Genetic testing for haemochromatosis in patients with chondrocalcinosis

Hereditary haemochromatosis (HH) is the most common lethal monogenic human disease, affecting roughly 1 in 300 white northern Europeans. Homozygosity for the C282Y polymorphism within the HFE gene causes more than 80% of cases, with compound heterozygosity of the C282Y and H63D polymorphism also increasing susceptibility to disease. The aim of this study was to determine the frequency of the C282Y and H63D polymorphisms in the disease, and to assess the risk of HH in heterozygotes for the C282Y polymorphism. 128 patients were recruited because of either radiographic chondrocalcinosis (at least bicompartmental knee disease or joints other than the knee involved) or CPPD pseudogout. Genotyping of the HFE C282Y and H63D mutations was performed using PCR/SSP and genotypes for the C282Y polymorphism confirmed by PCR/RFLP. Historical white European control data were used for comparison. Two previously undiagnosed C282Y homozygotes (1.6%), and 16 C282Y heterozygotes (12.5%), including four (3.1%) C282Y/ H63D compound heterozygotes were identified. This represents a significant overrepresentation of C282Y homozygotes (relative risk 3.4, p-0.037), but the number of heterozygotes was not significantly increased. At a cost per test of £1 for each subject, screening all patients with chondrocalcinosis using the above ascertainment criteria costs only £64 for each case of haemochromatosis identified, clearly a highly cost effective test given the early mortality associated with untreated haemochromatosis. Routine screening for haemochromatosis in patients with appreciable chondrocatcinosis is recommended.

Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population

Objective The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population. Methods A case-control study was performed in Han Chinese patients with AS (n = 527) and controls (n = 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend. Results Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P = 0.0048; for rs7711564, P = 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese. Conclusion Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

Spinal inflammation in the absence of sacroiliac joint inflammation on magnetic resonance imaging in patients with active nonradiographic axial spondyloarthritis

Objective: To evaluate the presence of spinal inflammation with and without sacroiliac (SI) joint inflammation on magnetic resonance imaging (MRI) in patients with active nonradiographic axial spondyloarthritis (SpA), and to compare the disease characteristics of these subgroups. Methods: ABILITY-1 is a multicenter, randomized, controlled trial of adalimumab versus placebo in patients with nonradiographic axial SpA classified using the Assessment of SpondyloArthritis international Society axial SpA criteria. Baseline MRIs were centrally scored independently by 2 readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) method for the SI joints and the SPARCC 6-discovertebral unit method for the spine. Positive evidence of inflammation on MRI was defined as a SPARCC score of >2 for either the SI joints or the spine. Results: Among patients with baseline SPARCC scores, 40% had an SI joint score of >2 and 52% had a spine score of >2. Forty-nine percent of patients with baseline SI joint scores of <2, and 58% of those with baseline SI joint scores of >2, had a spine score of >2. Comparison of baseline disease characteristics by baseline SI joint and spine scores showed that a greater proportion of patients in the subgroup with a baseline SPARCC score of >2 for both SI joints and spine were male, and patients with spine and SI joint scores of <2 were younger and had shorter symptom duration. SPARCC spine scores correlated with baseline symptom duration, and SI joint scores correlated negatively with the baseline Bath Ankylosing Spondylitis Disease Activity Index, but neither correlated with the baseline Ankylosing Spondylitis Disease Activity Score, total back pain, the patient's global assessment of disease activity, the Bath Ankylosing Spondylitis Functional Index, morning stiffness, nocturnal pain, or C-reactive protein level. Conclusion: Assessment by experienced readers showed that spinal inflammation on MRI might be observed in half of patients with nonradiographic axial SpA without SI joint inflammation.

Motorway crash duration and its determinants: Do durations vary across motorways?

Traffic congestion has been a growing issue in many metropolitan areas during recent years, which necessitates the identification of its key contributors and development of sustainable strategies to help decrease its adverse impacts on traffic networks. Road incidents generally and crashes specifically have been acknowledged as the cause of a large proportion of travel delays in urban areas and account for 25% to 60% of traffic congestion on motorways. Identifying the critical determinants of travel delays has been of significant importance to the incident management systems which constantly collect and store the incident duration data. This study investigates the individual and simultaneous differential effects of the relevant determinants on motorway crash duration probabilities. In particular, it applies parametric Accelerated Failure Time (AFT) hazard-based models to develop in-depth insights into how the crash-specific characteristic and the associated temporal and infrastructural determinants impact the duration. AFT models with both fixed and random parameters have been calibrated on one year of traffic crash records from two major Australian motorways in South East Queensland and the differential effects of determinants on crash survival functions have been studied on these two motorways individually. A comprehensive spectrum of commonly used parametric fixed parameter AFT models, including generalized gamma and generalized F families, have been compared to random parameter AFT structures in terms of goodness of fit to the duration data and as a result, the random parameter Weibull AFT model has been selected as the most appropriate model. Significant determinants of motorway crash duration included traffic diversion requirement, crash injury type, number and type of vehicles involved in a crash, day of week and time of day, towing support requirement and damage to the infrastructure. A major finding of this research is that the motorways under study are significantly different in terms of crash durations; such that motorway exhibits durations that are on average 19% shorter compared to the durations on motorway. The differential effects of explanatory variables on crash durations are also different on the two motorways. The detailed presented analysis confirms that, looking at the motorway network as a whole, neglecting the individual differences between roads, can lead to erroneous interpretations of duration and inefficient strategies for mitigating travel delays along a particular motorway.

Neuropsychological studies of late onset and subthreshold diagnoses of adult Attention-Deficit/Hyperactivity Disorder

Background Diagnosing attention-deficit/hyperactivity disorder (ADHD) in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve the DSM-IV threshold for diagnosis. Because neuropsychological deficits are associated with ADHD, we addressed the validity of the DSM-IV age at onset and symptom threshold criteria by using neuropsychological test scores as external validators. Methods We compared four groups of adults: 1) full ADHD subjects met all DSM-IV criteria for childhood-onset ADHD; 2) late-onset ADHD subjects met all criteria except the age at onset criterion; 3) subthreshold ADHD subjects did not meet full symptom criteria; and 4) non-ADHD subjects did not meet any of the above criteria. Results Late-onset and full ADHD subjects had similar patterns of neuropsychological dysfunction. By comparison, subthreshold ADHD subjects showed few neuropsychological differences with non-ADHD subjects. Conclusions Our results showing similar neuropsychological underpinning in subjects with late-onset ADHD suggest that the DSM-IV age at onset criterion may be too stringent. Our data also suggest that ADHD subjects who failed to ever meet the DSM-IV threshold for diagnosis have a milder form of the disorder.

Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population

Objective: Association between ankylosing spondylitis (AS) and two genes, ERAP1 and IL23R, has recently been reported in North American and British populations. The population attributable risk fraction for ERAP1 in this study was 25%, and for IL23R, 9%. Confirmation of these findings to ERAP1 in other ethnic groups has not yet been demonstrated. We sought to test the association between single nucleotide polymorphisms (SNPs) in these genes and susceptibility to AS among a Portuguese population. We also investigated the role of these genes in clinical manifestations of AS, including age of symptom onset, the Bath Ankylosing Spondylitis Disease Activity, Metrology and Functional Indices, and the modified Stoke Ankylosing Spondylitis Spinal Score. Methods: The study was conducted on 358 AS cases and 285 ethnically matched Portuguese healthy controls. AS was defined according to the modified New York Criteria. Genotyping of IL23R and ERAP1 allelic variants was carried out with TaqMan allelic discrimination assays. Association analysis was performed using the Cochrane-Armitage and linear regression tests of genotypes as implemented in PLINK for dichotomous and quantitative variables respectively. A meta-analysis for Portuguese and previously published Spanish IL23R data was performed using the StatsDirect® Statistical tools, by fixed and random effects models. Results: A total of 14 nsSNPs markers (8 for IL23R, 5 for ERAPl, 1 for LN-PEP) were analysed. Three markers (2 for IL23R and 1 for ERAP1) showed significant single-locus disease associations, confirming that the association of these genes with AS in the Portuguese population. The strongest associated SNP in IL23R was rs1004819 (OR=1.4, p=0.0049), and in ERAP1 was rs30187 (OR=1.26, p=0.035). The population attributable risk fractions in the Portuguese population for these SNPs are 11% and 9.7% respectively. No association was seen with any SNP in LN-PEP, which flanks ERAP1 and was associated with AS in the British population. No association was seen with clinical manifestations of AS. Conclusions: These results show that IL23R and ERAP1 genes are also associated with susceptibility to AS in the Portuguese population, and that they contribute a significant proportion of the population risk for this disease.

The ASAS criteria for axial spondyloarthritis: Strengths, weaknesses, and proposals for a way forward

Classification criteria should facilitate selection of similar patients for clinical and epidemiologic studies, therapeutic trials, and research on etiopathogenesis to enable comparison of results across studies from different centers. We critically appraise the validity and performance of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA). It is still debatable whether all patients fulfilling these criteria should be considered as having true axSpA. Patients with radiographically evident disease by the ASAS criteria are not necessarily identical with ankylosing spondylitis (AS) as classified by the modified New York criteria. The complex multi-arm selection design of the ASAS criteria induces considerable heterogeneity among patients so classified, and applying them in settings with a low prevalence of axial spondyloarthritis (SpA) greatly increases the proportion of subjects falsely classified as suffering from axial SpA. One of the unmet needs in non-radiographic form of axial SpA is to have reliable markers that can identify individuals at risk for progression to AS and thereby facilitate early intervention trials designed to prevent such progression. We suggest needed improvements of the ASAS criteria for axSpA, as all criteria sets should be regarded as dynamic concepts open to modifications or updates as our knowledge advances.

Validation and reliability of a Spanish version of Simple Shoulder Test (SST-Sp)

Background: The Simple Shoulder Test (SST-Sp) is a widely used outcome measure. Objective: The purpose of this study was to develop and validate a Spanish-version SST (SST-Sp). Methods: A two-stage observational study was conducted. The SST was initially cross-culturally adapted to Spanish through double forward and backward translation and then validated for its psychometric characteristics. Participants (n = 66) with several shoulder disorders completed the SST-Sp, DASH, VAS and SF-12. The full sample was employed to determine factor structure, internal consistency and concurrent criterion validity. Reliability was determined in the first 24–48 h in a subsample of 21 patients. Results: The SST-Sp showed three factors that explained the 56.1 % of variance, and the internal consistency for each factor was α = 0.738, 0.723 and 0.667, and reliability was ICC = 0.687–0.944. The factor structure was three-dimensional and supported construct validity. Criterion validity determined from the relationship between the SST-Sp and DASH was strong (r = −0.73; p < 0.001) and fair for VAS (r = −0.537; p < 0.001). Relationships between SST-Sp and SF-12 were weak for both physical (r = −0.47; p < 0.001) and mental (r = −0.43; p < 0.001) dimensions. Conclusions: The SST-Sp supports the findings of the original English version as being a valid shoulder outcome measure with similar psychometric properties to the original English version.

Do motor vehicle crashes arise from single or multiple unique risk processes? An inquiry into crash causes and modelling

Crashes at any particular transport network location consist of a chain of events arising from a multitude of potential causes and/or contributing factors whose nature is likely to reflect geometric characteristics of the road, spatial effects of the surrounding environment, and human behavioural factors. It is postulated that these potential contributing factors do not arise from the same underlying risk process, and thus should be explicitly modelled and understood. The state of the practice in road safety network management applies a safety performance function that represents a single risk process to explain crash variability across network sites. This study aims to elucidate the importance of differentiating among various underlying risk processes contributing to the observed crash count at any particular network location. To demonstrate the principle of this theoretical and corresponding methodological approach, the study explores engineering (e.g. segment length, speed limit) and unobserved spatial factors (e.g. climatic factors, presence of schools) as two explicit sources of crash contributing factors. A Bayesian Latent Class (BLC) analysis is used to explore these two sources and to incorporate prior information about their contribution to crash occurrence. The methodology is applied to the state controlled roads in Queensland, Australia and the results are compared with the traditional Negative Binomial (NB) model. A comparison of goodness of fit measures indicates that the model with a double risk process outperforms the single risk process NB model, and thus indicating the need for further research to capture all the three crash generation processes into the SPFs.

Australian data do not support current pharmaceutical benefits scheme criteria for use of tumour necrosis factor-α inhibitors in ankylosing spondylitis

On the basis of local data, we write in support of the conclusions of Smith and Ahern that current Pharmaceu- tical Benefits Scheme (PBS) criteria for tumour necrosis factor (TNF)-a inhibitors in ankylosing spondylitis (AS) are not evidence-based. 1 As a prerequisite to the appropriate use of biological therapy in AS, three aspects of the disease need to be defined: (i) diagnosis, (ii) activity and (iii) therapeutic failure (Table 1)....

The v-MFG test: Investigating maternal, offspring and maternal-fetal genetic incompatibility effects on disease and viability

The MFG test is a family-based association test that detects genetic effects contributing to disease in offspring, including offspring allelic effects, maternal allelic effects and MFG incompatibility effects. Like many other family-based association tests, it assumes that the offspring survival and the offspring-parent genotypes are conditionally independent provided the offspring is affected. However, when the putative disease-increasing locus can affect another competing phenotype, for example, offspring viability, the conditional independence assumption fails and these tests could lead to incorrect conclusions regarding the role of the gene in disease. We propose the v-MFG test to adjust for the genetic effects on one phenotype, e.g., viability, when testing the effects of that locus on another phenotype, e.g., disease. Using genotype data from nuclear families containing parents and at least one affected offspring, the v-MFG test models the distribution of family genotypes conditional on offspring phenotypes. It simultaneously estimates genetic effects on two phenotypes, viability and disease. Simulations show that the v-MFG test produces accurate genetic effect estimates on disease as well as on viability under several different scenarios. It generates accurate type-I error rates and provides adequate power with moderate sample sizes to detect genetic effects on disease risk when viability is reduced. We demonstrate the v-MFG test with HLA-DRB1 data from study participants with rheumatoid arthritis (RA) and their parents, we show that the v-MFG test successfully detects an MFG incompatibility effect on RA while simultaneously adjusting for a possible viability loss.

Criminal histories of crash and non-crash involved Queensland speeding offenders: Evidence supporting the idea that we drive as we live

Evidence increasingly suggests that our behaviour on the road mirrors our behaviour across other aspects of our life. The idea that we drive as we live, described by Tillman and Hobbs more than 65 years ago when examining off-road behaviours of taxi drivers (1949), is the focus of the current paper. As part of a larger study examining the impact of penalty changes on a large cohort of Queensland speeding offenders, criminal (lifetime) and crash history (10 year period) data for a sub-sample of 1000 offenders were obtained. Based on the ‘drive as we live’ maxim, it was hypothesised that crash-involved speeding offenders would be more likely to have a criminal history than non-crash involved offenders. Overall, only 30% of speeding offenders had a criminal history. However, crash-involved offenders were significantly more likely to have a criminal history (49.4%) than non-crash involved offenders (28.6%), supporting the hypothesis. Furthermore, those deemed ‘most at fault’ in a crash were the group most likely to have at least one criminal offence (52.2%). When compared to the non-crash involved offenders, those deemed ‘not most at fault’ in a crash were also more likely to have had at least one criminal offence (46.5%). Therefore, when compared to non-crash involved speeding offenders, those offenders involved in a crash were more likely to have been convicted of at least one criminal offence, irrespective of whether they were deemed ‘most at fault’ in that crash. Implications for traffic offender management and policing are discussed.

The impact of safety measures on the re-offence and crash rates of drink-driving offenders in Victoria

Alcohol is a major factor in road deaths and serious injuries. In Victoria, between 2008 and 2013, 30% of drivers killed were involved in alcohol-related crashes. From the early 1980s Victoria progressively introduced a series of measures, such as driver licence cancellation and alcohol interlocks, to reduce the level of drink-driving on Victoria's roads. This project tracked drink-driving offenders to measure and understand their re-offence and road trauma involvement levels during and after periods of licensing and driving interventions. The methodology controlled for exposure by aggregating crashes and traffic violations within relevant categories (e.g. licence cancelled/relicensed/relicensing not sought) and calculated as rates 'per thousand person-years'. Inferential statistical techniques were used to compare crash and offence rates between control and treatment groups across three distinct time periods, which coincided with the introduction of new interventions. This paper focuses on the extent to which the Victorian drink-driving measures have been successful in reducing re-offending and road trauma involvement during and after periods of licence interventions. It was found that a licence cancellation/ban is an effective drink-driving countermeasure as it reduced drink-driving offending and drink-driving crashes. Interlocks also had a positive effect on drink-driving offences as they were reduced during the interlock period as well as for the entire intervention period. Possible drink-driving policy implications are briefly discussed.

How serious are they? The use of data linkage to explore different definitions of serious road crash injuries

Over recent years, the focus in road safety has shifted towards a greater understanding of road crash serious injuries in addition to fatalities. Police reported crash data are often the primary source of crash information; however, the definition of serious injury within these data is not consistent across jurisdictions and may not be accurately operationalised. This study examined the linkage of police-reported road crash data with hospital data to explore the potential for linked data to enhance the quantification of serious injury. Data from the Queensland Road Crash Database (QRCD), the Queensland Hospital Admitted Patients Data Collection (QHAPDC), Emergency Department Information System (EDIS), and the Queensland Injury Surveillance Unit (QISU) for the year 2009 were linked. Nine different estimates of serious road crash injury were produced. Results showed that there was a large amount of variation in the estimates of the number and profile of serious road crash injuries depending on the definition or measure used. The results also showed that as the definition of serious injury becomes more precise the vulnerable road users become more prominent. These results have major implications in terms of how serious injuries are identified for reporting purposes. Depending on the definitions used, the calculation of cost and understanding of the impact of serious injuries would vary greatly. This study has shown how data linkage can be used to investigate issues of data quality. It has also demonstrated the potential improvements to the understanding of the road safety problem, particularly serious injury, by conducting data linkage.

Crash risk perception of sleepy driving and its comparisons with drink driving and speeding: Which behavior is perceived as the riskiest?

- Objective Driver sleepiness is a major crash risk factor, but may be under-recognized as a risky driving behavior. Sleepy driving is usually rated as less of a road safety issue than more well-known risky driving behaviors, such as drink driving and speeding. The objective of this study was to compare perception of crash risk of sleepy driving, drink driving, and speeding. - Methods In total, 300 Australian drivers completed a questionnaire that assessed crash risk perceptions for sleepy driving, drink driving, and speeding. Additionally, the participants perception of crash risk was assessed for five different contextual scenarios that included different levels of sleepiness (low, high), driving duration (short, long), and time of day/circadian influences (afternoon, night-time) of driving. - Results The analysis confirmed that sleepy driving was considered a risky driving behavior, but not as risky as high levels of speeding (p < .05). Yet, the risk of crashing at 4 am was considered as equally risky as low levels of speeding (10 km over the limit). The comparisons of the contextual scenarios revealed driving scenarios that would arguably be perceived as quite risky due to time of day/circadian influences were not reported as high risk. - Conclusions The results suggest a lack of awareness or appreciation of circadian rhythm functioning, particularly the descending phase of circadian rhythm that promotes increased sleepiness in the afternoon and during the early hours of the morning. Yet, the results suggested an appreciation of the danger associated with long distance driving and driver sleepiness. Further efforts are required to improve the community’s awareness of the impairing effects from sleepiness and in particular, knowledge regarding the human circadian rhythm and the increased sleep propensity during the circadian nadir.