Temporal trends in transcatheter aortic valve replacement use and outcomes by race, ethnicity, and sex.

OBJECTIVES: To identify trends in transcatheter aortic valve replacement (TAVR) use and outcomes by race (non-Hispanic White, Black), ethnicity (Hispanic), and sex over time. BACKGROUND: Despite rapid growth in TAVR use over time, our understanding of its use and outcomes among males and females of underrepresented racial/ethnic groups remains limited. METHODS: A retrospective analysis of hospitalizations from 2013 to 2017 from the Healthcare Cost and Utilization Project database was performed. RESULTS: White patients comprised 65% (n = 2.16 × 107 ) of all hospitalizations, yet they comprised 83% (n = 176,887) of the admissions for aortic stenosis (p < 0.0001). Among 91,693 hospitalizations for aortic valve replacement, 64,069 were surgical (34.0% female, 7.0% Hispanic, and 5.9% Black) and 27,624 were transcatheter (46.6% female, 4.5% Hispanic, and 4.4% Black). Growth in TAVR volumes was the slowest among minorities and females. Hispanic males, Hispanic females, and White females had the highest in-hospital mortality (2.7%-3.3%; compared to White males, adjusted odds ratio: Hispanic males 1.9 [1.2-3.0], Hispanic females 1.9 [1.2-3.1], and White females 1.4 [1.2-1.7]). Despite less baseline vascular disease, females of all races/ethnicities had more vascular complications than men (female 5% vs. male 3.5%, p ≤ 0.001). Further adjustment for vascular complications only partially attenuated mortality differences. Black and Hispanic patients had a longer mean length of hospital stay than White patients, which was most pronounced among females. Pacemaker requirements were consistently low among all groups. CONCLUSION: Differences in TAVR growth and outcomes by race, ethnicity, and sex over time highlight areas for focused efforts to close gaps in minimally invasive structural heart disease care.

Conserved motifs in a tombusvirus polymerase modulate genome replication, subgenomic transcription, and amplification of defective interfering RNAs.

UNLABELLED: The replication of plus-strand RNA virus genomes is mediated by virally encoded RNA-dependent RNA polymerases (RdRps). We have investigated the role of the C-proximal region in the RdRp of tomato bushy stunt virus (TBSV) in mediating viral RNA synthesis. TBSV is the prototype species in the genus Tombusvirus, family Tombusviridae, and its RdRp is responsible for replicating the viral genome, transcribing two subgenomic mRNAs, and supporting replication of defective interfering RNAs. Comparative sequence analysis of the RdRps of tombusvirids identified three highly conserved motifs in their C-proximal regions, and these sequences were subsequently targeted for mutational analysis in TBSV. The results revealed that these motifs are important for (i) synthesizing viral genomic RNA and subgenomic mRNAs, (ii) facilitating plus- and/or minus-strand synthesis, and (iii) modulating trans-replication of a defective interfering RNA. These motifs were also found to be conserved in other plant viruses as well as in a fungal and insect virus. The collective findings are discussed in relation to viral RNA synthesis and taxonomy. IMPORTANCE: Little is currently known about the structure and function of the viral polymerases that replicate the genomes of RNA plant viruses. Tombusviruses, the prototype of the tombusvirids, have been used as model plus-strand RNA plant viruses for understanding many of the steps in the infectious process; however, their polymerases remain poorly characterized. To help address this issue, the function of the C-terminal region of the polymerase of a tombusvirus was investigated. Three conserved motifs were identified and targeted for mutational analysis. The results revealed that these polymerase motifs are important for determining what type of viral RNA is produced, facilitating different steps in viral RNA production, and amplifying subgenomic RNA replicons. Accordingly, the C-terminal region of the tombusvirus polymerase is needed for a variety of fundamental activities. Furthermore, as these motifs are also present in distantly related viruses, the significance of these results extends beyond tombusvirids.

Establishment of orthotopic primary cervix cancer xenografts.

Standard treatment for women who are diagnosed with stage IIB through IVA cervical cancer consists of cisplatin-based chemotherapy and radiation. Current options for patients with recurrent and metastatic disease are limited, and their median overall survival is <12 months. To date, biologic therapy has had little impact on survival, so identification of potential new targets is urgently required to develop novel therapeutic strategies. Developing relevant animal models for human cervix cancer is important to further enhance our understanding of the characteristics of these tumors and for identification and assessment of novel therapies. We have established a panel of orthotopically passaged xenografts (OCICx) by implanting cervix tumor pieces from patient biopsies directly into the cervix of mice. The tumors have been passaged up to five generations, were characterized histologically for tumor and stromal content and, where possible, related to similar measurements in the original patient biopsy. The tumors were found to metastasize to the para-aortic lymphnodes allowing assessment of their metastatic potential. Preliminary studies demonstrate aberrant expression of genes in the Hedgehog (Hh) pathway in the xenografts similar to findings in primary cervix cancers. The OCICx xenografts represent unique models to test strategies for targeting essential pathways in cervix cancer and metastasis.

Cyclic hypoxia does not alter RAD51 expression or PARP inhibitor cell kill in tumor cells.

Solid tumors contain regions of chronic and cyclic hypoxia. Chronic hypoxia can downregulate RAD51 and sensitize cells to PARP inhibition. Herein, we show that RAD51 expression, cell survival and toxicity to PARP inhibition is not affected under cyclic hypoxic conditions. This suggests that PARP inhibition may be selectively toxic in tumor sub-regions associated with chronic hypoxia.