Visit-to-visit HbA1c variability and systolic blood pressure (SBP) variability are significantly and additively associated with mortality in individuals with type 1 diabetes: An observational study.

AIM: To investigate the relationship between variability in both visit-to-visit HbA1c and SBP and mortality in individuals with type 1 diabetes. METHODS: The Scottish Care Information (SCI) Diabetes dataset was used to identify 5952 individuals with type 1 diabetes for inclusion in this observational study. The SCI-Diabetes dataset allowed access to blood pressure values, HbA1c readings, demographic information and mortality rates for all study participants. Participants were dichotomized to above and below median values for both HbA1c coefficient of variation (CV) and SBP CV, thus dividing participants into 4 cohorts for survival analysis. Survival analysis was carried out over 1430 days. A Cox proportional hazard model was used to allow comparison of mortality between the 4 cohorts. RESULTS: Of the 5952 patients, death occurred in 416. CV for both HbA1c and SBP were significantly associated with mortality. The median values for HbA1c CV and SBP CV were 8.0 and 8.1, respectively. The hazard ratio for high HbA1c CV only (P = .0015) was 1.78 ± 0.36. The hazard ratio for high SBP CV only (P = .0018) was 1.69 ± 0.33. The hazard ratio for both high HbA1c CV and high SBP CV (P < .00001) was 2.37 ± 0.32. CONCLUSIONS: Our findings demonstrate that variability of both HbA1c and SBP is significantly and additively associated with mortality in individuals with type 1 diabetes. The variability of these parameters might be useful for risk stratification and is a potential target for future interventional studies.

Micromechanics of cellularized biopolymer networks.

Collagen gels are widely used in experiments on cell mechanics because they mimic the extracellular matrix in physiological conditions. Collagen gels are often characterized by their bulk rheology; however, variations in the collagen fiber microstructure and cell adhesion forces cause the mechanical properties to be inhomogeneous at the cellular scale. We study the mechanics of type I collagen on the scale of tens to hundreds of microns by using holographic optical tweezers to apply pN forces to microparticles embedded in the collagen fiber network. We find that in response to optical forces, particle displacements are inhomogeneous, anisotropic, and asymmetric. Gels prepared at 21 °C and 37 °C show qualitative difference in their micromechanical characteristics. We also demonstrate that contracting cells remodel the micromechanics of their surrounding extracellular matrix in a strain- and distance-dependent manner. To further understand the micromechanics of cellularized extracellular matrix, we have constructed a computational model which reproduces the main experiment findings.

Nanoporous Gold Biointerfaces: Modifying Nanostructure to Control Neural Cell Coverage and Enhance Electrophysiological Recording Performance.

Nanostructured neural interface coatings have significantly enhanced recording fidelity in both implantable and in vitro devices. As such, nano-porous gold (np-Au) has shown promise as a multifunctional neural interface coating due, in part, to its ability to promote nanostructure-mediated reduction in astrocytic surface coverage while not affecting neuronal coverage. The goal of this study is to provide insight into the mechanisms by which the np-Au nanostructure drives the differential response of neurons versus astrocytes in an in vitro model. Utilizing microfabricated libraries that display varying feature sizes of np-Au, it is demonstrated that np-Au influ-ences neural cell coverage through modulating focal adhesion formation in a feature size-dependent manner. The results here show that surfaces with small (≈30 nm) features control astrocyte spreading through inhibition of focal adhesion formation, while surfaces with large (≈170 nm and greater) features control astrocyte spreading through other mechanotransduction mechanisms. This cellular response combined with lower electrical impedance of np-Au electrodes significantly enhances the fidelity and stability of electrophysiological recordings from cortical neuronglia co-cultures relative to smooth gold electrodes. Finally, by leveraging the effect of nanostructure on neuronal versus glial cell attachment, the use of laser-based nanostructure modulation is demonstrated for selectively patterning neurons with micrometer spatial resolution.

Utilizing dynamic laser speckle to probe nanoscale morphology evolution in nanoporous gold thin films.

This paper demonstrates the use of dynamic laser speckle autocorrelation spectroscopy in conjunction with the photothermal treatment of nanoporous gold (np-Au) thin films to probe nanoscale morphology changes during the photothermal treatment. Utilizing this spectroscopy method, backscattered speckle from the incident laser is tracked during photothermal treatment and both the characteristic feature size and annealing time of the film are determined. These results demonstrate that this method can successfully be used to monitor laser-based surface modification processes without the use of ex-situ characterization.

Substrate Topography Guides Pore Morphology Evolution in Nanoporous Gold Thin Films.

This paper illustrates the effect of substrate topography on morphology evolution in nanoporous gold (np-Au) thin films. One micron-high silicon ridges with widths varying between 150 nm to 50 µm were fabricated and coated with 500 nm-thick np-Au films obtained by dealloying sputtered gold-silver alloy films. Analysis of scanning electron micrographs of the np-Au films following dealloying and thermal annealing revealed two distinct regimes where the ratio of film thickness to ridge width determines the morphological evolution of np-Au films.

Polymer Bioelectronics: A Solution for Both Stimulating and Recording Electrodes.

The advent of closed-loop bionics has created a demand for electrode materials that are ideal for both stimulating and recording applications. The growing complexity and diminishing size of implantable devices for neural interfaces have moved beyond what can be achieved with conventional metallic electrode materials. Polymeric electrode materials are a recent development based on polymer composites of organic conductors such as conductive polymers. These materials present exciting new opportunities in the design and fabrication of next-generation electrode arrays which can overcome the electrochemical and mechanical limitations of conventional electrode materials. This review will examine the recent developments in polymeric electrode materials, their application as stimulating and recording electrodes in bionic devices, and their impact on the development of soft, conformal, and high-density neural interfaces.

Electroactive Polymers for On-Demand Drug Release.

Conductive materials have played a significant role in advancing society into the digital era. Such materials are able to harness the power of electricity and are used to control many aspects of daily life. Conductive polymers (CPs) are an emerging group of polymers that possess metal-like conductivity yet retain desirable polymeric features, such as processability, mechanical properties, and biodegradability. Upon receiving an electrical stimulus, CPs can be tailored to achieve a number of responses, such as harvesting energy and stimulating tissue growth. The recent FDA approval of a CP-based material for a medical device has invigorated their research in healthcare. In drug delivery, CPs can act as electrical switches, drug release is achieved at a flick of a switch, thereby providing unprecedented control over drug release. In this review, recent developments in CP as electroactive polymers for voltage-stimuli responsive drug delivery systems are evaluated. The review demonstrates the distinct drug release profiles achieved by electroactive formulations, and both the precision and ease of stimuli response. This level of dynamism promises to yield "smart medicines" and warrants further research. The review concludes by providing an outlook on electroactive formulations in drug delivery and highlighting their integral roles in healthcare IoT.

Practical Guide to Glucocorticoid Induced Hyperglycaemia and Diabetes.

Glucocorticoids, also known as steroids, are a class of anti-inflammatory drugs utilised widely in clinical practice for a variety of conditions. They are associated with a range of side effects including abnormalities of glucose metabolism. Multiple guidelines have been published to illustrate best management of glucocorticoid-induced hyperglycaemia and diabetes in a variety of settings. This article discusses current best clinical practice including diagnosis, investigations and ongoing management of glucocorticoid-induced dysglycaemia in both in- and outpatient settings.

Endothelial cell vasodilator dysfunction mediates progressive pregnancy-induced hypertension in endothelial cell tetrahydrobiopterin deficient mice.

BACKGROUND AND PURPOSE: Pregnancy-associated vascular remodelling is essential for both maternal and fetal health. We have previously shown that maternal endothelial cell tetrahydrobiopterin (BH4) deficiency causes poor pregnancy outcomes. Here, we investigated the role and mechanisms of endothelial cell-mediated vasorelaxation function in these outcomes. EXPERIMENTAL APPROACH: The vascular reactivity of mouse aortas and uterine arteries from non-pregnant and pregnant endothelial cell-specific BH4 deficient mice (Gch1fl/flTie2cre mice) was assessed by wire myography. Systolic blood pressure was assessed by tail cuff plethysmography. KEY RESULTS: In late pregnancy, systolic blood pressure was significantly higher (∼24 mmHg) in Gch1fl/flTie2cre mice compared with wild-type littermates. This was accompanied by enhanced vasoconstriction and reduced endothelial-dependent vasodilation in both aorta and uterine arteries from pregnant Gch1fl/flTie2cre mice. In uterine arteries loss of eNOS-derived vasodilators was partially compensated by upregulation of intermediate and large-conductance Ca2+-activated K+ channels. In rescue experiments, oral BH4 supplementation alone did not rescue vascular dysfunction and pregnancy-induced hypertension in Gch1fl/flTie2cre mice. However, combination with the fully reduced folate, 5-methyltetrahydrofolate (5-MTHF), restored endothelial cell vasodilator function and blood pressure. CONCLUSIONS AND IMPLICATIONS: We identify a critical requirement for maternal endothelial cell Gch1/BH4 biosynthesis in endothelial cell vasodilator function in pregnancy. Targeting vascular Gch1 and BH4 biosynthesis with reduced folates may provide a novel therapeutic target for the prevention and treatment of pregnancy-related hypertension.

A Pilot In Vivo Study of Flexible Fully Polymeric Nerve Cuff Electrodes.

Recent trends in the field of bioelectronics have been focused on the development of electrodes that facilitate safe and efficient stimulation of nervous tissues. Novel conducting polymer (CP) based materials, such as flexible and fully polymeric conductive elastomers (CEs), constitute a promising alternative to improve on the limitations of current metallic devices. This pilot study demonstrates the performance of tripolar CE-based peripheral nerve cuffs compared to current commercial tripolar platinum-iridium (PtIr) nerve cuffs in vivo. CE and metallic cuff devices were implanted onto rodent sciatic nerves for a period of 8 weeks. Throughout the entire study, the CE device demonstrated improved charge transfer and electrochemical safety compared to the PtIr cuff, able to safely inject 2 to 3 times more charge. In comparison to the commercial control, the CE cuff was able to record in the in vivo setting with reduced noise and produced smaller voltages at all simulation levels. CE technologies provide a promising alternative to metallic devices for the development of bioelectronics with enhanced chronic device functionality.

Controlled electroactive release from solid-state conductive elastomer electrodes.

This work highlights the development of a conductive elastomer (CE) based electrophoretic platform that enables the transfer of charged molecules from a solid-state CE electrode directly to targeted tissues. Using an elastomer-based electrode containing poly (3,4-ethylenedioxythiophene) nanowires, controlled electrophoretic delivery of methylene blue (MB) and fluorescein (FLSC) was achieved with applied voltage. Electroactive release of positively charged MB and negatively charged FLSC achieved 33.19 ± 6.47 µg release of MB and 22.36 ± 3.05 µg release of FLSC, a 24 and 20-fold increase in comparison to inhibitory voltages over 1 h. Additionally, selective, and sequential release of the two oppositely charged molecules from a single CE device was demonstrated, showing the potential of this device to be used in multi-drug treatments.

Preparation of Rat Sciatic Nerve for Ex Vivo Neurophysiology.

Ex vivo preparations enable the study of many neurophysiological processes in isolation from the rest of the body while preserving local tissue structure. This work describes the preparation of rat sciatic nerves for ex vivo neurophysiology, including buffer preparation, animal procedures, equipment setup and neurophysiological recording. This work provides an overview of the different types of experiments possible with this method. The outlined method aims to provide 6 h of stimulation and recording on extracted peripheral nerve tissue in tightly controlled conditions for optimal consistency in results. Results obtained using this method are A-fibre compound action potentials (CAP) with peak-to-peak amplitudes in the millivolt range over the entire duration of the experiment. CAP amplitudes and shapes are consistent and reliable, making them useful to test and compare new electrodes to existing models, or the effects of interventions on the tissue, such as the use of chemicals, surgical alterations, or neuromodulatory stimulation techniques. Both conventional commercially available cuff electrodes with platinum-iridium contacts and custom-made conductive elastomer electrodes were tested and gave similar results in terms of nerve stimulus strength-duration response.

Mind the gap: State-of-the-art technologies and applications for EEG-based brain-computer interfaces.

Brain-computer interfaces (BCIs) provide bidirectional communication between the brain and output devices that translate user intent into function. Among the different brain imaging techniques used to operate BCIs, electroencephalography (EEG) constitutes the preferred method of choice, owing to its relative low cost, ease of use, high temporal resolution, and noninvasiveness. In recent years, significant progress in wearable technologies and computational intelligence has greatly enhanced the performance and capabilities of EEG-based BCIs (eBCIs) and propelled their migration out of the laboratory and into real-world environments. This rapid translation constitutes a paradigm shift in human-machine interaction that will deeply transform different industries in the near future, including healthcare and wellbeing, entertainment, security, education, and marketing. In this contribution, the state-of-the-art in wearable biosensing is reviewed, focusing on the development of novel electrode interfaces for long term and noninvasive EEG monitoring. Commercially available EEG platforms are surveyed, and a comparative analysis is presented based on the benefits and limitations they provide for eBCI development. Emerging applications in neuroscientific research and future trends related to the widespread implementation of eBCIs for medical and nonmedical uses are discussed. Finally, a commentary on the ethical, social, and legal concerns associated with this increasingly ubiquitous technology is provided, as well as general recommendations to address key issues related to mainstream consumer adoption.

Stretchable, Fully Polymeric Electrode Arrays for Peripheral Nerve Stimulation.

There is a critical need to transition research level flexible polymer bioelectronics toward the clinic by demonstrating both reliability in fabrication and stable device performance. Conductive elastomers (CEs) are composites of conductive polymers in elastomeric matrices that provide both flexibility and enhanced electrochemical properties compared to conventional metallic electrodes. This work focuses on the development of nerve cuff devices and the assessment of the device functionality at each development stage, from CE material to fully polymeric electrode arrays. Two device types are fabricated by laser machining of a thick and thin CE sheet variant on an insulative polydimethylsiloxane substrate and lamination into tubing to produce pre-curled cuffs. Device performance and stability following sterilization and mechanical loading are compared to a state-of-the-art stretchable metallic nerve cuff. The CE cuffs are found to be electrically and mechanically stable with improved charge transfer properties compared to the commercial cuff. All devices are applied to an ex vivo whole sciatic nerve and shown to be functional, with the CE cuffs demonstrating superior charge transfer and electrochemical safety in the biological environment.

Flexible Nanowire Conductive Elastomers for Applications in Fully Polymeric Bioelectronic Devices.

Soft, flexible polymer-based bioelectronics are a promising approach to minimize the chronic inflammatory reactions associated with metallic devices, impairing long-term device reliability and functionality. This work demonstrates the fabrication of conductive elastomers (CEs) consisting of chemically synthesized poly(3,4-ethylenedioxythiophene) (PEDOT) nanowires embedded within a polyurethane (PU) elastomeric matrix, resulting in soft and flexible, fully polymeric electrode materials. Increasing PEDOT nanowire loadings resulted in an improvement in electrochemical properties and conductivity, an increased Young's modulus and reduced strain at failure. Nanowire CEs were also found to have significantly improved electrochemical performance compared to one of the standard electrode materials, platinum (Pt). Indirect in vitro cytocompatibility test was carried out to investigate the effect of leachable substances from the CE on primary rodent cells. Nanowire CEs provide a promising alternative to metals for the fabrication of soft bioelectronics.

Model-based geometrical optimisation and in vivo validation of a spatially selective multielectrode cuff array for vagus nerve neuromodulation.

BACKGROUND: Neuromodulation by electrical stimulation of the human cervical vagus nerve may be limited by adverse side effects due to stimulation of off-target organs. It may be possible to overcome this by spatially selective stimulation of peripheral nerves. Preliminary studies have shown this is possible using a cylindrical multielectrode human-sized nerve cuff in vagus nerve selective neuromodulation. NEW METHOD: The model-based optimisation method for multi-electrode geometric design is presented. The method was applied for vagus nerve cuff array and suggested two rings of 14 electrodes, 3 mm apart, with 0.4 mm electrode width and separation and length 0.5-3 mm, with stimulation through a pair in the same radial position on the two rings. The electrodes were fabricated using PDMS-embedded stainless steel foil and PEDOT: pTS coating. RESULTS: In the cervical vagus nerve in anaesthetised sheep, it was possible to selectively reduce the respiratory breath rate (RBR) by 85 ± 5% without affecting heart rate, or selectively reduce heart rate (HR) by 20 ± 7% without affecting respiratory rate. The cardiac- and pulmonary-specific sites on the nerve cross-sectional perimeter were localised with a radial separation of 105 ± 5 degrees (P < 0.01, N = 24 in 12 sheep). CONCLUSIONS: Results suggest organotopic or function-specific organisation of neural fibres in the cervical vagus nerve. The optimised electrode array demonstrated selective electrical neuromodulation without adverse side effects. It may be possible to translate this to improved treatment by electrical autonomic neuromodulation for currently intractable conditions.

Admission Glucose Number (AGN): A Point of Admission Score Associated With Inpatient Glucose Variability, Hypoglycemia, and Mortality.

AIMS: We investigated a point of admission metric of glycemia, the Admission Glucose Number (AGN), and its relationship with both high risk inpatient glucose patterns and mortality in hospital inpatients with type 2 diabetes (T2DM). METHODS: Inpatient capillary blood glucose (CBG) data for patients with T2DM in our health board were identified for a 5-year period and associated with most recent preadmission HbA1c. AGN was calculated as first CBG measured during admission (mmol/L), subtracted from most recent preadmission HbA1c (converted to estimated median glucose mmol/l) within 15 months preadmission. The association between AGN and CBG variability (interquartile range), hypoglycemia free survival (HR) and both inpatient and 100-day mortality (HR) were investigated. RESULTS: A total of 21 045 first admissions with available HbA1c data were identified. A positive correlation between AGN and glycemic variability was described (partial correlation coefficient 0.25, P < .001), which was stronger than the correlation of either of AGNs' individual components: adjusted CBG1 = 0.07 ( P < .001), eAG = 0.08 ( P < .001). The hazard ratio for time to first recorded CBG < 3 mmol/L for high AGN versus low AGN was 1.74 (95% CI 1.55-1.96), P < .001. A high AGN was associated with increased 100-day mortality (HR 1.26, P = .005), however not with in-hospital mortality (HR = 1.31, P = .08). CONCLUSION: AGN is a simple metric that combines 2 readily available measures associated with adverse outcome in T2DM. AGN may be a useful tool to stratify patients for risk of hypoglycemia and postdischarge death.

Optimisation of bioimpedance measurements of neuronal activity with an ex vivo preparation of Cancer pagurus peripheral nerves.

BACKGROUND: In mammals, fast neural Electrical Impedance Tomography (EIT) can image the myelinated component of the compound action potentials (CAP) using a nerve cuff. If applied to unmyelinated fibres this has great potential to improve selective neuromodulation ("electroceuticals") to avoid off-target effects. Previously, bioimpedance recordings were averaged from unmyelinated crab leg nerve fibres, but the signal to noise ratio (SNR) needs improving. NEW METHOD: Currently, functional non-invasive neuronal imaging is accomplished through surface electrodes or genetically expressed indicators that provide good spatial, but poor temporal, resolution. Here is an improved method for bioimpedance measurements from a model of unmyelinated fibres to enable optimisation through improvement of the 1) signal processing measurement paradigm, 2) neurophysiology, and 3) electrode-nerve interface. RESULTS: For bioimpedance recordings, the recruitment and necessity of the CAP was quantified and saline significantly improved the SNR. An improved protocol resulted in averaging not being required, as sequentially recorded traces produced bioimpedance changes of -0.232 ± 0.064% that did not show phase or timing related artefacts. COMPARISON WITH EXISTING METHOD: Here, two bioimpedance traces displayed an SNR of ≥3:1, while previously over >100 averages were required with greater inter-experimental variability. 10 paired traces were averaged for an SNR of ≥9:1, or near real-time measurement. CONCLUSIONS: This method facilitates further studies aiming to enable non-invasive localization of fascicular activity in unmyelinated fibres within peripheral nerves. This technique could ultimately produce the first 3-D tomographic images to help guide selective neuromodulation using bioelectric devices.

Electrode fabrication and interface optimization for imaging of evoked peripheral nervous system activity with electrical impedance tomography (EIT).

OBJECTIVE: Non-invasive imaging techniques are undoubtedly the ideal methods for continuous monitoring of neural activity. One such method, fast neural electrical impedance tomography (EIT) has been developed over the past decade in order to image neural action potentials with non-penetrating electrode arrays. APPROACH: The goal of this study is two-fold. First, we present a detailed fabrication method for silicone-based multiple electrode arrays which can be used for epicortical or neural cuff applications. Secondly, we optimize electrode material coatings in order to achieve the best accuracy in EIT reconstructions. MAIN RESULTS: The testing of nanostructured electrode interface materials consisting of platinum, iridium oxide, and PEDOT:pTS in saline tank experiments demonstrated that the PEDOT:pTS coating used in this study leads to more accurate reconstruction dimensions along with reduced phase separation between recording channels. The PEDOT:pTS electrodes were then used in vivo to successfully image and localize the evoked activity of the recurrent laryngeal fascicle from within the cervical vagus nerve. SIGNIFICANCE: These results alongside the simple fabrication method presented here position EIT as an effective method to image neural activity.

In Vitro Neurochemical Assessment of Methylphenidate and Its "Legal High" Analogs 3,4-CTMP and Ethylphenidate in Rat Nucleus Accumbens and Bed Nucleus of the Stria Terminalis.

3,4-dichloromethylphenidate (3,4-CTMP) and ethylphenidate are new psychoactive substances and analogs of the attention deficit medication methylphenidate. Both drugs have been reported on online user fora to induce effects similar to cocaine. In the UK, 3,4-CTMP appeared on the drug market in 2013 and ethylphenidate has been sold since 2010. We aimed to explore the neurochemical effects of these drugs on brain dopamine and noradrenaline efflux. 3,4-CTMP and ethylphenidate, purchased from online vendors, were analyzed using gas chromatography and mass spectroscopy to confirm their identity. Drugs were then tested in adolescent male rat brain slices of the nucleus accumbens and stria terminalis for effects on dopamine and noradrenaline efflux respectively. Fast cyclic voltammetry was used to measure transmitter release. Methylphenidate (10 µM) increased evoked dopamine and noradrenaline efflux by 4- and 2-fold, respectively. 3,4-CTMP (0.1 and 1 µM) increased evoked dopamine and noradrenaline efflux by ~6-fold and 2-fold, respectively. Ethylphenidate (1 µM) doubled evoked dopamine and noradrenaline efflux in both cases. 3,4-CTMP's effect on dopamine efflux was greater than that of methylphenidate, but ethylphenidate appears to be a weaker dopamine transporter inhibitor. Experiments using the dopamine D2 antagonist haloperidol, the noradrenaline α2 receptor antagonist yohimbine, the dopamine transporter inhibitor GBR12909 and the noradrenaline transporter inhibitor desipramine confirmed that we were measuring dopamine in the accumbens and noradrenaline in the ventral BNST. All three psychostimulant drugs, through their effects on dopamine efflux, may have addictive liability although the effect of 3,4-CTMP on dopamine suggests that it might be most addictive and ethylphenidate least addictive.