Indirect and direct cannabinoid agonists differentially affect mesolimbic dopamine release and related behaviors.

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase inhibition while also inhibiting transient receptor potential vanilloid Type 1 channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor Type 1 agonist arachidonoyl-2'-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with seven daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA decreased rearing and decreased phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference, then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a conditioned place preference or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct cannabinoid receptor Type 1 agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Primary anterior lumbar interbody fusion, with and without posterior instrumentation: a 1,377-patient cohort from a multicenter spine registry.

BACKGROUND CONTEXT: Lumbar interbody instrumentation techniques are common and effective surgical options for a variety of lumbar degenerative pathologies. Anterior lumbar interbody fusion (ALIF) has become a versatile and powerful means of decompression, stabilization, and reconstruction. As an anterior only technique, the integrity of the posterior muscle and ligaments remain intact. Adding posterior instrumentation to ALIF is common and may confer benefits in terms of higher fusion rate but could contribute to adjacent segment degeneration due to additional rigidity. Large clinical studies comparing stand-alone ALIF with and without posterior supplementary fixation (ALIF+PSF) are lacking. PURPOSE: To compare rates of operative nonunion and adjacent segment disease (ASD) in ALIF with or without posterior instrumentation. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Adult patients (≥18 years old) who underwent primary ALIF for lumbar degenerative pathology between levels L4 to S1 over a 12-year period. Exclusion criteria included trauma, cancer, infection, supplemental decompression, noncontiguous fusions, prior lumbar fusions, and other interbody devices. OUTCOME MEASURES: Reoperation for nonunion and ASD compared between ALIF only and ALIF+PSF. METHODS: Reoperations were modeled as time-to-events where the follow-up time was defined as the difference between the primary ALIF procedure and the date of the outcome of interest. Crude cumulative reoperation probabilities were reported at 5-years follow-up. Multivariable Cox proportional hazard regression was used to evaluate risk of operative nonunion and for ASD adjusting for patient characteristics. RESULTS: The study consisted of 1,377 cases; 307 ALIF only and 1070 ALIF+PSF. Mean follow-up time was 5.6 years. The 5-year crude nonunion incidence was 2.4% for ALIF only and 0.5% for ALIF+PSF; after adjustment for covariates, a lower operative nonunion risk was observed for ALIF+PSF (HR=0.22, 95% CI=0.06-0.76). Of the patients who are deemed potentially suitable for ALIF alone, one would need to add posterior instrumentation in 53 patients to prevent one case of operative nonunion at a 5-year follow-up (number needed to treat). Five-year operative ASD incidence was 4.3% for ALIF only and 6.2% for ALIF+PSF; with adjustments, no difference was observed between the cohorts (HR=0.96, 95% CI=0.54-1.71). CONCLUSIONS: While the addition of posterior instrumentation in ALIFs is associated with lower risk of operative nonunion compared with ALIF alone, operative nonunion is rare in both techniques (<5%). Accordingly, surgeons should evaluate the added risks associated with the addition of posterior instrumentation and reserve the supplemental posterior fixation for patients that might be at higher risk for operative nonunion. Rates of operative ASD were not statistically higher with the addition of posterior instrumentation suggesting concern regarding future risk of ASD perhaps should not play a role in considering supplemental posterior instrumentation in ALIF.

The Role of Atypical Chemokine Receptors in Neuroinflammation and Neurodegenerative Disorders.

Neuroinflammation is associated with several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Neuroinflammation provides protection in acute situations but results in significant damage to the nervous system if chronic. Overexpression of chemokines within the brain results in the recruitment and activation of glial and peripheral immune cells which can propagate a cascading inflammatory response, resulting in neurodegeneration and the onset of neurodegenerative disorders. Recent work has identified the role of atypical chemokine receptors (ACKRs) in neurodegenerative conditions. ACKRs are seven-transmembrane domain receptors that do not follow canonical G protein signaling, but regulate inflammatory responses by modulating chemokine abundance, location, and availability. This review summarizes what is known about the four ACKRs and three putative ACKRs within the brain, highlighting their known expression and discussing the current understanding of each ACKR in the context of neurodegeneration. The ability of ACKRs to alter levels of chemokines makes them an appealing therapeutic target for neurodegenerative conditions. However, further work is necessary to understand the expression of several ACKRs within the neuroimmune system and the effectiveness of targeted drug therapies in the prevention and treatment of neurodegenerative conditions.

Using Immersive Virtual Reality Distraction to Reduce Fear and Anxiety before Surgery.

Presurgical anxiety is very common and is often treated with sedatives. Minimizing or avoiding sedation reduces the risk of sedation-related adverse events. Reducing sedation can increase early cognitive recovery and reduce time to discharge after surgery. The current case study is the first to explore the use of interactive eye-tracked VR as a nonpharmacologic anxiolytic customized for physically immobilized presurgery patients. Method: A 44-year-old female patient presenting for gallbladder surgery participated. Using a within-subject repeated measures design (treatment order randomized), the participant received no VR during one portion of her preoperative wait and interactive eye-tracked virtual reality during an equivalent portion of time in the presurgery room. After each condition (no VR vs. VR), the participant provided subjective 0-10 ratings and state-trait short form Y anxiety measures of the amount of anxiety and fear she experienced during that condition. Results: As predicted, compared to treatment as usual (no VR), the patient reported having 67% lower presurgical anxiety during VR. She also experienced "strong fear" (8 out of 10) during no VR vs. "no fear" (0 out of 10) during VR. She reported a strong sense of presence during VR and zero nausea. She liked VR, she had fun during VR, and she recommended VR to future patients during pre-op. Interactive VR distraction with eye tracking was an effective nonpharmacologic technique for reducing anticipatory fear and anxiety prior to surgery. The results add to existing evidence that supports the use of VR in perioperative settings. VR technology has recently become affordable and more user friendly, increasing the potential for widespread dissemination into medical practice. Although case studies are scientifically inconclusive by nature, they help identify new directions for future larger, carefully controlled studies. VR sedation is a promising non-drug fear and anxiety management technique meriting further investigation.

A Reappraisal of the Utility of L-012 to Measure Superoxide from Biologically Relevant Sources.

The detection of superoxide anion (O2●-) in biological tissues remains challenging. Barriers to convenient and reproducible measurements include expensive equipment, custom probes, and the need for high sensitivity and specificity. The luminol derivative, L-012, has been used to measure O2●- since 1993 with mixed results and concerns over specificity. The goal of this study was to better define the conditions for use and their specificity. We found that L-012 coupled with depolymerized orthovanadate, a relatively impermeable tyrosine phosphatase inhibitor, yielded a highly sensitive approach to detect extracellular O2●-. In O2●- producing HEK-NOX5 cells, orthovanadate increased L-012 luminescence 100-fold. The combination of L-012 and orthovanadate was highly sensitive, stable, scalable, completely reversed by superoxide dismutase, and selective for O2●- generating NOXes versus NOX4, which produces H2O2. Moreover, there was no signal from cells transfected with NOS3 (NO●) and NOS2(ONOO-). To exclude the effects of altered tyrosine phosphorylation, O2●- was detected using non-enzymatic synthesis with phenazine methosulfate and via novel coupling of L-012 with niobium oxalate, which was less active in inducing tyrosine phosphorylation. Overall, our data shows that L-012 coupled with orthovanadate or other periodic group 5 salts yields a reliable, sensitive, and specific approach to measuring extracellular O2●- in biological systems.

Galectin-3 Mediates Vascular Dysfunction in Obesity by Regulating NADPH Oxidase 1.

BACKGROUND: Obesity is associated with increased risk of cardiovascular disease, but underlying mechanisms remain elusive. Metabolic dysfunction, especially hyperglycemia, is thought to be a major contributor, but how glucose impacts vascular function is unclear. GAL3 (galectin-3) is a sugar-binding lectin upregulated by hyperglycemia, but its role as a causative mechanism of cardiovascular disease remains poorly understood. Therefore, the objective of this study was to determine the role of GAL3 in regulating microvascular endothelial vasodilation in obesity. METHODS: GAL3 was measured and found to be markedly increased in the plasma of overweight and obese patients, as well as in the microvascular endothelium of diabetic patients. To investigate causative mechanisms in cardiovascular disease, mice deficient in GAL3 were bred with obese db/db mice to generate lean, lean GAL3 knockout, obese, and obese GAL3 knockout genotypes. Endothelial cell-specific GAL3 knockout mice with novel AAV-induced obesity recapitulated whole-body knockout studies to confirm cell specificity. RESULTS: Deletion of GAL3 did not alter body mass, adiposity, or plasma indices of glycemia and lipidemia, but levels of plasma reactive oxygen species as assessed by plasma thiobarbituric acid reactive substances were normalized in obese GAL3 knockout mice. Obese mice exhibited profound endothelial dysfunction and hypertension, both of which were rescued by GAL3 deletion. Isolated microvascular endothelial cells from obese mice had increased expression of NOX1 (nicotinamide adenine dinucleotide phosphate oxidase 1), which we have previously shown to contribute to increased oxidative stress and endothelial dysfunction, which was normalized in microvascular endothelium from mice lacking GAL3. Cell-specific deletion confirmed that endothelial GAL3 regulates obesity-induced NOX1 overexpression and subsequent microvascular function. Furthermore, improvement of metabolic syndrome by increasing muscle mass, improving insulin signaling, or treating with metformin decreased microvascular GAL3, and thereby NOX1, expression levels. CONCLUSIONS: Deletion of GAL3 normalizes microvascular endothelial function in obese db/db mice, likely through a NOX1-mediated mechanism. Pathological levels of GAL3, and in turn NOX1, are amenable to improvements in metabolic status, presenting a potential therapeutic target to ameliorate pathological cardiovascular consequences of obesity.

Desktop Virtual Reality Offers a Novel Approach to Minimize Pain and Anxiety during Burn Wound Cleaning/Debridement in Infants and Young Children: A Randomized Crossover Pilot Study.

Although most scald burn injuries involve children under six, because of the challenges of using head mounted displays with young children there is very little research exploring the use of VR in children under six. The current clinical pilot study measured the analgesic effectiveness of our new desktop VR system (with no VR helmet) in children under six during burn wound care (a within-subjects design with randomized treatment order). Between December 2021-April 2022, nine children with burn injuries (10 months to 5 years age, mean = 18 months) participated. The mean burn size was 10% Total Body Surface Area, range 2-22%. Using nurse's ratings, VR significantly reduced children's pain during burn wound care by 40% on the observational Faces, Legs, Activity, Crying, and Consolability (FLACC) pain scale. Specifically, non-parametric within-subject sign tests compared nurse's ratings of the young patients' pain during burn wound care using usual pain medications with no VR = 6.67, (SD = 2.45) vs. adjunctive Animal Rescue World VR (VR = 4.00, SD = 2.24, p < 0.01). The observational Procedure-Behavior Checklist (PBCL) nurse's scale measured a 34% reduction in anxiety with VR as compared to pharmacologic treatment alone (p < 0.005). Similarly, when using single graphic rating scales the patients' parents reported a significant 36% decrease in their child's pain during VR (p < 0.05), a 38% (p < 0.005) decrease in their child's anxiety during VR, and a significant increase in patients' joy during VR. It can be concluded that during burn wound care with no distraction (traditional pain medications), children under 6 years old experienced severe pain during a 10 min burn wound cleaning session. During burn wound care combining desktop virtual reality and traditional pain medications, the same pediatric patients experienced only mild pain during burn wound cleaning/debridement. VR significantly reduced the children's pain and anxiety during burn wound care.

Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube.

OBJECTIVE: To determine whether transcutaneous auricular vagus nerve stimulation (taVNS) paired with twice daily bottle feeding increases the volume of oral feeds and white matter neuroplasticity in term-age-equivalent infants failing oral feeds and determined to need a gastrostomy tube. STUDY DESIGN: In this prospective, open-label study, 21 infants received taVNS paired with 2 bottle feeds for 2 - 3 weeks (2x). We compared 1) increase oral feeding volumes with 2x taVNS and previously reported once daily taVNS (1x) to determine a dose response, 2) number of infants who attained full oral feeding volumes, and 3) diffusional kurtosis imaging and magnetic resonance spectroscopy before and after treatment by paired t tests. RESULTS: All 2x taVNS treated infants significantly increased their feeding volumes compared with 10 days before treatment. Over 50% of 2x taVNS infants achieved full oral feeds but in a shorter time than 1x cohort (median 7 days [2x], 12.5 days [1x], P < .05). Infants attaining full oral feeds showed greater increase in radial kurtosis in the right corticospinal tract at the cerebellar peduncle and external capsule. Notably, 75% of infants of diabetic mothers failed full oral feeds, and their glutathione concentrations in the basal ganglia, a measure of central nervous system oxidative stress, were significantly associated with feeding outcome. CONCLUSIONS: In infants with feeding difficulty, increasing the number of daily taVNS-paired feeding sessions to twice-daily significantly accelerates response time but not the overall response rate of treatment. taVNS was associated with white matter motor tract plasticity in infants able to attain full oral feeds. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04643808).

Galectin-3 Mediates Vascular Dysfunction in Obesity by Regulating NADPH Oxidase 1.

Rationale: Obesity increases the risk of cardiovascular disease (CVD) through mechanisms that remain incompletely defined. Metabolic dysfunction, especially hyperglycemia, is thought to be a major contributor but how glucose impacts vascular function is unclear. Galectin-3 (GAL3) is a sugar binding lectin upregulated by hyperglycemia but its role as a causative mechanism of CVD remains poorly understood. Objective: To determine the role of GAL3 in regulating microvascular endothelial vasodilation in obesity. Methods and Results: GAL3 was markedly increased in the plasma of overweight and obese patients, as well as in the microvascular endothelium of diabetic patients. To investigate a role for GAL3 in CVD, mice deficient in GAL3 were bred with obese db/db mice to generate lean, lean GAL3 knockout (KO), obese, and obese GAL3 KO genotypes. GAL3 KO did not alter body mass, adiposity, glycemia or lipidemia, but normalized elevated markers of reactive oxygen species (TBARS) in plasma. Obese mice exhibited profound endothelial dysfunction and hypertension, both of which were rescued by GAL3 deletion. Isolated microvascular endothelial cells (EC) from obese mice had increased NOX1 expression, which we have previously shown to contribute to increased oxidative stress and endothelial dysfunction, and NOX1 levels were normalized in EC from obese mice lacking GAL3. EC-specific GAL3 knockout mice made obese using a novel AAV-approach recapitulated whole-body knockout studies, confirming that endothelial GAL3 drives obesity-induced NOX1 overexpression and endothelial dysfunction. Improved metabolism through increased muscle mass, enhanced insulin signaling, or metformin treatment, decreased microvascular GAL3 and NOX1. GAL3 increased NOX1 promoter activity and this was dependent on GAL3 oligomerization. Conclusions: Deletion of GAL3 normalizes microvascular endothelial function in obese db/db mice, likely through a NOX1-mediated mechanism. Pathological levels of GAL3 and in turn, NOX1, are amenable to improvements in metabolic status, presenting a potential therapeutic target to ameliorate pathological cardiovascular consequences of obesity.

Adding tactile feedback increases avatar ownership and makes virtual reality more effective at reducing pain in a randomized crossover study.

Severe pain is a widespread health problem in need of novel treatment approaches. In the current study we used real water to give virtual objects (i.e., animated virtual water) more realistic physical properties (wet liquid qualities). Healthy volunteers aged 18-34 participated in a within-subject randomized study comparing participants' worst pain during brief thermal stimuli with (1) No Immersive Virtual Reality (VR), versus (2) during VR + no tactile feedback versus (3) VR + real water (with tactile feedback from co-located real objects). Tactile feedback significantly decreased pain intensity (VR analgesia, p < 0.01), compared to VR with no tactile feedback, and compared to No VR (baseline). Tactile feedback made the virtual water feel significantly more real, increased participant's sense of presence, and both VR conditions were distracting (significantly reduced accuracy on an attention demanding task). As a non-pharmacologic analgesic, mixed reality reduced pain by 35% in the current study, comparable to the analgesia from a moderate dose of hydromorphone in previous published experimental studies. Tactile feedback also significantly increased avatar embodiment, the participants illusion of ownership of the virtual hands, which has potential to improve the effectiveness of avatar therapy for chronic pain in future studies. Mixed reality should be tested as treatment in pain patients.

Impulsive choice in two different rat models of ADHD-Spontaneously hypertensive and Lphn3 knockout rats.

Introduction: Impulsivity is a symptom of attention-deficit/hyperactivity disorder (ADHD) and variants in the Lphn3 (Adgrl3) gene (OMIM 616417) have been linked to ADHD. This project utilized a delay-discounting (DD) task to examine the impact of Lphn3 deletion in rats on impulsive choice. "Positive control" measures were also collected in spontaneously hypertensive rats (SHRs), another animal model of ADHD. Methods: For Experiment I, rats were given the option to press one lever for a delayed reward of 3 food pellets or the other lever for an immediate reward of 1 pellet. Impulsive choice was measured as the tendency to discount the larger, delayed reward. We hypothesized that impulsive choice would be greater in the SHR and Lphn3 knockout (KO) rats relative to their control strains - Wistar-Kyoto (WKY) and Lphn3 wildtype (WT) rats, respectively. Results: The results did not completely support the hypothesis, as only the SHRs (but not the Lphn3 KO rats) demonstrated a decrease in the percent choice for the larger reward. Because subsequent trials did not begin until the end of the delay period regardless of which lever was selected, rats were required to wait for the next trial to start even if they picked the immediate lever. Experiment II examined whether the rate of reinforcement influenced impulsive choice by using a DD task that incorporated a 1 s inter-trial interval (ITI) immediately after delivery of either the immediate (1 pellet) or delayed (3 pellet) reinforcer. The results of Experiment II found no difference in the percent choice for the larger reward between Lphn3 KO and WT rats, demonstrating reinforcement rate did not influence impulsive choice in Lphn3 KO rats. Discussion: Overall, there were impulsivity differences among the ADHD models, as SHRs exhibited deficits in impulsive choice, while the Lphn3 KO rats did not.

The Emerging Role of Virtual Reality as an Adjunct to Procedural Sedation and Anesthesia: A Narrative Review.

Over the past 20 years, there has been a significant reduction in the incidence of adverse events associated with sedation outside of the operating room. Non-pharmacologic techniques are increasingly being used as peri-operative adjuncts to facilitate and promote anxiolysis, analgesia and sedation, and to reduce adverse events. This narrative review will briefly explore the emerging role of immersive reality in the peri-procedural care of surgical patients. Immersive virtual reality (VR) is intended to distract patients with the illusion of "being present" inside the computer-generated world, drawing attention away from their anxiety, pain, and discomfort. VR has been described for a variety of procedures that include colonoscopies, venipuncture, dental procedures, and burn wound care. As VR technology develops and the production costs decrease, the role and application of VR in clinical practice will expand. It is important for medical professionals to understand that VR is now available for prime-time use and to be aware of the growing body in the literature that supports VR.

Purine synthesis suppression reduces the development and progression of pulmonary hypertension in rodent models.

AIMS: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of pulmonary hypertension (PH). Proliferative cells utilize purine bases from the de novo purine synthesis (DNPS) pathways for nucleotide synthesis; however, it is unclear whether DNPS plays a critical role in VSMC proliferation during development of PH. The last two steps of DNPS are catalysed by the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC). This study investigated whether ATIC-driven DNPS affects the proliferation of pulmonary artery smooth muscle cells (PASMCs) and the development of PH. METHODS AND RESULTS: Metabolites of DNPS in proliferative PASMCs were measured by liquid chromatography-tandem mass spectrometry. ATIC expression was assessed in platelet-derived growth factor-treated PASMCs and in the lungs of PH rodents and patients with pulmonary arterial hypertension. Mice with global and VSMC-specific knockout of Atic were utilized to investigate the role of ATIC in both hypoxia- and lung interleukin-6/hypoxia-induced murine PH. ATIC-mediated DNPS at the mRNA, protein, and enzymatic activity levels were increased in platelet-derived growth factor-treated PASMCs or PASMCs from PH rodents and patients with pulmonary arterial hypertension. In cultured PASMCs, ATIC knockdown decreased DNPS and nucleic acid DNA/RNA synthesis, and reduced cell proliferation. Global or VSMC-specific knockout of Atic attenuated vascular remodelling and inhibited the development and progression of both hypoxia- and lung IL-6/hypoxia-induced PH in mice. CONCLUSION: Targeting ATIC-mediated DNPS compromises the availability of purine nucleotides for incorporation into DNA/RNA, reducing PASMC proliferation and pulmonary vascular remodelling and ameliorating the development and progression of PH.

Optimized rectification of fiber orientation density function with background threshold.

PURPOSE: To describe an optimized fiber orientation density function (fODF) rectification procedure that removes negative values and absorbs all features below a specified threshold into a constant background. THEORY AND METHODS: The fODF for a white matter imaging voxel describes the angular density of axons. Because of signal noise and Gibbs ringing, fODFs estimated with diffusion MRI may take on unphysical negative values in some directions and contain spurious peaks. In order to suppress such artifacts, an fODF rectification procedure is proposed that both eliminates all negative values and incorporates all features below a specified threshold, η, into a constant background while at the same time minimizing the mean square deviation from the original, unrectified fODF. Calculating this fODF is straightforward, and the directions and shapes of peaks not absorbed into the background are preserved. The rectification method is illustrated for an analytic fODF model and for experimental diffusion MRI data obtained in healthy human brain, with the original fODFs being obtained from fiber ball imaging. RESULTS: Examples of optimal rectified fODFs are given for three choices of the background threshold referred to as minimal rectification (η = 0), average-level rectification (η ≈ 0.08), and fractional-anisotropy-axonal-based rectification (η ≈ 0.1). As η is increased, artifacts and other small features are more strongly suppressed, but the major fODF peaks are largely unaffected for the range of η values illustrated by these three alternatives. CONCLUSION: Artifactual features of fODFs estimated with diffusion MRI can be effectively suppressed by applying the proposed optimized rectification procedure. Since it minimizes fODF distortion in the mean square sense, it may be useful in the study of how fODF fine structure is affected by aging and disease.

Postless Hip Distraction Systems Decrease the Amount of Traction Force Needed to Obtain Adequate Hip Distraction Versus a Conventional Post Hip Distractor.

PURPOSE: To directly compare hip distraction distance and traction force data for hip arthroscopy performed using a post-basedsystem versus a postless system. METHODS: Adult patients undergoing primary hip arthroscopy for femoroacetabular impingement were prospectively enrolled. Before March 26, 2019, arthroscopy was performed using a post-based system. After this date, the senior author converted to using a postless system. Intraoperative traction force and fluoroscopic distraction distance were measured to calculate hip stiffness coefficients at holding traction (k-hold) and maximal traction (k-max). We used multivariable regression analysis to determine whether postless arthroscopy was predictive of lower stiffness coefficients when controlling for other relevant patient-specific factors. RESULTS: Hip arthroscopy was performed with a post-based system in 105 patients and with a postless system in 51. Mean holding traction force (67.5 ± 14.0 kilograms-force [kgf] vs 55.8 ± 15.3 kgf) and mean maximum traction force (96.0 ± 16.6 kgf vs 69.9 ± 14.1 kgf) were significantly lower in the postless group. On multivariable analysis, postless traction was an independent predictor of decreased k-hold (ß = -31.4; 95% confidence interval, -61.2 to -1.6) and decreased k-max (ß = -90.4; 95% confidence interval, -127.8 to -53.1). Male sex, Beighton score of 0, and poor hamstring flexibility were also predictors of increased k-hold and k-max in the multivariable model. CONCLUSIONS: Postless traction systems decrease the amount of traction force required for adequate hip distraction for both maximal and holding traction forces when compared with post-based systems. Postless traction systems may help further reduce distraction-type neurologic injuries and pain after hip arthroscopy by lowering the traction force required to safely distract the hip. LEVEL OF EVIDENCE: Level III, prospective cohort-historical control comparative study.

A comparison of interactive immersive virtual reality and still nature pictures as distraction-based analgesia in burn wound care.

PURPOSE: Non-pharmacologic adjuncts to opioid analgesics for burn wound debridement enhance safety and cost effectiveness in care. The current study explored the feasibility of using a custom portable water-friendly immersive VR hardware during burn debridement in adults, and tested whether interactive VR would reduce pain more effectively than nature stimuli viewed in the same VR goggles. METHODS: Forty-eight patients with severe burn injuries (44 adults and 4 children) had their burn injuries debrided and dressed in a wet wound care environment on Study Day 1, and 13 also participated in Study Day 2. INTERVENTION: The study used a within-subject design to test two hypotheses (one hypothesis per study day) with the condition order randomized. On Study Day 1, each individual (n = 44 participants) spent 5 min of wound care in an interactive immersive VR environment designed for burn care, and 5 min looking at still nature photos and sounds of nature in the same VR goggles. On Study Day 2 (n = 12 adult participants and one adolescent from Day 1), each participant spent 5 min of burn wound care with no distraction and 5 min of wound care in VR, using a new water-friendly VR system. On both days, during a post-wound care assessment, participants rated and compared the pain they had experienced in each condition. OUTCOME MEASURES ON STUDY DAYS 1 AND 2: Worst pain during burn wound care was the primary dependent variable. Secondary measures were ratings of time spent thinking about pain during wound care, pain unpleasantness, and positive affect during wound care. RESULTS: On Study Day 1, no significant differences in worst pain ratings during wound care were found between the computer-generated world (Mean = 71.06, SD = 26.86) vs. Nature pictures conditions (Mean = 68.19, SD = 29.26; t < 1, NS). On secondary measures, positive affect (fun) was higher, and realism was lower during computer-generated VR. No significant differences in pain unpleasantness or "presence in VR" between the two conditions were found, however. VR VS. NO VR. (STUDY DAY 2): Participants reported significantly less worst pain when distracted with adjunctive computer generated VR than during standard wound care without distraction (Mean = 54.23, SD = 26.13 vs 63.85, SD = 31.50, t(11) = 1.91, p < .05, SD = 17.38). In addition, on Study Day 2, "time spent thinking about pain during wound care" was significantly less during the VR condition, and positive affect was significantly greater during VR, compared to the No VR condition. CONCLUSION: The current study is innovative in that it is the first to show the feasibility of using a custom portable water-friendly immersive VR hardware during burn debridement in adults. However, contrary to predictions, interactive VR did not reduce pain more effectively than nature stimuli viewed in the same VR goggles.

Fiber Ball White Matter Modeling Reveals Microstructural Alterations in Healthy Brain Aging.

Age-related white matter degeneration is characterized by myelin breakdown and neuronal fiber loss that preferentially occur in regions that myelinate later in development. Conventional diffusion MRI (dMRI) has demonstrated age-related increases in diffusivity but provide limited information regarding the tissue-specific changes driving these effects. A recently developed dMRI biophysical modeling technique, Fiber Ball White Matter (FBWM) modeling, offers enhanced biological interpretability by estimating microstructural properties specific to the intra-axonal and extra-axonal spaces. We used FBWM to illustrate the biological mechanisms underlying changes throughout white matter in healthy aging using data from 63 cognitively unimpaired adults ages 45-85 with no radiological evidence of neurodegeneration or incipient Alzheimer's disease. Conventional dMRI and FBWM metrics were computed for two late-myelinating (genu of the corpus callosum and association tracts) and two early-myelinating regions (splenium of the corpus callosum and projection tracts). We examined the associations between age and these metrics in each region and tested whether age was differentially associated with these metrics in late- vs. early-myelinating regions. We found that conventional metrics replicated patterns of age-related increases in diffusivity in late-myelinating regions. FBWM additionally revealed specific intra- and extra-axonal changes suggestive of myelin breakdown and preferential loss of smaller-diameter axons, yielding in vivo corroboration of findings from histopathological studies of aged brains. These results demonstrate that advanced biophysical modeling approaches, such as FBWM, offer novel information about the microstructure-specific alterations contributing to white matter changes in healthy aging. These tools hold promise as sensitive indicators of early pathological changes related to neurodegenerative disease.

Virtual Reality Animal Rescue World: Pediatric virtual reality analgesia during just noticeable pressure pain in children aged 2-10 years old (crossover design).

Background and aims: Excessive pain during medical procedures is a worldwide medical problem. Most scald burns occur in children under 6, who are often undermedicated. Adjunctive Virtual Reality (VR) distraction has been shown to reduce pain in children aged 6-17, but little is known about VR analgesia in young children. This study tests whether desktop VR (VR Animal Rescue World) can reduce the just noticeable pressure pain of children aged 2-10. Methods: A within-subject repeated measures design was used. With treatment order randomized, each healthy volunteer pediatric participant underwent brief cutaneous pressure stimuli under three conditions: (1) no distraction, (2) a verbal color naming task (no VR), and (3) a large TV-based desktop VR distraction. A hand-held Wagner pressure pain stimulation device was used to generate just noticeable pain sensations. Participants indicated when a steadily increasing non-painful pressure stimulus first turned into a painful pressure sensation (just noticeable pain). Results: A total of 40 healthy children participated (43% aged 2-5 years; and 57% aged 6-10 years). Compared to the no distraction condition, the 40 children showed significant VR analgesia (i.e., a significant reduction in pain sensitivity during the VR Animal Rescue World condition), t(39) = 9.83, p < 0.001, SD = 6.24. VR was also significantly more effective at reducing pain sensitivity vs. an auditory color naming task, t(39) = 5.42, p < 0.001, SD = 5.94. The subset of children aged 2-5 showed significant reductions in pain during VR. Children under 6 showed greater sensitivity to pain during no distraction than children aged 6-10. Conclusion: During no distraction, children under 6 years old were significantly more sensitive to pain than children aged 6-10. Virtual reality (VR) significantly reduced the "just noticeable" pressure pain sensitivity of children in both age groups.

Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.

Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.