Lecanemab blocks the effects of the Aß/fibrinogen complex on blood clots and synapse toxicity in organotypic culture.

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimer's disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogen's interaction with the amyloid-beta (Aß) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, clears Aß plaque from the brain and slows cognitive decline. Here, we show that lecanemab blocks fibrinogen's binding to Aß protofibrils, preventing Aß/fibrinogen-mediated delayed fibrinolysis and clot abnormalities in vitro and in human plasma. Additionally, we show that lecanemab dissociates the Aß/fibrinogen complex and prevents fibrinogen from exacerbating Aß-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.

The Role of Ebola Virus VP24 Nuclear Trafficking Signals in Infectious Particle Production.

Ebola virus (EBOV) protein VP24 carries out at least two critical functions. It promotes condensation of viral nucleocapsids, which is crucial for infectious virus production, and it suppresses interferon (IFN) signaling, which requires interaction with the NPI-1 subfamily of importin-α (IMPA) nuclear transport proteins. Interestingly, over-expressed IMPA leads to VP24 nuclear accumulation and a carboxy-terminus nuclear export signal (NES) has been reported, suggesting that VP24 may undergo nuclear trafficking. For the first time, we demonstrate that NPI-1 IMPA overexpression leads to the nuclear accumulation of VP24 during EBOV infection. To assess the functional impact of nuclear trafficking, we generated tetracistronic minigenomes encoding VP24 nuclear import and/or export signal mutants. The minigenomes, which also encode Renilla luciferase and viral proteins VP40 and GP, were used to generate transcription and replication competent virus-like particles (trVLPs) that can be used to assess EBOV RNA synthesis, gene expression, entry and viral particle production. With this system, we confirmed that NES or IMPA binding site mutations altered VP24 nuclear localization, demonstrating functional trafficking signals. While these mutations minimally affected transcription and replication, the trVLPs exhibited impaired infectivity and formation of shortened nucleocapsids for the IMPA binding mutant. For the NES mutants, infectivity was reduced approximately 1000-fold. The NES mutant could still suppress IFN signaling but failed to promote nucleocapsid formation. To determine whether VP24 nuclear export is required for infectivity, the residues surrounding the wildtype NES were mutated to alanine or the VP24 NES was replaced with the Protein Kinase A Inhibitor NES. While nuclear export remained intact for these mutants, infectivity was severely impaired. These data demonstrate that VP24 undergoes nuclear trafficking and illuminates a separate and critical role for the NES and surrounding sequences in infectivity and nucleocapsid assembly.

Ten Years of Pathology on Twitter (X): Landscape and Evolution of Pathology on Twitter From 2012 to 2023.

CONTEXT.­: Social media is a powerful tool in pathology education and professional networking that connects pathologists and pathology trainees from around the world. Twitter (X) appears to be the most popular social media platform pathologists use to share pathology-related content and connect with other pathologists. Although there has been some published research on pathology-related activity on Twitter during short time frames, to date there has not been published research examining pathology-related Twitter activity in totality from its earliest days of activity to recently. OBJECTIVE.­: To comprehensively evaluate the use of pathology on Twitter (X) during the last 10 years. DESIGN.­: Pathology-related tweets were systematically scraped from Twitter from January 2012 to January 2023 using pathology hashtags as a surrogate measure for all pathology content on Twitter. COVID-related tweets were approximated by tweets containing the term "COVID." RESULTS.­: There were 591 812 unique pathology-related tweets identified during the time period, with #pathology being the most common hashtag used and #PathTwitter becoming more popular since 2020. There has been positive annual growth of pathology Twitter, with peaks in use during major pathology conferences. During the initial phases of the COVID-19 pandemic a sustained increase in pathology tweets was observed. CONCLUSIONS.­: Pathology Twitter has grown during the last 10 years and has become increasingly popular for pathology education and networking. With the changing landscape of social media platforms this study provides an understanding of how pathology medical education and professional networking uses of social media are used and evolve over time.

Reducing unwarranted chest x-rays in bronchiolitis: Importance of a robust analysis.

AIM: Bronchiolitis is the commonest reason for hospitalisation amongst infants and is often a target for low-value care (LVC) reduction. We aimed to assess the impact of a multifaceted intervention (clinician education, parent engagement, audit-feedback) on rates of chest x-rays (CXR) in bronchiolitis. METHODS: Longitudinal study of CXRs ordered in infants (1-12 months) diagnosed with bronchiolitis in the Emergency Department (ED) of an Australian paediatric hospital between May 2016 and February 2023. We used logistic regression to measure the impact of the intervention on unwarranted CXR orders, controlling for other potential impacting variables such as time, patient characteristics (age/sex), clinical variables (fever, hypoxia, tachypnoea), seasonal factors (month, day of the week, business hours) and time passed since intervention. RESULTS: Ten thousand one hundred and nine infants were diagnosed with bronchiolitis in the ED over the study period, with 939 (9.3%) receiving a CXR, of which 69% (n = 651) were considered unwarranted. Rates of unwarranted CXRs reduced from 7.9% to 5.4% post-intervention (P < 0.0001). Logistic regression showed the intervention had no significant effect (OR 0.89, 95% CI 0.65-1.23) once other variables and underlying time-based trends were accounted for. CONCLUSIONS: Although pre-post rates appeared significantly improved, a robust analysis demonstrated that our multi-faceted intervention was not effective in reducing CXRs in bronchiolitis. The decision to order CXR was associated with clinical features that overlap with pneumonia suggesting ongoing misconceptions regarding the role of CXR for this indication. Our study highlights the value of large electronic medical record datasets and robust methodology to avoid falsely attributing underlying trends to the LVC intervention.

Synergistic Binding of SARS-CoV-2 to ACE2 and Gangliosides in Native Lipid Membranes.

Viruses utilize cell surface glycans and plasma membrane receptors to attain an adequate attachment strength for initiating cellular entry. We show that SARS-CoV-2 particles bind to endogenous ACE2 receptors and added sialylated gangliosides in near-native membranes. This was explored using supported membrane bilayers (SMBs) that were formed using plasma membrane vesicles having endogenous ACE2 and GD1a gangliosides reconstituted in lipid vesicles. The virus binding rate to the SMBs is influenced by GD1a and inhibition of the ganglioside reduces the extent of virus binding to the membrane receptors. Using combinations of inhibition assays, we confirm that added GD1a in lipid membranes increases the availability of the endogenous ACE2 receptor and results in the synergistic binding of SARS-CoV-2 to the membrane receptors in SMBs.

Community health navigator-assisted transition of care from hospital to community: protocol for a randomised controlled trial.

INTRODUCTION: The objective of this parallel group, randomised controlled trial is to evaluate a community health navigator (CHN) intervention provided to patients aged over 40 years and living with chronic health conditions to transition from hospital inpatient care to their homes. Unplanned hospital readmissions are costly for the health system and negatively impact patients. METHODS AND ANALYSIS: Patients are randomised post hospital discharge to the CHN intervention or usual care. A comparison of outcomes between intervention and control groups will use multivariate regression techniques that adjust for age, sex and any independent variables that are significantly different between the two groups, using multiple imputation for missing values. Time-to-event analysis will examine the relationship between seeing a CHN following discharge from the index hospitalisation and reduced rehospitalisations in the subsequent 60 days and 6 months. Secondary outcomes include medication adherence, health literacy, quality of life, experience of healthcare and health service use (including the cost of care). We will also conduct a qualitative assessment of the implementation of the navigator role from the viewpoint of stakeholders including patients, health professionals and the navigators themselves. ETHICS APPROVAL: Ethics approval was obtained from the Research Ethics and Governance Office, Sydney Local Health District, on 21 January 2022 (Protocol no. X21-0438 and 2021/ETH12171). The findings of the trial will be disseminated through peer-reviewed journals and national and international conference presentations. Data will be deposited in an institutional data repository at the end of the trial. This is subject to Ethics Committee approval, and the metadata will be made available on request. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN 12622000659707). ARTICLE SUMMARY: The objective of this trial is to evaluate a CHN intervention provided to patients aged over 40 years and living with chronic health conditions to transition from hospital inpatient care to their homes.

Benchmarking Artificial Neural Network Architectures for High-Performance Spiking Neural Networks.

Organizations managing high-performance computing systems face a multitude of challenges, including overarching concerns such as overall energy consumption, microprocessor clock frequency limitations, and the escalating costs associated with chip production. Evidently, processor speeds have plateaued over the last decade, persisting within the range of 2 GHz to 5 GHz. Scholars assert that brain-inspired computing holds substantial promise for mitigating these challenges. The spiking neural network (SNN) particularly stands out for its commendable power efficiency when juxtaposed with conventional design paradigms. Nevertheless, our scrutiny has brought to light several pivotal challenges impeding the seamless implementation of large-scale neural networks (NNs) on silicon. These challenges encompass the absence of automated tools, the need for multifaceted domain expertise, and the inadequacy of existing algorithms to efficiently partition and place extensive SNN computations onto hardware infrastructure. In this paper, we posit the development of an automated tool flow capable of transmuting any NN into an SNN. This undertaking involves the creation of a novel graph-partitioning algorithm designed to strategically place SNNs on a network-on-chip (NoC), thereby paving the way for future energy-efficient and high-performance computing paradigms. The presented methodology showcases its effectiveness by successfully transforming ANN architectures into SNNs with a marginal average error penalty of merely 2.65%. The proposed graph-partitioning algorithm enables a 14.22% decrease in inter-synaptic communication and an 87.58% reduction in intra-synaptic communication, on average, underscoring the effectiveness of the proposed algorithm in optimizing NN communication pathways. Compared to a baseline graph-partitioning algorithm, the proposed approach exhibits an average decrease of 79.74% in latency and a 14.67% reduction in energy consumption. Using existing NoC tools, the energy-latency product of SNN architectures is, on average, 82.71% lower than that of the baseline architectures.

Lecanemab Blocks the Effects of the Aß/Fibrinogen Complex on Blood Clots and Synapse Toxicity in Organotypic Culture.

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimer's disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogen's interaction with the amyloid-beta (Aß) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, shows promising results in facilitating reduction of Aß from the brain and slowing cognitive decline. Here we show that lecanemab blocks fibrinogen's binding to Aß protofibrils, normalizing Aß/fibrinogen-mediated delayed fibrinolysis and clot abnormalities in vitro and in human plasma. Additionally, we show that lecanemab dissociates the Aß/fibrinogen complex and prevents fibrinogen from exacerbating Aß-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.

Disruption Mechanisms of Enveloped Viruses by Ionic and Nonionic Surfactants.

The world has witnessed multiple pandemics and endemics caused by enveloped viruses in the past century. To name a few, the ongoing COVID-19 pandemic and other pandemics/endemics caused by coronaviruses, influenza viruses, HIV-1, etc. The external and topical applications of surfactants have been effective in limiting the spread of viruses. While it is well-known that surfactants inactivate virus particles (virions), the mechanism of action of surfactants against enveloped virions has not yet been established. In this work, we have evaluated the surfactant-induced disruption mechanism of a cocktail of enveloped viruses containing particles of mumps, measles, and rubella viruses. We applied the total internal reflection fluorescence microscopy technique to trace the temporal changes in the fluorescence signal from single virions upon the addition of a surfactant solution. We report that surfactants solubilize either the viral lipid membrane, proteins, or both. Ionic surfactants, depending on their charge and interaction type with the viral lipids and proteins, can cause bursting or perforation of the viral envelope, whereas a nonionic surfactant can cause either symmetric expansion or perforation of the viral envelope depending on the surfactant concentration.

Sacituzumab Govitecan as a Second-Line Treatment in Relapsed/Refractory Metastatic Triple-Negative Breast Cancer Patients: A Systematic Review and Meta-analysis.

BACKGROUND: Chemotherapy, the only treatment option for metastatic triple-negative breast cancer (mTNBC), showed decreased survival rates. Trophoblast cell surface antigen-2 (Trop-2) could be a possible target for antibody-drug conjugates (ADCs). OBJECTIVE: Sacituzumab govitecan (SG), an anti-Trop-2 ADC for pretreating relapsed/refractory mTNBC patients, was studied to know the efficacy and safety profile of the drug in mTNBC. METHODS: The present review searched MEDLINE (via PubMed), WHO Clinical Trial Registry, Clinical Trials.gov, and Cochrane Central Register of Controlled Trials until December 25, 2022. The studies searched comprised randomized trials and observational studies (retrospective [case-control, cross-sectional] and prospective [cohort designs]). Efficacy assessment was performed in terms of complete response (CR), partial response (PR), objective response rate (ORR), stable disease (SD), progressive disease (PD), and clinical benefit rate (CBR), and safety in terms of adverse events. RESULTS: The overall random-effects pooled prevalence of CR was 4.9 (95% CI: 3.2-7.1), PR was 35.6 (95% CI: 31.5-39.9), ORR was 6.8 (95% CI: 5.9-7.8), SD was 8.0 (95% CI: 6.7-9.4), PD was 5.1 (95% CI: 4.1-6.3), and CBR was 13.4 (95% CI: 11.8-15.1). Adverse events associated with the drug were neutropenia, fatigue, anemia, nausea, and others. CONCLUSION AND RELEVANCE: This is the first meta-analysis conducted in relapsed/refractory mTNBC patients and found that SG is efficacious but associated with some adverse effects that are related to exposure to the drug. The application of these results will allow clinicians to use SG in the management of patients with mTNBC.

Retrospective analysis of the impact of electronic medical record alerts on low value care in a pediatric hospital.

OBJECTIVES: Hospital costs continue to rise unsustainably. Up to 20% of care is wasteful including low value care (LVC). This study aimed to understand whether electronic medical record (EMR) alerts are effective at reducing pediatric LVC and measure the impact on hospital costs. MATERIALS AND METHODS: Using EMR data over a 76-month period, we evaluated changes in 4 LVC practices following the implementation of EMR alerts, using time series analysis to control for underlying time-based trends, in a large pediatric hospital in Australia. The main outcome measure was the change in rate of each LVC practice. Balancing measures included the rate of alert adherence as a proxy measure for risk of alert fatigue. Hospital costs were calculated by the volume of LVC avoided multiplied by the unit costs. Costs of the intervention were calculated from clinician and analyst time required. RESULTS: All 4 LVC practices showed a statistically significant reduction following alert implementation. Two LVC practices (blood tests) showed an abrupt change, associated with high rates of alert adherence. The other 2 LVC practices (bronchodilator use in bronchiolitis and electrocardiogram ordering for sleeping bradycardia) showed an accelerated rate of improvement compared to baseline trends with lower rates of alert adherence. Hospital savings were $325 to $180 000 per alert. DISCUSSION AND CONCLUSION: EMR alerts are effective in reducing pediatric LVC practices and offer a cost-saving opportunity to the hospital. Further efforts to leverage EMR alerts in pediatric settings to reduce LVC are likely to support future sustainable healthcare delivery.

Morphogens enable interacting supracellular phases that generate organ architecture.

During vertebrate organogenesis, increases in morphological complexity are tightly coupled to morphogen expression. In this work, we studied how morphogens influence self-organizing processes at the collective or "supra"-cellular scale in avian skin. We made physical measurements across length scales, which revealed morphogen-enabled material property differences that were amplified at supracellular scales in comparison to cellular scales. At the supracellular scale, we found that fibroblast growth factor (FGF) promoted "solidification" of tissues, whereas bone morphogenetic protein (BMP) promoted fluidity and enhanced mechanical activity. Together, these effects created basement membrane-less compartments within mesenchymal tissue that were mechanically primed to drive avian skin tissue budding. Understanding this multiscale process requires the ability to distinguish between proximal effects of morphogens that occur at the cellular scale and their functional effects, which emerge at the supracellular scale.

Environmental Chemical-Induced Reactive Oxygen Species Generation and Immunotoxicity: A Comprehensive Review.

Significance: Reactive oxygen species (ROS), the reactive oxygen-carrying chemicals moieties, act as pleiotropic signal transducers to maintain various biological processes/functions, including immune response. Increased ROS production leads to oxidative stress, which is implicated in xenobiotic-induced adverse effects. Understanding the immunoregulatory mechanisms and immunotoxicity is of interest to developing therapeutics against xenobiotic insults. Recent Advances: While developmental studies have established the essential roles of ROS in the establishment and proper functioning of the immune system, toxicological studies have demonstrated high ROS generation as one of the potential mechanisms of immunotoxicity induced by environmental chemicals, including heavy metals, pesticides, aromatic hydrocarbons (benzene and derivatives), plastics, and nanoparticles. Mitochondrial electron transport and various signaling components, including NADH oxidase, toll-like receptors (TLRs), NF-κB, JNK, NRF2, p53, and STAT3, are involved in xenobiotic-induced ROS generation and immunotoxicity. Critical Issues: With many studies demonstrating the role of ROS and oxidative stress in xenobiotic-induced immunotoxicity, rigorous and orthogonal approaches are needed to achieve in-depth and precise understanding. The association of xenobiotic-induced immunotoxicity with disease susceptibility and progression needs more data acquisition. Furthermore, the general methodology needs to be possibly replaced with high-throughput precise techniques. Future Directions: The progression of xenobiotic-induced immunotoxicity into disease manifestation is not well documented. Immunotoxicological studies about the combination of xenobiotics, age-related sensitivity, and their involvement in human disease incidence and pathogenesis are warranted.

Analysis of Centralized Efficiency Improvement Practices in Australian Public Health Systems.

Aim: Analysis of centralized efficiency improvement practices in Australian public health systems. Introduction: Public health systems seek to maximize outcomes generated for resources used through efficiency improvement (EI) in response to funding and demand pressures. Despite this focus, evidence for EI approaches at the whole-of-system level is lacking in the literature. There is an urgent need for evidence-based approaches to centralized EI to address these pressures. This study aims to address this gap by answering the research question "How is EI conceptualized and managed by central public health system management entities in Australia?". Material and Methods: Document analysis was selected due to its suitability for systematically searching and appraising health system documentation, with this study following Altheide's approach focusing on whole-of-system strategic plan and management framework documents originating from Australian public health organizations. Results: Conceptualization of efficiency varied substantially with no consistent definition identified, however common attributes included resource use, management, service and delivery. Forty-two of 43 documents contained approaches associated with improving efficiency at the whole of system level. Discussion: While no comprehensive framework for centralized EI was evident, we identified nine core approaches which together characterize centralized EI. Together these approaches represent a comprehensive evidence-based approach to EI at the whole of system level. Conclusion: The approaches to whole-of-system EI identified in this study are likely to be highly transferable across health systems internationally with approaches including strategic priority setting, incentivization, performance support, use of EI evidence, digital enablement and workforce capability development.

Tribological Performance Evaluation of Greases on a Four-Ball Tester with Graphene Oxide Nanoparticles.

Conventional greases have an exceptional place in the field of lubrication. They are unique in the sense of their areas of application and are very difficult to replace with other lubricating substances for the same reason. The advancements in the field of nanoparticles and the results they provide as an additive in greases have great scientific interest as they improve the tribological properties of greases to a great extent. The current work's aim is to synthesize a nanogripe using graphene oxide (GO) nanoparticles to lithium grease (Li grease), which will increase the tribological properties of the plain Li grease. Steps were taken to investigate the impact of variation of load on the frictional and wear characteristics of nanogrease. Synthesis of nanogrease and tribological evaluation were performed with a magnetic stirrer with a hot plate and a four-ball tester. Results indicated that nanogrease exhibits better tribological properties. It is also found that the antiwear and frictional properties of grease are not proportional to the wt % of GO nanoparticles. It is also detected that with the increase in load, the tribological properties of nanogrease increase.

Efficiency Improvement Strategies for Public Health Systems: Developing and Evaluating a Taxonomy in the Australian Healthcare System.

INTRODUCTION: As demand for healthcare continues to grow, public health systems are increasingly required to drive efficiency improvement (EI) to address public service funding challenges. Despite this requirement, evidence of EI strategies that have been successful applied at the whole-of-system level is limited. This study reports the development, implementation and evaluation of a novel taxonomy of EI strategies used in public health systems to inform systemwide EI models. MATERIALS AND METHODS: The public health system in New South Wales, Australia, operates a centralised EI model statewide and was the setting for this study. An audit of EI strategies implemented in the NSW Health system between July 2016 and June 2019 was used to identify all available EI strategies within the study timeframe. A content management approach was applied to audit the strategies, with each strategy coded to an EI focus area. Codes were clustered according to similarity, and category names were assigned to each cluster to form a preliminary taxonomy. Each category was defined and examples were provided. The resulting taxonomy was distributed and evaluated by user feedback survey and pre-post study to assess the impact on EI strategy distribution. RESULTS: A total of 1127 EI strategies were identified and coded into 263 unique strategies, which were clustered into nine categories to form the taxonomy of EI strategies. Categories included the following: non-clinical contracts and supplies; avoided and preventable activity; clinical service delivery and patient outcomes; finance and operations; recruitment, vacancies and FTE; staffing models; leave management; staff engagement and development; premium staffing; and clinical contracts and supplies. Evaluative findings revealed a perceived reduction in the duplication of EI work, improved access to EI knowledge and improved engagement with EI processes when using the taxonomy. The taxonomy was also associated with wider use of EI strategies. CONCLUSIONS: Whole-of-system EI is an increasing requirement. Using a taxonomy to guide systemwide practice appears to be advanta-geous in reducing duplication and guiding practice, with implications for use in health systems internationally.

Kinetics of Ganglioside-Rich Supported Lipid Bilayer Formation with Tracer Vesicle Fluorescence Imaging.

Gangliosides, forming a class of lipids complemented by sugar chains, influence the lateral distribution of membrane proteins or membrane-binding proteins, act as receptors for viruses and bacterial toxins, and mediate several types of cellular signaling. Gangliosides incorporated into supported lipid bilayers (SLBs) have been widely applied as a model system to examine these biological processes. In this work, we explored how ganglioside composition affects the kinetics of SLB formation using the vesicle rupturing method on a solid surface. We imaged the attachment of vesicles and the subsequent SLB formation using the time-lapse total internal reflection fluorescence microscopy technique. In the early phase, the ganglioside type and concentration influence the adsorption kinetics of vesicles and their residence/lifetime on the surface before rupturing. Our data confirm that a simultaneous rupturing of neighboring surface-adsorbed vesicles forms microscopic lipid patches on the surface and it is triggered by a critical coverage of the vesicles independent of their composition. In the SLB growth phase, lipid patches merge, forming a continuous SLB. The propagation of patch edges catalyzes the process and depends on the ganglioside type. Our pH-dependent experiments confirm that the polar/charged head groups of the gangliosides have a critical role in these steps and phases of SLB formation kinetics.