Abass Eidizadeh

(1) Background: Bile acids, known as aids in intestinal fat digestion and as messenger molecules in serum, can be detected in cerebrospinal fluid (CSF), although the blood–brain barrier is generally an insurmountable obstacle for bile acids. The exact mechanisms of the occurrence, as well as possible functions of bile acids in the central nervous system, are not precisely understood. (2) Methods: We conducted a single-center observational trial. The concentrations of 15 individual bile acids were determined using an in-house LC-MS/MS method in 54 patients with various acute and severe disorders of the central nervous system. We analyzed CSF from ventricular drainage taken within 24 h after placement, and blood samples were drawn at the same time for the presence and quantifiability of 15 individual bile acids. (3) Results: At a median time of 19.75 h after a cerebral insult, the concentration of bile acids in the CSF was minute and almost negligible. The CSF concentrations of total bile acids (TBAs) were significantly lower compared to the serum concentrations (serum 0.37 µmol/L [0.24, 0.89] vs. 0.14 µmol/L [0.05, 0.43]; p = 0.033). The ratio of serum-to-CSF bile acid levels calculated from the respective total concentrations were 3.10 [0.94, 14.64] for total bile acids, 3.05 for taurocholic acid, 14.30 [1.11, 27.13] for glycocholic acid, 0.0 for chenodeoxycholic acid, 2.19 for taurochenodeoxycholic acid, 1.91 [0.68, 8.64] for glycochenodeoxycholic acid and 0.77 [0.0, 13.79] for deoxycholic acid; other bile acids were not detected in the CSF. The ratio of CSF-to-serum S100 concentration was 0.01 [0.0, 0.02]. Serum total and conjugated (but not unconjugated) bilirubin levels and serum TBA levels were significantly correlated (total bilirubin p = 0.031 [0.023, 0.579]; conjugated bilirubin p = 0.001 [0.193, 0.683]; unconjugated p = 0.387 [−0.181, 0.426]). No correlations were found between bile acid concentrations and age, delirium, intraventricular blood volume, or outcome measured on a modified Rankin scale. (4) Conclusions: The determination of individual bile acids is feasible using the current LC-MS/MS method. The results suggest an intact blood–brain barrier in the patients studied. However, bile acids were detected in the CSF, which could have been achieved by active transport across the blood–brain barrier.

Despite recent advances in prophylactic vaccination, SARS‐CoV‐2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS‐CoV‐2 breakthrough infection is urgently needed. CoV‐ADAPT is a prospective long‐term study comparing humoral (anti‐spike‐RBD‐IgG, neutralization capacity, avidity) and cellular (spike‐induced T‐cell interferon‐γ [IFN‐γ] release) immune responses in individuals vaccinated against SARS‐CoV‐2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS‐CoV‐2 breakthrough infections vs 151 without infection 3–7 months following third vaccination. Breakthrough infections significantly increased anti‐spike‐RBD‐IgG ( p < 0.01), but not spike‐directed T‐cell IFN‐γ release (TC) or antibody avidity. Despite comparable surrogate neutralization indices, the functional neutralization capacity against SARS‐CoV‐2—assessed via a tissue culture‐based assay—was significantly higher following breakthrough vs no breakthrough infection. Anti‐spike‐RBD‐IgG and antibody avidity decreased with age ( p < 0.01) and females showed higher anti‐spike‐RBD‐IgG ( p < 0.01), and a tendency towards higher antibody avidity ( p = 0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections ( p = 0.807). Finally, a machine‐learning approach based on our large immunological dataset (a total of 49 variables) from different time points was unable to predict breakthrough infections (area under the curve: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g., virus exposure) in individualized risk assessment.