Accuracy of heart rate measured by military-grade wearable ECG monitor compared with reference and commercial monitors.

INTRODUCTION: Physiological monitoring of soldiers can indicate combat readiness and performance. Despite demonstrated use of wearable devices for HR monitoring, commercial options lack desired military features. A newly developed OMNI monitor includes desired features such as long-range secure data transmission. This study investigated the accuracy of the OMNI to measure HR via accuracy of R-R interval duration relative to research-grade ECG and commercial products. METHODS: 54 healthy individuals (male/female=37/17, age=22.2±3.6 years, height=173.0±9.1 cm, weight=70.1±11.2 kg) completed a submaximal exercise test while wearing a reference ECG (Biopac) and a randomly assigned chest-based monitor (OMNI, Polar H10, Equivital EQ-02, Zephyr Bioharness 3). All participants also wore two wrist-based photoplethysmography (PPG) devices, Garmin fenix 6 and Empatica E4. Bland-Altman analyses of agreement, concordance correlation coefficient (CCC) and root-mean-squared error (RMSE) were used to determine accuracy of the OMNI and commercial devices relative to Biopac. Additionally, a linear mixed-effects model evaluated the effects of device and exercise intensity on agreement. RESULTS: Chest-based devices showed superior agreement with Biopac for measuring R-R interval compared with wrist-based ones in terms of mean bias, CCC and RMSE, with OMNI demonstrating the best scores on all metrics. Linear mixed-effects model showed no significant main or interaction effects for the chest-based devices. However, significant effects were found for Garmin and Empatica devices (p<0.001) as well as the interaction effects between both Garmin and Empatica and exercise intensity (p<0.001). CONCLUSIONS: Chest-based ECG devices are preferred to wrist-based PPG devices due to superior HR accuracy over a range of exercise intensities, with the OMNI device demonstrating equal, if not superior, performance to other commercial ECG monitors. Additionally, wrist-based PPG devices are significantly affected by exercise intensity as they underestimate HR at low intensities and overestimate HR at high intensities.

Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes.

Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune ß-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies.

Conjugation of a peptide autoantigen to gold nanoparticles for intradermally administered antigen specific immunotherapy.

Antigen specific immunotherapy aims to tolerise patients to specific autoantigens that are responsible for the pathology of an autoimmune disease. Immune tolerance is generated in conditions where the immune response is suppressed and thus gold nanoparticles (AuNPs) are an attractive drug delivery platform due to their anti-inflammatory effects and their potential to facilitate temporal and spatial delivery of a peptide autoantigen in conjunction with pro-tolerogenic elements. In this study we have covalently attached an autoantigen, currently under clinical evaluation for the treatment of type 1 diabetes (PIC19-A3 peptide), to AuNPs to create nanoscale (<5 nm), negatively charged (-40 to -60 mV) AuNP-peptide complexes for immunotherapy. We also employ a clinically approved microneedle delivery system, MicronJet600, to facilitate minimally-invasive intradermal delivery of the nanoparticle constructs to target skin-resident antigen presenting cells, which are known to be apposite target cells for immunotherapy. The AuNP-peptide complexes remain physically stable upon extrusion through microneedles and when delivered into ex vivo human skin they are able to diffuse rapidly and widely throughout the dermis (their site of deposition) and, perhaps more surprisingly, the overlying epidermal layer. Intracellular uptake was extensive, with Langerhans cells proving to be the most efficient cells at internalising the AuNP-peptide complex (94% of the local population within the treated region of skin). In vitro studies showed that uptake of the AuNP-peptide complexes by dendritic cells reduced the capacity of these cells to activate naïve T cells. This indicator of biological functionality encourages further development of the AuNP-peptide formulation, which is now being evaluated in clinical trials.

Hydrodynamic gene delivery in human skin using a hollow microneedle device.

Microneedle devices have been proposed as a minimally invasive delivery system for the intradermal administration of nucleic acids, both plasmid DNA (pDNA) and siRNA, to treat localised disease or provide vaccination. Different microneedle types and application methods have been investigated in the laboratory, but limited and irreproducible levels of gene expression have proven to be significant challenges to pre-clinical to clinical progression. This study is the first to explore the potential of a hollow microneedle device for the delivery and subsequent expression of pDNA in human skin. The regulatory approved MicronJet600® (MicronJet hereafter) device was used to deliver reporter plasmids (pCMVß and pEGFP-N1) into viable excised human skin. Exogenous gene expression was subsequently detected at multiple locations that were distant from the injection site but within the confines of the bleb created by the intradermal bolus. The observed levels of gene expression in the tissue are at least comparable to that achieved by the most invasive microneedle application methods e.g. lateral application of a microneedle. Gene expression was predominantly located in the epidermis, although also evident in the papillary dermis. Optical coherence tomography permitted real time visualisation of the sub-surface skin architecture and, unlike a conventional intradermal injection, MicronJet administration of a 50µL bolus appears to create multiple superficial microdisruptions in the papillary dermis and epidermis. These were co-localised with expression of the pCMVß reporter plasmid. We have therefore shown, for the first time, that a hollow microneedle device can facilitate efficient and reproducible gene expression of exogenous naked pDNA in human skin using volumes that are considered to be standard for intradermal administration, and postulate a hydrodynamic effect as the mechanism of gene delivery.