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1.  Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials 
Annals of the Rheumatic Diseases  2016;75(11):1964-1970.
To examine the overall treatment effect and the proportion attributable to contextual effect (PCE) in randomised controlled trials (RCTs) of diverse treatments for osteoarthritis (OA).
We searched Medline, Embase, Central, Science Citation Index, AMED and CINAHL through October 2014, supplemented with manual search of reference lists, published meta-analyses and systematic reviews. Included were RCTs in OA comparing placebo with representative complementary, pharmacological, non-pharmacological and surgical treatments. The primary outcome was pain. Secondary outcomes were function and stiffness. The effect size (ES) of overall treatment effect and the PCE were pooled using random-effects model. Subgroup analyses and meta-regression were conducted to examine determinants of the PCE.
In total, 215 trials (41 392 participants) were included. The overall treatment effect for pain ranged from the smallest with lavage (ES=0.46, 95% CI 0.24 to 0.68) to the largest with topical non-steroidal anti-inflammatory drugs (ES=1.37, 95% CI 1.19 to 1.55). On average, 75% (PCE=0.75, 95% CI 0.72 to 0.79) of pain reduction was attributable to contextual effect. It varied by treatment from 47% (PCE=0.47, 95% CI 0.32 to 0.70) for intra-articular corticosteroid to 91% (PCE=0.91, 95% CI 0.60 to 1.37) for joint lavage. Similar results were observed for function and stiffness. Treatment delivered by needle/injection and other means than oral medication, longer duration of treatment, large sample size (≥100 per arm) and public funding source were associated with increased PCE for pain reduction.
The majority (75%) of the overall treatment effect in OA RCTs is attributable to contextual effects rather than the specific effect of treatments. Reporting overall treatment effect and PCE, in addition to traditional ES, permits a more balanced, clinically meaningful interpretation of RCT results. This would help dispel the frequent discordance between conclusions from RCT evidence and clinical experience—the ‘efficacy paradox’.
PMCID: PMC5099197  PMID: 26882927
Osteoarthritis; Treatment; Epidemiology
2.  Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study 
Annals of the rheumatic diseases  2014;74(11):1968-1975.
Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein which has a co-stimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) such as systemic lupus erythematosus, psoriasis, multiple sclerosis, and inflammatory bowel disease, associated with DPP4i in patients with T2DM.
Using U.S. insurance claims data (2005–2012), we conducted a population-based cohort study that included initiators of combination therapy with DPP4i (DPP4i plus metformin) and non-DPP4i (non-DPP4i plus metformin). RA and other AD were identified with ≥2 diagnoses and ≥1 dispensing for AD-specific immunomodulating drugs or steroids. Composite AD includes RA or other AD. Propensity score (PS)-stratified Cox proportional hazards models compared the risk of AD in DPP4i initiators vs. non-DPP4i, controlling for potential confounders.
After asymmetric trimming on the PS, 73,928 patients with T2DM starting DPP4i combination therapy and 163,062 starting non-DPP4i combination therapy were selected. Risks of incident RA and composite AD were lower in the DPP4i group vs. non-DPP4i with the PS-stratified hazard ratio of 0.66 (95% CI 0.44–0.99) for RA, 0.73 (0.51–1.03) for other AD, and 0.68 (95% CI 0.52–0.89) for composite AD.
In this large cohort of diabetic patients, those initiating DPP4i combination therapy appear to have a decreased risk of incident AD including RA compared to those initiating non-DPP4i combination therapy. These results may suggest possible pharmacologic pathways for prevention or treatment of AD.
PMCID: PMC4263684  PMID: 24919467
dipeptidyl peptidase-4 inhibitors; autoimmune disease; rheumatoid arthritis; inflammatory bowel disease; psoriasis; multiple sclerosis; systemic lupus erythematosus; type 2 diabetes
3.  Identifying placebo responders and predictors of response in osteoarthritis: a protocol for individual patient data meta-analysis 
Systematic Reviews  2016;5:183.
The management of osteoarthritis (OA) is unsatisfactory, as most treatments are not clinically effective over placebo and most drugs have considerable side effects. On average, 75 % of the analgesic effect from OA treatments in clinical trials can be attributed to a placebo response, and this response varies greatly from patient to patient. This individual patient data (IPD) meta-analysis aims to identify placebo responders and the potential determinants of the placebo response in OA.
This study is undertaken in conjunction with the OA Trial Bank, an ongoing international consortium aiming to collect IPD from randomised controlled trials (RCTs) for all treatments of OA. RCTs for each treatment of OA have been systematically searched for, and authors of the relevant trials have been contacted to request the IPD. We will use the IPD of placebo-controlled RCTs held by the OA Trial Bank for this project. The IPD in placebo groups will be used to investigate the placebo response according to the minimum clinically important difference (MCID) threshold (e.g. 20 % pain reduction). Responders to placebo will be compared with non-responders to identify predictors of response. The quality of the trials will be assessed and potential determinants will be examined using multilevel logistic regression analyses.
This study explores the varying magnitude of the placebo response and the proportion of participants that experience a clinically important placebo effect in OA RCTs. Potential determinants of the placebo response will also be investigated. These determinants may be useful for future studies as it may allow participants to be stratified into groups based on their likely response to placebo. The results of this study may also be useful for pharmaceutical companies, who could improve the design of their studies in order to separate the specific treatment from the non-specific contextual (i.e. placebo) effects.
Systematic review registration
PROSPERO CRD42016033212
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0362-x) contains supplementary material, which is available to authorized users.
PMCID: PMC5084436  PMID: 27793184
Osteoarthritis; Placebo response; Individual patient data meta-analysis
4.  Familial risk of systemic sclerosis and co-aggregation of autoimmune diseases in affected families 
Systemic sclerosis (SSc) is a rare and devastating disease affecting skin and internal organs. Familial aggregation of SSc and co-aggregation with other autoimmune diseases is rarely reported.
We identified 23,658,577 beneficiaries registered with the National Health Insurance database in 2010, 1891 of whom had SSc. We identified 21,009,551 parent–child relationships and 17,168,340 full sibling pairs. The familial risks of SSc and other autoimmune diseases and familial transmission were estimated.
The prevalence of SSc in the general population was 0.008 %. There are 3801 individuals had at least one first-degree relative with SSc, among them 3 people had SSc which was equivalent to a prevalence of 0.08 %. The adjusted relative risk (RR) (95 % CI) for SSc was 81.21 (11.40–579.72) for siblings of SSc patients. The familial transmission (genetic plus shared environmental contribution to total phenotypic variance of SSc) was 0.72. However, 84.1 % of patients were expected to be sporadic cases. The RR (95 % CI) in first-degree relatives of SSc patients was 2.64 (1.46–4.75) for rheumatoid arthritis, 6.51 (4.05–10.46) for systemic lupus erythematosus, 2.77 (1.04–7.35) for Sjögren’s syndrome, 8.05 (2.03–31.92) for idiopathic inflammatory myositis, and 1.52 (1.15–2.01) for psoriasis.
The risks of SSc and other autoimmune diseases are increased in relatives of people with SSc, and family factors explain over two-thirds of the phenotypic variance of the disease. These findings may be useful in counselling families of patients with SSc and for further genetic studies.
PMCID: PMC5059914  PMID: 27729087
Systemic sclerosis; Familial aggregation; Familial transmission; Rheumatic diseases; Relative risk
5.  Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis 
PLoS Genetics  2016;12(10):e1006260.
Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
Author Summary
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of chronic disability in the western society affecting millions of people. OA is a degenerative joint disease characterized by changes in all joint tissues, including cartilage, bone and synovium, causing chronic pain and loss of function. There are no effective therapeutic treatments available for OA and therefore finding novel biological pathways through genetic association studies can open up new treatment options. The number of known DNA variants associated with OA-risk is limited.
To identify new loci, we have performed a Genome Wide Association Study meta-analysis on cartilage thickness, one of the joint tissues affected in OA in a total sample of more than 20,000 individuals from twelve cohorts. This analysis revealed six variants associated with cartilage thickness, four of these being novel associations, including TGFA as the most prominent one. A systematic prioritization for underlying causal genes, using diverse lines of evidence, highlighted genes underlying the disease associations, including TGFA, RUNX2 and PIK3R1. Large scale exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies
PMCID: PMC5049763  PMID: 27701424
6.  Genome-wide Association and Functional Studies Identify a Role for IGFBP3 in Hip Osteoarthritis 
Annals of the rheumatic diseases  2014;74(10):1861-1867.
To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.
The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (P-value ≤ 5x10−8) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.
The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR = 0.71, P-value = 2x10−8). The association replicated in five studies (OR = 0.92, P-value = 0.020), but the joint analysis of discovery and replication results was not genome-wide significant (P-value = 1x10−6). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (P-value = 4x10−13), suggesting that this SNP or a variant in linkage disequilibrium (LD) could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.
Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.
PMCID: PMC4449305  PMID: 24928840
Osteoarthritis of hip; genome-wide association study; functional study; chondrogenesis; IGFBP3
7.  Relative efficacy of topical non-steroidal anti-inflammatory drugs and topical capsaicin in osteoarthritis: protocol for an individual patient data meta-analysis 
Systematic Reviews  2016;5:165.
Pain is the most troubling issue to patients with osteoarthritis (OA), yet current pharmacological treatments offer only small-to-moderate pain reduction. Current guidelines therefore emphasise the need to identify predictors of treatment response. In line with these recommendations, an individual patient data (IPD) meta-analysis will be conducted. The study aims to investigate the relative treatment effects of topical non-steroidal anti-inflammatory drugs (NSAIDs) and topical capsaicin in OA and to identify patient-level predictors of treatment response.
IPD will be collected from randomised controlled trials (RCTs) of topical NSAIDs and capsaicin in OA. Multilevel regression modelling will be conducted to determine predictors for the specific and the overall treatment effect.
Through the identification of treatment responders, this IPD meta-analysis may improve the current understanding of the pain mechanisms in OA and guide clinical decision-making. Identifying and prescribing the treatment most likely to be beneficial for an individual with OA will improve the efficiency of patient management.
Systematic review registration
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0348-8) contains supplementary material, which is available to authorized users.
PMCID: PMC5043618  PMID: 27686859
Osteoarthritis; Topical; NSAIDs; Capsaicin; Individual patient data meta-analysis
8.  Familial Risk of Sjögren's Syndrome and Co‐aggregation of Autoimmune Diseases in Affected Families: A Nationwide Population Study 
To investigate familial aggregation of Sjögren's syndrome (SS) and the relative risks (RRs) of other autoimmune disease in relatives of patients with SS.
We identified 23,658,577 beneficiaries enrolled in the Taiwan National Health Insurance system in 2010, of whom 12,754 had SS. We identified 21,009,551 parent–child relationships and 17,168,340 pairs of full siblings. The familial risks of SS and other autoimmune diseases, tetrachoric correlation, and familial transmission were estimated.
We identified 105 patients with SS who had an affected first‐degree relative. The RR of SS was 18.99 (95% confidence interval [95% CI] 9.76–36.93) in siblings of patients with SS, 11.31 (95% CI 8.34–15.33) in offspring, and 12.46 (95% CI 9.34–16.62) in parents. Tetrachoric correlation coefficients were 0.53 (95% CI 0.41–0.65) for cotwins of affected individuals and 0.21 (95% CI 0.16–0.26) for full siblings. The familial transmission (heritability plus shared environmental contribution) was 0.54 (95% CI 0.44–0.77). In first‐degree relatives of patients with SS, the RRs were 2.95 (95% CI 2.33–3.73) for rheumatoid arthritis, 6.25 (95% CI 5.15–7.58) for systemic lupus erythematosus, 2.39 (95% CI 0.77–7.41) for systemic sclerosis, 0.71 (95% CI 0.10–5.07) for idiopathic inflammatory myopathy, 1.97 (95% CI 1.29–3.02) for type 1 diabetes mellitus, 3.38 (95% CI 1.26–9.05) for multiple sclerosis, 1.67 (95% CI 0.83–3.33) for myasthenia gravis, 1.25 (95% CI 1.04–1.50) for psoriasis, 1.21 (95% CI 0.39–3.76) for inflammatory bowel disease, and 2.29 (95% CI 1.19–4.40) for vasculitis.
The risk of SS and other autoimmune diseases is increased in relatives of patients with SS, and more than one‐half of phenotypic variance in SS can be explained by familial factors.
PMCID: PMC5034806  PMID: 25940005
9.  Relative efficacy of different types of exercise for treatment of knee and hip osteoarthritis: protocol for network meta-analysis of randomised controlled trials 
Systematic Reviews  2016;5(1):147.
‘Exercise’ is universally recommended as a core treatment for knee and hip osteoarthritis (OA). However, there are very few head-to-head comparative trials to determine the relative efficacy between different types of exercise. The aim of this study is to benchmark different types of exercises against each other through the use of a common comparator in a network meta-analysis of randomised controlled trials (RCTs).
This study will include only RCTs published in peer-reviewed journals. A systematic search will be conducted in several electronic databases and other relevant online resources. No limitations are imposed on language or publication date. Participants must be explicitly identified by authors as having OA. Interventions that involved exercise or comparators in any form will be included. Pain is the primary outcome of interest; secondary outcomes will include function and quality of life measures. Quality assessment of studies will be based on the modified Cochrane’s risk of bias assessment tool. At least two investigators will be involved throughout all stages of screening and data acquisition. Conflicts will be resolved through discussion. Conventional meta-analysis will be performed based on random effects model and network meta-analysis on a Bayesian model. Subgroup analysis will also be conducted based on study, patient and disease characteristics.
This study will provide for the first time comprehensive research evidence for the relative efficacy of different exercise regimens for treatment of OA. We will use network meta-analysis of existing RCT data to answer this question.
Systematic review registration
PROSPERO CRD42016033865
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0321-6) contains supplementary material, which is available to authorized users.
PMCID: PMC5010721  PMID: 27590834
Osteoarthritis; Lower limb; Exercise; Network meta-analysis; RCT; Hip; Knee; Pain
10.  Biophysical Mechanistic Modelling Quantifies the Effects of Plant Traits on Fire Severity: Species, Not Surface Fuel Loads, Determine Flame Dimensions in Eucalypt Forests 
PLoS ONE  2016;11(8):e0160715.
The influence of plant traits on forest fire behaviour has evolutionary, ecological and management implications, but is poorly understood and frequently discounted. We use a process model to quantify that influence and provide validation in a diverse range of eucalypt forests burnt under varying conditions. Measured height of consumption was compared to heights predicted using a surface fuel fire behaviour model, then key aspects of our model were sequentially added to this with and without species-specific information. Our fully specified model had a mean absolute error 3.8 times smaller than the otherwise identical surface fuel model (p < 0.01), and correctly predicted the height of larger (≥1 m) flames 12 times more often (p < 0.001). We conclude that the primary endogenous drivers of fire severity are the species of plants present rather than the surface fuel load, and demonstrate the accuracy and versatility of the model for quantifying this.
PMCID: PMC4986950  PMID: 27529789
11.  Toward understanding and exploiting tumor heterogeneity 
Nature medicine  2015;21(8):846-853.
The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here.
PMCID: PMC4785013  PMID: 26248267
12.  Individualizing therapies with responsive epilepsy neurostimulation — A mirtazapine case study of hippocampal excitability 
This study aimed to investigate mirtazapine-induced changes in responsive neurostimulator (RNS) recordings in a patient with epilepsy.
Materials and methods
Cortical detection/stimulation counts from an RNS implanted in a patient with bitemporal epilepsy were matched to mirtazapine use to see if that drug altered hippocampal excitability.
Mirtazapine decreased hippocampal stability; when mirtazapine was held after a washout period, DSC counts declined, but when it was retrialed, DSC counts increased. Responsive epilepsy neurostimulator system data helped design an optimal and individualized medication regimen for our patient with drug-resistant focal epilepsy.
Responsive neurostimulator systems in epilepsy may assess a medication's effect on hippocampal excitability. Mirtazapine worsened hippocampal excitability in a patient with bitemporal epilepsy.
PMCID: PMC5024316  PMID: 27668181
Neurostimulation; Epilepsy; Mirtazapine; Safety; Medication; Therapy
13.  Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis 
Genetic polymorphisms within the HLA region explain only a modest proportion of anti–cyclic citrullinated peptide (anti‐CCP)–negative rheumatoid arthritis (RA) heritability. However, few non‐HLA markers have been identified so far. This study was undertaken to replicate the associations of anti‐CCP–negative RA with non‐HLA genetic polymorphisms demonstrated in a previous study.
The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune‐related regions in 3,339 anti‐CCP–negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case–control replication study of the anti‐CCP–negative markers with the strongest associations in that discovery study, in an independent cohort of anti‐CCP–negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome‐wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel.
After genotyping and imputation quality control procedures, data were available for 15 non‐HLA single‐nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta‐analysis odds ratio [OR] 0.80; P = 2.8 × 10−13) and BLK (OR 1.13; P = 7.0 × 10−6) and identified new and specific markers of anti‐CCP–negative RA (prolactin [PRL] [OR 1.13; P = 2.1 × 10−6] and NFIA [OR 0.85; P = 2.5 × 10−6]). Neither of these loci is associated with other common, complex autoimmune diseases.
Anti‐CCP–negative RA and anti‐CCP–positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti‐CCP–negative RA.
PMCID: PMC4924598  PMID: 26895230
14.  Genome-Wide Association Meta-Analyses to Identify Common Genetic Variants Associated with Hallux Valgus in Caucasian and African Americans 
Journal of medical genetics  2015;52(11):762-769.
Hallux valgus (HV) affects ~36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV.
HV was assessed in 3 Caucasian cohorts (n=2,263, n=915, and n=1,231 participants, respectively). In each cohort, a GWAS was conducted using 2.5M imputed single nucleotide polymorphisms (SNPs). Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327).
The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV was sex-specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=5.46×10−7); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=7.21×10−7). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p-value =4.1×10−9). The association signals diminished when combining men and women.
Findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation.
PMCID: PMC4864963  PMID: 26337638
hallux valgus; GWAS; genetic variants; candidate genes
15.  Investigation of Association Between Hip Osteoarthritis Susceptibility Loci and Radiographic Proximal Femur Shape 
To test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits.
We used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome‐wide association study. We built 3 SSMs capturing the shape variation of the OA‐unaffected proximal femur in the entire mixed‐sex cohort and for male/female‐stratified cohorts. We selected 41 candidate single‐nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype–phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes.
The univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P = 0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed‐sex SSM (P = 0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed‐sex SSM (P = 0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA.
These de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.
PMCID: PMC4864451  PMID: 25939412
16.  The College of Podiatry Annual Conference 2015: meeting abstracts 
Tong, Jasper W. K. | Kong, Veni P. | Sze, Lily | Gale, Susie | Veto, John | McArdle, Carla | Tunprasert, Thanaporn | Bradley, Victoria | Strike, Siobhan | Tunprasert, Thanaporn | Bradley, Victoria | Strike, Siobhan | Ashford, Robert | Naemi, Roozbeth | Chocklingam, Nachiappan | de Blasc, Xavi | Farndon, Lisa | Robinson, Vicki | Nicholls, Emily | Birch, Tabitha | Birch, Ivan | Otter, Simon | Kumar, Sunil | Gow, Peter | Dalbeth, Nicola | Corkill, Michael | Davies, Kevin | Panthakalam, Sam | Rohan, Maheswaran | Rome, Keith | Egan, Chloe | Chandler, Lisa | Tehan, Peta | Chuter, Vivienne | Sonter, Jennifer | Lanting, Sean | Hicks, Lorna | Joyce, Christopher | Watterson, David | McIntosh, Caroline | Joyce, Christopher | Roberts, Nigel | Forss, Jacqueline | Charalambous, Chrystalla | Kirby, Jack | Ojo, Oluwakemi | Forss, Jacqueline | Caukill, Sarah | Capon, Jacqueline | Fong, Radiance | Loy, Louis | Diment, Matthew | Murray, Madeleine | Ellis, Mairghread | McArdle, Carla | Tehan, Peta | Chuter, Vivienne | Oldmeadow, Christopher | Carey, Nicola | Stenner, Karen | Gage, Heather | Brown, Jane | Williams, Peter | Otter, Simon | Moore, Ann | Edwards, Jude | Mold, Freda | Courtenay, Molly | Tehan, Peta | Bray, Alan | Chuter, Vivienne | Hindmoor, Pamela | Gwynne, Craig | Curran, Sarah | Bridgen, Andy | Fairhurst, Caroline | Adamson, Joy | Martin, Belen Corbacho | Cockayne, Sarah | Hewitt, Catherine | Hicks, Kate | Keenan, Anne-Maree | Loughrey-Green, Lorraine | Menz, Hylton | Redmond, Anthony | Rodgers, Sara | Watson, Jude | Torgerson, David | Hull, Robin | Lamb, Sarah | McIntosh, Caroline | Vernon, Wesley | Farndon, Lisa | Loughrey-Green, Lorraine | Cockayne, Sarah | Redmond, Anthony | Keenan, Anne-Maree | Rodgers, Sara | Farndon, Lisa | Vernon, Wesley | Torgerson, David | Fairhurst, Caroline | Watson, Jude | Menz, Hylton | Lamb, Sarah | Hull, Robin | Wylie, Gavin | Young, Zoe | Williams, Brian | Sullivan, Frank | Menz, Hylton | Ogston, Simon | Morris, Jacqui | Bowen, Cathy | Kunkel, Dorit | Cole, Mark | Donovan-Hall, Margaret | Pickering, Ruth | Burnett, Malcolm | Bader, Dan | Robison, Judy | Mamode, Louis | Ashburn, Ann | McQueen, Peter | Daniels, Maxine | Doherty, Michael | Arden, Nigel | Bowen, Cathy | Dando, Charlotte | Cherry, Lindsey | Bowen, Cathy | Stefanou, Nichola | Cockayne, Sarah | Adamson, Joy | Fairhurst, Caroline | Hewitt, Catherine | Keenan, Anne-Maree | Lamb, Sally | Loughrey-Green, Lorraine | McIntosh, Caroline | Menz, Hylton | Redmond, Anthony | Rodgers, Sara | Vernon, Wesley | Watson, Jude | Farndon, Lisa | Corbacho, Belen | Hull, Robin | Torgerson, David | Alcacer-Pitarch, Begonya | Redmond, Anthony | Buch, Maya | Keenan, Anne-Maree
Table of content
P3 Medial longitudinal arch development of school children
Jasper W.K. Tong, Veni P. Kong
P4 Is measuring the subtalar joint reliable?
Lily Sze, Susie Gale, John Veto, Carla McArdle
P5 Comparison of turning gait biomechanics between able-bodied and unilateral transtibial amputee participants
Thanaporn Tunprasert, Victoria Bradley, Siobhan Strike
P6 Comparison of walking gait biomechanics between able-bodied and unilateral transtibial amputee participants using a new model of energy-storage-and-return (ESAR) prosthetic
Thanaporn Tunprasert, Victoria Bradley, Siobhan Strike
P7 An observational study of in-shoe plantar and dorsal pressures of skilled downhill skiers on a dry ski slope
Robert Ashford, Roozbeth Naemi, Nachiappan Chocklingam, Xavi de Blasc
P8 If the shoe fits: a footwear choice toolkit informed by social science methodologies
Lisa Farndon, Vicki Robinson, Emily Nicholls
P9 The identification of emotions from gait
Tabitha Birch, Ivan Birch
P11 Experience of foot problems in patients with systemic lupus erythematosus
Simon Otter, Sunil Kumar, Peter Gow, Nicola Dalbeth, Michael Corkill, Kevin Davies, Sam Panthakalam, Maheswaran Rohan, Keith Rome
P14 Negative pressure wound therapy for the management of foot wounds in the diabetic population: a review of the literature
Chloe Egan, Lisa Chandler
P15 Lower limb vascular assessment in diabetes: a multifaceted assessment of objective screening techniques
Peta Tehan, Vivienne Chuter, Jennifer Sonter, Sean Lanting
P16 Improving outcomes for diabetes foot complications
Lorna Hicks
P17 Acupuncture… an alternative or adjunctive treatment option for diabetes-related neuropathic pain?
Christopher Joyce, David Watterson, Caroline McIntosh
P18 “My back is in agony” – A cross-sectional study into the relationship between musculoskeletal complaints and a whole body postural risk assessment in podiatry students
Christopher Joyce, Nigel Roberts
P19 Swabs of the treatment couches: Does the material type and texture of podiatric treatment couches increase microorganism contamination?
Jacqueline Forss, Chrystalla Charalambous, Jack Kirby, Oluwakemi Ojo
P20 Does increased exudate viscosity effect the absorption rate of exudate into four different wound dressings?
Jacqueline Forss, Sarah Caukill, Jacqueline Capon, Radiance Fong, Louis Loy
P21 An investigation into the microbial load of a 40 °C and 60 °C wash
Matthew Diment, Madeleine Murray, Mairghread Ellis, Carla McArdle
P23 The sensitivity and specificity of the toe brachial index in detecting peripheral arterial disease: a systematic review and meta-analysis
Peta Tehan, Vivienne Chuter, Christopher Oldmeadow
P24 Medicines management activities and non-medical prescribing within podiatry and physiotherapy: an integrative review of the literature
Nicola Carey, Karen Stenner, Heather Gage, Jane Brown, Peter Williams, Simon Otter, Ann Moore, Jude Edwards, Freda Mold, Molly Courtenay
A7.2 Non-invasive vascular assessment in the foot with Diabetes: Diagnostic accuracy of ankle brachial index, toe brachial index and continuous wave Doppler
Peta Tehan, Alan Bray, Vivienne Chuter
A7.5 The efficacy of dressings on post nail surgery phenolised wounds
Pamela Hindmoor
B7.1 Cross-sectional study investigating the role of proximal and distal factors in the development of patellofemoral joint pain
Craig Gwynne, Sarah Curran
B7.2 Podiatrist’s interpretation and use of evidence in MSK practice
Andy Bridgen
B7.4 Predictors of falling in older podiatry patients – findings from the REFORM study
Caroline Fairhurst, Dr Joy Adamson, Belen Corbacho Martin, Sarah Cockayne, Prof Catherine Hewitt, Kate Hicks, Anne-Maree Keenan, Lorraine Loughrey-Green, Hylton Menz, Anthony Redmond, Sara Rodgers, Jude Watson, David Torgerson, Robin Hull, Sarah Lamb, Caroline McIntosh, Wesley Vernon, Lisa Farndon
B7.5 The REFORM study: Insole preference, requirements and compliance of podiatry patient’s aged 65 and over and at risk of falling
Lorraine Loughrey-Green, Sarah Cockayne, Anthony Redmond, Anne-Maree Keenan, Sara Rodgers, Lisa Farndon, Wesley Vernon, David Torgerson, Caroline Fairhurst, Jude Watson, Hylton Menz, Sarah Lamb, Robin Hull
B7.6 A podiatry intervention to reduce falls in care home residents is feasible and demonstrates benefits: results from PIRFECT, a feasibility randomised controlled trial
Gavin Wylie, Zoe Young, Brian Williams, Frank Sullivan, Hylton Menz, Simon Ogston, Jacqui Morris
C7.1 A survey exploring footwear habits in people with stroke and people with Parkinson’s
Cathy Bowen, Dorit Kunkel, Mark Cole, Margaret Donovan-Hall, Ruth Pickering, Malcolm Burnett, Dan Bader, Judy Robison, Louis Mamode, Ann Ashburn
C7.2 Painful foot osteoarthritis; a common symptom in a common pathology?
Peter McQueen, Maxine Daniels, Michael Doherty, Nigel Arden, Cathy Bowen
C7.4 Clinical diagnosis of symptomatic forefoot neuroma in the general population: Delphi based recommendations
Charlotte Dando, Lindsey Cherry, Cathy Bowen
C7.5 The development and implementation of a Clinical Quality Improvement Framework suitable for use in community services
Nichola Stefanou
C7.6 The REFORM study - methodological considerations in running a cohort randomised controlled trial within a podiatry patient caseload
Sarah Cockayne, Joy Adamson, Caroline Fairhurst, Catherine Hewitt, Anne-Maree Keenan, Sally Lamb, Lorraine Loughrey-Green, Caroline McIntosh, Hylton Menz, Anthony Redmond, Sara Rodgers, Wesley Vernon, Jude Watson, Lisa Farndon, Belen Corbacho, Robin Hull, David Torgerson
A31 Jewel in the crown: Exploring the factors contributing to the development and impact of foot problems in Systemic Sclerosis (SSc)
Begonya Alcacer-Pitarch, Anthony Redmond, Maya Buch, Anne-Maree Keenan
PMCID: PMC4896266
17.  Mitigating bit flips or single event upsets in epilepsy neurostimulators☆ 
The objective of this study was to review software errors known as single event upsets (SEUs) or bit flips due to cosmic rays in epilepsy neurostimulators.
Materials and methods
A case report of a single event upset or bit flip is discussed; device manufacturers and publicly available data were queried for both incidence and types of error as well as strategies of software error mitigation.
Neurostimulators, like other implanted devices such as pacemakers, are prone to single event upsets. Strategies for SEU mitigation are reviewed.
Cosmic radiation can threaten RAM and settings of neurostimulators; neuromodulation teams and device designers need to take this threat into account when designing multifunctional neuromodulation systems.
PMCID: PMC4872716  PMID: 27222798
Neurostimulation; Epilepsy; Software; Cosmic; Neutron; Safety
18.  Paracetamol: not as safe as we thought? A systematic literature review of observational studies 
Annals of the Rheumatic Diseases  2015;75(3):552-559.
We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol.
We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome.
Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose–response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose–response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose–response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose–response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43).
Given the observational nature of the data, channelling bias may have had an important impact. However, the dose–response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.
PMCID: PMC4789700  PMID: 25732175
Epidemiology; Outcomes research; Osteoarthritis
19.  Comorbidities in patients with gout prior to and following diagnosis: case-control study 
Annals of the Rheumatic Diseases  2014;75(1):210-217.
To determine the burden of comorbidities in patients with gout at diagnosis and the risk of developing new comorbidities post diagnosis.
There were 39 111 patients with incident gout and 39 111 matched controls identified from the UK Clinical Practice Research Data-link. The risk of comorbidity before (ORs) and after the diagnosis of gout (HRs) were estimated, adjusted for age, sex, diagnosis year, body mass index, smoking and alcohol consumption.
Gout was associated with adjusted ORs (95% CIs) of 1.39 (1.34 to 1.45), 1.89 (1.76 to 2.03) and 2.51 (2.19 to 2.86) for the Charlson index of 1–2, 3–4 and ≥5, respectively. Cardiovascular and genitourinary diseases, in addition to hyperlipidaemia, hypothyroidism, anaemia, psoriasis, chronic pulmonary diseases, osteoarthritis and depression, were associated with a higher risk for gout. Gout was also associated with an adjusted HR (95% CI) of 1.41 (1.34 to 1.48) for having a Charlson index ≥1. Median time to first comorbidity was 43 months in cases and 111 months in controls. Risks for incident comorbidity were higher in cardiovascular, genitourinary, metabolic/endocrine and musculoskeletal diseases, in addition to liver diseases, hemiplegia, depression, anaemia and psoriasis in patients with gout. After additionally adjusting for all comorbidities at diagnosis, gout was associated with a HR (95% CI) for all-cause mortality of 1.13 (1.08 to 1.18; p<0.001).
The majority of patients with gout have worse pre-existing health status at diagnosis and the risk of incident comorbidity continues to rise following diagnosis. The range of associated comorbidities is broader than previously recognised and merits further evaluation.
PMCID: PMC4717388  PMID: 25398375
Gout; Epidemiology; Cardiovascular Disease
20.  The incidence and prevalence of systemic lupus erythematosus in the UK, 1999–2012 
Annals of the Rheumatic Diseases  2014;75(1):136-141.
To estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in the UK over the period 1999–2012.
A retrospective cohort study using the Clinical Practice Research Datalink (CPRD). The incidence was calculated per 100 000 person-years and the prevalence was calculated per 100 000 people for the period 1999–2012 and stratified by year, age group, gender, region and ethnicity. Three definitions of SLE were explored: (1) systemic lupus, (2) a fully comprehensive definition of lupus including cutaneous only lupus and (3) requiring supporting evidence of SLE in the medical record.
Using our primary definition of SLE, the incidence during the study period was 4.91/100 000 person-years (95% CI 4.73 to 5.09), with an annual 1.8% decline (p<0.001). In contrast, the prevalence increased from 64.99/100 000 in 1999 (95% CI 62.04 to 67.93) (0.065%) to 97.04/100 000 in 2012 (95% CI 94.18 to 99.90) (0.097%). SLE was six times more common in women. The peak age of incidence was 50–59 years. There was regional variation in both incidence and prevalence. People of Black Caribbean ethnicity had the highest incidence and prevalence. Alternative definitions of SLE increased (definition 2) or decreased (definition 3) estimates of incidence and prevalence, but similar trends were found.
The incidence of SLE has been declining but the prevalence has been increasing in the UK in recent years. Age, gender, region and ethnicity are risk factors for SLE. This is the first study to report ethnic differences on the incidence and prevalence of SLE using the CPRD.
PMCID: PMC4717400  PMID: 25265938
Systemic Lupus Erythematosus; Epidemiology; Autoimmune Diseases
22.  Profiling oral and digital lesions in sheep in Ireland 
During the FMD outbreak in Ireland and the UK in 2001, there was significant uncertainty amongstveterinary practitioners and government veterinary inspectors surrounding the clinical diagnosis of FMD insheep. This situation was complicated by reports of idiopathic oral ulcers that closely resembled FMD ongross appearance which at that time were referred to as ovine mouth and gum obscure disease.
A field and abattoir study was carried out to determine the frequency, appearance and significance of oraland digital lesions in sheep in Ireland. A total of 3, 263 sheep were examined in 22 flocks, including 1, 969lambs and 1, 294 adults. A further 2,403 animals were examined by abattoir inspections. Animals bearing lesions of interest were identified, samples of the lesions were taken and subsequently examined by bacteriology, electron microscopy, serology, immunohistochemistry and histopathology.
Forty four oral and 20 digital lesions were identified and characterised. Oral lesions were recorded mostfrequently in lambs, where the most common cause was orf virus infection. The majority of the oral lesions recorded in the adults was idiopathic and consistent with a diagnosis of idiopathic oral ulceration. A variety of digital lesions was observed, consistent with scald, foot-rot and contagious ovine digital dermatitis (CODD). All of the animals with lesions were seronegative to FMD virus (FMDV).
There was no difficulty in differentiating these lesions from those caused by FMDV on the basis of flockhistory and careful clinical examination.
Electronic supplementary material
The online version of this article (doi:10.1186/s13620-015-0055-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4682237  PMID: 26682039
Foot and mouth disease; Sheep; Oral lesions; Digital lesions; Differential diagnoses
23.  Superficial acral fibromyxoma 
Radiology Case Reports  2015;7(3):751.
We present a case of a superficial acral fibromyxoma (SAFM) of the distal aspect of the thumb with radiographic evidence of extrinsic pressure erosion of the underlying cortex. This 47-year-old woman presented with a slow-growing mass over the distal aspect of the right thumb that proved to be SAFM on surgical pathology. This is a relatively rare mesenchymal neoplasm of the periungual and subungual regions of fingers and toes.
PMCID: PMC4899681  PMID: 27326309
CT, computed tomography; SAFM, superficial acral fibromyxoma; MRI, magnetic resonance imaging
24.  Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies 
To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.
A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant.
SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.
Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
PMCID: PMC4660891  PMID: 24757145
25.  A method for accurate spatial registration of PET images and histopathology slices 
EJNMMI Research  2015;5:64.
Accurate alignment between histopathology slices and positron emission tomography (PET) images is important for radiopharmaceutical validation studies. Limited data is available on the registration accuracy that can be achieved between PET and histopathology slices acquired under routine pathology conditions where slices may be non-parallel, non-contiguously cut and of standard block size. The purpose of this study was to demonstrate a method for aligning PET images and histopathology slices acquired from patients with laryngeal cancer and to assess the registration accuracy obtained under these conditions.
Six subjects with laryngeal cancer underwent a 64Cu-copper-II-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) PET computed tomography (CT) scan prior to total laryngectomy. Sea urchin spines were inserted into the pathology specimen to act as fiducial markers. The specimen was fixed in formalin, as per standard histopathology operating procedures, and was then CT scanned and cut into millimetre-thick tissue slices. A subset of the tissue slices that included both tumour and fiducial markers was taken and embedded in paraffin blocks. Subsequently, microtome sectioning and haematoxylin and eosin staining were performed to produce 5-μm-thick tissue sections for microscopic digitisation. A series of rigid registration procedures was performed between the different imaging modalities (PET; in vivo CT—i.e. the CT component of the PET-CT; ex vivo CT; histology slices) with the ex vivo CT serving as the reference image. In vivo and ex vivo CTs were registered using landmark-based registration. Histopathology and ex vivo CT images were aligned using the sea urchin spines with additional anatomical landmarks where available. Registration errors were estimated using a leave-one-out strategy for in vivo to ex vivo CT and were estimated from the RMS landmark accuracy for histopathology to ex vivo CT.
The mean ± SD accuracy for registration of the in vivo to ex vivo CT images was 2.66 ± 0.66 mm, and the accuracy for registration of histopathology to ex vivo CT was 0.86 ± 0.41 mm. Estimating the PET to in vivo CT registration accuracy to equal the PET-CT alignment accuracy of 1 mm resulted in an overall average registration error between PET and histopathology slices of 3.0 ± 0.7 mm.
We have developed a registration method to align PET images and histopathology slices with an accuracy comparable to the spatial resolution of the PET images.
PMCID: PMC4648832  PMID: 26576995
Histopathology; PET; Registration; Methodology; Oncology

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