Monoaminergic modulation of decision-making under risk of punishment in a rat model.

The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision-making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision-making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision-making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between a small, 'safe' food reward and a large food reward associated with variable risks of punishment. Preference for the large, risky reward (risk-taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities but did not affect risk-taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision-making, decision-making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors.

Validation of a new American Association for the Surgery of Trauma (AAST) anatomic severity grading system for acute cholecystitis.

BACKGROUND: The American Association for the Surgery of Trauma (AAST) established anatomic grading to facilitate risk stratification and risk-adjusted outcomes in emergency general surgery. Cholecystitis severity was graded based on clinical, imaging, operative, and pathologic criteria. We aimed to validate the AAST anatomic grading system for acute cholecystitis. METHODS: This is a retrospective cohort study including consecutive patients admitted with acute cholecystitis at an urban, tertiary medical center between 2013 and 2016. Grade 1 is acute cholecystitis, Grade 2 is gangrenous or emphysematous cholecystitis, Grade 3 is localized perforation, and Grades 4 and 5 have regional and systemic peritonitis, respectively. Concordance between the AAST grade and outcome including mortality, length of stay (LOS), ICU use, readmission, and complications were assessed using logistic regression. RESULTS: A total of 315 patients were included. There was very good inter-rater (two independent raters) reliability for anatomic grading, κ = 1.00, p < 0.005. The majority of patients were Grade 1 or Grade 2 (94%). Incidence of complications, LOS, ICU use, and any adverse event increased with increasing anatomic grade. When compared to Grade 1 disease, patients with Grade 2 were more likely to undergo cholecystectomy (OR 4.07 [1.93-8.56]). Grade 3 patients were at higher risk of adverse events (OR 3.83 [1.34-10.94]), longer LOS (OR 1.73 [1.03-2.92]), and ICU use (OR 8.07 [2.43-26.80]). CONCLUSIONS: AAST severity scores were independently associated with clinical outcomes in patients with acute cholecystitis. Despite low-grade disease, complications were common, and therefore a refinement of the scoring system may be necessary for more granular prediction. LEVEL OF EVIDENCE: Epidemiologic/prognostic, level III.

Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli.

The transcription factor nuclear factor κB (NFκB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor-α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.