Locking Hemodialysis Catheters With Trimethoprim-Ethanol-Ca-EDTA to Prevent Bloodstream Infections: A Randomized, Evaluator-blinded Clinical Trial.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) often result from intraluminal microbial colonization and are associated with morbidity, mortality, and substantial costs. The use of antimicrobial catheter lock solutions may reduce the incidence of CLABSI. METHODS: Patients undergoing hemodialysis (HD) through a prevalent central venous catheter (CVC) were randomly assigned to have their CVC locked between dialysis sessions with an antimicrobial catheter lock solution that contained trimethoprim 5 mg/mL, ethanol 25%, and Ca-EDTA 3% (investigational medical device [IMD]) or heparin 5000 U/mL active control heparin (ACH). Exit site care was standardized by protocol-driven use of skin antiseptics and occlusive dressings. The composite primary endpoint consisted of the incidence of CLABSI and intracatheter thrombolytic treatment (TT). Given the viscosity and odor of the IMD, blinding was impossible. Therefore, a blinded endpoint committee adjudicated the incidence of CLABSI. RESULTS: A total of 270 patients on HD were enrolled and followed for 43738 CVC-days. Despite the low CLABSI incidence of 0.41/1000 CVC-days in patients randomized to ACH, the IMD further reduced the incidence 4.56-fold to 0.09/1000 CVC-days (P < .03). The product was well tolerated, and the frequency and severity of adverse events were comparable between groups. Intracatheter instillation of thrombolytics was more frequent in patients who received the IMD (12% ACH, 40% IMD; P < .001), but rates of catheter removal did not differ (13% ACH, 11% IMD). Overall, dialysis adequacy was comparable between groups. CONCLUSIONS: In patients on chronic HD, a trimethoprim, ethanol, and Ca-EDTA lock solution significantly reduced the incidence of CLABSI. CLINICAL TRIALS REGISTRATION: NCT01989091.

Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone.

Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA) may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs) or anti-TNF-α therapy. We used quantitative real-time PCR to compare peripheral blood gene expression profiles in active ("unstable") RA patients on DMARDs, stable RA patients on DMARDs, and stable RA patients treated with a combination of a disease-modifying anti-rheumatoid drug (DMARD) and an anti-TNF-α agent (infliximab or etanercept) to healthy human controls. The expression of 48 inflammatory genes were compared between healthy controls (N = 122), unstable DMARD patients (N = 18), stable DMARD patients (N = 26), and stable patients on combination therapy (N = 20). Expression of 13 genes was very low or undetectable in all study groups. Compared to healthy controls, patients with unstable RA on DMARDs exhibited increased expression of 25 genes, stable DMARD patients exhibited increased expression of 14 genes and decreased expression of five genes, and combined therapy patients exhibited increased expression of six genes and decreased expression of 10 genes. These findings demonstrate that active RA is associated with increased expression of circulating inflammatory markers whereas increases in inflammatory gene expression are diminished in patients with stable disease on either DMARD or anti-TNF-α therapy. Furthermore, combination DMARD and anti-TNF-α therapy is associated with greater reductions in circulating inflammatory gene expression compared to DMARD therapy alone. These results suggest that assessment of peripheral blood gene expression may prove useful to monitor disease progression and response to therapy.

Limited dynamic range of immune response gene expression observed in healthy blood donors using RT-PCR.

The use of quantitative gene expression analysis for the diagnosis, prognosis, and monitoring of disease requires the ability to distinguish pathophysiological changes from natural variations. To characterize these variations in apparently healthy subjects, quantitative real-time PCR was used to measure various immune response genes in whole blood collected from blood bank donors. In a single-time-point study of 131 donors, of 48 target genes, 43 were consistently expressed and 34 followed approximately log-normal distribution. Most transcripts showed a limited dynamic range of expression across subjects. Specifically, 36 genes had standard deviations (SDs) of 0.44 to 0.79 cycle threshold (C(T)) units, corresponding to less than a 3-fold variation in expression. Separately, a longitudinal study of 8 healthy individuals demonstrated a total dynamic range (> 2 standard error units) of 2- to 4-fold in most genes. In contrast, a study of whole blood gene expression in 6 volunteers injected with LPS showed 15 genes changing in expression 10- to 90-fold within 2 to 5 h and returning to within normal range within 21 hours. This work demonstrates that (1) the dynamic range of expression of many immune response genes is limited among healthy subjects; (2) expression levels for most genes analyzed are approximately log-normally distributed; and (3) individuals exposed to an infusion of bacterial endotoxin (lipopolysaccharide), show gene expression profiles that can be readily distinguished from those of a healthy population. These results suggest that normal reference ranges can be established for gene expression assays, providing critical standards for the diagnosis and management of disease.