Leray and LANS-α\alpha modeling of turbulent mixing

Mathematical regularisation of the nonlinear terms in the Navier-Stokes equations provides a systematic approach to deriving subgrid closures for numerical simulations of turbulent flow. By construction, these subgrid closures imply existence and uniqueness of strong solutions to the corresponding modelled system of equations. We will consider the large eddy interpretation of two such mathematical regularisation principles, i.e., Leray and LANS$-\alpha$ regularisation. The Leray principle introduces a {\bfi smoothed transport velocity} as part of the regularised convective nonlinearity. The LANS$-\alpha$ principle extends the Leray formulation in a natural way in which a {\bfi filtered Kelvin circulation theorem}, incorporating the smoothed transport velocity, is explicitly satisfied. These regularisation principles give rise to implied subgrid closures which will be applied in large eddy simulation of turbulent mixing. Comparison with filtered direct numerical simulation data, and with predictions obtained from popular dynamic eddy-viscosity modelling, shows that these mathematical regularisation models are considerably more accurate, at a lower computational cost.Comment: 42 pages, 12 figure

Overdracht van lood, cadmium, kwik en arseen van diervoeders naar dierlijke produkten van mestlammeren

In samemo1erking met het IVVO te Lelystad werd nagegaan wat het effekt bij mestlammeren was van toediening van zware metalen via het voer op het gehalte van deze metalen in een aantal dierlijke produkten. Lood, cadmium, kwik en arseen werden toegediend in de vorm van oplosbare verbindingen of zoals ze voorkomen in haven- en rioolslib. De toegediende hoeveelheden bedroegen voor lood, cadmium, kwik en arseen respektievelijk 10, 2, 0,1 en 2 mg/kg droge stof

De uitscheiding van anorganisch bromide, na orale dosering, in melk van lakterende koeien

Doel is het vaststellen van de overdracht van anorganisch bromide van voer naar melk om normen in veevoedergrondstoffen en dierlijke produkten op elkaar af te stemmen

Reported Challenges in Health Technology Assessment of Complex Health Technologies

Objectives: With complex health technologies entering the market, methods for health technology assessment (HTA) may require changes. This study aimed to identify challenges in HTA of complex health technologies.  Methods: A survey was sent to European HTA organizations participating in European Network for HTA (EUnetHTA). The survey contained open questions and used predefined potentially complex health technologies and 7 case studies to identify types of complex health technologies and challenges faced during HTA. The survey was validated, tested for reliability by an expert panel, and pilot tested before dissemination.  Results: A total of 22 HTA organizations completed the survey (67%). Advanced therapeutic medicinal products (ATMPs) and histology-independent therapies were considered most challenging based on the predefined complex health technologies and case studies. For the case studies, more than half of the reported challenges were “methodological,” equal in relative effectiveness assessments as in cost-effectiveness assessments. Through the open questions, we found that most of these challenges actually rooted in data unavailability. Data were reported as “absent,” “insufficient,” “immature,” or “low quality” by 18 of 20 organizations (90%), in particular data on quality of life. Policy and organizational challenges and challenges because of societal or political pressure were reported by 8 (40%) and 4 organizations (20%), respectively. Modeling issues were reported least often (n = 2, 4%).  Conclusions: Most challenges in HTA of complex health technologies root in data insufficiencies rather than in the complexity of health technologies itself. As the number of complex technologies grows, the urgency for new methods and policies to guide HTA decision making increases

When Reality Does Not Meet Expectations-Experiences and Perceived Attitudes of Dutch Stakeholders Regarding Payment and Reimbursement Models for High-Priced Hospital Drugs

This study aimed to identify the current experiences with and future preferences for payment and reimbursement models for high-priced hospital therapies in the Netherlands, where the main barriers lie and assess how policy structures facilitate these models. A questionnaire was sent out to Dutch stakeholders (in)directly involved in payment and reimbursement agreements. The survey contained statements assessed with Likert scales, rankings and open questions. The results were analyzed using descriptive statistics. Thirty-nine stakeholders (out of 100) (in)directly involved with reimbursement decision-making completed the survey. Our inquiry showed that currently financial-based reimbursement models are applied most, especially discounts were perceived best due to their simplicity. For the future, outcome-based reimbursement models were preferred, particularly pay-for-outcome models. The main stated challenge for implementation was generating evidence in practice. According to the respondents, upfront payments are currently implemented most often, whereas delayed payment models are preferred to be applied more frequently in the future. Particularly payment-at-outcome-achieved models are preferred; however, they were stated as administratively challenging to arrange. The respondents were moderately satisfied with the payment and reimbursement system in the Netherlands, arguing that the transparency of the final agreements and mutual trust could be improved. These insights can provide stakeholders with future direction when negotiating and implementing innovative reimbursement and payment models. Attention should be paid to the main barriers that are currently perceived as hindering a more frequent implementation of the preferred models and how national policy structures can facilitate a successful implementation

Real World Data in Health Technology Assessment of Complex Health Technologies

The available evidence on relative effectiveness and risks of new health technologies is often limited at the time of health technology assessment (HTA). Additionally, a wide variety in real-world data (RWD) policies exist among HTA organizations. This study assessed which challenges, related to the increasingly complex nature of new health technologies, make the acceptance of RWD most likely. A questionnaire was disseminated among 33 EUnetHTA member HTA organizations. The questions focused on accepted data sources, circumstances that allowed for RWD acceptance and barriers to acceptance. The questionnaire was validated and tested for reliability by an expert panel, and pilot-tested before dissemination via LimeSurvey. Twenty-two HTA organizations completed the questionnaire (67%). All reported accepting randomized clinical trials. The most accepted RWD source were patient registries (19/22, 86%), the least accepted were editorials and expert opinions (8/22, 36%). With orphan treatments or companion diagnostics, organizations tended to be most likely to accept RWD sources, 4.3-3.2 on a 5-point Likert scale, respectively. Additional circumstances were reported to accept RWD (e.g., a high disease burden). The two most important barriers to accepting RWD were lacking necessary RWD sources and existing policy structures. European HTA organizations seem positive toward the (wider) use of RWD in HTA of complex therapies. Expanding the use of patient registries could be potentially useful, as a large share of the organizations already accepts this source. However, many barriers still exist to the widespread use of RWD. Our results can be used to prioritize circumstances in which RWD might be accepted

Decision making under uncertainty: comparing regulatory and health technology assessment reviews of medicines in the United States and Europe

Assessments of clinical evidence vary between regulators and health technology assessment bodies, but precise differences remain unclear. To compare uncertainties raised on the clinical evidence of approved drugs, we analyzed assessments of regulators and health technology assessment (HTA) bodies in the United States and Europe. We found that US and European regulators report uncertainties related to safety for almost all drugs (85–94%), whereas HTA bodies reported these less (53–59%). By contrast, HTA bodies raised uncertainties related to effects against relevant comparators for almost all drugs (88–100%), whereas this was infrequently addressed by regulators (12–32%). Regulators as well as HTA bodies reported uncertainties related to the patient population for 60–95% of drugs. The patterns of regulator-HTA misalignment were comparable between the United States and Europe. Our results indicate that increased coordination between these complementary organizations is necessary to facilitate the collection of necessary evidence in an efficient and timely manner

Overdracht van cadmium vanuit diervoeders naar melk, bloed, vlees en organen van melkkoeien

In verband met het opstellen van een proefplan voor overdrachtsonderzoek met cadmium bij lacterende melkkoeien is een inventarisatie gemaakt van het voorkomen van cadmium in dierlijke produkten van weidende- en op stal gehuisveste melkkoeien die cadmium in oplosbare vorm of via haven- en rioolslib toegediend kregen