Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia Ankara vaccines: a systematic review.

BACKGROUND: Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines. METHODS: Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. 'Routine cardiac investigations' (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and 'Symptom-driven cardiac investigations' are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine. RESULTS: Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine. CONCLUSIONS: Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337.

Postmenopausal hormone use and the risk of nephrolithiasis: results from the Women's Health Initiative hormone therapy trials.

BACKGROUND: Observational studies examining the role of estrogen in the risk of kidney stone formation have shown conflicting results. However, randomized trial evidence on nephrolithiasis risk with estrogen therapy in postmenopausal women is lacking. METHODS: We reviewed the incidence of nephrolithiasis in the Women's Health Initiative estrogen-alone and estrogen plus progestin trials conducted at 40 US clinical centers. A total of 10 739 postmenopausal women with hysterectomy were randomized to receive 0.625 mg/d of conjugated equine estrogens (CEE) or placebo, and 16 608 postmenopausal women without hysterectomy were randomized to receive placebo or estrogen plus progestin given as CEE plus medroxyprogesterone acetate (2.5 mg/d). The incidence of nephrolithiasis was determined for an average follow-up of 7.1 years for the CEE trial and 5.6 years for the estrogen plus progestin trial. RESULTS: Baseline demographic characteristics and risk factors for nephrolithiasis were similar in the placebo and treatment arms. Estrogen therapy was associated with a significant increase in nephrolithiasis risk from 34 to 39 cases per 10 000 person-years (hazard ratio, 1.21; 95% confidence interval, 1.03-1.44). Censoring data from women when they ceased to adhere to study medication increased the hazard ratio to 1.39 (95% confidence interval, 1.08-1.78). The increased nephrolithiasis risk was independent of progestin coadministration, and effects did not vary significantly according to prerandomization history of nephrolithiasis. CONCLUSIONS: These data suggest that estrogen therapy increases the risk of nephrolithiasis in healthy postmenopausal women. These findings should be considered in decision making regarding postmenopausal estrogen use. The mechanisms underlying this higher susceptibility remain to be determined. Trial Registration clinicaltrials.gov Identifier: NCT0000611.

Comparing adaptive and non-adaptive algorithms for cancer early detection with novel biomarkers.

It may be possible to reduce cancer mortality by monitoring the concentrations of serum biomarkers over time in men and women to detect their cancer early, when it is most curable. The simplest approach to using a biomarker for screening is to sequentially use fixed thresholds as a means to determine an abnormal test (e.g., PSA exceeding 4 mg/ml, CA 125 exceeding 30 U/ml). Alternatives to the simplest single threshold (ST) rules include more sophisticated algorithms that make use of screening history that accumulates over time and determines abnormal tests using individualized reference ranges. Although in principle longitudinal algorithms should out perform fixed threshold rules, the actual benefit gained will depend on behavior of the biomarker, the screening algorithm, and the screening frequency. Little information has been available to help predict when conditions should compel the adoption of the more sophisticated algorithms and when conditions suggest the simpler algorithms should suffice, or indeed be preferred. In this manuscript we evaluate the conditions under which one should expect great benefit, and when one should not expect benefit, by comparing the ability of simple and complex algorithms to detect cancer early under a variety of biomarker behaviors and screening frequencies.