Search

Objectives: To estimate the cost of the hospital pharmacy's participation in clinical trials (CTs) and to compare it to the amount received in compensation from sponsors.To analyse the financial impact of CTs that end without recruiting any patients and without any financial compensation from promoters., Methods: This retrospective observational study analysed data from 5 years (2014-2018) at a tertiary university hospital.We established an allocation formula taking into account direct costs related to the pharmacy department's CT area's activity (reception, safekeeping, preparation, devolution, and destruction of medication, as well as patient monitoring) and indirect costs (facilities, resources, support staff). We calculated the costs to the department and the compensation received both overall and based on the type of promoter, clinical department involved in the trial, and the number of patients included., Results: We included 134 trials. Costs added up to €207 372.95 and the compensation to €149 128.93 (€58 244.02 loss for the department). Trials ending without recruiting patients (33.6%) and without compensation accounted for 57.45% of the deficit. The mean cost of trials ending without recruiting patients was €875. We plan to charge a reimbursable setup fee for opening CTs to safeguard against these losses (€875 for trials in all departments except oncology; €1100 for oncology because 38% of their trials end without recruiting patients) and to compensate for the costs incurred in participating in trials for cooperative groups without financial compensation (20%)., Conclusions: Billing sponsors based on costs incurred for each trial would be a fairer system than the current approach based on the number of patients included. Establishing an initial fee would make up for losses from trials that fail to recruit any patients., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop a relative value unit ( RVU)-based tool for the measurement and reimbursement of pharmacy services for clinical trials., Methods: A portfolio of activities was agreed by consensus in four tertiary hospitals. Related activities were pooled into several categories or intermediate products. We recorded the duration of each activity by multiple determinations. We then calculated the average time of all determinations. The reference activity was assigned a value of 1. All other activities were compared to the reference activity to obtain the RVU. To establish which items should be invoiced to third parties for the activities performed, we defined the final products (different types of clinical trials according to their complexity)., Results: Ten intermediate products and five final products were differentiated. Six intermediate products could be repeated over the course of a clinical trial and seven were performed whether or not the clinical trial had included patients. Each final product consisted of different categories. The total number of RVUs produced for a clinical trial was the sum of each constant category value plus the repetitive category values multiplied by the number of repetitions., Conclusion: The application of RVU methodology in investigational drug services allows a more precise quantification of services performed. After a prospective validation to confirm the applicability of this tool, it may contribute to more appropriate invoicing to third parties for these services., Competing Interests: Competing interests: None declared.

Objective: The purpose of this study was to assess mechanical properties along with microstructural modifications of the hyaline cartilage (HC), calcified cartilage (CC) and cortical plate (Ct.Pt), in an anterior cruciate ligament transection (ACLT) model. Medial femoral condyles of six healthy rabbits (control group) and of six ACLT rabbits 6 weeks after OA induction were explanted. The zone of interest (ZOI) for all experiments was defined as the weight bearing areas of the samples. Biomechanical properties were measured using nanoindentation and morphological changes were evaluated using biphotonic confocal microscopy (BCM)., Results: All rabbits of the ACLT group displayed early PTOA. The results indicate an overall decrease in the mechanical properties of the HC, CC and Ct.Pt in the ACLT group. The average equilibrium modulus and elastic fraction of the HC decreased by 42% and 35%, respectively, compared with control group. The elastic moduli of the CC and Ct.Pt decreased by 37% and 16%, respectively, compared with control group. A stiffness gradient between CC and Ct.Pt appeared in the ACLT group. The irregularity of the cement line, quantified by its tortuosity in BCM images, was accentuated in the ACLT group compared with the control group., Conclusions: In the ACLT model, weight-bearing stress was modified in the ZOI. This disruption of the stress pattern induced alterations of the tissues composing the bone-cartilage unit. In term of mechanical properties, all tissues exhibited changes. The most affected tissue was the most superficial: hyaline cartilage displayed the strongest relative decrease (42%) followed by calcified cartilage (37%) and cortical plate was slightly modified (16%). This supports the hypotheses that PTOA initiates in the hyaline cartilage., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The effects of mechanical stimuli to which cells are exposed in vivo are, at best, incompletely understood; in this respect, gene-level information regarding cell functions which are pertinent to new tissue formation is of special interest and importance in applications such as tissue engineering and tissue regeneration. Motivated by this need, the present study investigated the early responses of human mesenchymal stem cells (hMSCs) to intermittent shear stress (ISS) and to cyclic hydrostatic pressure (CHP) simulating some aspects of the biological milieu in which these cells exist in vivo. Production of nitric oxide (NO) and mRNA expression of several known mechanosensitive genes as well as ERK1/2 activation in the hMSC response to the two mechanical stimuli tested were monitored and compared. NO production depended on the type of the mechanical stimulus to which the hMSCs were exposed and was significantly higher after exposure to ISS than to CHP. At the conditions of NO peak release (i.e., at 0.7 Pa for ISS and 50,000 Pa for CHP), ISS was more effective than CHP in up-regulating mechanosensitive genes. ERK1/2 was activated by ISS but not by CHP. The present study is the first to report that PGTS2, IER3, EGR1, IGF1, IGFBP1, ITGB1, VEGFA and FGF2 are involved in the response of hMSCs to ISS. These findings establish that, of the two mechanical stimuli tested, ISS is more effective than CHP in triggering expression of genes from hMSCs which are bioactive and pertinent to several cell functions (such as cell differentiation and release of specific growth factors and cytokines) and also to tissue-related processes such as wound healing.

Controlling the mechanical environment in bioreactors represents a key element in the reactors' optimization. Positive effects of fluid flow in three-dimensional bioreactors have been observed, but local stresses at cell scale remain unknown. These effects led to the development of numerical tools to assess the micromechanical environment of cells in bioreactors. Recently, new possible scaffold geometry has emerged: granular packings. In the present study, the primary goal was to compare the efficiency of such a scaffold to the other ones from literature in terms of wall shear stress levels and distributions. To that aim, three different types of granular packings were generated through discrete element method, and computational fluid dynamics was used to simulate the flow within these packings. Shear stress levels and distributions were determined. A linear relationship between shear stress and inlet velocity was observed, and its slope was similar to published data. The distributions of normalized stress were independent of the inlet velocity and were highly comparable to those of widely used porous scaffolds. Granular packings present similar features to more classical porous scaffolds and have the advantage of being easy to manipulate and seed. The methods of this work are generalizable to the study of other granular packing configurations.

An engineered three dimensional (3D) in vitro cell culture system was designed with the goal of inducing and controlling in vitro osteogenesis in a reproducible manner under conditions more similar to the in vivo bone microenvironment than traditional two-dimensional (2D) models. This bioreactor allows efficient mechanical loading and perfusion of an original cubic calcium phosphate bioceramic of highly controlled composition and structure. This bioceramic comprises an internal portion containing homogeneously interconnected macropores surrounded by a dense layer, which minimises fluid flow bypass around the scaffold. This dense and flat layer permits the application of a homogeneous loading on the bioceramic while also enhancing its mechanical strength. Numerical modelling of constraints shows that the system provides direct mechanical stimulation of cells within the scaffold. Experimental results establish that under perfusion at a steady flow of 2 µL/min, corresponding to 3 ≤ Medium velocity ≤ 23 µm/s, mouse calvarial cells grow and differentiate as osteoblasts in a reproducible manner, and lay down a mineralised matrix. Moreover, cells respond to mechanical loading by increasing C-fos expression, which demonstrates the effective mechanical stimulation of the culture within the scaffold. In summary, we provide a "proof-of-concept" for osteoblastic cell culture in a controlled 3D culture system under perfusion and mechanical loading. This model will be a tool to analyse bone cell functions in vivo, and will provide a bench testing system for the clinical assessment of bioactive bone-targeting molecules under load.

Most of our knowledge of bone cell physiology is derived from experiments carried out in vitro on polystyrene substrates. However, these traditional monolayer cell cultures do not reproduce the complex and dynamic three-dimensional (3D) environment experienced by cells in vivo. Thus, there is a growing interest in the use of 3D culture systems as tools for understanding bone biology. These in-vitro-engineered systems, less complex than in vivo models, should ultimately recapitulate and control the main biophysical, biochemical, and biomechanical cues that define the in vivo bone environment, while allowing their monitoring. This review focuses on state-of-the-art and the current advances in the development of 3D culture systems for bone biology research. It describes more specifically advantages related to the use of such systems, and details main characteristics and challenges associated with its three main components, that is, scaffold, cells, and perfusion bioreactor systems. Finally, future challenges for noninvasive imaging technologies are addressed.