The host transcriptional response to superinfection by influenza A virus and Streptococcus pneumoniae.

Secondary bacterial challenges during influenza virus infection "superinfection") cause excessive mortality and hospitalization. Here, we present a longitudinal study of bulk gene expression changes in murine lungs during superinfection, with an initial influenza A virus infection and a subsequent Streptococcus pneumoniae infection. In addition to the well-characterized impairment of the host response, we identified superinfection-specific alterations in the global transcriptional program that are linked to the host's ability to resist the pathogens. Particularly, whereas superinfected mice manifested an excessive rapid induction of the resistance-to-infection program, there was a substantial tissue-level rewiring of this program: upon superinfection, interferon-regulated genes were switched from positive to negative correlations with the host's resistance state, whereas genes of fatty acid metabolism switched from negative to positive correlations with resistance states. Thus, the transcriptional resistance state in superinfection is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into a tissue-level remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions. IMPORTANCE: Secondary bacterial infections are the most frequent complications during influenza A virus (IAV) pandemic outbreaks, contributing to excessive morbidity and mortality in the human population. Most IAV-related deaths are attributed to Streptococcus pneumoniae (SP) infections, which usually begin within the first week of IAV infection in the respiratory tracts. Here, we focused on longitudinal transcriptional responses during a superinfection model consisting of an SP infection that follows an initial IAV infection, comparing superinfection to an IAV-only infection, an SP-only infection, and control treatments. Our longitudinal data allowed a fine analysis of gene expression changes during superinfection. For instance, we found that superinfected mice exhibited rapid gene expression induction or reduction within the first 12 h after encountering the second pathogen. Cell proliferation and immune response activation processes were upregulated, while endothelial processes, vasculogenesis, and angiogenesis were downregulated, providing promising targets for future therapeutic interventions. We further analyzed the longitudinal transcriptional responses in the context of a previously defined spectrum of the host's resistance state, revealing superinfection-specific reprogramming of resistance states, such as reprogramming of fatty acid metabolism and interferon signaling. The reprogrammed functions are compelling new targets for switching the pathogenic superinfection state into a single-infection state.

Improved 3 Year Heart Transplant Survival in Black Recipients Following the Affordable Care Act.

To improve healthcare access, the US government implemented the Affordable Care Act (ACA) in 2014. Previous studies investigating its impact on healthcare inequities showed significant improvement in Black transplant recipient outcomes. Our objective is to determine the ACA's impact on Black heart transplant (HTx) recipients. Using the United Network for Organ Sharing database, we analyzed 3,462 Black HTx recipients pre- and post-ACA (January 2009 to December 2012, and January 2014 to December 2017). Black recipient numbers and rates of overall HTx, insurance effects on survival, geographic changes in HTx, and post-HTx survival were compared pre- and post-ACA. Black recipients increased from 1,046 (15.3%) to 2,056 (22.2%) post-ACA ( p < 0.001). Three year survival increased among Black recipients (85.8-91.9%, p = 0.01; 79.4-87.7%, p < 0.01; 78.3-84.6%, p < 0.01). Affordable Care Act implementation was protective for survival (hazard ratio [HR] = 0.64 [95% confidence interval [CI], 0.51-0.81], p < 0.01). Publicly insured patient survival increased post-ACA to match that of privately insured (87.3-91.8%, p = 0.001). United Network for Organ Sharing (UNOS) Regions 2, 8, and 11 experienced improved survival post-ACA ( p = 0.047, p = 0.02, and p < 0.01, respectively). The post-ACA era showed improved HTx access and survival in Black recipients, indicating that national medical policy may play a strong role in eliminating racial disparities. Further attention is required to improve inequities in medical care. http://links.lww.com/ASAIO/B2.

Distinct gene programs underpinning disease tolerance and resistance in influenza virus infection.

When challenged with an invading pathogen, the host-defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs-one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in peritoneal macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.

Acceptability and utility of a virtual pediatric transplant peer mentoring program: A mixed-methods analysis of a novel quality improvement program.

BACKGROUND: Adolescent transplant patients are at increased risk for graft loss at a period when they also suffer from illness-related social isolation, which has been exacerbated by the COVID-19 pandemic. The Peer Mentoring Program (PMP), developed in 2018, was adapted to a virtual format in 2020 due to COVID-19. Our objective is to evaluate the acceptability, utility, and potential impact of the in-person and virtual versions of the PMP on participants. METHODS: We performed convergent mixed-methods analysis of the experiences of patients participating in the PMP for quality improvement purposes. RESULTS: Surveys and focus group invitations were sent to 18 current program participants, with 17 patients responding to the survey and 13 patients participating in focus groups. In this study, 82% were satisfied and 88% would recommend PMP; 76% identified other PMP members as people they would like to keep in touch with. Qualitative analysis revealed three themes: (1) a supportive community of peers, (2) reduced isolation, and (3) receiving accurate information from providers. CONCLUSIONS: There is a prominent need for greater peer support among adolescent transplant patients transitioning to adulthood, especially with the increased isolation associated with COVID-19. The virtual adaptation could be an important, permanent supplement to in-person events.