Predictive Value of HAS-BLED Score Regarding Bleeding Events and Graft Survival following Renal Transplantation.

Objective: Due to the high prevalence and incidence of cardio- and cerebrovascular diseases among dialysis-dependent patients with end-stage renal disease (ERSD) scheduled for kidney transplantation (KT), the use of antiplatelet therapy (APT) and/or anticoagulant drugs in this patient population is common. However, these patients share a high risk of complications, either due to thromboembolic or bleeding events, which makes adequate peri- and post-transplant anticoagulation management challenging. Predictive clinical models, such as the HAS-BLED score developed for predicting major bleeding events in patients under anticoagulation therapy, could be helpful tools for the optimization of antithrombotic management and could reduce peri- and postoperative morbidity and mortality. Methods: Data from 204 patients undergoing kidney transplantation (KT) between 2011 and 2018 at the University Hospital Leipzig were retrospectively analyzed. Patients were stratified and categorized postoperatively into the prophylaxis group (group A)­patients without pretransplant anticoagulation/antiplatelet therapy and receiving postoperative heparin in prophylactic doses­and into the (sub)therapeutic group (group B)­patients with postoperative continued use of pretransplant antithrombotic medication used (sub)therapeutically. The primary outcome was the incidence of postoperative bleeding events, which was evaluated for a possible association with the use of antithrombotic therapy. Secondary analyses were conducted for the associations of other potential risk factors, specifically the HAS-BLED score, with allograft outcome. Univariate and multivariate logistic regression as well as a Cox proportional hazard model were used to identify risk factors for long-term allograft function, outcome and survival. The calibration and prognostic accuracy of the risk models were evaluated using the Hosmer−Lemshow test (HLT) and the area under the receiver operating characteristic curve (AUC) model. Results: In total, 94 of 204 (47%) patients received (sub)therapeutic antithrombotic therapy after transplantation and 108 (53%) patients received prophylactic antithrombotic therapy. A total of 61 (29%) patients showed signs of postoperative bleeding. The incidence (p < 0.01) and timepoint of bleeding (p < 0.01) varied significantly between the different antithrombotic treatment groups. After applying multivariate analyses, pre-existing cardiovascular disease (CVD) (OR 2.89 (95% CI: 1.02−8.21); p = 0.04), procedure-specific complications (blood loss (OR 1.03 (95% CI: 1.0−1.05); p = 0.014), Clavien−Dindo classification > grade II (OR 1.03 (95% CI: 1.0−1.05); p = 0.018)), HAS-BLED score (OR 1.49 (95% CI: 1.08−2.07); p = 0.018), vit K antagonists (VKA) (OR 5.89 (95% CI: 1.10−31.28); p = 0.037), the combination of APT and therapeutic heparin (OR 5.44 (95% CI: 1.33−22.31); p = 0.018) as well as postoperative therapeutic heparin (OR 3.37 (95% CI: 1.37−8.26); p < 0.01) were independently associated with an increased risk for bleeding. The intraoperative use of heparin, prior antiplatelet therapy and APT in combination with prophylactic heparin was not associated with increased bleeding risk. Higher recipient body mass index (BMI) (OR 0.32 per 10 kg/m2 increase in BMI (95% CI: 0.12−0.91); p = 0.023) as well as living donor KT (OR 0.43 (95% CI: 0.18−0.94); p = 0.036) were associated with a decreased risk for bleeding. Regarding bleeding events and graft failure, the HAS-BLED risk model demonstrated good calibration (bleeding and graft failure: HLT: chi-square: 4.572, p = 0.802, versus chi-square: 6.52, p = 0.18, respectively) and moderate predictive performance (bleeding AUC: 0.72 (0.63−0.79); graft failure: AUC: 0.7 (0.6−0.78)). Conclusions: In our current study, we could demonstrate the HAS-BLED risk score as a helpful tool with acceptable predictive accuracy regarding bleeding events and graft failure following KT. The intensified monitoring and precise stratification/assessment of bleeding risk factors may be helpful in identifying patients at higher risks of bleeding, improved individualized anticoagulation decisions and choices of antithrombotic therapy in order to optimize outcome after kidney transplantation.

Subthreshold chemesthetic stimulation can enhance flavor lastingness of a soft chewable candy.

In addition to taste and aroma components of a flavor, FEMA GRAS approved chemesthetic flavor ingredients deliver a trigeminal experience or chemesthetic effect and provide a third dimension to overall flavor experience. In this study, we explored the impact of chemesthetic stimulation on dynamic flavor perception, acceptability and salivation, with two base flavors (mint, watermelon), using a soft chewable candy as a model food. Each base flavor was augmented with three increasing levels of a mixture of chemesthetic flavor ingredients, which provided a cooling sensation; subthreshold, detection threshold, and supra-threshold levels. Thirty-six panelists were asked to rate the perceived flavor intensity of each sample during eating and after swallowing using time intensity analysis. Lastingness after swallowing was measured as the time for the flavor intensity to drop below 25% of the maximum intensity perceived during chewing. Compared with the control, the addition of chemesthetic flavor ingredients increased the perceived flavor intensity during chewing and the flavor lastingness after swallowing for both mint and watermelon flavor. These effects started from the addition of subthreshold concentration of chemesthetic flavor ingredients and further increased with increasing the concentration of chemesthetic flavor ingredients added. By adding the subthreshold concentration of chemesthetic flavor ingredients, the flavor lastingness was increased by 32% for mint flavor and 22% for watermelon flavor. The acceptability of these weak-flavored soft chewable candy test samples was significantly increased towards 'just right' with increasing concentrations of chemesthetic flavor ingredients, even at subthreshold level. However, chew time and saliva flow rate were not affected by the addition of chemesthetic flavor ingredients. The increased flavor lastingness by the addition of chemesthetic flavor ingredients could therefore be explained by perceptual interaction between chemesthesis and flavor perception.

Dynamic flavor perception of encapsulated flavors in a soft chewable matrix.

Encapsulation is commonly used to protect flavor compounds against adverse environmental and processing conditions or to provide controlled release in processed foods. Flavor compounds are released during eating and the release rate depends on food breakdown dynamics in the mouth. Two sequential studies were designed to explore the flavor perception of the same flavor in different encapsulation systems. The studies were focused on the interactions between encapsulation technology, particle size and breakdown processes in the mouth. A peppermint flavor was used as a model flavor and encapsulated with different technologies (spray drying, melt extrusion and fluidized bed drying). The encapsulated flavors and a selected combination were incorporated into a soft chewable candy, keeping the total flavor concentration the same for each sample. The chewable candy samples were presented to naïve panelists (n > 30) for the following two evaluations; (1) comparison of overall flavor perception with a 2-alternative forced choice test; and (2) dynamic evaluation of perceived flavor intensity over time during eating and after swallowing using time intensity. The results showed that the overall and dynamic flavor perceptions are greatly affected by the encapsulation technologies and particle sizes, and can be modulated by combining flavor particles produced by different encapsulation technologies depending on the application and desired flavor profile. The results also showed a large perceived flavor intensity variation between panelists, resembling variation among consumers. In an effort to better understand the relationship between the oral processing patterns and flavor perception, we used the JBMB® typing tool which gives four "Mouth Behavior" groups ("Chewers", "Crunchers", "Smooshers" and "Suckers") and explored to determine whether they would account for the variation. Compared with "Chewers" and "Crunchers", "Smooshers" tended to have a slower increase of flavor intensity during eating and a more gradual drop after swallowing. However, this needs to be confirmed with larger numbers of consumers (including suckers who were excluded in this study because they were not sufficient in numbers) and samples with a longer chew time.

Palladium-Catalyzed Synthesis of Substituted Hydantoins-A New Carbonylation Reaction for the Synthesis of Amino Acid Derivatives.

One-step synthesis of substituted hydantoins can be achieved by the palladium-catalyzed "ureidocarbonylation" of aldehydes with urea derivatives and carbon monoxide [Eq. (1)]. This surprisingly selective protocol converts substituted ureas into 1,5- and 1,3,5-substituted hydantoins in yields of up to 93 %.