Defining anthropometric cut-off levels related to metabolic risk in a group of Sri Lankan children

Background: Body mass index (BMI) is widely used as a measure of adiposity. However, currently used cut-off values are not sensitive in diagnosing obesity in South Asian populations. Aim: To define BMI and waist circumference (WC), cut-off values representing percentage fat mass (%FM) associated with adverse health outcomes. Subjects and methods: A cross-sectional descriptive study of 285 5–14 year old Sri Lankan children (56% boys) was carried out. Fat mass (FM) was assessed using the isotope (D2O) dilution technique based on 2C body composition model. BMI and WC cut-off values were defined based on %FM associated with adverse health outcomes. Results: Sri Lankan children had a low fat free mass index (FFMI) and a high fat mass index (FMI). Individuals with the same BMI had %FM distributed over a wide range. Lean body tissue grew very little with advancing age and weight gain was mainly due to increases in body fat. BMI corresponding to 25% in males and 35% in females at 18 years was 19.2 kg/m2 and 19.7 kg/m2, respectively. WC cut-off values for males and females were 68.4 cm and 70.4 cm, respectively. Conclusion: This chart analysis clearly confirms that Sri Lankan children have a high %FM from a young age. With age, more changes occur in FM than in fat free mass (FFM). Although the newly defined BMI and WC cut-off values appear to be quite low, they are comparable to some recent data obtained in similar populations.

Eccentric knee-flexor strength and risk of hamstring injuries in Rugby Union: A prospective study

BACKGROUND Hamstring strain injuries (HSIs) represent the most common cause of lost playing time in rugby union. Eccentric knee-flexor weakness and between-limb imbalance in eccentric knee-flexor strength are associated with a heightened risk of hamstring injury in other sports; however these variables have not been explored in rugby union. PURPOSE To determine if lower levels of eccentric knee-flexor strength or greater between-limb imbalance in this parameter during the Nordic hamstring exercise are risk-factors for hamstring strain injury in rugby union. STUDY DESIGN Cohort study; level of evidence, 3. METHODS This prospective study was conducted over the 2014 Super Rugby and Queensland Rugby Union seasons. In total, 178 rugby union players (age, 22.6 ± 3.8 years; height, 185 ± 6.8 cm; mass, 96.5 ± 13.1 kg) had their eccentric knee-flexor strength assessed using a custom-made device during the pre-season. Reports of previous hamstring, quadriceps, groin, calf and anterior cruciate ligament injury were also obtained. The main outcome measure was prospective occurrence of hamstring strain injury. RESULTS Twenty players suffered at least one hamstring strain during the study period. Players with a history of hamstring strain injury had 4.1 fold (RR = 4.1, 95% CI = 1.9 to 8.9, p = 0.001) greater risk of subsequent hamstring injury than players without such history. Between-limb imbalance in eccentric knee-flexor strength of ≥ 15% and ≥ 20% increased the risk of hamstring strain injury 2.4 fold (RR = 2.4, 95% CI = 1.1 to 5.5, p = 0.033) and 3.4 fold (RR = 3.4, 95% CI = 1.5 to 7.6, p = 0.003), respectively. Lower eccentric knee flexor strength and other prior injuries were not associated with increased risk of future hamstring strain. Multivariate logistic regression revealed that the risk of re-injury was augmented in players with strength imbalances. CONCLUSION Previous hamstring strain injury and between-limb imbalance in eccentric knee-flexor strength were associated with an increased risk of future hamstring strain injury in rugby union. These results support the rationale for reducing imbalance, particularly in players who have suffered a prior hamstring injury, to mitigate the risk of future injury.

Is there evidence to support the use of the angle of peak torque as a marker of hamstring injury and re-injury risk?

Hamstring strain injuries are the predominant injury in many sports, costing athletes and clubs a significant financial and performance burden. Therefore the ability to identify and intervene with individuals who are considered at a high risk of injury is important. One measure which has grown in popularity as an outcome variable following hamstring intervention/prevention studies and rehabilitation is the angle of peak knee flexor torque. This current opinion article will firstly introduce the measure and the processes behind it. Secondly, this article will summarise how the angle of peak knee flexor torque has been suggested to measure hamstring strain injury risk. Finally various limitations will be presented and outlined as to how they may influence the measure. These include the lack of muscle specificity, the common concentric contraction mode of assessment, reliability of the measure, various neural contributions (such as rate of force development and neuromuscular inhibition) as well as the lack of prospective data showing any predictive value in the measure.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. © 2011 Duncan et al.

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ~2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10-9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10-12, and -0.16 SD per G allele, P = 1.2×10-15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10-9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10-6 and rs2707466: OR = 1.22, P = 7.2×10-6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16-/- mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10-13<P<5.9×10-4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture. © 2012 Zheng et al.

The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS. © 2015 Field et al.

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.

Identification of mechanism, PECARN risk factors and injury patterns in severe paediatric cervical spine injuries in Queensland

Introduction Canadian C spine rule and NEXUS criteria have identified risk factors for cervical spine injury in adults but not for children. PECARN has developed an 8 variable model for cervical spine injury in children. We sought to identify the mechanism, prevalence of PECARN risk factors, injury patterns, and management of severe Paediatric cervical spine injuries presenting to the major children’s hospitals in Brisbane, Australia. Methods This a retrospective study of the children with cervical spine injuries who presented directly or were referred to the major children’s hospitals in Brisbane over 5 years. Results There were 38 patients with 18 male and 20 female.The mean age was 8.6 years. They were divided into two groups according to their age, (Group 1 < =8 years had 18 (47%) patients, while group 2 (9-15 years) had 20 (53%) patients. Motor vehicle related injuries were the most common (61%) in Group 1 while it was sporting injuries (50%) in group 2. All patients in group 1 had upper cervical injury (C0-C2) while subaxial injuries were most common in group 2 (66.6%). 82% of the patients had 2 or more PECARN risk factors. 18 children (47%) had normal neurological assessment at presentation, 6 (16%) had radicular symptoms, 11 (29%) could not be assessed as they had already been intubated due to the severity of the injury, 3 (8%) had incomplete cord injury. 29 (69%) patients had normal neurological assessment at final follow up and 2 children died from their injuries. Conclusion Our study confirms that younger children sustain upper cervical injuries most commonly secondary to motor vehicle accidents, while the older sustain subaxial injuries from sporting activities. The significant prevalence of the PECARN risk factors among this cohort of patients have led to them being incorporated into a protocol at these hospitals used to assess patients with suspected cervical spinal injury.

Common polygenic variation contributes to risk of migraine in the Norfolk Island population

Migraine has been defined as a common disabling primary headache disorder. Epidemiology studies have provided with the undeniable evidence of genetic components as active players in the development of the disease under a polygenic model in which multiple risk alleles exert modest individual effects. Our objective was to test the contribution of a polygenic effect to migraine risk in the Norfolk Island population using a panel of SNPs reported to be disease associated in published migraine GWAS. We also investigated whether individual SNPs were associated with gene expression levels measured in whole-blood. Polygenic scores were calculated in a total of 285 related individuals (74 cases, 211 controls) from the Norfolk Island using 51 SNPs previously reported to be associated with migraine in published GWAS. The association between polygenic score and migraine case-control status was tested using logistic regression. Results indicate that a migraine polygenic risk score was associated with migraine case-control status in this population (P=0.016). This supports the hypothesis that multiple SNPs with weak effects collectively contribute to migraine risk in this population. Amongst the SNPs included in the polygenic model, 4 were associated with the expression of the USMG5 gene, including rs171251 (P = 0.012). Results from this study provide evidence for a polygenic contribution to migraine risk in an isolated population and highlight specific SNPs that regulate the expression of USMG5, a gene critical for mitochondrial function.

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.

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