Publications

Latently infected cells form the major obstacle to HIV eradication. Studies of HIV latency have been generally hindered by the lack of a robust and rapidly deployable cell model that involves primary human CD4 T lymphocytes. Latently infected cell lines have proven useful, but it is unclear how closely these proliferating cells recapitulate the conditions of viral latency in non-dividing CD4 T lymphocytes in vivo. Current primary lymphocyte models more closely reflect the in vivo state of HIV latency, but they are limited by protracted culture periods and often low cell yields. Additionally, these models are always established in a single latently infected cell type that may not reflect the heterogeneous nature of the latent reservoir. Here we describe a rapid, sensitive, and quantitative primary cell model of HIV-1 latency with replication competent proviruses and multiple reporters to enhance the flexibility of the system. In this model, post-integration HIV-1 latency can be established in all populations of CD4 T cells, and reactivation of latent provirus assessed within 7 days. The kinetics and magnitude of reactivation were evaluated after stimulation with various cytokines, small molecules, and T-cell receptor agonists. Reactivation of latent HIV proviruses was readily detected in the presence of strong activators of NF-κB. Latently infected transitional memory CD4 T cells proved more responsive to these T-cell activators than latently infected central memory cells. These findings reveal potentially important biological differences within the latently infected pool of memory CD4 T cells and describe a flexible primary CD4 T-cell system to evaluate novel antagonists of HIV latency.

BACKGROUND

Overuse, the provision of health care services for which harms outweigh benefits, represents poor quality and contributes to high costs. A better understanding of overuse in US health care could inform efforts to reduce inappropriate care. We performed an extensive search for studies of overuse of therapeutic procedures, diagnostic tests, and medications in the United States and describe the state of the literature.

METHODS

We searched MEDLINE (1978-2009) for studies measuring US rates of overuse of procedures, tests, and medications, augmented by author tracking, reference tracking, and expert consultation. Four reviewers screened titles; 2 reviewers screened abstracts and full articles and extracted data including overuse rate, type of service, clinical area, and publication year.

RESULTS

We identified 172 articles measuring overuse: 53 concerned therapeutic procedures; 38, diagnostic tests; and 81, medications. Eighteen unique therapeutic procedures and 24 diagnostic services were evaluated, including 10 preventive diagnostic services. The most commonly studied services were antibiotics for upper respiratory tract infections (59 studies), coronary angiography (17 studies), carotid endarterectomy (13 studies), and coronary artery bypass grafting (10 studies). Overuse of carotid endarterectomy and antibiotics for upper respiratory tract infections declined over time.

CONCLUSIONS

The robust evidence about overuse in the United States is limited to a few services. Reducing inappropriate care in the US health care system likely requires a more substantial investment in overuse research.