Transitions of care for older adults discharged home from the emergency department: an inductive thematic content analysis of patient comments.

OBJECTIVE: Improving care transitions for older adults can reduce emergency department (ED) visits, adverse events, and empower community autonomy. We conducted an inductive qualitative content analysis to identify themes emerging from comments to better understand ED care transitions. METHODS: The LEARNING WISDOM prospective longitudinal observational cohort includes older adults (≥ 65 years) who experienced a care transition after an ED visit from both before and during COVID-19. Their comments on this transition were collected via phone interview and transcribed. We conducted an inductive qualitative content analysis with randomly selected comments until saturation. Themes that arose from comments were coded and organized into frequencies and proportions. We followed the Standards for Reporting Qualitative Research (SRQR). RESULTS: Comments from 690 patients (339 pre-COVID, 351 during COVID) composed of 351 women (50.9%) and 339 men (49.1%) were analyzed. Patients were satisfied with acute emergency care, and the proportion of patients with positive acute care experiences increased with the COVID-19 pandemic. Negative patient comments were most often related to communication between health providers across the care continuum and the professionalism of personnel in the ED. Comments concerning home care became more neutral with the COVID-19 pandemic. CONCLUSION: Patients were satisfied overall with acute care but reported gaps in professionalism and follow-up communication between providers. Comments may have changed in tone from positive to neutral regarding home care over the COVID-19 pandemic due to service slowdowns. Addressing these concerns may improve the quality of care transitions and provide future pandemic mitigation strategies.

Collaborative writing applications in support of knowledge translation and management during pandemics: A scoping review.

OBJECTIVES: This study aimed to: (1) Map existing evidence about the use of collaborative writing applications (CWAs) during pandemics; (2) Describe CWAs' positive and negative effects on knowledge translation (KT) and knowledge management (KM) during pandemics; and (3) Inventory the barriers and facilitators that affect CWAs' use to support KT and KM during pandemics. MATERIALS AND METHODS: Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews, we conducted a scoping review of the literature reporting the use of CWAs during pandemics published between 2001 and 2021. Two reviewers undertook the screening, study selection and qualitative thematic analysis. RESULTS: We identified a total of 46 studies. CWAs were used for the following two purposes: KT and KM (23 of 46) anddisease surveillance and infodemiology (20 of 46). Three studies addressed both purposes. Influenza was the focus of most studies (15 of 46), followed by COVID-19 (10 of 46).We identified and classified 24 barriers and 66 facilitators into four categories (factors related to the CWAs, users' knowledge and attitude towards CWAs, human environment, and organizational environment). We also found 74 positive and 7 negative effects that were classified into processes and outcomes. CONCLUSION: CWAs offer the potential to accelerate KT and KM during pandemics. Their scalability and adaptability to different contexts makes them well suited to support the urgent KT and KM needed in the context of rapidly changing knowledge during pandemics. While their speed and cost as disease surveillance systems compare favorably with existing surveillance systems, the primary challenge is to ensure the accuracy of information shared.

Intention to Use Wiki-Based Knowledge Tools: Survey of Quebec Emergency Health Professionals.

BACKGROUND: Clinical decision support systems are information technologies that assist clinicians in making better decisions. Their adoption has been limited because their content is difficult to adapt to local contexts and slow to adapt to emerging evidence. Collaborative writing applications such as wikis have the potential to increase access to existing and emerging evidence-based knowledge at the point of care, standardize emergency clinical decision making, and quickly adapt this knowledge to local contexts. However, little is known about the factors influencing health professionals' use of wiki-based knowledge tools. OBJECTIVE: This study aims to measure emergency physicians' (EPs) and other acute care health professionals' (ACHPs) intentions to use wiki-based knowledge tools in trauma care and identify determinants of this intention that can be used in future theory-based interventions for promoting the use of wiki-based knowledge tools in trauma care. METHODS: In total, 266 EPs and 907 ACHPs (nurses, respiratory therapists, and pharmacists) from 12 Quebec trauma centers were asked to answer a survey based on the theory of planned behavior (TPB). The TPB constructs were measured using a 7-point Likert scale. Descriptive statistics and Pearson correlations between the TPB constructs and intention were calculated. Multiple linear regression analysis was conducted to identify the salient beliefs. RESULTS: Among the eligible participants, 57.1% (152/266) of EPs and 31.9% (290/907) of ACHPs completed the questionnaire. For EPs, we found that attitude, perceived behavioral control (PBC), and subjective norm (SN) were significant determinants of the intention to use wiki-based knowledge tools and explained 62% of its variance. None of the sociodemographic variables were related to EPs' intentions to use wiki-based knowledge tools. The regression model identified two normative beliefs ("approval by physicians" and "approval by patients") and two behavioral beliefs ("refreshes my memory" and "reduces errors"). For ACHPs, attitude, PBC, SN, and two sociodemographic variables (profession and the previous personal use of a wiki) were significantly related to the intention to use wiki-based knowledge tools and explained 60% of the variance in behavioral intention. The final regression model for ACHPs included two normative beliefs ("approval by the hospital trauma team" and "people less comfortable with information technology"), one control belief ("time constraints"), and one behavioral belief ("access to evidence"). CONCLUSIONS: The intentions of EPs and ACHPs to use wiki-based knowledge tools to promote best practices in trauma care can be predicted in part by attitude, SN, and PBC. We also identified salient beliefs that future theory-based interventions should promote for the use of wiki-based knowledge tools in trauma care. These interventions will address the barriers to using wiki-based knowledge tools, find ways to ensure the quality of their content, foster contributions, and support the exploration of wiki-based knowledge tools as potential effective knowledge translation tools in trauma care.

Developing and Evaluating a Capacity-Building Intervention for Healthcare Providers to Improve Communication Skills and Awareness of Hard of Hearing and D/deaf Populations: Protocol for a Participative Action Research-Based Study.

Background: D/deaf and hard of hearing populations are at higher risk for experiencing physical and mental health problems compared to hearing populations. In addition, they commonly encounter barriers to accessing and benefiting from health services, which largely stem from challenges they face in communicating with healthcare providers. Healthcare providers commonly lack tailored communication skills in caring for D/deaf and hard of hearing populations, which lead to difficulties and dissatisfaction for both staff and D/deaf and hard of hearing communities. This research project aims to develop and evaluate a capacity-building intervention for healthcare providers with the goal of increasing their awareness of D/deaf and hard of hearing individuals' experiences with the healthcare system, their distinct needs, and improving their capacity to communicate effectively with this patient population. Methods: This research project features a participative action research design using qualitative and quantitative methods. Consistent with participative action research, the study will actively involve the target populations, key stakeholders and representative associations. The intervention will be developed and tested through iterative phases. The Integrated Model of Training Evaluation and Effectiveness will guide prospective evaluation of the intervention. The latter will involve qualitative and quantitative assessments in participants before and after the intervention and at 6-months follow-up. Discussion: Results will contribute to research aimed at decreasing barriers to accessing and benefiting from healthcare services for D/deaf and hard of hearing individuals. Findings will be presented to representative associations and political authorities, as well as disseminated at research conferences and in peer-reviewed journals.

Learning Integrated Health System to Mobilize Context-Adapted Knowledge With a Wiki Platform to Improve the Transitions of Frail Seniors From Hospitals and Emergency Departments to the Community (LEARNING WISDOM): Protocol for a Mixed-Methods Implementation Study.

BACKGROUND: Elderly patients discharged from hospital experience fragmented care, repeated and lengthy emergency department (ED) visits, relapse into their earlier condition, and rapid cognitive and functional decline. The Acute Care for Elders (ACE) program at Mount Sinai Hospital in Toronto, Canada uses innovative strategies, such as transition coaches, to improve the care transition experiences of frail elderly patients. The ACE program reduced the lengths of hospital stay and readmission for elderly patients, increased patient satisfaction, and saved the health care system over Can $4.2 million (US $2.6 million) in 2014. In 2016, a context-adapted ACE program was implemented at one hospital in the Centre intégré de santé et de services sociaux de Chaudière-Appalaches (CISSS-CA) with a focus on improving transitions between hospitals and the community. The quality improvement project used an intervention strategy based on iterative user-centered design prototyping and a "Wiki-suite" (free web-based database containing evidence-based knowledge tools) to engage multiple stakeholders. OBJECTIVE: The objectives of this study are to (1) implement a context-adapted CISSS-CA ACE program in four hospitals in the CISSS-CA and measure its impact on patient-, caregiver-, clinical-, and hospital-level outcomes; (2) identify underlying mechanisms by which our context-adapted CISSS-CA ACE program improves care transitions for the elderly; and (3) identify underlying mechanisms by which the Wiki-suite contributes to context-adaptation and local uptake of knowledge tools. METHODS: Objective 1 will involve staggered implementation of the context-adapted CISSS-CA ACE program across the four CISSS-CA sites and interrupted time series to measure the impact on hospital-, patient-, and caregiver-level outcomes. Objectives 2 and 3 will involve a parallel mixed-methods process evaluation study to understand the mechanisms by which our context-adapted CISSS-CA ACE program improves care transitions for the elderly and by which our Wiki-suite contributes to adaptation, implementation, and scaling up of geriatric knowledge tools. RESULTS: Data collection started in January 2019. As of January 2020, we enrolled 1635 patients and 529 caregivers from the four participating hospitals. Data collection is projected to be completed in January 2022. Data analysis has not yet begun. Results are expected to be published in 2022. Expected results will be presented to different key internal stakeholders to better support the effort and resources deployed in the transition of seniors. Through key interventions focused on seniors, we are expecting to increase patient satisfaction and quality of care and reduce readmission and ED revisit. CONCLUSIONS: This study will provide evidence on effective knowledge translation strategies to adapt best practices to the local context in the transition of care for elderly people. The knowledge generated through this project will support future scale-up of the ACE program and our wiki methodology in other settings in Canada. TRIAL REGISTRATION: ClinicalTrials.gov NCT04093245; https://clinicaltrials.gov/ct2/show/NCT04093245. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17363.

microRNA-132/212 deficiency enhances Aß production and senile plaque deposition in Alzheimer's disease triple transgenic mice.

The abnormal regulation of amyloid-ß (Aß) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer's disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Aß production and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Aß metabolism, including Tau, Mapk, and Sirt1. Consistent with these findings, we show that the modulation of miR-132, or its target Sirt1, can directly regulate Aß production in cells. Finally, both miR-132 and Sirt1 levels correlated with Aß load in humans. Overall, our results support the hypothesis that the miR-132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Aß metabolism and senile plaque deposition in AD. This study strengthens the importance of miR-dependent networks in neurodegenerative disorders, and opens the door to multifactorial drug targets of AD by targeting Aß and Tau.

Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial, fatal neurodegenerative disorder characterized by the abnormal accumulation of Aß and Tau deposits in the brain. There is no cure for AD, and failure at different clinical trials emphasizes the need for new treatments. In recent years, significant progress has been made toward the development of miRNA-based therapeutics for human disorders. This study was designed to evaluate the efficiency and potential safety of miRNA replacement therapy in AD, using miR-15/107 paralogues as candidate drug targets. We identified miR-16 as a potent inhibitor of amyloid precursor protein (APP) and BACE1 expression, Aß peptide production, and Tau phosphorylation in cells. Brain delivery of miR-16 mimics in mice resulted in a reduction of AD-related genes APP, BACE1, and Tau in a region-dependent manner. We further identified Nicastrin, a γ-secretase component involved in Aß generation, as a target of miR-16. Proteomics analysis identified a number of additional putative miR-16 targets in vivo, including α-Synuclein and Transferrin receptor 1. Top-ranking biological networks associated with miR-16 delivery included AD and oxidative stress. Collectively, our data suggest that miR-16 is a good candidate for future drug development by targeting simultaneously endogenous regulators of AD biomarkers (i.e., Aß and Tau), inflammation, and oxidative stress.

miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo.

Alzheimer's disease (AD) and related tauopathies comprise a large group of neurodegenerative diseases associated with the pathological aggregation of tau protein. While much effort has focused on understanding the function of tau, little is known about the endogenous mechanisms regulating tau metabolism in vivo and how these contribute to disease. Previously, we have shown that the microRNA (miRNA) cluster miR-132/212 is downregulated in tauopathies such as AD. Here, we report that miR-132/212 deficiency in mice leads to increased tau expression, phosphorylation and aggregation. Using reporter assays and cell-based studies, we demonstrate that miR-132 directly targets tau mRNA to regulate its expression. We identified GSK-3ß and PP2B as effectors of abnormal tau phosphorylation in vivo. Deletion of miR-132/212 induced tau aggregation in mice expressing endogenous or human mutant tau, an effect associated with autophagy dysfunction. Conversely, treatment of AD mice with miR-132 mimics restored in part memory function and tau metabolism. Finally, miR-132 and miR-212 levels correlated with insoluble tau and cognitive impairment in humans. These findings support a role for miR-132/212 in the regulation of tau pathology in mice and humans and provide new alternatives for therapeutic development.

Memory formation and retention are affected in adult miR-132/212 knockout mice.

The miR-132/212 family is thought to play an important role in neural function and plasticity, while its misregulation has been observed in various neurodegenerative disorders. In this study, we analyzed 6-month-old miR-132/212 knockout mice in a battery of cognitive and non-cognitive behavioral tests. No significant changes were observed in reflexes and basic sensorimotor functions as determined by the SHIRPA primary screen. Accordingly, miR-132/212 knockout mice did not differ from wild-type controls in general locomotor activity in an open-field test. Furthermore, no significant changes of anxiety were measured in an elevated plus maze task. However, the mutant mice showed retention phase defects in a novel object recognition test and in the T-water maze. Moreover, the learning and probe phases in the Barnes maze were clearly altered in knockout mice when compared to controls. Finally, changes in BDNF, CREB, and MeCP2 were identified in the miR-132/212-deficient mice, providing a potential mechanism for promoting memory loss. Taken together, these results further strengthen the role of miR-132/212 in memory formation and retention, and shed light on the potential consequences of its deregulation in neurodegenerative diseases.

Extracellular Na(+) levels regulate formation and activity of the NaX/alpha1-Na(+)/K(+)-ATPase complex in neuronal cells.

MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as sensors of extracellular sodium concentration ([Na(+)]out). The mechanism underlying Na(+)-sensing involves Na(+)-flow through the NaX channel, directly regulated by the Na(+)/K(+)-ATPase α1-isoform which controls Na(+)-influx by modulating channel permeability. Together, these two partners form a complex involved in the regulation of intracellular sodium ([Na(+)]in). Here we aim to determine whether environmental changes in Na(+) could actively modulate the NaX/Na(+)/K(+)-ATPase complex activity. We investigated the complex activity using patch-clamp recordings from rat MnPO neurons and Neuro2a cells. When the rats were fed with a high-salt-diet, or the [Na(+)] in the culture medium was increased, the activity of the complex was up-regulated. In contrast, drop in environmental [Na(+)] decreased the activity of the complex. Interestingly under hypernatremic condition, the colocalization rate and protein level of both partners were up-regulated. Under hyponatremic condition, only NaX protein expression was increased and the level of NaX/Na(+)/K(+)-ATPase remained unaltered. This unbalance between NaX and Na(+)/K(+)-ATPase pump proportion would induce a bigger portion of Na(+)/K(+)-ATPase-control-free NaX channel. Thus, we suggest that hypernatremic environment increases NaX/Na(+)/K(+)-ATPase α1-isoform activity by increasing the number of both partners and their colocalization rate, whereas hyponatremic environment down-regulates complex activity via a decrease in the relative number of NaX channels controlled by the pump.

Gene network and pathway analysis of mice with conditional ablation of Dicer in post-mitotic neurons.

BACKGROUND: The small non-protein-coding microRNAs (miRNAs) have emerged as critical regulators of neuronal differentiation, identity and survival. To date, however, little is known about the genes and molecular networks regulated by neuronal miRNAs in vivo, particularly in the adult mammalian brain. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed whole genome microarrays from mice lacking Dicer, the enzyme responsible for miRNA production, specifically in postnatal forebrain neurons. A total of 755 mRNA transcripts were significantly (P<0.05, FDR<0.25) misregulated in the conditional Dicer knockout mice. Ten genes, including Tnrc6c, Dnmt3a, and Limk1, were validated by real time quantitative RT-PCR. Upregulated transcripts were enriched in nonneuronal genes, which is consistent with previous studies in vitro. Microarray data mining showed that upregulated genes were enriched in biological processes related to gene expression regulation, while downregulated genes were associated with neuronal functions. Molecular pathways associated with neurological disorders, cellular organization and cellular maintenance were altered in the Dicer mutant mice. Numerous miRNA target sites were enriched in the 3'untranslated region (3'UTR) of upregulated genes, the most significant corresponding to the miR-124 seed sequence. Interestingly, our results suggest that, in addition to miR-124, a large fraction of the neuronal miRNome participates, by order of abundance, in coordinated gene expression regulation and neuronal maintenance. CONCLUSIONS/SIGNIFICANCE: Taken together, these results provide new clues into the role of specific miRNA pathways in the regulation of brain identity and maintenance in adult mice.

MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy.

Tauopathies represent a large class of neurological and movement disorders characterized by abnormal intracellular deposits of the microtubule-associated protein tau. It is now well established that mis-splicing of tau exon 10, causing an imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms, can cause disease; however, the underlying mechanisms affecting tau splicing in neurons remain poorly understood. The small noncoding microRNAs (miRNAs), known for their critical role in posttranscriptional gene expression regulation, are increasingly acknowledged as important regulators of alternative splicing. Here, we identified a number of brain miRNAs, including miR-124, miR-9, miR-132 and miR-137, which regulate 4R:3R-tau ratios in neuronal cells. Analysis of miRNA expression profiles from sporadic progressive supranuclear palsy (PSP) patients, a major 4R-tau tauopathy, showed that miR-132 is specifically down-regulated in disease. We demonstrate that miR-132 directly targets the neuronal splicing factor polypyrimidine tract-binding protein 2 (PTBP2), which protein levels were increased in PSP patients. miR-132 overexpression or PTBP2 knockdown similarly affected endogenous 4R:3R-tau ratios in neuronal cells. Finally, we provide evidence that miR-132 is inversely correlated with PTBP2 during post-natal brain development at the time when 4R-tau becomes expressed. Taken together, these results suggest that changes in the miR-132/PTBP2 pathway could contribute to the abnormal splicing of tau exon 10 in the brain, and sheds light into the potential role played by miRNAs in a subset of tauopathies.

In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs.

The ß-amyloid peptide that accumulate in Alzheimer's disease (AD) brain derive from proteolytic processing of the amyloid precursor protein (APP). Recent evidence suggest that microRNAs (miRNAs) participate in the post-transcriptional regulation of APP expression. Because gene dosage effects of the APP gene can cause genetic AD, dysregulation of the miRNA network could contribute significantly to disease. Here, we present evidence that, besides APP expression regulation, miRNAs are equally involved in the regulation of neuronal APP mRNA alternative splicing. Lack of miRNAs in post-mitotic neurons in vivo is associated with APP exons 7 and 8 inclusion, while ectopic expression of miR-124, an abundant neuronal-specific miRNA, reversed these effects in cultured neurons. Similar results were obtained by depletion of endogenous polypyrimidine tract binding protein 1 (PTBP1) in cells, a recognized miR-124 target gene. Furthermore, PTBP1 levels correlate with the presence of APP exons 7 and 8, while PTBP2 levels correlate with the skipping of these exons during neuronal differentiation. Finally, we show that miR-124 is down-regulated in AD brain. In sum, our results suggest that specific miRNAs are involved in the fine-tuning of APP alternative splicing in neurons. Since abnormal neuronal splicing of APP affects ß-amyloid peptide production, these results could contribute to the understanding of the implication of miRNAs in brain health and disease.

Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration.

Type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well-documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here we show that the absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. Although neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Finally, we show that miR-15a is specifically downregulated in Alzheimer's disease brain. In summary, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation.