Publications

Finding the components of cellular circuits and determining their functions systematically remains a major challenge in mammalian cells. Here, we introduced genome-wide pooled CRISPR-Cas9 libraries into dendritic cells (DCs) to identify genes that control the induction of tumor necrosis factor (Tnf) by bacterial lipopolysaccharide (LPS), a key process in the host response to pathogens, mediated by the Tlr4 pathway. We found many of the known regulators of Tlr4 signaling, as well as dozens of previously unknown candidates that we validated. By measuring protein markers and mRNA profiles in DCs that are deficient in known or candidate genes, we classified the genes into three functional modules with distinct effects on the canonical responses to LPS and highlighted functions for the PAF complex and oligosaccharyltransferase (OST) complex. Our findings uncover new facets of innate immune circuits in primary cells and provide a genetic approach for dissection of mammalian cell circuits.

FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.

OBJECTIVE

Intraaortic balloon pumps (IABPs) are frequently used as an adjunctive device to extracorporeal membrane oxygenation (ECMO) and are routinely placed at the initiation of ECMO at many institutions. Evidence for the additive benefit of IABP therapy is limited and conflicting in part due to small sample sizes. In the absence of large randomized trials, a meta-analysis would best elucidate potential benefit.

METHODS

A systematic PubMed/Medline search was performed. Studies reporting on survival to hospital discharge for cardiogenic shock and cardiac arrest requiring ECMO with an IABP subgroup were included. Concomitant IABP was compared with patients on ECMO alone. Secondary analyses included acute myocardial infarction (AMI) and postcardiotomy cardiogenic shock (PCS) subgroups, as well as timing of IABP insertion.

RESULTS

Sixteen studies were included in the main analysis, encompassing 1517 patients. The cumulative survival rate for patients on ECMO was 256/683 (37.5%) compared with 294/834 (35.3%) for patients with adjunctive IABP. Concomitant IABP was not associated with improved survival (risk ratio [RR], 1.143; 95% confidence interval [CI], 0.973-1.343; P=.10). IABP was not associated with improved survival in AMI patients (RR, 1.120; 95% CI, 0.772-1.624; P=.55), PCS (RR, 1.121; 95% CI, 0.826-1.520; P=.46) when placed prior to ECMO initiation (RR, 0.948; 95% CI, 0.718-1.252; P=.71), or when routinely inserted (RR, 1.102; 95% CI, 0.806-1.506; P=.54).

CONCLUSION

Based on this observational analysis, the concomitant use of IABP with ECMO did not appear associated with a dramatic change in survival outcomes. The routine insertion of concomitant IABP with ECMO is not supported by our findings.