Search

BackgroundHomecare settings across the United States provide care to more than 5 million patients every year. About one in five homecare patients are rehospitalized during the homecare episode, with up to two-thirds of these rehospitalizations occurring within the first 2 weeks of services. Timely allocation of homecare services might prevent a significant portion of these rehospitalizations. The first homecare nursing visit is one of the most critical steps of the homecare episode. This visit includes an assessment of the patient’s capacity for self-care, medication reconciliation, an examination of the home environment, and a discussion regarding whether a caregiver is present. Hence, appropriate timing of the first visit is crucial, especially for patients with urgent health care needs. However, nurses often have limited and inaccurate information about incoming patients, and patient priority decisions vary significantly between nurses. We developed an innovative decision support tool called Priority for the First Nursing Visit Tool (PREVENT) to assist nurses in prioritizing patients in need of immediate first homecare nursing visits. ObjectiveThis study aims to evaluate the effectiveness of the PREVENT tool on process and patient outcomes and to examine the reach, adoption, and implementation of PREVENT. MethodsEmploying a pre-post design, survival analysis, and logistic regression with propensity score matching analysis, we will test the following hypotheses: compared with not using the tool in the preintervention phase, when homecare clinicians use the PREVENT tool, high-risk patients in the intervention phase will (1) receive more timely first homecare visits and (2) have decreased incidence of rehospitalization and have decreased emergency department use within 60 days. Reach, adoption, and implementation will be assessed using mixed methods including homecare admission staff interviews, think-aloud observations, and analysis of staffing and other relevant data. ResultsThe study research protocol was approved by the institutional review board in October 2019. PREVENT is currently being integrated into the electronic health records at the participating study sites. Data collection is planned to start in early 2021. ConclusionsMixed methods will enable us to gain an in-depth understanding of the complex socio-technological aspects of the hospital to homecare transition. The results have the potential to (1) influence the standardization and individualization of nurse decision making through the use of cutting-edge technology and (2) improve patient outcomes in the understudied homecare setting. Trial RegistrationClinicalTrials.gov NCT04136951; https://clinicaltrials.gov/ct2/show/NCT04136951 International Registered Report Identifier (IRRID)PRR1-10.2196/20184

IntroductionThe pace of innovation has accelerated in virtually every area of tau research in just the past few years.MethodsIn February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.ResultsRepresenting academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.DiscussionThe virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.

BackgroundAutosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins.ResultsTo test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates.ConclusionsTogether, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

AbstractPrimary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.

Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the human brain are covered by existing protocols, and it has been difficult to quantitatively assess organoid variation and fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated human neural organoid cell atlas totalling more than 1.7 million cells1–26. Mapping to developing human brain references27–30 shows primary cell types and states that have been generated in vitro, and estimates transcriptomic similarity between primary and organoid counterparts across protocols. We provide a programmatic interface to browse the atlas and query new datasets, and showcase the power of the atlas to annotate organoid cell types and evaluate new organoid protocols. Finally, we show that the atlas can be used as a diverse control cohort to annotate and compare organoid models of neural disease, identifying genes and pathways that may underlie pathological mechanisms with the neural models. The human neural organoid cell atlas will be useful to assess organoid fidelity, characterize perturbed and diseased states and facilitate protocol development.A human neural organoid cell atlas integrating 36 single-cell transcriptomic datasets shows cell types and states and estimates transcriptomic similarity between primary and organoid counterparts, showing potential to assess organoid fidelity and facilitate protocol development. [ABSTRACT FROM AUTHOR]

Study Aim: This study aims to describe the transition-in-care work process for sepsis survivors going from hospitals to home health care (HHC) and identify facilitators and barriers to enable practice change and safe care transitions using a human factors and systems engineering approach. Background: Despite high readmission risk for sepsis survivors, the transition-in-care work process from hospitals to HHC has not been described. Methods: We analyzed semi-structured needs assessment interviews with 24 stakeholders involved in transitioning sepsis survivors from two hospitals and one affiliated HHC agency participating in the parent implementation science study, I-TRANSFER. The qualitative data analysis was guided by the Systems Engineering Initiative for Patient Safety (SEIPS) framework to describe the work process and identify work system elements. Results: We identified 31 tasks characterized as decision making, patient education, communication, information, documentation, and scheduling tasks. Technological and organizational facilitators lacked in HHC compared to the hospitals. Person and organization elements in HHC had the most barriers but few facilitators. Additionally, we identified specific task barriers that could hinder sepsis information transfer from hospitals to HHC. Conclusion: This study explored the complex transition-in-care work processes for sepsis survivors going from hospitals to HHC. We identified barriers, facilitators, and critical areas for improvement to enable implementation and ensure safe care transitions. A key finding was the sepsis information transfer deficit, highlighting a critical issue for future study. Application: We recommend using the SEIPS framework to explore complex healthcare work processes before the implementation of evidence-based interventions. [ABSTRACT FROM AUTHOR]

Objectives To explore home healthcare (HHC) clinicians' needs for Clinical Decision Support Systems (CDSS) information delivery for early risk warning within HHC workflows. Methods Guided by the CDS "Five-Rights" framework, we conducted semi-structured interviews with multidisciplinary HHC clinicians from April 2023 to August 2023. We used deductive and inductive content analysis to investigate informants' responses regarding CDSS information delivery. Results Interviews with thirteen HHC clinicians yielded 16 codes mapping to the CDS "Five-Rights" framework (right information, right person, right format, right channel, right time) and 11 codes for unintended consequences and training needs. Clinicians favored risk levels displayed in color-coded horizontal bars, concrete risk indicators in bullet points, and actionable instructions in the existing EHR system. They preferred non-intrusive risk alerts requiring mandatory confirmation. Clinicians anticipated risk information updates aligned with patient's condition severity and their visit pace. Additionally, they requested training to understand the CDSS's underlying logic, and raised concerns about information accuracy and data privacy. Discussion While recognizing CDSS's value in enhancing early risk warning, clinicians highlighted concerns about increased workload, alert fatigue, and CDSS misuse. The top risk factors identified by machine learning algorithms, especially text features, can be ambiguous due to a lack of context. Future research should ensure that CDSS outputs align with clinical evidence and are explainable. Conclusion This study identified HHC clinicians' expectations, preferences, adaptations, and unintended uses of CDSS for early risk warning. Our findings endorse operationalizing the CDS "Five-Rights" framework to optimize CDSS information delivery and integration into HHC workflows. [ABSTRACT FROM AUTHOR]

Background: Organizational readiness for change, defined as the collective preparedness of organization members to enact changes, remains understudied in implementing sepsis survivor transition-in-care protocols. Effective implementation relies on collaboration between hospital and post-acute care informants, including those who are leaders and staff. Therefore, our cross-sectional study compared organizational readiness for change among hospital and post-acute care informants. Methods: We invited informants from 16 hospitals and five affiliated HHC agencies involved in implementing a sepsis survivor transition-in-care protocol to complete a pre-implementation survey, where organizational readiness for change was measured via the Organizational Readiness to Implement Change (ORIC) scale (range 12-60). We also collected their demographic and job area information. Mann-Whitney U-tests and linear regressions, adjusting for leadership status, were used to compare organizational readiness of change between hospital and post-acute care informants. Results: Eighty-four informants, 51 from hospitals and 33 from post-acute care, completed the survey. Hospital and post-acute care informants had a median ORIC score of 52 and 57 respectively. Post-acute care informants had a mean 4.39-unit higher ORIC score compared to hospital informants (p = 0.03). Conclusions: Post-acute care informants had higher organizational readiness of change than hospital informants, potentially attributed to differences in health policies, expertise, organizational structure, and priorities. These findings and potential inferences may inform sepsis survivor transition-in-care protocol implementation. Future research should confirm, expand, and examine underlying factors related to these findings with a larger and more diverse sample. Additional studiesmay assess the predictive validity of ORIC towards implementation success. [ABSTRACT FROM AUTHOR]

BACKGROUND: Caring for someone with heart failure takes an emotional and physical toll. Engaging in self-care may decrease stress and improve the health of informal caregivers. We conducted a randomized controlled trial testing the efficacy of a virtual health coaching intervention, compared with health information alone, on the self-care, stress, coping, and health status of heart failure caregivers. We enrolled 250 caregivers providing care at least 8 hours/week, reporting poor self-care, and able to use technology. All received a tablet device programmed with websites providing vetted information on heart failure and caregiving. Half were randomized to also receive 10 synchronous support sessions virtually with a health coach over 6 months. Data on self-care, stress, coping, and health status were collected at baseline and 3 and 6 months. Linear mixed-effects models were used to assess the interaction between time and treatment group. RESULTS: The sample was majority female (85.2%), White (62.2%), spouses (59.8%), and aged 55±13.6 years. Many were employed full time (41.8%). They had been caring for the patient 8 hours/day for a median of 3.25 years. In the intention-to-treat analysis, caregivers who received the health coach intervention had statistically and clinically greater improvement across 6 months compared with the control group in the primary outcome of self-care maintenance (5.05±1.99; P=0.01) and stress (-4.50±1.00; P<0.0001). Self-care neglect declined significantly (-0.65±0.32; P=0.04), but the difference between the treatment arms disappeared when the results were adjusted for multiple comparisons. Mental health status improved statistically but not clinically (3.35±1.61; P=0.04). Active coping improved in both groups but not significantly more in the intervention group (P=0.10). Physical health status was unchanged (P=0.27). CONCLUSIONS:' This virtual health coaching intervention was effective in improving self-care and stress in heart failure caregivers. [ABSTRACT FROM AUTHOR]