Evaluation of Normothermic Machine Perfusion of Porcine Livers as a Novel Preclinical Model to Predict Biliary Clearance and Transporter-Mediated Drug-Drug Interactions Using Statins.

There is a lack of translational preclinical models that can predict hepatic handling of drugs. In this study, we aimed to evaluate the applicability of normothermic machine perfusion (NMP) of porcine livers as a novel ex vivo model to predict hepatic clearance, biliary excretion, and plasma exposure of drugs. For this evaluation, we dosed atorvastatin, pitavastatin, and rosuvastatin as model drugs to porcine livers and studied the effect of common drug-drug interactions (DDIs) on these processes. After 120 minutes of perfusion, 0.104 mg atorvastatin (n = 3), 0.140 mg pitavastatin (n = 5), or 1.4 mg rosuvastatin (n = 4) was administered to the portal vein, which was followed 120 minutes later by a second bolus of the statin coadministered with OATP perpetrator drug rifampicin (67.7 mg). After the first dose, all statins were rapidly cleared from the circulation (hepatic extraction ratio > 0.7) and excreted into the bile. Presence of human-specific atorvastatin metabolites confirmed the metabolic capacity of porcine livers. The predicted biliary clearance of rosuvastatin was found to be closer to the observed biliary clearance. A rank order of the DDI between the various systems upon coadministration with rifampicin could be observed: atorvastatin (AUC ratio 7.2) > rosuvastatin (AUC ratio 3.1) > pitavastatin (AUC ratio 2.6), which is in good agreement with the clinical DDI data. The results from this study demonstrated the applicability of using NMP of porcine livers as a novel preclinical model to study OATP-mediated DDI and its effect on hepatic clearance, biliary excretion, and plasma profile of drugs. SIGNIFICANCE STATEMENT: This study evaluated the use of normothermic machine perfusion (NMP) of porcine livers as a novel preclinical model to study hepatic clearance, biliary excretion, plasma (metabolite) profile of statins, and OATP-mediated DDI. Results showed that NMP of porcine livers is a reliable model to study OATP-mediated DDI. Overall, the rank order of DDI severity indicated in these experiments is in good agreement with clinical data, indicating the potential importance of this new ex vivo model in early drug discovery.

[Series: Education and the dentist in 2025. An interfaculty National Progress Test for Dentistry as future method of testing?] / Serie: Onderwijs en de tandarts anno 2025. Een interfacultaire Landelijke Voortgangstoets Tandheelkunde als toekomstige toetsmethode?

The interuniversity Progress Test in Medicine is a measuring instrument consisting of about 200 test items, to measure the development of medical students' knowledge during their studies. The Progress Test consists of 4 tests per academic year. Future versions of the Progress Test will likely be based on computerised administration of the test. One of the main goals of the Progress Test is to counter the so-called 'learningto-the-test' effect. Additional benefits are that students and teachers get detailed feedback about command of knowledge and where omissions in knowledge or the curriculum exist at multiple institutions. A Progress Test for dental education in the Netherlands can easily be conceived because the goals of the Progress Test fit well with the common framework (Raamplan Tandheelkunde) shared among the current three dental programmes. The current 'Overalltoets' (general test) of ACTA (academic centre for dentistry Amsterdam) could form a foundation for starting a Progress Test for dental education.

The use of virtual patient scenarios as a vehicle for teaching professionalism.

OBJECTIVES: This study aimed to measure students' perceptions of virtual patient scenarios (VPs) for developing ethical reasoning skills and to explore features in VP design that are necessary to promote professionalism. METHODS: Sixty-five dental students participated in learning sessions that involved collaborative practice with five VPs (four high fidelity and one low fidelity), followed by reflection sessions. Students' perceptions towards the use of VPs in developing ethical reasoning skills were assessed using a questionnaire that involved 10 closed and three open-ended questions. RESULTS: High-fidelity VPs were perceived as significantly better for developing ethical reasoning skills than low-fidelity VPs. Analyses of answers to open-ended questions revealed two new features that are specific for VPs intended for teaching professionalism, which are VP dramatic structure and how it should end. CONCLUSION: VPs intended for teaching professionalism need to have high fidelity, follow a specific dramatic structure and should include multiple plausible endings. The use of VPs as part of a collaborative activity that is followed by a reflection session is perceived as an effective tool for the development of ethical reasoning skills in dental education.

Perception of bronchoconstriction in asthma patients measured during histamine challenge test.

This study investigated two aspects of the perception of bronchoconstriction ("sensitivity" and "absolute perceptual magnitude") in asthmatic patients and identified which clinical characteristics are related to these two aspects of perception of bronchoconstriction. The perception of histamine induced bronchoconstriction was measured in 128 asthmatic patients. Subjects quantified their breathlessness on a Visual Analogue Scale (VAS) before forced expiratory volume in one second (FEV1 was measured after each inhalation of histamine. The perceptive "sensitivity" for changes in FEV1 was analysed by the "VAS percentage fall in FEV1" slope. The "absolute perceptual magnitude" was determined by the VAS value at a 20% fall in FEV1. Spearman correlations were used for analysis between the two aspects of perception and asthma symptoms, peak flow variability, bronchial responsiveness and FEV1 % predicted. Patients with a low "sensitivity" for changes in FEV1 were more likely to show a frequent peak flow variability (Rs=-0.21; p<0.05), a high bronchial responsiveness (Rs= 0.37; p<0.001) and a low baseline FEV1 % pred (Rs=0.22; p<0.05). Patient's "absolute perceptual magnitude" correlated positively with symptoms during daily life (significant correlations varied 0.21-0.32) but not with the lung function parameters. The severity of asthma reflected by a low lung function and a high bronchial responsiveness, is associated with a low "sensitivity" for changes in forced expiratory volume in one second. A patient's "absolute perceptual magnitude" is positively related with asthma symptoms during daily life.

Energy intake, physical activity and body weight: a simulation model.

In adults, body mass (BM) and its components fat-free mass (FFM) and fat mass (FM) are normally regulated at a constant level. Changes in FM and FFM are dependent on energy intake (EI) and energy expenditure (EE). The body defends itself against an imbalance between EI and EE by adjusting, within limits, the one to the other. When, at a given EI or EE, energy balance cannot be reached, FM and FFM will change, eventually resulting in an energy balance at a new value. A model is described which simulates changes in FM and FFM using EI and physical activity (PA) as input variables. EI can be set at a chosen value or calculated from dietary intake with a database on the net energy of foods. PA can be set at a chosen multiple of basal metabolic rate (BMR) or calculated from the activity budget with a database on the energy cost of activities in multiples of BMR. BMR is calculated from FFM and FM and, if necessary, FFM is calculated from BM, height, sex and age, using empirical equations. The model uses existing knowledge on the adaptation of energy expenditure (EE) to an imbalance between EI and EE, and to resulting changes in FM and FFM. Mobilization and storage of energy as FM and FFM are functions of the relative size of the deficit (EI/EE) and of the body composition. The model was validated with three recent studies measuring EE at a fixed EI during an interval with energy restriction, overfeeding and exercise training respectively. Discrepancies between observed and simulated changes in energy stores were within the measurement precision of EI, EE and body composition. Thus the consequences of a change in dietary intake or a change in physical activity on body weight and body composition can be simulated.