Type-I-interferon-responsive microglia shape cortical development and behavior.

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.

Programmed Intermittent Bolus Regimen for Erector Spinae Plane Blocks in Children: A Retrospective Review of a Single-Institution Experience.

With few published reports on erector spinae plane block use in children, limited guidance on perioperative local anesthetic dosing exists. We present a series of 22 patients who received erector spinae plane catheters with programmed intermittent bolus for various surgeries. Median loading dose of 0.4 mL/kg (interquartile range [IQR], 0.1 mL/kg) ropivacaine 0.5%, intraoperative bolus of 0.3 mL/kg/h (IQR, 0.1 mL/kg) ropivacaine 0.2%, and a postoperative programmed intermittent bolus regimen of maximum 0.6 mg/kg/h resulted in highest pain scores on postoperative day 1 with a median score of 1.7 of 10 (IQR, 1.8) and highest morphine equivalents consumed on postoperative day 2 with a median score of 0.16 mg/kg up to 120 hours after surgery.

Virtual Reality Facilitated Exercise Increases Sympathetic Activity and Reduces Pain Perception: A Randomized Crossover Study.

OBJECTIVE: Both virtual reality (VR) and exercise reduce pain while avoiding the risks of traditional pharmacotherapy. The aim of this study was to assess how VR-facilitated exercise modulates sympathetic activity and pain perception. DESIGN: Healthy adult volunteers were randomized by hand dominance and then subjected to a standardized cold pressor test while experiencing a VR application. After a 5-minute washout, participants were crossed-over and repeated the test on their other hand while undergoing a VR-facilitated exercise application. Sympathetic activation, pain sensation, and pain tolerance data were collected identically during both conditions. RESULTS: 110 participants were analyzed. Sympathetic activity increased in both conditions but was higher in the VR-facilitated exercise condition (p < 0.0001). Pain sensation scores were initially higher with VR-facilitated exercise but dropped below the VR-only condition by the end of the intervention (p = 0.0175). There were no differences in pain tolerance between conditions (p = 0.18). CONCLUSION: The decrease in pain perception with VR-facilitated exercise condition compared to VR alone indicates VR-facilitated exercise can be a useful tool for managing pain. Though this effect did not translate into higher pain tolerance, VR-facilitated exercise may be a useful intervention in the setting of physical therapy or for patients with chronic pain.

A technology acceptance model to predict anesthesiologists' clinical adoption of virtual reality.

BACKGROUND: Virtual reality (VR) is a novel tool with demonstrated applications within healthcare; however its integration within clinical practice has been slow. Adoption patterns can be evaluated using a technology acceptance model (TAM). The primary study aim was to use VR TAM to assess factors that influence anesthesiologists' acceptance of VR for preoperative anxiolysis. The secondary aim assessed the model's reliability. METHODS: 109 clinical anesthesiologists at Stanford were exposed to a VR application developed as a distraction tool to reduce preoperative patient anxiety. Anesthesiologists were surveyed about their attitudes, beliefs, and behaviors as predictors of their likelihood to clinically use VR. The primary outcome assessed predictive validity using descriptive statistics, construct validity using confirmatory factor analysis, and standardized estimates of model relationships. The secondary outcome assessed reliability with Cronbach's α and composite reliability. RESULTS: Construct validity and reliability was assessed, where all values established acceptable fit and reliability. Hypothesized predictors of consumer use were evaluated with standardized estimates, looking at perceptions of usefulness, ease of use, and enjoyment in predicting attitudes and intentions toward using and purchasing. Past use and price willing to pay did not predict perceived usefulness. Participants in lower age ranges had higher levels of perceived ease of use than those >55 years. CONCLUSION: All confirmatory factor analysis testing for construct validity had good fit. Perceptions of usefulness and enjoyment predicted an anesthesiologist's attitude toward using and intention to purchase, while perceived ease of use predicted perceived usefulness and enjoyment, attitude toward purchasing and using, and intention to use. Past use and price willing to pay did not influence perceptions of usefulness. Lower age predicted greater perceived ease of use. All scales in the model demonstrated acceptable reliability. With good validity and reliability, the VR-TAM model demonstrated factors predictive of anesthesiologist's intentions to integrate VR into clinical settings.

Reducing Preoperative Caregiver Anxiety With Virtual Reality: A Pragmatic, Randomized Controlled Study.

Pediatric patients and their caregivers often experience perioperative anxiety. Interventions reduce caregiver anxiety improve cooperation and contribute to an improved patient experience. This study seeks to evaluate the efficacy of virtual reality (VR)-assisted mindfulness on perioperative caregiver anxiety. Participants were randomized into a standard of care (SOC) group, which included snacks but no technology-based distractions, or a VR group, which included snacks and a VR-guided meditation. Caregiver anxiety was measured before and after the intervention using the Visual Analogue Scale for Anxiety (VAS-A). Secondary aims explored participants' baseline anxiety with the State-Trait Anxiety Inventory (STAI). VR group participants completed a satisfaction survey. Linear regression models of VAS-A and STAI were used to compare group differences. Satisfaction survey results were reported with descriptive statistics. 26 participants were included, with 12 randomized to the SOC group and 14 to the VR group. VAS-A scores in the VR group were lower than those in the SOC group (p = .002). The STAI found no change in participants' state of anxiety in the SOC group (p = .7108), compared to a significant reduction (p = .014) in the VR group when controlling for anxiety traits. 12 of 14 caregivers in the VR group expressed satisfaction or strong satisfaction. This study supports the implementation of VR mindfulness as a method to reduce caregiver anxiety. VR use in the pediatric healthcare setting is safe and inexpensive, and the intervention had a high degree of participant satisfaction.

Augmented Reality Improves Pediatric Mask Induction: A Prospective, Matched Case-Control Study.

Introduction: Pediatric perioperative anxiety is a significant problem during mask induction for general anesthesia. Immersive technologies, such as extended reality headsets, are a promising strategy for alleviating anxiety. Our primary aim was to investigate mask acceptance during inhalational induction utilizing augmented reality (AR). Methods: This was a prospective, matched case-control study at a quaternary academic hospital. Fifty pediatric patients using AR for mask induction were matched to 150 standard-of-care (SOC) controls. The primary outcome was measured with the Mask Acceptance Scale (MAS). Secondary outcomes of cooperation and emergent delirium (ED) were assessed. Results: MAS scores ≥2 occurred at 4% (95% CI [0, 9.4%]) with AR versus 19.3%, (95% CI [13%, 25.7%]) with SOC (RR 0.21, 95% CI [0.05, 0.84], P = .027). Ninety-eight percent of AR patients were cooperative versus 91.3% with SOC (P = .457). Zero percent had ED with AR versus 0.7% with SOC (P = 1.000). Conclusions: AR during mask induction improved mask acceptance compared to SOC. No relationship was observed between AR and cooperation or ED. Future research will investigate the integration of AR into clinical practice as a nonpharmacologic intervention.

Virtual reality facilitated exercise improves pain perception: A crossover study.

STUDY OBJECTIVE: Both virtual reality (VR) and exercise are recognized for their analgesic and anxiolytic properties. The purpose of this study is to evaluate the ability of VR-facilitated exercise to modulate pain. DESIGN: Within-subject cross-over clinical trial. SETTING: The Stanford Chariot Program conducted this study at Lucile Packard Children's Hospital Stanford (LCPHS). PATIENTS: Healthy participants meeting inclusion criteria were recruited by volunteer solicitation from LCPHS. INTERVENTIONS: Participants were randomized by hand dominance and subjected to a standardized cold pressor test with no VR or exercise. After a 5-min wash-out period, participants repeated the test on their other hand while experiencing a VR-facilitated exercise condition. Pain sensitivity, pain tolerance, and sympathetic activation data were collected during both conditions. MEASUREMENTS: Pain sensitivity was scored 0-10 and collected every 30 s. Pain tolerance was recorded as the duration a participant could endure the painful stimuli. Sympathetic activation was measured by skin conductance response density (SCRD) and recorded in 30 s epochs by a biosensor. In all analyses, data were nested by participant. MAIN RESULTS: Forty-one participants completed both interventions. Pain sensitivity was reduced in the VR-facilitated exercise condition (p < 0.0001). There was no difference in pain tolerance between conditions. While both conditions resulted in an increase in sympathetic activity, SCRD was higher at all time points in the VR-facilitated exercise condition. CONCLUSIONS: The reduction in pain sensitivity indicates VR-facilitated exercise results in improved pain perception. VR-facilitated exercise may be especially useful for patients with chronic pain or other conditions requiring physical therapy, where pain may be exacerbated by exercise.

Predicting pediatric healthcare provider use of virtual reality using a technology acceptance model.

Objective: The primary aim of this study was to apply a novel technology acceptance model (TAM) for virtual reality (VR) in healthcare. The secondary aim was to assess reliability of this model to evaluate factors that predict the intentions of pediatric health providers' use of VR as an anxiolytic for hospitalized pediatric patients. Materials and Methods: Healthcare providers that interacted with pediatric patients participated in a VR experience available as anxiolysis for minor procedures and then completed a survey evaluating attitudes, behaviors, and technology factors that influence adoption of new technologies. Results: Reliability for all domain measurements were good, and all confirmatory factor analysis models demonstrated good fit. Usefulness, ease of use, curiosity, and enjoyment of the VR experience all strongly predict intention to use and purchase VR technologies. Age of providers, past use, and cost of technology did not influence future purchase or use, suggesting that VR technologies may be broadly adopted in the pediatric healthcare setting. Discussion: Previous VR-TAM models in non-healthcare consumers formulated that age, past use, price willing to pay, and curiosity impacted perceived ease of use. This study established that age, past use, and cost may not influence use in healthcare. Future studies should be directed at evaluating the social influences and facilitating conditions within healthcare that play a larger influence on technology adoption. Conclusion: The VR-TAM model demonstrated validity and reliability for predicting intent to use VR in a pediatric hospital.

Type I interferon responsive microglia shape cortical development and behavior.

Microglia are brain resident phagocytes that can engulf synaptic components and extracellular matrix as well as whole neurons. However, whether there are unique molecular mechanisms that regulate these distinct phagocytic states is unknown. Here we define a molecularly distinct microglial subset whose function is to engulf neurons in the developing brain. We transcriptomically identified a cluster of Type I interferon (IFN-I) responsive microglia that expanded 20-fold in the postnatal day 5 somatosensory cortex after partial whisker deprivation, a stressor that accelerates neural circuit remodeling. In situ, IFN-I responsive microglia were highly phagocytic and actively engulfed whole neurons. Conditional deletion of IFN-I signaling (Ifnar1fl/fl) in microglia but not neurons resulted in dysmorphic microglia with stalled phagocytosis and an accumulation of neurons with double strand DNA breaks, a marker of cell stress. Conversely, exogenous IFN-I was sufficient to drive neuronal engulfment by microglia and restrict the accumulation of damaged neurons. IFN-I deficient mice had excess excitatory neurons in the developing somatosensory cortex as well as tactile hypersensitivity to whisker stimulation. These data define a molecular mechanism through which microglia engulf neurons during a critical window of brain development. More broadly, they reveal key homeostatic roles of a canonical antiviral signaling pathway in brain development.

Quantifying virtual reality pain modulation in healthy volunteers: A randomized, crossover study.

STUDY OBJECTIVE: Virtual reality (VR) is an emerging tool to reduce pain and anxiety during procedures. Although VR's clinical benefits are reported, biometric data quantifying VR's effect on pain tolerance is lacking. We used time-lapse, subjective, and biometric data to evaluate VR's effect on modulating pain. DESIGN: Randomized, controlled crossover within-subject clinical trial. SETTING: This study was conducted in the Chariot Lab at Lucile Packard Children's Hospital and outdoors at Stanford University School of Medicine. PATIENTS: 156 healthy volunteers were included. INTERVENTIONS: Participants underwent pain-inducing ice immersions while connected to biometric sensors. Participants were randomized to immerse their dominant or non-dominant hand with VR or control (no VR) for one immersion, and then crossed-over to the other hand for the second immersion. We instructed participants to submerge their hand until they reached their pain tolerance or until four minutes elapsed. MEASUREMENTS: Outcomes included ice immersion duration, perceived pain scores, and skin conductance response density (SCRD), a marker of sympathetic arousal. We used survival analysis and mixed effects models to compare measurements with and without VR. MAIN RESULTS: 153 participants were included in the analysis. Participants with VR were 64% less likely to remove their hands from the ice bath throughout the immersion's duration compared to control (P < 0.001). Participants with VR reported significantly lower pain scores after controlling for dominant hand treatment assignment, VR vs. no VR treatment order, and gender (P < 0.001). SCRD increased as time progressed for both VR and control groups (P = 0.047 combined), with no significant mean group differences. CONCLUSIONS: Participants with VR were more likely to survive the 4-min ice bath challenge longer and with lower levels of pain perception, supporting VR's effectiveness as a distraction tool during painful procedures. We observed no differences in sympathetic response when comparing VR to no VR.

A guide to senolytic intervention in neurodegenerative disease.

Cellular senescence is a potential tumor-suppressive mechanism that generally results in an irreversible cell cycle arrest. Senescent cells accumulate with age and actively secrete soluble factors, collectively termed the 'senescence-associated secretory phenotype' (SASP), which has both beneficial and detrimental effects. Although the contribution of senescent cells to age-related pathologies has been well-established outside the brain, emerging evidence indicates that brain cells also undergo cellular senescence and contribute to neuronal loss in the context of age-related neurodegenerative diseases. Contribution of senescent cells in the pathogenesis of neurological disorders has led to the possibility of eliminating senescence cells via pharmacological compounds called senolytics. Recently several senolytics have been demonstrated to elicit improved cognitive performance and healthspan in mouse models of neurodegeneration. However, their translation for use in the clinic still holds several potential challenges. This review summarizes available senolytics, their purported mode of action, and possible off-target effects. We also discuss possible alternative strategies that may help minimize potential side-effects associated with the senolytics approach.

A Postoperative Care Bundle Reduces Surgical Site Infections in Pediatric Patients Undergoing Cardiac Surgeries.

BACKGROUND: Pediatric patients undergoing cardiac surgeries are at an increased surgical site infection (SSI) risk, given prolonged cardiopulmonary bypasses and delayed sternal closures. At one institution, the majority of cardiac patients developed SSIs during prolonged recoveries in the cardiovascular intensive care unit (CVICU). Although guidelines have been published to reduce SSIs in the perioperative period, there have been few guidelines to reduce the risk during prolonged hospital recoveries. The aim of this project was to study a postoperative SSI reduction care bundle, with a goal of reducing cardiac SSIs by 50%, from 3.4 to 1.7 per 100 procedures. METHODS: This project was conducted at a quaternary, pediatric academic center with a 20-bed CVICU. Historical control data were recorded from January 2013 through May 2015 and intervention/sustainment data from June 2015 through March 2017. A multidisciplinary SSI reduction team developed five key drivers that led to implementation of 11 postoperative SSI reduction care elements. Statistical process control charts were used to measure process compliance, and Pearson's chi-square test was used to determine differences in SSI rates. RESULTS: Prior to implementation, there were 27 SSIs in 799 pediatric cardiac surgeries (3.4 SSIs per 100 surgeries). After the intervention, SSIs significantly decreased to 5 in 570 procedures (0.9 SSIs per 100 surgeries; p = 0.0045). CONCLUSION: This project describes five key drivers and 11 elements that were dedicated to reducing the risk of SSI during prolonged CVICU recoveries from pediatric cardiac surgery, with demonstrated sustainability.