ORCID Profile
0000-0001-9344-7749
Current Organisation
Primary Health Tasmania
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Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
Publisher: Consortium of Multiple Sclerosis Centers
Date: 31-12-2021
DOI: 10.7224/1537-2073.2020-075
Abstract: People with multiple sclerosis and neuroimmunologic disorders (herein referred to as patients) are increasingly treated with infusible monoclonal antibodies. This rise in demand has placed increased loads on current infusion services and mandates careful strategic planning. This study examined patient preferences for the timing and location of infusions and their association with demographic and disease variables to facilitate patient-focused strategic planning. Ninety-one patients receiving an infusible therapy at an infusion service during March 2019 were asked to complete a questionnaire exploring eight domains, including preferences for time of infusions and location of infusion centers. Potential access to home-based treatment was included as an option. Unstructured (free-text) feedback on current service was also obtained. Eighty-three patients completed the survey (mean age, 42 years 75% women). Infusions were predominantly natalizumab (66%) and ocrelizumab (25%). Of these patients, 71% were engaged in some form of work or study, and 83% of this group had to arrange time off from work or study to attend treatment. Seventy percent of patients would prefer their infusion before noon, and 60% would consider home-based infusions. Most used a car as their transport to the infusion service. These results suggest that patients are more likely to prefer infusible treatment in the morning and are open to home-based infusions. This study provides information for health services to target service delivery at peak preference times and consider alternate ways of delivering infusible treatments.
Publisher: American Chemical Society (ACS)
Date: 25-01-2003
DOI: 10.1021/LA026641K
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.EPLEPSYRES.2010.06.003
Abstract: Computer-assisted-telephone-interviewing (CATI), widely used in market research, could be a useful alternative for conducting diagnostic interviews in epilepsy epidemiology. We administered a diagnostic seizure questionnaire by CATI, interpreting the responses with standardized classification guidelines, compared against an epilepsy specialist's assessment, for agreement [Kappa statistic (kappa)], sensitivity, specificity, positive predictive value, negative predictive value and Youden's Index (YI). 99 outpatients with 382 lifetime events participated: 22 generalized-onset epilepsy [16 Idiopathic Generalized Epilepsy (IGE)], 59 partial-onset epilepsy, 12 non-epileptic and 6 uncertain. We observed almost perfect agreement in diagnosing epilepsy (kappa=0.94), seizure-onset types (kappa=0.84), simple or complex partial seizures (kappa=0.87), any generalized non-convulsive seizure (kappa=0.82), and IGE (kappa=0.82). Although substantial, agreement was not as close for secondarily generalized seizures (kappa=0.74), and generalized tonic-clonic seizures (kappa=0.79). This related more to under-recognition of in idual generalized non-convulsive seizures rather than misinterpretation of partial seizures. Epilepsy diagnostic questionnaires administered by CATI and interpreted with standardized diagnostic guidelines can effectively classify epilepsy, most seizure types and IGE in outpatients with suspected seizures. Applying this diagnostic method in 'field' settings will allow firmer conclusions to be drawn on its wider epidemiological utility.
Publisher: BMJ
Date: 07-2004
Publisher: Informa UK Limited
Date: 30-06-2016
Publisher: Springer Science and Business Media LLC
Date: 16-01-2014
DOI: 10.1038/GENE.2013.70
Abstract: Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not in idually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.
Publisher: Oxford University Press (OUP)
Date: 08-11-2022
Abstract: Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for multiple sclerosis. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3,301) and brain proteomics (n = 376 discovery n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14,802 cases and 26,703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31,684) and brain (n = 1,194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (dataset 1: n = 73 cases and 97 controls dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (dataset 1: n = 4 cases and 5 controls dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared to controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins, and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development.
Publisher: SAGE Publications
Date: 07-2019
Publisher: Public Library of Science (PLoS)
Date: 13-04-2020
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.JSBMB.2013.01.011
Abstract: Vitamin D deficiency is common and implicated in risk of several human diseases. Evidence on the relative quantitative contribution of environmental, genetic and phenotypic factors to vitamin D status (assessed by the serum concentration of 25-hydroxyvitamin D, 25(OH)D) in free-living populations is sparse. We conducted a cross-sectional study of 494 Caucasian adults aged 18-61years, randomly selected from the Australian Electoral Roll according to groups defined by age, sex and region (spanning 27°-43°South). Data collected included personal characteristics, sun exposure behaviour, biomarkers of skin type and past sun exposure, serum 25(OH)D concentration and candidate single nucleotide polymorphisms. Ambient ultraviolet radiation (UVR) levels in the month six weeks before blood s ling best predicted vitamin D status. Serum 25(OH)D concentration increased by 10nmol/L as reported time in the sun doubled. Overall, 54% of the variation in serum 25(OH)D concentration could be accounted for: 36% of the variation was explained by sun exposure-related factors 14% by genetic factors (including epistasis) and 3.5% by direct measures of skin phenotype. Novel findings from this study are demonstration of gene epistasis, and quantification of the relative contribution of a wide range of environmental, constitutional and genetic factors to vitamin D status. Ambient UVR levels and time in the sun were of prime importance but it is nonetheless important to include the contribution of genetic factors when considering sun exposure effects. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2018
Publisher: Wiley
Date: 19-06-2015
DOI: 10.1111/AEHR.12071
Publisher: Springer Science and Business Media LLC
Date: 25-01-2007
DOI: 10.1007/S00439-007-0323-5
Abstract: Dense sets of hundreds of thousands of markers have been developed for genome-wide association studies. These marker sets are also beneficial for linkage analysis of large, deep pedigrees containing distantly related cases. It is impossible to analyse jointly all genotypes in large pedigrees using the Lander-Green Algorithm, however, as marker density increases it becomes less crucial to analyse all in iduals' genotypes simultaneously. In this report, an approximate multipoint non-parametric technique is described, where large pedigrees are split into many small pedigrees, each containing just two cases. This technique is demonstrated, using phased data from the International Hapmap Project to simulate sets of 10,000, 50,000 and 250,000 markers, showing that it becomes increasingly accurate as more markers are genotyped. This method allows routine linkage analysis of large families with dense marker sets and represents a more easily applied alternative to Monte Carlo Markov Chain methods.
Publisher: American Society of Civil Engineers (ASCE)
Date: 1995
Publisher: Elsevier BV
Date: 06-1994
Publisher: Springer Science and Business Media LLC
Date: 05-10-2012
Publisher: Elsevier BV
Date: 08-2002
DOI: 10.1016/S1011-1344(02)00331-7
Abstract: Recent advances have enabled quite accurate estimations of cutaneous melanin density by spectrophotometry using reflectance of light at wavelengths 400 and 420 nm. Our purpose was to assess the effect of body hair and seasonal variation at the upper inner arm and buttock on measurements of melanin density. We estimated melanin density of 104 volunteers at 3-monthly intervals over 12 months both before and after shaving. Removing body hair at the upper inner arm had no effect, but substantially reduced melanin estimates at the buttock in men. Significant seasonal variation was only observed at the upper inner arm, with highest readings in summer-autumn. In case-control studies, misclassification due to body hair at the buttock and seasonal variation at the upper inner arm could affect the observed odds ratio substantially. However, both sources of error can be reduced by careful attention to key aspects of study design.
Publisher: Elsevier BV
Date: 12-2016
Publisher: CSIRO Publishing
Date: 19-11-2020
DOI: 10.1071/AH19290
Abstract: Objective Clinicians across all health professions increasingly strive to add value to the care they deliver through the application of the central tenets of people-centred care (PCC), namely the ‘right care’, in the ‘right place’, at the ‘right time’ and ‘tailored to the needs of communities’. This ideal is being h ered by a lack of a structured, evidence-based means to formulate policy and value the commissioning of services in an environment of increasing appreciation for the complex health needs of communities. This creates significant challenges for policy makers, commissioners and providers of health services. Communities face a complex intersection of challenges when engaging with healthcare. Increasingly, complexity is gaining prominence as a significant factor in the delivery of PCC. Based on the World Health Organization (WHO) components of health policy, this paper proposes a policy framework that enables policy makers, commissioners and providers of health care to integrate a model of complexity into policy, subsequent service planning and development of models of care. Methods The WHO components of health policy were used as the basis for the framework. Literature was drawn on to develop a policy framework that integrates complexity into health policy. Results Within the framework, complexity is juxtaposed between the WHO components of ‘vision’, ‘priorities’ and ‘roles’. Conclusion This framework, supported by the literature, provides a means for policy makers and health planners to conduct analyses of and for policy. Further work is required to better model complexity in a manner that integrates consumer needs and provider capabilities. What is known about the topic? There is a growing body of evidence regarding patient complexity and its impact on the delivery of health services, but there is little consideration of patient complexity in policy, which is an important consideration for service provision. What does this paper add? This paper presents an argument for the inclusion of patient complexity in health policy and provides a framework for how that might occur. What are the implications for practitioners? The inclusion of patient complexity in policy could provide a means for policy makers to consider the factors that contribute to patient complexity in service provision decisions.
Publisher: Oxford University Press (OUP)
Date: 27-02-2010
DOI: 10.1093/HMG/DDQ090
Abstract: Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these s les. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40 the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.NCL.2010.12.007
Abstract: In this review, the evidence for the leading environmental and lifestyle factors thought to play a role in multiple sclerosis (MS) onset, including Epstein-Barr virus, sun exposure or vitamin D, and smoking, will be discussed. The Causal Pie Model is used as a conceptual framework to understand the causation. Given that no single factor leads to the development of MS, the joint action or interaction of these factors, along with genetic factors, most particularly the HLA-DR15*1501 genotype, is a primary focus.
Publisher: Elsevier BV
Date: 08-1999
Publisher: Wiley
Date: 2004
DOI: 10.1002/ART.20108
Abstract: To estimate the heritability of muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis (ROA), and to assess whether heritability of the knee structural components is independent of ROA. A sibpair design was utilized. Sagittal T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine cartilage volume and bone size. Standing semiflexed radiographs of the same knee were obtained to assess the presence of ROA. Knee pain was assessed by questionnaire and muscle strength by dynamometry. Heritability was estimated using the genetic analysis program SOLAR. A total of 128 subjects (61 men, 67 women mean age 45 years) from 51 families representing 115 sibpairs were studied. Lower limb muscle strength had high heritability (42% P = 0.02), as did knee pain (44% P = 0.07). Heritability estimates for cartilage volume were 65% for medial tibial cartilage, 77% for lateral tibial cartilage, and 84% for patellar cartilage, and heritability estimates for bone size were 85% for medial tibial bone area, 57% for lateral tibial bone area, and 70% for patella bone volume (all P < or = 0.004). For ROA, heritability was 61% for presence (with a large standard error) (P = 0.16) and 61% for severity (P = 0.02). The estimates for tibial bone areas were the only ones markedly reduced after adjustment for body size, while all estimates with the exception of knee pain were independent of ROA. Cartilage and, to a lesser extent, bone sites investigated by MRI were largely under independent genetic control, with a lesser shared genetic component. With the exception of prevalent ROA, all knee modalities assessed had high heritability, most likely reflecting a strong genetic component. Cartilage volume, bone size, and muscle strength all have the potential to be studied in quantitative trait linkage analyses, but their exact relevance with regard to OA remains uncertain at this time.
Publisher: Wiley
Date: 16-04-2014
DOI: 10.1111/IMJ.12428
Publisher: Wiley
Date: 13-12-2018
DOI: 10.1111/NEP.13537
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJMG.2017.06.002
Abstract: Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected in iduals in the family. Identification of COL18A1 mutations in in iduals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2237
Publisher: Springer Science and Business Media LLC
Date: 10-2020
Publisher: BMJ
Date: 12-2002
Abstract: Previous studies have suggested a strong genetic component to osteoarthritis (OA), especially that of the hand, and three linkage studies have suggested the existence of susceptibility loci in disparate regions of chromosome 2q. To examine for linkage to 2q in a Tasmanian population of women and men with familial hand OA. Hand OA (distal interphalangeal, carpometacarpal, and Heberden's nodes) was assessed by a combination of hand photographs and radiographs. A non-parametric linkage (NPL) analysis was performed on chromosome 2q of 69 members in 22 families with severe distal interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis of a larger group of 456 members in 68 families was also performed using SOLAR. The maximum non-parametric linkage score was 1.05 (p=0.15) at marker IL1R1, close to the centromere. All components of hand OA scores had significant heritability in this dataset (28%-35%, all p<0.001). Despite this, the quantitative trait analysis (after adjustment for age and, where appropriate, sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes combined), and 1.19 for carpometacarpal OA score (women only). These results do not provide confirmation of linkage on chromosome 2q in the larger white population with hand OA. They suggest that there are regional variations in the genetic cause of hand OA and that other loci not on 2q may be important in this disease.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.YEBEH.2022.108571
Abstract: To evaluate the utility of electroencephalography (EEG) changes as diagnostic and prognostic biomarkers in acute autoimmune encephalitis (AIE). One hundred and thirty-one patients with AIE were recruited retrospectively across 7 hospitals. Clinical data were collected during admission and at 12 months. EEGs were reviewed using a standard reporting proforma. Associations between EEG biomarkers, AIE subtypes, and clinical outcomes were assessed using logistic regression modeling. Presence of superimposed fast activity (OR 34.33 95% CI 3.90, 4527.27 p < 0.001), fluctuating EEG abnormality (OR 6.60 95% CI 1.60, 37.59 p = 0.008), and hemispheric focality (OR 28.48 95% CI 3.14, 3773.14 p < 0.001) were significantly more common in N-methyl-d-aspartate receptor (NMDAR) antibody-associated patients with AIE compared to other AIE subtypes. Abnormal background rhythm was associated with a poor mRS (modified Rankin score) at discharge (OR 0.29 95% CI 0.10, 0.75 p = 0.01) and improvement in mRS at 12 months compared with admission mRS (3.72 95% CI 1.14, 15.23 p = 0.04). We have identified EEG biomarkers that differentiate NMDAR AIE from other subtypes. We have also demonstrated EEG biomarkers that are associated with poor functional outcomes.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 08-2002
DOI: 10.1016/S1011-1344(02)00331-7
Abstract: Recent advances have enabled quite accurate estimations of cutaneous melanin density by spectrophotometry using reflectance of light at wavelengths 400 and 420 nm. Our purpose was to assess the effect of body hair and seasonal variation at the upper inner arm and buttock on measurements of melanin density. We estimated melanin density of 104 volunteers at 3-monthly intervals over 12 months both before and after shaving. Removing body hair at the upper inner arm had no effect, but substantially reduced melanin estimates at the buttock in men. Significant seasonal variation was only observed at the upper inner arm, with highest readings in summer-autumn. In case-control studies, misclassification due to body hair at the buttock and seasonal variation at the upper inner arm could affect the observed odds ratio substantially. However, both sources of error can be reduced by careful attention to key aspects of study design.
Publisher: American Society of Hematology
Date: 27-01-2011
DOI: 10.1182/BLOOD-2010-07-296475
Abstract: We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-2005
DOI: 10.1167/IOVS.05-0312
Abstract: The purpose of this study was to identify genetic contributions to primary open-angle glaucoma (POAG) through investigations of two quantitative components of the POAG phenotype. Genome-wide multipoint variance-components linkage analyses of maximum recorded intraocular pressure (IOP) and maximum vertical cup-to-disc ratio were conducted on data from a single, large Australian POAG pedigree that has been found to segregate the myocilin Q368X mutation in some in iduals. Multipoint linkage analysis of maximum recorded IOP produced a peak LOD score of 3.3 (P = 0.00015) near marker D10S537 on 10q22, whereas the maximum cup-to-disc ratio produced a peak LOD score of 2.3 (P = 0.00056) near markers D1S197 to D1S220 on 1p32. Inclusion of the myocilin Q368X mutation as a covariate provided evidence of an interaction between this mutation and the IOP and cup-to-disc ratio loci. Significant linkage has been identified for maximum IOP and suggestive linkage for vertical cup-to-disc ratio. Identification of genes contributing to the variance of these traits will enhance understanding of the pathophysiology of POAG as a whole.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2003
DOI: 10.1097/00061198-200306000-00010
Abstract: To demonstrate the effect in vivo of the myocilin gene mutation Thr377Met on outflow facility of aqueous humor, as measured by tonography. Forty-two members of a pedigree known to carry the Thr377Met mutation were examined for glaucoma, evaluated with tonography, and screened for myocilin mutations. Tonography was used to calculate the coefficient of aqueous outflow facility (C), as well as the ratio of the resting intraocular pressure to C (P(0)/C). Subjects were reexamined for glaucoma 5 years after tonography. Seven subjects were excluded because of previous treatment known to alter facility of aqueous outflow. The mean outflow facility of the eyes of the 12 subjects carrying the Thr377Met mutation was significantly reduced compared with the 23 non-carriers' eyes using both C (P<0.001) and P(0)/C (P<0.001). Reduced outflow facility was also demonstrated in those mutation carriers who were not yet expressing clinical signs of glaucoma or ocular hypertension when measured using C (P = 0.015) and P(0)/C (P = 0.001). After 5 years, progression towards glaucoma had occurred in 5 of the myocilin mutation-carriers, 2 of whom showed bilateral progression 3 carriers remained completely normal. Four subjects had bilateral glaucoma at the outset and remained unchanged. The carriers' eyes that progressed towards glaucoma had reduced outflow facility compared with those that remained normal, although the difference was not statistically significant. Carriers of the myocilin Thr377Met mutation have reduced outflow facility, which may be detected prior to developing glaucoma. Tonography was not seen to be clinically useful in predicting progression towards glaucoma.
Publisher: Life Science Alliance, LLC
Date: 09-06-2020
Abstract: At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.
Publisher: SAGE Publications
Date: 21-04-2009
Abstract: Multiple studies have provided evidence for an association between reduced sun exposure and increased risk of multiple sclerosis (MS), an association likely to be mediated, at least in part, by the vitamin D hormonal pathway. Herein, we examine whether the vitamin D receptor ( VDR), an integral component of this pathway, influences MS risk in a population-based s le where winter sun exposure in early childhood has been found to be an important determinant of MS risk. Three polymorphisms within the VDR gene were genotyped in 136 MS cases and 235 controls, and associations with MS and past sun exposure were examined by logistic regression. No significant univariate associations between the polymorphisms, rs11574010 ( Cdx-2A G), rs10735810 ( Fok1T C), or rs731236 ( Taq1C T) and MS risk were observed. However, a significant interaction was observed between winter sun exposure during childhood, genotype at rs11574010, and MS risk ( P = 0.012), with the ‘G’ allele conferring an increased risk of MS in the low sun exposure group (≤2 h/day). No significant interactions were observed for either rs10735810 or rs731236, after stratification by sun exposure. These data provide support for the involvement of the VDR gene in determining MS risk, an interaction likely to be dependent on past sun exposure.
Publisher: Oxford University Press (OUP)
Date: 17-07-2015
DOI: 10.1093/HMG/DDV278
Abstract: Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.
Publisher: SAGE Publications
Date: 28-01-2013
Abstract: This study investigates the influences of the strategy tripod, an established concept in the international business (IB) literature, on a corporate social responsibility (CSR)-based differentiation strategy for export firms. This strategy is conceived as consisting of product-level and firm-level CSR. Using a s le of 195 Brazilian export firms, the authors find that innovation capabilities, international market exposure, and institutional pressures significantly influence product-level CSR however, the latter two factors influence firm-level CSR only through their mediating effects on product-level CSR. This study contributes to the existing CSR and IB literature in three ways. First, it integrates and systematizes the factors influencing CSR-based strategies into the three categories represented by the legs of the strategy tripod to help elucidate the previous research on the factors that drive CSR. Second, it suggests that exporters’ CSR strategies can be affected by social and environmental institutions based outside their home countries. Third, this study contributes to filling an important empirical gap in the research on CSR by focusing on export ventures from emerging countries.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.YEBEH.2022.108729
Abstract: To evaluate the prevalence and biomarkers of drug-resistant epilepsy (DRE) in patients with autoimmune encephalitis (AIE). Sixty-nine patients with AIE were recruited retrospectively and electroencephalographies (EEGs) were reviewed using a standard reporting proforma. Associations between EEG biomarkers and DRE development at 12 months were examined using logistic regression modeling and were utilized to create a DRE risk score. Sixteen percent of patients with AIE developed DRE at 12-month follow-up. The presence of status epilepticus (SE) (OR 11.50, 95% CI [2.81, 51.86], p-value <0.001), temporal lobe focality (OR 9.90, 95% CI [2.60, 50.71], p-value 0.001) and periodic discharges (OR 19.12, 95% CI [3.79, 191.10], p-value 0.001) on the admission EEG were associated with the development of DRE at 12 months. These variables were utilized to create a clinically applicable risk score for the prediction of DRE development. Drug-resistant epilepsy is an infrequent complication of AIE. Electroencephalography changes during the acute illness can predict the risk of DRE at 12 months post-acute AIE. The identified EEG biomarkers provide the basis to generate a clinically applicable prediction tool which could be used to inform treatment, prognosis, and select patients for acute treatment trials.
Publisher: Informa UK Limited
Date: 18-03-2013
DOI: 10.1111/JSBM.12013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-06-2021
DOI: 10.1212/WNL.0000000000012084
Abstract: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. Using data from the MSBase Registry, we included pregnancies conceived after December 31, 2010, in women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses. We included 1,998 pregnancies from 1,619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% confidence interval 0.27–0.32), fell to 0.19 (0.14–0.24) in the third trimester, and increased to 0.59 (0.51–0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28–0.49) and 0.29 (0.22–0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (odds ratio 0.76 per month [0.60–0.95], p = 0.017). DMT reinitiation with natalizumab protected against postpartum relapse (hazard ratio [HR] 0.11 [0.04–0.32], p 0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41–0.91], p = 0.016). We found that 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum. Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation with early reinitiation after delivery is an effective option to minimize relapse risks. Strategies of disease-modifying therapy use have to be balanced against potential fetal/neonatal complications.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Wiley
Date: 05-08-2020
DOI: 10.1111/BPH.15201
Publisher: Academy of Management
Date: 08-2020
Publisher: MDPI AG
Date: 04-05-2022
Abstract: This retrospective cohort study analyzed the administrative hospital records of 91,500 patients with the aim of assessing adverse drug reaction (ADR)-related hospital admission risk after discharge from ADR and non-ADR-related admission. Patients aged ≥18 years with an acute admission to public hospitals in Tasmania, Australia between 2011 and 2015 were followed until May 2017. The index admissions (n = 91,550) were stratified based on whether they were ADR-related (n = 2843, 3.1%) or non-ADR-related (n = 88,707, 96.9%). Survival analysis assessed the post-index ADR-related admission risk using (1) the full dataset, and (2) a matched subset of patients using a propensity score analysis. Logistic regression was used to identify the risk factors for ADR-related admissions within 90 days of post-index discharge. The patients with an ADR-related index admission were almost five times more likely to experience another ADR-related admission within 90 days (p 0.001). An increased risk persisted for at least 5 years (p 0.001), which was substantially longer than previously reported. From the matched subset of patients, the risk of ADR-related admission within 90 and 365 days more than doubled in the patients with an ADR-related index admission (p 0.0001). These admissions were often attributed to the same drug class as the patients’ index ADR-related admission. Cancer was a major risk factor for ADR-related re-hospitalization within 90 days other factors included heart failure and increasing age.
Publisher: FapUNIFESP (SciELO)
Date: 2005
DOI: 10.1590/S1679-39512005000500013
Abstract: O objetivo do presente estudo de caso é mostrar que as melhorias incrementais do processo de desenvolvimento de produto podem ser entendidas em função das fortes pressões de concorrência originadas no ambiente externo da subsidiária assim como na organização interna de pesquisa e desenvolvimento (P& D) da empresa multinacional. Do ponto de vista teórico, o artigo revela uma organização de P& D interna pouco comum que combina os três as formas conhecidas de estudos sobre governança: a hierarquia, o mercado e a cooperação. Nesse sentido, a empresa estudada é distinta da organização "clássica" baseada exclusivamente no controle hierárquico. Em linha com o objetivo mencionado, será mostrado que esta forma de organização é um dos principais fatores que fomentam a aprendizagem e as melhorias do processo de desenvolvimento de produtos. Este último ponto e a visão integral da organização de P& D em uma multinacional podem comunicar alguns insights instigantes para a comunidade de gestores de atividades inovadoras.
Publisher: S. Karger AG
Date: 21-12-2005
DOI: 10.1159/000089271
Abstract: Primary open-angle glaucoma (POAG) is genetically heterogeneous, with 6 named POAG loci GLC1A-F mapped and genes myocilin i (MYOC) /i and optineurin i (OPTN) /i identified at 2 of the loci. Using penetrance-model-free methods, we screened the POAG loci GLC1A-F in an extended Australian pedigree, using 3–5 markers within each locus. p values of less than 0.05 were obtained empirically using SimWalk2 and exactly using Genehunter for 2 markers within the GLC1B region on chromosome 2. Fine mapping of this region produced pvalues of 0.01 or less at 5 markers flanked by D2S1897 and D2S2269. The 9 cM haplotype of interest overlaps the original GLC1B region. These results provide supportive evidence for the GLC1B locus on chromosome 2cen-q13 and verify the existence of POAG susceptibility gene in this region, increasing the likelihood of gene identification.
Publisher: Juniper Publishers
Date: 09-02-2018
Publisher: Wiley
Date: 30-01-2004
DOI: 10.1111/J.1464-5491.2004.01099.X
Abstract: To compare diabetes management practices in 2001 among in iduals from Tasmania, Australia, with a previous management survey conducted in 1995-7. Subjects were ascertained through the Tasmanian Insulin-Treated Diabetes Register. General demographic data were collected by telephone interview, and participants mailed a questionnaire on their diabetes management practices. The response rate in 2001 was 80.8% (n=1336). There was a trend to more frequent blood glucose self-monitoring, notably in those less than 25 years (P 2 times/day), together with continued uptake of the pen system of insulin administration. More intensive shared management by general practitioner and diabetes specialist was noted, including a greater proportion visiting their doctor more than five times per year (P=0.006 for those <50 years). Most patients continue to be appropriately screened for hypertension and retinopathy. Dietitian visits declined overall (P=0.03 for at least annual visits), and there appeared to be an inadequate level of foot examination by patients and doctors. The survey indicated that most patients were taking greater responsibility for their metabolic control, and intensive management practices and more convenient methods of administration may be contributors. Two areas of possible concern are access to dietitian services, and patient and health provider education on appropriate foot care.
Publisher: Springer Science and Business Media LLC
Date: 05-01-2007
DOI: 10.1007/S00439-006-0312-0
Abstract: To examine the familial correlations, heritability (h(2)) and common environmental components (c(2)) of myopia and ocular biometric traits (all treated as continuous outcomes) in families collected through the Genes in Myopia (GEM) family study in Australia. A total of 132 pedigrees (723 participants) were recruited for this study. All in iduals completed a risk factor questionnaire and underwent a detailed eye examination including spherical equivalent (SphE) and ocular biometric measurements of axial length (AL), anterior chamber depth (ACD) and corneal curvature (CC). Familial correlations were calculated and h(2) and c(2) were estimated using a variance component model that assumes a multivariate t distribution within each pedigree. Two definitions of common environments (c(2)) were considered: nuclear family (current) shared environment (Model 1) and sib-ship (childhood) shared environment (Model 2). Population ascertainment adjustment was performed using the Blue Mountains eye study dataset. The trends observed for familial correlations suggested that SphE is influenced by both environmental and genetic factors whereas AL, ACD and CC are predominantly genetically determined. This was largely confirmed by variance components modelling. Heritability estimates (adjusted for age, sex and years of education) from the best fitting ACE model (Model 2, childhood shared environment) were 0.50 +/- 0.05 for SphE, 0.73 +/- 0.04 for AL, 0.78 +/- 0.04 for ACD and 0.16 +/- 0.06 for CC. Childhood environmental effects were significant with c(2) estimated to be 0.33 +/- 0.04 for SphE, 0.06 +/- 0.03 for AL, 0.22 +/- 0.04 for ACD and 0.10 +/- 0.05 for CC. Age was associated with SphE, total years of education was associated with AL and sex was associated with all traits studied. We used a novel and conservative approach to account for and estimate common environmental effects by specifying either nuclear family or sib-ship environment when estimating heritability estimates and showed that all traits examined (SphE, AL, ACD and CC) are heritable, thus reflecting a genetic component. These traits therefore all represent candidates for quantitative trait linkage analyses.
Publisher: Oxford University Press (OUP)
Date: 05-2004
DOI: 10.1093/AJE/KWH120
Abstract: The authors quantified improvement in predicting cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin made possible by information on common variants of the melanocortin-1 receptor gene (MC1R) in a 1998-1999 population-based case-control study of subjects aged 20-59 years of northern European ancestry in Tasmania, Australia. Melanin density at the upper inner arm was estimated by spectrophotometry. DNA s les were genotyped for five MC1R variants: Val60Leu, Asp84Glu, Arg151Cys, Arg160Trp, and Asp294His. Among controls (n = 267), variant carriers, versus noncarriers, had lower (p < 0.01) mean melanin concentrations. Increased risk conferred by genotype was restricted mainly to those with the darkest skins: for subjects with at least 2% melanin, the odds of carrying each additional variant were higher for cutaneous malignant melanoma (n = 39 odds ratio = 1.45, 95% confidence interval: 0.87, 2.44), basal cell carcinoma (n = 35 odds ratio = 1.86, 95% confidence interval: 1.14, 3.02), and squamous cell carcinoma (n = 42 odds ratio = 2.67, 95% confidence interval: 1.50, 4.74) cases than for controls (n = 135). Adding MC1R information to prediction based on age, sex, and cutaneous melanin increased the area under the receiver operating characteristic curve by 1.4% (cutaneous malignant melanoma), 3.2% (basal cell carcinoma), or 2.0% (squamous cell carcinoma). The improvement in prediction was probably too small to be valuable in a clinical setting.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2020
DOI: 10.1186/S12882-020-01862-1
Abstract: Chronic kidney disease (CKD) affects drug elimination and patients with CKD require appropriate adjustment of renally cleared medications to ensure safe and effective pharmacotherapy. The main objective of this study was to determine the extent of potentially inappropriate prescribing (PIP defined as the use of a contraindicated medication or inappropriately high dose according to the kidney function) of renally-cleared medications commonly prescribed in Australian primary care, based on two measures of kidney function. A secondary aim was to assess agreement between the two measures. Retrospective analysis of routinely collected de-identified Australian general practice patient data (NPS MedicineWise MedicineInsight from January 1, 2013, to June 1, 2016 collected from 329 general practices). All adults (aged ≥18 years) with CKD presenting to general practices across Australia were included in the analysis. Patients were considered to have CKD if they had two or more estimated glomerular filtration rate (eGFR) recorded values 60 mL/min/1.73m 2 , and/or two urinary albumin/creatinine ratios ≥3.5 mg/mmol in females (≥2.5 mg/mmol in males) at least 90 days apart. PIP was assessed for 49 commonly prescribed medications using the Cockcroft-Gault (CG) equation/eGFR as per the instructions in the Australian Medicines Handbook. A total of 48,731 patients met the Kidney Health Australia (KHA) definition for CKD and had prescriptions recorded within 90 days of measuring serum creatinine (SCr)/estimated glomerular filtration rate (eGFR). Overall, 28,729 patients were prescribed one or more of the 49 medications of interest. Approximately 35% ( n = 9926) of these patients had at least one PIP based on either the Cockcroft-Gault (CG) equation or eGFR (CKD-EPI CKD-Epidemiology Collaboration Equation). There was good agreement between CG and eGFR while determining the appropriateness of medications, with approximately 97% of the medications classified as appropriate by eGFR also being considered appropriate by the CG equation. This study highlights that PIP commonly occurs in primary care patients with CKD and the need for further research to understand why and how this can be minimised. The findings also show that the eGFR provides clinicians a potential alternative to the CG formula when estimating kidney function to guide drug appropriateness and dosing.
Publisher: Public Library of Science (PLoS)
Date: 30-08-2018
Publisher: Elsevier BV
Date: 30-05-2008
Publisher: Wiley
Date: 02-2010
DOI: 10.1002/ANA.21849
Publisher: Public Library of Science (PLoS)
Date: 05-03-2013
Publisher: Elsevier BV
Date: 06-2013
Publisher: S. Karger AG
Date: 11-10-2012
DOI: 10.1159/000341902
Abstract: A genetic contribution to susceptibility is well established in multiple sclerosis (MS) and 57 associated genetic loci have been identified. We have undertaken a meta-analysis of familial risk studies with the aims of providing definitive figures for risks to relatives, performing a segregation analysis and estimating the proportion of the overall genetic risk that currently identified genes represent. We have used standard methods of meta-analysis combined with novel approaches to age adjustment to provide directly comparable estimates of lifetime risk. The overall recurrence risk for monozygotic twins was 18.2% and for siblings 2.7%. The recurrence risk for dizygotic twins was significantly higher than for siblings. The overall estimate of sibling relative risk (λ sub S /sub ) was 16.8. Risks for older relatives (parents, siblings, aunts, uncles and cousins) show a latitudinal gradient, in line with population risk. No latitudinal gradient for λ sub S /sub was seen. Segregation analysis supports a multiplicative model of one locus of moderate effect with many loci of small effect. The estimated contribution of the 57 known MS loci is 18–24% of λ sub S /sub . This meta-analysis supports the notion of MS being in part the result of multiple genetic susceptibility factors and environmental factors.
Publisher: Wiley
Date: 03-07-2020
Abstract: To help prevent future morbidity and mortality, this study examined Australian Antarctic expeditioners' first aid credentials and self-efficacy in providing emergency first aid in extreme environments. A mixed method survey assessed Australian personnel working on Antarctic stations. Volunteer participants (n = 83) provided data on first aid training, self-confidence of first aid readiness, and first aid preparations. The Extreme Conditions First Aid Confidence Scale (EC-FACS) was developed and validated for this study. Multivariate analyses tested associations between first aid background, demographics and EC-FACS. Open-ended comments were subjected to thematic analysis. Over one-third of participants did not hold current first aid certificates at expedition commencement. Factor analysis demonstrated the EC-FACS was unidimensional, and internal consistency was high (α = 0.94), and showed first aid self-efficacy was moderately high, but participants' confidence decreased as first aid scenarios became more complex. Experience providing emergency first aid and level of first aid qualification were the strongest predictors of overall first aid self-efficacy. Thematic analysis revealed expeditioners support higher first aid qualifications and want Antarctic-specific wilderness first aid training. These findings revealed that many Antarctic expeditioners may not be adequately prepared for first aid emergencies and have low confidence in handling complex medical situations. Based on these findings, we recommend higher first aid qualifications and training tailored to the Antarctic context. These modest steps can help prevent unnecessary and costly morbidity and mortality for extreme-condition expeditioners.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JNS.2018.12.021
Abstract: To describe literature pertaining to urban-rural differences in both the quality of care and outcomes of acute stroke patients. We systematically searched CINAHL, PubMed, ProQuest Dissertations & Theses, and Scopus for published and unpublished literature until 9th December 2017. Studies were included if they compared the acute care provided to, or outcomes of, patients hospitalised for stroke in urban versus rural settings. Abstract, full-text review, and data extraction were conducted in duplicate. Findings are presented in the form of narrative syntheses. A total of 28 studies were included in the review (16 on care, 12 on outcomes). With few exceptions, studies addressing the provision of care suggested that rural patients have less access to most aspects of acute stroke care. Studies reporting urban-rural differences in patient outcomes were inconsistent in their findings, however, few of these studies were primarily focused on the issue of urban-rural disparities. Overall, study findings did not appear to differ in line with study quality ratings, stroke subtypes included, or how inter-facility patient transfers were accounted for. There is convincing, albeit not unanimous, evidence to suggest that stroke patients in rural areas receive less acute care than their urban counterparts. Despite this, the available data and methodology have largely not been used to study urban-rural differences in patient outcomes. PROSPERO registration information: URL: www.crd.york.ac.uk rospero. Unique identifier: CRD42017073262.
Publisher: Springer Science and Business Media LLC
Date: 10-2014
Publisher: American Diabetes Association
Date: 05-2006
DOI: 10.2337/DC05-2101
Abstract: OBJECTIVE—Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing. RESEARCH DESIGN AND METHODS—Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA−) (aged 30–75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a “LADA clinical risk score,” based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA. RESULTS—In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset & years (P & 0.0001), 2) acute symptoms (P & 0.0001), 3) BMI & kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score ≥2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score ≤1 of 99%. CONCLUSIONS—At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.
Publisher: Springer Science and Business Media LLC
Date: 18-06-2020
Publisher: BMJ
Date: 26-05-2017
Abstract: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.
Publisher: The Royal Australian College of General Practitioners
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 08-2011
DOI: 10.1038/NATURE10251
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1186/AR2027
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.MSARD.2019.101522
Abstract: The assessment of cognitive information processing speed (IPS) is complicated in MS, with altered performance on tests such as the Symbol Digit Modalities Test (SDMT) potentially representing changes not only within cognitive networks but in the initial sensorial transmission of information to cognitive networks, and/or efferent transmission of the motor response. We aimed to isolate and characterise cognitive IPS deficits in MS using ocular motor tasks a prosaccade task (used to assess and control for sensorial and motor IPS) which was then used to adjust performance on the Simon task (cognitive IPS). All participants (22 MS patients with early disease, 22 healthy controls) completed the ocular motor tasks and the SDMT. The Simon task assessed cognitive IPS by manipulating the relationship between a stimulus location and its associated response direction. Two trial types were interleaved: (1) congruent, where stimulus location = response direction or (2) incongruent, where stimulus location ≠ response direction. RESULTS MS patients did not perform differently to controls on the SDMT. For OM tasks, when sensorial and motor IPS was controlled, MS patients had significantly slower cognitive IPS (incongruent trials only) and poorer conflict resolution. SDMT performance did not correlate with slower cognitive IPS in MS patients, highlighting the limitation of using SDMT performance to interpret cognitive IPS changes in patients with MS. Cognitive IPS deficits in MS patients are dissociable from changes in other processing stages, manifesting as impaired conflict resolution between automatic and non-automatic processes. Importantly, these results raise concerns about the SDMT as an accurate measure of cognitive IPS in MS.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Elsevier BV
Date: 12-2007
Publisher: Elsevier BV
Date: 07-2021
Publisher: Wiley
Date: 15-09-2008
DOI: 10.1002/PROS.20798
Abstract: Examination of variants of the alpha-methylacyl-CoA racemase (AMACR) gene, as genetic contributors to prostate cancer risk, has been of considerable interest given the gene's recently established role as a diagnostic biomarker for prostate cancer. The AMACR gene variants, M9V and D175G, were genotyped in a familial dataset comprising 127 cases and in a second sporadic prostate cancer dataset comprising 414 cases and 319 controls. Genotype-disease associations were examined employing the M(QLS) test and unconditional logistic regression. Differences in allele frequencies were examined using the Fisher's exact test. Association between the AMACR haplotypes and prostate cancer risk was also investigated using haplo.score. Significant evidence for association with prostate cancer risk for both the M9V and D175G variants was observed in the Tasmanian prostate cancer dataset. Whilst this association remained significant, it was diminished when relatedness amongst the familial prostate cancer cases was considered. This study, performed in a relatively genetically homogenous Tasmanian population, provides further evidence for a significant association between variants within the AMACR gene and prostate cancer risk. Risk was found to be more significantly associated with AMACR gene variants in sporadic compared to familial prostate cancer cases. These findings again highlight that genetic heterogeneity in the study population should be considered when examining genetic risk factors in prostate cancer.
Publisher: Bristol University Press
Date: 04-2021
DOI: 10.1332/175795920X16000977636901
Abstract: Attrition is common in longitudinal studies and can lead to bias when the missingness pattern affects the distributions of analysed variables. Characterisation of factors predictive of attrition is vital to longitudinal research. Few studies have investigated the factors predictive of attrition from childhood cohorts with large-scale loss to follow-up. Methods to remove potential bias are available and have been well studied in scenarios of short intervening periods between contact and follow-up. Less is known about the performance of such techniques when there is a large initial loss of participants after a long intervening period. The Australian Schools Health and Fitness Survey (ASHFS) was conducted in 1985 when participants were school children aged 7–15 years. The first follow-up occurred 20 years later with substantial loss of participants: 80% were traced, 61% enrolled and provided brief questionnaire information, 47% provided more extensive questionnaire information and 28% attended clinics. Factors associated with attrition were examined and two common techniques, multiple imputation (MI) and inverse probability weighting (IPW) were used to determine the potential for correcting the bias in the estimate of the association between self-rated fitness and BMI in childhood. Attrition from childhood to adulthood was found to be influenced by the same factors that operate in adult cohorts: lower education, lower socio-economic position and male sex. Attrition patterns varied by the stage of follow-up. Estimated childhood associations biased by adulthood attrition were able to be corrected using MI, but IPW was unsuccessful due to a lack of completely observed informative variables.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2010
DOI: 10.1007/S00439-010-0821-8
Abstract: Leber hereditary optic neuropathy (LHON) is the most common mitochondrially inherited disease causing blindness, preferentially in young adult males. Most of the patients carry the G11778A mitochondrial DNA (mtDNA) mutation. However, the marked incomplete penetrance and the gender bias indicate some additional genetic and/or environmental factors to disease expression. Herein, we first conducted a genome-wide linkage scan with 400 microsatellite markers in 9 large Thai LHON G11778A pedigrees. Using an affecteds-only nonparametric linkage analysis, 4 regions on chromosomes 3, 12, 13 and 18 showed Zlr scores greater than 2 (P 2 in 10 of 16 allele sharing models tested) was then expanded to include the region 3q26.2-3q28 covering SLC7A14 (3q26.2), MFN1 (3q26.32), MRPL47 (3q26.33), MCCC1 (3q27.1), PARL (3q27.1) and OPA1 (3q28-q29). All of these candidate genes were selected from the Maestro database and had known to be localized in mitochondria. Sixty tag SNPs were genotyped in 86 cases, 211 of their relatives and 32 unrelated Thai controls, by multiplex-PCR-based Invader assay. Analyses using a powerful association testing tool that adjusts for relatedness (the M(QLS) statistic) showed the most evidence of association between two SNPs, rs3749446 and rs1402000 (located in PARL presenilins-associated rhomboid-like) and LHON expression (both P = 8.8 x 10(-5)). The mitochondrial PARL protease has been recently known to play a role with a dynamin-related OPA1 protein in preventing apoptotic events by slowing down the release of cytochrome c out of mitochondrial cristae junctions. Moreover, PARL is required to activate the intramembranous proteolyses resulting in the degradation of an accumulated pro-apoptotic protein in the outer mitochondrial membrane. Under these circumstances, variants of PARL are suggested to influence cell death by apoptosis which has long been believed to intrigue the neurodegeneration of LHON.
Publisher: Public Library of Science (PLoS)
Date: 11-08-2010
Publisher: FapUNIFESP (SciELO)
Date: 03-2010
Publisher: The Royal Australian College of General Practitioners
Date: 03-2019
Publisher: Springer Science and Business Media LLC
Date: 02-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-08-2008
DOI: 10.1212/01.WNL.0000323928.57408.93
Abstract: Low past sun exposure, fair skin type, and polymorphisms of the MC1R gene have been associated with multiple sclerosis (MS) risk. We aimed to investigate the interplay between melanocortin 1 receptor gene variants, red hair/fair skin phenotype, and past environmental sun exposure in MS. Population-based case-control study in Tasmania, Australia, involving 136 cases with MS and 272 controls randomly drawn from the community and matched on sex and year of birth. Measures included past sun exposure by calendar and questionnaire, spectrophotometric skin type, and MC1R genotype, with any MC1R Arg151Cys, Arg160Trp, or Asp294His alleles present denoted as red hair color (RHC) variant. The association between RHC variant genotype and MS was more evident for women (odds ratio 2.02 [1.15-3.54]) than for men (odds ratio 0.65 [0.27-1.57]) (difference in effect, p = 0.03). The RHC variant genotype was associated with behavioral sun avoidance. In addition, increasing summer sun exposure at ages 6 through 10 years was associated with reduced MS risk among those with no RHC variant (p = 0.03), but not among those with RHC variant genotype (p = 0.15 difference in effect, p = 0.02). Similar findings were evident for other past sun exposure measures and when the s le was restricted to women only. The interplay between red hair color variant genotype, red hair/fair skin phenotype, and multiple sclerosis (MS) is complex. The modification of past sun exposure by MC1R genotype provides further support that ultraviolet radiation or derivatives such as vitamin D may be causally related to a reduced MS risk.
Publisher: Wiley
Date: 08-2010
DOI: 10.1111/J.1365-2141.2010.08267.X
Abstract: A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected in iduals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P 53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0.009).
Publisher: Springer Science and Business Media LLC
Date: 19-03-2008
Publisher: SAGE Publications
Date: 08-10-2022
DOI: 10.1177/13524585211049986
Abstract: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
Publisher: SAGE Publications
Date: 2021
Abstract: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. Natalizumab is highly effective for the treatment of relapsing–remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment. Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia ( n = 865) and 11 MS treatment centres in Brazil ( n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion. From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1% 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7% 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk [adjusted hazard ratio 2.09 (95% confidence interval 1.17–3.71) p = 0.012]. In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-2007
DOI: 10.1167/IOVS.06-1188
Abstract: Myopia is a common disorder with a large public health impact. Although 12 myopia loci have been reported and heterogeneity for high myopia loci have been demonstrated, replication of high-myopia loci with a common myopia phenotype has not been successful. This study reports the successful replication of MYP12 in three large, multigenerational families with autosomal dominant (AD) common myopia (spherical equivalent [SphE] </= -0.50 D). These families contained 49 participants (35 affected). The average spherical equivalent was -2.76 D (range, -0.50 to -10.25 D), average axial length was 24.52 mm (range, 23.05-27.11 mm), and average keratometry was 43.21 D (range, 39.12-47.31 D). Only five in iduals in the three families presented with myopia of SphE </= -6.00 D. Glaucoma, keratoconus, lenticonus, and dislocated lens were not present in any study participants. A genomewide scan was performed using a mapping set with 400 markers at approximately 10 cM coverage. Merlin software was used for multipoint linkage analysis based on an AD model with a penetrance of 0.9 and disease allele frequency of 0.013. Significant linkage with a multipoint parametric LOD score of 3.428 (P = 0.000035) and a multipoint nonparametric (Kong and Cox) LOD score of 2.37 (empiric P < 0.001) was obtained on 2q37.1, with a 1-LOD support interval that overlapped the previously reported MYP12 locus for high myopia. This study provided evidence that some high-myopia loci may contribute to all degrees of myopia and indicated the likely location of a myopia gene for the low/moderate as well as the high form of myopia.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.IENJ.2017.09.001
Abstract: Emergency department crowding and associated adverse outcomes are major issues in health care systems worldwide. The Australian government has highlighted the need to analyse emergency presentations to inform system redesign. To describe the profile of emergency department presentations by Tasmanian residents to emergency departments over four years, and examine regional variations. A retrospective analysis of emergency department data for Tasmania's public hospitals over four financial years, 2010-11 to 2013-14, was undertaken. Descriptive statistics were used to identify patterns in Tasmanian state-wide emergency presentations, as well as disparities between Tasmania's three regions (South, North and North-West). Regression analysis was undertaken to test if changes were significant. State-wide presentations increased by 3.4% (139,352-144,130) over the four years. Regional variations included an increase in presentations of 16% in the South, 5.1% in the North and a decrease of 3.9% in the North-West. Per capita presentations were consistently lowest in the South and highest in the North-West. The South recorded a significant increase in per capita presentations of those aged 75 and over (p=0.001), increasing at a rate of 12.5 per 1000 residents per annum (95% CI 5.8-19.2). There is regional variation in emergency demand and utilisation in Tasmania. The results indicate that recent increases are predominantly occurring in the South, including in the elderly, and the reasons for this warrant further investigation.
Publisher: FapUNIFESP (SciELO)
Date: 03-2007
DOI: 10.1590/S1415-65552007000100006
Abstract: Este artigo busca identificar e entender as influências do ambiente no processo de inovação de produtos e propor um modo de classificar estas diferentes formas de influências. A inovação em produtos requer capacidades tecnológicas e estas resultam de processos de aprendizagem. Contrastando as perspectivas que tratam de processos internos de aprendizagem, este artigo enfoca estímulos externos que impulsionam e sustentam esses processos. A principal contribuição consiste na classificação de diferentes tipos de estímulos externos, que podem ser atribuídos a três categorias: o ambiente operacional, o ambiente institucional e o ambiente corporativo da subsidiária. Da combinação desses ambientes resulta uma tipologia com oito categorias, as quais serão ilustradas, usando evidências empíricas de subsidiárias localizadas no Brasil. Como segunda contribuição deste estudo, será explorada a possibilidade de reforço mútuo dos estímulos desses três ambientes. Quando houver uma combinação sinérgica entre eles, mais sustentáveis serão as atividades inovadoras da subsidiária ao longo do tempo. Nesse sentido, a análise de mudanças nos três ambientes pode explicar por que as atividades inovadoras da subsidiária têm sido reduzidas, eliminadas ou liadas.
Publisher: Oxford University Press (OUP)
Date: 30-11-2022
Abstract: Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1,813 in iduals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β=-0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273 βfemale =0.8289, P = 3.52 × 10-08), the other in males (rs698805 βmale = -1.5395, P = 4.35 × 10-08), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in central nervous system compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and g-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.
Publisher: Cold Spring Harbor Laboratory
Date: 06-02-2022
DOI: 10.1101/2022.02.04.22270362
Abstract: Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international MS Registry, MSBase. We assembled a cohort of deeply phenotyped in iduals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 in iduals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 – 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.
Publisher: Oxford University Press (OUP)
Date: 04-2002
Abstract: Recent advances have enabled quite accurate estimation by spectrophotometry of the density of cutaneous melanin. The relation between skin cancers and this objective measure of skin phenotype is examined here. For this purpose, a population-based case-control study of subjects aged 20-59 years of northern European ancestry was conducted in Tasmania, Australia. Cases (n = 244) of cutaneous malignant melanoma during 1998-1999, and a s le of cases of basal cell carcinoma (n = 220) and squamous cell carcinoma (n = 195) of the skin were identified from cancer registrations. Controls (n = 483) were selected from a comprehensive population listing. Melanin at the upper inner arm was estimated from skin reflectance of light of 400 and 420 nm wavelengths. For melanoma, basal cell carcinoma, and squamous cell carcinoma, respectively, the odds ratios comparing the least with the highest of four melanin categories were 6.2 (95% confidence interval (CI): 2.3, 16.6), 6.3 (95% CI: 2.6, 15.1), and 4.2 (95% CI: 1.7, 10.8) for men and 1.9 (95% CI: 1.0, 3.7), 1.4 (95% CI: 0.7, 3.0), and 0.7 (95% CI: 0.3, 1.7) for women. The gender differences were not due to disparities in site of occurrence or (for melanoma) in thickness of the lesion. The authors conclude that, particularly for men, cutaneous melanin density at the upper inner arm is a strong predictor of risk of skin cancer.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JSTROKECEREBROVASDIS.2017.09.055
Abstract: Aneurysmal subarachnoid hemorrhage (aSAH) incidence is not well studied. Varied definitions of "subarachnoid hemorrhage" have led to a lack of clarity regarding aSAH incidence. The impact of area-level socioeconomic disadvantage and geographical location on the incidence of aSAH also remains unclear. Using a population-based statewide study, we examined the incidence of aSAH in relation to socioeconomic disadvantage and geographical location. A retrospective cohort study of nontraumatic subarachnoid hemorrhages from 2010 to 2014 was undertaken. Researchers manually collected data from multiple overlapping sources including statewide administrative databases, in idual digital medical records, and death registers. Age-standardized rates (ASRs) per 100,000 person years were calculated using the 2001 Australian population. Differences in incidence rate ratios were calculated by age, sex, area-level socioeconomic status, and geographical location using Poisson regression. The cohort of 237 cases (mean age, 61.0 years) with a female predominance of 166 (70.04%) included 159 confirmed aSAH, 52 community-based deaths, and 26 probable cases. The ASR for aSAH was 9.99 (95% confidence interval [CI], 8.69-11.29). A significant association between area-level socioeconomic disadvantage and incidence was observed, with the rate of aSAH in disadvantaged geographical areas being 1.40 times higher than that in advantaged areas (95% CI, 1.11-1.82 P = .012). This study uses a comprehensive search of multiple data sources to define a new baseline of aSAH within an Australian population. This study presents a higher incidence rate of aSAH with socioeconomic variations. As a key risk factor that may explain this paradox, addressing socioeconomic inequalities is important for effective prevention and management interventions.
Publisher: Public Library of Science (PLoS)
Date: 08-02-2011
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 10-1997
Abstract: We explore the influence of electrolyte concentration on the adsorption of charged spheres using modeling techniques based on random sequential adsorption (RSA). We present a parametric study of the effects of double layer interactions between the charged particles and between the particle and the substrate on the jamming limit using a two-dimensional RSA simulation similar to that of Z. Adamczyk et al. (1990, J. Colloid Interface Sci. 140, 123) along with a simple method of estimating jamming limit coverages. In addition, we present a more realistic RSA algorithm that includes explicit energetic interaction in three dimensions, that is, particle-particle and particle-surface interactions during the approach of a particle to the substrate. The calculation of interaction energies in the 3-D RSA model is achieved with the aid of a three-body superposition approximation. The 3-D RSA model differs from the 2-D model in that the extent of coverage is controlled by kinetic rather than energetic considerations. Results of both models capture the experimentally observed trend of increased surface coverage with increased electrolyte concentration, and both models require the value of a key model parameter to be specified for a quantitative match to experimental data. However, the 3-D model more effectively captures the governing physics, and the parameter in this case takes on more meaningful values than for the 2-D model. Copyright 1997 Academic Press. Copyright 1997Academic Press
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: Springer Science and Business Media LLC
Date: 02-2010
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 10-02-2023
DOI: 10.1186/S13148-023-01438-4
Abstract: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS. We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5–44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4 + and eight in CD8 + T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women. Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential ‘CNS signature’ of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S0378-5122(03)00151-8
Abstract: To describe the association of reproductive and hormonal factors with the presence and severity of hand osteoarthritis (OA) in Tasmanian women. Cross-sectional study of 348 women from 76 families. A structured questionnaire collected information regarding reproductive history and the use of estrogen containing medications. Hand OA was assessed by two observers using the Altman atlas for joint space narrowing and osteophytes at distal interphalangeal (DIP) and carpometacarpal (CMC) joints, as well as Heberden's nodes (HN) based on hand photography. The prevalence of hand OA was high in this s le at 65-70%. Parity, increasing age at menopause and years of menstruation were associated with both symptomatic hand OA and a more severe DIP score (but not presence of radiographic disease) while both current and ever use of hormone replacement therapy (HRT) were significantly associated with increased prevalence of HN and severity of HN and DIP OA (all P<0.05). HRT usage less than 5 years was associated with increased severity of both DIP disease and HN. No factors were associated with CMC disease apart from ever breast-feeding which was protective (OR 0.37, 95% CI 0.18-0.79). These results require confirmation in clinical trials or carefully controlled longitudinal studies but suggest that estrogen exposure around the time of disease onset (either endogenous or exogenous) may have a "priming" effect on the severity of DIP OA while breast-feeding in earlier life may be protective for CMC OA.
Publisher: Wiley
Date: 09-2005
DOI: 10.1002/ART.21267
Abstract: To estimate the heritability of longitudinal changes in knee cartilage volume, chondral defects, subchondral bone size, and lower limb muscle strength. A sibpair design was used. Longitudinal changes in lateral and medial tibial cartilage volume and bone size, as well as progression of chondral defects, were determined on serial magnetic resonance images. Radiographs were obtained and scored for in idual features of radiographic osteoarthritis (OA) at baseline. Lower limb muscle strength was measured by dynamometry. Heritability was estimated using the SOLAR software package. A total of 115 subjects (55 men and 60 women, mean age 45 years) from 48 families representing 95 sibling pairs were successfully followed up for a mean of 2.4 years. The adjusted heritability estimates for changes in cartilage volume were 73% for the medial compartment (P < 0.01) and 40% for the lateral compartment (P = 0.10). The adjusted heritability estimates for changes in bone size were 62% for the lateral compartment (P = 0.03) and 20% for the medial compartment (P = 0.22). The adjusted heritability estimate for changes in muscle strength was 64% (P = 0.01). The adjusted heritability estimates for progression of chondral defects were 80% for the lateral compartment (P = 0.06) and 98% for the medial compartment (P = 0.03). These estimates changed little after adjusting for each other and for the predominantly mild radiographic OA, with the exception of progression of chondral defects in the lateral compartment. Early longitudinal changes in knee structures of relevance to later OA, such as changes in medial tibial cartilage volume, lateral tibial bone size, progression of chondral defects, and muscle strength, have high heritability, most likely reflecting a strong genetic component and suggesting their potential to be studied in quantitative trait linkage and association analysis.
Publisher: Oxford University Press (OUP)
Date: 13-11-2013
DOI: 10.1093/HMG/DDT574
Abstract: Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within in iduals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control in iduals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.
Publisher: Public Library of Science (PLoS)
Date: 12-2010
Publisher: Springer Science and Business Media LLC
Date: 12-2022
DOI: 10.1186/S13148-022-01397-2
Abstract: The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene–environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker. We conducted an epigenome-wide association study between 235 females with mild ( n = 119) or severe ( n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis using ToppGene . We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance. Females with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity. RMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.
Publisher: Elsevier BV
Date: 10-2022
Publisher: SAGE Publications
Date: 31-10-2020
Abstract: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis. Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data ( The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.
Publisher: Elsevier BV
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 02-11-2017
DOI: 10.1038/HGV.2017.41
Publisher: Springer Science and Business Media LLC
Date: 27-09-2002
Abstract: Syndrome X (clustering of insulin resistance, dyslipidaemia and hypertension) in adults with central obesity has been suggested to be a consequence of poor foetal development. We investigated clustering of syndrome X factors in a s le of 8-y-old Australian children, and whether the clusters were associated with size at birth and childhood obesity. Longitudinal, 1997 follow-up of children enrolled as singleton-born neonates in 1989. A total of 298 healthy Australian children (208 boys, 90 girls, age range 7.4-8.9 y). Anthropometry at birth and at 4 weeks. In 1997, at 8 y of age: fasting insulin and glucose, total and HDL-cholesterol, triglycerides and blood pressure. Adverse levels of insulin and glucose, cholesterol and triglycerides co-existed more often than expected by chance (P<0.01). Three factors were identified in factor analysis: one loading on systolic and diastolic blood pressure ('blood pressure') a second loading on insulin and glucose ('insulin resistance') and a third loading negatively on HDL-cholesterol and positively on triglycerides ('dyslipidaemia'). The blood pressure factor was correlated with fatness at age 8 y (eg fat mass estimated from skin folds, r=0.11) and, after adjustment for current size, with birth weight (r=-0.15). Fat mass was also correlated with both 'insulin resistance' (r=0.24) and 'dyslipidaemia' (r=0.19). The increase in 'insulin resistance' (P=0.03) and 'dyslipidaemia' (P<0.01) per category of fat mass was greatest for subjects with higher-than-median subscapular-to-triceps ratio of skin folds. Neither 'insulin resistance' nor 'dyslipidaemia' was associated with anthropometry at birth. The Syndrome X risk variables clustered among children who had a tendency to deposit fat on the trunk. There was no evidence in this s le that infant size predicts development of the insulin resistance or dyslipidaemic components of the syndrome by age 8.
Publisher: Mary Ann Liebert Inc
Date: 12-2001
Publisher: Emerald
Date: 05-09-2008
DOI: 10.1108/00251740810901381
Abstract: The main purpose of this article is to identify some emergent issues when sustainability is introduced into global value chains. These issues deal with the conditions under which a sustainable global value chain might gain international competitiveness. An exploratory research was conducted, based on a case study. The main players of the JOBEK's Global Value Chain were identified and interviews were carried out with representatives of these players. A thematic content analysis was developed, supported by Atlas TI software, using interview data and documents. Three main themes have emerged, which can be considered as underlying issues of an emerging concept that the authors call the “sustainable global value chain”. These are: bargaining power between the chain's players a differentiation strategy along the global value chain and a collaborative awareness‐building process along the global value chain. Although the findings result from a single case study, the characteristics of this case have allowed the authors to suggest an emergent concept for the field of international business: the concept of a sustainable global value chain. This has implications for the development of a new research field and for the introduction of some ethical concerns into this field. Managers of organizations that participate in sustainable global value chains may consider the emerging concepts and their interrelationships as a guideline for strategic decision‐making. In particular, managers need to be aware of how the relationships between power balance, CSR product differentiation strategies and awareness building may influence the competitiveness of their sustainable global value chain. The article proposes the emergence of a new concept that has important ethical implications for international business: the sustainable global value chain. The authors suggest that the further development of this new concept is likely to stimulate the development of an emergent research field.
Publisher: Oxford University Press (OUP)
Date: 28-11-2012
DOI: 10.1093/HMG/DDS491
Publisher: Oxford University Press (OUP)
Date: 12-02-2013
DOI: 10.1093/HMG/DDT062
Abstract: Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in in iduals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 s les and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10(-11), OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools this result has important implications for the design of future fine-mapping studies.
Publisher: Informa UK Limited
Date: 03-04-2015
Publisher: BMJ
Date: 03-2020
DOI: 10.1136/BMJOPEN-2019-032567
Abstract: To investigate whether sex, age, medical specialty and seasonal variations in serum concentration of 25-hydroxy vitamin D (25(OH)D) are evident among an Australian patient population. Retrospective study analysing the results of serum 25(OH)D lab tests and vitamin D supplementation from Royal Melbourne Hospital (RMH) between 2014 and 2017. Tertiary healthcare centre in Victoria, Australia. 30 023 patients (inpatient and outpatient) who had their serum 25(OH)D levels measured at RMH between 2014 and 2017. Serum 25(OH)D levels stratified according to patients’ sex, age and medical specialty admitted to, as well as the season and year (2014 to 2017) 25(OH)D level was measured. Mean serum 25(OH)D level of study population was 69.9 nmol/L (95% CI 69.5 to 70.2). Only 40.2% patients in this cohort were sufficient in vitamin D ( nmol/L). On average, 25(OH)D levels in male patients were 6.1 units (95% CI 5.4 to 6.9) lower than in females. Linear regression analysis found that 25(OH)D levels increased by 0.16 unit (95% CI 0.14 to 0.18) for every year increase in age. One-way analysis of variance showed patients from neurology had the highest average 25(OH)D level, 76.8 nmol/L (95% CI 74.2 to 79.3) compared with other medical specialties. Mean 25(OH)D level during winter, 64.9 nmol/L (95% CI 64.2 to 65.6) was significantly lower compared with other seasons despite supplementation. Average 25(OH)D level measured in 2014, 71.5 nmol/L (95 CI% 70.8 to 72.2) was significantly higher than levels measured in 2016–2017. There is a sex, age, medical specialty, seasonal and yearly variation in vitamin D status in an Australian patient population. The association between low vitamin D status and winter despite supplementation suggests other interventions are required to boost serum 25(OH)D levels.
Publisher: BMJ
Date: 07-05-2011
Abstract: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia. Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15° of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (λ(s)) was similar across all sites. The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture.
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1086/379381
Abstract: Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-11-2021
DOI: 10.1212/WNL.0000000000012850
Abstract: Longitudinal cognitive trajectories in multiple sclerosis are heterogeneous and difficult to measure. We aimed to identify discrete longitudinal reaction time trajectories in relapsing-remitting multiple sclerosis using a computerized cognitive battery and to assess the association between trajectories of reaction time and disability progression. All participants serially completed computerized reaction time tasks measuring psychomotor speed, visual attention, and working memory. Participants completed at least 3 testing sessions over a minimum of 180 days. Longitudinal reaction times were modeled with latent class mixed models to identify groups of in iduals sharing similar latent characteristics. Optimal models were validated for consistency and baseline associations with class membership tested using multinomial logistic regression. Interclass differences in the probability of reaction time worsening and the probability of 6-month confirmed disability progression were assessed with survival analysis. A total of 460 people with relapsing-remitting multiple sclerosis were included in the analysis. For each task of the MSReactor battery, the optimal model comprised 3 latent classes. All MSReactor tasks could identify a group with high probability of reaction time slowing. The visual attention and working memory tasks could identify a group of participants who were 3.7 and 2.6 times more likely to experience a 6-month confirmed disability progression, respectively. Participants could be classified into predicted cognitive trajectories after just 5 tests with 64% to 89% accuracy. Latent class modeling of longitudinal cognitive data collected by a computerized battery identified patients with worsening reaction times and increased risk of disability progression. Slower baseline reaction time, age, and disability increased assignment into this trajectory. Monitoring of cognition in clinical practice with computerized tests may enable detection of cognitive change trajectories and people with relapsing-remitting multiple sclerosis at risk of disability progression.
Location: Australia
Start Date: 2011
End Date: 2011
Funder: Royal Hobart Hospital Research Foundation
View Funded ActivityStart Date: 2010
End Date: 2010
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2009
End Date: 2009
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2008
End Date: 2008
Funder: Cancer Council of Tasmania
View Funded ActivityStart Date: 2008
End Date: 2008
Funder: Royal Hobart Hospital Research Foundation
View Funded ActivityStart Date: 2007
End Date: 2009
Funder: Australian Research Council
View Funded Activity