Changing device regulations in the European Union – impact on research, innovation and clinical practice

Background Up until 2017, medical devices were placed on the European Union’s (EU) single market in accordance with either Medical Device Directive 93/42/EEC for general medical devices or Medical Device Directive 90/385/EEC for active implantable devices. However, some devices that complied with these directives still failed catastrophically. In the orthopaedic device field, these failures were most pronounced in metal-on-metal hip devices causing severe patient morbidity with increased need for revision surgery which had unpredictable outcomes. Subsequently, the newly introduced Medical Device Regulations 2017/745 are aimed at addressing patient safety based on previous experience and thorough device assessment prior to and post-release on the EU single market; to accommodate for this they are substantially different (and more stringent). This poses a greater challenge for manufacturers and regulatory bodies in terms of time and resources. Methods A review of the EU directives and published literature was undertaken. This review provides the rationale behind this change and its potential impact on research, industry, and clinical practice. Discussion The change in legal requirements for the medical devices to be put on the EU single market ultimately leads to increased patient safety, which is supported by clinical professionals. The new requirements for data transparency, post-market surveillance, and implant information availability increase the chance of catastrophic failure prevention. However, the exact method of implementation remains uncertain, and some essential rules on the data requirements for compliance have not yet been published by the EU. These limitations may limit the availability of products on the market including withdrawal of existing devices and a decrease in new medical device innovation. It is speculated that lack of new technologies within the medical device area can dramatically affect patient safety itself by not allowing potentially safer materials and methods on the EU single market, as the focus for the manufacturer becomes existing devices

Subject-specific multi-validation of a Finite Element model of ovine cervical functional spinal units

The complex motion and geometry of the spine in the cervical region makes it difficult to determine how loads are distributed through adjacent vertebrae or between the zygapophysial (facet) joints and the intervertebral disc. Validated finite element modes can give insight on this distribution. The aim of this contribution was to produce direct validation of subject-specific finite element models of Functional Spinal Units (FSU’s) of the cervical spine and to evaluate the importance of including fibre directionality in the mechanical description of the annulus fibrosus. Eight specimens of cervical FSU’s were prepared from five ovine spines and mechanically tested in axial compression monitoring overall load and displacements as well as local facet joints pressure and displacement. Subject-specific finite element models were produced from microCT image data reproducing the experimental setup and measuring global axial force and displacement as well as local facet joints displacement and contact forces. Material models and parameters were taken from the literature, testing isotropic and anisotropic materials for the annulus fibrosus. The validated models showed that adding the direction of the fibres to their non-linear behaviour in the description of the annulus fibrosus improves the predictions at large strain values but not at low strain values. The load transferred through the facet joints was always accurate, irrespective of the annulus material model, while the predicted facet displacement was larger than the measured one but not significantly. This is, to the authors’ knowledge, the first subject-specific direct validation study on a group of specimens, accounting for inter-subject variability

Surface Functionality Features of Nanosized Silica Obtained by Electron Beam Evaporation at Ambient Pressure

A series of nanosized silica powders with different specific surface values are synthesized by electron beam evaporation in air at ambient pressure. The obtained silica samples are featured with relatively low apparent density and high content of oxygen and hydroxyl groups on the surface making these materials promising for specific applications

Primary T-Cell Cutaneus Lymphoma at Three-Month-Old Child

Primary T-cell cutaneus lymphoma presents in 10-15% of children with malignant tumour. This disease is results of the neoplastic proliferation T-lymphocytes in skin. Diagnostics has based on the histology, immunology and immunohistochemistry methods. We describe a clinical case of three-month-old child with Primary T-cell cutaneus lymphoma of skin

Dynamic Acetabular Cup Orientation during Gait: A Study of Fast- and Slow-Walking Total Hip Replacement Patients

The dynamic orientation of total hip replacement acetabular cups during walking may vary substantially from their assumed position at surgical implantation and may vary between individuals. The scale of this effect is of interest for both pre-clinical device testing and for pre-operative surgical planning. This work aimed to evaluate (1) patient variation in dynamic cup orientation; (2) whether walking speed was a candidate proxy measure for the dynamic cup orientation; and (3) the relationships between dynamic cup orientation angles and planar pelvic angles. Pelvic movement data for patients with fast (20 patients) and slow (19 patients) self-selected walking speeds were used to calculate acetabular cup inclination and version angles through gait. For aim 1, the range and extremes of acetabular cup orientation angles were analysed for all patients. A large patient-to-patient variation was found in the ranges of both inclination angle (1° to 11°) and version angle (4° to 18°). The version angle was typically retroverted in comparison to the implantation position (greatest deviation 27°). This orientation is substantially different to the static, 0° version, simplifying assumptions in pre-clinical ‘edge loading’ testing. For aim 2, the cup orientation angles were compared between the fast- and slow-walking groups using statistical parametric mapping. The only significant differences observed were for cup version angle, during ~12% of the gait cycle before toe-off (p < 0.05). Therefore, self-selected walking speed, in isolation, is not a sufficient proxy measure for dynamic acetabular orientation. For aim 3, correlations were recorded between the acetabular cup orientation angles and the planar pelvic angles. The cup inclination angle during gait was strongly correlated (Spearman’s coefficient −1) with pelvic obliquity alone, indicating that simple planar assessment could be used to anticipate inclination angle range. The cup version angle was correlated with both pelvic rotation and tilt (Spearman’s coefficient 0.8–1), indicating that cup version cannot be predicted directly from any single pelvic movement. This complexity, along with the interaction between inclination angle and range of version angle, supports the use of computational tools to aid clinical understanding

A NEW METHOD TO ASSESS FUNCTIONAL ACTIVITY OF SERUM COMPLEMENT SYSTEM

Complement system is an important component of innate immunity, providing primary protection against pathogens invading the body. In addition, it was shown that the complement system is associated with many diseases, not only autoimmune and infectious, but also mental disorders. In this regard, it is necessary to develop affordable and fast method of measuring activity of the complement system in real-time mode. We present a new semi-automated method for assessment of serum complement activity. The assay is based on cytolytic action of complement system upon the ciliate organism Tetrahymena pyriformis. This method consists in repeated counting of live Tetrahymena motile cells by means of specially developed Biolat device, which consists of two video cameras, light sources, and movable round plate. The plate has two rows of holes. The device also includes microprocessor control unit based on AutoCiliata software, intended for control of operation module and counting the surviving cell. The calculations are based on fixation of two sequential video-frames, with subsequent software image processing. Cell death events were observed upon incubation in triethanolamine (TEA) buffer containing 5% of blood serum. We have also compared complement activity in different buffers, i.e., standard medium for culturing of ciliates, Veronal-Medinalum buffer, and the TEA buffer. TEA buffer was found superior to the Veronal buffer when applied in the test system. The time of cell death in the TEA-buffered medium containing 5% serum was &lt; 15 minutes for all the sera studied. The parameters denoting serum complement activity were as follows: a half-life time for the moving cells (TLD50), and a similar value for 100% cell inactivation (1/TLD50, functional activity of the complement system, ACS). The sensitivity of this assay was calculated from dependencies between TLD50 and ACS, and actual serum concentrations. We have suggested an opportunity for evaluation of an integral complement activity, and interrelations between the intensity of synthesis and consumption of its major effector proteins. In the course of this study, we have tested different concentrations of Ca++ and Mg++ ions in the incubation buffer, with optimal physiological concentrations of2.5 mMand1.5 mM, respectively. We have also estimated statistical precision characteristics for pre-analytical and analytical steps of the method. The average coefficients of variation (CV) were 3.9% and 2.7%, respectively, thus satisfying the reliability criteria in research. A short performance time of the study suggests its potential application in clinical practice, including online examination regimens. A method for semi-automatic measurement of serum complement activity could be applicable in daily clinical practice, including the online performance

Insertion of EGFP into the replicase gene of Semliki Forest virus results in a novel, genetically stable marker virus

Alphavirus-based vector and replicon systems have been extensively used experimentally and are likely to be used in human and animal medicine. Whilst marker genes can be inserted easily under the control of a duplicated subgenomic promoter, these constructs are often genetically unstable. Here, a novel alphavirus construct is described in which an enhanced green fluorescent protein (EGFP) marker gene is inserted into the virus replicase open reading frame between nsP3 and nsP4, flanked by nsP2 protease-recognition sites. This construct has correct processing of the replicase polyprotein, produces viable virus and expresses detectable EGFP fluorescence upon infection of cultured cells and cells of the mouse brain. In comparison to parental virus, the marker virus has an approximately 1 h delay in virus RNA and infectious virus production. Passage of the marker virus in vitro and in vivo demonstrates good genetic stability. Insertion of different markers into this novel construct has potential for various applications

Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families

Abstract Introduction: A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. Methods: GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene. Results: The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer. Conclusions: Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction

HEMITSELLYULOZA AND THEIR NANOBIOCOMPOSITES - PERSPECTIVE NANOSTRUCTURED SINBIOTICS

Natural nanocomposites hemicellulose arabinogalactan and flavonoids isolated (from Siberian larch) and characterized. Additionally nitro- and sulfo-esters of arabinogalactan and its calcium salt are synthesized and. characterized. All of the derivatives of the beta-hemicellulose arabinogalactan. are water-soluble and are promising prebiotics on the example test-strain Bifidobacterium bifidum. (except for the nitrate esters of arabinogalactan)

Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization.

We have previously demonstrated that Stat3 regulates lysosomal-mediated programmed cell death (LM-PCD) during mouse mammary gland involution in vivo. However, the mechanism that controls the release of lysosomal cathepsins to initiate cell death in this context has not been elucidated. We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride. Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness. Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3-ablated mammary glands and loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo. We propose that Stat3 regulates LM-PCD in mouse mammary gland by switching cellular function from secretion to uptake of MFGs. Thereafter, perturbation of lysosomal vesicle membranes by high levels of free fatty acids results in controlled leakage of cathepsins culminating in cell death.This work was supported by a grant from the Medical Research Council programme grant no. MR/J001023/1 (T.J.S. and B. L-L.) and a Cancer Research UK Cambridge Cancer Centre PhD studentship (H.K.R.).This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3043.html