Systemic delivery of mutant huntingtin lowering antisense oligonucleotides to the brain using apolipoprotein A-I nanodisks for Huntington disease.

Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD.

Delivery of mutant huntingtin-lowering antisense oligonucleotides to the brain by intranasally administered apolipoprotein A-I nanodisks.

Lowering mutant huntingtin (mHTT) in the central nervous system (CNS) using antisense oligonucleotides (ASOs) is a promising approach currently being evaluated in clinical trials for Huntington disease (HD). However, the therapeutic potential of ASOs in HD patients is limited by their inability to cross the blood-brain barrier (BBB). In non-human primates, intrathecal infusion of ASOs results in limited brain distribution, with higher ASO concentrations in superficial regions and lower concentrations in deeper regions, such as the basal ganglia. To address the need for improved delivery of ASOs to the brain, we are evaluating the therapeutic potential of apolipoprotein A-I nanodisks (apoA-I NDs) as novel delivery vehicles for mHTT-lowering ASOs to the CNS after intranasal administration. Here, we have demonstrated the ability of apoA-I nanodisks to bypass the BBB after intranasal delivery in the BACHD model of HD. Following intranasal administration of apoA-I NDs, apoA-I protein levels were elevated along the rostral-caudal brain axis, with highest levels in the most rostral brain regions including the olfactory bulb and frontal cortex. Double-label immunohistochemistry indicates that both the apoA-I and ASO deposit in neurons. Most importantly, a single intranasal dose of apoA-I ASO-NDs significantly reduces mHTT levels in the brain regions most affected in HD, namely the cortex and striatum. This approach represents a novel non-invasive means for improving delivery and brain distribution of oligonucleotide therapies and enhancing likelihood of efficacy. Improved ASO delivery to the brain has widespread application for treatment of many other CNS disorders.

Climate variables are not the dominant predictor of Arctic shorebird distributions.

Competing theoretical perspectives about whether or not climate is the dominant factor influencing species' distributions at large spatial scales have important consequences when habitat suitability models are used to address conservation problems. In this study, we tested how much variables in addition to climate help to explain habitat suitability for Arctic-breeding shorebirds. To do this we model species occupancy using path analyses, which allow us to estimate the indirect effects of climate on other predictor variables, such as land cover. We also use deviance partitioning to quantify the total relative importance of climate versus additional predictors in explaining species occupancy. We found that individual land cover variables are often stronger predictors than the direct and indirect effects of climate combined. In models with both climate and additional variables, on average the additional variables accounted for 57% of the explained deviance, independent of shared effects with the climate variables. Our results support the idea that climate-only models may offer incomplete descriptions of current and future habitat suitability and can lead to incorrect conclusions about the size and location of suitable habitat. These conclusions could have important management implications for designating protected areas and assessing threats like climate change and human development.

Climate-related range shifts in Arctic-breeding shorebirds.

Aim: To test whether the occupancy of shorebirds has changed in the eastern Canadian Arctic, and whether these changes could indicate that shorebird distributions are shifting in response to long-term climate change. Location: Foxe Basin and Rasmussen Lowlands, Nunavut, Canada. Methods: We used a unique set of observations, made 25 years apart, using general linear models to test if there was a relationship between changes in shorebird species' occupancy and their species temperature Index, a simple version of a species climate envelope. Results: Changes in occupancy and density varied widely across species, with some increasing and some decreasing. This is despite that overall population trends are known to be negative for all of these species based on surveys during migration. The changes in occupancy that we observed were positively related to the species temperature index, such that the warmer-breeding species appear to be moving into these regions, while colder-breeding species appear to be shifting out of the regions, likely northward. Main Conclusions: Our results suggest that we should be concerned about declining breeding habitat availability for bird species whose current breeding ranges are centered on higher and colder latitudes.

Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice.

Huntington disease (HD) is a neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene encoding an elongated polyglutamine tract in the huntingtin (HTT) protein. Expanded mutant HTT (mHTT) is toxic and leads to regional atrophy and neuronal cell loss in the brain, which occurs earliest in the striatum. Therapeutic lowering of mHTT in the central nervous system (CNS) has shown promise in preclinical studies, with multiple approaches currently in clinical development for HD. Quantitation of mHTT in the cerebrospinal fluid (CSF) is being used as a clinical pharmacodynamic biomarker of target engagement in the CNS. We have previously shown that the CNS is a major source of mHTT in the CSF. However, little is known about the specific brain regions and cell types that contribute to CSF mHTT. Therefore, a better understanding of the origins of CSF mHTT and whether therapies targeting mHTT in the striatum would be expected to be associated with significant lowering of mHTT in the CSF is needed. Here, we use complementary pharmacological and genetic-based approaches to either restrict expression of mHTT to the striatum or selectively deplete mHTT in the striatum to evaluate the contribution of this brain region to mHTT in the CSF. We show that viral expression of a mHTT fragment restricted to the striatum leads to detectable mHTT in the CSF. We demonstrate that targeted lowering of mHTT selectively in the striatum using an antisense oligonucleotide leads to a significant reduction of mHTT in the CSF of HD mice. Furthermore, using a transgenic mouse model of HD that expresses full length human mHTT and wild type HTT, we show that genetic inactivation of mHTT selectively in the striatum results in a significant reduction of mHTT in the CSF. Taken together, our data supports the conclusion that the striatum contributes sufficiently to the pool of mHTT in the CSF that therapeutic levels of mHTT lowering in the striatum can be detected by this measure in HD mice. This suggests that CSF mHTT may represent a pharmacodynamic biomarker for therapies that lower mHTT in the striatum.

Modeling and prediction of pressure injury in hospitalized patients using artificial intelligence.

BACKGROUND: Hospital-acquired pressure injuries (PIs) induce significant patient suffering, inflate healthcare costs, and increase clinical co-morbidities. PIs are mostly due to bed-immobility, sensory impairment, bed positioning, and length of hospital stay. In this study, we use electronic health records and administrative data to examine the contributing factors to PI development using artificial intelligence (AI). METHODS: We used advanced data science techniques to first preprocess the data and then train machine learning classifiers to predict the probability of developing PIs. The AI training was based on large, incongruent, incomplete, heterogeneous, and time-varying data of hospitalized patients. Both model-based statistical methods and model-free AI strategies were used to forecast PI outcomes and determine the salient features that are highly predictive of the outcomes. RESULTS: Our findings reveal that PI prediction by model-free techniques outperform model-based forecasts. The performance of all AI methods is improved by rebalancing the training data and by including the Braden in the model learning phase. Compared to neural networks and linear modeling, with and without rebalancing or using Braden scores, Random forest consistently generated the optimal PI forecasts. CONCLUSIONS: AI techniques show promise to automatically identify patients at risk for hospital acquired PIs in different surgical services. Our PI prediction model provide a first generation of AI guidance to prescreen patients at risk for developing PIs. CLINICAL IMPACT: This study provides a foundation for designing, implementing, and assessing novel interventions addressing specific healthcare needs. Specifically, this approach allows examining the impact of various dynamic, personalized, and clinical-environment effects on PI prevention for hospital patients receiving care from various surgical services.

Telemedicine-guided thoracentesis of tension pneumothorax in a term newborn.

We describe a case of a term female infant born in a rural community hospital and who developed a left-sided spontaneous tension pneumothorax shortly after birth. We used telemedicine to guide the family physician and healthcare team at the referring hospital to perform a life-saving thoracentesis using an intravenous cannula. The cannula was kept in place to drain the persistent pneumothorax during transportation to the pediatric intensive care unit at the tertiary hospital.

Reliable Resolution of Full-Length Huntingtin Alleles by Quantitative Immunoblotting.

BACKGROUND: Therapeutics that lower mutant huntingtin (mHTT) have shown promise in preclinical studies and are in clinical development for the treatment of Huntington disease (HD). Multiple assays have been developed that either quantify mHTT or total HTT but may not accurately measure levels of wild type HTT (wtHTT) in biological samples. OBJECTIVE: To optimize a method that can be used to resolve, quantify and directly compare levels of full length wtHTT and mHTT in HD samples. METHODS: We provide a detailed quantitative immunoblotting protocol to reproducibly resolve full length wtHTT and mHTT in multiple HD mouse and patient samples. RESULTS: We show that this assay can be modified, depending on the sample, to resolve wtHTT and mHTT with a wide range of polyglutamine length differences (ΔQs 22-179). We also demonstrate that this method can be used to quantify allele-selective lowering of mHTT using an antisense oligonucleotide in HD patient-derived cells. CONCLUSION: This quantitative immunoblotting method can be used to reliably resolve full-length HTT alleles with ΔQs≥22 and allows for direct comparison of wtHTT and mHTT levels in HD samples.

Bridging research and practice in conservation.

Calls for biodiversity conservation practice to be more evidence based are growing, and we agree evidence use in conservation practice needs improvement. However, evidence-based conservation will not be realized without improved access to evidence. In medicine, unlike in conservation, a well-established and well-funded layer of intermediary individuals and organizations engage with medical practitioners, synthesize primary research relevant to decision making, and make evidence easily accessible. These intermediaries prepare targeted evidence summaries and distribute them to practitioners faced with time-sensitive and value-laden decisions. To be effective, these intermediaries, who we refer to as evidence bridges, should identify research topics based on the priorities of practitioners; synthesize evidence; prepare and distribute easy-to-find and easy-to-use evidence summaries; and develop and maintain networks of connections with researchers and practitioners. Based on a review of the literature regarding evidence intermediaries in conservation and environmental management, as well as an anonymous questionnaire searching for such organizations, we found few intermediaries that met all these criteria. Few evidence bridges that do exist are unable to reach most conservation practitioners, which include resource managers in government and industry, conservation organizations, and farmers and other private landowners. We argue that the lack of evidence bridges from research to practitioners contributes to evidence complacency and limits the use of evidence in conservation action. Nevertheless, several existing organizations help reduce the gap between evidence and practice and could serve as a foundation for building additional components of evidence bridges in conservation. Although evidence bridges need expertise in research and evidence synthesis, they also require expertise in identifying and communicating with the community of practitioners most in need of clear and concise syntheses of evidence. Article Impact Statement: Evidence-based conservation will not be realized without improved access to evidence. We call for intermediary evidence bridges.

Vinculación entre la Investigación y la Práctica en la Conservación Resumen Cada vez existen más peticiones para que las prácticas de conservación de la biodiversidad estén más basadas en evidencias, además de que apoyamos la idea de que el uso de evidencias en la práctica de la conservación necesita mejorar. Sin embargo, la conservación basada en la evidencia no se logrará sin un acceso mejorado a las evidencias. En la medicina, no como en la conservación, un estrato bien establecido y financiado de individuos y organizaciones intermediarias interactúan con los médicos, sintetizan las investigaciones primarias relevantes para la toma de decisiones y hacen que las evidencias sean de fácil acceso. Estos intermediarios preparan resúmenes de evidencias específicas y los distribuyen a los médicos que enfrentan decisiones urgentes y muy valiosas. Para que sean efectivos, estos intermediarios, a quienes nos referimos como puentes de evidencias, deben poder identificar los temas de estudio con base en las prioridades de los practicantes, sintetizar evidencias, preparar y distribuir resúmenes fáciles de encontrar y fáciles de usar, y desarrollar y mantener redes de conexiones con los investigadores y los practicantes. Con base en una revisión de la literatura correspondiente a los intermediarios de evidencias en la conservación y el manejo ambiental, así como en un cuestionario anónimo que busca a dichas organizaciones, encontramos a pocos intermediarios que cumplieran con estos criterios. Los pocos puentes de evidencias que existen no son capaces de llegar a la mayoría de los practicantes de la conservación, los cuales incluyen a los gestores de recursos en el gobierno y en la industria, a las organizaciones de conservación y a los agricultores y otros terratenientes privados. Argumentamos que la falta de puentes de evidencia entre los investigadores y los practicantes contribuye a la indulgencia de evidencias y limita el uso de evidencias en las acciones de conservación. Sin embargo, varias organizaciones existentes ayudan a reducir la brecha entre la evidencia y la práctica y podrían funcionar como base para la construcción de componentes adicionales para los puentes de evidencia en la conservación. Aunque los puentes de evidencias necesitan experiencia con la investigación y con la síntesis de evidencias, también requieren experiencia con la identificación de y comunicación con la comunidad de practicantes que más necesitan una síntesis clara y concisa de la evidencia.

Implementation of a Protocol: Dexmedetomidine for Use in Long-Term Procedural Sedation in Non-Intubated Pediatric Patients.

The objective of this quality initiative was to evaluate the process of implementing a new protocol using the Iowa model and evidence-base interventions. The first aim included deploying a protocol guiding sedation with dexmedetomidine for up to 24 h; the procedure involved non-intubated pediatric patients in the pediatric intensive care unit (PICU) while monitored by certified registered nurses. Dexmedetomidine is supported within the literature to be a safe and effective medication for pediatric patients, exceeding 24 h, without the adverse event of respiratory depression. The second aim was to then evaluate the implementation process. A pre-post educational approach was used, over a five-month period. Thirty-two nurses were educated and surveyed on their knowledge and attitudes regarding the use and administration of dexmedetomidine. The evaluation of pre and post knowledge surrounding dexmedetomidine was concluded following the post-survey. The evaluation of pre-post education showed, greater than 90% of the attending nurses, had an increase in their knowledge and understanding of safe use and monitoring for dexmedetomidine sedations in children. This quality initiative further supports effective application of evidence-based interventions. Moreover, using the Iowa model allowed for the effective execution in driving change, promoting sustainability, and improving safety in the delivery of care for pediatric patients receiving dexmedetomidine for long-term sedation.

Both short and long distance migrants use energy-minimizing migration strategies in North American herring gulls.

BACKGROUND: Recent studies have proposed that birds migrating short distances migrate at an overall slower pace, minimizing energy expenditure, while birds migrating long distances minimize time spent on migration to cope with seasonal changes in environmental conditions. METHODS: We evaluated variability in the migration strategies of Herring Gulls (Larus argentatus), a generalist species with flexible foraging and flight behaviour. We tracked one population of long distance migrants and three populations of short distance migrants, and compared the directness of their migration routes, their overall migration speed, their travel speed, and their use of stopovers. RESULTS: Our research revealed that Herring Gulls breeding in the eastern Arctic migrate long distances to spend the winter in the Gulf of Mexico, traveling more than four times farther than gulls from Atlantic Canada during autumn migration. While all populations used indirect routes, the long distance migrants were the least direct. We found that regardless of the distance the population traveled, Herring Gulls migrated at a slower overall migration speed than predicted by Optimal Migration Theory, but the long distance migrants had higher speeds on travel days. While long distance migrants used more stopover days overall, relative to the distance travelled all four populations used a similar number of stopover days. CONCLUSIONS: When taken in context with other studies, we expect that the migration strategies of flexible generalist species like Herring Gulls may be more influenced by habitat and food resources than migration distance.

Advancing health policy education in nursing: American Association of Colleges of Nursing Faculty Policy Think Tank.

Based upon an awareness of the need to increase its policy footprint, the American Association of Colleges of Nursing's (AACN) Board of Directors convened a think tank of nurse experts in the field of policy curriculum to advise the Board. The goal of the think tank was to review the current landscape, analyze trends, and create a set of recommendations for AACN's Board to consider. The Faculty Policy Think Tank (FPTT) met between 2016 and 2017 to review and reflect on methods to increase expertise of nursing faculty and students in health policy and make recommendations to the AACN Board to advance the agenda of the organization, member schools, and the profession. This article describes the methods and processes the Think Tank employed to develop a set of recommendations for the AACN Board of Directors.

The pressure injury predictive model: A framework for hospital-acquired pressure injuries.

BACKGROUND: Despite decades of research, pressure injuries continue to be a source of significant pain and delayed recovery for patients and substantial quality and cost issues for hospitals. Consideration of the current thinking around pressure injury risk must be evaluated to improve risk assessments and subsequent nursing interventions aimed at reducing hospital-acquired pressure injuries. DESIGN: This is a discursive paper using Walker and Avant's (2005) theory synthesis framework to examine the relevance of existing pressure injury models as they align with the current literature. METHODS: PubMed and CINAHL indexes were searched, first for conceptual models and then for pressure injury research conducted on hospitalised patients for the years 2006-2016. A synthesis of the searches culminated into a new pressure injury risk model. CONCLUSIONS: Gaps in previous models include lack of attention to the environment, contributing episode-of-care factors and the dynamic nature of injury risk for patients. Through theory synthesis, the need for a new model representing the full risk for pressure injury was identified. The Pressure Injury Predictive Model is a representation of the complex and dynamic nature of pressure injury risk that builds on previous models and addresses new patient, contextual and episode-of-care process influences. The Pressure Injury Predictive Model (PIPM) provides a more accurate picture of the complexity of contextual and process factors associated with pressure injury development. RELEVANCE TO CLINICAL PRACTICE: Using the PIPM to determine risk can result in improved risk identification. This information can be used to implement targeted, evidence-based pressure injury prevention interventions specific to the patient risk profile, thus limiting unwarranted and unnecessary care.

Epithelial tumor suppressor ELF3 is a lineage-specific amplified oncogene in lung adenocarcinoma.

Gene function in cancer is often cell type-specific. The epithelial cell-specific transcription factor ELF3 is a documented tumor suppressor in many epithelial tumors yet displays oncogenic properties in others. Here, we show that ELF3 is an oncogene in the adenocarcinoma subtype of lung cancer (LUAD), providing genetic, functional, and clinical evidence of subtype specificity. We discover a region of focal amplification at chromosome 1q32.1 encompassing the ELF3 locus in LUAD which is absent in the squamous subtype. Gene dosage and promoter hypomethylation affect the locus in up to 80% of LUAD analyzed. ELF3 expression was required for tumor growth and a pan-cancer expression network analysis supports its subtype and tissue specificity. We further show that ELF3 displays strong prognostic value in LUAD but not LUSC. We conclude that, contrary to many other tumors of epithelial origin, ELF3 is an oncogene and putative therapeutic target in LUAD.

Arctic cleansing diet: Sex-specific variation in the rapid elimination of contaminants by the world's champion migrant, the Arctic tern.

Contamination of Arctic marine environments continues to be a concern for wildlife managers. Because the Arctic is a sink for the long-range transport of persistent organic pollutants (POPs), many studies have detected high concentrations of POPs in various Arctic birds. In this study from high Arctic Canada, we show that male Arctic terns (Sterna paradisaea), which migrate from the Antarctic to the Arctic annually to breed, decline in concentrations of many hepatic POPs through the breeding season. This suggests that local Arctic food webs are less contaminated than regions where terns fed during or migration, despite that the terns appear to feed at a higher trophic level near their colony.

Correction to: Winter home range and habitat selection differs among breeding populations of herring gulls in eastern North America.

[This corrects the article DOI: 10.1186/s40462-019-0152-x.].

Winter home range and habitat selection differs among breeding populations of herring gulls in eastern North America.

Background: Recognizing the factors influencing migratory individuals throughout their annual cycle is important for understanding the drivers of population dynamics. Previous studies have found that Herring Gulls (Larus argentatus) in the Atlantic region have lower survival rates than those in the Great Lakes and the Arctic. One possible explanation for divergent survival rates among these populations is differences in their non-breeding habitats. Methods: We tracked Herring Gulls from five populations, breeding in the eastern Arctic, the Great Lakes, Newfoundland, Sable Island, and the Bay of Fundy. We assessed the extent of migratory connectivity between breeding and wintering sites, and tested if there were differences in home range size or habitat selection among these populations during the winter. Results: The tracked Herring Gulls had strong migratory connectivity between their breeding and wintering areas. We found that Herring Gulls from the Arctic spent most of the winter in marine habitats, while the other populations used a wider variety of habitats. However, the Newfoundland and Sable Island populations selected for urban habitats, and almost all individuals the specialized in urban habitats came from one of the three Atlantic populations. Conclusions: Our results suggest that there could potentially be a link between urban habitat use during the winter and reduced adult survival in Atlantic Canada Herring Gulls.

Older Adults' Perceptions of Their Fall Risk and Prevention Strategies After Transitioning from Hospital to Home.

Falls are common adverse events following hospital discharge. However, prevention programs are not tailored for older patients transitioning home. To inform development of transitional fall prevention programs, nine older adults designated as being at risk of falls during hospitalization who were recently discharged home were asked about their perceptions of fall risk and prevention, as well as their knowledge and opinion of materials from the Centers for Disease Control and Prevention Stopping Elderly Accidents, Deaths & Injuries Initiative. Using the constant comparative method, five themes were identified: Sedentary Behaviors and Limited Functioning; Prioritization of Social Involvement; Low Perceived Fall Risk and Attribution of Risk to External Factors; Avoidance and Caution as Fall Prevention; and Limited Falls Prevention Information During Transition from Hospital to Home. Limited awareness of and engagement in effective fall prevention may heighten recently discharged older adults' risks for falls. Prevention programs tailored to the post-discharge period may engage patients in fall prevention, promote well-being and independence, and link hospital and community efforts. [Journal of Gerontological Nursing, 45(1), 23-30.].