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Objective: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.Methods: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).Results: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).Interpretation: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA). METHODS: Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework. RESULTS: The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P < 0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P < 0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001). CONCLUSION: PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice. [ABSTRACT FROM AUTHOR]

Actuarial risk assessments yield valid numerical information about violence risk, but research suggests that forensic clinicians prefer to communicate risk using nonnumerical information (i.e., verbal terms such as high risk). In an experimental questionnaire study, 60 forensic clinicians disagreed on the interpretation of nonnumerical terms, and their nonnumerical risk estimates for one group of violent offenders were influenced by comparison with another group. Adding nonnumerical terms to numerical probability statements had no effect on hypothetical forensic decisions. These findings suggest that nonnumerical descriptive terms do not aid effective communication of violence risk and that contextual information might artificially affect estimated risk. [ABSTRACT FROM AUTHOR]

A 51-year-old man suffered a rupture of the long-head tendon of the left biceps and a small rotator cuff tear while rock climbing. The typical signs and symptoms of a ruptured long-head biceps tendon include anterior shoulder pain, tenderness in the bicipital groove, and unusual bulging of the injured biceps. The history and physical exam are generally sufficient to make the diagnosis, but x-rays and MRI may be helpful to rule out related disorders. Because the injury is often associated with rotator cuff tendinitis, a complete shoulder exam is necessary. Conservative treatment will enable most patients to regain normal strength. [ABSTRACT FROM AUTHOR]

AIMS: To determine the influence of metformin treatment on plasma C-reactive protein (CRP) and complement factor C3. METHODS: A double-blind, placebo-controlled trial of metformin in patients with poorly controlled Type 2 diabetes mellitus and body mass index > 25 kg/m2. CRP and C3 were analysed in stored plasma samples by in-house ELISAs. Patients attended two baseline visits before randomization and subsequently attended at 3, 6, 12 and 24 weeks post randomization. All patients gave informed consent according to a protocol approved by the Leeds Teaching Hospitals Research Ethics Committee. RESULTS: Baseline CRP in the patients randomized to placebo [1.33 (0.79, 2.25) mg/l] and metformin [1.24 (0.89, 1.71) mg/l] were similar (P = 0.8). Baseline CRP correlated with baseline C3 (r = 0.366) and HbA1c (r = 0.327). The difference in ratios of CRP levels at each visit to baseline between placebo- (n = 16) and metformin-treated (n = 26) subjects was significantly different at the 12-week (P = 0.002) and 24-week (P = 0.03) visits. The difference in CRP ratios between the two treatment groups remained significant after accounting for glycaemic control at both visits (P = 0.001 and P = 0.003, respectively). Baseline C3 was correlated with CRP. Baseline C3 was lower in the placebo-treated group [0.97 (0.88, 1.05) mg/ml] compared with the metformin-treated group [1.09 (1.02, 1.17) mg/ml, P = 0.03]. There was no difference in the mean change in C3 at any visit from baseline between placebo- and metformin-treated groups. CONCLUSION: Metformin may have a specific interaction with mechanisms involved in CRP synthesis or secretion, not directly related to improved insulin sensitivity and dampening of chronic inflammation. [ABSTRACT FROM AUTHOR]