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.

Awe Inducing Elements in Virtual Reality Applications: A Prospective Study of Hospitalized Children and Caregivers.

Background: Hospitalized pediatric patients and their caregivers often experience anxiety and fear, resulting in withdrawal and aggression. Despite virtual reality (VR) being a safe and effective anxiolytic, it is unknown what software design aspects contribute to its effectiveness. This prospective observational study evaluated which VR application elements increased awe, which is correlated with improved behavior and satisfaction. Methods: Patients aged 6 to 25 years and their caregivers at an academic pediatric hospital interacted with a custom VR application that compared design aspects, including environment, graphics fidelity, and presence of a motivational character. Outcomes investigated self-reported awe, vastness, accommodation, and engagement. Data were analyzed using repeated measure ANOVA tests and correlation analyses. Results: A total of 202 participants were enrolled, and 179 (88 pediatric patients, 91 adult caregivers) were included in the final analysis. A fictional environment was more effective at increasing awe in pediatric patients (P = 0.030) compared with a realistic environment. However, increased graphics fidelity was more effective at increasing awe in caregiver adults (P = 0.023) compared with low resolution graphics. Presence of a motivational character did not influence awe in either patients or caregivers (P = 0.432, P = 0.904, respectively). All measures of awe were positively correlated with application engagement (P < 0.005). Conclusion: In conclusion, when software developers design VR software for pediatric patients and their caregivers, fictional settings and increased graphic fidelity should be considered for pediatric patients and adults, respectively. Future studies will explore other VR elements in gameplay settings.

Elevating Lower Extremity Reconstruction: An Algorithmic Approach to Free Flap Re-Elevation.

BACKGROUND: Free flap (FF) reconstruction is frequently required for soft tissue coverage after significant orthopedic trauma of the lower extremity (LE). While usually the final step in limb salvage, re-elevation of the previously inset FF may be necessary to restore a functional limb. In this study, we present our algorithm for LE FF re-elevation and review our experience to identify factors associated with successful limb salvage and return to ambulation. METHODS: A retrospective, single-institution review was conducted of adult patients with LE wounds who required FF reconstruction from 2016-2021. From this cohort, patients that required re-elevation of their LE FF were identified. Successful FF re-elevation was defined by limb salvage and return to ambulation. RESULTS: During the study period, 412 patients with LE wounds required flap reconstruction. Of these patients, 205 (49.8%) underwent free tissue transfer, and 39 (9.5%) met our inclusion criteria. From this cohort, 34 had successful FF re-elevations, while 1 was non-weight bearing and 4 elected for amputation due to chronic complications unrelated to their FF. Univariate analysis revealed the total number of FF re-elevations (p < 0.001), the frequency of re-elevation indicated for orthopedic access (p < 0.001), and infections necessitating return to the operating room (p = 0.001) were each negatively associated with limb salvage and return to ambulation. CONCLUSION: The described algorithm highlights the preoperative planning and meticulous flap preservation necessary for the successful coverage of critical structures following FF re-elevation. Our data demonstrates that LE FFs can be safely re-elevated for hardware access or flap revision. In these complex cases of LE trauma, management by a multidisciplinary team is essential for successful limb salvage.

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.

Artificial Intelligence Methods for the Argenta Classification of Deformational Plagiocephaly to Predict Severity and Treatment Recommendation.

INTRODUCTION: Deformational plagiocephaly (DP) can be classified into 5 severity types using the Argenta scale (AS). Patients with type III or higher require referral to craniofacial surgery for management. Primary care pediatricians (PCPs) are often the first to encounter patients with DP, but current screening methods are subjective, increasing the risk of bias, especially for clinicians with little exposure to this population. The authors propose the use of artificial intelligence (AI) to classify patients with DP using the AS and to make recommendations for referral to craniofacial surgery. METHODS: Vertex photographs were obtained for patients diagnosed with unilateral DP from 2019 to 2020. Using the photographs, an AI program was created to characterize the head contour of these infants into 3 groups based on the AS. The program was trained using photographs from patients whose DP severity was confirmed clinically by craniofacial surgeons. To assess the accuracy of the software, the AS predicted by the program was compared with the clinical diagnosis. RESULTS: Nineteen patients were assessed by the AI software. All 3 patients with type I DP were correctly classified by the program (100%). In addition, 4 patients with type II were correctly identified (67%), and 7 were correctly classified as type III or greater (70%). CONCLUSIONS: Using vertex photographs and AI, the authors were able to objectively classify patients with DP based on the AS. If converted into a smartphone application, the program could be helpful to PCPs in remote or low-resource settings, allowing them to objectively determine which patients require referral to craniofacial surgery.

Correlation of Orthognathic Surgical Movements to Perception of Facial Appearance in Patients With Cleft Lip and Palate.

STUDY DESIGN: Cephalometric scans were compared before and after surgery to assess the degree of correction. Correlations between skeletal movements and survey outcomes were determined using multivariate regression analysis. OBJECTIVE: This study aims to identify relationships between subjective observer-reported improvements in esthetics and emotional appearance with specific surgical movements. METHODS: Ten patients at a single tertiary institution (average age: 18.1 ± 0.8), 9 males and 1 female, underwent orthognathic repair and had comprehensive cephalometric records. Standardized anterior posterior and lateral pre and postoperative photographs of patients were included in a survey to clinicians to assess noncognitive domains on a Likert Scale (1-10). CLEFT-Q was administered to gauge patient satisfaction in categories of appearance, speech, and quality of life. RESULTS: Per clinicians, multiple domains increased including facial attractiveness (4.1 ± 0.7 versus 7.3 ± 0.7, P < 0.001), friendliness (4.5 ± 0.4 versus 7.3 ± 0.5, P < 0.001), confidence (4.1 ± 0.4 versus 7.1 ± 0.4, P < 0.001), and recommendation for surgery decreased (8.9 ± 0.1 versus 3.6 ± 0.5, P < 0.001). Speech distress decreased with increased SNA and convexity, whereas Psychological and Social scores decreased with an increased ANB. Functional eating and drinking scores increased with maxillary depth. CONCLUSIONS: Orthognathic surgery improves many noncognitive domains in patients with cleft lip and palate as assessed by both patients and clinicians on all aspects of facial attractiveness and perception. These findings demonstrate objective bases of skeletal adjustments for perceived improvements in facial appearance and emotion.

Astrocyte CCN1 stabilizes neural circuits in the adult brain.

Neural circuits in many brain regions are refined by experience. Sensory circuits support higher plasticity at younger ages during critical periods - times of circuit refinement and maturation - and limit plasticity in adulthood for circuit stability. The mechanisms underlying these differing plasticity levels and how they serve to maintain and stabilize the properties of sensory circuits remain largely unclear. By combining a transcriptomic approach with ex vivo electrophysiology and in vivo imaging techniques, we identify that astrocytes release cellular communication network factor 1 (CCN1) to maintain synapse and circuit stability in the visual cortex. By overexpressing CCN1 in critical period astrocytes, we find that it promotes the maturation of inhibitory circuits and limits ocular dominance plasticity. Conversely, by knocking out astrocyte CCN1 in adults, binocular circuits are destabilized. These studies establish CCN1 as a novel astrocyte-secreted factor that stabilizes neuronal circuits. Moreover, they demonstrate that the composition and properties of sensory circuits require ongoing maintenance in adulthood, and that these maintenance cues are provided by astrocytes.

Science-informed Policy Making for Protecting People and the Environment from Radiation.

ABSTRACT: The process to arrive at the radiation protection practices of today to protect workers, patients, and the public, including sensitive populations, has been a long and deliberative one. This paper presents an overview of the US Environmental Protection Agency's (US EPA) responsibility in protecting human health and the environment from unnecessary exposure to radiation. The origins of this responsibility can be traced back to early efforts, a century ago, to protect workers from x rays and radium. The system of radiation protection we employ today is robust and informed by the latest scientific consensus. It has helped reduce or eliminate unnecessary exposures to workers, patients, and the public while enabling the safe and beneficial uses of radiation and radioactive material in diverse areas such as energy, medicine, research, and space exploration. Periodic reviews and analyses of research on health effects of radiation by scientific bodies such as the National Academy of Sciences, National Council on Radiation Protection and Measurements, United Nations Scientific Committee on the Effects of Atomic Radiation, and the International Commission on Radiological Protection continue to inform radiation protection practices while new scientific information is gathered. As a public health agency, US EPA is keenly interested in research findings that can better elucidate the effects of exposure to low doses and low dose rates of radiation as applicable to protection of diverse populations from various sources of exposure. Professional organizations such as the Health Physics Society can provide radiation protection practitioners with continuing education programs on the state of the science and describe the key underpinnings of the system of radiological protection. Such efforts will help equip and prepare radiation protection professionals to more effectively communicate radiation health information with their stakeholders.

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.

Perceived discrimination and multiple indicators of positive development among second-generation Chinese-American youth: The moderating role of ethnic identity.

BACKGROUND: The present study examined the associations among ethnic identity, perceived discrimination and multiple indicators of positive youth development (PYD; i.e., intrapersonal-oriented competence, interpersonal-oriented competence, confidence, caring, character, family connection, peer connection, school and community connection, positive attitudes towards diversity and cultural pride) that were specifically identified among second-generation Chinese-American youth. METHODS: Participants were 196 second-generation Chinese-American youth (N girl = 93; M age = 14.56, SD age = 1.75) primarily from the greater Boston area in MA, United States. Multivariate regression models were estimated to examine the associations between ethnic identity, perceived discrimination, and each potential indicator of PYD, as well as the moderating role of ethnic identity, controlling for key demographics. RESULTS: (1) Ethnic identity was positively related to all PYD indicators, ßs = .32 to .72, ps < .01; (2) perceived discrimination was negatively associated with all indicators of PYD (ßs = -.15 to -.32, ps < .05), except for interpersonal-oriented competence and caring; and (3) ethnic identity significantly moderated the relationship between perceived discrimination and family connection (ß = .23, p < .01). CONCLUSIONS: Findings indicate that whereas discrimination has potential negative effects on the positive development of second-generation Chinese-American youth, ethnic identity may be a key strength that should be considered in PYD promotion practices for these youth.

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.

Proposing a framework to quantify the potential impact of pharmacokinetic drug-drug interactions caused by a new drug candidate by using real world data about the target patient population.

Drug development teams must evaluate the risk/benefit profile of new drug candidates that perpetrate drug-drug interactions (DDIs). Real-world data (RWD) can inform this decision. The purpose of this study was to develop a predicted impact score for DDIs perpetrated by three hypothetical drug candidates via CYP3A, CYP2D6, or CYP2C9 in type 2 diabetes mellitus (T2DM), obesity, or migraine. Optum Market Clarity was analyzed to estimate use of CYP3A, CYP2D6, or CYP2C9 substrates classified in the University of Washington Drug Interaction Database as moderate sensitive, sensitive, narrow therapeutic index, or QT prolongation. Scoring was based on prevalence of exposure to victim substrates and characteristics (age, polypharmacy, duration of exposure, and number of prescribers) of those exposed. The study population of 14,163,271 adults included 1,579,054 with T2DM, 3,117,753 with obesity, and 410,436 with migraine. For T2DM, 71.3% used CYP3A substrates, 44.3% used CYP2D6 substrates, and 44.3% used CYP2C9 substrates. For obesity, 57.1% used CYP3A substrates, 34.6% used CYP2D6 substrates, and 31.0% used CYP2C9 substrates. For migraine, 64.1% used CYP3A substrates, 44.0% used CYP2D6 substrates, and 28.9% used CYP2C9 substrates. In our analyses, the predicted DDI impact scores were highest for DDIs involving CYP3A, followed by CYP2D6, and CYP2C9 substrates, and highest for T2DM, followed by migraine, and obesity. Insights from RWD can be used to estimate a predicted DDI impact score for pharmacokinetic DDIs perpetrated by new drug candidates currently in development. This score can inform the risk/benefit profile of new drug candidates in a target patient population.

A prospective, observational validation of HRAD±, a novel pediatric affect and cooperation scale.

STUDY OBJECTIVE: HRAD± was developed to quickly assess pediatric perioperative affect and cooperation. HRAD± represents: Happy, Relaxed, Anxious, Distressed, with a yes/no answer to cooperativity. The primary aim of this study was to investigate the clinical utility of HRAD± as an affect and cooperation assessment tool for inhalational mask induction. Secondary aims examined inter-rater reliability (IRR) of HRAD± and predictive validity of induction HRAD± with emergence delirium. DESIGN: This was a prospective observational investigation. SETTING: We conducted this investigation at Lucile Packard Children's Hospital Stanford, an academic, quaternary care children's hospital in Northern California. PATIENTS: A total of 197 patients were included in this investigation. Children 1-14 years of age, who underwent daytime procedures with inhalational induction of anesthesia and American Society of Anesthesiologists physical status I-III were eligible. INTERVENTIONS: During mask induction, two trained research assistants (RAs) independently scored the patient's affect and cooperation. After extubation, the same investigators observed the patient's emergence. MEASUREMENTS: RAs scored each mask induction using the following scales: HRAD±, modified Yale Preoperative Anxiety Scale (mYPAS), Observation Scale of Behavioral Distress (OSBD), and Induction Compliance Checklist (ICC). Correlations were calculated to HRAD±. IRR of HRAD± between the RAs as well as predictive validity of HRAD± to Pediatric Anesthesia Emergence Delirium (PAED), Watcha and Cravero scales were calculated. MAIN RESULTS: HRAD± scores strongly correlated with mYPAS (r = 0.840, p < 0.0001) with moderate correlation to OSBD (r = 0.685, p < 0.0001) and ICC (-0.663, p < 0.0001). IRR was moderate for the affect and cooperation portion of the HRAD± scale, respectively (κ = 0.595 [p < 0.0001], κ = 0.478 [p < 0.0001]). A weak correlation was observed with PAED (r = 0.134 [p = 0.0597]) vs HRAD±. No correlations were observed between Watcha (r = 0.013 [p = 0.8559]) and Cravero and HRAD± scales (r = 0.002 [p = 0.9767]). CONCLUSIONS: HRAD± is a clinically useful and simple scale for evaluating pediatric affect and cooperation during inhalational mask induction. Results demonstrate correlation with commonly utilized research assessment scales.

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.

Prehospital Pediatric Emergency Training Using Augmented Reality Simulation: A Prospective, Mixed Methods Study.

OBJECTIVE: Pediatric emergencies are high-stakes yet low-volume clinical encounters for emergency medical services (EMS) clinicians, necessitating innovative approaches to training. We sought to explore the acceptability, usability, and ergonomics of a novel augmented reality (AR) software for EMS crisis management training. METHODS: This was a prospective, mixed-methods study employing qualitative and quantitative analyses. We enrolled emergency medical technicians (EMTs) and paramedics at a municipal fire service in Northern California. We ran the Chariot Augmented Reality Medical simulation software (Stanford Chariot Program, Stanford University, Stanford, CA) on the ML1 headset (Magic Leap, Inc., Plantation, FL), which enabled participants to view an AR image of a patient overlaid with real-world training objects. Participants completed a simulation of a pediatric hypoglycemia-induced seizure and cardiac arrest. Participants subsequently engaged in structured focus group interviews assessing acceptability, which we coded and thematically analyzed. We evaluated the usability of the AR system and ergonomics of the ML1 headset using previously validated scales, and we analyzed findings with descriptive statistics. RESULTS: Twenty-two EMS clinicians participated. We categorized focus group interview statements into seven domains after an iterative thematic analysis: general appraisal, realism, learning efficacy, mixed reality feasibility, technology acceptance, software optimization, and alternate use cases. Participants valued the realism and the mixed reality functionality of the training simulation. They reported that AR could be effective for practicing pediatric clinical algorithms and task prioritization, building verbal communication skills, and promoting stress indoctrination. However, participants also noted challenges with integrating AR images with real-world objects, the learning curve required to adapt to the technology, and areas for software improvement. Participants favorably evaluated the ease of use of the technology and comfortability of wearing the hardware; however, most participants reported that they would need technical support. CONCLUSION: Participants positively evaluated the acceptability, usability, and ergonomics of an AR simulator for pediatric emergency management training, and participants identified current technological limitations and areas for improvement. AR simulation may serve as an effective training adjunct for prehospital clinicians.

Perioperative Regional Anesthesia Pain Outcomes in Children: A Retrospective Study of 3160 Regional Anesthetics in Routine Practice.

OBJECTIVE: Randomized controlled trials indicate regional anesthesia (RA) improves postoperative outcomes with reduced pain and opioid consumption. Therefore, we hypothesized children who received RA, regardless of technique, would have reduced pain/opioid use in routine practice. METHODS: Using a retrospective cohort, we assessed the association of RA with perioperative outcomes in everyday practice at our academic pediatric hospital. Patients 18 years or below undergoing orthopedic, urologic, or general surgeries with and without RA from May 2014 to September 2021 were categorized as single shot, catheter based, or no block. Outcomes included intraoperative opioid exposure and dose, preincision anesthesia time, postanesthesia care unit (PACU) opioid exposure and dose, PACU antiemetic/antipruritic administration, PACU/inpatient pain scores, PACU/inpatient lengths of stay, and cumulative opioid exposure. Regression models estimated the adjusted association of RA with outcomes, controlling for multiple variables. RESULTS: A total of 11,292 procedures with 3160 RAs were included. Compared with no-block group, single-shot and catheter-based blocks were associated with opioid-free intraoperative anesthesia and opioid-free PACU stays. Post-PACU (ie, while inpatient), single-shot blocks were not associated with improved pain scores or reduced opioid use. Catheter-based blocks were associated with reduced PACU and inpatient opioid use until 24 hours postop, no difference in opioid use from 24 to 36 hours, and a higher probability of use from 36 to 72 hours. RA was not associated with reduced cumulative opioid consumption. DISCUSSION: Despite adjustment for confounders, the association of RA with pediatric pain/opioid use outcomes was mixed. Further investigation is necessary to maximize the benefits of RA.

A Phase Ib First-In-Patient Study Assessing the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ponsegromab in Participants with Cancer and Cachexia.

PURPOSE: Cachexia is common in patients with advanced cancer and is associated with elevated serum growth differentiation factor 15 (GDF-15) concentrations. This first-in-patient (phase Ib), 24-week study assessed use of ponsegromab, a mAb against GDF-15, in adults with advanced cancer, cachexia, and elevated GDF-15 serum concentration. PATIENTS AND METHODS: Participants (n = 10) received open-label ponsegromab subcutaneous 200 mg every 3 weeks for 12 weeks in addition to standard-of-care anticancer treatment. Ponsegromab safety, tolerability, and pharmacokinetics were assessed in addition to serum GDF-15 concentrations and exploratory measures of efficacy. RESULTS: No treatment-related treatment-emergent adverse events, injection site reactions, or adverse trends in clinical laboratory tests, vital signs, or electrocardiogram parameters attributable to ponsegromab were identified. Median serum unbound GDF-15 concentration at baseline was 2.269 ng/mL. Following initiation of study treatment, median unbound GDF-15 concentrations were below the lower limit of quantification (0.0424 ng/mL) from day 1 (3 hours postdose) through week 15. Increases in body weight were observed at all time points during the treatment and follow-up periods. A least-squares mean (SE) increase of 4.63 (1.98) kg was observed at week 12, an increase of approximately 6.6% relative to baseline. Ponsegromab-mediated improvements in actigraphy-based assessments of physical activity and in quality of life, including appetite as assessed by Functional Assessment of Anorexia-Cachexia Therapy total and subscale scores, were also observed. CONCLUSIONS: Ponsegromab was well tolerated, suppressed serum GDF-15 concentrations, and demonstrated preliminary evidence of efficacy. These findings support the continued development of ponsegromab for the treatment of cachexia.

A Quality Improvement Project to Improve the Utilization of an Intraoperative Rapid Response System.

Introduction: Rapid response teams (RRTs) improve morbidity by reducing the incidence of cardiac arrests. Although providers commonly activate RRTs on acute care wards, they are infrequently used perioperatively. At our institution, two intraoperative calls for help exist: staff assists (SAs) and code blues (CBs). The SA functions analogously to an RRT, and the CB indicates cardiopulmonary arrest. Given the success of RRTs, this project aimed to increase the use of the SA system. Our primary goal was to increase the ratio of SA to CB alerts by 50% within 6 months. Methods: A quality improvement team led this project at an academic pediatric hospital in Northern California. The team analyzed the current state and identified an achievable goal. After developing key drivers, they implemented monthly simulations to teach providers the signs of clinical deterioration and to practice activating the SA system. In addition to measuring the ratio of SA to CB alerts, the team surveyed the etiologies of SA and measured process satisfaction. Results: Before the introduction of this initiative, the ratio of SA to CB alerts were 1:13.3. These improvements efforts led to an increase of SA to CB alerts to 1.5:1 (P = 0.0003). Twenty-three anesthesiologists provided etiologies for SA, reporting laryngospasm as the most common reason (30.4%). Nineteen nurses completed the SA survey and reported high satisfaction. Conclusion: This project successfully increased the utilization of a rapid response protocol in a pediatric perioperative setting using improvement methodologies and a simulation-based educational program.

Effect of digital monitoring and counselling on self-management ability in patients with rheumatoid arthritis: a randomised controlled trial.

OBJECTIVES: To assess a remote physiotherapist (PT) counselling intervention using self-monitoring tools for improving self-management ability, physical activity participation, and health outcomes in people with rheumatoid arthritis (RA). METHODS: Eligible participants were randomly assigned to receive group education, a Fitbit®, a self-monitoring app, and PT counselling phone calls (Immediate Group). The Delayed Group received a monthly e-newsletter until week 26, and then the intervention. The primary outcome was Patient Activation Measure (PAM-13). Participants were assessed at baseline, 27 weeks (the primary end point) and 53 weeks. Secondary outcomes included disease activity, pain, fatigue, depression, sitting/walking habits, daily physical activity time, and daily awake sedentary time. Generalized Linear Mixed-effect Models (GLMMs) were used to assess the effect of the intervention on the change of each outcome measure from the initiation to 27 weeks after the intervention. RESULTS: Analysis included 131 participants (91.6% women; 80.2% completed during the COVID-19 pandemic). The mean change of PAM-13 at 27 weeks was 4.6 (SD = 14.7) in the Immediate Group vs -1.6 (SD = 12.5) in the Delayed Group. The mean change in Delayed Group at 53 weeks (after the 26-week intervention) was 3.6 (SD = 14.6). Overall, the intervention improved PAM-13 at 27 weeks post-intervention from the GLMM analysis (adjusted coefficient: 5.3; 95% CI: 2.0, 8.7; p = <0.001). Favourable intervention effects were also found in disease activity, fatigue, depression, and self-reported walking habit. CONCLUSION: Remote counselling paired with self-monitoring tools improved self-management ability in people with RA. Findings of secondary outcomes indicate that the intervention had a positive effect on symptom management.

Population PK/PD modeling of low-density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti-PCSK9 monoclonal antibody.

We sought to characterize the population pharmacokinetic/pharmacodynamic (PK/PD) relationship of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody that binds to secreted human proprotein convertase subtilisin kexin type 9 (PCSK9), using data derived from 16 phase I, II, and III clinical studies (36,066 bococizumab observations, 46,790 low-density lipoprotein cholesterol [LDL-C] measurements, 3499 participants). A two-compartment disposition model with parallel linear and Michaelis-Menten elimination and an indirect response model was used to characterize the population PK and LDL-C response of bococizumab. Potential model parameters and covariate relationships were explored, and visual predictive checks were used for model assessment and validation. Key covariates included the effect of anti-drug antibodies (ADAs) on exposure through impact on clearance and bioavailability; impact of statins on bococizumab elimination (maximal rate of metabolism); and impact of statins, Asian race, and male sex on LDL-C efficacy (maximum effect). ADAs and neutralizing ADAs did not have additional effects on LDL-C beyond the influence on bococizumab exposure. In conclusion, the population PK/PD model adequately describes bococizumab concentration and LDL-C efficacy. The covariate effects are consistent with the presumed mechanism of action of PCSK9 inhibitors. With increasing availability of antibody-based therapeutics, improved understanding of the effect of ADAs and statins on bococizumab PK/PD adds to the literature and enhances our pharmacological understanding of how immunogenicity and concomitant medications may impact the PK/PD of biotherapeutics.