LoCoMoTe - a Framework for Classification of Natural Locomotion in VR by Task, Technique and Modality.

Virtual reality (VR) research has provided overviews of locomotion techniques, how they work, their strengths and overall user experience. Considerable research has investigated new methodologies, particularly machine learning to develop redirection algorithms. To best support the development of redirection algorithms through machine learning, we must understand how best to replicate human navigation and behaviour in VR, which can be supported by the accumulation of results produced through live-user experiments. However, it can be difficult to identify, select and compare relevant research without a pre-existing framework in an ever-growing research field. Therefore, this work aimed to facilitate the ongoing structuring and comparison of the VR-based natural walking literature by providing a standardised framework for researchers to utilise. We applied thematic analysis to study methodology descriptions from 140 VR-based papers that contained live-user experiments. From this analysis, we developed the LoCoMoTe framework with three themes: navigational decisions, technique implementation, and modalities. The LoCoMoTe framework provides a standardised approach to structuring and comparing experimental conditions. The framework should be continually updated to categorise and systematise knowledge and aid in identifying research gaps and discussions.

Virtual Reality as a Pain Distraction Modality for Experimentally Induced Pain in a Chronic Pain Population: An Exploratory Study.

Virtual reality (VR) has shown promising results as an adjunct therapy for pain management. Recent literature exploring the use of VR for pain management among a chronic pain (CP) population has produced encouraging results, although little has been done to explore what about a VR intervention is the provider of the analgesic response. Furthermore, as has been suggested in the literature previously, little has been said of the association between pain tolerance and presence. This study primarily aimed to investigate pain tolerance differentiation between VR-head-mounted display (HMD) active and control interventions. Secondarily, this study looked to report on whether presence correlates to pain tolerance, among a CP population. A repeated-measures study design was used. Twelve participants received two 5-minute interventions while being subjected to experimentally induced pain. The interventions were as follows: (a) "active intervention," an immersive and interactive experience (b) "control intervention," and a nonimmersive controlled experience with no interaction. Tolerance to pain was assessed via the total time the participant continued the intervention. Presence was assessed via the Witmer and Singer's presence questionnaire. Participants also completed the Simulator Sickness Questionnaire, the Presence Questionnaire, and the Brief Pain Inventory. Pain tolerance was significantly higher in the active intervention compared with the control intervention (p = 0.005). There was a positive correlation between pain tolerance and presence during the active VR intervention. The media as opposed to the medium was determined to be responsible for greater tolerance to pain, as well as greater sense of presence, which was positively correlated to an increase in pain tolerance.

Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype.

AIMS/HYPOTHESIS: The aim of this study was to characterise islet autoantibody profiles and immune cell phenotypes in slow progressors to type 1 diabetes. METHODS: Immunological variables were compared across peripheral blood samples obtained from slow progressors to type 1 diabetes, individuals with newly diagnosed or long-standing type 1 diabetes, and healthy individuals. Polychromatic flow cytometry was used to characterise the phenotypic attributes of B and T cells. Islet autoantigen-specific B cells were quantified using an enzyme-linked immunospot (ELISpot) assay and islet autoantigen-specific CD8+ T cells were quantified using peptide-HLA class I tetramers. Radioimmunoassays were used to detect islet autoantibodies. Sera were assayed for various chemokines, cytokines and soluble receptors via ELISAs. RESULTS: Islet autoantibodies were lost over time in slow progressors. Various B cell subsets expressed higher levels of CD95 in slow progressors, especially after polyclonal stimulation, compared with the corresponding B cell subsets in healthy donors (p < 0.05). The phenotypic characteristics of CD4+ and CD8+ T cells were similar in slow progressors and healthy donors. Lower frequencies of CD4+ T cells with a central memory phenotype (CD27int, CD127+, CD95int) were observed in slow progressors compared with healthy donors (mean percentage of total CD4+ T cells was 3.00% in slow progressors vs 4.67% in healthy donors, p < 0.05). Autoreactive B cell responses to proinsulin were detected at higher frequencies in slow progressors compared with healthy donors (median no. of spots was 0 in healthy donors vs 24.34 in slow progressors, p < 0.05) in an ELISpot assay. Islet autoantigen-specific CD8+ T cell responses were largely absent in slow progressors and healthy donors. Serum levels of DcR3, the decoy receptor for CD95L, were elevated in slow progressors compared with healthy donors (median was 1087 pg/ml in slow progressors vs 651 pg/ml in healthy donors, p = 0.06). CONCLUSIONS/INTERPRETATION: In this study, we found that slow progression to type 1 diabetes was associated with a loss of islet autoantibodies and a distinct B cell phenotype, consistent with enhanced apoptotic regulation of peripheral autoreactivity via CD95. These phenotypic changes warrant further studies in larger cohorts to determine their functional implications.

The Accessibility of Commercial Off-The-Shelf Virtual Reality for Low Vision Users: A Macular Degeneration Case Study.

Virtual reality (VR) is demonstrating increasing potential for therapeutic benefit in elderly care, but it is still generally considered to be the domain of the visually unimpaired. Even where VR and augmented reality (AR) are being explored for use with low vision, it is generally with a focus on creating bespoke software and hardware. However, the properties of commercial off-the-shelf (COTS) headsets, such as high luminance, may render them accessible even to very low vision users. Using a case-study approach, we explored the differences in visual perception from baseline to pass-through AR and commercial VR applications for an elderly female (Mrs. M) with advanced age-related macular degeneration. We found notable improvements in object, face, and color recognition, particularly with higher display brightness. Furthermore, Mrs. M was able to engage fully and enthusiastically with a number of (unmodified) VR applications, providing detailed descriptions of both static and moving elements. We suggest that the high luminance available in COTS VR may support more stable fixation closer to the fovea, improving visual resolution. Furthermore, the improvements we noted in color perception support previous suggestions that increasing luminance may improve photosensitivity by reducing the uptake of limited oxygen by the rod cells. We conclude that low vision should not automatically preclude users from engaging in VR research or entertainment, and that they may be able to use well-illuminated VR applications without any special modifications.

Loss of CXCR3 expression on memory B cells in individuals with long-standing type 1 diabetes.

AIMS/HYPOTHESIS: Islet-specific autoantibodies can predict the development of type 1 diabetes. However, it remains unclear if B cells, per se, contribute to the causal pancreatic immunopathology. We aimed to identify phenotypic signatures of disease progression among naive and memory B cell subsets in the peripheral blood of individuals with type 1 diabetes. METHODS: A total of 69 participants were recruited across two separate cohorts, one for discovery purposes and the other for validation purposes. Each cohort comprised two groups of individuals with type 1 diabetes (one with newly diagnosed type 1 diabetes and the other with long-standing type 1 diabetes) and one group of age- and sex-matched healthy donors. The phenotypic characteristics of circulating naive and memory B cells were investigated using polychromatic flow cytometry, and serum concentrations of various chemokines and cytokines were measured using immunoassays. RESULTS: A disease-linked phenotype was detected in individuals with long-standing type 1 diabetes, characterised by reduced C-X-C motif chemokine receptor 3 (CXCR3) expression on switched (CD27+IgD-) and unswitched (CD27intermediateIgD+) memory B cells. These changes were associated with raised serum concentrations of B cell activating factor and of the CXCR3 ligands, chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11. A concomitant reduction in CXCR3 expression was also identified on T cells. CONCLUSIONS/INTERPRETATION: Our data reveal a statistically robust set of abnormalities that indicate an association between type 1 diabetes and long-term dysregulation of a chemokine ligand/receptor system that controls B cell migration.

Altering User Movement Behaviour in Virtual Environments.

In immersive Virtual Reality systems, users tend to move in a Virtual Environment as they would in an analogous physical environment. In this work, we investigated how user behaviour is affected when the Virtual Environment differs from the physical space. We created two sets of four environments each, plus a virtual replica of the physical environment as a baseline. The first focused on aesthetic discrepancies, such as a water surface in place of solid ground. The second focused on mixing immaterial objects together with those paired to tangible objects. For example, barring an area with walls or obstacles. We designed a study where participants had to reach three waypoints laid out in such a way to prompt a decision on which path to follow based on the conflict between the mismatching visual stimuli and their awareness of the real layout of the room. We analysed their performances to determine whether their trajectories were altered significantly from the shortest route. Our results indicate that participants altered their trajectories in presence of surfaces representing higher walking difficulty (for example, water instead of grass). However, when the graphical appearance was found to be ambiguous, there was no significant trajectory alteration. The environments mixing immaterial with physical objects had the most impact on trajectories with a mean deviation from the shortest route of 60 cm against the 37 cm of environments with aesthetic alterations. The co-existance of paired and unpaired virtual objects was reported to support the idea that all objects participants saw were backed by physical props. From these results and our observations, we derive guidelines on how to alter user movement behaviour in Virtual Environments.

Auditory and visual cueing modulate cycling speed of older adults and persons with Parkinson's disease in a Virtual Cycling (V-Cycle) system.

BACKGROUND: Evidence based virtual environments (VEs) that incorporate compensatory strategies such as cueing may change motor behavior and increase exercise intensity while also being engaging and motivating. The purpose of this study was to determine if persons with Parkinson's disease and aged matched healthy adults responded to auditory and visual cueing embedded in a bicycling VE as a method to increase exercise intensity. METHODS: We tested two groups of participants, persons with Parkinson's disease (PD) (n = 15) and age-matched healthy adults (n = 13) as they cycled on a stationary bicycle while interacting with a VE. Participants cycled under two conditions: auditory cueing (provided by a metronome) and visual cueing (represented as central road markers in the VE). The auditory condition had four trials in which auditory cues or the VE were presented alone or in combination. The visual condition had five trials in which the VE and visual cue rate presentation was manipulated. Data were analyzed by condition using factorial RMANOVAs with planned t-tests corrected for multiple comparisons. RESULTS: There were no differences in pedaling rates between groups for both the auditory and visual cueing conditions. Persons with PD increased their pedaling rate in the auditory (F 4.78, p = 0.029) and visual cueing (F 26.48, p < 0.000) conditions. Age-matched healthy adults also increased their pedaling rate in the auditory (F = 24.72, p < 0.000) and visual cueing (F = 40.69, p < 0.000) conditions. Trial-to-trial comparisons in the visual condition in age-matched healthy adults showed a step-wise increase in pedaling rate (p = 0.003 to p < 0.000). In contrast, persons with PD increased their pedaling rate only when explicitly instructed to attend to the visual cues (p < 0.000). CONCLUSIONS: An evidenced based cycling VE can modify pedaling rate in persons with PD and age-matched healthy adults. Persons with PD required attention directed to the visual cues in order to obtain an increase in cycling intensity. The combination of the VE and auditory cues was neither additive nor interfering. These data serve as preliminary evidence that embedding auditory and visual cues to alter cycling speed in a VE as method to increase exercise intensity that may promote fitness.

Virtual carers for the elderly: A case study review of ethical responsibilities.

Intelligent digital healthcare systems are becoming an increasingly considered approach to facilitating continued support of our ageing population. Within the remit of such digital systems, 'Virtual Carer' is one of the more consistent terms that refers to an artificial system capable of providing various assistive living and communicative functionalities, embodied within a graphical avatar displayed on a screen. As part of the RITA (Responsive Interactive Advocate) project - a proof of concept for one such virtual carer system - a series of semi-structured discussions with various stakeholders was conducted. This paper presents the results of these discussions to highlight data security, replacement of human/physical care and always acting in the user's best interest. These three ethical concerns and designer responsibilities are identified as highly relevant to both individuals and groups that may, in the future, utilise a system like RITA either as a care receiver or provider. This paper also presents some initial, theoretical safeguard processes relevant to these key concerns.

Antibody stabilization of peptide-MHC multimers reveals functional T cells bearing extremely low-affinity TCRs.

Fluorochrome-conjugated peptide-MHC (pMHC) multimers are commonly used in combination with flow cytometry for direct ex vivo visualization and characterization of Ag-specific T cells, but these reagents can fail to stain cells when TCR affinity and/or TCR cell-surface density are low. pMHC multimer staining of tumor-specific, autoimmune, or MHC class II-restricted T cells can be particularly challenging, as these T cells tend to express relatively low-affinity TCRs. In this study, we attempted to improve staining using anti-fluorochrome unconjugated primary Abs followed by secondary staining with anti-Ab fluorochrome-conjugated Abs to amplify fluorescence intensity. Unexpectedly, we found that the simple addition of an anti-fluorochrome unconjugated Ab during staining resulted in considerably improved fluorescence intensity with both pMHC tetramers and dextramers and with PE-, allophycocyanin-, or FITC-based reagents. Importantly, when combined with protein kinase inhibitor treatment, Ab stabilization allowed pMHC tetramer staining of T cells even when the cognate TCR-pMHC affinity was extremely low (KD >1 mM) and produced the best results that we have observed to date. We find that this inexpensive addition to pMHC multimer staining protocols also allows improved recovery of cells that have recently been exposed to Ag, improvements in the recovery of self-specific T cells from PBMCs or whole-blood samples, and the use of less reagent during staining. In summary, Ab stabilization of pMHC multimers during T cell staining extends the range of TCR affinities that can be detected, yields considerably enhanced staining intensities, and is compatible with using reduced amounts of these expensive reagents.

Role of serine proteases in the regulation of interleukin-877 during the development of bronchopulmonary dysplasia in preterm ventilated infants.

RATIONALE: The chemokine interleukin-8 is implicated in the development of bronchopulmonary dysplasia in preterm infants. The 77-amino acid isoform of interleukin-8 (interleukin-877) is a less potent chemoattractant than other shorter isoforms. Although interleukin-877 is abundant in the preterm circulation, its regulation in the preterm lung is unknown. OBJECTIVES: To study expression and processing of pulmonary interleukin-877 in preterm infants who did and did not develop bronchopulmonary dysplasia. METHODS: Total interleukin-8 and interleukin-877 were measured in bronchoalveolar lavage fluid from preterm infants by immunoassay. Neutrophil serine proteases were used to assess processing. Neutrophil chemotaxis assays and degranulation of neutrophil matrix metalloproteinase-9 were used to assess interleukin-8 function. MAIN RESULTS: Peak total interleukin-8 and interleukin-877 concentrations were increased in infants who developed bronchopulmonary dysplasia compared to those who did not. Shorter forms of interleukin-8 predominated in the preterm lung (96.3% No-bronchopulmonary dysplasia vs 97.1% bronchopulmonary dysplasia, p>0.05). Preterm bronchoalveolar lavage fluid significantly converted exogenously added interleukin-877 to shorter isoforms (p<0.001). Conversion was greater in bronchopulmonary dysplasia infants (p<0.05). This conversion was inhibited by α-1 antitrypsin and antithrombin III (p<0.01). Purified neutrophil serine proteases efficiently converted interleukin-877 to shorter isoforms in a time- and dose-dependent fashion; shorter interleukin-8 isoforms were primarily responsible for neutrophil chemotaxis (p<0.001). Conversion by proteinase-3 resulted in significantly increased interleukin-8 activity in vitro (p<0.01). CONCLUSIONS: Shorter, potent, isoforms interleukin-8 predominate in the preterm lung, and are increased in infants developing bronchopulmonary dysplasia, due to conversion of interleukin-877 by neutrophil serine proteases and thrombin. Processing of interleukin-8 provides an attractive therapeutic target to prevent development of bronchopulmonary dysplasia.

Virtual reality and musculoskeletal pain: manipulating sensory cues to improve motor performance during walking.

Musculoskeletal pain (MSP) is the most expensive nonmalignant health problem and the most common reason for activity limitation. Treatment approaches to improve movement without aggravating pain are urgently needed. Virtual reality (VR) can decrease acute pain, as well as influence movement speed. It is not clear whether VR can improve movement speed in individuals with MSP without aggravating pain. This study investigated the extent to which different audio and optic flow cues in a VR environment influenced walking speed in people with and without MSP. A total of 36 subjects participated, 19 with MSP and 17 controls. All walked on a motorized self-paced treadmill interfaced with a three-dimensional virtual walkway. The audio tempo was scaled (75%, 100%, and 125%) from baseline cadence, and optic flow was either absent, or scaled to 50% or 100% of preferred walking speed. Gait speed was measured during each condition, and pain was measured before and after the experiment. Repeated measures analysis of variance showed that audio tempo above baseline cadence significantly increased walking speed in both groups, F(3, 99)=10.41, p<0.001. Walking speed increases of more than 25% occurred in both groups in the 125% audio tempo condition, without any significant increase in pain. There was also a trend toward increased walking speeds with the use of optic flow, but the results in this study did not achieve significance at the p<0.05 level, F(2, 66)=2.01, p=0.14. Further research is needed to establish the generalizability of increasing movement speed across different physical performance tasks in VR.

Sounding better: fast audio cues increase walk speed in treadmill-mediated virtual rehabilitation environments.

Music or sound effects are often used to enhance Virtual Environments, but it is not known how this audio may influence gait speed. This study investigated the influence of audio cue tempo on treadmill walking with and without visual flow. The walking speeds of 11 individuals were recorded during exposure to a range of audio cue rates. There was a significant effect of audio tempo without visual flow, with a 16% increase in walk speed with faster audio cue tempos. Audio with visual flow resulted in a smaller but still significant increase in walking speed (8%). The results suggest that the inclusion of faster rate audio cues may be of benefit in improving walk speed in virtual rehabilitation.

Inactivation of IL-6 and soluble IL-6 receptor by neutrophil derived serine proteases in cystic fibrosis.

The ability of IL-6 to signal via both membrane bound and soluble receptors is thought to explain the capacity of this cytokine to act in both the initiation and resolution of acute inflammatory responses. In cystic fibrosis (CF), poorly resolved neutrophillic inflammation of the lungs is a primary cause of morbidity and mortality. Expression of IL-6 has been reported to be low in CF lung secretions, despite ongoing inflammation, but the status of soluble IL-6 receptor (sIL-6R) in these patients is unknown. We hypothesised that sIL-6R may be an important potentiator of IL-6 activity in CF associated lung disease. IL-6, sIL-6R and sgp130 (a natural antagonist of responses mediated by the sIL-6R) were analysed by ELISA and Western blot in bronchoalveolar lavage fluid (BALF) from 28 paediatric CF patients and nine non-CF controls. Total cell counts in CF were four fold higher compared to controls (median: 1.4 x 10(6) cells/ml v. 0.35 x 10(6) cells/ml in controls) (p<0.001) and the infiltrate was dominated by neutrophils which were elevated by 89 fold (0.62 x 10(6) cells/ml v. 0.007 x 10(6) cells/ml in controls) (p<0.001). Other markers of inflammation such as IL-8 and MCP-1 were elevated 17.5 and 3.8 fold respectively (IL-8; median: 1122 pg/ml v. 64 pg/ml in controls, p<0.01 and MCP-1; median: 692 pg/ml v. 182 pg/ml in controls, p<0.05). IL-6, although present in 23/32 CF BALF specimens compared to 1/9 controls (p<0.01), was weakly expressed (median: 50 pg/ml). Expression of sIL-6R and sgp130 in CF was no different to control patients. We tested whether weak expression of all three molecules was due to degradation by CF BALF. Degradative activity was observed in association with BALF elastase activity and could be specifically blocked by serine protease inhibitors. Degradation of sIL-6R by purified serine proteases (elastase, cathepsin G and proteinase 3) was also observed leading to a loss of trans-signalling activity. Interestingly, sIL-6R was protected from proteolysis by interaction with IL-6. Our data identify and define a novel protease mediated deficiency of IL-6 signalling in the CF lung.

Treadmill Interface for Virtual Reality vs. Overground Walking: A Comparison of Gait in Individuals with and without Pain.

A treadmill (TR) interfaced with a virtual reality (VR) system can provide an engaging environment that could improve activity adherence and walking function for individuals with pain. Furthermore, inclusion of discrete visual and auditory cues into the VR environment (e.g. manipulation of optic flow speed or audio beat frequency) could improve walking. This study compared gait characteristics (speed and cadence) of a baseline over ground walk (OVR) with a TR walk as part of a project to develop gait referenced visual and auditory frequency cues. Thirty-six participants aged between 22 and 80 years, with pain (n=19) and without pain (n=17) took part. A 2 x 2 MANOVA conducted on the speed and cadence for all participants showed a significant difference between pain and control groups for speed (F1,34=9.56, p<0.01) and cadence (F1,34=5.75, p<0.05), as well as a significant decrease from overground to treadmill conditions for both speed (F1,34=81.39, p<0.01) and cadence (F1,34=25.46, p<0.01). Differences between OVR and TR walking indicate that visual or auditory cues for VR walk training should be referenced according to TR baseline measures.

Antineutrophil cytoplasm antibody-stimulated neutrophil adhesion depends on diacylglycerol kinase-catalyzed phosphatidic acid formation.

Patients with certain forms of systematic vasculitis, such as Wegener's granulomatosis, have circulating antineutrophil cytoplasmic antibodies (ANCA). These inappropriately stimulate circulating neutrophils adhere to and thereby obstruct small vessels. This, together with ANCA-induced degranulation and an oxidative burst, leads to local tissue damage. The signaling pathways that are activated by ANCA IgG are distinct from those that are involved in normal neutrophil activation. This study shows that diacylglycerol kinase is selectively activated by ANCA and that the generated phosphatidic acid is responsible for promoting neutrophil adhesion, in part through integrin activation. The data presented point to diacylglycerol kinase alpha as a novel but selective target for the development of drugs to treat this potentially fatal disorder.

Melanin inhibits cytotoxic effects of doxorubicin and daunorubicin in MOLT 4 cells.

In the present study we have developed a simple method to elucidate the melanin binding ability of different chemotherapeutic agents. The anthracyclines, doxorubicin and daunorubicin, or the alkylating agent cisplatin were preincubated with melanin (Sepia). Melanin and free drug was then separated through centrifugation and the cytotoxic effects of corresponding drug were evaluated in a MTT (3-(4,5-dimetyltiazol-2-yl)-2,5-difenyl-tetrazoliumbromide) assay using MOLT-4 cells. Our results show that melanin pretreatment shifted the IC50 value for doxorubicin from 0.06 to 0.97 microM and for daunorubicin from 0.04 to 0.80 microM. In contrast, the IC50 values of cisplatin was not influenced by melanin pre-treatment indicating that cisplatin does not bind to melanin. By comparing equi-active concentrations from concentration-response curves with or without melanin pretreatment an approximate binding capacity of melanin could be estimated. Our results show that melanin binds about 900 nmol/mg doxorubicin and 760 nmol/mg daunorubicin. Chloroquine, which is known to bind to melanin with high affinity, was found to inhibit melanin binding of both daunorubicin and doxorubicin, thereby leading to an increased sensitivity of the anthracyclines. The clinical implications of melanin binding regarding unwanted accumulation of anthracyclines in the skin as well as chemoprotective effects against chemotherapy are discussed.