Age-related macular degeneration (AMD), the leading cause of severe vision loss in the elderly, is a complex disease that results from genetic modifications that increase susceptibility to environmental exposures. Smoking, a major source of oxidative stress, increases the incidence and severity of AMD, and antioxidants slow progression, suggesting that oxidative stress plays a major role. Polymorphisms in the complement factor H (CFH) gene that reduce activity of CFH increase the risk of AMD. In this study we demonstrate an interaction between these two risk factors, because oxidative stress reduces the ability of an inflammatory cytokine, interferon-␥, to increase CFH expression in retinal pigmented epithelial cells. The interferon-␥-induced increase in CFH is mediated by transcriptional activation by STAT1, and its suppression by oxidative stress is mediated by acetylation of FOXO3, which enhances FOXO3 binding to the CFH promoter, reduces its binding to STAT1, inhibits STAT1 interaction with the CFH promoter, and reduces expression of CFH. Expression of SIRT1, a mammalian homolog of NAD-dependent protein deacetylase sir2, attenuated FOXO3 recruitment to the CFH regulatory region and reversed the H 2 O 2 -induced repression of CFH gene expression. These data suggest an important interaction between environmental exposure and genetic susceptibility in the pathogenesis of AMD and, by elucidating molecular signaling involved in the interaction, provide potential targets for therapeutic intervention.

A preapproval antimicrobial stewardship program effectively reduces the number of doses and subsequent charges due to restricted antimicrobials years after implementation. Hospitals with reduced resources for implementing postprescription review may benefit from a preapproval antimicrobial stewardship program. Targeting specific units, drugs, and seasons may optimize preapproval programs for additional cost savings.

WHAT'S KNOWN ON THIS SUBJECT:Existing data do not demonstrate a need for combination therapy after antimicrobial susceptibility data indicate adequate in vitro activity with b-lactam monotherapy. However, the role of empirical combination therapy for the treatment of Gram-negative bacteremia in children remains unsettled. WHAT THIS STUDY ADDS:We conducted a retrospective, propensityscore matched study demonstrating no improvement in 10-day mortality of children who have Gram-negative bacteremia receiving empirical b-lactam and aminoglycoside combination therapy compared with b-lactam monotherapy, unless the bacteremic episode was attributable to a multidrug-resistant organism. METHODS:We conducted a retrospective cohort study of children treated for Gram-negative bacteremia at The Johns Hopkins Hospital from 2004 through 2012. We compared the estimated odds of 10-day mortality and the relative duration of bacteremia for children receiving empirical combination therapy versus empirical monotherapy using 1:1 nearest-neighbor propensity-score matching without replacement, before performing regression analysis. RESULTS:We identified 226 matched pairs of patients well balanced on baseline covariates. Ten-day mortality was similar between the groups (odds ratio, 0.84; 95% confidence interval [CI], 0.28 to 1.71). Use of empirical combination therapy was not associated with a decrease in the duration of bacteremia (20.51 days; 95% CI, 22.22 to 1.48 days). There was no survival benefit when evaluating 10-day mortality for the severely ill (pediatric risk of mortality III score $15) or profoundly neutropenic patients (absolute neutrophil count #100 cells/mL) receiving combination therapy. However, a survival benefit was observed when empirical combination therapy was prescribed for children growing multidrug-resistant Gram-negative organisms from the bloodstream (odds ratio, 0.70; 95% CI, 0.51 to 0.84). CONCLUSIONS:Although there appears to be no advantage to the routine addition of an aminoglycoside to a b-lactam as empirical therapy for children who have Gram-negative bacteremia, children who have risk factors for MDRGN organisms appear to benefit from this practice.