Background: Transition probabilities are the engine within many health economics decision models. However, the probabilities of progression of disability due to multiple sclerosis (MS) have not previously been estimated in Australia. Objectives: To estimate annual probabilities of changing disability levels in Australians with relapsing-remitting MS (RRMS). Methods: Combining data from Ausimmune/Ausimmune Longitudinal (2003–2011) and Tasmanian MS Longitudinal (2002–2005) studies ( n = 330), annual transition probabilities were obtained between no/mild (Expanded Disability Status Scale (EDSS) levels 0–3.5), moderate (EDSS 4–6.0) and severe (EDSS 6.5–9.5) disability. Results: From no/mild disability, 6.4% (95% confidence interval (CI): 4.7–8.4) and 0.1% (0.0–0.2) progressed to moderate and severe disability annually, respectively. From moderate disability, 6.9% (1.0–11.4) improved (to no/mild state) and 2.6% (1.1–4.5) worsened. From severe disability, 0.0% improved to moderate and no/mild disability. Male sex, age at onset, longer disease duration, not using immunotherapies greater than 3 months and a history of relapse were related to higher probabilities of worsening. Conclusion: We have estimated probabilities of changing disability levels in Australians with RRMS. Probabilities differed between various subgroups, but due to small sample sizes, results should be interpreted with caution. Our findings will be helpful in predicting long-term disease outcomes and in health economic evaluations of MS.

Aim: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). Methods: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. Results: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11–4.03), 4.31 (95% CI, 2.24–8.31), 7.96 (95% CI, 3.84–16.49), and 21.24 (95% CI, 5.48–82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9–91.4) of FCD onset. High anti-EBNA IgG was another important contributor. Conclusions: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre casecontrol study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n=282) were aged 1859 years; controls (n=558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR)=3 center dot 11; 95% confidence interval (CI) 1 center dot 11, 8 center dot 71]. Having any younger siblings showed reduced odds of FCD (OR=0 center dot 68; 95% CI: 0 center dot 49, 0 center dot 95) but not asthma (OR=1 center dot 47; 95% CI: 0 center dot 91, 2 center dot 38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend=0 center dot 04) but not FCD (P trend=0 center dot 66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative sibling effect'.

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 sampling 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'.

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003-2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25; also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered.

Introduction: Lifestyle factors prior to a first clinical demyelinating event (FCD), a disorder often preceding the development of clinically definite multiple sclerosis (MS), have not previously been examined in detail. Past tobacco smoking has been consistently associated with MS. Methods: This was a multicentre incident case-control study. Cases ( n = 282) were aged 18–59 years with an FCD and resident within one of four Australian centres (from latitudes 27°S to 43°S), from 1 November 2003 to 31 December 2006. Controls ( n = 558) were matched to cases on age, sex and study region, without CNS demyelination. Exposures measured included current and past tobacco and marijuana, alcohol and beverage use, physical activity patterns, blood pressure and physical anthropometry. Results: A history of smoking ever was associated with FCD risk (AOR 1.89 (95%CL 1.82, 3.52)). Marijuana use was not associated with FCD risk after adjusting for confounders such as smoking ever but the estimates were imprecise because of a low prevalence of use. Alcohol consumption was common and not associated with FCD risk. No case-control differences in blood pressure or physical anthropometry were observed. Conclusions: Past tobacco smoking was positively associated with a risk of FCD but most other lifestyle factors were not. Prevention efforts against type 2 diabetes and cardiovascular disease by increasing physical activity and reducing obesity are unlikely to alter MS incidence, and more targeted campaigns will be required.

INTRODUCTION:Multiple sclerosis (MS) is a debilitating disease that causes significant morbidity within a young demographic. Diagnostic guidelines for MS have evolved, and imaging has played an increasingly important role in diagnosis over the last two decades. For imaging to contribute to diagnosis in a meaningful way, it must be reproducible. Consensus guidelines for MRI in MS exist to define correct sequence type and imaging technique, but it is not clear to what extent they are followed. This study reviewed MRI studies performed on Australian individuals presenting with a first clinical diagnosis of central nervous system demyelination (FCD) for adherence to published guidelines and discussed practical implementation of MS guidelines in light of recent updates.METHODS:The Ausimmune study was a prospective case control study of Australian participants presenting with FCD from 2003 to 2006. Baseline cranial and spinal cord MRI studies of 226 case participants from four separate Australian regions were reviewed. MRI sequences were classified according to anatomical location, slice plane, tissue weighting and use of gadolinium-containing contrast media. Results were compared with the 2003 Consortium of Multiple Sclerosis Centres MRI protocol for the diagnosis of MS.RESULTS:The composition of core cranial MRI sequences performed varied across the 226 scans. Of the studies, 91% included sagittal fluid attenuated inversion recovery (FLAIR) sequences. Cranial axial T2-weighted, axial FLAIR and axial proton density-weighted sequences were performed in 88%, 60% and 16% (respectively) of scans. Only 25% of the studies included a T1-weighted contrast-enhanced sequence. Concordance with the guidelines in all sequences was very low (2).CONCLUSION:Only a small number of MRI investigations performed included all of the sequences stipulated by consensus guidelines. This is likely due to poor awareness in the imaging community of the guidelines and the rationale behind certain sequences. Radiologists with a sub-speciality interest in neuroradiology should take ownership of this issue and ensure that recommended imaging guidelines are followed.

To cite this article: Hughes AM, Lucas RM, Ponsonby A‐L, Chapman C, Coulthard A, Dear K, Dwyer T, Kilpatrick TJ, McMichael AJ, Pender MP, Taylor BV, Valery P, van der Mei IAF, Williams D. The role of latitude, ultraviolet radiation exposure and vitamin D in childhood asthma and hayfever: an Australian multicenter study. Pediatr Allergy Immunol 2011; 22 : 327–333. Abstract Observations of increasing allergy prevalence with decreasing distance from the Equator and positive associations with ambient ultraviolet radiation have contributed to a growing interest in the possible role of vitamin D in the etiology of allergy. The aims of this study were to describe any latitudinal variation in the prevalence of childhood allergy in Australia and to evaluate, in parallel, the individual associations between ultraviolet radiation (UVR)‐ and vitamin D‐related measures and hayfever asthma and both conditions. Participants were population‐based controls who took part in a multicenter case–control study, aged 18–61 yr and resident in one of four study regions ranging in latitude from 27°S to 43°S. Data were derived from a self‐administered questionnaire, interview and examination by a research officer and biologic sampling. Latitude and longitude coordinates were geocoded from participants’ residential locations and climatic data were linked to postcodes of current residence. Stored serum was analyzed for 25‐hydroxyvitamin D concentrations and silicone rubber casts of the skin were used as an objective measure of cumulative actinic damage. There was an inverse latitude gradient for asthma (a 9% decrease per increasing degree of latitude); however, this pattern did not persist after adjusting for average daily temperature. There was no association between any of the UVR‐ or vitamin D‐related measures and childhood asthma, but greater time in the sun in winter between the ages 6–15 yr was associated with an increase in the odds of having hayfever [adjusted odds ratios (OR) 1.29; 95% CI 1.01–1.63]. Oral supplementation with cod liver oil in childhood increased the odds of a history of having both asthma and hayfever (2.87; 1.00–8.32). Further investigation of the possible role of early vitamin D supplementation in the development of allergy is warranted. Our results also suggest that solar exposure during childhood may be important in allergic sensitization. Plausible explanations, including biologic mechanisms, exist for both observations.

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 samples. 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.

Increasing prevalence and variable geographic patterns of occurrence of multiple sclerosis suggest an environmental role in causation. There are few descriptive, population-level, data on whether such variability applies to first demyelinating events (FDEs). We recruited 216 adults (18-59 years), with a FDE between 1 November 2003 and 31 December 2006 in a multi-center incident case-control study in four locations on the south-eastern and eastern seaboard of Australia, spanning latitudes 27 degrees south to 43 degrees south. Population denominators were obtained from the Australian Bureau of Statistics censuses of 2001 and 2006. Age and sex adjusted FDE incidence rates increased by 9.55% (95% confidence interval (CI) 7.37-11.78, p<0.001) per higher degree of latitude. The incidence rate gradient per higher degree of latitude varied by gender (male: 14.69% (95% CI 9.68-19.94, p<0.001); female 8.13% (95% CI 5.69-10.62, p<0.001)); and also by the presenting FDE type: optic neuritis 11.39% (95% CI 7.15-15.80, p<0.001); brainstem/cerebellar syndrome 9.47% (95% CI 5.18-13.93, p<0.001); and spinal cord syndrome 5.36% (95% CI 1.78-9.06, p = 0.003). Differences in incidence rate gradients were statistically significant between males and females (p = 0.02) and between optic neuritis and spinal cord syndrome (p = 0.04). The male to female ratio varied from 1 : 6.7 at 27 degrees south to 1 : 2.5 at 43 degrees south. The study establishes a positive latitudinal gradient of FDE incidence in Australia. The latitude-related factor(s) influences FDE incidence variably according to subtype and gender, with the strongest influence on optic neuritis presentations and for males. These descriptive case analyses show intriguing patterns that could be important for understanding the etiology of multiple sclerosis.

Background: The clinical diagnosis of encephalitis is often difficult and identification of a causative organism is infrequent. The encephalitis syndrome may herald the emergence of novel pathogens with outbreak potential. Individual treatment and an effective public health response rely on identifying a specific pathogen. In Australia there have been no studies to try to improve the identification rate of encephalitis pathogens. This study aims to review the diagnostic assessment of adult suspected encephalitis cases.Methods: A retrospective clinical audit was performed, of all adult encephalitis presentations between July 1998 and December 2007 to the three hospitals with adult neurological services in the Hunter New England area, northern New South Wales, Australia. Case notes were examined for evidence of relevant history taking, clinical features, physical examination, laboratory and neuroradiology investigations, and outcomes.Results: A total of 74 cases were included in the case series. Amongst suspected encephalitis cases, presenting symptoms and signs included fever (77.0%), headache (62.1%), altered consciousness (63.5%), lethargy (32.4%), seizures (25.7%), focal neurological deficits (31.1%) and photophobia (17.6%). The most common diagnostic laboratory test performed was cerebrospinal fluid (CSF) analysis (n = 67, 91%). Herpes virus polymerase chain reaction (n = 53, 71.6%) and cryptococcal antigen (n = 46, 62.2%) were the antigenic tests most regularly performed on CSF. Neuroradiological procedures employed were computerized tomographic brain scanning (n = 68, 91.9%) and magnetic resonance imaging of the brain (n = 35, 47.3%). Thirty-five patients (47.3%) had electroencephalograms. The treating clinicians suspected a specific causative organism in 14/74 cases (18.9%), of which nine (12.1%) were confirmed by laboratory testing.Conclusions: The diagnostic assessment of patients with suspected encephalitis was not standardised. Appropriate assessment is necessary to exclude treatable agents and identify pathogens warranting public health interventions, such as those transmitted by mosquitoes and those that are vaccine preventable. An algorithm and guidelines for the diagnostic workup of encephalitis cases would assist in optimising laboratory testing so that clinical management can be best tailored to the pathogen, and appropriate public health measures implemented.

BackgroundSeveral lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls.Methodology/principal findingsWe have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5).Conclusions/significanceOur analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.

Background: Previous work has shown high levels of anti-Epstein Barr Virus (EBV) antibodies in individuals with multiple sclerosis (MS).Objectives: To examine history of glandular fever, anti-EBV antibody profile and whole blood viral load at first clinical diagnosis of central nervous system demyelination (FCD), compared to community controls. Methods: The Australian Multicentre Study of Environment and Immune Function (Ausimmune Study) recruited FCD cases and unaffected controls matched on age (18–59 years), sex and study region, between 1 November 2003 and 31 December 2006. Data included history of glandular fever (yes/no), serum IgG antibody titres for EBNA complex, viral capsid antigen (VCA) and early antigen (EA), and whole blood quantitative EBV DNA viral load (measured using real-time polymerase chain reaction [PCR], primers and probe derived from BamH1 of the EBV genome and Namalwa cell line with 2 EBV copies per cell for the standard curve) expressed as EBV copies per ug of DNA. Conditional logistic regression was used to analyse case-control differences. Results: Past history of glandular fever (n=277 cases, n=538 controls) was associated with increased odds of being a FCD case (OR=1.87, 95% confidence interval [CI] 1.30–2.67). In a subsample (n=204 cases, n=210 controls), higher titres (log2) of anti-EBNA (OR=1.26, 95% CI 1.13–1.40), anti-VCA (OR=1.16, 95% CI 1.03– .32) and anti-EA-restricted (OR=1.16, 95% CI 1.04–1.29) but not anti-EAdiffuse (OR=1.06, 95% CI 0.93–1.21) antibodies, were associated with increased risk of being a FCD case. EBV load (n=215 cases, n=216 controls) was more likely to be positive in FCD cases than controls (56.3% vs. 49.5%), and was significantly correlated with anti-EBNA (p=0.02), anti-VCA (p<0.001) and anti-EA-restricted (p=0.001), but not anti-EAdiffuse (p=0.16) antibodies. Multivariate analyses are underway. Conclusions: History of glandular fever, or evidence of prior infection with EBV is associated with increased odds of being a FCD case, strengthening evidence that EBV infection is a risk factor for MS onset.

Introduction: Encephalitis is an uncommon yet important syndrome from both the clinical and public health perspectives. The aetiology of up to 70% of cases of suspected encephaltis remains unknown. From a public health perspective, this means that preventative measures cannot be implemented in the majority of cases. We retrospectively ascertained and reviewed all identified cases of encephalitis admitted to three major hospitals in the Hunter New England area, NSW over a ten year period, and examined the diagnostic work-up in each case.

Past sun exposure is linked to a wide range of disease outcomes but is difficult to measure accurately. Silicone skin casts measure skin damage, but some studies show that age rather than sun exposure is the most important determinant of cast score. We examined skin damage scores from silicone casts of the back of the hand in a large adult sample (n = 534) with a broad range of past cumulative UV radiation (UVR) doses. Participants were ages 18 to 61 years and resided in one of four locations down the eastern Australian seaboard, spanning 27-43°S. Data were collected by questionnaire and during a nurse-led interview and examination. Silicone casts were graded from 1 to 6, where higher score represents greater damage. Higher skin damage score was associated with lighter skin pigmentation [adjusted odds ratio (AOR), 4.51; 95% confidence interval (95% CI), 2.33-8.75], fairer natural hair color, particularly red hair (AOR, 11.31; 95% CI, 4.08-31.36), and blue/gray eyes (AOR, 1.72; 95% CI, 1.14-2.59). Higher cumulative UVR dose, particularly before age 18 years, was associated with higher skin damage score (AOR, 2.06; 95% CI, 1.15-2.67 per 1,000 KJ/m2), as was number of sunburns, even after adjustment for cumulative UVR dose (AOR, 2.86; 95% CI, 1.50-5.43 for >10 sunburns ever compared with no sunburns ever). Silicone casts of the dorsum of the hand provide a measure of cumulative UVR dose and number of sunburns over the lifetime, which persists after adjustment for chronological age. They can be used as an objective measure of cumulative past sun exposure in epidemiologic studies, but other determinants of skin damage, such as skin pigmentation, should be concurrently evaluated. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2887–94)

Encephalitis is a clinical syndrome commonly caused by emerging pathogens, which are not under surveillance in Australia. We reviewed rates of hospitalization for patients with encephalitis in Australia's most populous state, New South Wales, from January 1990 through December 2007. Encephalitis was the primary discharge diagnosis for 5,926 hospital admissions; average annual hospitalization rate was 5.2/100,000 population. The most commonly identified pathogen was herpes simplex virus (n = 763, 12.9%). Toxoplasma encephalitis and subacute sclerosing panencephalitis showed notable declines. The average annual encephalitis case-fatality rate (4.6%) and the proportion of patients hospitalized with encephalitis with no identified pathogen (69.8%, range 61.5%-78.7%) were stable during the study period. The nonnotifiable status of encephalitis in Australia and the high proportion of this disease with no known etiology may conceal emergence of novel pathogens. Unexplained encephalitis should be investigated, and encephalitis hospitalizations should be subject to statutory notification in Australia.

The acute encephalitis syndrome has heralded the emergence of multiple virulent pathogens, including Murray Valley encephalitis, Hendra virus and Australian bat lyssavirus, which may result in severe morbidity and mortality. In Australia, encephalitis is not notifiable and there has been no analysis of trends in encephalitis death rates or causation. Australian Bureau of Statistics mortality and population data for the period 1979-2006 were obtained and cause of death data were extracted using ICD-9 (1979-1998) and ICD-10 (1999-2006) codes that included all relevant encephalitis related diagnoses. Encephalitis-associated deaths were analysed by cause, year, age and gender. Between 1979 and 2006 there were 1,118 encephalitis-associated deaths in Australia. The average annual death rate was 2.3 per 1 million population (range 1.3-3.6). There was a significant decline in encephalitis-associated deaths, particularly due to 'known' pathogens (4.3% decline per year, 95% CI 3.1-5.4%, P<0.0001). The aetiology of 576 deaths were unknown and the proportion of deaths due to 'unknown' encephalitis increased from 47.0% between 1979 and 1992, to 57.2% from 1993 to 2006. Downward trends in encephalitis deaths due to 'known' causes can largely be explained by changes in treatment and prevention methods, particularly for herpes encephalitis (use of acyclovir), and measles encephalitis and subacute sclerosing panencephalitis (measles vaccination). The high proportion of encephalitis deaths from 'unknown' pathogens in Australia highlights the importance of monitoring encephalitis morbidity and mortality with a view to improving pathogen diagnosis and identifying emerging infectious diseases.