Pretransplant survival of patients with end-stage heart failure under competing risks.

Heart transplantation is the gold standard of care for end-stage heart failure in the United States. Donor hearts are a scarce resource, however the current allocation policy-proposed in 2016 and implemented in 2018-has not addressed certain disparities. Between 2005 and 2016, the number of active candidates increased 127%, whereas transplant rates decreased 27.8%. Pretransplant mortality rates declined steadily for that period from 14.6 to 9.7, especially for candidates with mechanical circulatory assistive devices (MCSDs). This study reports survival analyses of candidates for heart transplantation list under competing events of transplantation and MCSD implantation. We queried the transplant data for a cohort of adult patients (age ≥ 16) without MCSDs prior to listing for transplantation between 2005 and 2014 (n = 23,373). We used cause-specific and subdistribution hazards models as multivariate regressions for all competing events. Patients listed as low priority for transplantation are less likely to require implantation but less likely to survive after 1,000 days of listing than patients listed at higher priorities. The current policy does not address this disparity as it focuses on stratifying patients with different types of MCSD. Clinical characteristics must be considered in prioritization.

Genetic capitalism and stabilizing selection of antimicrobial resistance genotypes in Escherichia coli.

Antimicrobial resistance (AMR) in pathogenic strains of bacteria, such as Escherichia coli (E. coli), adversely impacts personal and public health. In this study, we examine competing hypotheses for the evolution of AMR including (i) 'genetic capitalism' in which genotypes that confer antibiotic resistance are gained and not often lost in lineages, and (ii) 'stabilizing selection' in which genotypes that confer antibiotic resistance are gained and lost often. To test these hypotheses, we assembled a dataset that includes annotations for 409 AMR genotypes and a phylogenetic tree based on genome-wide single nucleotide polymorphisms from 29 255 isolates of E. coli collected over the past 134 years. We used phylogenetic methods to count the times each AMR genotype was gained and lost across the tree and used model-based clustering of the genotypes with respect to their gain and loss rates. We demonstrate that many genotypes cluster to support the hypothesis for genetic capitalism while a few genotypes cluster to support the hypothesis for stabilizing selection. Comparing the sets of genotypes that fall under each of the hypotheses, we found a statistically significant difference in the breakdown of resistance mechanisms through which the AMR genotypes function. The result that many AMR genotypes cluster under genetic capitalism reflects that strong positive selective forces, primarily induced by human industrialization of antibiotics, outweigh the potential fitness costs to the bacterial lineages for carrying the AMR genotypes. We expect genetic capitalism to further drive bacterial lineages to resist antibiotics. We find that antibiotics that function via replacement and efflux tend to behave under stabilizing selection and thus may be valuable in an antibiotic cycling strategy.