Background: Sepsis and septic shock are life-threatening global health challenges associated with high mortality rates. Early identification of high-risk patients is critical for improving outcomes. In the present study, the association between the neutrophil-to-lymphocyte-to-albumin ratio (NLAR) and mortality in septic patients was evaluated. Methods: A retrospective study was performed at a tertiary hospital in Vietnam. Patients ≥18 years of age diagnosed with sepsis or septic shock based on the Sepsis-3 criteria were included. Exclusion criteria included recent corticosteroid use within 7 days, autoimmune diseases, hematological disorders, and active cancer within 5 years. NLAR was calculated from complete blood counts and albumin levels within the first 24 hours of intensive care unit admission. Receiver operating characteristic (ROC) curves were used to determine the predictive ability of NLAR for in-hospital mortality. Results: The present study included 141 patients with a mean age of 72 years. Non-survivors were significantly older with higher rates of mechanical ventilation. NLAR was significantly elevated in non-survivors compared with survivors (0.88 [0.57–1.24] vs. 0.44 [0.28–0.77], P<0.001). In ROC analysis, the area under the curve for NLAR was 0.70 (P<0.001). Using a cutoff value of 0.56, NLAR showed a sensitivity of 77.8% and a specificity of 61.5% for predicting in-hospital mortality. Conclusions Elevated NLAR on admission was associated with a higher mortality rate in sepsis patients. NLAR could be used as an early prognostic marker for sepsis mortality.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M₄) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M₄ positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M₄ PET ligand that allows the non-invasive visualization of M₄ in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [¹⁸F] 12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [¹⁸F] 12 for the M₄-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [¹⁸F] 12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [¹⁸F] 12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [¹⁸F] 12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M₄ PET radioligand with promising attributes. The availability of a clinically validated M₄ PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.