APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aß plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

Virtual Interprofessional Education: Team Collaboration in Discharge Planning Simulation.

PURPOSE OF STUDY: This study assessed the effectiveness of a virtual interprofessional education (IPE) discharge planning simulation, focusing on collaborative patient education, and recommendations for hospital discharge. PRIMARY PRACTICE SETTING: An acute care hospital. METHODOLOGY AND SAMPLE: The study utilized a virtual IPE discharge planning simulation for health care students from six different programs. The simulation involved prebriefing, icebreaker, team meeting, patient interaction, and debriefing. Assessment included pre- and post-IPE surveys that included the Interprofessional Education Collaborative (IPEC) Competency Self-Assessment Tool, and video analysis using the Modified McMaster-Ottawa Rating Scale. RESULTS: Student participants from diverse health care programs (n =143) included nursing (n = 20), occupational therapy (n = 21), physical therapy (n = 42), physician assistant (n = 38), respiratory therapy (n = 3), and social work (n = 19). All programs except respiratory therapy showed significant improvement in IPEC Competency scores post-IPE, with positive outcomes for understanding other professions' roles. Students' self-reported perceptions of team performance were rated highly in various categories. Video analysis demonstrated strong interrater reliability for team scores. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Effective hospital discharge planning is vital for cost reduction and patient care improvement. IPE emphasizes collaborative learning among health care students. Previous studies highlight positive outcomes from IPE discharge planning, including virtual formats. This virtual IPE discharge planning simulation significantly improved students' understanding and collaboration competencies, evident in increased IPEC scores across five professions.

The Impact of Nursing Education on Ventilator-Associated Pneumonia Prevention Bundle to Reduce Incidence of Infection: A Quality Improvement Project.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a health care-acquired infection that leads to poor patient outcomes, increased length of hospital stay, exhaustion of health care resources, and unnecessary increases in health care costs. OBJECTIVES: This project was designed to educate registered nurses on the importance of an evidence-based VAP prevention bundle that reduces the overall incidence of VAP infections. METHODS: Patients (N = 146) were enrolled in this quasi-experimental project that took place in a 14-bed neuro trauma surgical burn intensive care unit (ICU) at a level 1 trauma center. Data were collected from the chart review of patients admitted to the neuro trauma surgical burn ICU prior to and after nursing education intervention. The difference in VAP rate and enhanced nursing knowledge were the primary outcome measures. RESULTS: Data suggest improvement in several patient outcomes. Ventilator days were shortened from 17.45 days to 13.42 days (P = .085), and ICU length of stay decreased from 24.77 days to 17.62 days (P = .035). Patient laboratory data show improved white blood cell values (P < .001), less oxygen requirements (P < .001), and fewer patients meeting the diagnostic criteria for VAP (P = .073). DISCUSSION: Results suggest there were no statistically significant changes in the knowledge of registered nurses or oral care bundle compliance; however, improvements in patient data following the provider education suggest that continued education to nursing staff will have a positive impact on reducing hospital stay and significant costs associated with a VAP infection.

Use of Care Guides to Reduce Emergency Department Visits by High-Frequency Utilizers.

BACKGROUND: High-frequency utilizers are defined as patients who present 10 or more times to the emergency department in a rolling 12-month period. High-frequency utilizers contribute to emergency department overcrowding and misuse of resources, and reduce the efficiency of health care systems. Care guides have proven to be an effective tool in reducing high-frequency utilizers. OBJECTIVE: The objective of this quality improvement project was to determine if implementing a care guide for high-frequency utilizers to address the core needs of the patient and facilitate resources through case management consultation decreases the number of visits and the cost of unreimbursed care to the emergency department from high-frequency utilizers. METHODS: We implemented care guides for high-frequency utilizers in September 2014. Prior to initiating the care guides, we educated the physicians, nurses, case managers, and social workers in the emergency department. RESULTS: Following the implementation of the care guides, there was a steady decline in the number of high-frequency utilizers (338 in 2013-68 in 2021), the number of total emergency department visits by high-frequency utilizers (6025 in 2013-1033 in 2021), and unreimbursed care ($2,068,063 in 2013-$589,298 in 2021). CONCLUSION: The use of care guides was a successful strategy in reducing emergency department visits and the cost of unreimbursed care by high-frequency utilizers by providing them with the education and resources they require to receive health care services in appropriate settings.

APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings than others with Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, as well as a more aggressive clinical course and notably more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Even one APOE ε2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by APOE ε2, or if APOE ε2 has a protective, neuro-modulatory effect. Here, we demonstrate that brain exposure to APOE2 via a gene therapy approach which bathes the entire cortical mantle in the gene product after transduction of the ependyma, rapidly ameliorates established Aß plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE4. This result suggests a promising protective effect of exogenous APOE2, revealing a cell non-autonomous effect of the protein on microglial activation. We also show that plaque associated microglia in the brain of patients who inherit APOE2 similarly have less microglial reactivity to plaques. These data raise the potential that an APOE2 therapeutic could be effective in Alzheimer disease even in individuals born with the risk ε4 allele. One Sentence Summary: Introduction of ApoE2 using an AAV that transduces the ependymal cells of the ventricle causes a reduction in amyloid load and plaque associated synapse loss, and reduces neuroinflammation by modulating microglial responsiveness to plaques.

VWA3A-derived ependyma promoter drives increased therapeutic protein secretion into the CSF.

Recombinant adeno-associated viral vectors (rAAVs) are a promising strategy to treat neurodegenerative diseases because of their ability to infect non-dividing cells and confer long-term transgene expression. Despite an ever-growing library of capsid variants, widespread delivery of AAVs in the adult central nervous system remains a challenge. We have previously demonstrated successful distribution of secreted proteins by infection of the ependyma, a layer of post-mitotic epithelial cells lining the ventricles of the brain and central column of the spinal cord, and subsequent protein delivery via the cerebrospinal fluid (CSF). Here we define a functional ependyma promoter to enhance expression from this cell type. Using RNA sequencing on human autopsy samples, we identified disease- and age-independent ependyma gene signatures. Associated promoters were cloned and screened as libraries in mouse and rhesus macaque to reveal cross-species function of a human DNA-derived von Willebrand factor domain containing 3A (VWA3A) promoter. When tested in mice, our VWA3A promoter drove strong, ependyma-localized expression of eGFP and increased secreted ApoE protein levels in the CSF by 2-12× over the ubiquitous iCAG promoter.

Erratum: Haplotyping SNPs for allele-specific gene editing of the expanded huntingtin allele using long-read sequencing.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100146.].

Evaluating the Impact of a Multifaceted Distracted Driving Prevention Program.

OBJECTIVE: The aim of this study is to evaluate undergraduate college students' attitude changes toward distracted driving after participating in a multifaceted distracted driving prevention program. METHODS: This study used a quasi-experimental, pre- post-test design. Participants were undergraduate college students who were aged 18 or older and had a valid driver's license. The Questionnaire Assessing Distracted Driving was used to measure participants' attitudes and behaviors. All participants completed the entire Questionnaire Assessing Distracted Driving survey and then participated in the distracted driving prevention program that consisted of a 10-minute narrated recorded PowerPoint lecture followed by a distracted driving simulation. Descriptive statistics were calculated to describe the study sample. The Questionnaire Assessing Distracted Driving data were analyzed to ascertain any statistically significant changes in responses from pre- to postintervention. RESULTS: From pre- to post-test, there were statistically significant increases in the number of participants who reported they would tell friends to stop texting and driving if they were a passenger, refrain from texting while driving, and wait until reaching home before retrieving their cell phones from the floor of the vehicle. Participants perceived a greater threat from drivers talking on phones or texting/emailing from pre- to post-test. Moreover, attitudes toward talking on a handheld device, talking on a hands-free phone, and texting/emailing became more negative from pre- to post-test. CONCLUSION: The intervention helped promote negative attitudes toward distracted driving in a sample of college students immediately after participating in a distracted driving prevention program.

Evaluating the FRAIL Questionnaire as a Trigger for Palliative Care Consultation After Acute Stroke.

The American Heart Association and the American Stroke Association jointly released guidelines stating that all patients with a new diagnosis of stroke should receive palliative care consultation starting in the acute phase of care. The purpose of this project was to increase palliative care consultation rates for patients after an acute stroke by using a frailty score to trigger a palliative care consult. Provider education on palliative care and a 5-question fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) questionnaire was delivered by a presentation, handouts, and a follow-up email using previously developed content. Patients included adults admitted to the neuroscience critical care unit of a Midwestern comprehensive stroke center with an admission diagnosis of acute stroke (n = 120). The charge nurse completed the FRAIL questionnaire as a screening tool to trigger a palliative care consult. A survey was also distributed to providers (n = 54) to understand their knowledge, thoughts, and feelings toward palliative care. There was an increase in patients who received palliative care consultation from 14.9% to 21.7% after implementation of the FRAIL questionnaire. Also, providers felt better able to provide symptom management to patients after acute stroke. Further research is necessary to determine if the FRAIL survey is an adequate trigger for palliative care consultation.

Frailty Screening in Geriatric Trauma: A Pilot Feasibility Study.

BACKGROUND: Frailty in older adult trauma patients is associated with increased complications and worsened outcomes. Frailty screening can help guide care. Yet, trauma center assessment of frailty is relatively new, can be challenging to implement, and is not yet standard practice. OBJECTIVES: The purpose of this pilot feasibility study is to assess the impact of implementing frailty screening for older adult trauma patients and to evaluate the effect of frailty screening on palliative care consultation, inhospital complications, hospital length of stay, and discharge disposition. METHODS: We conducted a 3-month (July 2019 to September 2019) prospective observational pilot feasibility study of geriatric trauma patients 65 years and older presenting to a Level I trauma center. The Trauma-Specific Frailty Index score was completed within 24 hr of patient admission. Inferential statistics were used to assess the relationships. RESULTS: Fifty subjects were included. Between frail and nonfrail patient groups, there was no significant correlation between mean Trauma-Specific Frailty Index score and palliative care consultation, χ2(1,N=50) = 2.32, p = .149; inpatient complications, χ2(1,N=50) = 0.000, p = 1.000; hospital length of stay, t(48) = 0.95, p = .345; or discharge disposition (receiver operating characteristic curve, p = .337). There was a significant negative relationship between Trauma-Specific Frailty Index Scores and Injury Severity Scores, t(15) = 2.33, p = .035. CONCLUSION: This pilot study demonstrates that frailty screening can be implemented to help guide older adult trauma care but is not without challenges. Barriers to frailty screening should be addressed to ensure trauma team engagement. Additional research with a larger sample size is warranted to explore the benefits of frailty screening in guiding care.

Haplotyping SNPs for allele-specific gene editing of the expanded huntingtin allele using long-read sequencing.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG trinucleotide repeat expansions in exon-1 of huntingtin (HTT). Currently, there is no cure for HD, and the clinical care of individuals with HD is focused on symptom management. Previously, we showed allele-specific deletion of the expanded HTT allele (mHTT) using CRISPR-Cas9 by targeting nearby (<10 kb) SNPs that created or eliminated a protospacer adjacent motif (PAM) near exon-1. Here, we comprehensively analyzed all potential PAM sites within a 10.4-kb genomic region flanking exon-1 of HTT in 983 individuals with HD using a multiplex targeted long-read sequencing approach on the Oxford Nanopore platform. We developed computational tools (NanoBinner and NanoRepeat) to de-multiplex the data, detect repeats, and phase the reads on the expanded or the wild-type HTT allele. One SNP common to 30% of individuals with HD of European ancestry emerged through this analysis, which was confirmed as a strong candidate for allele-specific deletion of the mHTT in human HD cell lines. In addition, up to 57% HD individuals may be candidates for allele-specific editing through combinatorial SNP targeting. Cumulatively, we provide a haplotype map of the region surrounding exon-1 of HTT in individuals affected with HD. Our workflow can be applied to other repeat expansion diseases to facilitate the design of guide RNAs for allele-specific gene editing.

Implementation of an Evidence-Based Prenotification Process for Patients With Stroke to Improve Neurological Outcomes.

ABSTRACT: BACKGROUND: Endovascular mechanical thrombectomy can improve clinical outcomes in eligible patients with acute ischemic stroke (AIS), but its efficacy is time dependent. This quality improvement project aimed to examine whether a revised evidence-based neurological deficit algorithm initiated in the emergency department could reduce door-to-groin puncture time to less than 90 minutes and improve neurological outcomes in AIS patients who received mechanical thrombectomy. METHODS: Retrospective chart reviews occurred between September 2020 and April 2021, which included 25 patients. Clinical and time data were collected from AIS patients who were 18 years and older, presented for care with AIS symptoms, and deemed candidates for thrombectomy for a period of 6 months. A revised neurological deficit algorithm was initiated, and education was presented to appropriate staff. Postintervention chart reviews occurred from August 2021 to January 2022, which included 25 patients. RESULTS: Door-to-groin puncture time did not improve to less than 90 minutes; however, there was a slight improvement in time from 106 minutes in the preintervention to 98 minutes in the postintervention ( P = .534). Although the outcome measures were not clinically significant, there was a statistically significant decrease in response time to acute stroke call down ( P < .01). Door-to-computed tomography also improved, which was 14.42 minutes for the preintervention group and 5.25 minutes for the postintervention group ( P < .001). Finally, the mean National Institutes of Health Stroke Scale on discharge for the preintervention group was 11.92, and that of the postintervention group was 6.05 on discharge ( P < .01). CONCLUSIONS: Implementation of the revised neurological deficit algorithm did not decrease the door-to-groin puncture time to less than 90 minutes. After implementation of the revised neurologic deficit algorithm, there were single variable improvements in several benchmarks, and this is a starting point for future quality improvement projects.

Using Interprofessional Simulation with Telehealth to Enhance Teamwork and Communication in Home Care.

Interpersonal communication and teamwork are critical to patient safety. There is evidence supporting the effectiveness of formalized team training strategies such as simulation-based learning experiences to permit opportunities for deliberate practice and skill acquisition. However, there is a paucity of evidence examining the best method for delivery of simulation-based interprofessional education activities (Sim-IPE). The purpose of this project was to explore the effectiveness of using a Sim-IPE with a home-based patient assessment and intervention for students in undergraduate nursing, nurse practitioner, and physical therapy programs with the goal of enhancing interprofessional team communication and team performance. A mixed-methods, observational research design was used to evaluate teamwork and communication following virtual/web-based deliberate practice and a subsequent face-to-face Sim-IPE with telehealth. There were two distinct stages: (1) provision of interprofessional education elements of teamwork and communication via a virtual web-based platform to interprofessional student teams; (2) participation of all 29 student teams in a Sim-IPE activity using a standardized patient in a simulated home-based setting. Teams scored very high on an interprofessional communication and teamwork scale, and students strongly agreed that the prebriefing, scenario, and debriefing assisted in their learning. Students also valued exposure to telehealth and the ability to work with students from other health professions.

Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a (CAG) repeat expansion in the coding sequence of ATXN1. The primary mechanism of disease in SCA1 is toxic gain of function by polyglutamine-expanded mutant ATXN1 and is compounded by partial loss of wild-type function. Addressing both disease mechanisms, we have shown that virally expressed RNA interference targeting ATXN1 can both prevent and reverse disease phenotypes in SCA1 mice, and that overexpression of the ATXN1 homolog, ataxin 1-like (ATXN1L), improves disease readouts when delivered pre-symptomatically. Here, we combined these therapeutic approaches into two, dual component recombinant adeno-associated virus (rAAV) vectors and tested their ability to reverse disease in symptomatic SCA1 mice using behavior, pathological, and next-generation sequencing assays. Mice treated with vectors expressing human ATXN1L (hATXN1L) alone showed motor improvements and changes in gene expression that reflected increases in pro-development pathways. When hATN1L was combined with miS1, a previously validated microRNA targeting h ATXN1, there was added normalization of disease allele-induced changes in gene expression along with motor improvements. Our data show the additive nature of this two-component approach for a more effective SCA1 therapy.

Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain.

RNA interference (RNAi) for spinocerebellar ataxia type 1 can prevent and reverse behavioral deficits and neuropathological readouts in mouse models, with safety and benefit lasting over many months. The RNAi trigger, expressed from adeno-associated virus vectors (AAV.miS1), also corrected misregulated microRNAs (miRNA) such as miR150. Subsequently, we showed that the delivery method was scalable, and that AAV.miS1 was safe in short-term pilot nonhuman primate (NHP) studies. To advance the technology to patients, investigational new drug (IND)-enabling studies in NHPs were initiated. After AAV.miS1 delivery to deep cerebellar nuclei, we unexpectedly observed cerebellar toxicity. Both small-RNA-seq and studies using AAVs devoid of miRNAs showed that this was not a result of saturation of the endogenous miRNA processing machinery. RNA-seq together with sequencing of the AAV product showed that, despite limited amounts of cross-packaged material, there was substantial inverted terminal repeat (ITR) promoter activity that correlated with neuropathologies. ITR promoter activity was reduced by altering the miS1 expression context. The surprising contrast between our rodent and NHP findings highlight the need for extended safety studies in multiple species when assessing new therapeutics for human application.

Responding to COVID-19: Developing a Virtual "On-Campus" Experience for Adult-Geriatric Acute Care Nurse Practitioner Students.

BACKGROUND: The coronavirus disease 2019 pandemic prevented in-person activities at colleges and universities in the spring/summer 2020 semester. Therefore, adult-geriatric acute care nurse practitioner students were unable to have on-campus clinical experiences. METHOD: An innovative virtual experience was developed, using synchronous platforms for lectures and a virtual patient (VP) encounter. RESULTS: Eight students participated in the experience, composed of three interactive lectures and a VP encounter. Students spent an average of 24.88 minutes (range = 20.88 to 35.48) with the VP, followed by debriefing. Students who became frustrated with the technology were identified as those who did not perform the practice session within the virtual platform. CONCLUSION: Faculty determined that the virtual experience was a success. They were able to evaluate students' critical thinking and clinical decision-making. Next steps include refinement of the avatar platform as well as forcing completion of a practice session prior to the actual synchronous graded activity. [J Nurs Educ. 2021;60(10):586-589.].

Use of a Structured Approach to Develop Best Practices in Interprofessional Education.

BACKGROUND: Providing interprofessional education (IPE) is mandated by accrediting agencies for health professions education; however, pedagogical, logistical, and financial challenges exist in implementing and sustaining high-quality IPE. After executing several IPE activities, an IPE team developed a structured approach for organizing, sustaining, and ensuring high-quality IPE. This article introduces the Design-Implement-Assess-Modify (DIAM) Model. A portfolio spreadsheet was developed and includes components from each of the DIAM phases. METHOD: The team documented characteristics from five IPE activities conducted annually for 5 years and tracked progress. RESULTS: The DIAM approach has allowed the team to develop a detailed and living portfolio to design, implement, assess, and modify several IPE activities across different professions. CONCLUSION: This approach has led to the intentional planning and development of multiple IPE activities that include the integration of standards of best practice and accreditation, while preparing practitioners for collaborative practice. [J Nurs Educ. 2021;60(6):309-316.].

Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain.

Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 µL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.

Report and Prevent: A Quality Improvement Project to Protect Nurses From Violence in the Emergency Department.

INTRODUCTION: Most nurses experience some form of workplace violence resulting in a stressful work environment, employee injury, and turnover. The aims of this project were to develop and evaluate strategies to improve the reporting of workplace violence as well as to empower emergency nurses to prevent assaults and protect themselves. METHODS: This quality improvement project had 2 phases. The phase I educational intervention focused on the importance of reporting workplace violence. Pre- and postintervention surveys measured experiences with workplace violence and reporting. The phase II educational intervention focused on de-escalation and self-protection strategies, training, safety, confidence, and emergency nurses' preparedness to defend themselves. Responses were analyzed using Wilcoxon signed-rank and McNemar tests. RESULTS: Twenty-five emergency nurses participated in phase I, with >90% reporting that they had been assaulted in the past month. Most did not report a workplace assault, which was unchanged after the intervention. Thirty-four emergency nurses participated in phase II, with a postintervention increase reported in the perceived helpfulness of learning self-protection techniques for the emergency nurses' work life (Z = -2.179, P = 0.029). DISCUSSION: This study was consistent with the literature in that emergency nurses often do not report workplace assaults. Most of the emergency nurses surveyed had been assaulted. Although the educational interventions did not achieve the desired outcome, it is clear that additional interventions for individual nurses and institutions need to be developed and refined to increase reporting and prevent workplace assaults.