Young infants are highly susceptible to systemic dissemination of enteric pathogens such as Salmonella typhimurium when compared with older individuals. The mechanisms underlying this differential susceptibility have not been defined clearly. To better understand this phenomenon, we examined the responses of adult mice and preweaned pups to oral infection by S. typhimurium. We found clear age-specific differences, namely, an attenuated intestinal inflammatory response and a higher systemic bacterial burden in the pups compared with the adults. To elucidate the molecular basis for these differences, we obtained a microarray-based profile of gene expression in the small intestines of uninfected adult and preweaned animals. The results indicated a striking age-dependent increase in the intestinal expression of a number of IFN-γ-regulated genes involved in antimicrobial defense. This finding was confirmed by real-time quantitative PCR, which also demonstrated an age-dependent increase in intestinal expression of IFN-γ. The developmental up-regulation of the IFN-γ-regulated genes was dependent on both IFN-γ and a normal commensal microflora, as indicated by experiments in IFN-γ-knockout mice and germfree mice, respectively. However, the increase in expression of IFN-γ itself was independent of the commensal flora. The functional importance of IFN-γ in the immunological maturation of the intestine was confirmed by the observation that the response of adult IFN-γ-knockout animals to S. typhimurium infection resembled that of the wild-type pups. Our findings thus reveal a novel role for IFN-γ in the developmental regulation of antimicrobial responses in the intestine.

This comparison, while not conclusive, suggests that we might be missing opportunities to reduce pediatric waitlist mortality without decreasing access for adults-using split liver transplant. Barriers are significant, but further work on strategies to increase split liver transplant is warranted.

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Non-standard exceptions requests (NSERs), in which transplant centers appeal on a case-by-case basis for PELD/MELD points, have been highly utilized for pediatric liver transplant candidates. We evaluated whether NSE outcomes, are associated with waitlist and post-transplant mortality. UNOS Scientific Registry of Transplant Recipients data on pediatric liver transplant candidates listed 2009-2014 were analyzed after excluding those granted automatic UNOS exceptions. Of 2,581 pediatric waitlist candidates, 44% had an NSE request. Of the 1,134 children with NSERs, 93% were approved and 7% were denied. For children 2-18 years at listing, NSER denial increased the risk of waitlist mortality or removal for being too sick (SHR 2.99, 95% CI 1.26-7.07, p=0.01 in multivariate analysis). For children younger than 2, NSER denial did not impact waitlist mortality/removal. Children with NSER approved had reduced risk of graft loss 3 years post-transplant in univariate but not multivariable analysis (OR 0.73, 95% CI 0.53-1.01, p=06). Those with NSER denial had a higher risk of post-transplant death than those with no NSER (HR 2.43, 95% CI 0.99-5.95, p=0.05, multivariable analysis), but NSER approval did not impact post-transplant death. Further research on NSER utilization in pediatric liver transplant is needed to optimize organ allocation and outcomes for children.