Quantitative diffusion imaging and genotype-by-sex interactions in a rat model of Alexander disease.

PURPOSE: The clinical diagnosis and classification of Alexander disease (AxD) relies in part on qualitative neuroimaging biomarkers; however, these biomarkers fail to distinguish and discriminate different subtypes of AxD, especially in the presence of overlap in clinical symptoms. To address this gap in knowledge, we applied neurite orientation dispersion and density imaging (NODDI) to an innovative CRISPR-Cas9 rat genetic model of AxD to gain quantitative insights into the neural substrates and brain microstructural changes seen in AxD and to potentially identify novel quantitative NODDI biomarkers of AxD. METHODS: Multi-shell DWI of age- and sex-matched AxD and wild-type Sprague Dawley rats (n = 6 per sex per genotype) was performed and DTI and NODDI measures calculated. A 3 × 2 × 2 analysis of variance model was used to determine the effect of genotype, biological sex, and laterality on quantitative measures of DTI and NODDI across regions of interest implicated in AxD. RESULTS: There is a significant effect of genotype in the amygdala, hippocampus, neocortex, and thalamus in measures of both DTI and NODDI brain microstructure. A genotype by biological sex interaction was identified in DTI and NODDI measures in the corpus callosum, hippocampus, and neocortex. CONCLUSION: We present the first application of NODDI to the study of AxD using a rat genetic model of AxD. Our analysis identifies alterations in NODDI and DTI measures to large white matter tracts and subcortical gray nuclei. We further identified genotype by sex interactions, suggesting a possible role for biological sex in the neuropathogenesis of AxD.

Anastasis Drives Senescence and Non-Cell Autonomous Neurodegeneration in the Astrogliopathy Alexander Disease.

Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues are not clearly understood. Using Drosophila, rat and human cells and tissues, including analyses of both males and females, we present evidence that glia undergoing anastasis in the primary astrogliopathy Alexander disease subsequently express hallmarks of senescence. These senescent glia promote non-cell autonomous death of neurons by secreting interleukin family cytokines. Our findings demonstrate that anastasis can be dysfunctional in neurologic disease by inducing a toxic senescent population of astroglia.SIGNIFICANCE STATEMENT Under some conditions cells otherwise destined to die can be rescued just before death in a process called anastasis, or "rising from the dead." The fate and function of cells undergoing a near death experience is not well understood. Here, we find that in models and patient cells from Alexander disease, an important brain disorder in which glial cells promote neuronal dysfunction and death, anastasis of astrocytic glia leads to secretion of toxic signaling molecules and neurodegeneration. These studies demonstrate a previously unexpected deleterious consequence of rescuing cells on the brink of death and suggest therapeutic strategies for Alexander disease and related disorders of glia.

A social media microinfluencer intervention to reduce coronavirus disease 2019 vaccine hesitancy in underserved Tennessee communities: A protocol paper.

BACKGROUND: Central to effective public health policy and practice is the trust between the population served and the governmental body leading health efforts, but that trust has eroded in the years preceding the pandemic. Vaccine hesitancy among adults is also a growing concern across the United States. Recent data suggest that the trustworthiness of information about the coronavirus 2019 (COVID-19) vaccine was a larger concern than the vaccine's adverse effects or risks. OBJECTIVE: This study aims to describe the methods used to create a public health microinfluencer social media vaccine confidence campaign for the COVID-19 vaccine in underserved Tennessee communities. A secondary objective is to describe how the Social-Ecological Model (SEM) and Social Cognitive Theory may address vaccine hesitancy using community pharmacies. METHODS: In late 2020, 50 independent community pharmacies in underserved communities across Tennessee were involved in a public health project with the State of Tennessee Department of Health and the University of Tennessee Health Science Center College of Pharmacy. The project involved a 3-pronged, pharmacy-based COVID-19 vaccination outreach project, including (1) social media messaging (i.e., microinfluencer approach), (2) community partner collaboration, and (3) in-pharmacy promotion. Quantitative and qualitative data will assess the quality and effectiveness of the program. Social media outcomes will also be assessed to measure the impact of the microinfluencer social media training. RESULTS: Project implementation is planned for 6 months (January 2021 to June 2021) after an initial month of planning by the research team (December 2020) and preceding several months of assessment (July 2021 and beyond). CONCLUSIONS: Novel, theory-based approaches will be necessary to improve vaccine confidence. One approach to promoting public health, derived from the SEM, may be to use trusted microinfluencers on social media platforms, such as local community pharmacists and community leaders.

Pexidartinib treatment in Alexander disease model mice reduces macrophage numbers and increases glial fibrillary acidic protein levels, yet has minimal impact on other disease phenotypes.

BACKGROUND: Alexander disease (AxD) is a rare neurodegenerative disorder that is caused by dominant mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament that is primarily expressed by astrocytes. In AxD, mutant GFAP in combination with increased GFAP expression result in astrocyte dysfunction and the accumulation of Rosenthal fibers. A neuroinflammatory environment consisting primarily of macrophage lineage cells has been observed in AxD patients and mouse models. METHODS: To examine if macrophage lineage cells could serve as a therapeutic target in AxD, GFAP knock-in mutant AxD model mice were treated with a colony-stimulating factor 1 receptor (CSF1R) inhibitor, pexidartinib. The effects of pexidartinib treatment on disease phenotypes were assessed. RESULTS: In AxD model mice, pexidartinib administration depleted macrophages in the CNS and caused elevation of GFAP transcript and protein levels with minimal impacts on other phenotypes including body weight, stress response activation, chemokine/cytokine expression, and T cell infiltration. CONCLUSIONS: Together, these results highlight the complicated role that macrophages can play in neurological diseases and do not support the use of pexidartinib as a therapy for AxD.

Facilitating pneumococcal vaccination among high-risk adults: Impact of an assertive communication training program for community pharmacists.

BACKGROUND: Community pharmacies are vital access points to provide a range of vaccines to adults, including pneumococcal vaccines; however, despite a growth in the number of vaccines given at these sites, the most recent rates of adults being immunized against pneumococcal disease remain below the goals set by Health People 2020. Low patient awareness is a leading reason for suboptimal vaccination rates, suggesting that a need exists to improve provider communication in recommending pneumococcal vaccination in high-risk adults. OBJECTIVES: To evaluate the impact of a communication training program to improve pharmacist promotion of the pneumococcal vaccine among high-risk adults in Tennessee. METHODS: A multiphase training program was initiated in partnership with 2 regions of a nationwide community pharmacy chain (n = 100) focusing on improving evidence-based, presumptive recommendations related to pneumococcal vaccination. All locations were randomized to one of 3 arms on the basis of training intensity: (1) no training; (2) online training only; and (3) online and in-person simulation training. The program focused on improving evidence-based, pharmacist vaccine recommendations using health behavior theories, sales techniques, and improvisation provided through online and in-person simulation training. Changes in vaccinations (compared with the same 6-month period in the previous year) and provider self-efficacy were evaluated by Mann-Whitney U tests, chi-square tests, and general linear models. RESULTS: Completing the full training program led to nominal changes in pharmacist self-efficacy across the 6 items measured (P > 0.05). Overall counts of all pneumococcal vaccines were lower (-11.3%) across all stores in the period after training; however, a small increase (2.1%) was observed in the stores that underwent the full training, versus changes of -22.0% (P = 0.084) and -9.4% (P = 0.199) in control and online-only training comparisons, respectively. CONCLUSIONS: Pharmacists' vaccine-related self-efficacy may be improved through an evidence-based communication training program, but a more holistic focus on all recommended adult vaccines may be necessary to realize meaningful improvements.

Comparison of Clinical Outcomes and Medication Use of Obese Versus Nonobese Children Admitted to the Pediatric Intensive Care Unit.

Background: Few studies have compared clinical outcomes and medication use between obese and nonobese children in the pediatric intensive care unit (PICU). Objectives: The primary objective was to compare clinical outcomes including mortality, PICU length of stay (LOS), and mechanical ventilation (MV) requirement between obese and nonobese children. Secondary objectives included analysis of factors associated with these outcomes and medication use between groups. Methods: This retrospective study included children 2 to 17 years old admitted to the PICU over a 1-year time frame. Patients were categorized as obese, body mass index (BMI) ≥ 95th percentile, and nonobese (BMI < 95th percentile). Three binary regression models assessed the impact of obesity on clinical outcomes. Results: There were 834 admissions, with 22.1% involving obese children. There was no difference in mortality, MV requirement, or PICU LOS between groups. There were no associations with obesity and clinical outcomes found, but an association was noted for medication classes and receipt of continuous infusions on clinical outcomes. There was no difference noted in the median number (interquartile range [IQR]) of medications between obese and nonobese children, 8 (6-13) versus 9 (6-15), P = .38, but there was a difference in patients receiving a continuous infusion between obese and nonobese children, 24.4% versus 8.8%, P < .01. The 15 most used medications in both groups included analgesics, antimicrobials, corticosteroids, bronchodilators, and gastrointestinal agents. Conclusions: One-fifth of all admissions included obese children. Obesity was not associated with mortality, PICU LOS, and MV requirement, but the number of medication classes and continuous infusions were associated with these outcomes.

Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform.

Alexander disease results from gain-of-function mutations in the gene encoding glial fibrillary acidic protein (GFAP). At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. We describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre-messenger RNA (mRNA) and result in the upregulation of a previously uncharacterized GFAP lambda isoform (NM_001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM_001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini-gene splicing reporter assay, we demonstrate both variants result in the upregulation of the lambda isoform. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease.

Exploring the early phase of implementation of a vaccine-based clinical decision support system in the community pharmacy.

OBJECTIVE: To explore the implementation strategy of a recombinant zoster vaccine (RZV) clinical decision support (CDS) intervention in community pharmacy workflow to increase second-dose vaccination rates. SETTING: The level of analysis was the unit (e.g., pharmacy). The participants were selected from across approximately 2200 pharmacies in 37 states on the basis of criteria believed to affect implementation success (e.g., size, location) using a sampling matrix. PRACTICE DESCRIPTION: Large supermarket pharmacy chain. PRACTICE INNOVATION: Vaccine-based CDS intervention in community pharmacy workflow. EVALUATION: A mixed-methods contextual inquiry approach explored the implementation of a new RZV CDS workflow intervention. Data collection involved key informant, semistructured interviews and an electronic, Web-based survey. The survey was based on a validated instrument and was made available to all pharmacists nationwide within the study organization to assess views of the implementation's appropriateness, acceptability, and feasibility during early implementation. Afterward, a series of semistructured, in-depth interviews were conducted until a point of saturation was reached. The interview guide was based on selected constructs of the Consolidated Framework for Implementation Research. RESULTS: A total of 1128 survey responses were collected. Survey respondents agreed or strongly agreed that the implementation was acceptable (78.34%), appropriate (79.92%), and feasible (80.53%). Twelve pharmacist participants were interviewed via telephone. Five themes emerged from the interviews, revealing facilitators and barriers that affected implementation of the intervention: intervention characteristics, outer setting, inner setting, characteristics of individuals, and process. CONCLUSION: The implementation of the RZV CDS "nudge" intervention was welcomed, suitable, and operable in the community pharmacy setting to meet the needs of the organization, employees, and patients. The contextual factors identified during the implementation process of this CDS intervention in a community pharmacy setting may be used in scaling this and future CDS interventions for public health initiatives aimed at pharmacists in this setting.

Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease.

OBJECTIVE: Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is overexpression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease. METHODS: In this study, we use GFAP mutant mouse models of Alexander disease to test the efficacy of antisense suppression and evaluate the effects on molecular and cellular phenotypes and non-cell-autonomous toxicity. Antisense oligonucleotides were designed to target the murine Gfap transcript, and screened using primary mouse cortical cultures. Lead oligonucleotides were then tested for their ability to reduce GFAP transcripts and protein, first in wild-type mice with normal levels of GFAP, and then in adult mutant mice with established pathology and elevated levels of GFAP. RESULTS: Nearly complete and long-lasting elimination of GFAP occurred in brain and spinal cord following single bolus intracerebroventricular injections, with a striking reversal of Rosenthal fibers and downstream markers of microglial and other stress-related responses. GFAP protein was also cleared from cerebrospinal fluid, demonstrating its potential utility as a biomarker in future clinical applications. Finally, treatment led to improved body condition and rescue of hippocampal neurogenesis. INTERPRETATION: These results demonstrate the efficacy of antisense suppression for an astrocyte target, and provide a compelling therapeutic approach for Alexander disease. Ann Neurol 2018;83:27-39.

An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease.

The role that glia play in neurological disease is poorly understood but increasingly acknowledged to be critical in a diverse group of disorders. Here we use a simple genetic model of Alexander disease, a progressive and severe human degenerative nervous system disease caused by a primary astroglial abnormality, to perform an in vivo screen of 1987 compounds, including many FDA-approved drugs and natural products. We identify four compounds capable of dose-dependent inhibition of nervous system toxicity. Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic cholinergic signaling in pathogenesis using additional pharmacologic reagents and genetic approaches. We further demonstrate that muscarinic cholinergic signaling works through downstream Gαq to control oxidative stress and death of neurons and glia. Importantly, we document increased muscarinic cholinergic receptor expression in Alexander disease model mice and in postmortem brain tissue from Alexander disease patients, and that blocking muscarinic receptors in Alexander disease model mice reduces oxidative stress, emphasizing the translational significance of our findings. We have therefore identified glial muscarinic signaling as a potential therapeutic target in Alexander disease, and possibly in other gliopathic disorders as well. SIGNIFICANCE STATEMENT: Despite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scale in vitro screens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles.

Prophylaxis and treatment recommendations for sinusoidal obstruction syndrome in adult and pediatric patients undergoing hematopoietic stem cell transplant: a review of the literature.

Sinusoidal obstruction syndrome, a complication occurring early after hematopoietic stem cell transplantation, is a concern for clinicians. There are no guidelines to direct clinicians on the optimal way to prevent and treat this disease. Newer data show that defibrotide is a promising drug both for prevention and treatment, although it is not yet FDA approved.

Deficits in adult neurogenesis, contextual fear conditioning, and spatial learning in a Gfap mutant mouse model of Alexander disease.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament of mature astrocytes in the mammalian CNS. Dominant gain of function mutations in GFAP lead to the fatal neurodegenerative disorder, Alexander disease (AxD), which is characterized by cytoplasmic protein aggregates known as Rosenthal fibers along with variable degrees of leukodystrophy and intellectual disability. The mechanisms by which mutant GFAP leads to these pleiotropic effects are unknown. In addition to astrocytes, GFAP is also expressed in other cell types, particularly neural stem cells that form the reservoir supporting adult neurogenesis in the hippocampal dentate gyrus and subventricular zone of the lateral ventricles. Here, we show that mouse models of AxD exhibit significant pathology in GFAP-positive radial glia-like cells in the dentate gyrus, and suffer from deficits in adult neurogenesis. In addition, they display impairments in contextual learning and spatial memory. This is the first demonstration of cognitive phenotypes in a model of primary astrocyte disease.

External validation of the medication taper complexity score for methadone tapers in children with opioid abstinence syndrome.

BACKGROUND: Methadone is commonly prescribed for children with opioid abstinence syndrome (OAS) as a taper schedule over several days to weeks. The Medication Taper Complexity Score (MTCS) was developed to evaluate outpatient methadone tapers. OBJECTIVE: To further validate the MTCS and determine if it is a reliable tool for clinicians to use to assess the complexity of methadone tapers for OAS. METHODS: An expert panel of pediatric clinical pharmacists was convened. Panel members were provided 9 methadone tapers (ie, "easy," "medium," and "difficult") to determine construct and face validity of the MTCS. The primary objective was to further establish reliability and construct/face validity of the MTCS. The secondary objective was to assess the reliability of the MTCS within and between tapers. Instrument reliability was assessed using a Pearson correlation coefficient; with 0.8 as the minimum acceptable coefficient. Construct (divergent) validity was assessed via a repeated-measures ANOVA analysis (Bonferroni post hoc analyses) of the mean scores provided by panel members. RESULTS: Six panel members were recruited from various geographical locations. Panel members had 18.3 ± 5.5 years of experience, with practice expertise in general pediatrics, hematology/oncology, and the pediatric and neonatal intensive care unit. The MTCS had a reliability coefficient of .9949. There was vivid discrimination between the easy, medium, and difficult tapers; P = .001. The panel recommended minor modifications to the MTCS. CONCLUSIONS: The MTCS was found to be a reliable and valid tool. Overall, the panel felt that the MTCS was easy to use and had potential applications in both practice and research.

Association of fentanyl with neurodevelopmental outcomes in very-low-birth-weight infants.

BACKGROUND: Opioids are commonly used in the neonatal intensive care unit (NICU). Negative neurodevelopmental effects in the short-term setting have been associated with opioids ; however, long-term studies have been limited. OBJECTIVE: The primary objective was to determine if there is a dose relationship between fentanyl and neurodevelopmental outcomes, as measured by Bayley Scales of Infant and Toddler Development (Bayley-III) composite scores for language, cognition, and motor skills. Secondary objectives included comparison of Bayley-III scores and neurodevelopmental impairment classification based on fentanyl exposure. METHODS: A retrospective evaluation of 147 very-low-birth-weight infants with Bayley-III scores obtained at a chronological age of 6 months to 2 years at clinic follow-up was conducted. Univariate and multivariable linear regression analyses were used to determine if there was a dose-related association between fentanyl and neurodevelopmental outcomes. To evaluate secondary outcomes, patients were divided based on cumulative fentanyl dose ("high-dose" versus "low/no-dose"). RESULTS: The univariate analysis found a statistically significant decrease in cognition (P = .034) and motor skills scores (P = .006). No association was found in the multi-variable regression between fentanyl cumulative dose and Bayley-III scores. There was a significant decrease in the motor skills score between the high-dose versus low/no-dose group, 94 ± 20 versus 102 ± 15, respectively (P = .026); however, no statistical differences were noted for language or cognition scores or neurological impairment classification. CONCLUSIONS: When controlling for other variables, the cumulative fentanyl dose did not correlate with neurodevelopmental outcomes. Further evaluation of benefits and risks of opioids in premature infants are needed.

Influenza vaccination by pharmacists in a health sciences center: A 3-year experience.

OBJECTIVE: To assess the design and implementation of influenza vaccination clinics across campus, assess participant satisfaction with the pharmacist-led clinics, and educate and increase visibility of the role of pharmacists as vaccinators. SETTING: University of Oklahoma Health Sciences Center (OUHSC), a comprehensive health sciences center. PRACTICE INNOVATION: The College of Pharmacy on the OUHSC campus developed and implemented a vaccination program to increase influenza vaccination of OUHSC employees. MAIN OUTCOME MEASURES: Number of employees receiving influenza vaccination, employee satisfaction with the pharmacist-led clinics, and employee awareness of the pharmacist's role in vaccination. RESULTS: Reported OUHSC employee influenza vaccination rates increased from approximately 35% before implementation of the pharmacy-based program to 54% in 2012 after implementation. The increase was attributed to maintaining no out-of-pocket costs for employees, offering various clinic locations, and using media resources to educate employees about influenza infection and vaccination. Employees reported high satisfaction with the influenza vaccination clinics and with receiving vaccinations from pharmacists and student pharmacists. In the first 2 years of the program, the percentage of surveyed employees "very familiar" with the pharmacist's role in vaccinations increased from 23% to 66%. CONCLUSION: A college of pharmacy on a large health sciences center developed and successfully implemented an influenza vaccination program, providing an accessible and convenient route for influenza prevention to employees, as well as enhanced the visibility of pharmacists as vaccination providers.

Views of the Pharmacists' Role in HPV Vaccinations: A Qualitative Study in Tennessee.

The Human Papillomavirus (HPV) is a frequently occurring sexually transmitted infection in adults and is associated with various cancers that can affect both males and females. Recently, the Advisory Committee on Immunization Practices (ACIP) expanded its recommendations for the HPV vaccine to include patients aged 27-45 years with shared clinical decision-making. A commonly reported obstacle to receiving the HPV vaccine among adults is a lack of healthcare provider recommendations. Considering the suboptimal HPV vaccine coverage figures and noting that the vast majority of hesitancy research has been conducted among children and adolescents, limited research is available on the adult perception of HPV vaccination in pharmacies. This study focuses on understanding adults' opinions and perceptions regarding the role of pharmacists in the uptake of the HPV vaccine and awareness of its availability in the pharmacy setting. METHODS: After receiving approval from the Institutional Review Board (IRB), the qualitative study was initiated using virtual focus groups (FGs). Concepts from the Transtheoretical Model, the Health Belief Model, and the Social Cognitive Theory guided the study design. The corpus of data was collected in 2021 and 2022 by two researchers, and a third party transcribed the FGs to avoid any biases. The data were analyzed using Braun and Clarke's Thematic Analysis. RESULTS: Out of 35 subjects that participated in six FGDs, most identified as female, with ages ranging from 18 to 45 years. The following four themes emerged: (1) HPV vaccine awareness; (2) stigmas leading to reduced education and vaccination rates; (3) education preferences; (4) follow-up in vaccination series reminders and preferences. CONCLUSION: Participants' views of the HPV vaccine and the ability to receive the vaccine in a pharmacy are influenced by a myriad of factors. Common factors include improved awareness, preferences for educational modalities, avoiding stigmas associated with HPV vaccination, combating gender-focused biases, and preferences for the location of vaccination. These barriers provide opportunities for pharmacists to promote and enhance vaccine uptake.

Large-scale gene expression changes in APP/PSEN1 and GFAP mutation models exhibit high congruence with Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with both genetic and non-genetic causes. Animal research models are available for a multitude of diseases and conditions affecting the central nervous system (CNS), and large-scale CNS gene expression data exist for many of these. Although there are several models specifically for AD, each recapitulates different aspects of the human disease. In this study we evaluate over 500 animal models to identify those with CNS gene expression patterns matching human AD datasets. Approaches included a hypergeometric based scoring system that rewards congruent gene expression patterns but penalizes discordant gene expression patterns. The top two models identified were APP/PS1 transgenic mice expressing mutant APP and PSEN1, and mice carrying a GFAP mutation that is causative of Alexander disease, a primary disorder of astrocytes in the CNS. The APP/PS1 and GFAP models both matched over 500 genes moving in the same direction as in human AD, and both had elevated GFAP expression and were highly congruent with one another. Also scoring highly were the 5XFAD model (with five mutations in APP and PSEN1) and mice carrying CK-p25, APP, and MAPT mutations. Animals with the APOE3 and 4 mutations combined with traumatic brain injury ranked highly. Bulbectomized rats scored high, suggesting anosmia could be causative of AD-like gene expression. Other matching models included the SOD1G93A strain and knockouts for SNORD116 (Prader-Willi mutation), GRID2, INSM1, XBP1, and CSTB. Many top models demonstrated increased expression of GFAP, and results were similar across multiple human AD datasets. Heatmap and Uniform Manifold Approximation Plot results were consistent with hypergeometric ranking. Finally, some gene manipulation models, including for TYROBP and ATG7, were identified with reversed AD patterns, suggesting possible neuroprotective effects. This study provides insight for the pathobiology of AD and the potential utility of available animal models.

A Narrative Review of Pain in Pediatric Oncology: The Opioid Option.

Opioid therapy is the mainstay for managing pain in pediatric oncology. This narrative review describes the current literature regarding opioids for pediatric cancer pain. The review explores the multifaceted landscape of opioid utilization in this population, including the role of opioids in certain clinical circumstances, modalities of opioid delivery, unique opioids, outpatient and at-home pain management strategies, and other key concepts such as breakthrough pain. This review highlights the importance of individualized dosing and multimodal approaches to enhance efficacy and minimize adverse effects. Drawing from a wide range of evidence, this review offers insights to optimize pediatric oncology pain management.

Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease.

Alexander disease is a fatal neurodegenerative disease caused by dominant mutations in glial fibrillary acidic protein (GFAP). The disease is characterized by protein inclusions called Rosenthal fibers within astrocyte cell bodies and processes, and an antioxidant response mediated by the transcription factor Nrf2. We sought to test whether further elevation of Nrf2 would be beneficial in a mouse model of Alexander disease. Forcing overexpression of Nrf2 in astrocytes of R236H GFAP mutant mice decreased GFAP protein in all brain regions examined (olfactory bulb, hippocampus, cerebral cortex, brainstem, cerebellum, and spinal cord) and decreased Rosenthal fibers in olfactory bulb, hippocampus, corpus callosum, and brainstem. Nrf2 overexpression also restored body weights of R236H mice to near wild-type levels. Nrf2 regulates several genes involved in homeostasis of the antioxidant molecule glutathione, and the neuroprotective effects of Nrf2 in other neurological disorders may reflect restoration of glutathione to normal levels. However, glutathione levels in R236H mice were not decreased. Nrf2 overexpression did not change glutathione levels or ratio of reduced to oxidized glutathione (indicative of oxidative stress) in olfactory bulb, where Nrf2 dramatically reduced GFAP. Depletion of glutathione through knock-out of the GCLM (glutamate-cysteine ligase modifier subunit) also did not affect GFAP levels or body weight of R236H mice. These data suggest that the beneficial effects of Nrf2 are not mediated through glutathione.