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1.  High Revision and Reoperation Rates Using the AgilityTM Total Ankle System 
Background
Total ankle arthroplasty (TAA) is an evolving treatment for end-stage ankle arthritis, however, there is controversy regarding its longevity.
Questions/purposes
We determined survival of the Agility™ TAA, the overall reoperation rate, and function in patients who retained their implant.
Methods
We retrospectively reviewed 64 patients who had 65 TAAs between June 1999 and May 2001. Information was gathered through chart reviews, mailed-in questionnaires, and telephone interviews. Nine patients had died; data were available for 41 of the remaining 55 patients. Survival was based on revision as an end point. The minimum followup was 0.5 years (median, 8 years; range, 0.5–11 years).
Results
Sixteen of the 41 patients (39%) needed revisions. The average time to revision surgery was 4 years with six of the revisions (38%) occurring within 1 year of the TAA. Of the 25 patients who retained their implants, 12 required secondary surgery for an overall reoperation rate of 28 of 41 (68%) at an average of 8 years followup. The average VAS pain score was 4, the average Foot and Ankle Ability Measure (FAAM) sports subscale score was 33, and the average FAAM activities of daily living subscale score was 57.
Conclusion
TAA had high revision and reoperation rates. Patients who retained their implant had only moderate pain relief and function. TAA must be approached with caution. More research is needed to elucidate the role of contemporary TAA.
Level of Evidence
Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-012-2242-6
PMCID: PMC3369092  PMID: 22270469
2.  Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy 
Arthritis and rheumatism  2010;62(7):1849-1861.
Objective
Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.
Methods
A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.
Results
Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99).
Conclusion
Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.
doi:10.1002/art.27457
PMCID: PMC3652476  PMID: 20309874
3.  Most Common SNPs Associated with Rheumatoid Arthritis in Subjects of European Ancestry Confer Risk of Rheumatoid Arthritis in African-Americans 
Arthritis and Rheumatism  2010;62(12):3547-3553.
Objective
Large-scale genetic association studies have identified over 20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African-Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA in an African-American population.
Methods
27 candidate SNPs were genotyped in 556 autoantibody-positive African-Americans with RA and 791 healthy African-American controls. Odds ratios (OR) and 95% confidence intervals (CI) for each SNP were compared to previously published ORs of RA patients of European ancestry. We then calculated a composite Genetic Risk Score (GRS) for each individual based on the sum of all risk alleles.
Results
There was overlap in the OR and 95% CI between the European and African-American populations in 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, TNFAIP3 rs6920220) demonstrated an OR in the opposite direction from those reported in RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African-American cases were enriched for the European RA risk alleles relative to controls (p=0.00005).
Conclusion
The majority of RA risk alleles previously validated among European ancestry RA patients showed similar ORs in our population of African-Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African-American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel risk alleles for RA in African-Americans.
doi:10.1002/art.27732
PMCID: PMC3030622  PMID: 21120996
4.  Genetic variants at CD28, PRDM1, and CD2/CD58 are associated with rheumatoid arthritis risk 
Nature genetics  2009;41(12):1313-1318.
To discover novel RA risk loci, we systematically examined 370 SNPs from 179 independent loci with p<0.001 in a published meta-analysis of RA GWAS of 3,393 cases and 12,462 controls1. We used GRAIL2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3-11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three validate convincingly: CD2/CD58 (rs11586238, p=1×10−6 replication, p=1×10−9 overall), and CD28 (rs1980422, p=5×10−6 replication, p=1×10−9 overall), PRDM1 (rs548234, p=1×10−5 replication, p=2×10−8 overall). An additional four replicate (p<0.0023): TAGAP (rs394581, p=0.0002 replication, p=4×10−7 overall), PTPRC (rs10919563, p=0.0003 replication, p=7×10−7 overall), TRAF6/RAG1 (rs540386, p=0.0008 replication, p=4×10−6 overall), and FCGR2A (rs12746613, p=0.0022 replication, p=2×10−5 overall). Many of these loci are also associated to other immunologic diseases.
doi:10.1038/ng.479
PMCID: PMC3142887  PMID: 19898481
5.  Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci 
PLoS Genetics  2011;7(2):e1002004.
Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Author Summary
Celiac disease (CD) and rheumatoid arthritis (RA) are two autoimmune diseases characterized by distinct clinical features but increased co-occurrence in families and individuals. Genome-wide association studies (GWAS) performed in CD and RA have identified the HLA region and 26 non-HLA genetic risk loci in each disease. Of the 26 CD and 26 RA risk loci, previous studies have shown that six are shared between the two diseases. In this study we aimed to identify additional shared risk alleles and, in doing so, gain more insight into shared disease pathogenesis. We first empirically investigated the distribution of putative risk alleles from GWAS across both diseases (after removing known risk loci for both diseases). We found that CD risk alleles are non-randomly distributed in the RA GWAS (and vice versa), indicating that CD risk alleles have an increased prior probability of being associated with RA (and vice versa). Next, we performed a GWAS meta-analysis to search for shared risk alleles by combing the RA and CD GWAS, performing both directional and opposite allelic effect analyses, followed by replication testing in independent case-control datasets in both diseases. In addition to the already established six non-HLA shared risk loci, we observed statistically robust associations at eight SNPs, thereby increasing the number of shared non-HLA risk loci to fourteen. Finally, we used gene expression studies and pathway analysis tools to identify the plausible candidate genes in the fourteen associated loci. We observed remarkable overrepresentation of T-cell signaling molecules among the shared genes.
doi:10.1371/journal.pgen.1002004
PMCID: PMC3044685  PMID: 21383967
6.  General practice characteristics associated with rates of testing and detection of hepatitis C: cross-sectional study in Nottingham and Derbyshire 
The aim of this study was to determine general practice characteristics associated with testing rates for hepatitis C virus (HCV) and the proportion of tests with a positive result. The study included all patients tested for HCV from all general practices in the primary care trusts in Nottingham and Southern Derbyshire, UK over 2 years. There was a large variation between practices in HCV testing rates and the proportion of positive tests. Single-handed practices had higher testing rates and rates of positive results. Practices where at least half of the GPs were female had higher testing rates but lower positivity rates. The variation observed was not explained by deprivation or rurality of the practice.
PMCID: PMC1874527  PMID: 16882381
diagnosis; hepatitis C; primary health care
7.  Identification of Conserved Residues in the E2 Envelope Glycoprotein of the Hepatitis C Virus That Are Critical for CD81 Binding 
Journal of Virology  2006;80(17):8695-8704.
Hepatitis C virus (HCV) cell entry involves interaction between the viral envelope glycoprotein E2 and the cell surface receptor CD81. Knowledge of conserved E2 determinants important for successful binding will facilitate development of entry inhibitors designed to block this interaction. Previous studies have assigned the CD81 binding function to a number of discontinuous regions of E2. To better define specific residues involved in receptor binding, a panel of mutants of HCV envelope proteins was generated, where conserved residues within putative CD81 binding regions were sequentially mutated to alanine. Mutant proteins were tested for binding to a panel of monoclonal antibodies and CD81 and for their ability to form noncovalent heterodimers and confer infectivity in the retroviral pseudoparticle (HCVpp) assay. Detection by conformation-sensitive monoclonal antibodies indicated that the mutant proteins were correctly folded. Mutant proteins fell into three groups: those that bound CD81 and conferred HCVpp infectivity, those that abrogated both CD81 binding and HCVpp infectivity, and a final group containing mutants that were able to bind CD81 but were noninfectious in the HCVpp assay. Specific amino acids conserved across all genotypes that were critical for CD81 binding were W420, Y527, W529, G530, and D535. These data significantly increase our understanding of the CD81 receptor-E2 binding process.
doi:10.1128/JVI.00271-06
PMCID: PMC1563869  PMID: 16912317
8.  Injecting drug users 
PMCID: PMC1472745  PMID: 15970076
9.  The Role of the Scapula in the Rehabilitation of Shoulder Injuries 
Journal of Athletic Training  2000;35(3):364-372.
Objective:
To present a clinical understanding of the role the scapula plays in the mechanics of shoulder function and specialized techniques for the rehabilitation of injuries around the shoulder girdle.
Background:
The scapular musculature is often neglected in the evaluation and treatment of shoulder injuries. This lack of attention often degenerates into the incomplete evaluation and rehabilitation of scapular dysfunction. Dysfunction or weakness of the scapular stabilizers often results in altered biomechanics of the shoulder girdle. The altered biomechanics can result in (1) abnormal stresses to the anterior capsular structures, (2) the increased possibility of rotator cuff compression, and (3) decreased performance.
Description:
We review the anatomy and role of the scapula, the pathomechanics of injury and dysfunction, and the evaluation and rehabilitation of the scapula.
Clinical Advantage:
Knowledge of how the scapular muscles influence function at the shoulder builds a strong foundation for the clinician to develop rehabilitation programs for the shoulder.
Images
PMCID: PMC1323398  PMID: 16558649
scapular rehabilitation; shoulder rehabilitation; impingement syndrome; rotator cuff

Results 1-9 (9)