Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers

Tendonitis and Tendon Rupture in Low-Profile Dorsal versus Volar Plating for Distal Radius Fractures: A Systematic Review and Meta-Analysis

INTRODUCTION: Dorsal plating of distal radius fractures has been associated with high rates of hardware removal, tendonitis, and tendon rupture. Much of this research was performed using 2.5mm thick distal radius plating, whereas modern dorsal plates are thinner (1.2mm-1.5mm). We examine whether modern plates have higher rates of complications than volar plates. METHODS: We search Ovid MEDLINE, Web of Science, and EMBASE for literature describing tendon complications associated with plating of distal radius fractures. Inclusion criteria included any comparison between volar and dorsal plating and report of tendon complication. Exclusion criteria included: failure to specify low-profile dorsal plates; lack of volar plating comparison arm; no reporting of tendon complications. All studies were assessed for quality using MINOR’s criteria. RESULTS: All 5 included studies were retrospective cohorts, totaling 806 subjects; 584 received volar plates and 222 received dorsal plates. Minimum average follow-up was 5 months. Of the volar plate group, 2% had symptoms consistent with tendonitis, 1% experienced a tendon rupture, and 4% underwent hardware removal. In the dorsal group, 6% had tendonitis, 1% had tendon ruptures, and 11% underwent hardware removal. Meta-analysis showed no significant difference in rates of tendonitis (4 studies, Z=0.79, P=0.43) or tendon rupture (5 studies, Z=0.59, P=0.56). DISCUSSION: To our knowledge, this review provides the largest comparison of modern dorsal and volar distal radius plates to date. Our results do not demonstrate increased risk of tendon complications in patients who underwent dorsal plating. This study sets a precedent for more routine use of dorsal plating

Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models

Necroptosis is a regulated form of cell death that has been observed in Alzheimer's disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)-Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as "GVD-necroptosis" may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD

Finite Element Analysis and Machine Learning Guided Design of Carbon Fiber Organosheet-based Battery Enclosures for Crashworthiness

Carbon fiber composite can be a potential candidate for replacing metal-based battery enclosures of current electric vehicles (E.V.s) owing to its better strength-to-weight ratio and corrosion resistance. However, the strength of carbon fiber-based structures depends on several parameters that should be carefully chosen. In this work, we implemented high throughput finite element analysis (FEA) based thermoforming simulation to virtually manufacture the battery enclosure using different design and processing parameters. Subsequently, we performed virtual crash simulations to mimic a side pole crash to evaluate the crashworthiness of the battery enclosures. This high throughput crash simulation dataset was utilized to build predictive models to understand the crashworthiness of an unknown set. Our machine learning (ML) models showed excellent performance (R2 > 0.97) in predicting the crashworthiness metrics, i.e., crush load efficiency, absorbed energy, intrusion, and maximum deceleration during a crash. We believe that this FEA-ML work framework will be helpful in down select process parameters for carbon fiber-based component design and can be transferrable to other manufacturing technologies

Development and Validation of a Novel Decision Aid for WALANT Hand Surgeries: Investigating Patient Preferences

INTRODUCTION: This study aims to develop a novel decision aid packet (DAP) for hand surgery patients deciding between Wide-Awake-Local-Anesthesia-No-Tourniquet (WALANT) and traditional anesthesia. METHODS: Development: The DAP was developed following International Patient Decision Aid Standards. Validation: Alpha Testing Seven hand surgeons experienced in WALANT and traditional surgeries belonging to the WALANT Research Consortium in the U.S. commented on the DAP through three rounds of editing utilizing the Delphi method. Seven patient advocates provided readability feedback. Beta Testing Orthopedic hand surgery patients were assigned to the control or experimental group. The experimental group was given the DAP pre-surgery. Both groups completed a validated regret scale at follow-up. A paired t-test was conducted to analyze the difference between average scores on the regret scale and pre- and post-DAP knowledge tests (p RESULTS: The experimental group (n=58) demonstrated a 145% increase (p DISCUSSION: Increased knowledge test scores following the DAP suggest that patients are better informed after DAP usage. Low decisional conflict scores suggest that the DAP increases patients’ confidence. Lower average regret scale scores among the experimental group indicate a relationship between DAP administration and reduced post-surgical regret. The greater patient preference for WALANT following DAP usage, alongside the lower postoperative regret, elucidates a general preference in informed patients towards the WALANT modality

The γ-secretase substrate proteome and its role in cell signaling regulation

γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell

Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology

Microglia are central players in Alzheimer’s disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aβ oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer’s disease risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in a multipronged response to Alzheimer’s disease-related pathology, which should be taken into account in translational studies

Impact of natural killer cells on outcomes after allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

Background: Natural killer (NK) cells play a vital role in early immune reconstitution following allogeneic hematopoietic stem cell transplantation (HSCT). Methods: A literature search was performed on PubMed, Cochrane, and Clinical trials.gov through April 20, 2022. We included 21 studies reporting data on the impact of NK cells on outcomes after HSCT. Data was extracted following the PRISMA guidelines. Pooled analysis was done using the meta-package (Schwarzer et al.). Proportions with 95% confidence intervals (CI) were computed. Results: We included 1785 patients from 21 studies investigating the impact of NK cell reconstitution post-HSCT (8 studies/1455 patients), stem cell graft NK cell content (4 studies/185 patients), therapeutic NK cell infusions post-HSCT (5 studies/74 patients), and pre-emptive/prophylactic NK cell infusions post-HSCT (4 studies/77 patients). Higher NK cell reconstitution was associated with a better 2-year overall survival (OS) (high: 77%, 95%CI 0.73-0.82 vs low: 55%, 95%CI 0.37-0.72; n=899), however, pooled analysis for relapse rate (RR) or graft versus host disease (GVHD) could not be performed due to insufficient data. Higher graft NK cell content demonstrated a trend towards a better pooled OS (high: 65.2%, 95%CI 0.47-0.81 vs low: 46.5%, 95%CI 0.24-0.70; n=157), lower RR (high: 16.9%, 95%CI 0.10-0.25 vs low: 33%, 95%CI 0.04-0.72; n=157), and lower acute GVHD incidence (high: 27.6%, 95%CI 0.20-0.36 vs low: 49.7%, 95%CI 0.26-0.74; n=157). Therapeutic NK or cytokine-induced killer (CIK) cell infusions for hematologic relapse post-HSCT reported an overall response rate (ORR) and complete response (CR) of 48.9% and 11% with CIK cell infusions and 82.8% and 44.8% with NK cell infusions, respectively. RR, acute GVHD, and chronic GVHD were observed in 55.6% and 51.7%, 34.5% and 20%, and 20.7% and 11.1% of patients with CIK and NK cell infusions, respectively. Pre-emptive donor-derived NK cell infusions to prevent relapse post-HSCT had promising outcomes with 1-year OS of 69%, CR rate of 42%, ORR of 77%, RR of 28%, and acute and chronic GVHD rates of 24.9% and 3.7%, respectively. Conclusion: NK cells have a favorable impact on outcomes after HSCT. The optimal use of NK cell infusions post-HSCT may be in a pre-emptive fashion to prevent disease relapse

Mapping the research landscape: energy storage of bio-nanoparticle-enhanced phase change materials for solar desalination—a scientometric framework

Solar desalination is an economical and eco-friendly approach to producing potable water, particularly in remote areas. Nevertheless, the limited efficiency of traditional solar panels restricts their ability to fulfill the growing demand for clean water. This study focuses on improving the performance of single-basin solar stills (SBS) by incorporating paraffin wax as a phase change material (PCM) with copper nanoparticles (Cu NPs) and agro-based materials in a stepped design. A scientometric analysis framework was applied to map the research landscape, followed by an experimental evaluation in which SBS units were fabricated and tested under controlled solar exposure with varying combinations of PCM, Cu NPs, and concentrators. The research is tailored to accommodate diverse climatic and operational conditions. Results reveal that the combination of PCM and Cu NPs significantly enhances freshwater output compared to traditional setups. The modified SBS demonstrated a productivity improvement of 67.18% for single-effect and 125% for double-effect configurations. The use of PCM alone resulted in a 21.5% boost in productivity, while the SBS design excluding CuO-based nanofluids achieved approximately 32% higher freshwater generation by utilizing solar energy. Moreover, combining a concentrator with PCM led to an additional 26% increase in efficiency. These results highlight the potential of integrating PCM and nanoparticles as an effective strategy to optimize SBS performance for sustainable water desalination

Evaluation of FluSight influenza forecasting in the 2021–22 and 2022–23 seasons with a new target laboratory-confirmed influenza hospitalizations

Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021–22 and 2022–23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021–22 and 12 out of 18 models in 2022–23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021–22 and the 5th most accurate in the 2022–23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change