Publications

Entry inhibitors of human immunodeficiency virus, type 1 (HIV-1) have been the focus of much recent research. C34, a potent fusion inhibitor derived from the HR2 region of gp41, was engineered into a 1:1 human serum albumin conjugate through stable covalent attachment of a maleimido-C34 analog onto cysteine 34 of albumin. This bioconjugate, PC-1505, was designed to require less frequent dosing and less peptide than T-20 and was assessed for its antifusogenic activity both in vitro and in vivo in the SCID-hu Thy/Liv mouse model. PC-1505 was essentially equipotent to the original C34 peptide and to T-20 in vitro. In HIV-1-infected SCID-hu Thy/Liv mice, T-20 lost activity with infrequent dosing, whereas the antiviral potency of PC-1505 was sustained, and PC-1505 was active against T-20-resistant ("DIV") virus with a G36D substitution in gp41. The in vivo results are the direct result of a significantly improved pharmacokinetic profile for the C34 peptide following albumin conjugation. Contrary to previous reports that the gp41 NHR trimer is poorly accessible to C34 fused to protein cargoes of increasing size (Hamburger, A. E., Kim, S., Welch, B. D., and Kay, M. S. (2005) J. Biol. Chem. 280, 12567-12572), these results are the first demonstration of the capacity for a large, endogenous serum protein to gain unobstructed access to the transient gp41 intermediates that exist during the HIV fusion process, and it supports further development of albumin conjugation as a promising approach to inhibit HIV-1 entry.

OBJECTIVES

Self-reported exposure to vapours, gas, dust or fumes (VGDF) has been widely used as an occupational exposure metric in epidemiological studies of chronic lung diseases. Our objective was to characterise the performance of VGDF for repeatability, systematic misclassification, and sensitivity and specificity against exposure likelihood by a job-exposure matrix (JEM).

METHODS

We analysed data from two interviews, 24 months apart, of adults with asthma and chronic rhinitis. Using distinct job as the unit of analysis, we tested a single response item (exposure to VGDF) against assignment using a JEM. We further analysed VGDF and the JEM among a subset of 199 subjects who reported the same job at both interviews, using logistic regression analysis to test factors associated with VGDF inconsistency and discordance with the JEM.

RESULTS

VGDF was reported for 193 (44%) of 436 distinct jobs held by the 348 subjects studied; moderate to high exposure likelihood by JEM was assigned to 120 jobs (28%). The sensitivity and specificity of VGDF against JEM were 71% and 66%, respectively. Among 199 subjects with the same job at both interviews, 32% had a discordant VGDF status (kappa = 0.35). Those with chronic rhinitis without concomitant asthma compared to asthma alone were more likely to have a VGDF report discordant with the JEM (OR 3.6, 95% CI 1.4 to 9.0; p = 0.01). Rhinitis was also associated with reported VGDF in a job classified by the JEM as low exposure (OR 3.9, 95% CI 1.6 to 9.4; p = 0.003).

CONCLUSION

The VGDF item is moderately sensitive measured against JEM as a benchmark. The measure is a useful assessment method for epidemiological studies of occupational exposure risk.

BACKGROUND

Differences in pathophysiology, diagnosis, and treatment of women with cardiovascular disease compared with men has become a major focus during the past decade. Nevertheless, little attention has focused on improving the quality of healthcare in women compared with other areas of cardiovascular medicine.

METHODS

To address this deficit, Duke University Medical Center convened a national Duke Clinical Research Institute (DCRI) Think Tank meeting, including basic science and clinical researchers, payers, legislators, clinical experts, government regulators, and members of the pharmaceutical and device industries. This report provides an overview of the discussions and proposed solutions.

RESULTS

Discussion concentrated on the development of strategies to improve the quality of health care for women with heart disease. Key components to improve quality care include: (1) enhance the quantity and quality of evidence-based medicine to guide care in women through improvements in trial design, enrollment and retention of women subjects, results analysis and reporting, and better incentives to perform research in women; (2) provide incentives to develop better data in women through mandating changes in the drug and device development and approval processes; (3) incorporate specific recommendations for women into guidelines when data are sufficient; and (4) apply proven sex-based differences in risk stratification, diagnostic testing, and drug usage and dosing in clinical care. Examples of possible strategies are included.

CONCLUSION

The above approach represents a necessary, but not sufficient, platform to improve the overall quality of healthcare in women with cardiovascular disease.