Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).

Sapje-like (sap(cl100)) was one of eight potential zebrafish muscle mutants isolated as part of an early-pressure screen of 500 families. This mutant shows a muscle tearing phenotype similar to sapje (dys-/-) and both mutants fail to genetically complement suggesting they have a mutation in the same gene. Protein analysis confirms a lack of dystrophin in developing sapje-like embryos. Sequence analysis of the sapje-like dystrophin mRNA shows that exon 62 is missing in the dystrophin transcript causing exon 63 to be translated out of frame terminating translation at a premature stop codon at the end of exon 63. Sequence analysis of sapje-like genomic DNA identified a mutation in the donor splice junction at the end of dystrophin exon 62. This mutation is similar to splicing mutations associated with human forms of Duchenne Muscular Dystrophy. Sapje-like is the first zebrafish dystrophin splicing mutant identified to date and represents a novel disease model which can be used in future studies to identify therapeutic compounds for treating diseases caused by splicing defects.

Background: Damage-associated molecular patterns (DAMPs) stimulate endothelial syndecan-1 shedding and neutrophil extracellular traps (NET) formation. The role of NETs in trauma and trauma-induced hypercoagulability is unknown. We hypothesized that trauma patients with accelerated thrombin generation would have increased NETosis and syndecan-1 levels. Methods: In this pilot study, we analyzed 50 citrated plasma samples from 30 trauma patients at 0 h (n ¼ 22) and 6 h (n ¼ 28) from time of injury (TOI) and 21 samples from healthy volunteers, for a total of 71 samples included in analysis. Thrombin generation was quantified using calibrated automated thrombogram (CAT) and reported as lag time (LT), peak height (PH), and time to peak (ttPeak). Nucleosome calibrated (H3NUC) and free histone standardized (H3Free) ELISAs were used to quantify NETs. Syndecan-1 levels were quantified by ELISA. Results are presented as median [interquartile range] and Spearman rank correlations. Results: Plasma levels of H3NUC were increased in trauma patients as compared with healthy volunteers both at 0 h (89.8 ng/mL [35.4, 180.3]; 18.1 ng/mL [7.8, 37.4], P ¼ 0.002) and at 6 h (86.5 ng/mL [19.2, 612.6]; 18.1 ng/mL [7.8, 37.4], P ¼ 0.003) from TOI. H3Free levels were increased in trauma patients at 0 h (5.74 ng/mL [3.19, 8.76]; 1.61 ng/mL [0.66, 3.50], P ¼ 0.002) and 6 h (5.52 ng/mL [1.46, 11.37]; 1.61 ng/mL [0.66, 3.50], P ¼ 0.006). Syndecan-1 levels were greater in trauma patients (4.53 ng/mL [3.28, 6.28]; 2.40 ng/mL [1.66, 3.20], P < 0.001) only at 6 h from TOI. H3Free and syndecan-1 levels positively correlated both at 0 h (0.376, P ¼ 0.013) and 6 h (0.583, P < 0.001) from TOI. H3NUC levels and syndecan-1 levels were positively correlated at 6 h from TOI (0.293, P ¼ 0.041). TtPeak correlated inversely to H3 NUC (À0.358, P ¼ 0.012) and syndecan-1 levels (À0.298, P ¼ 0.038) at 6 h from TOI. Conclusions: Our pilot study demonstrates that trauma patients have increased NETosis, measured by H3NUC and H3Free levels, increased syndecan-1 shedding, and accelerated thrombin generation kinetics early after injury.

Background Recent studies on perioperative fluid administration in patients undergoing major abdominal surgery have suggested that increased fluid loads are associated with worse perioperative outcomes. However, results of retrospective analyses of the relationship between intraoperative fluid (IOF) administration and perioperative outcomes in patients undergoing pancreaticoduodenectomy (PD) are conflicted. We sought to investigate this relationship in patients undergoing PD at our academic center. Methods A retrospective analysis of 124 patients undergoing PD from 2007 to 2012 was performed. IOF administration rate (ml/kg/hr) was correlated with perioperative outcomes. Outcomes were also stratified by preoperative serum albumin level. Results Regression analyses were performed comparing independent perioperative variables, including IOF rate, to four outcomes variables: length of stay, severity of complications, number of complications per patient, and 30-day mortality. Both univariate and multivariate regression analyses showed IOF rate correlated with one or more perioperative outcomes. Patients with an albumin ≤3.0 g/dl who received more than the median IOF rate experienced more severe complications, while patients with an albumin >3.0 g/dl did not. Conclusion Increased IOF administration is associated with worse perioperative outcomes in patients undergoing PD. Patients with low preoperative serum albumin levels (≤3.0 g/dl) may be a group particularly sensitive to volume overload.

There is increasing evidence that novel coronavirus disease 2019 (COVID-19) leads to a significant coagulopathy, a phenomenon termed “COVID-19 associated coagulopathy”. COVID-19 has been associated with increased rates of both venous and arterial thromboembolic events, a source of significant morbidity and mortality in this disease. Further evidence suggests a link between the inflammatory response and coagulopathy associated with COVID-19. This presents a unique set of challenges for diagnosis, prevention, and treatment of thrombotic complications. In this review, we summarize and discuss the current literature on laboratory coagulation disruptions associated with COVID-19 and the clinical effects of thromboembolic events including pulmonary embolism (PE), deep vein thrombosis (DVT), peripheral arterial thrombosis, and acute ischemic stroke in COVID-19. Endothelial injury and augmented innate immune response are implicated in the development of diffuse macro- and microvascular thrombosis in COVID-19. The pathophysiology of COVID-19 associated coagulopathy is an important determinant of appropriate treatment and monitoring of these complications. We highlight the importance of diagnosis and management of dysregulated coagulation in COVID-19 in order to improve outcomes in COVID-19 patients with thromboembolic complications.

These findings provide a novel mechanism by which IRF-1 regulates Rab27a transcription and EV secretion, leading to OxPL activation of neutrophils and subsequent hepatic IR injury. (Hepatology 2018;67:1056-1070).

The IRF-1 priming of TEXs enhances antitumour immune response.

Introduction Previous studies have shown benefit not only from postoperative chemotherapy but also from a short interval to initiation of treatment after resection of primary colorectal cancer. The aim of this study was to determine difference in timing to postoperative chemotherapy for minimally invasive resection (MIR) vs. open resection (OR) of colorectal cancer liver metastases (CRCLM). Methods This is a retrospective review of 1:1 matched patients undergoing MIR (n=66) and OR (n=66) for CRCLM at a single institution. Results Patients undergoing MIR of CRCLM had significantly shorter length of hospital stay, fewer major complications, and shorter interval to postoperative chemotherapy (median 42 vs. 63 days, p<0.001). Univariable analysis showed that surgical approach, postoperative complications, blood loss, number of lesions, and length of stay were associated with timing to chemotherapy. On multivariable analysis, surgical approach was still associated with timing to chemotherapy, and postoperative complications resulted in a delay of chemotherapy among patients who underwent OR but not among those who underwent MIR. In addition, worse disease-free survival was seen among patients who received postoperative chemotherapy more than 60 days after surgery. Conclusion By modifying the deleterious effects of postoperative complications on timing of postoperative chemotherapy, patients undergoing MIR for CRCLM are treated with chemotherapy sooner after surgery compared to those undergoing OR.