Association Between Pulmonary Hypertension and Its Effect on 30-Day Mortality, Readmission, and Cost After Transcatheter Aortic Valve Replacement: A Multicenter Study.

Background Pulmonary hypertension (PH) is commonly seen in patients with severe aortic stenosis. Transcatheter aortic valve replacement (TAVR) has been shown to improve PH, however, its impact on clinical outcomes and cost remains unclear. Methods We did a multicenter, retrospective analysis of patients undergoing TAVR in our system between December 2012 to November 2020. The initial sample size was 1356. We excluded patients with prior history of heart failure, with a left ventricular ejection fraction of 40% or less, and patients who had active symptoms of heart failure within two weeks of the procedure. Patients were divided into four groups based on their pulmonary pressures, using right ventricular systolic pressure (RVSP) as a surrogate for PH. Groups included patients with normal pulmonary pressures (<35mmHg), mild (35-45mmHg) moderate (46-60mmHg), and severe PH (>60mmHg). Primary outcomes included 30-day mortality and readmission. Secondary outcomes included length of ICU stay and cost of admission. We used Chi-square and T-tests for demographic analysis of categorical continuous variables respectively. Adjusted regression was used for the reliability of correlation between variables. Multivariate analysis was used for final outcomes. Results Final sample size was 474. Average age was 78.9 years (SD: 8.2, 53% Male). Thirty-one percent (n=150) had normal pulmonary pressures, 33% (n=156) had mild PH, 25% (n=122) had moderate and 10% (n=46) had severe PH. Patients with history of hypertension (p-value<0.001), diabetes (p-value<0.001), chronic lung disease (p-value=0.006) and those on supplemental oxygen (p-value=0.046), had significantly higher proportion of patients with moderate and severe PH. We found significantly higher odds of 30-day mortality in patients with severe PH (OR: 6.77, CI: 1.09-41.98: p-value 0.04) compared with normal or mild PH. There was no significant difference in 30-day readmission (p-value=0.859) between the four groups. Cost did not change with severity of PH (Avg: $261,075: p-value=0.810). Patients with severe PH spent a significantly higher number of hours in ICU, compared with the other three groups (Mean: 18.2, p=value <0.001). Conclusions Severe pulmonary hypertension significantly increased the odds of 30-day mortality and ICU stay in TAVR patients. We did not see any significant difference in 30-day readmission and cost of admission, based on PH severity.

The Legacy of Infectious Disease Exposure on the Genomic Diversity of Indigenous Southern Mexicans.

To characterize host risk factors for infectious disease in Mesoamerican populations, we interrogated 857,481 SNPs assayed using the Affymetrix 6.0 genotyping array for signatures of natural selection in immune response genes. We applied three statistical tests to identify signatures of natural selection: locus-specific branch length (LSBL), the cross-population extended haplotype homozygosity (XP-EHH), and the integrated haplotype score (iHS). Each of the haplotype tests (XP-EHH and iHS) were paired with LSBL and significance was determined at the 1% level. For the paired analyses, we identified 95 statistically significant windows for XP-EHH/LSBL and 63 statistically significant windows for iHS/LSBL. Among our top immune response loci, we found evidence of recent directional selection associated with the major histocompatibility complex (MHC) and the peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway. These findings illustrate that Mesoamerican populations' immunity has been shaped by exposure to infectious disease. As targets of selection, these variants are likely to encode phenotypes that manifest themselves physiologically and therefore may contribute to population-level variation in immune response. Our results shed light on past selective events influencing the host response to modern diseases, both pathogenic infection as well as autoimmune disorders.

Transcriptome-wide changes in gene expression, splicing, and lncRNAs in response to a live attenuated dengue virus vaccine.

The tetravalent dengue vaccine candidate, TAK-003, induces a functional antibody response, but the titers of antibodies against the four serotypes of the dengue virus (DENV) can vary. Here, through a transcriptomic analysis on whole blood collected from recipients of a two-dose schedule of TAK-003, we examine gene expression, splicing, and transcript isoform-level changes for both protein-coding and noncoding genes to broaden our understanding of the immune response. Our analysis reveals a dynamic pattern of vaccine-associated regulation of long noncoding RNAs (lncRNAs), differential splicing of interferon-stimulated gene exons, and gene expression changes related to multiple signaling pathways that detect viral infection. Co-expression networks isolate immune cell-type-related and interferon-response modules that represent specific biological processes that correlate with more robust antibody responses. These data provide insights into the early determinants of the variable immune response to the vaccine, highlighting the significance of splicing and isoform-level gene regulatory mechanisms in defining vaccine immunogenicity.