Publications

BACKGROUND

Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed.

METHODS

In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison).

RESULTS

The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003).

CONCLUSIONS

When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).

Formalizing eligibility criteria in a computer-interpretable language would facilitate eligibility determination for study subjects and the identification of studies on similar patient populations. Because such formalization is extremely labor intensive, we transform the problem from one of fully capturing the semantics of criteria directly in a formal expression language to one of annotating free-text criteria in a format called ERGO annotation. The annotation can be done manually, or it can be partially automated using natural-language processing techniques. We evaluated our approach in three ways. First, we assessed the extent to which ERGO annotations capture the semantics of 1000 eligibility criteria randomly drawn from ClinicalTrials.gov. Second, we demonstrated the practicality of the annotation process in a feasibility study. Finally, we demonstrate the computability of ERGO annotation by using it to (1) structure a library of eligibility criteria, (2) search for studies enrolling specified study populations, and (3) screen patients for potential eligibility for a study. We therefore demonstrate a new and practical method for incrementally capturing the semantics of free-text eligibility criteria into computable form.

RATIONALE

Smear-positive tuberculosis (TB) case detection rates are far below targets in most low-income countries. The standard approach to smear microscopy involves sputum collection over multiple days and examination of sputum smears by light microscopy (LM), an insensitive and time-consuming technique.

OBJECTIVE

To determine whether two alternative approaches can increase smear-positive case detection by increasing the efficiency (single-specimen microscopy) or sensitivity (light-emitting diode [LED] fluorescence microscopy [FM]) of TB suspect evaluation.

METHODS

We enrolled patients with cough of 2 weeks or more admitted to Mulago Hospital in Kampala, Uganda and collected spot and early morning sputum specimens. We compared the diagnostic accuracy of four prespecified strategies based on the number of sputum specimens collected (one specimen versus two specimens) and the type of microscopy (LM versus LED FM) using mycobacterial culture as a reference standard.

MEASUREMENTS AND MAIN RESULTS

Two hundred thirty-three of 464 (50%) patients had culture-positive TB. There was no difference in sensitivity between single-specimen and two-specimen strategies when smears were examined with LM (55 vs. 56%; difference, -1%; 95% confidence interval [CI], -5 to +2%) or LED FM (61 vs. 64%; difference, -3%; 95% CI, -7 to +1%). LED FM was more sensitive than LM with both the single-specimen (61 vs. 55%; difference, 6%; 95% CI, 2-10%) and two-specimen strategies (64 vs. 56%; difference, 8%; 95% CI, 3-12%). Findings were similar among the HIV-infected patient subset (n = 321 patients).

CONCLUSIONS

In low-income, high TB burden settings, single-specimen microscopy and LED FM, either alone or in combination, could considerably increase identification of smear-positive TB cases.