Purpose Bleeding complications are a serious adverse effect of medications that prevent abnormal blood clotting. To facilitate epidemiologic investigations of bleeding complications, we developed and validated an automated database case definition for bleeding-related hospitalizations. Methods The case definition utilized information from an in-progress retrospective cohort study of warfarin-related bleeding in Tennessee Medicaid enrollees 30 years of age or older. It identified inpatient stays during the study period of January 1990 through December 2005 with diagnoses and/or procedures that indicated a current episode of bleeding. The definition was validated by medical record review for a sample of 236 hospitalizations. Results We reviewed 186 hospitalizations that had medical records with sufficient information for adjudication. Of these, 165 (89% [95% CI, 83%-92%]) were clinically confirmed bleeding-related hospitalizations. An additional 19 hospitalizations (10% [7%-15%]) were adjudicated as possibly bleeding-related. Of the 165 clinically confirmed bleeding-related hospitalizations, the automated database and clinical definitions had concordant anatomical sites (gastrointestinal, cerebral, genitourinary, other) for 163 (99% [96%-100%]). For those hospitalizations with sufficient information to distinguish between upper/lower gastrointestinal bleeding, the concordance was 89%(76%-96%) for upper gastrointestinal sites and 91%(77%-97%) for lower gastrointestinal sites. Conclusion A case definition for bleeding-related hospitalizations suitable for automated databases had a positive predictive value of between 89% and 99% and could distinguish specific bleeding sites.

IntroductionRheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance. Experimental evidence indicates that the relationship between insulin resistance and inflammation is bidirectional: Inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that pioglitazone, a thiazolidinedione peroxisome proliferator-activated receptor γ agonist, would decrease inflammation and disease activity and improve insulin resistance in patients with RA.MethodsIn a single-center, randomized, double-blind, placebo-controlled crossover study patients with RA (N = 34) receiving stable therapy were randomized to also receive either pioglitazone 45 mg daily (n = 17) or matching placebo (n = 17) for eight weeks. This was followed by a four-week washout period and alternative treatment for eight weeks. Outcomes included change in Disease Activity Score in 28 joints (DAS28) score, individual components of the DAS28 score and homeostatic model assessment for insulin resistance (HOMA). Intention-to-treat analysis and linear mixed-effects models were used.ResultsPatients had a mean (±SD) age of 51 (±14.2) years, 82.4% were female and baseline DAS28 high-sensitivity C-reactive protein (DAS28-CRP) was 4.58 (±1.1) units. Addition of pioglitazone was associated with a 9.3% reduction (95% confidence interval (CI) = 0.17% to 17.6%) in DAS28-CRP (P = 0.046), but no significant change in DAS28 erythrocyte sedimentation rate (DAS28-ESR) (P = 0.92). There was a 10.7mm (95% CI = 0.4 to 20.9 mm) improvement in patient-reported global health (P = 0.042), a 48.6% decrease (95% CI = 27.6% to 63.5%) in CRP (P < 0.001) and a 26.4% decrease (95% CI = 3.7% to 43.8%) in insulin resistance as measured by HOMA (P = 0.025), but no significant reduction in swollen or tender joint count or in ESR (all P > 0.05). Lower-extremity edema was more common during pioglitazone treatment (16%) than placebo (0%).ConclusionAddition of pioglitazone to RA therapy improves insulin resistance and modestly reduces RA disease activity measured by DAS28-CRP and two of its components, including patient-reported global health and CRP, but not DAS28-ESR or ESR.Trial registrationNCT00763139

Aim To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. Materials & methods Using Vanderbilt’s DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. Results CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). Conclusion The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.

The widespread use of multidose vaccine containers in low and middle income countries' immunization programs is assumed to have multiple benefits and efficiencies for health systems, yet the broader impacts on immunization coverage, costs, and safety are not well understood. To document what is known on this topic, how it has been studied, and confirm the gaps in evidence that allow us to assess the complex system interactions, the authors undertook a review of published literature that explored the relationship between doses per container and immunization systems. The relationships examined in this study are organized within a systems framework consisting of operational costs, timely coverage, safety, product costs/wastage, and policy/correct use, with the idea that a change in dose per container affects all of them, and the optimal solution will depend on what is prioritized and used to measure performance. Studies on this topic are limited and largely rely on modeling to assess the relationship between doses per container and other aspects of immunization systems. Very few studies attempt to look at how a change in doses per container affects vaccination coverage rates and other systems components simultaneously. This article summarizes the published knowledge on this topic to date and suggests areas of current and future research to ultimately improve decision making around vaccine doses per container and increase understanding of how this decision relates to other program goals.

Introduction: Difficult intravenous (IV) access (DIVA) is frequently encountered in the hospital setting. Ultrasound-guided peripheral IV catheter (USGPIV) insertion has emerged as an effective procedure to establish access in patients with DIVA. Despite the increased use of USGPIV, little is known about the optimal training paradigms for bedside nurses. Therefore, we developed and evaluated a novel, sustainable, USGPIV simulation-based mastery learning (SBML) curriculum for nurses. Methods: This is a prospective cohort study of an USGPIV SBML training program for bedside nurses over a 12-month period. We evaluated skills and self-confidence before and after training and measured the proportion of the nurses achieving independent, proctor, and instructor status. Procedure logs and surveys were used to explore the nurse experience and utilization of USGPIV on real patients with DIVA 3 months after the intervention. Results: Two hundred thirty-eight nurses enrolled in the study. The USGPIV skill checklist scores increased from median of 6.0 [interquartile range = 4.0-9.0 (pretest) to 29.0, interquartile range = 28-30 (posttest), P < 0.001]. The USGPIV confidence improved from before (mean = 2.32, SD = 1.17) to after (mean = 3.85, SD = 0.73, P < 0.001) training (5-point Likert scale). Sixty-two percent of the nurses enrolled achieved independent status, 47.5% became proctors, and 11.3% course trainers. At 3-month posttraining, the nurses had attempted a mean of 35.6 USGPIV insertions with an 89.5% success rate. Conclusions: This novel USGPIV SBML curriculum improves nurses' insertion skills, selfconfidence, and progresses patient care through USGPIV insertions on hospitalized patients with DIVA.

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Objective To examine the hypothesis that improving insulin sensitivity would improve vascular function in rheumatoid arthritis (RA). Methods We performed a 20-week, single center, randomized, double-blind, placebo-controlled, crossover study. Patients with RA (n=34) and moderate disease activity on stable disease modifying anti-rheumatic drug therapy were randomized to drug sequence, receiving either pioglitazone 45mg daily or matching placebo for 8 weeks, followed by a 4-week washout period and the alternative treatment for 8 weeks. We measured change in vascular stiffness (augmentation index and aortic pulse wave velocity), endothelial function (reactive hyperemia index), and blood pressure. High sensitivity C-reactive protein (CRP), and the homeostatic model assessment of insulin resistance (HOMA) were also measured. The treatment effect of pioglitazone on outcomes was analyzed using linear mixed effect models. Results Pioglitazone reduced augmentation index by −4.7% units (95% CI, −7.9, −1.5% units) P=0.004 and diastolic blood pressure by −3.0 mmHg (−5.7, −0.2 mmHg) P=0.03, but did not change aortic pulse wave velocity (P=0.33), or reactive hyperemia index (P=0.46) significantly. The improvements in augmentation index and diastolic blood pressure were not mediated by pioglitazone's effect on insulin resistance or inflammation. Conclusion Pioglitazone improved some indices of vascular function, including augmentation index and diastolic blood pressure, in patients with RA; this was not mediated by improved insulin sensitivity.

Aims A common, functionally significant polymorphism in GRK5 (Gln41Leu) encodes a gain-of-function enzyme that enhances desensitization of the β1-adrenergic receptor. GRK5 Leu41 has been postulated to confer endogenous ‘genetic β-blockade’ and contribute to an attenuated response to β-blockers in black subjects. The effects of this GRK5 variant on sensitivity to a β-blocker have not been studied in humans. We hypothesized that the GRK5 Gln41Leu variant contributes to interindividual variability in response to β-blockade and to the ethnic difference in sensitivity between black and Caucasian individuals. Materials & methods We measured the heart rate at rest and during a graded incremental exercise in 154 healthy subjects (85 white and 69 black) before and after an oral administration of 25 mg atenolol. We determined the genotypes of GRK5 (Gln41Leu), β1-adrenergic receptor (ADRB1 Ser49Gly and Arg389Gly) genotypes and plasma atenolol concentrations. The effects of genotype and covariates on sensitivity to atenolol, measured as the reduction in exercise-induced tachycardia, were determined using multiple regression analyses. Results The minor allele frequency of GRK5 Leu41 was 32.6% in blacks and 0% in whites. Black individuals were less sensitive to atenolol than white individuals (p ≤ 0.011) but this was not explained by the GRK5 genotype. The GRK5 genotype had no effect on resting heart rate before (p = 0.61) and after adjustment for age, sex, ethnicity, atenolol concentrations, BMI and ADRB1 genotypes (p = 0.81). The decrease in heart rate after atenolol administration did not differ significantly according to the GRK5 genotype at rest or after exercise, before (all p > 0.14) and after statistical adjustment for covariates (all p > 0.17). Conclusion The GRK5 Gln41Leu polymorphism does not affect sensitivity to the β1-adrenergic blocker, atenolol, during acute physiological adrenergic stimulation, nor does it contribute to the ethnic differences in sensitivity to atenolol among black and Caucasian individuals.