Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.

Background: Intensive care unit (ICU) physicians have extended the minimum alveolar concentration (MAC) to deliver and monitor long-term volatile sedation in critically ill patients. There is limited evidence of MAC’s reliability in controlling sedation depth in this setting. We hypothesized that sedation depth, measured by the electroencephalography (EEG)-derived Narcotrend-Index (burst-suppression N_Index 0—awake N_Index 100), might drift downward over time despite constant MAC values. Methods: This prospective single-centre randomized clinical study was conducted at a University Hospital Surgical Intensive Care Unit and included consecutive, postoperative ICU patients fulfilling the inclusion criteria. Patients were randomly assigned to receive uninterrupted inhalational sedation with isoflurane, sevoflurane, or desflurane. The end-expiratory concentration of the anaesthetics and the EEG-derived index were measured continuously in time-stamped pairs. Sedation depth was also monitored using Richmond-Agitation-Sedation-Scale (RASS). The paired t-test and linear models (bootstrapped or multilevel) have been employed to analyze MAC, N_Index and RASS across the three groups. Results: Thirty patients were recruited (female/male: 10/20, age 64 ± 11, Simplified Acute Physiology Score II 30 ± 10). In the first 24 h, 21.208 pairs of data points (N_Index and MAC) were recorded. The median MAC of 0.58 ± 0.06 remained stable over the sedation time in all three groups. The t-test indicated in the isoflurane and sevoflurane groups a significant drop in RASS and EEG-derived N_Index in the first versus last two sedation hours. We applied a multilevel linear model on the entire longitudinal data, nested per patient, which produced the formula N_Index = 43 − 0.7·h (R² = 0.76), showing a strong negative correlation between sedation’s duration and the N_Index. Bootstrapped linear models applied for each sedation group produced: N_Index of 43–0.9, 45–0.8, and 43–0.4·h for isoflurane, sevoflurane, and desflurane, respectively. The regression coefficient for desflurane was almost half of those for isoflurane and sevoflurane, indicating a less pronounced time-effect in this group. Conclusions: Maintaining constant MAC does not guarantee stable sedation depth. Thus, the patients necessitate frequent clinical assessments or, when unfeasible, continuous EEG monitoring. The differences across different volatile anaesthetics regarding their time-dependent negative drift requires further exploration. Trial registration: NCT03860129.

Background: Donation after circulatory death (DCD) hearts have to withstand ischemia/reperfusion injury that is partially driven by proinflammatory cytokines and decreases ventricular contractility. We hypothesize that cytokine adsorption during normothermic ex vivo blood perfusion of DCD hearts reduces the cytokine levels and improves ventricular contractility. Methods and Results: Porcine DCD hearts were maintained 4 hours by ex vivo blood perfusion with (DCD‐BP ^CytoS , all groups: N=8) or without (DCD‐BP) CytoSorb, followed by 2 hours reperfusion with fresh blood, including left ventricular functional analysis using a balloon catheter. In a control and a DCD group, hearts were evaluated after procurement. We determined lactate and cytokines after ex vivo blood perfusion and the myocardial and left anterior descending artery transcriptome using microarrays after reperfusion. In DCD‐BP ^CytoS , the developed pressure (control: 124±7 mm Hg/s, DCD: 86±4 mm Hg/s, DCD‐BP: 69±11 mm Hg/s, DCD‐BP ^CytoS : 112±9 mm Hg/s; P <0.05) and maximal slope of pressure increment (control: 2010±39 mm Hg/s, DCD: 1219±164 mm Hg/s, DCD‐BP: 964±163 mm Hg/s, DCD‐BP ^CytoS : 1794±205 mm Hg/s; P <0.05) were higher compared with DCD‐BP and DCD hearts. However, contractility decreased later during reperfusion without CytoSorb. After 4 hours, troponin, lactate (45±5% versus 69±9%, P <0.05), IL (interleukin)‐1β, ‐1ra, and ‐8 were lower in DCD‐BP ^CytoS hearts. In the myocardium of DCD‐BP ^CytoS compared with DCD‐BP hearts, inflammatory mediator receptor activity/binding pathways were enriched, and pathways for collagen‐containing extracellular matrix and contractile fiber were underrepresented. In the left anterior descending artery of DCD‐BP ^CytoS hearts, serine/threonine/tyrosine kinase activity and wound‐healing pathways were enriched, and mitochondrial protein‐containing complex and respiratome‐associated pathways were underrepresented. Conclusions: CytoSorb during ex vivo blood perfusion enhances the maintenance of DCD hearts and is likely to improve graft function after transplantation.

Background and Objectives: Xerostomia is common among institutionalized older adults, but the relative contributions of comorbidity burden and medication-class burden remain incompletely clarified. This study evaluated their associations with Xerostomia Inventory (XI) severity and explored related salivary dysfunction and clinical oral health findings. Materials and Methods: We conducted a cross-sectional study of 90 institutionalized older adults in Bucharest, Romania. Xerostomia Inventory (XI) scores, a binary dry-mouth question, chairside salivary assessments, comorbidity categories, medication classes, oral mucosal findings, and complete denture retention and stability were recorded. Primary analyses used hierarchical regression and bootstrap statistical decomposition; secondary and exploratory analyses evaluated salivary concordance, medication classes, denture-related findings, and oral mucosal conditions. Results: Medication-class count remained associated with XI severity after adjustment for comorbidity burden (partial r = 0.445, p < 0.001), whereas the association between comorbidity burden and XI was no longer significant after adjustment for medication-class count (partial r = −0.063, p = 0.557). Inclusion of medication-class count increased the explained variance in XI scores (ΔR² = 0.253, p < 0.001). Bootstrap decomposition yielded similar findings, with a significant indirect estimate and a non-significant direct estimate. Among complete denture wearers, XI severity was associated with maxillary denture instability (ρ = −0.687, n = 44). Conclusions: In this cohort, medication-class burden showed the strongest association with xerostomia severity, whereas comorbidity burden was not independently associated after adjustment. Given the cross-sectional design, these findings should be interpreted as exploratory associations and support future prospective studies integrating medication review with geriatric-prosthodontic assessment.

The Children's and Infant's Postoperative Pain Scale (CHIPPS) and the German version of the Parent's Postoperative Pain Measure (PPPM-D) are used to assess postoperative pain intensity in preschool children. However, they have shown low concordance in previous prospective studies on quality improvement. Our secondary analysis aimed to estimate the association strength between the pain score items and indication for rescue medication defined as CHIPPS ≥4 and/or PPPD-D ≥ 6. Thus, we intended to create a further developed pain instrument with fewer variables for easier routine use. We analyzed 1067 pain intensity assessments of hospitalized children for the development of our novel tool in two steps using modern statistical and machine-learning methods: (1) Boruta variable selection to analyze the association strength between CHIPPS score, PPPM-D items, age, weight, and elapsed time after surgery, including their interactions and pattern stability, and the binary outcome (analgesics required yes/no). (2) Symbolic regression to generate a short formula with the least number of variables and highest accuracy for rescue medication indication. Additional analgesics were required in 19.96% of pain intensity assessments, whereby the PPPM-D showed higher variance than CHIPPS. Boruta identified PPPM-D score, CHIPPS score, 9 of the 15 PPPM-D variables, and time of assessment as associated with the indication for RM. Symbolic regression revealed that additional analgesics are required if CHIPPS is ≥4 OR PPPM-D item "less energy than usual" AND one of the items "more easily cry" or "more groan/moan" are answered with "yes." These PPPM-D items were not redundant and showed nonlinear course over time. The cross-validated accuracy for this assessment tool was 94.94%. The new instrument is easy to use and may improve postoperative pain intensity assessment in children. However, it requires prospective validation in a new cohort.

Background: Diabetic neuropathy affects almost half of diabetic patients, yet the relative contributions of metabolic, vascular and clinical factors remain controversial. We aimed to investigate which risk factors are more associated with reduced corneal nerve fiber length (CNFL). Methods: This is a cross-sectional study of 30 patients with type 2 diabetes. We assessed metabolic parameters (HbA1c, lipids), vascular measurements (Doppler ultrasonography of carotid and ophthalmic arteries, central vessel density measured by optical coherence tomography angiography), and corneal epithelial thickness. We explored the data using network analysis, then applied penalized mixed-effect regression (in which $\beta$ represents the standardized coefficients with mean 0 and unit standard deviation), followed by generalized additive models and polynomial transformations. Results: Penalized regression identified vascular parameters as dominant predictors: carotid plaques ($\beta$ = −0.609) and intima-media thickness ($\beta$ = −0.574) showed the strongest associations with CNFL. Traditional metabolic markers including HbA1c failed to meet selection thresholds. Bifurcation velocity ($\beta$ = −0.313) and corneal sensitivity measures ($\beta$ = 0.278–0.135) were also significant. The non-linear modeling showed complex vascular–structural interactions. Conclusions: Vascular compromise, particularly carotid disease, had the highest association with CNFL in our cohort. Thus, our study reports a higher effect of vascular parameters than HbA1c in patients with a longer history of diabetes. This may reflect the progression of diabetic complications, where initial metabolic insults are followed by vascular pathology as the primary driver of end-organ damage. Our findings highlight the need for carotid artery screening in diabetic patients for a better estimation of the neuropathy risk.