Multiple Routes Research Articles

2,7-Phloroglucinol-6,6′-bieckol from Ecklonia cava ameliorates nanoplastics-induced premature endothelial senescence and dysfunction

Nanoplastics (NPs), plastic particles ranging from 1 to 100 nm are ubiquitous environmental pollutants infiltrating ecosystems. Their small size and widespread use in various products raise concerns for human health, particularly their association with cardiovascular diseases (CVD). NPs can enter the human body through multiple routes, causing oxidative stress, and leading to the senescence and dysfunction of endothelial cells (ECs). Although there are potential natural compounds for treating CVD, there is limited research on preventing CVD induced by NPs. This study investigates the efficacy of Ecklonia cava extract (ECE) in preventing NPs-induced premature vascular senescence and dysfunction. Exposure of porcine coronary arteries (PCAs) and porcine coronary ECs to NPs, either alone or in combination with ECE, demonstrated that ECE mitigates senescence-associated β-galactosidase (SA-β-gal) activity induced by NPs, thus preventing premature endothelial senescence. ECE also improved NPs-induced vascular dysfunction. The identified active ingredient in Ecklonia cava, 2,7’-Phloroglucinol-6,6′-bieckol (PHB), a phlorotannin, proved to be pivotal in these protective effects. PHB treatment ameliorated SA-β-gal activity, reduced oxidative stress, restored cell proliferation, and decreased the expression of cell cycle regulatory proteins such as p53, p21, p16, and angiotensin type 1 receptor (AT1), well known triggers for EC senescence. Moreover, PHB also improved NPs-induced vascular dysfunction by upregulating endothelial nitric oxide synthase (eNOS) expression and restoring endothelium-dependent vasorelaxation. In conclusion, Ecklonia cava and its active ingredient, PHB, exhibit potential as therapeutic agents against NPs-induced premature EC senescence and dysfunction, indicating a protective effect against environmental pollutants-induced CVDs associated with vascular dysfunction.

Advancing Microfluidic Immunity Testing Systems: New Trends for Microbial Pathogen Detection.

Pathogenic microorganisms play a crucial role in the global disease burden due to their ability to cause various diseases and spread through multiple transmission routes. Immunity tests identify antigens related to these pathogens, thereby confirming past infections and monitoring the host's immune response. Traditional pathogen detection methods, including enzyme-linked immunosorbent assays (ELISAs) and chemiluminescent immunoassays (CLIAs), are often labor-intensive, slow, and reliant on sophisticated equipment and skilled personnel, which can be limiting in resource-poor settings. In contrast, the development of microfluidic technologies presents a promising alternative, offering automation, miniaturization, and cost efficiency. These advanced methods are poised to replace traditional assays by streamlining processes and enabling rapid, high-throughput immunity testing for pathogens. This review highlights the latest advancements in microfluidic systems designed for rapid and high-throughput immunity testing, incorporating immunosensors, single molecule arrays (Simoas), a lateral flow assay (LFA), and smartphone integration. It focuses on key pathogenic microorganisms such as SARS-CoV-2, influenza, and the ZIKA virus (ZIKV). Additionally, the review discusses the challenges, commercialization prospects, and future directions to advance microfluidic systems for infectious disease detection.

Optimization Algorithms in SDN: Routing, Load Balancing, and Delay Optimization

Software-Defined Networking is today a mature technology, which is developed in many networks and also embedded in novel architectures like 5G and 6G. The SDN control centralization concept brings significant advantages for management and control in SDN together with the programmability of the data plane. SDN represents a paradigm shift towards agile, efficient, and secure network infrastructures, moving away from traditional, hardware-centric models to embrace dynamic, software-driven paradigms. SDN is compliant also with the virtualization architecture defined in the Network Function Virtualization framework. However, SDN should cooperate seamlessly for some years with the distributed TCP/IP control developed during the years all over the world. Among others, the traditional tasks of routing, forwarding, load balancing, QoS assurance, security, and privacy should be solved. The SDN native centralization brings also some new challenges and problems which are different from the traditional distributed control IP networks. The algorithms and protocols usable in SDN should meet requirements like scalability, convergence, redundancy assurance, sustainability, and good real-time response, and allow orchestrated automation in enhancing network resilience and adaptability. This work presents a theoretical review of state-of-the-art SDN optimization techniques, offering a critical and comparative discussion of various algorithms having tasks such as routing (including dynamic ones), forwarding, load balancing and traffic optimization, and forwarding delay minimization. Attention is pointed to general algorithms which can offer pragmatic solutions for large systems or multiple metric routing.

The role of the fecal microbiota in inflammatory bowel disease.

The understanding of the potential role of the microbiota in the pathogenesis of inflammatory bowel disease (IBD) is ever-evolving. Traditionally, the management of IBD has involved medical therapy and/or surgical intervention. IBD can be characterized by gut microbiome alterations through various pathological processes. Various studies delve into nontraditional methods such as probiotics and fecal microbiota transplant and their potential therapeutic effects. Fecal microbiota transplant involves the delivery of a balanced composition of gut microorganisms into an affected patient via multiple possible routes and methods, while probiotics consist of live microorganisms given via the oral route. At present, neither method is considered first-line treatment, however, fecal microbiota transplant has shown potential success in inducing and maintaining remission in ulcerative colitis. In a study by Kruis and colleagues, Escherichia coli Nissle 1917 was considered to be equivalent to mesalamine in mild ulcerative colitis. Alteration of the microbiome in the management of Crohn's disease is less well defined. Furthermore, variation in the clinical usefulness of 5-aminosalicylic acid medication has been attributed, in part, to its acetylation and inactivation by gut microbes. In summary, our understanding of the microbiome's role is continually advancing, with the possibility of paving the way for personalized medicine based on the microbiome.

Widening research participation: a survey exploring stakeholders' views about opportunities for older adults living in UK care homes to participate in research

Background/Aims Older adults living in care homes are underrepresented in research, resulting in a poorer evidence base for their care. Increasing opportunities and ability for care home residents to be included in research is urgently needed. This survey explored the views and experiences of relevant stakeholders in the UK about opportunities for residents to participate in research, decisions about participation, and the barriers and facilitators to their involvement. Methods The survey was conducted from September to December 2022 using an online survey tool or paper-based format. Participants were recruited via multiple routes, including social media and contact with care homes. Quantitative data were analysed using descriptive statistics and free-text responses were analysed using content analysis. Results A total of 80 participants responded to the survey, of which 46 were suitable for analysis from care home residents (n=6), relatives (n=11), care home staff (n=14), other health and social care professionals who work with care homes (n=7), and researchers (n=8). The main barriers identified were the discordance between stakeholders' awareness of research opportunities and difficulties with residents' communication needs. Facilitators included effective communication between stakeholders, positive staff engagement and researchers' flexibility. Conclusions There are a number of barriers to the inclusion of care home residents in research. There is a need to develop strategies to improve communication and relationships between stakeholders, as well as training programmes to educate stakeholders about care home-based research and its benefits. Implications for practice These findings can support the development of strategies to improve communication and relationships between stakeholders, training programmes to educate stakeholders about care home research and its benefits, and targeted interventions to improve research inclusion for UK care home residents.

Hospital-Associated Transmission of Candida auris from Adult to Pediatric Patient

Background: Candida auris, an emerging multidrug-resistant fungus, is often difficult to control in hospital outbreaks. We report the hospital investigation and findings of a transmission of C. auris from patients hospitalized in an adult unit to a pediatric unit, the first in Maryland. Methods: Between June and September 2023, C. auris was recovered from two patients admitted to an adult Neuroscience Intensive Care Unit (ICU) and a patient admitted to a pediatric ICU. Infection control initiated an investigation involving staff interviews, observations and chart reviews. Cases were defined as any patient with clinical or surveillance cultures growing C. auris. Point prevalence surveillance was conducted by collecting nares and composite axilla/groin swabs from patients on the affected units. Environmental cultures collected using moistened E-Swabs (Copan, Murrieta, CA) from shared supplies were plated on CHROMagar Candida (BD, Sparks, MD). C. auris isolates from patients hospitalized at the facility between February 2022 and October 2023 were analyzed by WGS for relatedness. WGS was performed using Illumina NextSeq 300 bp paired-end sequencing (Illumina, San Diego, CA). Single nucleotide polymorphism (SNP) analysis was performed by comparing raw reads to the reference C. auris B8441 genome for subsequent clustering analysis (Ares Genetics, Vienna, Austria). Results: WGS demonstrated isolates from two adults and one pediatric patient were less than three SNPs different, suggesting a shared isolate. One additional pediatric case was identified from surveillance cultures collected from 27 patients. Investigation into possible transmission routes revealed healthcare personnel serving both units, specifically clinical teams and continuous electroencephalography (cEEG) technologists. Additionally, cEEG equipment was used on both adult and pediatric patients and twelve equipment surface swabs and three samples each of measuring tape and gel were collected. C. auris was not isolated, however sensitivity of environmental sampling is unclear and suspicion for possible fomite/environmental transmission persisted. Other possible transmission routes included gaps in hand hygiene, isolation, disinfection of shared equipment, and reuse of single-use items. Interventions included improving and monitoring infection prevention practices, educating multi-disciplinary personnel and heightened environmental cleaning. Conclusion: This case highlights the feasibility of transmission of C. auris between patients admitted to a geographically distant unit. Our investigation revealed multiple possible routes of transmission including direct contact (from healthcare personnel or equipment) or indirect environmental sources. Prevention of hospital-associated C. auris transmission likely necessitates meticulous adherence to hand hygiene, contact precautions, and careful cleaning and disinfection of patient environments and equipment used by all disciplines.Disclosure: Patricia Simner: Research Contracts: BD Diagnostics, OpGen Inc., Qiagen Sciences Inc, T2 Diagnostics, Accelerate Diagnostics; Research Collaborators:Ares Genetics, CosmosID, IDbyDNA, Illumina; Consulting: OpGen Inc., BD Diagnostics, Shionogi Inc., GeneCapture, Qiagen Sciences Inc, Entasis, Day Zero Diagnostics, Next Gen Diagnostics

On the resolution of sexual conflict over shared traits.

Anisogamy, different-sized male and female gametes, sits at the heart of sexual selection and conflict between the sexes. Sperm producers (males) and egg producers (females) of the same species generally share most, if not all, of the same genome, but selection frequently favours different trait values in each sex for traits common to both. The extent to which this conflict might be resolved, and the potential mechanisms by which this can occur, have been widely debated. Here, we summarize recent findings and emphasize that once the sexes evolve, sexual selection is ongoing, and therefore new conflict is always possible. In addition, sexual conflict is largely a multivariate problem, involving trait combinations underpinned by networks of interconnected genes. Although these complexities can hinder conflict resolution, they also provide multiple possible routes to decouple male and female phenotypes and permit sex-specific evolution. Finally, we highlight difficulty in the study of sexual conflict over shared traits and promising directions for future research.

Investigate the Relationship Between the Presence of JCV DNA and the Immunohistochemical Expression of CK2 0, CK7, and CDX2 in Colorectal Cancer

Abstract Background: Globally, colorectal cancer (CRC) is the most common malignancy and has a high fatality rate. Early childhood the John Cunningham virus or JC virus (JCV) infection persists throughout life and has been linked through multiple routes to colorectal cancer. The expression of cytokeratins 7 (CK7), 20 (CK20), and CDX2 have been investigated in a variety of primary and metastatic carcinomas, and their patterns of expression may be used to determine the site of origin of metastatic carcinomas. Objectives: The aim is to assess the relationship between JCV DNA and tumor markers (CK7, CK20, and CDX2) in patients with colorectal cancer, this study was carried out. Materials and Methods: Ninety CRCs (45 of which were squamous cell carcinomas and 45 of which were adenocarcinomas) had their paraffin sections randomly chosen, extracted, and immunostained for CK7, CK20, CDX2, and for the detection of JCV DNA by real-time (PCR). Results: JCV DNA was detected in 22 (24.4%) of AD-CRC and 24 (26.7%) of SCC-CRC (P = 0.004). The presence of JCV was significantly correlated with tumor stages (P = 0.04) and age categories (P = 0.05). Moreover, JCV presence was significantly correlated with all studied tumor markers (P < 0.05). Conclusion: JCV might play a role in the development of colorectal cancer, and CDX2, which is highly specific and sensitive as markers of colorectal origin should be helpful in the detection of intestinal adenocarcinomas.

Electrophoretic Deposition and Characterization of Curcumin/Chitosan Coatings

The purpose of the study was to investigate the electrophoretic deposition (EPD) route, microstructure and surface properties of composite curcumin/chitosan coatings on commercially pure titanium substrates for biomedical applications. Multiple routes of preparation of the dispersed systems for the EPD process and their electrokinetic properties have been investigated to obtain homogeneous coatings. The zeta potential of solutions with various curcumin content in ethanol or isopropanol proved their relatively low electrophoretic mobility. Thus, curcumin was co-deposited with chitosan molecules on the cathode. The surface morphology of the coatings consisted of submicrometric curcumin particles embedded in the chitosan matrix. The increase in the curcumin content in the ethanol caused large agglomerates and undissolved curcumin particles to appear on the coating surface. The coatings were characterized by high adhesion to the substrate and a water contact angle in the range of 85° to 95°. The coatings changed the zeta potential of the titanium surface from significantly negative (−46.7 ± 2.3 mV) to less negative values (−20.6 ± 2.6 mV). The developed coatings are promising for mitigating biofilm formation on the surface of titanium bone implants.

Implementation of automation configuration of enterprise networks as software defined network

Software defined network (SDN) is a new computer network configuration concept in which the data plane and control plane are separated. In Cisco system, the SDN concept is implemented in Cisco Application Centric Infrastructure (Cisco ACI), which by default can be configured through the main controller, namely the Application Policy Infrastructure Controller (APIC). Conventional configuration on Cisco ACI creates problems, i.e.: the large number of required configurations causes the increase of time required for configuration and the risk of misconfiguration due to repetitive works. This problem reduces the productivity of network engineers in managing Cisco system. In overcoming these problems, this research work proposes an automation tool for Cisco ACI configuration using Ansible and Python as an SDN implementation for optimizing enterprise network configuration. The SDN is implemented and experimented at PT. NTT Indonesia Technology network, as a case study. The experimental result shows the proposed SDN successfully performs multiple routers configurations accurately and automatically. Observations on manual configuration takes 50 minutes and automatic configuration takes 6 minutes, thus, the proposed SDN achieves 833.33% improvement.

Implementation of automation configuration of enterprise networks as software defined network

Software defined network (SDN) is a new computer network configuration concept in which the data plane and control plane are separated. In Cisco system, the SDN concept is implemented in Cisco Application Centric Infrastructure (Cisco ACI), which by default can be configured through the main controller, namely the Application Policy Infrastructure Controller (APIC). Conventional configuration on Cisco ACI creates problems, i.e.: the large number of required configurations causes the increase of time required for configuration and the risk of misconfiguration due to repetitive works. This problem reduces the productivity of network engineers in managing Cisco system. In overcoming these problems, this research work proposes an automation tool for Cisco ACI configuration using Ansible and Python as an SDN implementation for optimizing enterprise network configuration. The SDN is implemented and experimented at PT. NTT Indonesia Technology network, as a case study. The experimental result shows the proposed SDN successfully performs multiple routers configurations accurately and automatically. Observations on manual configuration takes 50 minutes and automatic configuration takes 6 minutes, thus, the proposed SDN achieves 833.33% improvement.

Sharing Data from the Human Tumor Atlas Network through Standards, Infrastructure, and Community Engagement.

The Data Coordinating Center (DCC) of the Human Tumor Atlas Network (HTAN) has played a crucial role in enabling the broad sharing and effective utilization of HTAN data within the scientific community. Data from the first phase of HTAN are now available publicly. We describe the diverse datasets and modalities shared, multiple access routes to HTAN assay data and metadata, data standards, technical infrastructure and governance approaches, as well as our approach to sustained community engagement. HTAN data can be accessed via the HTAN Portal, explored in visualization tools-including CellxGene, Minerva, and cBioPortal-and analyzed in the cloud through the NCI Cancer Research Data Commons nodes. We have developed a streamlined infrastructure to ingest and disseminate data by leveraging the Synapse platform. Taken together, the HTAN DCC's approach demonstrates a successful model for coordinating, standardizing, and disseminating complex cancer research data via multiple resources in the cancer data ecosystem, offering valuable insights for similar consortia, and researchers looking to leverage HTAN data.

Evaluation of Hematotoxicity in Female Wistar Rats Following Sub-Acute Inhalation Exposure to Polyethylene Microplastic

Polyethylene (PE) becomes a source of microplastics that can be widely distributed through the digestive and respiratory systems. However, its effects on blood cells are still being investigated. This study aims to analyze the impact of Polyethylene Microplastic (PE-MPs) exposure on the blood of female rats, including erythrocytes, leukocytes, and platelets. This study used female Wistar rats, which were divided into control and PE-MP groups. PE-MP was administered via whole-body inhalation at a concentration of 15 mg/m³ for 4 hours daily for 28 days. The absorption of plastic particles detected in the human bloodstream is likely to occur through mucosal contact (either through ingestion or inhalation). After the exposure period, the rats were euthanized to collect blood samples through the heart. A complete blood count was performed using an automatic hematology analyzer, and blood morphology was analyzed using thin blood smears. This study used the Mann-Whitney test. PE-MP exposure increased erythrocyte and platelet counts without a corresponding rise in leukocytes. Erythrocytes showed abnormal morphology (12.73% with ovalocytes and tear-shaped cells). Erythrocyte indices (MCV, MCH, MCHC) showed no significant differences. Platelet count rose by 1.7% (p-value= 0.017). Leukocyte and neutrophil counts were lower (0.84 and 0.94 times lower, respectively), while lymphocytes and monocytes were higher (1.03 and 1.61 times higher, respectively) in the PE-MP group compared to controls. The neutrophil-to-lymphocyte ratio did not differ significantly. PE-MP exposure in rats disrupts blood parameters, altering erythrocyte morphology and increasing platelet counts. Potential causes include oxidative stress, immune responses, and compensatory mechanisms. Study limitations include a small sample size and exclusive focus on inhalation exposure. Integrating multiple exposure routes (inhalation, ingestion, dermal) could offer a broader view of microplastic impacts. Future research with larger samples, diverse doses and durations, and exploration of additional markers or organ-specific effects is crucial for understanding PE-MP toxicity in real-world scenarios.

A study of uncertain 4D transportation problems with rough interval parameters and additional real-life factors

In developing countries like India and Nepal, a vehicle document verification system is implicated at the checkpoints and border crossings that allows users to authenticate and verify the validity of vehicle related documents such as registration certificates, driving licenses, pollution under control certificates, and insurance policies. This results in the formation of long queues of the vehicles and hence a significant time wastage. These vehicles waiting in the long queues, continue to emit carbon dioxide and other greenhouse gases into the atmosphere. To address these issues, the government has introduced the Automated Number Plate Recognition (ANPR) technology which plays a significant role in the efficient and accurate document verification by identifying and validating vehicle registration details. It also automates toll collection by capturing the vehicle’s number plate, reducing waiting times and congestion at toll barriers. To analyze all these benefits, in this study, for the first time, ANPR technology has been introduced in the multi-objective model of transportation problem and its impact on various objectives has been observed. Also, real-life factors: fixed-charge cost, carbon emission, multiple routes have been considered in the proposed model and the problem is named as multi-objective fixed-charge four dimensional green transportation problem. Rough set theory has been employed as a tool for effectively addressing the indeterminacy and facilitating the modeling of real-life transportation problems. Two methods: the expected value method and the rough chance constrained programming method, are proposed to transform the suggested model of multi-objective transportation problem into a deterministic form. To solve these transformed models, a new multi-objective optimization approach based on the neutrosophic theory, named as neutrosophic goal programming has been introduced. To further demonstrate the practicality of the proposed study, an application for the apple fruit transportation has been solved. Detailed comparisons between obtained results are done on the basis of different modeling perspectives, different solution techniques and also with/and without ANPR technology. Based on the outcomes, the suggested neutrosophic goal programming technique proved to be superior to the existing techniques in the literature.

Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 μg/mL (25.2, 33.4), 58.5 μg/mL (49.4, 69.3), and 257.2 μg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 μg/mL (8.8, 13.3) and 22.8 μg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 μg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 μg/mL (2.5, 4.6), 6.5 μg/mL (5.6, 7.5), and 27.2 μg/mL (23.9, 31.0) with IV dosing; 0.97 μg/mL (0.65, 1.4) and 3.1 μg/mL (2.2, 4.3) with SC dosing, and 2.6 μg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

DIPG-29. PHENOTYPIC SCREENS IDENTIFY GENETIC REGULATORS OF NANOPARTICLE DELIVERY IN DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND Diffuse midline gliomas (DMGs) are a universally fatal pediatric brain tumor with a median survival of 12 months. There is a dire need to develop novel treatment strategies for these patients. Nanomedicine harbors great potential to encapsulate cargoes across tissue barriers and selectively target cells of interest. To effectively utilize existing nanomedicines and develop design criteria for novel formulations, an improved understanding of nano-bio interactions within the context of disease and development is required. METHODS We harnessed a lentiviral all-in-one CRISPR/Cas9 knock-out library paired with fluorescence-activated cell sorting to probe the functional impact of 700 genes on the delivery of lipid-based nanoparticles to DMGs. Layer-by-layer electrostatic assembly was utilized to synthesize a library of liposomal nanoparticles with polymer surface coatings. RESULTS Two patient-derived neurosphere models of DMG were transduced with the pooled, barcoded all-in-one CRISPR/Cas9 library. Following selection, cells were incubated with nanoparticles for 1, 4, or 24 hours and dynamically sorted into populations based on nanoparticle affinity. Genomic DNA was isolated from sorted cells and subjected to next generation sequencing for barcode identification. The relative enrichment of each single guide RNA in each population was determined relative to matched controls. We found strong agreement between biologic replicates and both cell lines, and our phenotypic screens revealed strong genetic regulators of nanoparticle uptake. We identified formulation-dependent and independent regulators, as well as regulators that were time-dependent. The top target genes are currently being validated in DMG and human neural stem cell models. CONCLUSIONS In ongoing work, we are leveraging genetic and chemical inhibition to sensitize DMG cells to nanoparticle therapeutics. We plan to leverage our screening technique to develop novel combination therapy approaches that could be implemented across multiple administration routes to enhance the use of nanomedicine for DMG and other pediatric brain tumors.

Multiple Constraint Hybrid Travel Route Recommendation Model Based on Collaborative Filtering Recommendation Algorithm

The study presents a hybrid model for recommending travel routes that takes into account multiple constraints. This model is based on a collaborative filtering recommendation algorithm and addresses the issue of disorganized travel route recommendations. To improve upon the k-mean clustering algorithm, the proposed model introduces the Dynamic Gaussian Kernel Density K-means algorithm. After the data was processed, the initial clustering center was determined and k-means clustering was performed. Subsequently, the travel route recommendation model was created by integrating various constraints. The study’s proposed algorithm was compared with alternative algorithms, and the experimental results demonstrated superior performance across a range of datasets, with the minimum sum of squared errors and a running time of approximately 1.4 seconds - a noteworthy improvement. Comparative experiments were conducted on various forgetting coefficients in the model, and the forgetting coefficient with the lowest sum-of-squares of errors was selected to replace the existing one. Upon comparing the proposed research model with other models, it was found that the former had greater accuracy and recall, amounting to 98.1% and 96.8% respectively. This suggests that the proposed research model serves as a more efficient solution for travel route recommendation.

Operation risk assessment of Flexible Manufacturing Networks subject to quality-reliability coupling

In flexible manufacturing network (FMN), the growth of product types increases the diversity of interacting behaviors between machine reliability and product quality, and the product diversity and machine flexibility promote the explosion of processing routes and processing sequences, increasing the gap between current risk evaluation of manufacturing systems and engineering practice. To fill this gap, a novel operation risk assessment framework is constructed for the complex FMN. In detail, to model the reliability-quality interactions, a mathematical framework describing a complete manufacturing process involving "feedstock quality (Q1) - machine degradation (R) - product processing quality (Q2) - quality inspection status (I)" is proposed for complex FMN, solving the measurement of interacting behaviors between machine reliability and product quality in an FMN that suffers from both multiple process routes and multi-type products. Then, an effective evaluation framework is proposed to evaluate the connectivity risk of multiple process routes and the quality risk of multiple product types in a complex FMN, providing a concurrent solution for risk evaluation under both complex system structures and complex quality-reliability interrelationships. At last, a simulation experiment verifies the effectiveness of our proposed methods and reveals differences in the operation risk of different product types in an FMN.

Comparative Analysis of Nebulized Versus Intravenous Fentanyl for Pain Control After Tonsillectomy: A Double-Blind, Randomized, Controlled Trial.

Effective posttonsillectomy analgesia is crucial for patient comfort and recovery. Fentanyl, notable for its potency, rapid action, and lipophilicity, has been successfully used in various procedures through multiple administration routes. However, the use of its nebulized form for posttonsillectomy pain has not been extensively explored. This study sought to compare the analgesic efficacy, onset time, and complications between nebulized and intravenous fentanyl in posttonsillectomy patients. In this randomized controlled trial, adult patients who underwent tonsillectomy were assigned to either an intravenous fentanyl group (1 mcg/kg) or a nebulized fentanyl group (4 mcg/kg). In both groups, fentanyl was administered when pain scores exceeded three. Pain levels were monitored every 5 minutes until they fell below four. The study also recorded the duration until the next analgesia request and noted complications (such as respiratory depression, bradycardia, chest tightness, drowsiness, nausea, pruritus, sweating, and flushing) within 24 hours. Patient exclusions were based on predetermined criteria. From an initial cohort of 59 patients, 22 in the intravenous group and 27 in the nebulizer group were eligible for analysis after applying the exclusion criteria. The nebulizer group exhibited a significantly prolonged period before the next analgesia request, with a median of 683.5 minutes (interquartile range 260-1440), in contrast to the 326.7 minutes (145.0-504.7) observed in the intravenous group (P = .009). The time to achieve a pain score less than 4 and the incidence of side effects did not differ significantly between the groups. Nebulized fentanyl provided a longer duration of analgesia than intravenous fentanyl in posttonsillectomy pain management, with similar onset times and side effect profiles. These findings underscore the potential of nebulized fentanyl as an effective alternative for pain control in posttonsillectomy patients.

“If it wasn’t for them, I don’t think I would be here”: experiences of the first year of a safer supply program during the dual public health emergencies of COVID-19 and the drug toxicity crisis

BackgroundIn response to the devastating drug toxicity crisis in Canada driven by an unregulated opioid supply predominantly composed of fentanyl and analogues, safer supply programs have been introduced. These programs provide people using street-acquired opioids with prescribed, pharmaceutical opioids. We use six core components of safer supply programs identified by people who use drugs to explore participant perspectives on the first year of operations of a safer supply program in Victoria, BC, during the dual public health emergencies of COVID-19 and the drug toxicity crisis to examine whether the program met drug-user defined elements of an effective safer supply model.MethodsThis study used a community-based participatory research approach to ensure that the research was reflective of community concerns and priorities, rather than being extractive. We interviewed 16 safer supply program participants between December 2020 and June 2021. Analysis was structured using the six core components of effective safer supply from the perspective of people who use drugs, generated through a prior study.ResultsEnsuring access to the ‘right dose and right drugs’ of medications was crucial, with many participants reporting success with the available pharmaceutical options. However, others highlighted issues with the strength of the available medications and the lack of options for smokeable medications. Accessing the safer supply program allowed participants to reduce their use of drugs from unregulated markets and manage withdrawal, pain and cravings. On components related to program operations, participants reported receiving compassionate care, and that accessing the safer supply program was a non-stigmatizing experience. They also reported receiving support to find housing, access food, obtain ID, and other needs. However, participants worried about long term program sustainability.ConclusionsParticipants in the safer supply program overwhelmingly appreciated it and felt it was lifesaving, and unlike other healthcare or treatment services they had previously accessed. Participants raised concerns that unless a wider variety of medications and ability to consume them by multiple routes of administration became available, safer supply programs would remain unable to completely replace substances from unregulated markets.