Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis

Objectives - It has long been suspected that susceptibility to ankylosing spondylitis (AS) is influenced by genes lying distant to the major histocompatibility complex. This study compares genetic models of AS to assess the most likely mode of inheritance, using recurrence risk ratios in relatives of affected subjects. Methods - Recurrence risk ratios in different degrees of relatives were determined using published data from studies specifically designed to address the question. The methods of Risch were used to determine the expected recurrence risk ratios in different degrees of relatives, assuming equal first degree relative recurrence risk between models. Goodness of fit was determined by χ2 comparison of the expected number of affected subjects with the observed number, given equal numbers of each type of relative studied. Results - The recurrence risks in different degrees of relatives were: monozygotic (MZ) twins 63% (17/27), first degree relatives 8.2% (441/5390), second degree relatives 1.0% (8/834), and third degree relatives 0.7% (7/997). Parent-child recurrence risk (7.9%, 37/466) was not significantly different from the sibling recurrence risk (8.2%, 404/4924), excluding a significant dominance genetic component to susceptibility. Poor fitting models included single gene, genetic heterogeneity, additive, two locus multiplicative, and one locus and residual polygenes (χ2 > 32 (two degrees of freedom), p < 10-6 for all models). The best fitting model studied was a five locus model with multiplicative interaction between loci (χ2 = 1.4 (two degrees of freedom), p = 0.5). Oligogenic multiplicative models were the best fitting over a range of population prevalences and first degree recurrence risk rates. Conclusions - This study suggests that of the genetic models tested, the most likely model operating in AS is an oligogenic model with predominantly multiplicative interaction between loci.

Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis

Objective: To determine the influence of HLA-B27 homozygosity and HLA-DRB1 alleles in the susceptibility to, and severity of, ankylosing spondylitis in a Finnish population. Methods: 673 individuals from 261 families with ankylosing spondylitis were genotyped for HLA-DRB1 alleles and HLA-B27 heterozygosity/ homozygosity. The frequencies of HLA-B27 homozygotes in probands from these families were compared with the expected number of HLA-B27 homozygotes in controls under Hardy-Weinberg equilibrium (HWE). The effect of HLA-DRB1 alleles was assessed using a logistic regression procedure conditioned on HLA-B27 and case-control analysis. Results: HLA-B27 was detected in 93% of cases of ankylosing spondylitis. An overrepresentation of HLA-B27 homozygotes was noted in ankylosing spondylitis (11%) compared with the expected number of HLA-B27 homozygotes under HWE (4%) (odds ratio (OR) = 3.3 (95% confidence interval, 1.6 to 6.8), p = 0.002). HLA-B27 homozygosity was marginally associated with reduced BASDAI (HLA-B27 homozygotes, 4.5 (1.6); HLA-B27 heterozygotes, 5.4 (1.8) (mean (SD)), p = 0.05). Acute anterior uveitis (AAU) was present in significantly more HLA-B27 positive cases (50%) than HLA-B27 negative cases (16%) (OR = 5.4 (1.7 to 17), p<0.004). HLA-B27 positive cases had a lower average age of symptom onset (26.7 (8.0) years) compared with HLA-B27 negative cases (35.7 (11.2) years) (p<0.0001). Conclusions: HLA-627 homozygosity is associated with a moderately increased risk of ankylosing spondylitis compared with HLA-β27 heterozygosity. HLA-B27 positive cases had an earlier age of onset of ankylosing spondylitis than HLA-B27 negative cases and were more likely to develop AAU. HLA-DRB1 alleles may influence the age of symptom onset of ankylosing spondylitis.

Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans

Objective To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans. Methods A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations. Results Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 × 10 -21), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 × 10-16), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 × 10-15). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 × 10-18), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 × 10-8). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis. Conclusion This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants. Copyright © 2014 by the American College of Rheumatology.

Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis

Introduction: The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptor molecules. High concentrations of three of its putative proinflammatory ligands, S100A8/A9 complex (calprotectin), S100A8, and S100A12, are found in rheumatoid arthritis (RA) serum and synovial fluid. In contrast, soluble RAGE (sRAGE) may prevent proinflammatory effects by acting as a decoy. This study evaluated the serum levels of S100A9, S100A8, S100A12 and sRAGE in RA patients, to determine their relationship to inflammation and joint and vascular damage. Methods: Serum sRAGE, S100A9, S100A8 and S100A12 levels from 138 patients with established RA and 44 healthy controls were measured by ELISA and compared by unpaired t test. In RA patients, associations with disease activity and severity variables were analyzed by simple and multiple linear regressions. Results: Serum S100A9, S100A8 and S100A12 levels were correlated in RA patients. S100A9 levels were associated with body mass index (BMI), and with serum levels of S100A8 and S100A12. S100A8 levels were associated with serum levels of S100A9, presence of anti-citrullinated peptide antibodies (ACPA), and rheumatoid factor (RF). S100A12 levels were associated with presence of ACPA, history of diabetes, and serum S100A9 levels. sRAGE levels were negatively associated with serum levels of C-reactive protein (CRP) and high-density lipoprotein (HDL), history of vasculitis, and the presence of the RAGE 82Ser polymorphism. Conclusions: sRAGE and S100 proteins were associated not just with RA inflammation and autoantibody production, but also with classical vascular risk factors for end-organ damage. Consistent with its role as a RAGE decoy molecule, sRAGE had the opposite effects to S100 proteins in that S100 proteins were associated with autoantibodies and vascular risk, whereas sRAGE was associated with protection against joint and vascular damage. These data suggest that RAGE activity influences co-development of joint and vascular disease in rheumatoid arthritis patients.

The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood

Bone mass acquired during childhood is the primary determinant of adult bone mineral density (BMD) and osteoporosis risk. Bone accrual is subject to genetic influences. Activating and inactivating LRP5 gene mutations elicit extreme bone phenotypes, while more common LRP5 polymorphisms are associated with normal variation of BMD. Our aim was to test the hypothesis that LRP5 gene polymorphisms influence bone mass acquisition during childhood. The association between LRP5 gene polymorphisms and bone size and mineralization was examined in 819 unrelated British Caucasian children (n = 429 boys) aged 9 years. Height, weight, pubertal status (where available), total-body and spinal bone area, bone mineral content (BMC), BMD, and area-adjusted BMC (aBMC) were assessed. Dual-energy X-ray absorptiometry (DXA)-gene associations were assessed by linear regression, with adjustment for age, gender, pubertal status, and body size parameters. There were 140, 79, 12, and 2 girls who achieved Tanner stages I-IV, respectively, and 179 and 32 boys who achieved Tanner stages I and II, respectively. The rs2306862 (N740N) coding polymorphism in exon 10 of the LRP5 gene was associated with spinal BMD and aBMC (each P = 0.01) and total-body BMD and aBMC (P = 0.04 and 0.03, respectively). Adjusting for pubertal stage strengthened associations between this polymorphism and spinal BMD and aBMC (P = 0.01 and 0.002, respectively). Individuals homozygous for the T allele had greater spinal BMD and aBMC scores than those homozygous for the C allele. A dose effect was apparent as the mean spinal BMD and aBMC of heterozygous TC individuals were intermediate between those of their TT and CC counterparts. The N740N polymorphism in exon 10 of LRP5 was associated with spinal BMD and aBMC in pre- and early pubertal children. These results indicate that LRP5 influences volumetric bone density in childhood, possibly through effects on trabecular bone formation.

Critical risk factors affecting the implementation of PPP waste-to-energy projects in China

Since 2003, Mainland China has been promoting the public–private partnership (PPP) procurement model in the waste-to-energy incineration sector to reduce the waste burying rate and improve environmental quality. Five critical risk factors (CRFs) that affect the construction and operation of waste-to-energy incineration projects have been identified from real-life risk events of 14 PPP waste-to-energy incineration plants through content analysis. These risk factors are insufficient waste supply, disposal of non-licensed waste, environmental risk, payment risk, and lack of supporting infrastructure. A recently completed PPP waste-to-energy incineration plant, the Shanghai Tianma project, was investigated to learn from the effective management of CRFs. First-hand data about the Shanghai Tianma project was collected, with a focus on project negotiation and concession agreement. Lessons learned about risk management were acquired. This paper presents a detailed study of the contractual structure, risk sharing scheme, risk response measures to CRFs, and project transfer of a PPP project. The study results will provide governments with management implications to prepare equitable concession agreements and benefit private investors by effectively mitigating and managing risks in future PPP waste-to-energy incineration projects.

Limited utility of exercise stress testing in the evaluation of suspected acute coronary syndrome in patients aged less than 40 years with intermediate risk features

Objective National guidelines for management of intermediate risk patients with suspected acute coronary syndrome, in whom AMI has been excluded, advocate provocative testing to final risk stratify these patients into low risk (negative testing) or high risk (positive testing suggestive of unstable angina). Adults less than 40 years have a low pretest probability of acute coronary syndrome. The utility of exercise stress testing in young adults with chest pain suspected of acute coronary syndrome who have National Heart Foundation intermediate risk features was evaluated Methods A retrospective analysis of exercise stress testing performed on patients less than 40 years was evaluated. Patients were enrolled on a chest pain pathway and had negative serial ECGs and cardiac biomarkers before exercise stress testing to rule-out acute coronary syndrome. Chart review was completed on patients with positive stress tests. Results The 3987 patients with suspected intermediate risk acute coronary syndrome underwent exercise stress testing. One thousand and twenty-seven (25.8%) were aged less than 40 years (age 33.3 ± 4.8 years). Four of these 1027 patients had a positive exercise stress test (0.4% incidence of positive exercise stress testing). Of those, three patients had subsequent non-invasive functional testing that yielded a negative result. One patient declined further investigations. Assuming this was a true positive exercise stress test, the incidence of true positive exercise stress testing would have been 0.097% (95% confidence interval: 0.079–0.115%) (one of 1027 patients). Conclusions Routine exercise stress testing has limited value in the risk stratification of adults less than 40 years with suspected intermediate risk of acute coronary syndrome

Prevalence and risk factors for foot and ankle musculoskeletal disorders experienced by nurses

Background Nurses are at high risk of musculoskeletal disorders (MSDs). Although the prevalence of MSDs of the lower back, upper limbs, neck and shoulders have been reported previously in nursing, few studies have evaluated MSDs of the foot and ankle. This study evaluated the prevalence of foot and ankle MSDs in nurses and their relation to individual and workplace risk factors. Methods A self-administered survey incorporating the Nordic Musculoskeletal Questionnaire (NMQ) was distributed, over a nine-week period, to all eligible nurses (n = 416) working in a paediatric hospital in Brisbane, Australia. The prevalence of MSDs for each of the NMQ body regions was determined. Bivariate and multivariable logistic regression analyses were conducted to examine the relationships between activity-limiting foot/ankle MSDs and risk factors related to the individual (age, body mass index, number of existing foot conditions, smoking history, general physical health [SF36 Physical Component Scale], footwear features) or the workplace (level of nursing position, work location, average hours worked, hours worked in previous week, time since last break from work). Results A 73% response rate was achieved with 304 nurses completing surveys, of whom 276 were females (91%). Mean age of the nurses was 37 years (±10), younger than the state average of 43 years. Foot/ankle MSDs were the most prevalent conditions experienced by nurses during the preceding seven days (43.8%, 95% CI 38.2-49.4%), the second most prevalent MSDs to impair physical activity (16.7%, 95% CI 13.0-21.3%), and the third most prevalent MSD, after lower-back and neck problems, during the preceding 12 months (55.3%, 95% CI 49.6-60.7%). Of the nurse and work characteristics investigated, obesity, poor general physical health, existing foot conditions and working in the intensive care unit emerged as statistically significant (p < 0.05) independent risk factors for activity-limiting foot/ankle MSDs. Conclusions Foot/ankle MSDs are common in paediatric hospital nurses and resulted in physical activity limitations in one out of every six nurses. We recommend targeted education programs regarding the prevention, self-management and treatment strategies for foot/ankle MSDs. Further research is needed into the impact of work location and extended shift durations on foot/ankle MSDs.

Mobile medical applications for melanoma risk assessment: False assurance or valuable tool?

With the smartphone revolution, consumer-focused mobile medical applications (apps) have flooded the market without restriction. We searched the market for commercially available apps on all mobile platforms that could provide automated risk analysis of the most serious skin cancer, melanoma. We tested 5 relevant apps against 15 images of previously excised skin lesions and compared the apps' risk grades to the known histopathologic diagnosis of the lesions. Two of the apps did not identify any of the melanomas. The remaining 3 apps obtained 80% sensitivity for melanoma risk identification; specificities for the 5 apps ranged from 20%-100%. Each app provided its own grading and recommendation scale and included a disclaimer recommending regular dermatologist evaluation regardless of the analysis outcome. The results indicate that autonomous lesion analysis is not yet ready for use as a triage tool. More concerning is the lack of restrictions and regulations for these applications.

Association of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms with the risk of COPD: An updated meta-analysis of 2,644 cases and 4,804 controls

A series of observational studies have been made to investigate the association of the ADAM33 gene polymorphisms with the risk of COPD, but their results were conflicting. Therefore, we performed an updated meta-analysis to quantitatively summarize the associations of ADAM33 gene polymorphisms with the risk of COPD. Thirteen case–control studies referring to nine SNPs were identified: V4 (rs2787094), T+1 (rs2280089), T2 (rs2280090), T1 (rs2280091), S2 (rs528557), S1 (rs3918396), Q−1 (rs612709), F+1 (rs511898) and ST+5 (rs597980). A dominant model (AA+Aa vs. aa), recessive model (AA vs. Aa+aa), additive model (AA vs. aa) and allelic model (A vs. a) were used to evaluate the association of ADAM33 polymorphism with the risk of COPD. The results indicated that significant associations were found for ADAM33 T1, T2, S1, Q−1, F+1 and ST+5 polymorphisms associated with the risk of COPD in different populations. However, no significant associations were found for V4, T+1 and S2 polymorphisms with the risk of COPD in all genetic models, even in the subgroup analysis by ethnicity. This meta-analysis provided evidence that the ADAM33 T1, T2, S1, Q−1, F+1 and ST+5 six locus polymorphisms association with the risk of COPD. Furthermore, T2, Q−1 and ST+5 indicated an association with the risk of COPD in the European populations, whereas T1, T2, S1, F+1 and Q−1 indicated an association with the risk of COPD in the Asian populations.

Occupational injury risk among Australian paramedics: An analysis of national data

Objective To identify the occupational risks for Australian paramedics, by describing the rate of injuries and fatalities and comparing those rates with other reports. Design and participants Retrospective descriptive study using data provided by Safe Work Australia for the period 2000–2010. The subjects were paramedics who had been injured in the course of their duties and for whom a claim had been made for workers compensation payments. Main outcome measures Rates of injury calculated from the data provided. Results The risk of serious injury among Australian paramedics was found to be more than seven times higher than the Australian national average. The fatality rate for paramedics was about six times higher than the national average. On average, every 2 years during the study period, one paramedic died and 30 were seriously injured in vehicle crashes. Ten Australian paramedics were seriously injured each year as a result of an assault. The injury rate for paramedics was more than two times higher than the rate for police officers. Conclusions The high rate of occupational injuries and fatalities among paramedics is a serious public health issue. The risk of injury in Australia is similar to that in the United States. While it may be anticipated that injury rates would be higher as a result of the nature of the work and environment of paramedics, further research is necessary to identify and validate the strategies required to minimise the rates of occupational injury for paramedics.

Increased risk of emergency hospital admissions for children with renal diseases during heatwaves in Brisbane, Australia

Background Heatwaves have a significant impact on population health including both morbidity and mortality. In this study we examined the association between heatwaves and emergency hospital admissions (EHAs) for renal diseases in children (aged 0–14 years) in Brisbane, Australia. Methods Daily data on EHAs for renal diseases in children and exposure to temperature and air pollution were obtained for Brisbane city from January 1, 1996 to December 31, 2005. A time-stratified case-crossover design was used to compare the risks for renal diseases between heatwave and non-heatwave periods. Results There were 1565 EHAs for renal diseases in children during the study period. Heatwaves exhibited a significant impact on EHAs for renal diseases in children after adjusting for confounding factors (odds ratio: 3.6; 95% confidence interval: 1.4–9.5). The risk estimates differed with lags and the use of different heatwave definitions. Conclusions There was a significant increase in EHAs for renal diseases in children during heatwaves in Brisbane, a subtropical city where people are well accustomed to warm weather. This finding may have significant implications for pediatric renal care, particularly in subtropical and tropical regions.

Current research: Neurocognitive risk assessment

The current research began from the starting point that what we are grappling with when we are dealing with violent extremists by and large is essentially ‘normal people’. What follows in this third major section of this research paper is the theoretical and conceptual search for making researchable the following question: ‘How do you assess someone who is normal?’

Missing in space: An evaluation of imputation methods for missing data in spatial analysis of risk factors for type II diabetes

Background Spatial analysis is increasingly important for identifying modifiable geographic risk factors for disease. However, spatial health data from surveys are often incomplete, ranging from missing data for only a few variables, to missing data for many variables. For spatial analyses of health outcomes, selection of an appropriate imputation method is critical in order to produce the most accurate inferences. Methods We present a cross-validation approach to select between three imputation methods for health survey data with correlated lifestyle covariates, using as a case study, type II diabetes mellitus (DM II) risk across 71 Queensland Local Government Areas (LGAs). We compare the accuracy of mean imputation to imputation using multivariate normal and conditional autoregressive prior distributions. Results Choice of imputation method depends upon the application and is not necessarily the most complex method. Mean imputation was selected as the most accurate method in this application. Conclusions Selecting an appropriate imputation method for health survey data, after accounting for spatial correlation and correlation between covariates, allows more complete analysis of geographic risk factors for disease with more confidence in the results to inform public policy decision-making.

The Queensland high risk foot form (QHRFF): Is it a reliable and valid clinical research tool for foot disease?

Background Foot disease complications, such as foot ulcers and infection, contribute to considerable morbidity and mortality. These complications are typically precipitated by “high-risk factors”, such as peripheral neuropathy and peripheral arterial disease. High-risk factors are more prevalent in specific “at risk” populations such as diabetes, kidney disease and cardiovascular disease. To the best of the authors’ knowledge a tool capturing multiple high-risk factors and foot disease complications in multiple at risk populations has yet to be tested. This study aimed to develop and test the validity and reliability of a Queensland High Risk Foot Form (QHRFF) tool. Methods The study was conducted in two phases. Phase one developed a QHRFF using an existing diabetes foot disease tool, literature searches, stakeholder groups and expert panel. Phase two tested the QHRFF for validity and reliability. Four clinicians, representing different levels of expertise, were recruited to test validity and reliability. Three cohorts of patients were recruited; one tested criterion measure reliability (n = 32), another tested criterion validity and inter-rater reliability (n = 43), and another tested intra-rater reliability (n = 19). Validity was determined using sensitivity, specificity and positive predictive values (PPV). Reliability was determined using Kappa, weighted Kappa and intra-class correlation (ICC) statistics. Results A QHRFF tool containing 46 items across seven domains was developed. Criterion measure reliability of at least moderate categories of agreement (Kappa > 0.4; ICC > 0.75) was seen in 91% (29 of 32) tested items. Criterion validity of at least moderate categories (PPV > 0.7) was seen in 83% (60 of 72) tested items. Inter- and intra-rater reliability of at least moderate categories (Kappa > 0.4; ICC > 0.75) was seen in 88% (84 of 96) and 87% (20 of 23) tested items respectively. Conclusions The QHRFF had acceptable validity and reliability across the majority of items; particularly items identifying relevant co-morbidities, high-risk factors and foot disease complications. Recommendations have been made to improve or remove identified weaker items for future QHRFF versions. Overall, the QHRFF possesses suitable practicality, validity and reliability to assess and capture relevant foot disease items across multiple at risk populations.