A W McCaskie

University of Cambridge, Cambridge, England, United Kingdom

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Publications (97)

  • Sarah E. Johnson-Lynn · Sudipta Roy · Andrew W. McCaskie · Mark A. Birch
    [Show abstract] [Hide abstract] ABSTRACT: Ti alloy surfaces that ranged from rough (average Ra 1.65 μm) to smooth (Ra 0.03 μm) were created by electrochemical processing. Rat osteoblasts were cultured on the Ti alloy for up to 7 days and cell adhesion events (24 hours) demonstrated significant differences in cell polarity, area, mean focal adhesion area and mean number of focal adhesions per unit cell area between untreated and electrochemically polished Ti alloy. To address the mechanisms underlying phenotypic differences between cells on these surfaces, the activities of Rho-family GTPases and the localisation of cadherin-11 were investigated. Elevated RhoA activity was detected in cells on the smoother surfaces whilst on all surfaces inhibition of both RhoA and Rac1 compromised cell morphology but this was especially pronounced on the rougher surfaces. Significant differences in staining for cadherin-11 were observed in cells cultured for 7 days. On rougher surfaces, there was little evidence of cadherin-11 positive structures at the periphery of the cells however on the smoother surfaces there were extensive adherens junctions. These data illustrate that modifying implant surface structure not only influences initial cell adhesion but also has consequences for the cellular activity of intracellular mediators and the way in which cells interact with each other.
    Article · Nov 2015 · Journal of Biomaterials and Tissue Engineering
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    Zeiad Alshameeri · Andrew McCaskie
    [Show abstract] [Hide abstract] ABSTRACT: The potential regenerative role of different orthobiologics is becoming more recognized for the treatment of chronic and degenerative musculoskeletal conditions. Over the last few years there has been an increasing number of publications on cell therapy and other orthobiologics for the treatment of avascular necrosis of the femoral head and other hip conditions with promising short–term clinical results. In this article, we have used a systematic search of the literature to identify potentially relevant topics on orthobiologics and then selected those most applicable to hip preservation surgery. We identified several innovative strategies and present a summary of the currently available evidence on their potential role in hip preservation surgery. For many of these treatment strategies there was a lack of clinical evidence and therefore we suggest that there is a need for comparative studies in this field.
    Full-text Article · Aug 2015
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    Full-text Article · Dec 2014
  • [Show abstract] [Hide abstract] ABSTRACT: The assessment of surgical skills is an essential part of medical training. The prevalent manual evaluations by expert surgeons are time consuming and often their outcomes vary substantially from one observer to another. We present a video-based framework for automated evaluation of surgical skills based on the Objective Structured Assessment of Technical Skills (OSATS) criteria. We encode the motion dynamics via frame kernel matrices, and represent the motion granularity by texture features. Linear discriminant analysis is used to derive a reduced dimensionality feature space followed by linear regression to predict OSATS skill scores. We achieve statistically significant correlation (p-value <0.01) between the ground-truth (given by domain experts) and the OSATS scores predicted by our framework.
    Conference Paper · Apr 2014
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    [Show abstract] [Hide abstract] ABSTRACT: 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.
    Full-text Article · Apr 2014 · Arthritis and Rheumatology
  • [Show abstract] [Hide abstract] ABSTRACT: Chondropathies of the hip, whether on the femoral head or the acetabulum, are believed to be a frequent cause of hip pain and precedent to osteoarthritis (OA). There are approximately 80,000 hip replacements performed each year in England and Wales, the majority for OA [19]. The incidence of OA is set to double by 2030 with changing demographics and altered lifestyles; it is estimated that one in five OA patients gives up work or retires early because of his or her condition [20]. Over the last 5 years, there has been a 49 % increase in revisions of hip arthroplasty, which are costly, complex and time consuming in theatre usage, in addition to having a less successful outcome than primary arthroplasties. There is a need to develop treatments at an earlier stage which can delay, or better still alleviate, the need for a hip arthroplasty. The treatments must deliver patient benefit and be cost-effective.
    Article · Jan 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis). Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
    Full-text Article · Aug 2013 · Annals of the rheumatic diseases
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    Full-text Dataset · Aug 2013
  • [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVES: Obesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height variation. We investigated whether this relationship is due to a shared genetic aetiology on a genome-wide scale. METHODS: We compared genetic association summary statistics (effect size, p value) for BMI and height from the GIANT consortium genome-wide association study (GWAS) with genetic association summary statistics from the arcOGEN consortium osteoarthritis GWAS. Significance was evaluated by permutation. Replication of osteoarthritis association of the highlighted signals was investigated in an independent dataset. Phenotypic information of height and BMI was accounted for in a separate analysis using osteoarthritis-free controls. RESULTS: We found significant overlap between osteoarthritis and height (p=3.3×10(-5) for signals with p≤0.05) when the GIANT and arcOGEN GWAS were compared. For signals with p≤0.001 we found 17 shared signals between osteoarthritis and height and four between osteoarthritis and BMI. However, only one of the height or BMI signals that had shown evidence of association with osteoarthritis in the arcOGEN GWAS was also associated with osteoarthritis in the independent dataset: rs12149832, within the FTO gene (combined p=2.3×10(-5)). As expected, this signal was attenuated when we adjusted for BMI. CONCLUSIONS: We found a significant excess of shared signals between both osteoarthritis and height and osteoarthritis and BMI, suggestive of a common genetic aetiology. However, only one signal showed association with osteoarthritis when followed up in a new dataset.
    Article · Jun 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Purpose: Poor knee extension function after total knee arthroplasty (TKA) is associated with factors including articular geometry and alignment. Femoral trochlear geometry has evolved from symmetrical to become more prominent proximal-laterally, with the groove aligned proximal-lateral to distal-medial. This study in vitro tested the hypothesis that a modern asymmetrical prosthesis would restore patellar tracking and stability to more natural behaviour than an older symmetrical prosthesis. Methods: Six knees had their patellar tracking measured optically during active knee extension. Medial-lateral force versus displacement stability was measured at fixed angles of knee flexion. The measurements were repeated after inserting each of the symmetrical and asymmetrical TKAs. Results: Significant differences of patellar lateral displacement stability, compared to normal, were not found at any angle of knee flexion. The patella tracked medial-laterally within 2.5 mm of the natural path with both TKAs. However, for both TKAs near knee extension, the patella was tilted laterally by approximately 6° and was also flexed approximately 8° more than in the natural knee. Conclusion: The hypothesis was not supported: The more anatomical component design did not provide more anatomical patellar kinematics and stability.
    Article · Jun 2013 · Knee Surgery Sports Traumatology Arthroscopy
  • [Show abstract] [Hide abstract] ABSTRACT: There continues to be some dissatisfaction with the function of total knee arthroplasties (TKA). "Mid-range instability" has been linked to multi-radius femoral components allowing transient ligament slackness and instability during knee flexion. Single-radius designs have been introduced to avoid this. We compared the kinematics and stability of eight natural knees versus multi-radius and single-radius TKAs in vitro. The loading conditions imposed across the range of active knee extension were anterior-posterior drawer forces, internal-external rotation torques, and varus-valgus moments. Significant differences were not found between the biomechanical behavior of the two TKAs. Both were significantly different from the natural knee in allowing greater anterior drawer laxity near extension, probably caused by excision of the anterior cruciate ligament, but no difference occurred beyond 30° flexion. No differences were found for any of the other degrees-of-freedom of movement. A geometric analysis suggested that the multi-radius design may tense the MCL more than the single-radius in mid-flexion, contrary to expectation. These kinematic and stability tests did not find mid-range instability of the knees, and so they could not demonstrate enhanced mid-range stability of the single-radius TKA over the older multi-radius implant. This suggests that mid-range instability may relate to unrecognized ligament laxity during surgery, rather than being inherent to a specific feature of implant design. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
    Article · Jan 2013 · Journal of Orthopaedic Research
  • [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVES: Osteoarthritis (OA) has a complex aetiology with a strong genetic component. Genome-wide association studies implicate several nuclear genes in the aetiology, but a major component of the heritability has yet to be defined at the molecular level. Initial studies implicate maternally inherited variants of mitochondrial DNA (mtDNA) in subgroups of patients with OA based on gender and specific joint involvement, but these findings have not been replicated. METHODS: The authors studied 138 maternally inherited mtDNA variants genotyped in a two cohort genetic association study across a total of 7393 OA cases from the arcOGEN consortium and 5122 controls genotyped in the Wellcome Trust Case Control consortium 2 study. RESULTS: Following data quality control we examined 48 mtDNA variants that were common in cohort 1 and cohort 2, and found no association with OA. None of the phenotypic subgroups previously associated with mtDNA haplogroups were associated in this study. CONCLUSIONS: We were not able to replicate previously published findings in the largest mtDNA association study to date. The evidence linking OA to mtDNA is not compelling at present.
    Article · Jan 2013
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    Full-text Dataset · Sep 2012
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    [Show abstract] [Hide abstract] ABSTRACT: Objectives Osteoarthritis (OA) has a complex aetiology with a strong genetic component. Genome-wide association studies implicate several nuclear genes in the aetiology, but a major component of the heritability has yet to be defined at the molecular level. Initial studies implicate maternally inherited variants of mitochondrial DNA (mtDNA) in subgroups of patients with OA based on gender and specific joint involvement, but these findings have not been replicated. Methods The authors studied 138 maternally inherited mtDNA variants genotyped in a two cohort genetic association study across a total of 7393 OA cases from the arcOGEN consortium and 5122 controls genotyped in the Wellcome Trust Case Control consortium 2 study. Results Following data quality control we examined 48 mtDNA variants that were common in cohort 1 and cohort 2, and found no association with OA. None of the phenotypic subgroups previously associated with mtDNA haplogroups were associated in this study. Conclusions We were not able to replicate previously published findings in the largest mtDNA association study to date. The evidence linking OA to mtDNA is not compelling at present.
    Full-text Article · Sep 2012 · Annals of the rheumatic diseases
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    Full-text Dataset · Sep 2012
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    Katherine S Elliott · Kay Chapman · Aaron Day-Williams · [...] · Eleftheria Zeggini
    [Show abstract] [Hide abstract] ABSTRACT: Objectives Obesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height variation. We investigated whether this relationship is due to a shared genetic aetiology on a genome-wide scale. Methods We compared genetic association summary statistics (effect size, p value) for BMI and height from the GIANT consortium genome-wide association study (GWAS) with genetic association summary statistics from the arcOGEN consortium osteoarthritis GWAS. Significance was evaluated by permutation. Replication of osteoarthritis association of the highlighted signals was investigated in an independent dataset. Phenotypic information of height and BMI was accounted for in a separate analysis using osteoarthritis-free controls. Results We found significant overlap between osteoarthritis and height (p=3.3×10−5 for signals with p≤0.05) when the GIANT and arcOGEN GWAS were compared. For signals with p≤0.001 we found 17 shared signals between osteoarthritis and height and four between osteoarthritis and BMI. However, only one of the height or BMI signals that had shown evidence of association with osteoarthritis in the arcOGEN GWAS was also associated with osteoarthritis in the independent dataset: rs12149832, within the FTO gene (combined p=2.3×10−5). As expected, this signal was attenuated when we adjusted for BMI. Conclusions We found a significant excess of shared signals between both osteoarthritis and height and osteoarthritis and BMI, suggestive of a common genetic aetiology. However, only one signal showed association with osteoarthritis when followed up in a new dataset.
    Full-text Article · Sep 2012 · Annals of the rheumatic diseases
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    Full-text Dataset · Sep 2012
  • [Show abstract] [Hide abstract] ABSTRACT: The relevance of Henry's pelvic deltoid and its contribution to hip abductor strength is often not considered in hip arthroplasty. This small cadaveric study (n = 11) aimed to quantify the relative contributions of the pelvic deltoid muscles to abductor strength and to assess how different surgical approaches(anterolateral, direct lateral and posterior) impact on each of these muscle groups. We inspected the path of each approach and measured the cross-sectional area of the hip abductors, from which the contribution of each muscle to abductor moment was derived. We concluded that the posterior approach has the least impact on the pelvic deltoid and overall abductor moment.
    Article · Aug 2012 · The Journal of arthroplasty
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    [Show abstract] [Hide abstract] ABSTRACT: Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p=5.0×10 -8) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1.12 [95% CI 1.08-1.16]; p=7.24×10 -11), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.
    Full-text Article · Jul 2012 · The Lancet
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    [Show abstract] [Hide abstract] ABSTRACT: Topography and surface chemistry have a profound effect on the way in which cells interact with an implant, which in turn impacts on clinical use and performance. In this paper we examine an electrochemical polishing approach in H2SO4/methanol that can be applied to the widely used orthopaedic/dentistry implant material, Ti6Al4V, to produce structured surfaces. The surface roughness, as characterized by R(a), was found to be dependent on the time of electropolishing but not on the voltage parameters used here. The surface chemistry, however, was dependent on the applied electrochemical potential. It was found that the chemical composition of the surface layer was modified during the electrochemical process, and at high potentials (9.0 V) a pure TiO2 layer of at least 10 nm was created on top of the bulk alloy. Characterization of these surfaces with rat cells from the osteoblast lineage provided further evidence of contact guidance by microscale topography with morphology analysis correlating with surface roughness (R(a) 300–550 nm). Formation of a bone-like matrix after long-term culture on these surfaces was not strongly dependent upon R(a) values but followed the voltage parameter. These findings suggest that the surfaces created by treatment at higher voltages (9.0 V) produced a nanoscale layer of pure TiO2 on the Ti6Al4V surface that influenced the programme of cellular differentiation culminating in osteogenesis.
    Full-text Article · Apr 2012 · Biomedical Materials

Publication Stats

1k Citations

Institutions

  • 2015
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2006
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
  • 2003
    • Durham University
      Durham, England, United Kingdom
  • 1998
    • University of Leicester
      Leiscester, England, United Kingdom