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Background Access to rapid diagnosis is key to the control and management of SARS-CoV-2. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) testing usually requires a centralised laboratory and significant infrastructure. We describe the development and diagnostic accuracy assessment of a novel, rapid point-of-care RT-PCR test, the DnaNudge® platform CovidNudge test, which requires no laboratory handling or sample pre-processing. Methods Nasopharyngeal swabs are inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as positive control. Between April and May 2020, swab samples were tested in parallel using the CovidNudge direct-to-cartridge platform and standard laboratory RT-PCR using swabs in viral transport medium. Samples were collected from three groups: self-referred healthcare workers with suspected COVID-19 (Group 1, n=280/386; 73%); patients attending the emergency department with suspected COVID-19 (Group 2, n=15/386; 4%) and hospital inpatient admissions with or without suspected COVID-19 (Group 3, n=91/386; 23%). Results Of 386 paired samples tested across all groups, 67 tested positive on the CovidNudge platform and 71 with standard laboratory RT-PCR. The sensitivity of the test varied by group (Group 1 93% [84-98%], Group 2 100% [48-100%] and Group 3 100% [29-100%], giving an average sensitivity of 94.4% (95% confidence interval 86-98%) and an overall specificity of 100% (95%CI 99-100%; Group 1 100% [98-100%]; Group 2 100% [69-100%] and Group 3 100% [96-100%]). Point of care testing performance was comparable during a period of high (25%) and low (3%) background prevalence. Amplification of the viral nucleocapsid (n1, n2, n3) targets were most sensitive for detection of SARS-CoV2, with the assay able to detect 1×104 viral particles in a single swab. Conclusions The CovidNudge platform offers a sensitive, specific and rapid point of care test for the presence of SARS-CoV-2 without laboratory handling or sample pre-processing. The implementation of such a device could be used to enable rapid decisions for clinical care and testing programs. Evidence before this study The WHO has highlighted the development of rapid, point-of-care diagnostics for detection of SARS-CoV-2 as a key priority to tackle COVID-19. The Foundation for Innovative Diagnostics (FIND) has identified over 90 point-of-care, near patient or mobile tests for viral detection of SARS-CoV-2. However, the most widely available rapid tests to date require some sample handling which limits their use at point-of-care. In addition, pressure on supply chains is restricting access to current diagnostics and alternatives are needed urgently. Added value of this study We describe the development and clinical validation of COVID nudge, a novel point-of-care RT-PCR diagnostic, evaluated during the first wave of the SARS-CoV-2 epidemic. The platform is able to achieve high analytic sensitivity and specificity from dry swabs within a self-contained cartridge. The lack of downstream sample handling makes it suitable for use in a range of clinical settings, without need for a laboratory or specialized operator. Multiplexed assays within the cartridge allow inclusion of a positive human control, which reduces the false negative testing rate due to insufficient sampling. Implication of the available evidence Point-of-care testing can relieve pressure on centralized laboratories and increase overall testing capacity, complementing existing approaches. These findings support a role for COVID Nudge as part of strategies to improve access to rapid diagnostics to SARS-CoV-2. Since May 2020, the system has been implemented in UK hospitals and is being rolled out nationwide. Competing Interest Statement CT, RS, MS, CI, MK, TH, SDM, FL, JB and AO are employees of DnaNudge. CT is named on the patent for method and apparatus for analyzing biological specimens on the DnaNudge platform (US Patent No: US 10,093,965 B216. LSPM has consulted for bioMerieux (2013 to 2020), DNAelectronics (2015), Dairy Crest (2017 to 2018), Pfizer (2018-2020), and Umovis Lab (2020), received speaker fees from Profile Pharma (2018), received research grants from the National Institute for Health Research (2013 to 2019), Leo Pharma (2016), and CW+ Charity (2018 to 2019), and received educational support from Eumedica (2016 to 2017). NM has received speaker fees from Beyer (2016) and Pfizer (2019) and received educational support from Eumedica (2016) and Baxter (2017). All other authors have no conflicts of interest to declare. Funding Statement The work was supported by the Biomedical Research Centre of Imperial College NHS Trust. M.M.G. is supported in part by the NIHR Imperial Biomedical Research Centre. GC is an NIHR Research Professor and Investigator within the NIHR London In-vitro Diagnostic Collaborative. Part of this work was supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with Public Health England (PHE) [grant HPRU-2012-10041] and the NIHR Biomedical Research Centre, Oxford. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Department of Health or Public Health England.

Background: Antimicrobial Resistance is threatening our ability to treat common infectious diseases and overuse of antimicrobials to treat human infections in hospitals is accelerating this process. Clinical Decision Support Systems (CDSSs) have been proven to enhance quality of care by promoting change in prescription practices through antimicrobial selection advice. However, bypassing an initial assessment to determine the existence of an underlying disease that justifies the need of antimicrobial therapy might lead to indiscriminate and often unnecessary prescriptions. Methods: From pathology laboratory tests, six biochemical markers were selected and combined with microbiology outcomes from susceptibility tests to create a unique dataset with over one and a half million daily profiles to perform infection risk inference. Outliers were discarded using the inter-quartile range rule and several sampling techniques were studied to tackle the class imbalance problem. The first phase selects the most effective and robust model during training using four-fold stratified cross-validation. The second phase evaluates the final model after isotonic calibration in scenarios with missing inputs and imbalanced class distributions. Results: More than 50\% of infected profiles have daily requested laboratory tests for the six biochemical markers with very promising infection inference results: area under the receiver operating characteristic curve (0.80-0.83), sensitivity (0.64-0.75) and specificity (0.92-0.97). Standardization consistently outperforms normalization and sensitivity is enhanced by using the SMOTE sampling technique. Furthermore, models operated without noticeable loss in performance if at least four biomarkers were available. Conclusion: The selected biomarkers comprise enough information to perform infection risk inference with a high degree of confidence even in the presence of incomplete and imbalanced data. Since they are commonly available in hospitals, Clinical Decision Support Systems could benefit from these findings to assist clinicians in deciding whether or not to initiate antimicrobial therapy to improve prescription practices.

Objective: Vagal nerve stimulation (VNS) has shown potential benefits for obesity treatment; however, current devices lack physiological feedback, which limit their efficacy. Changes in extracellular pH (pHe) have shown to be correlated with neural activity, but have traditionally been measured with glass microelectrodes, which limit their in vivo applicability. Approach. Iridium oxide has previously been shown to be sensitive to fluctuations in pH and is biocompatible. Iridium oxide microelectrodes were inserted into the subdiaphragmatic vagus nerve of anaesthetised rats. Introduction of the gut hormone cholecystokinin (CCK) or distension of the stomach was used to elicit vagal nerve activity. Main results. Iridium oxide microelectrodes have sufficient pH sensitivity to readily detect changes in pHe associated with both CCK and gastric distension. Furthermore, a custom-made Matlab script was able to use these changes in pHe to automatically trigger an implanted VNS device. Significance. This is the first study to show pHe changes in peripheral nerves in vivo. In addition, the demonstration that iridium oxide microelectrodes are sufficiently pH sensitive as to measure changes in pHe associated with physiological stimuli means they have the potential to be integrated into closed-loop neurostimulating devices.

Key circuit techniques are developed for the modification of high frequency, transconductor/multiplier circuit building blocks. A semi-nonlinear analysis technique is developed and a novel technique for cascoding such circuits is presented. The techniques are illustrated by application to a four-quadrant analog multiplier.

A general principle and some basic circuit techniques suitable for the implementation of the four-quadrant analogue multiplier using gallium arsenide depletion-mode MESFET technology are presented. A version of the circuit achieves a simulated accuracy of the order of 2% and a 3 dB bandwidth of 6.5 GHz using level 1 MESFET models in HSPICE.

This paper describes a novel partial-current-steering stimulation circuit for implantable vestibular prostheses. The drive hardware momentarily delivers a charge-balanced asymmetric stimulus to a dummy load before steering towards the stimulation electrodes. In this fashion, power is conserved while still gaining from the benefits of current steering. The circuit has been designed to be digitally programmable as part of an implantable vestibular prosthesis. The hardware has been implemented in AMS 0.35 mum 2P4M CMOS technology.

Accepted version

Accepted version

This paper describes an ASIC developed as part of a neural prosthesis to restore balance to individuals with a dysfunctional vestibular end-organ. The device interfaces with inertia sensors; sensing acceleration in five degrees of freedom (three radial and two linear axis), and then conditions, processes and converts the signals to provide the artificial stimulus to the vestibulocochlear nerve. The IC described herein has been realised as part of a board-level solution, also including the sensors, power source and DC blocking capacitors. It is envisaged that this can be later implemented in a System-in-Package (SiP) form to provide a totally implantable solution. We describe the design and implementation of the integrated circuit in a standard 0.35µm CMOS technology.

This paper presents a fully-integrated semicircular canal processor for an implantable vestibular prosthesis. The system includes the entire processing chain required from the microsensor interface, through the required biomimetic transfer characteristics, to a current-mode signal, suitable for feeding the stimulator. Using a switched-capacitor implementation, the circuit is inherently tunable, whilst maintaining low power operation and overcoming the need for off-chip components. The entire system core occupies an area of 0.23 mm2 in a commercially available 0.35 mum CMOS technology.

This paper describes a novel partial-current-steering stimulation drive for implantable neural prosthetics. The drive hardware momentarily delivers a charge-balanced asymmetric stimulus to a dummy load before steering towards the stimulation electrodes. In this fashion, power is conserved whilst still gaining from the benefits of current steering. The circuit has been designed to be digitally programmable as part of an implantable vestibular prosthesis. The hardware has been implemented in AMS 0.35 mum 2P4M CMOS technology.

A front-end circuit for interfacing to differential capacitive sensors, including certain microelectromechanical systems, is presented. The system combines a self-resetting, biphasic integrator with a difference timer, producing a word parallel output representing the differential capacitance. The measurable capacitance range is tunable by means of an input current bias and system clock frequency. For an input bias of 10 nA and system clock of 128 KHz, the measurable capacitance range is +/-5pF (to 8 bit resolution) consuming below 26 µW total system power.

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Restoring the sensation of inertia in individuals with balance-related impairments is achievable through development of an artificial vestibular prosthesis, based on the cochlear implant paradigm. The vestibular system, however, involves added complexity in surgical methods required for reliable implantation, thus limiting widespread feasibility. This work aims to support research in developing surgical technology for precisely accessing inside the vestibular organ. Issues relating to surgical procedure, microrobotics and medical imaging are discussed, with the goal being the precise and safe implantation of microelectrode arrays. This paper presents the challenges modern surgical technology would encounter in adopting such a procedure and proposes possible solutions, aiming to promote and motivate research in this direction.

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A useful nano-power circuit is presented for edge detection in integrated vision systems. Based on a compact front-end of only five MOS devices, this circuit features a tunable threshold and discrete output and is ideal for interfacing to digital electronics.

Commercially available cochlear prosthesis systems consist of an external digital speech processor and an implanted receiver stimulator. This paper presents ultra low power mixed signal implementation of a cochlear prosthesis system suitable for total implantation. The typical measured system power consumption is 126 /spl mu/W (excluding the stimulation currents).