Publications

BACKGROUND

Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients.

METHODS

We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran's Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates.

RESULTS

Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27-0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36-1.87) or overall mortality (RR 0.95, 95% CI 0.46-1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing.

CONCLUSIONS

Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.

Nucleotide changes in gene regulatory elements can have a major effect on interindividual differences in drug response. For example, by reviewing all published pharmacogenomic genome-wide association studies, we show here that 96.4% of the associated single nucleotide polymorphisms reside in noncoding regions. We discuss how sequencing technologies are improving our ability to identify drug response-associated regulatory elements genome-wide and to annotate nucleotide variants within them. We highlight specific examples of how nucleotide changes in these elements can affect drug response and illustrate the techniques used to find them and functionally characterize them. Finally, we also discuss challenges in the field of drug-responsive regulatory elements that need to be considered in order to translate these findings into the clinic.

BACKGROUND

We hypothesized that a fully automated mobile health (mHealth) intervention with tracking and texting components would increase physical activity.

METHODS AND RESULTS

mActive enrolled smartphone users aged 18 to 69 years at an ambulatory cardiology center in Baltimore, Maryland. We used sequential randomization to evaluate the intervention's 2 core components. After establishing baseline activity during a blinded run-in (week 1), in phase I (weeks 2 to 3), we randomized 2:1 to unblinded versus blinded tracking. Unblinding allowed continuous access to activity data through a smartphone interface. In phase II (weeks 4 to 5), we randomized unblinded participants 1:1 to smart texts versus no texts. Smart texts provided smartphone-delivered coaching 3 times/day aimed at individual encouragement and fostering feedback loops by a fully automated, physician-written, theory-based algorithm using real-time activity data and 16 personal factors with a 10 000 steps/day goal. Forty-eight outpatients (46% women, 21% nonwhite) enrolled with a mean±SD age of 58±8 years, body mass index of 31±6 kg/m(2), and baseline activity of 9670±4350 steps/day. Daily activity data capture was 97.4%. The phase I change in activity was nonsignificantly higher in unblinded participants versus blinded controls by 1024 daily steps (95% confidence interval [CI], -580 to 2628; P=0.21). In phase II, participants receiving texts increased their daily steps over those not receiving texts by 2534 (95% CI, 1318 to 3750; P<0.001) and over blinded controls by 3376 (95% CI, 1951 to 4801; P<0.001).

CONCLUSIONS

An automated tracking-texting intervention increased physical activity with, but not without, the texting component. These results support new mHealth tracking technologies as facilitators in need of behavior change drivers.

CLINICAL TRIAL REGISTRATION

URL: http://ClinicalTrials.gov/. Unique identifier: NCT01917812.