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.

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.

Innovative P-wave detection for discrimination between ventricular and supraventricular tachycardia in single-chamber ICDs: is the P-wave invisible during tachycardia?

AIMS: Differentiation between supraventricular tachycardia (SVT) and ventricular tachycardia (VT) remains a substantial clinical challenge in patients with single-chamber implantable cardioverter-defibrillators (ICDs) due to absence of visible P waves. Innovative optimization of intrathoracic electrogram (EGM) configuration will facilitate P-wave detection and rhythm differentiation during tachycardia. METHODS AND RESULTS: Innovative optimization of EGM configuration was originally performed to improve patient care. In this retrospective cohort study, we examined our database for records of 140 consecutive patients undergoing single-chamber ICD implantation. During the follow-ups of 61 included patients with optimized EGM configuration, 27 patients were identified to have VT and/or SVT. EGMs in the Can (generator) to superior vena cava (Can-SVC) configuration were compared with those conventionally from the Can to right ventricular coil (Can-RV coil) source in the same patients. In Can-SVC EGMs, the ratio of P/QRS amplitude was 14-fold higher (0.57 ± 0.08 vs. 0.04 ± 0.00, P < 0.001) compared with those in Can-RV coil EGMs during sinus rhythm. With Can-SVC configuration, the odds of atrioventricular dissociation detection in patients with VT was increased 15-fold (61.9% vs. 9.5% with Can-RV coil; odds ratio, 15.4; 95% confidence interval, 2.8 to 84.7; P = 0.0009). In patients with SVT, P-waves or retrograde P-waves were markedly more identifiable in Can-SVC configuration compared with Can-RV coil (odds ratio, 40; 95% confidence interval, 3.6 to 447.1; P = 0.0010). CONCLUSION: P-wave recognition by optimizing EGM configuration provides a novel diagnostic tool for differentiation between VT and SVT in single-chamber ICDs. A potential discrimination algorithm would provide a cost-effective approach to improving the qualitative outcomes.

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.

Synthesis and characterization of new permanently charged poly(amidoammonium) salts and evaluation of their DNA complexes for gene transport.

A new series of linear and permanently charged poly(amidoammonium) salts were synthesized in order to investigate the influence of their ionic and hydrophobic contents on both the cytotoxicity and the transfection mediated by polycation-DNA complexes. The poly(amidoammonium) salts were prepared by chemical modification of a parent poly(amidoamine) containing two tertiary amino groups per structural unit: one incorporated into the main chain and the other fixed at the end of a short bismethylene spacer. The permanent charges were introduced through a quaternization reaction involving iodomethane or 1-iodododecane as an alkylating agent. Under appropriate conditions, the methylation reaction was found to be regioselective, allowing the quaternization of either the side chains or both the side chains and the backbone. Under physiological salt conditions (150 mM NaCl), all of the poly(amidoammonium) salts self-assembled with DNA to form complexes. High proportions of highly quaternized polycation provided better defined morphology to the polycation-DNA complexes. Complexes formed from unquaternized polycation were less cytotoxic than branched poly(ethyleneimine) (25 kDa). At high polycation-DNA weight ratios, the introduction of permanent charges generated a significant increase in the cytotoxicity, but no patent correlation could be established with the amount and the position of the permanent charges. Only complexes formed from polycations with quaternized backbone were able to generate significant gene expression, which was putatively attributed to a better defined toroidal-like morphology together with a higher stability, as suggested by zeta potential measurements. The incorporation of dodecane side chains on highly charged polycations severely amplified the cytotoxicity so that, in return, the transfection level was dramatically affected.

Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors.

The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.

Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: novel PDE4 inhibitors.

A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v.

Molecular dynamics of NPY Y1 receptor activation.

A three-dimensional model of the human neuropeptide Y(NPY)Y1 receptor (hY1) was constructed, energy refined and used to simulate molecular receptor interactions of the peptide ligands NPY, [L31, P34]NPY, peptide YY (PYY) and pancreatic polypeptide (PP), and of the nonpeptide antagonist R-N2-(diphenylacetyl)-N-(4-hydroxyphenyl)methyl-argininamide (BIBP3226) and its S-enantiomer BIBP3435. The best complementarity in charges between the receptor and the peptides, and the best structural accordance with experimental studies, was obtained with amino acid 1-4 of the peptides interacting with Asp194, Asp200, Gln201, Phe202 and Trp288 in the receptor. Arg33 and Arg35 of the peptides formed salt bridges with Asp104 and Asp287, respectively, while Tyr36 interacted in a binding pocket formed by Phe41, Thr42, Tyr100, Asn297, His298 and Phe302. Calculated electrostatic potentials around NPY and hY1 molecules indicated that ligand binding is initiated by electrostatic interactions between a highly positive region in the N- and C-terminal parts of the peptides, and a negative region in the extracellular receptor domains. Molecular dynamics simulations of NPY and BIBP3226 interactions with the receptor indicated rigid body motions of TMH5 and TMH6 upon NPY binding as mechanisms of receptor activation, and that BIBP3226 may act as an antagonist by constraining these motions.