Publications

Drug discovery and development to date has relied on animal models, which are useful but are often expensive, slow, and fail to mimic human physiology. The discovery of human induced pluripotent stem (iPS) cells has led to the emergence of a new paradigm of drug screening using human and disease-specific organ-like cultures in a dish. Although classical static culture systems are useful for initial screening and toxicity testing, they lack the organization of differentiated iPS cells into microphysiological, organ-like structures deemed necessary for high-content analysis of candidate drugs. One promising approach to produce these organ-like structures is the use of advanced microfluidic systems, which can simulate tissue structure and function at a micron level, and can provide high-throughput testing of different compounds for therapeutic and diagnostic applications. Here, we provide a brief outline on the different approaches, which have been used to engineer in vitro tissue constructs of iPS cell-based myocardium and liver functions on chip. Combining these techniques with iPS cell biology has the potential of reducing the dependence on animal studies for drug toxicity and efficacy screening.

OBJECTIVE

Even in the setting of duplex ultrasound (DUS) surveillance, a significant number of lower extremity vein bypass grafts (LEVBGs) become occluded as a first event. We sought to identify factors that may contribute to these primary occlusions.

METHODS

This was a retrospective analysis of the Project of Ex Vivo Graft Engineering via Transfection III (PREVENT III) multicenter randomized clinical trial, in which 1404 patients with critical limb ischemia (CLI) underwent LEVBG with 1-year follow-up. Subjects were to undergo DUS at regular intervals (1, 3, 6, and 12 months), with reintervention based on prespecified DUS criteria. Patients who had nontechnical graft occlusion as the initial graft-related event were identified, and multivariate analysis was used to determine factors associated with primary graft occlusion.

RESULTS

Primary vein graft occlusion occurred in 200 subjects and accounted for 36% of all primary patency events and 64% of all graft occlusions in the trial. Primary occlusion events were evenly distributed throughout the first postoperative year. Rates of recurrent CLI, loss of secondary patency, and major amputation in those with primary occlusion were 55%, 79%, and 22% respectively as compared to 18%, 10%, and 10% for subjects without primary occlusion (P < .001). On multivariate analysis, African-American race (subdistribution hazard ratio [SHR], 1.50; 95% confidence interval [CI], 1.06-2.12), a graft diameter <3 mm (SHR, 2.31; 95% CI, 1.33-4.01), and nonadherence with ultrasound surveillance (SHR, 1.58; 95% CI, 1.10-2.27) were independently associated with primary graft occlusion. Of the 123 subjects who received their last scheduled surveillance DUS prior to a primary occlusion event, 39 had a critical ultrasound abnormality identified but failed to undergo graft revision, while 84 had no critical ultrasound abnormality identified. Among these 84 subjects, female gender (SHR, 1.65; 95% CI, 1.07-2.54), and graft diameter <3 mm (SHR, 2.12; 95% CI, 1.03-4.37) were independent factors associated with unheralded graft occlusion.

CONCLUSIONS

Among patients undergoing LEVBG for CLI, almost half of primary patency events are occlusions even in the setting of a DUS surveillance protocol. African Americans, patients with smaller-diameter grafts, and those who are nonadherent with surveillance ultrasound are at increased risk. Failure to intervene on critical findings, and lack of sensitivity of DUS threshold criteria to predict thrombosis, are also important contributors. These findings suggest that prevention of vein graft thrombosis requires further improvements in risk stratification, surveillance, and the timing of reinterventions.

BACKGROUND

Treatment adherence may influence the therapeutic effect that is observed in a randomized controlled trial (RCT). Adherence may also be an indicator of research quality and treatment acceptance by participants. Despite the importance of adherence in RCT research, little is known about current practices for its measurement and reporting.

PURPOSE

The objective of this study was to determine and evaluate adherence measurement and reporting practices in RCTs involving oral pharmacologic interventions published in high impact factor journals.

METHODS

We conducted a systematic review of RCTs involving oral pharmacotherapy published during 2010 in 10 high-impact general medicine and subspecialty journals. Two investigators independently abstracted data regarding trial characteristics, adherence monitoring, and adherence reporting. Differences were reconciled in conference. Descriptive statistics were calculated, statistical comparisons were made using chi-square analysis, and associations assessed using Spearman's rank correlation coefficient.

RESULTS

Of 111 RCT manuscripts included in the sample, 51 (45.9%) reported study-drug adherence among participants. Studies that reported adherence results were more likely to report negative findings (i.e., no significant treatment effect in a superiority trial, non-equivalence in an equivalence trial) (p = 0.032). The most common method for adherence monitoring was pill count-back on returned bottles. Among the studies that reported adherence, the median adherence was 88.4% (range: 48%-100%), and trials with longer follow-up time reported lower adherence (r = -0.45; p = 0.0015). A minority of the 51 studies described a strategy for calculating adherence that accounted for participants who were lost to follow-up (11/51 studies; 21.6%), discontinued the study medication temporarily (6/51 studies; 11.8%), or discontinued the study drug permanently (1/51 study; 2%).

LIMITATIONS

This study is limited by the inclusion of a small set of journals with the highest impact factors in specific fields of clinical medicine, including general medicine. Although the analysis pertains to studies published in 2010, no new guidelines in the field since the last Consolidated Standards of Reporting Trials (CONSORT) statement have been issued that would be expected to change practices for adherence monitoring, analysis, and reporting.

CONCLUSIONS

Adherence measurement methodology and results are underreported in published RCTs. In the minority of RCTs that provided adherence information, there was substantial heterogeneity in how adherence was defined, analyzed, and reported. Improved reporting of adherence may enhance the interpretation of study quality and results.

BACKGROUND

Completion of the recommended 9-month course of isoniazid to treat latent tuberculosis infection in children remains poor and is often affected by adverse effects, including hepatitis, to medication. We evaluated the frequency of isoniazid therapy completion and factors associated with failure to complete therapy in patients aged 0-18 years.

METHODS

We performed a retrospective review of medical records for patients aged 0-18 years who were referred for isoniazid therapy between January 2005 and August 2011 at 2 California county sites: a public health department and a pediatric latent tuberculosis infection clinic. Medication adherence to isoniazid therapy was measured by monthly pill count.

RESULTS

There were 1872 eligible patients who were referred for isoniazid therapy. Of the 1587 patients who met inclusion criteria and initiated treatment, 1235 patients (78%) completed the 9-month therapy, including 1046 of 1308 patients aged <15 years (80%) and 189 of 268 patients aged 15-18 years (71%). Factors that were significantly associated with failure to complete therapy included age 15-18 years, non-Hispanic race, development of hepatitis, and symptoms of adverse effects. The association between age and the development of hepatitis was similar for male and female patients.

CONCLUSION

Failure to complete isoniazid therapy in patients aged 0-18 years is affected by older age, non-Hispanic race, development of hepatitis, and symptoms of adverse effects. Additional support is needed for adolescents to complete therapy for latent tuberculosis infection.