FIMCAR X: MDB Test Procedure: Test and Simulation Results

One of the test modes investigated during the FIMCAR project to improve frontal impact and compatibility is a so-called Moving Deformable Barrier test (MDB test). This is a frontal test with a moving test vehicle and moving trolley equipped with a deformable element. In various initiatives in Europe and the US this type of test is seen as a next step in the future evaluation of vehicle safety with a good possibility for harmonisation. Based on the experience of various projects prior to the FIMCAR project, a test protocol has been drafted in the FIMCAR project. Two main parameters: test speed and trolley mass, key factor to define the severity of the MDB tests, were defined during the FIMCAR program. Using the draft protocol a number of MDB tests were carried out, the main objectives of the test were: • Analysis of the feasibility of the test set up and protocol • Definition of the test severity; trolley mas and impact speed • Assessment of repeatability and reproducibility • Development of compatibility metric / horizontal load spreading The results of 15 MPDB test were used for the FIMCAR investigations. In general terms, the tests according to the draft protocol were feasible in various laboratories using different test trollies. Special attention is needed for the wheel alignment of trolley and test vehicles to avoid incorrect offsets. For the explored vehicle mass range, kerb weight from 1000kg to 2200 kg, a fixed trolley mass of 1500 kg and a test speed of 50 km/h (for vehicle and trolley) results in an acceptable test severity. For vehicles outside this range, for example light electrical vehicles and heavy SUV’s, an update of these specifications must be considered in the future. Only two repeatability and two reproducibility tests were carried out to date. These series of tests both showed good results, giving an indication for good R&R, however, more tests are needed to make this statement statistically relevant

FIMCAR XV: Fleet Studies

Subject of this study is the development of a generic method to evaluate the characteristics of future vehicle fleets, which assist in vehicle compatibility research. The ever increasing demands for occupant safety have led to improved crashworthiness of vehicles. However, vehicles have become increasingly stiff over the last decades. In combination with a trend of heavier and higher vehicles this results in more aggressive and incompatible vehicles. Also the trend of smaller and lighter vehicles results in a mismatch of vehicles. Compatibility research focuses on improvement of crashworthiness while taking the safety of a possible crash partner into account with the aim to reduce the injury risks off all crash partners. In this regard it is important to conduct research of behaviour on a fleet wide basis. The generic vehicle modelling procedure developed in FIMCAR was used to generate a set of MADYMO models of various vehicles. Due to the limited available data, only three different car models could be made, the Supermini 2, Small Family Car 2 and SUV 4. The created models are tuned with the test data of Full Width Rigid Barrier (FWRB) and checked with test data of Offset Deformable Barrier (ODB) tests. To compensate the limited amount of vehicles additional simulations were ran with variable masses. The available models are used to run two large sets of simulations with various vehicle parameters, like longitudinal stiffness, overlap and speed. These simulations are used to evaluate the performance of the vehicle fleet. For crash severity evaluations the Vehicle Pulse Index (VPI) is used, in which higher VPI values represent a lower crash performance with higher risk of injury

Coronary Heart Disease in Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) (OMIM #143890) is an autosomal dominant disorder present in 1:500 Caucasians. FH is caused by defective low-density lipoprotein (LDL) receptors, leading to a diminished uptake of LDL cholesterol by the liver. As a result, FH patients have high LDL cholesterol levels and a high risk of contracting cardiovascular disease (CVD), mainly coronary heart disease (CHD). FH can be diagnosed on the basis of clinical criteria (Table 1) or by detection of the causal mutation in the LDL-receptor gene. Despite the homogenous background of hypercholesterolemia, the onset and severity of CHD among FH patients varies considerably. This introduction provides a short update of the classic and genetic factors influencing CHD risk in heterozygous FH patients. Besides the importance of CHD risk prediction for FH patients, FH being the most common monogenetic disorder, FH can also be considered a high-risk model population in which CHD risk factors can more easily be detected. Risk factors identified in FH patients might consequently be translated to the general population

DiffErenCes in AntihypertenSive Drug Blood Levels in Patients with HypertensiON (DECISION):Protocol for a Prospective Observational Study Comparing Pharmacokinetics and Pharmacodynamics Between Young and Elderly Patients

Adequate controlled blood pressure decreases the risk of cardiovascular events. However, the elderly are more vulnerable and thereby more prone to side effects of antihypertensive drugs. A lack of pharmacokinetic and pharmacodynamic (PK/PD) studies in older patients makes specific and tailored advices towards antihypertensive drug therapy difficult. The aim of our study, DiffErenCes In antihypertenSive drug levels In patients with hypertensiON (DECISION), is to fill in this PK/PD knowledge gap and move towards precision dosing. DECISION is a prospective observational PK/PD study set up to determine the difference in exposure to the antihypertensive drugs, losartan and perindopril, measured by drug levels in blood. The area under the curve (AUC; PK) and furthermore the association between the AUC and the effect on blood pressure (PD) will be compared between elderly and younger patients

FIMCAR XI: FIMCAR Final Assessment Approach

The objectives of the FIMCAR (Frontal Impact and Compatibility Assessment Research) project are to answer the remaining open questions identified in earlier projects (such as understanding of the advantages and disadvantages of force based metrics and barrier deformation based metrics, confirmation of specific compatibility issues such as structural interaction, investigation of force matching) and to finalise the frontal impact test procedures required to assess compatibility. Research strategies and priorities were based on earlier research programs and the FIMCAR accident data analysis. The identified real world safety issues were used to develop a list of compatibility characteristics which were then prioritised within the consortium. This list was the basis for evaluating the different test candidates. This analysis resulted in the combination of the Full Width Deformable Barrier test (FWDB) with compatibility metrics and the existing Offset Deformable Barrier (ODB) as described in UN-ECE Regulation 94 with additional cabin integrity requirement as being proposed as the FIMCAR assessment approach. The proposed frontal impact assessment approach addresses many of the issues identified by the FIMCAR consortium but not all frontal impact and compatibility issues could be addressed

A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

PURPOSE: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. METHODS: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. RESULTS: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug concentrations, the CsA dosage needed to be reduced, on average, by 27 % after initiation of imatinib (p = 0.004). CONCLUSIONS: Imatinib significantly increases CsA concentrations in HSCT patients, putting these patients at increased risk of CsA toxicity. We recommend intensive monitoring of CsA concentrations after initiation of imatinib; a pre-emptive CsA dose reduction of 25 % might be considered

Lessons learned from conducting a randomized controlled trial to improve non-adherence to antihypertensive drug treatment

Purpose: Hypertension significantly contributes to cardiovascular diseases and premature deaths. Effective treatment is crucial to reduce cardiovascular risks, but poor adherence to antihypertensive drugs is a major issue. Numerous studies attempted to investigate interventions for identifying non-adherence, but often failed to address the issue effectively. The RHYME-RCT trial sought to bridge this gap by measuring non-adherence by determining antihypertensive drug concentrations in blood through a dried blood spot (DBS) method in patients with resistant hypertension. This measurement was followed by personalized feedback to improve adherence. During the course of this trial several challenges emerged, including selection bias, the gatekeeper role of physicians, the Hawthorne effect and the role of randomization.Aim: This communication aims to inform fellow researchers and clinicians of challenges that can arise when conducting clinical trials to improve adherence and offer insights for refining study designs to avoid these issues in forthcoming adherence studies