Publications

BACKGROUND

A positive tuberculin skin test (TST) is often defined by skin induration of ≥10 mm in people who are HIV-seronegative. However, to increase sensitivity for detection of Mycobacterium tuberculosis infection in the context of impaired immune function, a revised cut-off of ≥5 mm is used for people living with HIV infection. The incremental proportion of patients who are included by this revised definition and the association between this proportion and CD4+ cell count are unknown.

METHODS

The literature was systematically reviewed to determine the proportion of people living with HIV (PLWH) without evidence of active tuberculosis in low and middle-income countries who tested TST-positive using cut-offs of ≥5 mm and ≥10 mm of induration. The difference in the proportion testing TST-positive using the two cut-off sizes was calculated for all eligible studies and was stratified by geographical region and CD4+ cell count.

RESULTS

A total of 32 studies identified meeting criteria were identified, providing data on 10,971 PLWH from sub-Saharan Africa, Asia and the Americas. The median proportion of PLWH testing TST-positive using a cut-off of ≥5 mm was 26.8% (IQR, 19.8-46.1%; range, 2.5-81.0%). Using a cut-off of ≥10 mm, the median proportion of PLWH testing TST-positive was 19.6% (IQR, 13.7-36.8%; range 0-52.1%). The median difference in the proportion of PLWH testing TST-positive using the two cut-offs was 6.0% (IQR, 3.4-10.1%; range, 0-37.6%). Among those with CD4+ cell counts of <200, 200-499 and ≥500 cells/μL, the proportion of positive tests defined by the ≥5 mm cut-off that were between 5.0 and 9.9 mm in diameter was similar (12.5%, 12.9% and 10.5%, respectively).

CONCLUSIONS

There is a small incremental yield in the proportion of PLWH who test TST-positive when using an induration cut-off size of ≥5 mm compared to ≥10 mm. This proportion was similar across the range of CD4+ cell strata, supporting the current standardization of this cut-off at all levels of immunodeficiency.

Current models of tumor cell invasion propose that oncogenic signaling converges upon key orchestrators of cytoskeletal dynamics, including c-Jun N-terminal kinase (Jnk) and RhoGTPase family members; these signals dynamically direct Actin remodeling proteins (ARPs) to catalyze the cytoskeletal changes required for migration. Src is a key driver of tumor aggression, metastasis and patient mortality. To clarify how Src regulates Actin dynamics to promote invasive migration, we performed a genetic modifier screen in a Drosophila model of invasion. Nine genes linked to Actin dynamics were identified that mediate invasion in situ. We found that ARPs were required for many oncogenic effects of Src including Mmp1 expression and initiation of apoptosis. Surprisingly, they were also regulators of Jnk pathway activity: both Src and the small GTPase Rho1 activated Jnk in a manner dependent on ARPs during invasion. Our results suggest that ARPs are not simply downstream executors of signal transduction pathways. Rather, they participate in a positive feedback network involving canonical oncogenic signaling pathways that promote tumor invasion.