A rapid assessment of the National Regulatory Systems for medical products in the Southern African Development Community.

BACKGROUND: Access to quality-assured, safe and efficacious medical products is fundamental for Universal Health Coverage and attaining Sustainable Development Goal 3: Ensure Healthy Lives and Well-being for All. To guarantee this right, there is a need for robust and efficiently performing national regulatory systems for the regulation of medical products. Well-functioning regulatory systems apply globally accepted standards which ensure that the level of control is proportionate to the level of public health risk. OBJECTIVE OF THE STUDY: The study aimed at analysing the regulatory systems for medical products in the 16 Member States of the Southern African Development Community (SADC). It provides an overview of the national regulatory systems for medical products in the region in 2017 and outlines the institutional frameworks, which enable the implementation of regulatory functions. METHODOLOGY: A survey was conducted in March-December 2017 in English, French and Portuguese. National Regulatory Authorities for medical products (NMRAs) of the 16 Member States within SADC responded to the questions asked and sent in their answers. The survey was constructed around five themes instrumental for implementation of the Universal Health Coverage actions framework. Three of the themes are discussed in this article. RESULTS: The outcome of the survey demonstrates that within SADC, NMRAs vary in terms of organisational set-up and modalities of medical product regulation. The majority are within the Ministries of Health, and a few are either semi-autonomous or autonomous. Legal frameworks for medical products are in place for some of the SADC NMRAs, although they vary in the scope of products subject to regulation. Traditional medicines, biologicals and medical devices are regulated, however not uniformly across the region. CONCLUSION: Despite major progress over the years, the survey demonstrates variable levels of governance and regulatory framework among NMRAs in SADC. The survey supports the need for shifting from the broad strengthening of the regulatory systems which exist and are underpinned by the mandates, to more product-type focused approaches. This shift will ensure that medical products are quality-assured, safe and effective for a performant Health Systems attainment of the Universal Health Coverage and Sustainable Development Goals.

Electrical detection of current generated spin in topological insulator surface states: Role of interface resistance.

Current generated spin polarization in topological insulator (TI) surface states due to spin-momentum locking has been detected recently using ferromagnet/tunnel barrier contacts, where the projection of the TI spin onto the magnetization of the ferromagnet is measured as a voltage. However, opposing signs of the spin voltage have been reported, which had been tentatively attributed to the coexistence of trivial two-dimensional electron gas states on the TI surface which may exhibit opposite current-induced polarization than that of the TI Dirac surface states. Models based on electrochemical potential have been presented to determine the sign of the spin voltage expected for the TI surface states. However, these models neglect critical experimental parameters which also affect the sign measured. Here we present a Mott two-spin current resistor model which takes into account these parameters such as spin-dependent interface resistances, and show that such inclusion can lead to a crossing of the voltage potential profiles for the spin-up and spin-down electrons within the channel, which can lead to measured spin voltages of either sign. These findings offer a resolution of the ongoing controversy regarding opposite signs of spin signal reported in the literature, and highlight the importance of including realistic experimental parameters in the model.

Electrical Detection of Charge-to-spin and Spin-to-Charge Conversion in a Topological Insulator Bi2Te3 Using BN/Al2O3 Hybrid Tunnel Barrier.

One of the most striking properties of three-dimensional topological insulators (TIs) is spin-momentum locking, where the spin is locked at right angles to momentum and hence an unpolarized charge current creates a net spin polarization. Alternatively, if a net spin is injected into the TI surface state system, it is distinctively associated with a unique carrier momentum and hence should generate a charge accumulation, as in the so-called inverse Edelstein effect. Here using a Fe/Al2O3/BN tunnel barrier, we demonstrate both effects in a single device in Bi2Te3: the electrical detection of the spin accumulation generated by an unpolarized current flowing through the surface states, and that of the charge accumulation generated by spins injected into the surface state system. This work is the first to utilize BN as part of a hybrid tunnel barrier on TI, where we observed a high spin polarization of 93% for the TI surfaces states. The reverse spin-to-charge measurement is an independent confirmation that spin and momentum are locked in the surface states of TI, and offers additional avenues for spin manipulation. It further demonstrates the robustness and versatility of electrical access to the spin system within TI surface states, an important step towards its utilization in TI-based spintronics devices.

Spatial patterning of the Notch ligand Dll4 controls endothelial sprouting in vitro.

Angiogenesis, the formation of new blood vessels, is a vital process for tissue growth and development. The Notch cell-cell signalling pathway plays an important role in endothelial cell specification during angiogenesis. Dll4 - Notch1 signalling directs endothelial cells into migrating tip or proliferating stalk cells. We used the directing properties of Dll4 to spatially control endothelial cell fate and the direction of endothelial sprouts. We created linear arrays of immobilized Dll4 using micro contact printing. HUVECs were seeded perpendicular to these Dll4 patterns using removable microfluidic channels. The Notch activating properties of surface immobilized Dll4 were confirmed by qPCR. After induction of sprouting, microscopic images of fluorescently labelled endothelial sprouts were analysed to determine the direction and the efficiency of controlled sprouting (Ecs). Directionality analysis of the sprouts showed the Dll4 pattern changes sprout direction from random to unidirectional. This was confirmed by the increase of Ecs from 54.5 ± 3.1% for the control, to an average of 84.7 ± 1.86% on the Dll4 patterned surfaces. Our data demonstrates a surface-based method to spatially pattern Dll4 to gain control over endothelial sprout location and direction. This suggests that spatial ligand patterning can be used to provide control over (neo) vascularization.

Shear stress induces expression, intracellular reorganization and enhanced Notch activation potential of Jagged1.

Notch signaling and blood flow regulate vascular formation and maturation, but how shear stress affects the different components of the Notch pathway in endothelial cells is poorly understood. We show that laminar shear stress results in a ligand specific gene expression profile in endothelial cells (HUVEC). JAG1 expression increases while DLL4 expression decreases. Jagged1 shows a unique response by clustering intracellularly six to nine hours after the onset of flow. The formation of the Jagged1 clusters requires protein production, ER export and endocytosis. Clustering is associated with reduced membrane levels but is not affected by Notch signaling activity. Jagged1 relocalization is reversible, the clusters disappear and membrane levels increase upon removal of shear stress. We further demonstrate that the signaling potential of endothelial cells is enhanced after exposure to shear stress. Together we demonstrate a Jagged1 specific shear stress response for Notch signaling in endothelial cells.

Microfabricated tuneable and transferable porous PDMS membranes for Organs-on-Chips.

We present a novel and highly reproducible process to fabricate transferable porous PDMS membranes for PDMS-based Organs-on-Chips (OOCs) using microelectromechanical systems (MEMS) fabrication technologies. Porous PDMS membranes with pore sizes down to 2.0 µm in diameter and a wide porosity range (2-65%) can be fabricated. To overcome issues normally faced when using replica moulding and extend the applicability to most OOCs and improve their scalability and reproducibility, the process includes a sacrificial layer to easily transfer the membranes from a silicon carrier to any PDMS-based OOC. The highly reliable fabrication and transfer method does not need of manual handling to define the pore features (size, distribution), allowing very thin (<10 µm) functional membranes to be transferred at chip level with a high success rate (85%). The viability of cell culturing on the porous membranes was assessed by culturing two different cell types on transferred membranes in two different OOCs. Human umbilical endothelial cells (HUVEC) and MDA-MB-231 (MDA) cells were successfully cultured confirming the viability of cell culturing and the biocompatibility of the membranes. The results demonstrate the potential of controlling the porous membrane features to study cell mechanisms such as transmigrations, monolayer formation, and barrier function. The high control over the membrane characteristics might consequently allow to intentionally trigger or prevent certain cellular responses or mechanisms when studying human physiology and pathology using OOCs.

Current Challenges in Translating Tissue-Engineered Heart Valves.

OPINION STATEMENT: Heart valve disease is a major health burden, treated by either valve repair or valve replacement, depending on the affected valve. Nearly 300,000 valve replacements are performed worldwide per year. Valve replacement is lifesaving, but not without complications. The in situ tissue-engineered heart valve is a promising alternative to current treatments, but the translation of this novel technology to the clinic still faces several challenges. These challenges originate from the variety encountered in the patient population, the conversion of an implant into a living tissue, the highly mechanical nature of the heart valve, the complex homeostatic tissue that has to be reached at the end stage of the regenerating heart valve, and all the biomaterial properties that can be controlled to obtain this tissue. Many of these challenges are multidimensional and multiscalar, and both the macroscopic properties of the complete heart valve and the microscopic properties of the patient's cells interacting with the materials have to be optimal. Using newly developed in vitro models, or bioreactors, where variables of interest can be controlled tightly and complex mixtures of cell populations similar to those encountered in the regenerating valve can be cultured, it is likely that the challenges can be overcome.

Comparative pharmacokinetic and pharmacodynamic characteristics of amlodipine besylate and amlodipine nicotinate in healthy subjects.

BACKGROUND AND AIM: Amlodipine, a dihydropyridine calcium antagonist, is prescribed for the management of angina and hypertension, and is sold as amlodipine besylate. However, a new salt formulation, amlodipine nicotinate, has recently been developed. Here, we evaluated the comparative pharmacokinetic and pharmacodynamic characteristics of the nicotinate and besylate forms of amlodipine. SUBJECTS AND METHODS: A randomized, 2-way crossover study was conducted in 18 healthy male volunteers to compare the pharmacokinetics and pharmacodynamics of these two forms, i.e. amlodipine nicotinate (test) and amlodipine besylate (reference), after administration of a single dose of 5 mg of each drug and a washout period between doses of 4 weeks. Blood samples for the pharmacokinetic analysis of amlodipine were obtained over the 144-hour period after administration. Systolic and diastolic blood pressures and pulse rates were recorded immediately prior to each blood sampling. RESULTS: All participants completed both treatment periods, and no serious adverse events occurred during the study period. After administering a single dose of each formulation, mean AUC0-infinity and Cmax values were 190.91+/-60.49 ng x h/ml and 3.87+/-1.04 ng/ml for the test formulation and 203.15+/-52.05 ng x h/ml and 4.01+/-0.60 ng/ml for the reference formulation, respectively. The 90% confidence intervals of test/reference mean ratios for AUC0- infinity and Cmax fell within the predetermined equivalence range of 80 - 125%. Pharmacodynamic profiles including systolic and diastolic blood pressures and pulse rates exhibited no significant differences between the two formulations. CONCLUSION: The two amlodipine formulations showed similar pharmacokinetic and pharmacodynamic characteristics and the new amlodipine formulation, amlodipine nicotinate, was found to be equivalent for pharmacokinetics to the currently available amlodipine besylate with respect to the rate and extent of amlodipine absorption.

Electrical Detection of the Helical Spin Texture in a p-type Topological Insulator Sb2Te3.

The surface states of 3D topological insulators (TIs) exhibit a helical spin texture with spin locked at right angles with momentum. The chirality of this spin texture is expected to invert crossing the Dirac point, a property that has been experimentally observed by optical probes. Here, we directly determine the chirality below the Dirac point by electrically detecting spin-momentum locking in surface states of a p-type TI, Sb2Te3. A current flowing in the Sb2Te3 surface states generates a net spin polarization due to spin-momentum locking, which is electrically detected as a voltage on an Fe/Al2O3 tunnel barrier detector. Measurements of this voltage as a function of current direction and detector magnetization indicate that hole spin-momentum locking follows the right-hand rule, opposite that of electron, providing direct confirmation that the chirality is indeed inverted below Dirac point. The spin signal is linear with current, and exhibits a temperature dependence consistent with the semiconducting nature of the TI film and freeze-out of bulk conduction below 100 K. Our results demonstrate that the chirality of the helical spin texture of TI surface states can be determined electrically, an enabling step in the electrical manipulation of spins in next generation TI-based quantum devices.

Direct comparison of current-induced spin polarization in topological insulator Bi2Se3 and InAs Rashba states.

Three-dimensional topological insulators (TIs) exhibit time-reversal symmetry protected, linearly dispersing Dirac surface states with spin-momentum locking. Band bending at the TI surface may also lead to coexisting trivial two-dimensional electron gas (2DEG) states with parabolic energy dispersion. A bias current is expected to generate spin polarization in both systems, although with different magnitude and sign. Here we compare spin potentiometric measurements of bias current-generated spin polarization in Bi2Se3(111) where Dirac surface states coexist with trivial 2DEG states, and in InAs(001) where only trivial 2DEG states are present. We observe spin polarization arising from spin-momentum locking in both cases, with opposite signs of the measured spin voltage. We present a model based on spin dependent electrochemical potentials to directly derive the sign expected for the Dirac surface states, and show that the dominant contribution to the current-generated spin polarization in the TI is from the Dirac surface states.

Intelligent speed adaptation: accident savings and cost-benefit analysis.

The UK External Vehicle Speed Control (EVSC) project has made a prediction of the accident savings with intelligent speed adaptation (ISA), and estimated the costs and benefits of national implementation. The best prediction of accident reduction was that the fitting on all vehicles of a simple mandatory system, with which it would be impossible for vehicles to exceed the speed limit, would save 20% of injury accidents and 37% of fatal accidents. A more complex version of the mandatory system, including a capability to respond to current network and weather conditions, would result in a reduction of 36% in injury accidents and 59% in fatal accidents. The implementation path recommended by the project would lead to compulsory usage in 2019. The cost-benefit analysis carried out showed that the benefit-cost ratios for this implementation strategy were in a range from 7.9 to 15.4, i.e. the payback for the system could be up to 15 times the cost of implementing and running it.

Spin transport and Hanle effect in silicon nanowires using graphene tunnel barriers.

Spin-based devices offer non-volatile, scalable, low power and reprogrammable functionality for emerging device technologies. Here we fabricate nanoscale spintronic devices with ferromagnetic metal/single-layer graphene tunnel barriers used to generate spin accumulation and spin currents in a silicon nanowire transport channel. We report the first observation of spin precession via the Hanle effect in both local three-terminal and non-local spin-valve geometries, providing a direct measure of spin lifetimes and confirmation of spin accumulation and pure spin transport. The use of graphene as the tunnel barrier provides a low-resistance area product contact and clean magnetic switching characteristics, because it smoothly bridges the nanowire and minimizes complicated magnetic domains that otherwise compromise the magnetic behaviour. Utilizing intrinsic two-dimensional layers such as graphene or hexagonal boron nitride as tunnel contacts on nanowires offers many advantages over conventional materials deposited by vapour deposition, enabling a path to highly scaled electronic and spintronic devices.

[Eosinophilic otitis media]. / Eosinofiele otitis media.

BACKGROUND: Eosinophilic otitis media (EOM) is a rare middle ear disease that may closely resemble therapy-resistant otitis media with effusion (OME). The diagnosis is made if eosinophil-rich fluid is present with two or more of the following minor criteria: (a) history of nasal polyps or, (b) bronchial asthma, with (c) viscous fluid in the middle-ear, or (d) conventional otitis media treatment has no effect. CASE DESCRIPTION: A 70-year-old male with a history of the ASA triad (bronchial asthma, nasal/ethmoidal polyposis and aspirin intolerance) presented with progressive mixed hearing loss. Otoscopy showed bilateral otitis media with effusion (OME). Conventional treatment of this had no effect. Myringotomy resulted in the evacuation of highly viscous middle-ear effusion containing abundant eosinophils. After treatment with oral corticosteroids his symptoms improved considerably. Following later optimisation of his asthma treatment, corticosteroid treatment was stopped and his hearing remained stable. CONCLUSION: The adequate recognition and treatment of EOM will result in the prevention of permanent hearing loss.

Electrical detection of charge-current-induced spin polarization due to spin-momentum locking in Bi2Se3.

Topological insulators exhibit metallic surface states populated by massless Dirac fermions with spin-momentum locking, where the carrier spin lies in-plane, locked at right angles to the carrier momentum. Here, we show that a charge current produces a net spin polarization via spin-momentum locking in Bi2Se3 films, and this polarization is directly manifested as a voltage on a ferromagnetic contact. This voltage is proportional to the projection of the spin polarization onto the contact magnetization, is determined by the direction and magnitude of the charge current, scales inversely with Bi2Se3 film thickness, and its sign is that expected from spin-momentum locking rather than Rashba effects. Similar data are obtained for two different ferromagnetic contacts, demonstrating that these behaviours are independent of the details of the ferromagnetic contact. These results demonstrate direct electrical access to the topological insulators' surface-state spin system and enable utilization of its remarkable properties for future technological applications.

Low-resistance spin injection into silicon using graphene tunnel barriers.

Spin manipulation in a semiconductor offers a new paradigm for device operation beyond Moore's law. Ferromagnetic metals are ideal contacts for spin injection and detection, but the intervening tunnel barrier required to accommodate the large difference in conductivity introduces defects, trapped charge and material interdiffusion, which severely compromise performance. Here, we show that single-layer graphene successfully circumvents the classic issue of conductivity mismatch between a metal and a semiconductor for electrical spin injection and detection, providing a highly uniform, chemically inert and thermally robust tunnel barrier. We demonstrate electrical generation and detection of spin accumulation in silicon above room temperature, and show that the contact resistance-area products are two to three orders of magnitude lower than those achieved with oxide tunnel barriers on silicon substrates with identical doping levels. Our results identify a new route to low resistance-area product spin-polarized contacts, a key requirement for semiconductor spintronic devices that rely on two-terminal magnetoresistance, including spin-based transistors, logic and memory.

Electrical injection and detection of spin accumulation in silicon at 500 K with magnetic metal/silicon dioxide contacts.

The International Technology Roadmap for Semiconductors has identified the electron's spin angular momentum as a new state variable that should be explored as an alternative to the electron's charge for use beyond the size scaling of Moore's Law. A major obstacle has been achieving control of the spin variable at temperatures required for practical applications. Here we demonstrate electrical injection, detection and precession of spin accumulation in silicon, the cornerstone material of device technology, at temperatures that easily exceed these requirements. We observe Hanle precession of electron spin accumulation in silicon for a wide range of bias, show that the magnitude of the Hanle signal agrees well with theory, and that the spin lifetime varies with silicon carrier density. These results confirm spin accumulation in the silicon transport channel to 500 K rather than trapping in localized interface states, and enable utilization of the spin variable in practical device applications.

Interface, volume, and thermal attenuation of hot-electron spins in Ni80Fe20 and Co.

The relative importance of interface, volume, and thermal scattering in spin-dependent hot-electron transmission of magnetic trilayers is quantified. While interfaces produce significant attenuation (factor 2.2 per interface), the spin asymmetry is dominated by volume scattering. Extracted thermal attenuation lengths (130 A at 300 K for Ni80Fe20) show that thermal spin-wave scattering is stronger than hitherto assumed. This suggests that spontaneous spin-wave emission, rather than the details of the spin-dependent band structure, may cause the strong filtering of minority hot-electron spins.