Delirium commonly occurs in critical illness and is associated with significant morbidity and mortality. Although risk reduction measures can mitigate the risk of delirium, identifying patients in whom delirium will develop remains clinically challenging. In critically ill patients with respiratory failure, are central nervous system (CNS)-related biomarkers measured at admission associated with delirium diagnosis? We performed a secondary analysis of a cohort of patients with respiratory failure in the medical ICU enrolled at a single medical center. Using serum collected at ICU admission, we measured CNS-related biomarkers including brain-derived neurotrophic factor (BDNF), chitinase-3-like protein 1, glial fibrillary acidic protein, neurofilament light chain (NF-L), neurogranin, S100 calcium-binding protein B, and triggering receptor expressed on myeloid cells 2 via a multiplex immunoassay. The primary outcome was diagnosis of in-hospital delirium, defined using validated methods. Associations between individual biomarkers and delirium diagnosis were examined using multivariable logistic regressions, adjusting for factors known to predispose and precipitate delirium. Secondary outcomes included in-hospital mortality, ventilator-free days, ICU-free days, and hospital-free days. Serum biomarkers were measured in 100 patients. Delirium occurred in 73% of the cohort. Patients with vs without delirium did not differ significantly in terms of age, sex, comorbidities, severity of illness, or unhealthy alcohol use. After adjustment, NF-L was associated positively with delirium diagnosis (adjusted OR, 1.86; 95% CI, 1.09-3.43), whereas BDNF was associated negatively with delirium (adjusted OR, 0.43; 95% CI, 0.15-0.82). No associations were found between other measured biomarkers and delirium diagnosis. NF-L levels were associated negatively with ICU-free and hospital-free days. Our results indicate that CNS-related biomarkers measured at ICU admission are associated with delirium diagnosis in critically ill patients. Prospective investigations are necessary to validate the role of these biomarkers in predicting delirium.

In derived bony vertebrates, activation of the melanocortin-2 receptor (Mc2r) by its ACTH ligand requires chaperoning by the Mc2r accessory protein (Mrap1). The N-terminal domain of the non-mammalian tetrapod MRAP1 from chicken (c; Gallus gallus) has the putative activation motif, W¹⁸D¹⁹Y²⁰I²¹, and the N-terminal domain in the neopterygian ray-finned fish Mrap1 from bowfin (bf; Amia calva) has the putative activation motif, Y¹⁸D¹⁹Y²⁰I²¹. The current study used an alanine-substitution paradigm to test the hypothesis that only the Y²⁰ position in the Mrap1 ortholog of these non-mammalian vertebrates is required for activation of the respective Mc2r ortholog. Instead, we found that for cMRAP1, single alanine-substitution resulted in a gradient of inhibition of activation (Y²⁰ >> D¹⁹ = W¹⁸ > I²¹). For bfMrap1, single alanine-substitution also resulted in a gradient of inhibition of activation (Y²⁰ >> D¹⁹ > I²¹ > Y¹⁸). This study also included an analysis of Mc2r activation in an older lineage of ray-finned fish, the paddlefish (p), Polyodon spathula (subclass Chondronstei). Currently no mrap1 gene has been found in the paddlefish genome. When pmc2r was expressed alone in our CHO cell/cAMP reporter gene assay, no activation was observed following stimulation with ACTH. However, when pmc2r was co-expressed with either cmrap1 or bfmrap1 robust dose response curves were generated. These results indicate that the formation of an Mc2r/Mrap1 heterodimer emerged early in the radiation of the bony vertebrates.