Clinical School (Royal Melbourne Hospital) - Research Publications
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Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status
(PUBLIC LIBRARY SCIENCE, 2016-03-01)
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.
Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration
(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2017-04-01)
Purpose: Reduction of the ellipsoid zone (EZ) intensity has been reported in eyes with age-related macular degeneration (AMD). This study determined whether overall EZ intensity, in retinal locations undisturbed by pathologic features, is associated with the presence of clinical features, which are known important phenotypic risk factors for disease progression, large drusen, reticular pseudodrusen (RPD), and pigmentary abnormalities. Methods: A horizontal B-scan through the foveola on spectral-domain optical coherence tomography (SD-OCT) was performed in both eyes of 75 participants with bilateral intermediate AMD and 10 age-similar control participants. Eyes with AMD were classified as per the presence of large drusen, RPD, and hyperpigmentary changes. The relative EZ intensity profile, up to an eccentricity of 3400 μm, was averaged over seven 1000-μm retinal segments. The association between relative EZ intensity profile over seven retinal segments and AMD pathologic features was analyzed. Results: The average relative EZ intensities were significantly reduced in eyes with intermediate AMD compared to normal eyes (P ≤ 0.025) and with increasing age (P ≤ 0.020). On multivariate analyses, only the presence of hyperpigmentary changes and increasing age were significantly associated with reduced overall relative intensities (P ≤ 0.024), but not the presence of large drusen or RPD (P ≥ 0.115). Conclusions: The presence of hyperpigmentary change in the macula in association with large drusen, not large drusen alone, nor large drusen with RPD, was significantly associated with a generalised reduction in EZ intensity. Quantitative assessment of the relative EZ intensity may serve as an effective biomarker of disease severity and progression.
Undernutrition and malaria in pregnancy - a dangerous dyad?
BACKGROUND: In low-resource settings, malaria and macronutrient undernutrition are major health problems in pregnancy, contributing significantly to adverse pregnancy outcomes such as preterm birth and fetal growth restriction. Affected pregnancies may result in stillbirth and neonatal death, and surviving children are at risk of poor growth and infection in infancy, and of non-communicable diseases in adulthood. Populations exposed to macronutrient undernutrition frequently reside in malaria-endemic areas, and seasonal peaks of low food supply and malaria transmission tend to coincide. Despite these geographic and temporal overlaps, integrated approaches to these twin challenges are infrequent. DISCUSSION: This opinion article examines the current evidence for malaria-macronutrition interactions and discusses possible mechanisms whereby macronutrient undernutrition and malaria may interact to worsen pregnancy outcomes. Macronutrient undernutrition dysregulates the immune response. In pregnant women, undernutrition may worsen the already increased susceptibility to malarial infection and could impair development of protective immunity to malaria, and is likely to exacerbate the impact of placental malaria on fetal growth. Malarial infection, in turn, can drive nutritional depletion; poor gestational weight gain and weight loss in pregnancy increases the risk of adverse pregnancy outcomes. Despite a commendable number of studies and trials that, in isolation, attempt to address the challenges of malaria and undernutrition in pregnancy, few dare to venture beyond the 'single disease - single solution' paradigm. We believe that this may be a lost opportunity: researching malaria-nutrition interactions, and designing and implementing integrated interventions to prevent and treat these commonly co-existing and intertwining conditions, may markedly reduce the high burden of preterm birth and fetal growth restriction in affected areas. CONCLUSION: We call for more collaboration between researchers studying malaria and nutrition in pregnancy, and propose a research agenda to address this important twin health problem.
A Tablet-Based Retinal Function Test in Neovascular Age-Related Macular Degeneration Eyes and At-Risk Fellow Eye
(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-03-01)
Purpose: To determine the feasibility of a tablet-based application to detect changes in retinal sensitivity and correlations with underlying pathology in neovascular age-related macular degeneration (nAMD) eyes undergoing treatment and in at-risk fellow eyes. Method: Participants with nAMD in at least one eye were recruited, examined, and imaged using spectral-domain optical coherence tomography (SD-OCT). Retinal sensitivity was measured within the central 5° at 12 locations using a customized test delivered on an iPad. Test points were superimposed on SD-OCT locations to investigate structure/function relationships. Results: Included in the study were 53 nAMD eyes and 21 at-risk fellow eyes. In nAMD eyes, the mean retinal sensitivity was 24.1 ± 1.8 dB with reduced retinal sensitivity associated with the presence of atrophy (P < 0.01), retinal pigment epithelium (RPE) disruption (P < 0.01), and absent ellipsoid zone (EZ) (P < 0.01), but not with the presence of subretinal fluid (P = 0.94) nor intraretinal fluid (P = 0.52). In at-risk eyes, the average retinal sensitivity was 28.8 ± 0.6 dB, with reduced sensitivity significantly associated with the presence of drusen, atrophy, RPE disruption, and absent EZ (P < 0.01). Conclusion: The tablet-based test of retinal sensitivity was able to be performed by an elderly cohort with nAMD. The ability to correlate differences in sensitivity with pathology is encouraging when considering using the tablet devices as a home monitoring tool with remote surveillance. Dual pathology often present with retinal fluid confounded our ability to correlate fluid with sensitivity. Translational Relevance: These findings highlight the potential of tablet-based devices in performing visual function measures as a home monitoring tool with remote surveillance for the earlier detection of nAMD.
e Analysis of Platelet-Rich Plasma Extraction Variations in Platelet and Blood Components Between 4 Common Commercial Kits
(SAGE PUBLICATIONS INC, 2017-01-01)
BACKGROUND: Platelet-rich plasma (PRP) has been extensively used as a treatment in tissue healing in tendinopathy, muscle injury, and osteoarthritis. However, there is variation in methods of extraction, and this produces different types of PRP. PURPOSE: To determine the composition of PRP obtained from 4 commercial separation kits, which would allow assessment of current classification systems used in cross-study comparisons. STUDY DESIGN: Controlled laboratory study. METHODS: Three normal adults each donated 181 mL of whole blood, some of which served as a control and the remainder of which was processed through 4 PRP separation kits: GPS III (Biomet Biologics), Smart-Prep2 (Harvest Terumo), Magellan (Arteriocyte Medical Systems), and ACP (Device Technologies). The resultant PRP was tested for platelet count, red blood cell count, and white blood cell count, including differential in a commercial pathology laboratory. Glucose and pH measurements were obtained from a blood gas autoanalyzer machine. RESULTS: Three kits taking samples from the "buffy coat layer" were found to have greater concentrations of platelets (3-6 times baseline), while 1 kit taking samples from plasma was found to have platelet concentrations of only 1.5 times baseline. The same 3 kits produced an increased concentration of white blood cells (3-6 times baseline); these consisted of neutrophils, leukocytes, and monocytes. This represents high concentrations of platelets and white blood cells. A small drop in pH was thought to relate to the citrate used in the sample preparation. Interestingly, an unexpected increase in glucose concentrations, with 3 to 6 times greater than baseline levels, was found in all samples. CONCLUSION: This study reveals the variation of blood components, including platelets, red blood cells, leukocytes, pH, and glucose in PRP extractions. The high concentrations of cells are important, as the white blood cell count in PRP samples has frequently been ignored, being considered insignificant. The lack of standardization of PRP preparation for clinical use has contributed at least in part to the varying clinical efficacy in PRP use. CLINICAL RELEVANCE: The variation of platelet and other blood component concentrations between commercial PRP kits may affect clinical treatment outcomes. There is a need for standardization of PRP for clinical use.
A good resource for parents, but will clinicians use it?: Evaluation of a resource for paediatric end-of-life decision making
BACKGROUND: Communication with parents about end-of-life care and decisions is a difficult and sensitive process. The objective of the present study was to ascertain clinicians' views on the acceptability and usefulness of a handbook and web-based resource (Caring Decisions) that was designed as an aid for parents facing end-of-life decisions for their child. METHODS: Qualitative interviews were conducted with a range of health professionals who provide care to children facing life-limiting conditions. RESULTS: Data analysis confirmed the acceptability and usefulness of the resource. Two major themes were revealed: 1. Family empowerment, with sub-themes Giving words and clarity, Conversation starter, 'I'm not alone in this', and A resource to take away, highlighted how the resource filled a gap by supporting and enabling families in a multitude of ways; 2. Not just for families, with sub-themes A guide for staff, When to give the resource?, How to give the resource and Who should give the resource?, explored the significant finding that participants viewed the resource as a valuable tool for themselves, but its presence also brought into relief potential gaps in communication processes around end-of-life care. CONCLUSION: The interview data indicated the positive reception and clear value and need for this type of resource. However, it is likely that successful resource uptake will be contingent on discussion and planning around dissemination and use within the health care team.
The relationship between interfragmentary movement and cell differentiation in early fracture healing under locking plate fixation
(Springer Netherlands, 2016)
Interfragmentary movement (IFM) at the fracture site plays an important role in fracture healing, particularly during its early stage, via influencing the mechanical microenvironment of mesenchymal stem cells within the fracture callus. However, the effect of changes in IFM resulting from the changes in the configuration of locking plate fixation on cell differentiation has not yet been fully understood. In this study, mechanical experiments on surrogate tibia specimens, manufactured from specially formulated polyurethane, were conducted to investigate changes in IFM of fractures under various locking plate fixation configurations and loading magnitudes. The effect of the observed IFM on callus cell differentiation was then further studied using computational simulation. We found that during the early stage, cell differentiation in the fracture callus is highly influenced by fracture gap size and IFM, which in turn, is highly sensitive to locking plate fixation configuration. The computational model predicted that a small gap size (e.g. 1 mm) under a relatively flexible configuration of locking plate fixation (larger bone-plate distances and working lengths) could experience excessive strain and fluid flow within the fracture site, resulting in excessive fibrous tissue differentiation and delayed healing. By contrast, a relatively flexible configuration of locking plate fixation was predicted to improve cartilaginous callus formation and bone healing for a relatively larger gap size (e.g. 3 mm). If further confirmed by animal and human studies, the research outcome of this paper may have implications for orthopaedic surgeons in optimising the application of locking plate fixations for fractures in clinical practice.
The role of impairment of mesenchymal stem cell function in osteoporotic bone fracture healing
With demographic change and increasing life expectancy, osteoporotic fractures have become one of the most prevalent trauma conditions seen in daily clinical practice. A variety of factors are known to affect the rate of healing in osteoporotic conditions (e.g. both biochemical and biomechanical environment of callus cells). However, the influence of impairment of mesenchymal stem cell function in the osteoporotic condition on bone fracture healing has not been fully understood. In the present study, we develop a mathematical model that quantifies the change in biological processes within the fracture callus as a result of osteoporosis. The model includes special features of osteoporosis such as reduction in mesenchymal stem cell (MSC) number in osteoporotic bone, impaired response of osteoporotic MSCs to their biomechanical microenvironment and the effects of configuration of locking compression plate (LCP) system on healing in this context. The results presented here suggest that mechanically-mediated MSCs differentiation at early stages of healing are significantly affected under osteoporotic conditions, while it is predicted that the flexible fixation achieved by increasing bone-plate distance of LCP could alleviate the negative effects of osteoporosis on healing. The outcomes of this study could potentially lead to patient specific surgical solutions, and thus achieve optimal healing outcomes in osteoporotic conditions.
Diagnosis of interstitial cystitis/bladder pain syndrome in women with chronic pelvic pain: a prospective observational study
(SPRINGER LONDON LTD, 2012-10-01)
INTRODUCTION AND HYPOTHESIS: This study assesses the prevalence of interstitial cystitis (IC)/bladder pain syndrome (BPS) in women with chronic pelvic pain (CPP). METHODS: This was a prospective study of 150 women undergoing laparoscopy as investigation for CPP in an Endometriosis and Pelvic Pain unit. Preoperative questionnaires [demographic details, pelvic pain symptoms, the Pelvic Pain and Urgency/Frequency (PUF) and O'Leary-Sant (OLS) Symptom and Problem Index scores] were completed, and concurrent standardized cystoscopy with hydrodistention performed at laparoscopy. The primary outcome measures the proportion of IC in this group, defined by presence of glomerulations with CPP and urinary symptoms (urinary frequency, nocturia, urgency). The secondary outcome measures the proportion of BPS [defined by the European Society of the Study of Interstitial Cystitis (ESSIC)]. RESULTS: IC was diagnosed in 48/150 (32%) individuals, and 80/150 (53%) had BPS. There were no significant differences in symptomatology or questionnaire results between groups with and without IC. Women with BPS had higher PUF (17.2 vs 12.9, p < 0.001), OLS Symptom (8.2 vs 6.0, p = 0.001) and Problem (7.5 vs 4.2, p < 0.001) scores and more severe pain symptoms. Visually proven endometriosis was seen in 90/150 (60%), and 27/150 (18%) had both endometriosis and IC. Of the 80 women with BPS, 45/80 (60%) had endometriosis. CONCLUSIONS: The prevalence of IC/BPS varies depending on the definition used. This study showed IC in 32% of women with CPP based on symptoms and presence of glomerulations. BPS as defined by ESSIC was diagnosed in 53%. History and questionnaires did not correlate with positive cystoscopic findings.
Early acid-base and blood pressure effects of continuous renal replacement therapy intensity in patients with metabolic acidosis
PURPOSE: In acute kidney injury patients, metabolic acidosis is common. Its severity, duration, and associated changes in mean arterial pressure (MAP) and vasopressor therapy may be affected by the intensity of continuous renal replacement therapy (CRRT). We aimed to compare key aspects of acidosis and MAP and vasopressor therapy in patients treated with two different CRRT intensities. METHODS: We studied a nested cohort of 115 patients from two tertiary intensive care units (ICUs) within a large multicenter randomized controlled trial treated with lower intensity (LI) or higher intensity (HI) CRRT. RESULTS: Levels of metabolic acidosis at randomization were similar [base excess (BE) of -8 ± 8 vs. -8 ± 7 mEq/l; p = 0.76]. Speed of BE correction did not differ between the two groups. However, the HI group had a greater increase in MAP from baseline to 24 h (7 ± 3 vs. 0 ± 3 mmHg; p < 0.01) and a greater decrease in norepinephrine dose (from 12.5 to 3.5 vs. 5 to 2.5 μg/min; p < 0.05). The correlation (r) coefficients between absolute change in MAP and norepinephrine (NE) dose versus change in BE were 0.05 and -0.37, respectively. CONCLUSIONS: Overall, LI and HI CRRT have similar acid-base effects in patients with acidosis. However, HI was associated with greater improvements in MAP and vasopressor requirements (clinical trial no. NCT00221013).
Intensive care discharge delay is associated with increased hospital length of stay: A multicentre prospective observational study
(PUBLIC LIBRARY SCIENCE, 2017-07-27)
BACKGROUND: Some patients experience a delayed discharge from the intensive care unit (ICU) where the intended and actual discharge times do not coincide. The clinical implications of this remain unclear. OBJECTIVE: To determine the incidence and duration of delayed ICU discharge, identify the reasons for delay and evaluate the clinical consequences. METHODS: Prospective multi-centre observational study involving five ICUs over a 3-month period. Delay in discharge was defined as >6 hours from the planned discharge time. The primary outcome measure was hospital length stay after ICU discharge decision. Secondary outcome measures included ICU discharge after-hours, incidence of delirium, survival to hospital discharge, discharge destination, the incidence of ICU acquired infections, revocation of ICU discharge decision, unplanned readmissions to ICU within 72 hours, review of patients admitting team after ICU discharge decision. RESULTS: A total of 955 out of 1118 patients discharged were included in analysis. 49.9% of the patients discharge was delayed. The most common reason (74%) for delay in discharge was non-availability of ward bed. The median duration of the delay was 24 hours. On univariable analysis, the duration of hospital stay from the time of ICU discharge decision was significantly higher in patients who had ICU discharge delay (Median days-5 vs 6; p = 0.003). After-hours discharge was higher in patients whose discharge was delayed (34% Vs 10%; p<0.001). There was no statistically significant difference in the other secondary outcomes analysed. Multivariable analysis adjusting for known confounders revealed delayed ICU discharge was independently associated with increased hospital length of stay. CONCLUSION: Half of all ICU patients experienced a delay in ICU discharge. Delayed discharge was associated with increased hospital length of stay.
Understanding factors influencing physical activity and exercise in lung cancer: a systematic review
PURPOSE: Despite evidence and clinical practice guidelines supporting physical activity (PA) for people with lung cancer, this evidence has not translated into clinical practice. This review aims to identify, evaluate and synthesise studies examining the barriers and enablers for patients with lung cancer to participate in PA from the perspective of patients, carers and health care providers (HCPs). METHODS: Systematic review of articles using electronic databases: MEDLINE (1950-2016), CINAHL (1982-2016), EMBASE (1980-2016), Scopus (2004-2016) and Cochrane (2016). Quantitative and qualitative studies, published in English in a peer-reviewed journal, which assessed the barriers or enablers to PA for patients with lung cancer were included. Registered-PROSPERO (CRD4201603341). RESULTS: Twenty-six studies (n = 9 cross-sectional, n = 4 case series, n = 11 qualitative) including 1074 patients, 23 carers and 169 HCPs were included. Barriers and enablers to PA were identified (6 major themes, 18 sub-themes): Barriers included patient-level factors (physical capability, symptoms, comorbidities, previous sedentary lifestyle, psychological influences, perceived relevance), HCP factors (time/knowledge to deliver information) and environmental factors (access to services, resources, timing relative to treatment). Enablers included anticipated benefits, opportunity for behaviour change and influences from HCPs and carers. CONCLUSION: This systematic review has identified the volume of literature demonstrating that barriers and enablers to PA in lung cancer are multidimensional and span diverse factors. These include patient-level factors, such as symptoms, comorbidities, sedentary lifestyle, mood and fear, and environmental factors. These factors should be considered to identify and develop suitable interventions and clinical services in attempt to increase PA in patients with lung cancer.