CSF1 Restores Innate Immunity Following Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure

Background & Aims: Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods: We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results: Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions: Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury

The experience of using the Scrip Concordance Test in educational research.

Introduction: The Script Concordance Test (SCT) is a well-regarded yet relatively novel method of assessing clinical reasoningskills. There is a wide range of studies focusing on the SCT as an assessment method but few instances of itsuse in research as a longitudinal measure of development of clinical reasoning.Methods: This study explored the use of the SCT as a pre and post measure to evaluate the impact of an educationalintervention designed to enhance clinical reasoning skills. The study was conducted within a general practicetraining program, on two cohorts of trainees at two separate training sites that enabled an intervention (n= 11) /delayed intervention (n=12) design.Results: There were no statistically significant differences in the mean SCT scores between the two cohorts. Regressionanalysis revealed differences in the patterns of improvement of SCT scores, which correlated with baseline SCTscores (those with lower initial scores showed greatest improvements). This pattern was more pronounced in theintervention group with a differential impact based on the content domain of the SCT items.Conclusions: The findings highlight a number of opportunities and challenges in using the SCT in educational research. Thestudy raises important questions regarding the sensitivity of the SCT to change in clinical reasoning skills and thetypes of analysis that can best investigate such change.Take-home message: The SCT has the potential to play a significant role in educational research but the design of items and methodsof analysis need careful consideration