Pharmacology of PACAP and VIP receptors in the spinal cord highlights the importance of the PAC1 receptor.

BACKGROUND AND PURPOSE: The spinal cord is a key structure involved in the transmission and modulation of pain. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP), are expressed in the spinal cord. These peptides activate G protein-coupled receptors (PAC1, VPAC1 and VPAC2) that could provide targets for the development of novel pain treatments. However, it is not clear which of these receptors are expressed within the spinal cord and how these receptors signal. EXPERIMENTAL APPROACH: Dissociated rat spinal cord cultures were used to examine agonist and antagonist receptor pharmacology. Signalling profiles were determined for five signalling pathways. The expression of different PACAP and VIP receptors was then investigated in mouse, rat and human spinal cords using immunoblotting and immunofluorescence. KEY RESULTS: PACAP, but not VIP, potently stimulated cAMP, IP1 accumulation and ERK and cAMP response element-binding protein (CREB) but not Akt phosphorylation in spinal cord cultures. Signalling was antagonised by M65 and PACAP6-38. PACAP-27 was more effectively antagonised than either PACAP-38 or VIP. The patterns of PAC1 and VPAC2 receptor-like immunoreactivity appeared to be distinct in the spinal cord. CONCLUSIONS AND IMPLICATIONS: The pharmacological profile in the spinal cord suggested that a PAC1 receptor is the major functional receptor subtype present and thus likely mediates the nociceptive effects of the PACAP family of peptides in the spinal cord. However, the potential expression of both PAC1 and VPAC2 receptors in the spinal cord highlights that these receptors may play differential roles and are both possible therapeutic targets.

Calcitonin receptor, calcitonin gene-related peptide and amylin distribution in C1/2 dorsal root ganglia.

BACKGROUND: The upper cervical dorsal root ganglia (DRG) are important for the transmission of sensory information associated with the back of the head and neck, contributing to head pain. Calcitonin receptor (CTR)-based receptors, such as the amylin 1 (AMY1) receptor, and ligands, calcitonin gene-related peptide (CGRP) and amylin, have been linked to migraine and pain. However, the contribution of this system to nociception involving the cervical DRG is unclear. Therefore, this study aimed to determine the relative distribution of the CTR, CGRP, and amylin in upper cervical DRG. METHODS: CTR, CGRP, and amylin immunofluorescence was examined relative to neural markers in C1/2 DRG from male and female mice, rats, and human cases. Immunofluorescence was supported by RNA-fluorescence in situ hybridization examining amylin mRNA distribution in rat DRG. RESULTS: Amylin immunofluorescence was observed in neuronal soma and fibres. Amylin mRNA (Iapp) was also detected. Amylin and CGRP co-expression was observed in 19% (mouse), 17% (rat), and 36% (human) of DRG neurons in distinct vesicle-like neuronal puncta from one another. CTR immunoreactivity was present in DRG neurons, and both peptides produced receptor signalling in primary DRG cell cultures. CTR-positive neurons frequently co-expressed amylin and/or CGRP (66% rat; 84% human), with some sex differences. CONCLUSIONS: Amylin and CGRP could both be local peptide agonists for CTR-based receptors in upper cervical DRG, potentially acting through autocrine and/or paracrine signalling mechanisms to modulate neuron function. Amylin and its receptors could represent novel pain targets.

Long COVID in long-term care: a rapid realist review.

OBJECTIVES: The goals of this rapid realist review were to ask: (a) what are the key mechanisms that drive successful interventions for long COVID in long-term care (LTC) and (b) what are the critical contexts that determine whether the mechanisms produce the intended outcomes? DESIGN: Rapid realist review. DATA SOURCES: Medline, CINAHL, Embase, PsycINFO and Web of Science for peer-reviewed literature and Google for grey literature were searched up to 23 February 2023. ELIGIBILITY CRITERIA: We included sources focused on interventions, persons in LTC, long COVID or post-acute phase at least 4 weeks following initial COVID-19 infection and ones that had a connection with source materials. DATA EXTRACTION AND SYNTHESIS: Three independent reviewers searched, screened and coded studies. Two independent moderators resolved conflicts. A data extraction tool organised relevant data into context-mechanism-outcome configurations using realist methodology. Twenty-one sources provided 51 intervention data excerpts used to develop our programme theory. Synthesised findings were presented to a reference group and expert panel for confirmatory purposes. RESULTS: Fifteen peer-reviewed articles and six grey literature sources were eligible for inclusion. Eleven context-mechanism-outcome configurations identify those contextual factors and underlying mechanisms associated with desired outcomes, such as clinical care processes and policies that ensure timely access to requisite resources for quality care delivery, and resident-centred assessments and care planning to address resident preferences and needs. The underlying mechanisms associated with enhanced outcomes for LTC long COVID survivors were: awareness, accountability, vigilance and empathetic listening. CONCLUSIONS: Although the LTC sector struggles with organisational capacity issues, they should be aware that comprehensively assessing and monitoring COVID-19 survivors and providing timely interventions to those with long COVID is imperative. This is due to the greater care needs of residents with long COVID, and coordinated efficient care is required to optimise their quality of life.

Safety and anti-tumour activity of the IgE antibody MOv18 in patients with advanced solid tumours expressing folate receptor-alpha: a phase I trial.

All antibodies approved for cancer therapy are monoclonal IgGs but the biology of IgE, supported by comparative preclinical data, offers the potential for enhanced effector cell potency. Here we report a Phase I dose escalation trial (NCT02546921) with the primary objective of exploring the safety and tolerability of MOv18 IgE, a chimeric first-in-class IgE antibody, in patients with tumours expressing the relevant antigen, folate receptor-alpha. The trial incorporated skin prick and basophil activation tests (BAT) to select patients at lowest risk of allergic toxicity. Secondary objectives were exploration of anti-tumour activity, recommended Phase II dose, and pharmacokinetics. Dose escalation ranged from 70 µg-12 mg. The most common toxicity of MOv18 IgE is transient urticaria. A single patient experienced anaphylaxis, likely explained by detection of circulating basophils at baseline that could be activated by MOv18 IgE. The BAT assay was used to avoid enrolling further patients with reactive basophils. The safety profile is tolerable and maximum tolerated dose has not been reached, with evidence of anti-tumour activity observed in a patient with ovarian cancer. These results demonstrate the potential of IgE therapy for cancer.

Electrically responsive release of proteins from conducting polymer hydrogels.

Electrically modulated delivery of proteins provides an avenue to target local tissues specifically and tune the dose to the application. This approach prolongs and enhances activity at the target site whilst reducing off-target effects associated with systemic drug delivery. The work presented here explores an electrically active composite material comprising of a biocompatible hydrogel, gelatin methacryloyl (GelMA) and a conducting polymer, poly(3,4-ethylenedioxythiophene), generating a conducting polymer hydrogel. In this paper, the key characteristics of electroactivity, mechanical properties, and morphology are characterized using electrochemistry techniques, atomic force, and scanning electron microscopy. Cytocompatibility is established through exposure of human cells to the materials. By applying different electrical-stimuli, the short-term release profiles of a model protein can be controlled over 4 h, demonstrating tunable delivery patterns. This is followed by extended-release studies over 21 days which reveal a bimodal delivery mechanism influenced by both GelMA degradation and electrical stimulation events. This data demonstrates an electroactive and cytocompatible material suitable for the delivery of protein payloads over 3 weeks. This material is well suited for use as a treatment delivery platform in tissue engineering applications where targeted and spatio-temporal controlled delivery of therapeutic proteins is required. STATEMENT OF SIGNIFICANCE: Growth factor use in tissue engineering typically requires sustained and tunable delivery to generate optimal outcomes. While conducting polymer hydrogels (CPH) have been explored for the electrically responsive release of small bioactives, we report on a CPH capable of releasing a protein payload in response to electrical stimulus. The composite material combines the benefits of soft hydrogels acting as a drug reservoir and redox-active properties from the conducting polymer enabling electrical responsiveness. The CPH is able to sustain protein delivery over 3 weeks, with electrical stimulus used to modulate release. The described material is well suited as a treatment delivery platform to deliver large quantities of proteins in applications where spatio-temporal delivery patterns are paramount.

PAC1, VPAC1, and VPAC2 Receptor Expression in Rat and Human Trigeminal Ganglia: Characterization of PACAP-Responsive Receptor Antibodies.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide expressed in the trigeminal ganglia (TG). The TG conducts nociceptive signals in the head and may play roles in migraine. PACAP infusion provokes headaches in healthy individuals and migraine-like attacks in patients; however, it is not clear whether targeting this system could be therapeutically efficacious. To effectively target the PACAP system, an understanding of PACAP receptor distribution is required. Therefore, this study aimed to characterize commercially available antibodies and use these to detect PACAP-responsive receptors in the TG. Antibodies were initially validated in receptor transfected cell models and then used to explore receptor expression in rat and human TG. Antibodies were identified that could detect PACAP-responsive receptors, including the first antibody to differentiate between the PAC1n and PAC1s receptor splice variants. PAC1, VPAC1, and VPAC2 receptor-like immunoreactivity were observed in subpopulations of both neuronal and glial-like cells in the TG. In this study, PAC1, VPAC1, and VPAC2 receptors were detected in the TG, suggesting they are all potential targets to treat migraine. These antibodies may be useful tools to help elucidate PACAP-responsive receptor expression in tissues. However, most antibodies exhibited limitations, requiring the use of multiple methodologies and the careful inclusion of controls.

Synthesis and Biological Evaluation of Termini-Modified and Cyclic Variants of the Connexin43 Inhibitor Peptide5.

Peptide5 is a 12-amino acid mimetic peptide that corresponds to a region of the extracellular loop 2 (EL2) of connexin43. Peptide5 regulates both cellular communication with the cytoplasm (hemichannels) and cell-to-cell communication (gap junctions), and both processes are implicated in neurological pathologies. To address the poor in vivo stability of native peptide5 and to improve its activity, twenty-five novel peptide5 mimetics were designed and synthesized. All the analogues underwent biological evaluation as a hemichannel blocker and as a gap junction disruptor, and several were assessed for stability in human serum. From this study, it was established that several acylations on the N-terminus were tolerated in the hemichannel assay. However, the replacement of the L-Lys with an N-methylated L-Lys to give H-VDCFLSRPTE-N-MeKT-OH showed good hemichannel and gap junction activity and was more stable in human serum. The cyclic peptide variants generally were not tolerated in either the hemichannel and gap junction assay although several possessed outstanding stability in human serum.

Development of agarose-gelatin bioinks for extrusion-based bioprinting and cell encapsulation.

Three-dimensional bioprinting continues to advance as an attractive biofabrication technique to employ cell-laden hydrogel scaffolds in the creation of precise, user-defined constructs that can recapitulate the native tissue environment. Development and characterisation of new bioinks to expand the existing library helps to open avenues that can support a diversity of tissue engineering purposes and fulfil requirements in terms of both printability and supporting cell attachment. In this paper, we report the development and characterisation of agarose-gelatin (AG-Gel) hydrogel blends as a bioink for extrusion-based bioprinting. Four different AG-Gel hydrogel blend formulations with varying gelatin concentration were systematically characterised to evaluate suitability as a potential bioink for extrusion-based bioprinting. Additionally, autoclave and filter sterilisation methods were compared to evaluate their effect on bioink properties. Finally, the ability of the AG-Gel bioink to support cell viability and culture after printing was evaluated using SH-SY5Y cells encapsulated in bioprinted droplets of the AG-Gel. All bioink formulations demonstrate rheological, mechanical and swelling properties suitable for bioprinting and cell encapsulation. Autoclave sterilisation significantly affected the rheological properties of the AG-Gel bioinks compared to filter sterilisation. SH-SY5Y cells printed and differentiated into neuronal-like cells using the developed AG-Gel bioinks demonstrated high viability (>90%) after 23 d in culture. This study demonstrates the properties of AG-Gel as a printable and biocompatible material applicable for use as a bioink.

CGRP and the Calcitonin Receptor are Co-Expressed in Mouse, Rat and Human Trigeminal Ganglia Neurons.

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed in the trigeminal ganglia, a key site in craniofacial pain and migraine. CGRP potently activates two receptors: the CGRP receptor and the AMY1 receptor. These receptors are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with either the calcitonin receptor-like receptor (CLR) to form the CGRP receptor or the calcitonin receptor (CTR) to form the AMY1 receptor. The expression of the CGRP receptor in trigeminal ganglia has been described in several studies; however, there is comparatively limited data available describing AMY1 receptor expression and in which cellular subtypes it is found. This research aimed to determine the relative distributions of the AMY1 receptor subunit, CTR, and CGRP in neurons or glia in rat, mouse and human trigeminal ganglia. Antibodies against CTR, CGRP and neuronal/glial cell markers were applied to trigeminal ganglia sections to investigate their distribution. CTR-like and CGRP-like immunoreactivity were observed in both discrete and overlapping populations of neurons. In rats and mice, 30-40% of trigeminal ganglia neurons displayed CTR-like immunoreactivity in their cell bodies, with approximately 78-80% of these also containing CGRP-like immunoreactivity. Although human cases were more variable, a similar overall pattern of CTR-like immunoreactivity to rodents was observed in the human trigeminal ganglia. CTR and CGRP appeared to be primarily colocalized in small to medium sized neurons, suggesting that colocalization of CTR and CGRP may occur in C-fiber neurons. CGRP-like or CTR-like immunoreactivity were not typically observed in glial cells. Western blotting confirmed that CTR was expressed in the trigeminal ganglia of all three species. These results confirm that CTR is expressed in trigeminal ganglia neurons. The identification of populations of neurons that express both CGRP and CTR suggests that CGRP could act in an autocrine manner through a CTR-based receptor, such as the AMY1 receptor. Overall, this suggests that a trigeminal ganglia CTR-based receptor may be activated during migraine and could therefore represent a potential target to develop treatments for craniofacial pain and migraine.

A Subdural Bioelectronic Implant to Record Electrical Activity from the Spinal Cord in Freely Moving Rats.

Bioelectronic devices have found use at the interface with neural tissue to investigate and treat nervous system disorders. Here, the development and characterization of a very thin flexible bioelectronic implant inserted along the thoracic spinal cord in rats directly in contact with and conformable to the dorsal surface of the spinal cord are presented. There is no negative impact on hind-limb functionality nor any change in the volume or shape of the spinal cord. The bioelectronic implant is maintained in rats for a period of 12 weeks. The first subdural recordings of spinal cord activity in freely moving animals are presented; rats are plugged in via a recording cable and allowed to freely behave and move around on a raised platform. Recordings contained multiple distinct voltage waveforms spatially localize to individual electrodes. This device has great potential to monitor electrical signaling in the spinal cord after an injury and in the future, this implant will facilitate the identification of biomarkers in spinal cord injury and recovery, while enabling the delivery of localized electroceutical and chemical treatments.

The involvement of extracellular vesicles in the transcytosis of nanoliposomes through brain endothelial cells, and the impact of liposomal pH-sensitivity.

Despite the demonstrated effectiveness of nano-materials for drug delivery to the brain, a comprehensive understanding of their transport processes across the blood brain barrier (BBB) remains undefined. This multidisciplinary study aimed to gain an insight into the transport processes across BBB, focusing on the transcytosis of liposomes and the impact of liposomal pH-sensitivity. Glutathione-PEGylated pH-sensitive (GSH-PEG-pSL) and non pH-sensitive liposomes (GSH-PEG-L) were fluorescently labelled with rhodamine-DOPE and calcein, both impermeable to biomembranes. Following exposure to brain microvascular endothelial cells (hBMECs), the key functional component of the BBB, intracellular trafficking were evaluated by confocal live-cell imaging. The exocytosed liposomes, including naturally-occurring extracellular vesicles (EVs), were collected using differential centrifugation and and characterised regarding the EV yield, morphology and EVs origin using nanoparticle tracking analysis, transmission electron microscopy and flow cytometry. The transcytosis of liposomes through a verified BBB model comprising of hBMECs monolayer was also quantified. GSH-PEG-L was initially retained in the endo-lysosomes before exocytosed while packed in EVs of different sizes (<100 â€‹nm to >1 â€‹µm) while GSH-PEG-pSL underwent endosome escape with less degree of exocytosis with more fluorescence remaining in the cytoplasm. Compared with the untreated, hBMECs treated with GSH-PEG-L increased the yield of nano-EV and medium-EV by 7.9-fold and 4.6-fold, respectively. Conversely, GSH-pSL-treated cells produced 2.9-fold more nano-EVs but 2-fold less medium-EVs than the control cells. These vesicles were CD144-positive confirming their endothelial cell-origin. GSH-PEG-L demonstrated 2-fold higher efficiencies than GSH-PEG-pSL to cross the in vitro BBB model via exocytosis. Taken together, GSH-PEG-L might utilize EV secretion pathway to achieve transcytosis across brain endothelial cells of the BBB while liposomal pH-sensitivity favors cytoplasmic delivery.

Soft Hydrogel Environments that Facilitate Cell Spreading and Aggregation Preferentially Support Chondrogenesis of Adult Stem Cells.

Mesenchymal stem/stromal cells (MSCs) represent a promising cell type for treating damaged synovial joints. The therapeutic potential of MSCs will be facilitated by the engineering of biomaterial environments capable of directing their fate. Here the interplay between matrix elasticity and cell morphology in regulating the chondrogenic differentiation of MSCs when seeded onto or encapsulated within hydrogels made of interpenetrating networks (IPN) of alginate and collagen type I is explored. This IPN system enables the independent control of substrate stiffness (in 2D and in 3D) and cell morphology (3D only). The expression of chondrogenic markers SOX9, ACAN, and COL2 increases when MSCs are cultured onto the soft substrate, which correlates with increased SMAD2/3 nuclear localization, enhanced MSCs condensation, and the formation of larger cellular aggregates. The encapsulation of spread MSCs within a soft IPN increases the expression of cartilage-specific genes, which is linked to cellular condensation and nuclear SMAD2/3 localization. Surprisingly, cells forced to adopt a more rounded morphology within the same soft IPNs expressed higher levels of the osteogenic markers RUNX2 and COL1. The insight provided by this study suggests that a mechanobiology informed approach to biomaterial development will be integral to the development of successful cartilage tissue engineering strategies.

Tracking Antioxidant Status in Spinal Cord Injured Rodents: A Voltammetric Method Suited for Clinical Translation.

BACKGROUND: Spinal cord injury (SCI) triggers a signalling cascade that produces oxidative stress and damages the spinal cord. Voltammetry is a clinically accessible technique to detect, monitor, and guide correction of this potentially reversible secondary injury mechanism. Voltammetry is well suited for clinical translation because the method is inexpensive, simple, rapid, and portable. Voltammetry relies on the measurement of anodic current from a reagent-free, electrochemical reaction on the surface of a small electrode. METHODS: The present study tested the use of new disposable carbon nanotube based screen printed electrodes (CNT-SPE) for the voltammetric measurement of antioxidant current (AC). Spinal cord, cerebrospinal fluid, and plasma were obtained from Sprague-Dawley rats after SCI. Locomotor function after SCI was assessed by using the Basso, Beattie, Bresnahan (BBB) score. RESULTS: The more severe SCI caused a decline in spinal cord AC419 at 10 minutes (P < 0.05), 4 hours (P < 0.0001), and 1 day (P < 0.01) after injury compared with sham controls. It also caused a decline in plasma AC375 at 1 (P < 0.001) and 3 days (P < 0.05) after injury compared with their pre-injury baseline. Spinal cord AC419 correlated with plasma AC375 (r = 0.49, P < 0.01) and BBB score (r = 0.66, P < 0.0001) at 1 day after SCI. CONCLUSIONS: AC measured by CNT-SPE demonstrated a time- and severity-dependent decline after SCI. Plasma AC could serve as a surrogate marker for spinal cord AC.

Evaluation of a co-culture of rapidly isolated chondrocytes and stem cells seeded on tri-layered collagen-based scaffolds in a caprine osteochondral defect model.

Cartilage has poor regenerative capacity and thus damage to the joint surfaces presents a major clinical challenge. Recent research has focussed on the development of tissue-engineered and cell-based approaches for the treatment of cartilage and osteochondral injuries, with current clinically available cell-based approaches including autologous chondrocyte implantation and matrix-assisted autologous chondrocyte implantation. However, these approaches have significant disadvantages due to the requirement for a two-stage surgical procedure and an in vitro chondrocyte expansion phase which increases logistical challenges, hospital times and costs. In this study, we hypothesized that seeding biomimetic tri-layered scaffolds, with proven regenerative potential, with chondrocyte/infrapatellar fat pad stromal cell co-cultures would improve their regenerative capacity compared to scaffolds implanted cell-free. Rapid cell isolation techniques, without the requirement for long term in vitro culture, were utilised to achieve co-cultures of chondrocytes and stromal cells and thus overcome the limitations of existing cell-based techniques. Cell-free and cell-seeded scaffolds were implanted in osteochondral defects, created within the femoral condyle and trochlear ridge, in a translational large animal goat model. While analysis showed trends towards delayed subchondral bone healing in the cell-seeded scaffold group, by the 12 month timepoint the cell-free and cell-seeded groups yield cartilage and bone tissue with comparable quality and quantity. The results of the study reinforce the potential of the biomimetic tri-layered scaffold to repair joint defects but failed to demonstrate a clear benefit from the addition of the CC/FPMSC co-culture to this scaffold. Taking into consideration the additional cost and complexity associated with the cell-seeded scaffold approach, this study demonstrates that the treatment of osteochondral defects using cell-free tri-layered scaffolds may represent a more prudent clinical approach.

Optimised techniques for high-throughput screening of differentiated SH-SY5Y cells and application for neurite outgrowth assays.

Neuronal models are a crucial tool in neuroscientific research, helping to elucidate the molecular and cellular processes involved in disorders of the nervous system. Adapting these models to a high-throughput format enables simultaneous screening of multiple agents within a single assay. SH-SY5Y cells have been widely used as a neuronal model, yet commonly in an undifferentiated state that is not representative of mature neurons. Differentiation of the SH-SY5Y cells is a necessary step to obtain cells that express mature neuronal markers. Despite this understanding, the absence of a standardised protocol has limited the use of differentiated SH-SY5Y cells in high-throughput assay formats. Here, we describe techniques to differentiate and re-plate SH-SY5Y cells within a 96-well plate for high-throughput screening. SH-SY5Y cells seeded at an initial density of 2,500 cells/well in a 96-well plate provide sufficient space for neurites to extend, without impacting cell viability. Room temperature pre-incubation for 1 h improved the plating homogeneity within the well and the ability to analyse neurites. We then demonstrated the efficacy of our techniques by optimising it further for neurite outgrowth analysis. The presented methods achieve homogenously distributed differentiated SH-SY5Y cells, useful for researchers using these cells in high-throughput screening assays.

A Rapid Realist Review of Effective Mental Health Interventions for Individuals with Chronic Physical Health Conditions during the COVID-19 Pandemic Using a Systems-Level Mental Health Promotion Framework.

The 2020 global outbreak of COVID-19 exposed and heightened threats to mental health across societies. Research has indicated that individuals with chronic physical health conditions are at high risk for suffering from severe COVID-19 illness and from the adverse consequences of public health responses to COVID-19, such as social isolation. This paper reports on the findings of a rapid realist review conducted alongside a scoping review to explore contextual factors and underlying mechanisms or drivers associated with effective mental health interventions within and across macro-meso-micro systems levels for individuals with chronic physical health conditions. This rapid realist review extracted 14 qualified studies across 11 countries and identified four key mechanisms from COVID-19 literature-trust, social connectedness, accountability, and resilience. These mechanisms are discussed in relation to contextual factors and outcomes reported in the COVID literature. Realist reviews include iterative searches to refine their program theories and context-mechanism-outcome explanations. A purposive search of pre-COVID realist reviews on the study topic was undertaken, looking for evidence of the robustness of these mechanisms. There were differences in some of the pre-COVID mechanisms due to contextual factors. Importantly, an additional mechanism-power-sharing-was highlighted in the pre-COVID literature, but absent in the COVID literature. Pre-existing realist reviews were used to identify potential substantive theories and models associated with key mechanisms. Based on the overall findings, implications are provided for mental health promotion policy, practice, and research.

Stretchable microchannel-on-a-chip: A simple model for evaluating the effects of uniaxial strain on neuronal injury.

BACKGROUND: Axonal injury is a major component of traumatic spinal cord injury (SCI), associated with rapid deformation of spinal tissue and axonal projections. In vitro models enable us to examine these effects and screen potential therapies in a controlled, reproducible manner. NEW METHOD: A customized, stretchable microchannel system was developed using polydimethylsiloxane microchannels. Cortical and spinal embryonic rat neurons were cultured within the microchannel structures, allowing a uniaxial strain to be applied to isolated axonal processes. Global strains of up to 52% were applied to the stretchable microchannel-on-a-chip platform leading to local strains of up to 12% being experienced by axons isolated in the microchannels. RESULTS: Individual axons exposed to local strains between 3.2% and 8.7% developed beading within 30-minutes of injury. At higher local strains of 9.8% and 12% individual axons ruptured within 30-minutes of injury. Axon bundles, or fascicles, were more resistant to rupture at each strain level, compared to individual axons. At lower local strain of 3.2%, axon bundles inside microchannels and neuronal cells near entrances of them progressively swelled and degenerated over a period of 7 days after injury. COMPARISON WITH EXISTING METHOD(S): This method is simple, reliable and reproducible with good control and measurement of injury tolerance and morphological deformations using standard laboratory equipment. By measuring local strains, we observed that axonal injuries occur at a lower strain magnitude and a lower strain rate than previous methods reporting global strains, which may not accurately reflect the true axonal strain. CONCLUSIONS: We describe a novel stretchable microchannel-on-a-chip platform to study the effect of varying local strain on morphological characteristics of neuronal injury.

Interventions to Support Mental Health among Those with Health Conditions That Present Risk for Severe Infection from Coronavirus Disease 2019 (COVID-19): A Scoping Review of English and Chinese-Language Literature.

This study aimed to address knowledge gaps related to the prevention and management of mental health responses among those with a condition that presents risk of severe COVID-19 infection. A scoping review that mapped English and Chinese-language studies (2019-2020) located in MEDLINE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, Sociological Abstracts, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, and Airiti Library was undertaken. Search terms related to COVID-19, mental health, and physical health were used and articles that included all three of these factors were extracted (n = 77). With the exception of one hospital-based pilot study, there were no intervention studies targeting mental health in those at risk of severe COVID-19 infection. Promising practices such as integrated care models that appropriately screen for mental health issues, address health determinants, and include use of digital resources were highlighted. Patient navigator programs, group online medical visits, peer support, and social prescribing may also support those with complex needs. Future policies need to address digital health access inequities and the implementation of multi-integrated health and social care. Furthermore, research is needed to comprehensively assess multi-integrated interventions that are resilient to public health crises.

Clinical interventions for tungiasis (sand flea disease): a systematic review.

Tungiasis (sand flea disease) is an epidermal parasitic skin disease occurring in resource-limited communities. There is no standard treatment for tungiasis, and available treatment options are scarce. To our knowledge, this is the first systematic review aimed to assess randomised controlled trials (RCTs) investigating interventions for tungiasis. We systematically searched databases including MEDLINE (EBSCOhost), CENTRAL, CINAHL, PubMed, Web of Science, SciELO, LILACS and Embase (Scopus) for RCTs in any language, from inception of the databases until June 12, 2021. RCTs exploring preventive and therapeutic interventions for tungiasis were eligible. We used the revised Cochrane Collaboration's risk of bias tool to assess the risk of bias and Jadad scale to quantify the methodological quality of the RCTs. Of the 1839 identified records, only eight RCTs involving 808 participants were included, and several methodological deficiencies were identified in most of the trials. Trial interventions included: oral drugs niridazole and ivermectin and topical interventions of ivermectin lotion, metrifonate lotion, thiabendazole lotion, thiabendazole ointment, dimeticones (NYDA), and a neem seed and coconut oils-based mixture for treatment and coconut oil-based lotion (Zanzarin) for prevention. The coconut oil-based lotion for prevention and dimeticones for treatment of tungiasis have displayed the most promise. Most of the RCTs included in this study had low methodological quality. There is a clear unmet need for high-quality RCTs examining safe and effective prevention and treatment alternatives of tungiasis in endemic settings.