Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition.

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural beta-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

Identifying the Factors Influencing Patients' Telehealth Visit Satisfaction: Survey Validation Through a Structural Equation Modeling Approach.

Introduction: The COVID-19 pandemic accelerated the adoption of telehealth as an alternative to in-person hospital visits. To understand the factors impacting the quality of telehealth services, there is a need for validated survey instruments and conceptual frameworks. The objective of this study is to validate a telehealth patient satisfaction survey by structural equation modeling (SEM) and determine the relationship between the factors in the proposed telehealth patient satisfaction model (TPSM). Methods: We conducted a cross-sectional survey of pediatric patients and families receiving care from a comprehensive pediatric hospital in the Midwest between September 2020 and January 2021. In total, 2,039 usable responses were collected. We used an SEM approach by performing confirmatory factor analysis with Diagonally Weighted Least Squares modeling and Partial Least Squares-Path Modeling to establish the structural validity and examined the relationships among the constructs of "Admission Process" (AP), "Perceived Quality of Service" (PQS), and "Telehealth Satisfaction" (TS). Results: Participants were predominantly White (75%) and English-speaking (95%) parents (85%) of patients (mean age of patients was 10.2 years old). The survey responses were collected from patients visiting 43 department specialties, whereas 50% were behavioral and occupational therapy patients. The structural model showed that the admission process (AP) had a strong positive impact on perceived quality of service (PQS) (p = 0.67, t = 36.1, p < 0.001). The PQS had a strong positive impact on telehealth satisfaction (TS) (p = 0.66, t = 31.8, p < 0.001). The AP had a low positive direct impact on TS (p = 0.16, t = 7.46, p < 0.05). Overall, AP and PQS explained 61% variances (R2) of TS. Conclusions: We validated a newly proposed TS assessment model by using SEM. The TPSM will inform researchers to better understand the influencing factors in TS and help health care systems to improve telehealth patient satisfaction through a validated model.

Rapid Development of a Telehealth Patient Satisfaction Survey Using a Multi-Stakeholder Approach.

Introduction: The COVID-19 pandemic has hastened the adoption of telehealth and the drastic shift to an unfamiliar process may impose significant impact to the quality-of-care delivery. Many providers are interested in understanding the quality of their telehealth services from the patients' experience. Materials and Methods: A telehealth patient satisfaction survey (TPSS) was developed by using an iterative stakeholder-centered design approach, incorporating elements from validated telemedicine and customer service survey instruments, and meeting the operational needs and constraints. A cross-sectional study design was employed to collect survey responses from patients and families of a large pediatric hospital. Finally, we performed exploratory factor analysis (EFA) to extract latent constructs and factor loadings of the survey items to further explain relationships. Results: A 22-item TPSS closely matched the existing in-person patient satisfaction survey and mapped to a revised SERVPERF conceptual model that was proposed by the interdisciplinary committee. Survey was implemented in the HIPAA-compliant online platform REDCap® with survey link embedded in an automated Epic MyChart (Verona, WI) visit follow-up message. In total, 2,394 survey responses were collected between July 7, 2020, and September 2, 2020. EFA revealed three constructs (with factor loadings >0.30): admission process, perceived quality of services, and telehealth satisfaction. Conclusions: We reported the development of TPSS that met the operational needs of compatibility with existing data and possible comparison to in-person survey. The survey is short and yet covers both the clinical experience and telehealth usability, with acceptable survey validity.

Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1.

Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.

Associations of Telehealth Care Delivery with Pediatric Health Care Provider Well-Being.

BACKGROUND: The rapid, large-scale deployment of new health technologies can introduce challenges to clinicians who are already under stress. The novel coronavirus disease 19 (COVID-19) pandemic transformed health care in the United States to include a telehealth model of care delivery. Clarifying paths through which telehealth technology use is associated with change in provider well-being and interest in sustaining virtual care delivery can inform planning and optimization efforts. OBJECTIVE: This study aimed to characterize provider-reported changes in well-being and daily work associated with the pandemic-accelerated expansion of telehealth and assess the relationship of provider perceptions of telehealth effectiveness, efficiency, and work-life balance with desire for future telehealth. METHODS: A cross-sectional survey study was conducted October through November 2020, 6 months after the outbreak of COVID-19 at three children's hospitals. Factor analysis and structural equation modeling (SEM) were used to examine telehealth factors associated with reported change in well-being and desire for future telehealth. RESULTS: A total of 947 nontrainee physicians, advanced practice providers, and psychologists were surveyed. Of them, 502 (53.0%) providers responded and 467 (49.3%) met inclusion criteria of telehealth use during the study period. Of these, 325 (69.6%) were female, 301 (65.6%) were physicians, and 220 (47.1%) were medical subspecialists. Providers were 4.77 times as likely (95% confidence interval [CI]: 3.29-7.06) to report improved versus worsened well-being associated with telehealth. Also, 95.5% of providers (95% CI: 93.2-97.2%) wish to continue performing telehealth postpandemic. Our model explains 66% of the variance in telehealth-attributed provider well-being and 59% of the variance for future telehealth preference and suggests telehealth resources significantly influence provider-perceived telehealth care effectiveness which in turn significantly influences provider well-being and desire to perform telehealth. CONCLUSION: Telehealth has potential to promote provider well-being; telehealth-related changes in provider well-being are associated with both provider-perceived effectiveness of telemedicine for patients and adequacy of telehealth resources.

Glycosylation and S-palmitoylation regulate SARS-CoV-2 spike protein intracellular trafficking.

Post-translational modifications (PTMs), such as glycosylation and palmitoylation, are critical to protein folding, stability, intracellular trafficking, and function. Understanding regulation of PTMs of SARS-CoV-2 spike (S) protein could help the therapeutic drug design. Herein, the VSV vector was used to produce SARS-CoV-2 S pseudoviruses to examine the roles of the 611LYQD614 and cysteine-rich motifs in S protein maturation and virus infectivity. Our results show that 611LY612 mutation alters S protein intracellular trafficking and reduces cell surface expression level. It also changes S protein glycosylation pattern and decreases pseudovirus infectivity. The S protein contains four cysteine-rich clusters with clusters I and II as the main palmitoylation sites. Mutations of clusters I and II disrupt S protein trafficking from ER-to-Golgi, suppress pseudovirus production, and reduce spike-mediated membrane fusion activity. Taken together, glycosylation and palmitoylation orchestrate the S protein maturation processing and are critical for S protein-mediated membrane fusion and infection.

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection.

An effective COVID-19 vaccine against broad SARS-CoV-2 variants is still an unmet need. In the study, the vesicular stomatitis virus (VSV)-based vector was used to express the SARS-CoV-2 Spike protein to identify better vaccine designs. The replication-competent of the recombinant VSV-spike virus with C-terminal 19 amino acid truncation (SΔ19 Rep) was generated. A single dose of SΔ19 Rep intranasal vaccination is sufficient to induce protective immunity against SARS-CoV-2 infection in hamsters. All the clones isolated from the SΔ19 Rep virus contained R682G mutation located at the Furin cleavage site. An additional S813Y mutation close to the TMPRSS2 cleavage site was identified in some clones. The enzymatic processing of S protein was blocked by these mutations. The vaccination of the R682G-S813Y virus produced a high antibody response against S protein and a robust S protein-specific CD8+ T cell response. The vaccinated animals were protected from the lethal SARS-CoV-2 (delta variant) challenge. The S antigen with resistance to enzymatic processes by Furin and TMPRSS2 will provide better immunogenicity for vaccine design.

Feasibility and usability study of a pilot immersive virtual reality-based empathy training for dental providers.

PURPOSE: Social determinants of health (SDOH) significantly impact individuals' engagement with the healthcare system. To address SDOH-related oral health disparities, providers must be equipped with knowledge, skills, and attitudes (KSAs) to understand how SDOH affect patients and how to mitigate these effects. Traditional dental school curricula provide limited training on recognizing SDOH or developing empathy for those with SDOH-related access barriers. This study describes the design and evaluation of such a virtual reality (VR)-based simulation in dental training. We hypothesize the simulation will increase post-training KSAs. METHODS: We developed "MPATHI" (Making Professionals Able THrough Immersion), a scripted VR simulation where participants take the role of an English-speaking caregiver with limited socioeconomic resources seeking dental care for a child in a Spanish-speaking country. The simulation is a combination of 360° video recording and virtual scenes delivered via VR headsets. A pilot was conducted with 29 dental residents/faculty, utilizing a pre-post design to evaluate effectiveness in improving immediate and retention of KSAs toward care delivery for families facing barriers. RESULTS: MPATHI led to increased mean scores for cognitive (pre = 3.48 ± 0.80, post = 4.56 ± 0.51, p < 0.001), affective (pre = 4.20 ± 0.4, post = 4.47 ± 0.44, p < 0.001), and skill-based learning (pre = 4.00 ± 0.47, post = 4.52 ± 0.37, p < 0.001) immediately post-training. There was not a significant difference between skills measured immediately post-training and in the 1-month post-training survey (p = 0.41). Participants reported high satisfaction with the content and methods used in this training. CONCLUSIONS: This pilot study supports using VR SDOH training in dental education. VR technology provides new opportunities for innovative content design.

Virtual Reality-Based Executive Function Rehabilitation System for Children With Traumatic Brain Injury: Design and Usability Study.

BACKGROUND: Traumatic brain injury (TBI) poses a significant threat to children's health. Cognitive rehabilitation for pediatric TBI has the potential to improve the quality of life following the injury. Virtual reality (VR) can provide enriched cognitive training in a life-like but safe environment. However, existing VR applications for pediatric TBIs have primarily focused on physical rehabilitation. OBJECTIVE: This study aims to design and develop an integrative hardware and software VR system to provide rehabilitation of executive functions (EF) for children with TBI, particularly in 3 core EF: inhibitory control, working memory, and cognitive flexibility. METHODS: The VR training system was developed by an interdisciplinary team with expertise in best practices of VR design, developmental psychology, and pediatric TBI rehabilitation. Pilot usability testing of this novel system was conducted among 10 healthy children and 4 children with TBIs. RESULTS: Our VR-based interactive cognitive training system was developed to provide assistive training on core EF following pediatric TBI. Pilot usability testing showed adequate user satisfaction ratings for both the hardware and software components of the VR system. CONCLUSIONS: This project designed and tested a novel VR-based system for executive function rehabilitation that is specifically adapted to children following TBI.

Activity-dependent volume transmission by transgene NPY attenuates glutamate release and LTP in the subiculum.

Neuropeptide Y (NPY) gene transduction of the brain using viral vectors in epileptogenic regions can effectively suppress seizures in animals, and is being considered as a promising alternative treatment strategy for epilepsy. Therefore, it is fundamental to understand the detailed mechanisms governing the release and action of transgene NPY in neuronal circuitries. Using whole-cell recordings from subicular neurons, we show that in animals transduced by recombinant adeno-associated viral (rAAV) vector carrying the NPY gene, transgene NPY is released during high-frequency activation of CA1-subicular synapses. Released transgene NPY attenuates excitatory synaptic transmission not only in activated, but also in neighboring, non-activated synapses. Such broad action of transgene NPY may prevent recruitment of excitatory synapses in epileptic activity and could play a key role in limiting the spread and generalization of seizures.