Dynamic Regulatory Assessment: Unpacking the Process Reveals Readiness to Pilot for Europe-An EFPIA View.

The medicines regulatory network of the European Economic Area comprises 30 countries, their National Competent Authorities (NCA), and the European Medicines Agency (EMA). The NCAs and EMA are involved at different stages of the medicine life cycle; not all are engaged in a particular medicine's development discussions. As a result, knowledge management (ie, acquisition and transfer between medicine developer and the NCAs) is fragmented and inefficient. Dynamic regulatory assessment (DRA), a regulatory science concept developed by the European Federation of Pharmaceutical Industries and Associations (EFPIA), could drive increased connectedness supporting more continuous knowledge building. DRA works via iterative release and assessment of discrete data packets (DDPs) at mutually agreed milestones during development, culminating in more efficient development and faster authorization. This commentary seeks to build on an earlier article by unpacking the DRA concept, with a particular focus on DDPs. Its aim is to show how DDPs can support efficient and predictable release of data to encourage development and assessment of promising medicines, and it makes the case for piloting the DRA concept with European regulators now.

Controlling grain structure in metallic additive manufacturing using a versatile, inexpensive process control system.

Additive manufacturing (AM), commonly termed 3D printing, is a revolutionary manufacturing technology with great industrial relevance in the aerospace, medical and automotive sectors. Metallic AM allows creation of complex intricate parts and repair of large components; however, certification is currently a concern due to lack of process consistency. A versatile, inexpensive process control system was developed and integrated, reducing variability in melt pool fluctuation and improving microstructural homogeneity of components. Remnant microstructural variation can be explained by the change in heat flow mechanism with geometry. The grain area variability was reduced by up to 94% at a fraction of the cost of a typical thermal camera, with control software written in-house and made publically available. This decreases the barrier to implementation for process feedback control, which can be implemented in many manufacturing processes, from polymer AM to injection moulding to inert-gas heat treatment.

Effect of Process Parameters and Build Orientation on Microstructure and Impact Energy of Electron Beam Powder Bed Fused Ti-6Al-4V.

To fully exploit the benefits of additive manufacturing (AM), an understanding of its processing, microstructural, and mechanical aspects, and their interdependent characteristics, is necessary. In certain instances, AM materials may be desired for applications where impact toughness is a key property, such as in gas turbine fan blades, where foreign or direct object damage may occur. In this research, the impact energy of a series of Ti-6Al-4V specimens produced via electron beam powder bed fusion (EBPBF) was established via Charpy impact testing. Specimens were produced with five different processing parameter sets, in both the vertical and horizontal build orientation, with microstructural characteristics of prior ß grain area, prior ß grain width, and α lath width determined in the build direction. The results reveal that horizontally oriented specimens have a lower impact energy compared to those built in the vertical orientation, due to the influence of epitaxial grain growth in the build direction. Relationships between process parameters, microstructural characteristics, and impact energy results were evaluated, with beam velocity displaying the strongest trend in terms of impact energy results, and normalised energy density exhibiting the most significant influence across all microstructural measurements.

Reconstruction of Microscopic Thermal Fields from Oversampled Infrared Images in Laser-Based Powder Bed Fusion.

This article elucidates the need to consider the inherent spatial transfer function (blur), of any thermographic instrument used to measure thermal fields. Infrared thermographic data were acquired from a modified, commercial, laser-based powder bed fusion printer. A validated methodology was used to correct for spatial transfer function errors in the measured thermal fields. The methodology was found to make a difference of 40% to the measured signal levels and a 174 °C difference to the calculated effective temperature. The spatial gradients in the processed thermal fields were found to increase significantly. These corrections make a significant difference to the accuracy of validation data for process and microstructure modeling. We demonstrate the need for consideration of image blur when quantifying the thermal fields in laser-based powder bed fusion in this work.

An inter-disciplinary approach to the energy transition in South Africa.

The compelling need to tackle climate change is well-established. It is a challenge which is being faced by all nations. This requires an approach which is truly inter-disciplinary in nature, drawing on the expertise of politicians, social scientists, and technologists. We report how the pace of the energy transition can be influenced significantly by both the operation of societal barriers, and by policy actions aimed at reducing these effects. Using the case study of South Africa, a suite of interviews has been conducted with diverse energy interests, to develop and analyse four key issues pertinent to the energy transition there. We do so primarily through the lens of delivering energy justice to that society. In doing so, we emphasise the need to monitor, model, and modify the dynamic characteristic of the energy transition process and the delivery of energy justice; a static approach which ignores the fluid nature of transition will be insufficient. We conclude that the South African fossil fuel industry is still impeding the development of the country's renewable resources, and the price of doing so is being met by those living in townships and in rural areas.

Investigation into using resonant frequency measurements to predict the mechanical properties of Ti-6Al-4V manufactured by selective laser melting.

There is a need to qualify additively manufactured parts that are used in highly regulated industries such as aerospace and nuclear power. This paper investigates the use of resonant ultrasound measurements to predict the mechanical properties of Ti-6Al-4V manufactured by selective laser melting using a Renishaw AM 250. It is first demonstrated why R2 should not be used to assess the predictive capability of a model, before introducing a method for calculating predicted R2, which is then used to assess the models. It is found that a linear model with the resonant frequency peaks as predictors cannot be used to predict elongation at failure or reduction in area. However, linear models did demonstrate better predictive capabilities for Young's modulus, yield strength, and especially ultimate tensile strength.

Publisher Correction: Damage-tolerant architected materials inspired by crystal microstructure.

In Fig. 4a of this Article, owing to an error in the production process, the scale bar inadvertently read 1 mm instead of 1 m. This error has been corrected online.

Damage-tolerant architected materials inspired by crystal microstructure.

Architected materials that consist of periodic arrangements of nodes and struts are lightweight and can exhibit combinations of properties (such as negative Poisson ratios) that do not occur in conventional solids. Architected materials reported previously are usually constructed from identical 'unit cells' arranged so that they all have the same orientation. As a result, when loaded beyond the yield point, localized bands of high stress emerge, causing catastrophic collapse of the mechanical strength of the material. This 'post-yielding collapse' is analogous to the rapid decreases in stress associated with dislocation slip in metallic single crystals. Here we use the hardening mechanisms found in crystalline materials to develop architected materials that are robust and damage-tolerant, by mimicking the microscale structure of crystalline materials-such as grain boundaries, precipitates and phases. The crystal-inspired mesoscale structures  in our architected materials are as important for their mechanical properties as are crystallographic microstructures in metallic alloys. Our approach combines the hardening principles of metallurgy and architected materials, enabling the design of materials with desired properties.

Atomic structure of Mg-based metallic glasses from molecular dynamics and neutron diffraction.

We use a combination of classical molecular dynamics simulation and neutron diffraction to identify the atomic structure of five different Mg-Zn-Ca bulk metallic glasses, covering a range of compositions with substantially different behaviour when implanted in vitro. There is very good agreement between the structures obtained from computer simulation and those found experimentally. Bond lengths and the total correlation function do not change significantly with composition. The zinc and calcium bonding shows differences between composition: the distribution of Zn-Ca bond lengths becomes narrower with increasing Zn content, and the preference for Zn and Ca to avoid bonding to themselves or each other becomes less strong, and, for Zn-Ca, transforms into a positive preference to bond to each other. This transition occurs at about the same Zn content at which the behaviour on implantation changes, hinting at a possible structural connection. A very broad distribution of Voronoi polyhedra are also found, and this distribution broadens with increasing Zn content. The efficient cluster packing model, which is often used to describe the structure of bulk metallic glasses, was found not to describe these systems well.

The Effect of Electronic Structure on the Phases Present in High Entropy Alloys.

Multicomponent systems, termed High Entropy Alloys (HEAs), with predominantly single solid solution phases are a current area of focus in alloy development. Although different empirical rules have been introduced to understand phase formation and determine what the dominant phases may be in these systems, experimental investigation has revealed that in many cases their structure is not a single solid solution phase, and that the rules may not accurately distinguish the stability of the phase boundaries. Here, a combined modelling and experimental approach that looks into the electronic structure is proposed to improve accuracy of the predictions of the majority phase. To do this, the Rigid Band model is generalised for magnetic systems in prediction of the majority phase most likely to be found. Good agreement is found when the predictions are confronted with data from experiments, including a new magnetic HEA system (CoFeNiV). This also includes predicting the structural transition with varying levels of constituent elements, as a function of the valence electron concentration, n, obtained from the integrated spin-polarised density of states. This method is suitable as a new predictive technique to identify compositions for further screening, in particular for magnetic HEAs.

Thermal expansion coefficients in Invar processed by selective laser melting.

This work investigates whether the unique low thermal expansion property of Invar (64Fe-36Ni) is retained after processing using the additive manufacturing process selective laser melting (SLM). Using this process, near-full-density components (99.96%) were formed by melting thin (20 µm) layers of powdered Invar (15-45 µm particle size). The mechanical properties of SLM Invar were comparable to that of cold-drawn Invar36®; however, the thermal coefficient of expansion was observed to be a lower value and negative up until 100 °C. This negative value was attributed to residual stress in the as-deposited parts. The low thermal expansion property of Invar was still maintained when processed using a non-conventional layer-based additive manufacturing technique.

Mechanical and electrochemical characterisation of new Ti-Mo-Nb-Zr alloys for biomedical applications.

The development and characterisation of new metallic biomaterials that contain non-toxic and non-allergic elements but possess low elastic modulus and low biodegradation rates, has become a topic of serious investigation in orthopaedic implant application. The lowering of elastic modulus and improving of corrosion resistance can be achieved by specific chemical alloying and super-elasticity effects, associated with a stress-induced phase transformation from the BCC metastable beta phase to the orthorhombic α″ martensite. Using this framework, this paper focuses on the effect of Nb and/or Zr micro-additions on the elastic modulus/yield strength balance and discusses microstructure, and the mechanical and electrochemical behaviour of four new ß-Ti-8Mo-xNb-xZr (x=2-5) alloys, using tensile tests, X-ray diffraction, SEM characterisation, ultrasound technique and potentiodynamic polarisation methods. The results reveal that the alloys exhibit a pronounced microstructural sensitivity response, with alloying elements and excellent agreement between ß-stability and high mechanical strength, with increasing Nb additions. Although all the alloys possess excellent corrosion resistance and low Young׳s modulus, Ti-8Mo-4Nb-2Zr alloy, which consists of ß+α'' phases, exhibits a low Young modulus of 35GPa, which is lower than those of the commercial alloys already used in biomedical implantation. The significant corrosion resistance, nontoxicity and better mechanical compatibility are properties pertinent to preventing stress shielding and bone resorption in orthopaedic implant applications.

A feasibility study to investigate the clinical application of functional electrical stimulation (FES), for dropped foot, during the sub-acute phase of stroke - A randomized controlled trial.

PURPOSE: Functional electrical stimulation (FES), for dropped foot, has been shown to have positive benefits in chronic stroke. It has been suggested that similar benefits may be seen earlier after stroke. The aim of this feasibility study was to evaluate the trial methodology of undertaking a randomized controlled trial (RCT) of FES in sub-acute stroke. METHOD: This was a randomized feasibility study with non-blinded outcomes at 6 and 12 weeks. Sixteen sub-acute stroke in-patients with dropped foot were randomized into two groups (control, n = 7; intervention, n = 9). Both groups received routine gait re-education and an orthotic device, the control group used an ankle foot orthosis and the intervention group used FES. Outcome measures included gait velocity and cadence, Functional Ambulation Classification, Visual Analogue Scale of perception of walking, and the Stroke Impact Scale. RESULTS: Eligibility criteria developed for inclusion of participants in the trial were appropriate. Set-up of FES during sub-acute stroke was feasible but more challenging than with chronic patients. Outcome measures were suitable and have informed the choice of measures for future work. CONCLUSIONS: It is feasible to undertake a trial evaluating FES during the sub-acute phase of recovery after stroke. A larger RCT is required.

Formation of microporous NiTi by transient liquid phase sintering of elemental powders.

Porous metallic structures are attractive for biomedical implant applications as their open porosity simultaneously improves the degree of fixation and decreases the mismatch in stiffness between bone and implant, improving bonding and reducing stress-shielding effects respectively. NiTi alloys exhibit both the shape memory effect and pseudoelasticity, and are of particular interest, though they pose substantial problems in their processing. This is because the shape memory and pseudoelastic behaviours are exceptionally sensitive to the presence of oxygen, and other minor changes in alloy chemistry. Thus in processing careful control of composition and contamination is vital. In this communication, we investigate these issues in a novel technique for producing porous NiTi parts via transient liquid phase sintering following metal injection moulding (MIM) of elemental Ni and Ti powders, and report a new mechanism for pore formation in the powder processing of metallic materials from elemental powders.

Depression and anxiety symptoms after lower limb amputation: the rise and fall.

OBJECTIVE: To examine the time course of anxiety and depressive symptoms over a three year period after amputation. DESIGN AND SETTINGS: A prospective study in inpatients admitted to a rehabilitation ward after lower limb amputation. SUBJECTS: Successive admissions over a one-year period of whom 68 were alive at follow-up, 2-3 years later. INTERVENTIONS: Nil. MAIN MEASURES: Hospital Anxiety and Depression Scale (HADS) on admission and discharge from inpatient rehabilitation and at a 2.7(SD=0.4) year mean follow-up period with correlation to demographic and patient features. RESULTS: Of the 68 responding patients, 12 (17.6%) and 13 (19.1%) had symptoms of depression and anxiety respectively. This compared to an original incidence of 16 (23.5%) for both on admission and 2 (2.9%) on discharge. This rise in incidence from time of discharge was highly significant for both depression (P<0.001) and anxiety (P<0.001). Depression at follow-up was correlated to depressive symptoms at admission (P=0.03) and to having other significant comorbidities (P=0.02). Anxiety symptoms were commoner in younger patients (P=0.03). There was no association with age, gender, living in isolation, vascular cause for amputation, wearing a limb prosthesis or length of original inpatient stay. CONCLUSIONS: Depression and anxiety are common after lower limb amputation but resolve during inpatient rehabilitation. The incidence then rises again after discharge.

Predicting those who will walk after rehabilitation in a specialist stroke unit.

OBJECTIVE: To establish whether the ability to use a wheelchair shortly after a stroke or continence are related to the likelihood of walking by time of discharge. DESIGN AND SUBJECTS: An observational study in patients admitted to a stroke rehabilitation unit for under-65s over a three-year period. METHODS: Functional Independence Measure (FIM) subscores for walking were examined on all patients at time of admission and discharge. Walking was defined by an FIM > or = 5 in that section. Comparisons were then made between those who could self-propel a wheelchair within a week of admission with those who could not. Continence (defined by an FIM subscore of > or = 6 in that category) was also correlated to walking at discharge. MAIN OUTCOME MEASURE: Walking at time of discharge defined by an FIM > or = 5 in that section. RESULTS: From 393 admissions, 135 were excluded because they could already walk (FIM subscore > or = 5 in that particular section) and three died during their admission. Out of the remaining 255 patients, 108 could self-propel on admission and 147 could not. While 105 (97%) of the self-propellors could walk by time of discharge, only 91 (62%) of the non-propellors could do so (chi2 = 42.237, df = 1, P < 0.001, odds ratio (OR) 21.54 (6.52-71.51)). Although continence also predicted improved likelihood of walking, this was at a lower level of significance and correspondingly lower odds ratio (chi2=5.894, df = 1, P= 0.015, OR 1.94 (1.13-3.32)). CONCLUSIONS: The ability to self-propel a wheelchair shortly after a stroke is a significant predictor of eventually being able to walk. Our data suggest that it is even more significant than continence, which is the most consistent predictor previously found.