An estimated 70% of critically ill patients receive antibiotics, most frequently beta-lactams. The pharmacokinetic properties of these substances in this patient population are poorly predictable. Therapeutic drug monitoring (TDM) is helpful in making personalized decisions in this field, but its overall impact as a clinical decision-supporting tool is debated. We aimed to evaluate the clinical implications of adjusting beta-lactam dosages based on TDM in the critically ill population by performing a systematic review and meta-analysis of available investigations. Randomized controlled trials and observational studies were retrieved by searching three major databases. The intervention group received TDM-guided beta-lactam treatment, that is, at least one dose reconsideration based on the result of the measurement of drug concentrations, while TDM-unadjusted dosing was employed in the comparison group. The outcomes were evaluated using forest plots with random-effects modeling and subgroup analysis. Eight eligible studies were identified, including 1044 patients in total. TDM-guided beta-lactam treatment was associated with improved clinical cure from infection [odds ratio (OR): 2.22 (95% confidence interval (CI): 1.78–2.76)] and microbiological eradication [OR: 1.72 (CI: 1.05–2.80)], as well as a lower probability of treatment failure [OR: 0.47 (CI: 0.36–0.62)], but the heterogeneity of studies was remarkably high, especially in terms of mortality (70%). The risk of bias was moderate. While the TDM-guided administration of beta-lactams to critically ill patients has a favorable impact, standardized study designs and larger sample sizes are required for developing evidence-based protocols in this field.

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB₁Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB₁R knockout (CB₁R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-β) were performed. Conjugated E2 levels were higher in CB₁R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB₁R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB₁R KO. Effects of indomethacin on E2-relaxation in CB₁R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-β density in CB₁R KO than in WT mice. CB₁R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB₁Rs may have beneficial vascular effects.

Context: The promising perspective of storing dried blood spot (DBS) for evaluating 25-hydroxyvitamin D (25OHD) levels is increasingly being realized. While strong correlations have been demonstrated between 25OHD levels measured in DBS and in systemic serum samples in earlier works, the clinical concordance of the assay results has not been evaluated. Moreover, the utility of dried serum spot (DSS), a highly suitable matrix for sample archiving, has not been investigated in this respect. Methods: 25-hydroxycholecalciferol and 25-hydroxyergocalciferol levels were established selectively in DBS (n = 73) and DSS (n = 67) specimens obtained from deidentified whole blood and serum using a previously validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. In addition, total 25OHD levels were determined in the serum samples using the LIAISON 25OH Total Vitamin D Assay (LIA, n = 73). The analytical and clinical performance of the three approaches was compared pairwise. Results: Deming regression, Bland–Altman analysis, and concordance correlation coefficients consistently demonstrated the lack of analytical equivalence among the three result sets. The overall percentage agreement of the clinical classifications (hypovitaminosis or euvitaminosis) was moderate (67.1%–83.6%). The delivery of positive cases was decreasing significantly in the order LIA>DSS>DBS (p < 0.05). Conclusions: The approaches tested did not deliver equivalent outputs either in an analytical or a clinical context. Therefore, specific reference ranges must be established for each matrix to avoid false clinical evaluation. 25OHD can be quantified when assay results are scaled by a factor of 1.60–1.67. Considering the convenience and efficiency of the storage and processing of DSS, along with the difficulties of quantifying 25OHD in real-life DBS samples accurately, DSS is proposed as an alternative for the long-term archiving of specimens.