Selective regulation of a defined subset of inflammatory and immunoregulatory genes by an NF-κB p50-IκBζ pathway.

The five NF-κB family members and three nuclear IκB proteins play important biological roles, but the mechanisms by which distinct members of these protein families contribute to selective gene transcription remain poorly understood, especially at a genome-wide scale. Using nascent transcript RNA-seq, we observed considerable overlap between p50-dependent and IκBζ-dependent genes in Toll-like receptor 4 (TLR4)-activated macrophages. Key immunoregulatory genes, including Il6, Il1b, Nos2, Lcn2, and Batf, are among the p50-IκBζ-codependent genes. IκBζ-bound genomic sites are occupied at earlier time points by NF-κB dimers. However, p50-IκBζ codependence does not coincide with preferential binding of either p50 or IκBζ, as RelA co-occupies hundreds of genomic sites with the two proteins. A common feature of p50-IκBζ-codependent genes is a nearby p50/RelA/IκBζ-cobound site exhibiting p50-dependent binding of both RelA and IκBζ. This and other results suggest that IκBζ acts in concert with RelA:p50 heterodimers. Notably, p50-IκBζ-codependent genes comprise a high percentage of genes exhibiting the greatest differential expression between TLR4-stimulated and tumor necrosis factor receptor (TNFR)-stimulated macrophages. Thus, our genome-centric analysis reveals a defined p50-IκBζ pathway that selectively activates a set of key immunoregulatory genes and serves as an important contributor to differential TNFR and TLR4 responses.

Fluorescent cholangiography significantly improves patient outcomes for laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the most common elective abdominal surgery in the USA, with over 750,000 performed annually. Fluorescent cholangiography (FC) using indocyanine green dye (ICG) permits identification of extrahepatic biliary structures to facilitate dissection without requiring cystic duct cannulation. Achieving the "critical view of safety" with assistance of ICG cholangiogram may support identification of anatomy, safely reduce conversion to open procedures, and decrease operative time. We assess the utility of FC with respect to anatomic visualization during LC and its effects on patient outcomes. METHODS: A retrospective review of a prospectively maintained database identified patients undergoing laparoscopic cholecystectomy at a single academic center from 2013 to 2019. Exclusion criteria were primary open and single incision cholecystectomy. Patient factors included age, sex, BMI, and Charlson Comorbidity Index. Outcomes included operative time, conversion to open procedure, length of stay (LOS), mortality rate, and 30-day complications. A multivariable logistic regression was performed to determine independent predictors for open conversion. RESULTS: A total of 1389 patients underwent laparoscopic cholecystectomy. 69.8% were female; mean age 48.6 years (range 15-94), average BMI 29.4 kg/m2 (13.3-55.6). 989 patients (71.2%) underwent LC without fluorescence and 400 (28.8%) underwent FC with ICG. 30-day mortality detected 2 cases in the non-ICG group and zero with ICG. ICG reduced operative time by 26.47 min per case (p < 0.0001). For patients with BMI ≥ 30 kg/m2, operative duration for ICG vs non-ICG groups was 75.57 vs 104.9 min respectively (p < 0.0001). ICG required conversion to open at a rate of 1.5%, while non-ICG converted at a rate of 8.5% (p < 0.0001). Conversion rate remained significant with multivariable analysis (OR 0.212, p = 0.001). A total of 19 cases were aborted (1.35%), 8 in the ICG group (1.96%) and 11 in the non-ICG group (1.10%), these cases were not included in LC totals. Average LOS was 0.69 vs 1.54 days in the ICG compared to non-ICG LCs (p < 0.0001), respectively. Injuries were more common in the non-ICG group, with 9 patients sustaining Strasberg class A injuries in the non-ICG group and 2 in the ICG group. 1 CBDI occurred in the non-ICG group. There was no significant difference in 30-day complication rates between groups. CONCLUSION: ICG cholangiography is a non-invasive adjunct to laparoscopic cholecystectomy, leading to improved patient outcomes with respect to operative times, decreased conversion to open procedures, and shorter length of hospitalization. Fluorescence cholangiography improves visualization of biliary anatomy, thereby decreasing rate of CBDI, Strasberg A injuries, and mortality. These findings support ICG as standard of care during laparoscopic cholecystectomy.