2 availability in circulation is therefore essential to understanding the performance of PfHRP2-detecting RDTs. METHODS: The possibility that pre-formed host anti-PfHRP2 antibodies may block target antigen detection, thereby causing false negative test results was investigated in this study. RESULTS: Anti-PfHRP2 antibodies were detected in 19/75 (25%) of plasma samples collected from patients with acute malaria from Cambodia, Nigeria and the Philippines, as well as in 3/28 (10.7%) asymptomatic Solomon Islands residents. Pre-incubation of plasma samples from subjects with high-titre anti-PfHRP2 antibodies with soluble PfHRP2 blocked the detection of the target antigen on two of the three brands of RDTs tested, leading to false negative results. Pre-incubation of the plasma with intact parasitized erythrocytes resulted in a reduction of band intensity at the highest parasite density, and a reduction of lower detection threshold by ten-fold on all three brands of RDTs tested. CONCLUSIONS: These observations indicate possible reduced sensitivity for diagnosis of P. falciparum malaria using PfHRP2-detecting RDTs among people with high levels of specific antibodies and low density infection, as well as possible interference with tests configured to detect soluble PfHRP2 in saliva or urine samples. Further investigations are required to assess the impact of pre-formed anti-PfHRP2 antibodies on RDT performance in different transmission settings.
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    Assessment of Anthelmintic Efficacy of Mebendazole in School Children in Six Countries Where Soil-Transmitted Helminths Are Endemic
    Levecke, B ; Montresor, A ; Albonico, M ; Ame, SM ; Behnke, JM ; Bethony, JM ; Noumedem, CD ; Engels, D ; Guillard, B ; Kotze, AC ; Krolewiecki, AJ ; McCarthy, JS ; Mekonnen, Z ; Periago, MV ; Sopheak, H ; Tchuem-Tchuente, L-A ; Tran, TD ; Nguyen, TH ; Zeynudin, A ; Vercruysse, J ; Olliaro, PL (PUBLIC LIBRARY SCIENCE, 2014-10-01)
    BACKGROUND: Robust reference values for fecal egg count reduction (FECR) rates of the most widely used anthelmintic drugs in preventive chemotherapy (PC) programs for controlling soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm) are still lacking. However, they are urgently needed to ensure detection of reduced efficacies that are predicted to occur due to growing drug pressure. Here, using a standardized methodology, we assessed the FECR rate of a single oral dose of mebendazole (MEB; 500 mg) against STHs in six trials in school children in different locations around the world. Our results are compared with those previously obtained for similarly conducted trials of a single oral dose of albendazole (ALB; 400 mg). METHODOLOGY: The efficacy of MEB, as assessed by FECR, was determined in six trials involving 5,830 school children in Brazil, Cambodia, Cameroon, Ethiopia, United Republic of Tanzania, and Vietnam. The efficacy of MEB was compared to that of ALB as previously assessed in 8,841 school children in India and all the above-mentioned study sites, using identical methodologies. PRINCIPAL FINDINGS: The estimated FECR rate [95% confidence interval] of MEB was highest for A. lumbricoides (97.6% [95.8; 99.5]), followed by hookworm (79.6% [71.0; 88.3]). For T. trichiura, the estimated FECR rate was 63.1% [51.6; 74.6]. Compared to MEB, ALB was significantly more efficacious against hookworm (96.2% [91.1; 100], p<0.001) and only marginally, although significantly, better against A. lumbricoides infections (99.9% [99.0; 100], p = 0.012), but equally efficacious for T. trichiura infections (64.5% [44.4; 84.7], p = 0.906). CONCLUSIONS/SIGNIFICANCE: A minimum FECR rate of 95% for A. lumbricoides, 70% for hookworm, and 50% for T. trichiura is expected in MEB-dependent PC programs. Lower FECR results may indicate the development of potential drug resistance.
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    Production and characterization of specific monoclonal antibodies binding the Plasmodium falciparum diagnostic biomarker, histidine-rich protein 2
    Leow, CH ; Jones, M ; Cheng, Q ; Mahler, S ; McCarthy, J (BMC, 2014-07-18)
    BACKGROUND: Early and accurate diagnosis of Plasmodium falciparum infection is important for providing appropriate treatment to patients with malaria. However, technical limitations of currently available diagnostic tests limit their use in control programs. One possible explanation for the vulnerability of current antibodies used in RDTs is their propensity to degrade at high ambient temperatures. Isolation of new antibodies with better thermal stability represents an appealing approach to improve the performance of RDTs. METHODS: In this study, phage display technology was deployed to isolate novel binders by screening a human naïve scFv antibody library against recombinant Plasmodium falciparum histidine rich protein 2 (rPfHRP2). The isolated scFv clones were reformatted to whole IgG and the recombinant mAbs were produced in a mammalian CHO cell expression system. To verify the biological activity of these purified recombinant mAbs, range of functional assays were characterized. RESULTS: Two unique clones (D2 and F9) were isolated after five rounds of biopanning. The reformatted and expressed antibodies demonstrated high binding specificity to malaria recombinant PfHRP2 and native proteins. When 5 μg/mL of mAbs applied, mAb C1-13 had the highest sensitivity, with an OD value of 1, the detection achieved 5 ng/mL of rPfHRP2, followed by mAbs D2 and F9 at 10 ng/mL and 100 ng/mL of rPfHRP2, respectively. Although the sensitivity of mAbs D2 and F9 was lower than the control, these recombinant human mAbs have shown better stability compared to mouse mAb C1-13 at various temperatures in DSC and blot assays. In view of epitope mapping, the predominant motif of rPfHRP2 recognized by mAb D2 was AHHAADAHHA, whereas mAb F9 was one amino acid shorter, resulting in AHHAADAHH. mAb F9 had the strongest binding affinity to rPfHRP2 protein, with a KD value of 4.27 × 10(-11) M, followed by control mAb C1-13 at 1.03 × 10(-10) M and mAb D2 at 3.05 × 10(-10) M. CONCLUSIONS: Overall, the performance of these mAbs showed comparability to currently available PfHRP2-specific mouse mAb C1-13. The stability of these novel binders indicate that they merit further work to evaluate their utility in the development of new generation point of care diagnosis of malaria.
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    Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting
    Cheng, Q ; Gatton, ML ; Barnwell, J ; Chiodini, P ; McCarthy, J ; Bell, D ; Cunningham, J (BMC, 2014-07-22)
    Malaria rapid diagnostic tests (RDTs) play a critical role in malaria case management, surveillance and case investigations. Test performance is largely determined by design and quality characteristics, such as detection sensitivity, specificity, and thermal stability. However, parasite characteristics such as variable or absent expression of antigens targeted by RDTs can also affect RDT performance. Plasmodium falciparum parasites lacking the PfHRP2 protein, the most common target antigen for detection of P. falciparum, have been reported in some regions. Therefore, accurately mapping the presence and prevalence of P. falciparum parasites lacking pfhrp2 would be an important step so that RDTs targeting alternative antigens, or microscopy, can be preferentially selected for use in such regions. Herein the available evidence and molecular basis for identifying malaria parasites lacking PfHRP2 is reviewed, and a set of recommended procedures to apply for future investigations for parasites lacking PfHRP2, is proposed.