Publications

New genetic tools are needed to understand the functional interactions between HIV and human host factors in primary cells. We recently developed a method to edit the genome of primary CD4 T cells by electroporation of CRISPR/Cas9 ribonucleoproteins (RNPs). Here, we adapted this methodology to a high-throughput platform for the efficient, arrayed editing of candidate host factors. CXCR4 or CCR5 knockout cells generated with this method are resistant to HIV infection in a tropism-dependent manner, whereas knockout of LEDGF or TNPO3 results in a tropism-independent reduction in infection. CRISPR/Cas9 RNPs can furthermore edit multiple genes simultaneously, enabling studies of interactions among multiple host and viral factors. Finally, in an arrayed screen of 45 genes associated with HIV integrase, we identified several candidate dependency/restriction factors, demonstrating the power of this approach as a discovery platform. This technology should accelerate target validation for pharmaceutical and cell-based therapies to cure HIV infection.

OBJECTIVES

The aim of this study was to investigate the efficacy and safety of intraprocedural embolic protection (EP) during transcatheter aortic valve replacement (TAVR).

BACKGROUND

Randomized controlled trials (RCTs) investigating the efficacy of EP devices during TAVR were relatively underpowered.

METHODS

A systematic review and study-level meta-analysis was performed of randomized controlled trials that tested the efficacy and safety of EP during TAVR. Trials using any type of EP and TAVR vascular access were included. Primary imaging efficacy endpoints were total lesion volume and number of new ischemic lesions. Primary clinical efficacy endpoints were any deterioration in National Institutes of Health Stroke Scale and Montreal Cognitive Assessment scores at hospital discharge. Primary analyses were performed using the intention-to-treat approach.

RESULTS

Four randomized clinical trials (total n = 252) were included. Use of EP was associated with lower total lesion volume (standardized mean difference -0.65; 95% confidence interval [CI]: -1.06 to -0.25; p = 0.002) and smaller number of new ischemic lesions (standardized mean difference -1.27; 95% CI: -2.45 to -0.09; p = 0.03). EP was associated with a trend toward lower risk for deterioration in National Institutes of Health Stroke Scale score at discharge (risk ratio: 0.55; 95% CI: 0.27 to 1.09; p = 0.09) and higher Montreal Cognitive Assessment score (standardized mean difference 0.40; 95% CI: 0.04 to 0.76; p = 0.03). Risk for overt stroke and all-cause mortality were nonsignificantly lower in the EP group.

CONCLUSIONS

Use of EP seems to be associated with reductions in imaging markers of cerebral infarction and early clinical neurological effectiveness in patients undergoing TAVR.

Lung transplant recipients (LTR) are at high risk of cutaneous squamous cell carcinoma (SCC). Voriconazole exposure after lung transplant has recently been reported as a risk factor for SCC. We sought to study the relationship between fungal prophylaxis with voriconazole and the risk of SCC in sequential cohorts from a single center. We evaluated 400 adult LTR at UCLA between 7/1/2005 and 12/22/2012. On 7/1/2009, our center instituted a protocol switch from targeted to universal antifungal prophylaxis for at least 6 months post-transplant. Using Cox proportional hazards models, time to SCC was compared between targeted (N = 199) and universal (N = 201) prophylaxis cohorts. Cox models were also used to assess SCC risk as a function of time-dependent cumulative exposure to voriconazole and other antifungal agents. The risk of SCC was greater in the universal prophylaxis cohort (HR 2.02, P < 0.01). Voriconazole exposure was greater in the universal prophylaxis cohort, and the cumulative exposure to voriconazole was associated with SCC (HR 1.75, P < 0.01), even after adjustment for other important SCC risk factors. Voriconazole did not increase the risk of advanced tumors. Exposure to other antifungal agents was not associated with SCC. Voriconazole should be used cautiously in this population.