To describe the integration of the Fundamentals of Care framework into clinical quality development in a large hospital department and explore how it contributed to shared understanding, implications for nursing leadership, and operationalization. The study was a descriptive organizational case study combining top-down policy direction with bottom-up operationalization of a nursing framework in routine clinical settings. The study was conducted in a Danish regional university hospital department encompassing four medical specialties. Methods for integration included a professional governance structure with steering group meetings and inter-ward networks. Data on integration outcomes included the products developed under this governance structure as well as surveys of hospital-wide opinions about framework implementation. Integration outcomes included reflective tools, shared quality improvement themes, use of appreciative inquiry-guided engagement processes, and quarterly improvement cycles that addressed fundamental care topics across diverse clinical contexts. Furthermore, hospital-wide surveys indicated that the framework provided a shared language and values base for quality improvement but required operationalization to achieve clinical relevance. Integration was supported by the professional governance attributes accountability, professional obligation, collateral relationships, and decentralized decision-making. While direct impacts on patient outcomes were difficult to isolate, the Fundamentals of Care framework fostered reflective practice and alignment with core nursing values. Integrating a theoretical framework like Fundamentals of Care into clinical quality development is feasible but requires deliberate translation, leadership support, and organizational structures that prioritize professional autonomy and cross-level collaboration. The Fundamentals of Care framework can serve as catalyst for cultural transformation when integrated through professional governance structures. Local adaptation, reflective tools, and relationship-based approaches support sustainability and clinical anchoring.
Mucous boundary layers on epithelial tissues facilitate mechanical interactions during sliding contact in the mouth, while the loss of mucous lubrication may lead to lubrication failure, tissue exposure and mechanical trauma from direct contact between sliding tissues. This study introduces a biofidelic model created by adhering human oral squamous epithelial cells onto polydimethylsiloxane (PDMS) in the presence of a lubricating layer provided by either porcine gastric mucins (PGM) or bovine submaxillary mucins (BSM). The integration of mucous lubrication and a cell monolayer in tribological studies offers a novel approach for simultaneously evaluating friction and cell monolayer damage induced by alterations in the lubricating layer. Dynamic light scattering (DLS), tribometry, and live-dead cell assays revealed that BSM outperformed PGM in reducing friction and minimizing cell damage. BSM showed the lowest coefficient of friction (COF) compared to the absence of mucins which resulted in a 300% increase in COF (p = 0.01) and a 150% increase compared to PGM (p = 0.04). PGM mucous layers increased cell damage from 17% to 38%, while BSM mucous layers reduced cell damage to about 7%, demonstrating a protective effect, superior to both the absence of mucins and the presence of PGM.
Particulate matter (PM2.5), an environmental pollutant composed of various components, can affect multiple organs. In particular, PM2.5 generated in pig farms contains substances produced in enclosed livestock environments, such as decomposed feed and manure, animal hair, and byproducts of animal activity. However, comprehensive studies investigating the effects of PM2.5 concentration, composition, and metal content on female reproductive function remain limited. In this study, we evaluated the impact of metal components in pig farm-derived PM2.5 on ovarian function and oocyte quality by exposing mice to intratracheal instillation. One week after exposure to metal components (calcium, iron, aluminum, zinc, and lead), ovarian development, apoptosis, and related molecular mechanisms were examined. We investigated their effects on oocyte maturation and developmental competence. The results showed that metal exposure induced ovarian inflammation and apoptosis via the PI3K/AKT signaling pathway. Furthermore, impaired oocyte maturation, spindle abnormalities, abnormal mitochondrial distribution, elevated reactive oxygen species (ROS) levels, and activation of mitochondrial membrane potential (MMP) and TGF-β were observed. In conclusion, our findings indicate that the metal components of PM2.5 from a pig farm can adversely affect ovarian function and oocyte maturation.
Our objective was to examine the association between mid-pregnancy leptin concentration and preeclampsia risk, adjusting for maternal risk factors. We studied 1504 women with singleton pregnancies in the Project Viva cohort. The exposure was mid-pregnancy plasma leptin concentration (mean gestational age 28 weeks), categorized into tertiles. The primary outcome was preeclampsia during that pregnancy. The secondary outcome was self-reported preeclampsia during subsequent pregnancies. We used multivariable logistic regression to assess the association of leptin tertiles with preeclampsia, adjusting for pre-pregnancy BMI, first trimester gestational weight gain, history of hypertension, age, and parity. There were two (0.4%) cases of preeclampsia among participants in the lowest leptin tertile, 20 (4.0%) in the middle tertile, and 29 (5.8%) in the highest tertile. Higher leptin levels were associated with higher odds of preeclampsia after adjustment for confounders. Compared to the lowest tertile, odds ratios were 7.5 (95% CI 1.7, 32.7) for the middle tertile and 7.0 (95% CI 1.5, 31.9) for the highest tertile. Higher leptin levels were also associated with higher odds of preeclampsia in subsequent pregnancies (6.1% vs 0.9% in the middle vs. lowest tertile, OR 6.4, 95% CI 0.7, 57.0), although the estimates were highly imprecise due to the small sample size. Higher mid-pregnancy leptin concentrations were associated with increased risk of preeclampsia, independent of maternal age, pre-pregnancy BMI, first trimester gestational weight gain, history of hypertension, and parity. Additionally, our results suggest that elevated leptin during a prior pregnancy may increase preeclampsia risk in subsequent pregnancies.
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Nano-sized particles and elongated mineral particles (EMPs) pose significant inhalation hazards in mineral extraction and processing, and are key contributors to pneumoconiosis, yet their inhalation risks remain inadequately characterized. In this study, a high-fidelity CFD-based modelling framework was developed to systematically investigate inhalation and deposition characteristics of ultrafine and EMPs in an all-in-one human airway model coupled with a breathing region. The size distribution and morphology of mineral dusts were first experimentally examined. A wide range of micro- and nano-sized spherical particles, together with elongated particles with varying aspect ratios, were then numerically simulated with various breathing rates using User-Defined Function. Their transport and deposition patterns were qualitatively visualized and deposition efficiency in total and regional airway areas was systematically evaluated. The outcomes revealed that in the upper airway, micro-sized particles 10μm exhibited high deposition (up to ∼80% in the nasal cavity), while nanoparticles remained below 3% and insensitive to breathing rate. In contrast, nanoparticles showed enhanced deep lung penetration, with deposition up to ∼4% in the trachea and individual lobes and ∼52% reaching pulmonary regions. For EMPs, deposition was strongly morphology-dependent and non-monotonic. High-aspect-ratio particles (β=50) showed up to ∼20% higher deposition in the nasal cavity compared to other β values, while moderate aspect ratio (β=5) yielded the highest deposition efficiency (∼7%) in the lower airway. This study is expected to highlight the necessity of explicitly accounting for nanoscale effects and particle morphology in assessing inhalation risks associated with mineral dust exposure.
Cancer and its treatment-related effects may impair fertility and increase reproductive concerns (RCs) among adolescent and young adult (AYA) survivors at their peak reproductive years. To assess RCs in survivors and examine their associated factors and pathways. A cross-sectional study was conducted with 209 AYA cancer survivors aged 15-39 years from June 2023 to December 2024. Participants' RCs, cancer-related sexual and reproductive health knowledge, attitudes, and needs were measured. Multiple linear regression and structural equation modeling were performed. Participants' mean RCs score was 70.17 ± 6.70. Regression showed that cancer-related sexual and reproductive health attitudes (B = 0.646, p < 0.001), needs (B = 0.516, p = 0.001) were positively associated with RCs. Awareness of fertility preservation options, including sperm donation (B = 2.034, p = 0.005) and testicular replacement (B = 2.224, p = 0.044), was also positively associated with RCs. Conversely, endorsement of artificial uterus technology (B = -3.032, p = 0.007), perceived impact of habitual sleep deprivation on fertility (B = -1.491, p = 0.030), and a history of hematologic malignancy (B = -6.256, p = 0.003) were negatively associated with RCs. Structural equation modeling showed that attitudes (β = 0.531, p < 0.001), knowledge (β = 0.201, p = 0.003), and needs (β = 0.295, p = 0.006) were significantly associated with RCs. RCs among AYA cancer survivors are associated with sexual and reproductive health-related attitudes, knowledge, needs. Integrated education and supportive care may be relevant for addressing RCs in this population.
Sleepiness, fatigue, and shiftwork are three aspects of daily life that might affect individuals' safety when driving. Driving behaviours are commonly assessed via self-report measures. In this study, different self-reported measures of driving behaviours are compared to test their sensitivity to measures of sleepiness, fatigue, and night shiftwork. Police shiftworkers from English forces completed a survey that included questions about shiftwork, sleep, fatigue, and included three measures of driving behaviour: The Driver Behaviour Questionnaire (DBQ - Lawton et al., 1997; Reason et al., 1990), Smith's (2016) measures of poor and fatigued driving, and self-reported collision frequencies. Hierarchical regressions confirmed that the driving behaviour measures were differentially sensitive to aspects of sleepiness, fatigue, and shiftwork. Responses to Smith's components of driver fatigue and risk taking, and questions on collision frequencies, but not responses to the DBQ, could be predicted from the proportion of night shifts a person worked. Conversely, only the DBQ was sensitive to fatigue as a predictor of poor driving. All measures were sensitive to aspects of sleepiness and the extent to which it predicted driving outcomes (Adj. R2) differed between scales. Self-reported collision data was least sensitive to contexts of shiftwork, sleepiness and fatigue and such data should be used cautiously to explore effects of sleep and shiftwork on driving behaviour. The present findings highlight the importance of using scales that are sensitive to the context of investigations (e.g., shiftwork). Relying on inappropriate scales could lead to the underreporting of poor driving behaviours in sleepy and shiftworking drivers.
Novel psychoactive substances (NPSs), due to rapid emergence and evolving use patterns, pose a significant public health surveillance challenge. Traditional surveillance lags street-level reality, necessitating the exploration of novel strategies and data sources like Reddit for continuous NPS trend monitoring and presenting a public dashboard. We mined data from 60,601 subreddits between January 2015 and June 2025 for seven NPSs (kratom, xylazine, medetomidine, nitazenes, tianeptine, bromazolam, and 2C-B) using keyword-variants. We performed Mann-Kendall trend tests to assess temporal patterns, computed correlations to compare post volumes with National Forensic Laboratory Information System (NFLIS) drug report counts (2015-2024), conducted cross-correlation analyses at ±2-year lags to identify lead-lag relationships, and created a public dashboard for data visualization. The dataset comprised 328,223 posts from 139,901 accounts. We observed moderate to strong correlations between Reddit volumes and three out of five NPSs with NFLIS reports: bromazolam (ρ = 0.81, p < 0.001), tianeptine (ρ = 0.48, p = 0.04), xylazine (ρ = 0.60, p < 0.001). Cross-correlation analyses indicated Reddit discussions preceded NFLIS reports for medetomidine (ρ = 0.93, lag = -2 years), bromazolam (ρ = 0.86, lag = -1year), tianeptine (ρ = 0.81, lag = -2years), and xylazine (ρ = 0.62, lag = -2years), suggesting Reddit discussions as a potential leading indicator. Co-mention of other substances with NPSs often matched known trends from retrospective data. Reddit-based surveillance provides timely and complementary signals to traditional forensic systems for NPS monitoring. Interactive visualizations and downloadable aggregated statistics are available via our dashboard.
Microvascular thromboinflammation is a pervasive yet under-recognized driver of multisystem morbidity that links focal endothelial injury to distal organ dysfunction through interacting cellular and plasmatic networks. Contemporary paradigms remain fragmented: clinicians often treat symptoms or isolated pathways, trials enroll biologically heterogenous populations, and candidate biomarkers lack harmonized standards-together impeding translation from mechanistic insight to durable patient benefit. In this review we synthesize the evidence into a cohesive, systems-level architecture in which endothelial activation, platelet hyperreactivity, innate immune effectors (including NETosis), and impaired fibrinolysis form predictable feed-forward circuits that generate organ-selective vulnerability. We propose an integrated diagnostic-translational toolkit that anchors spatially resolved imaging endophenotypes (molecular PET, quantitative perfusion MRI, advanced flow imaging) to fluid-phase molecular readouts (cfDNA topology, NET fragments, platelet transcriptomes, endothelial microparticles) and multi-omic modules. This framework enables reproducible endotype discovery and supports biomarker-guided, stage-specific interventions. Translational strategies prioritized here include targeted anti-NET approaches, precision layering of antiplatelet/anticoagulant therapy, endothelial-directed redox and metabolic reprogramming, selective epigenetic modulation, and lesion-directed nanoparticle delivery; each is linked to companion biomarker and imaging readouts and tailored safety considerations-especially for reproductive-age populations. To accelerate clinical impact we recommend a coordinated roadmap: (i) rigorous causal validation across human-relevant platforms and scaled animal models; (ii) consensus preanalytic and analytic standards with reference materials for key thromboinflammatory biomarkers; (iii) prospective cohorts embedding serial imaging and liquid-biopsy multi-omics to derive and validate endotypes; and (iv) adaptive, biomarker-enriched clinical trials with organ-relevant surrogate endpoints and long-term vascular surveillance. By aligning mechanistic clarity, diagnostic fidelity, and pragmatic trial design, this integrated approach aims to convert mechanistic knowledge into precision diagnostics and therapies-and to transform microvascular thromboinflammation from an intractable clinical problem into a tractable target for prevention and repair.
Alcohol use disorder (AUD) is a serious public health challenge associated with increased morbidity and mortality. While AUD is more common among males, the sex gap is narrowing; nevertheless, AUD remains underdiagnosed in females. Identifying sex-specific multimorbidity patterns could improve targeted screening and identification. Using the Norwegian Patient Registry, we identified 67,358 individuals with AUD (31.2% female) and age- and sex-matched controls. We compared sex differences in the prevalence of the 20 most common mental and somatic diagnoses within and between the AUD group and controls. We analysed multimorbidity using upset plots and correlation networks. Females with AUD had higher overall multimorbidity than males (median 9 [IQR: 5-14] vs. 6 [3-11] diagnoses). Asthma, eating disorders, and dementia were overrepresented among females with AUD. The most common diagnosis combinations in females with AUD involved overlaps between mental and somatic conditions, particularly other substance use disorders or depression combined with soft tissue disorders, urinary tract infections, or medical abortion. Males predominantly showed within-domain combinations. Correlation network analyses revealed a distinct pain-related cluster linking mental and somatic conditions in females with AUD, but not in control females. Females with AUD experience a disproportionately high level of multimorbidity, with distinct patterns, often involving combinations of somatic and mental diagnoses. Pain conditions serve as important links between mental and somatic comorbidity, especially for females. These findings support further investigation into sex-specific screening protocols, recognition of distinct clinical contact points, and integrated treatment approaches for AUD.
Liver cancer is one of the most prevalent malignant tumors worldwide that poses significant challenges to conventional treatment due to issues such as poor biocompatibility, inadequate targeting, and the limited efficacy of single-agent therapies. These limitations can reduce treatment effectiveness and make accurate antitumor therapy more difficult. In recent years, the rapid development of multifunctional nanotechnology have substantially improved liver cancer treatment. This study designed folic acid (FA) and triformylcholic acid (TCA) targeted nanocomposites (GO-AuNSs-FA-TCA@BSA-Cu, GSFT@BCu) for liver cancer. This nanosystem integrates photothermal therapy (PTT), photodynamic therapy (PDT) and chemodynamic therapy (CDT) to construct a multimodal therapeutic platform, and introducing cuproptosis and apoptosis as a novel approach for precise modulation of tumor cell death. Transmission electron microscopy (TEM) and ultraviolet-visible (UV-Vis) spectroscopy were employed to characterize the morphological features and optical properties of the as-prepared nanocomposites. In vitro experiments confirmed that GSFT@BCu possessed a high photothermal conversion efficiency of 27.26% and can release copper ions in an NIR/GSH-responsive manner, further inducing oxidative stress and changes in mitochondrial membrane potential. In vivo liver cancer models showed that this combined multimodal therapy yielded a tumor inhibition rate of 82.47%. Additionally, the nanocomposite displayed outstanding blood compatibility and biosafety toward normal tissues. Overall, GSFT@BCu demonstrates excellent biocompatibility and prominent synergistic therapeutic effects against liver cancer, which providing a critical nanoplatform for multimodal synergistic therapy and precision medicine in oncology.
Human papillomavirus (HPV) vaccination is a key component of the World Health Organization's global strategy for cervical cancer elimination. The effect of malaria, a known immunomodulator, on HPV vaccine immunogenicity is poorly understood. This study assessed the effect of malaria parasitaemia at the time of vaccination on HPV vaccine immune responses among participants in a dose-reduction immunogenicity trial (DoRIS). 930 HIV-negative Tanzanian schoolgirls aged 9-14 years were randomised to receive one, two or three doses of Cervarix® or Gardasil®9 (155 per arm) and followed to month (M)36. One-dose and two-dose arms participants were enrolled in a long-term extension and are included in this malaria sub-study. Dried blood spots at each vaccination visit were tested for malaria parasitaemia by quantitative polymerase chain reaction. HPV16/18 antibody responses were measured at M12, 24, 36 and 60. In the one-dose arms, there was no evidence of a difference in antibody geometric mean concentrations (GMC) or avidity index (AI) between participants with and without malaria at the time of vaccination. In the two-dose Cervarix® arm, M36 HPV16 antibody GMCs and AI results were lower in participants with malaria at either vaccination visit (HPV16 GMC ratio = 0.74, 95%CI = 0.55-0.99; AI ratio = 0.95, 95%CI = 0.91-0.99). In the two-dose Gardasil®9 arm, M36 HPV18 antibody GMCs and AI results were lower in participants with malaria at the first vaccine dose than those without malaria (HPV18 GMC ratio = 0.58, 95%CI = 0.37-0.92; AI ratio = 0.93, 95%CI = 0.87-0.99). These trends were also observed at M60. Whilst some effect of malaria on antibody responses was observed in the two-dose arms, these were mostly small in magnitude and unlikely to have clinical significance. Single-dose arms results are reassuring but further evaluations in larger populations would be valuable to confirm the findings. The potential for an effect of moderate or severe infection with greater parasite burden remains unclear. (NCT02834637).
Antibody Fc glycosylation critically influences effector functions, motivating the development of chemoenzymatic strategies to generate homogeneous glycoforms. However, limited availability and high cost of mammalian glycosyltransferases remain to be significant constraints. Here, we report the high-yield expression of human and bovine β-1,4-galactosyltransferases (B4GalT1) and their single-point mutants (Y285L and Y289L, respectively) as maltose-binding protein fusions in Escherichia coli. A comparative analysis revealed that human B4GalT1 and its Y285L mutant exhibited substantially higher activity than bovine enzymes in transferring galactose (Gal) and N-acetylgalactosamine (GalNAc) from the corresponding UDP-sugar to terminal N-acetylglucosamine residues on Fc N-glycans of intact antibodies. These enzymes enabled the synthesis of antibody glycoforms bearing GalNAcβ1-4GlcNAc (LacdiNAc) in place of LacNAc. An unexpected finding was that the α-2,6-sialyltransferase from Photobacterium damselae (Pd2,6ST) and the α-2,3-sialyltransferase mutant PmST1 M144D from Pasteurella multocida recognized terminal GalNAc, but not Gal, in the intact antibody for sialylation. Interestingly, sialylation of terminal Gal was restored Pd2,6ST for the trastuzumab variant carrying a point F241A mutation. These results suggest that the intramolecular interaction between the terminal galactose and aromatic residues such as F241 in the Fc domain may hinder the enzymatic sialylation, while the F241A mutation partially releases such an interaction thus enhancing the sialylation efficiency. Receptor binding analysis showed that the antibodies carrying a LacdiNAc moiety exhibited comparable affinity to the FcγIIIA receptor and C1q protein as the LacNAc terminated glycoform, while the sialylated LacdiNAc glycoform could still bind to Siglec-2, albeit at lower affinity than the common sialylated LacNAc glycoform. These results expand the enzymatic toolkit for antibody glycoengineering and highlight the functional impact of LacdiNAc incorporation.
Hypofractionated stereotactic radiosurgery (HF-SRS) has become a mainstay of treatment for patients with brain metastases (BM). However, HF-SRS schedules involving 3-5 fractions may not align with conventional 5-day clinical workflows due to interruptions over weekends or holidays. We seek to compare the rate of local failure (LF) and radiation necrosis (RN) in patients using HF-SRS for BM, treated on consecutive or non-consecutive days. A retrospective review from 2018 to 2023 identified adult patients who underwent HF-SRS for lung and breast cancer BM with more than 3 months of radiological imaging follow-up at a single center. Demographic data, tumor and treatment characteristics including biologically equivalent dose with α/β of 10 (BED10), and imaging-based progression outcomes were collected; LF and RN were assessed via log-rank test. Of the 197 included lesions from 76 patients, 84 (42.6%) experienced interruptions (median: 3.0 days) in HF-SRS treatment. There were 49 (64.5%) lung and 27 (35.5%) breast cancer patients. Between consecutive and non-consecutively treated groups, the median radiological follow-up was 11 versus 14.5 months (p = 0.42), mean gross tumor volume (GTV) was 1.6 versus 2.8 cc (p = 0.30), and mean BED10 was 51.3 versus 51.3 Gy (p = 0.34). There was no significant difference between the interrupted and non-interrupted subgroups for the probability of LF (p = 0.620) nor probability of RN (p = 0.717). BED10 was inversely associated with LF on univariable (p = 0.005) and multivariable analysis (p = 0.003). GTV trended towards increased risk of RN on univariable analysis (p = 0.08). Sub-group analysis did not demonstrate an effect of treatment interruption on LF or RN in surgically resected lesions (p = 0.721, p = 0.509) or lesions treated with SRS only (p = 0.436, p = 0.790). Despite potential differences in radiobiological parameters, there was no significant difference in LF or RN in patients with BM from lung or breast carcinoma treated with consecutive versus nonconsecutive HF-SRS. Brief interruptions do not appear to need avoidance in patients undergoing HF-SRS when necessitated by workplace factors.
Pedestrian safety is a major concern, especially in heterogeneous traffic conditions like those commonly seen in India. In such complex environments, how the visual attention is directed to different traffic elements, especially under time pressure, plays a key role in understanding their decision-making and improving their situational awareness. To analyze these visual patterns, the present study examines Average Fixation Duration (AFD) as an indicator of visual attention across several Areas of Interest (AOIs), including two-wheelers, cars, heavy vehicles, signal heads, and the intersection area. Experiments were conducted in a virtual environment that simulated a real-world signalised intersection, using a projector-based pedestrian simulator integrated with an eye-tracker. A total of 62 participants completed crossing trials under three experimentally manipulated time pressure levels: No Time Pressure (NTP), Low Time Pressure (LTP), and High Time Pressure (HTP). The results showed that different levels of time pressure had a clear and significant impact on how pedestrians directed their visual attention toward various Areas of Interest (AOIs). In addition, the study examined other influencing factors, including head-turning behavior before and during crossing, as well as different temporal compliance categories: temporal compliance, non-dangerous temporal non-compliance (TNC), and dangerous TNC. These factors were also found to have a noticeable effect on pedestrians' visual attention patterns. Ultimately, this study provides new insights into pedestrian situational awareness and visual strategies, with practical implications for intersection design.
Dairy farm waste may serve as a reservoir for multidrug-resistant (MDR) Escherichia coli clones, but the genomic characteristics and dissemination potential of such clones remain incompletely understood. Here, we performed whole-genome sequencing and comprehensive genomic analysis of 64 MDR E. coli strains isolated from feces and sewage samples collected from two large dairy farms in Gansu Province, China. Genomic analysis revealed that strains carried 16-32 antibiotic resistance genes (ARGs), 1-6 plasmid replicon types, and 26-96 virulence genes (VGs), with numerically higher (though not statistically significant) counts in feces compared to sewage isolates. Multi-locus sequence typing (MLST) identified globally disseminated clones (ST10, ST38, ST58, ST155) and, for the first time in China, documented the presence of ST1508 (the predominant clone, 42% of isolates), as well as ST2520, ST7207, and ST7588 from dairy farm waste. Network analysis showed co-occurrence of these clones with transferable IncF plasmids harboring broad-spectrum resistance genes (e.g., rmtB, blaCTX-M-55) and multidrug efflux systems (e.g., acrAB-tolC). Contig-level analysis suggested that tet(A) and aph(3')-IIa were located on IncX1 plasmids, blaTEM-1B on IncFIC(FII), and blaCTX-M-55 on IncI1 plasmids, indicating potential for horizontal gene transfer. These findings identify dairy farm waste as a potential environmental reservoir of MDR E. coli clones with genomic features associated with resistance and virulence. While functional validation of transferability and environmental persistence is needed, the presence of these clones - particularly the emerging ST1508 lineage in untreated farm waste suggests that improved waste management, enhanced surveillance, and integrated One Health strategies may help mitigate dissemination risks. Further studies incorporating environmental sampling, persistence assays, and conjugation experiments are required to establish the actual hazard status.
Bacterial toxin-mediated severe systemic diseases, such as Shiga toxin-induced hemolytic uremic syndrome (HUS), are associated with an exceptionally high mortality rate due to life-threatening multi-organ failure and a profound inflammatory surge. Despite this severe clinical burden, targeted therapeutic drugs remain unavailable. Here, we investigated the therapeutic potential of Auranofin (AUR), an FDA-approved compound, in mitigating systemic lethality by targeting the Caspase-9/GSDME-mediated cell death axis. Utilizing a high-throughput screening of 2819 FDA-approved drugs, we identified AUR as a potent inhibitor of Stx2-induced cytotoxicity in THP-1 macrophages. In vitro, AUR pre-treatment (2.5 μM) significantly preserved cell viability, stabilized mitochondrial membrane potential, and suppressed the release of pro-inflammatory IL-1β and LDH. Mechanistic analysis revealed that AUR abrogated the activation of Caspase-9 and Caspase-3, effectively blocking GSDME-mediated pyroptosis. In a C57BL/6 mouse model of Stx2-induced systemic injury, AUR administration significantly prolonged survival time and ameliorated renal and intestinal dysfunction. Histological evaluation confirmed that AUR reduced renal tubular necrosis, fibrin deposition, and the infiltration of macrophages and neutrophils. Western blot analysis of kidney tissues further corroborated the inhibition of the Caspase-9/GSDME axis in vivo. Our findings elucidate that AUR represents a promising drug-repurposing strategy for treating severe systemic syndromes by intercepting the crosstalk between apoptosis and pyroptosis, highlighting a novel, translational therapeutic paradigm for acute toxemia.
Mixed poly(ethylene terephthalate)/poly(butylene terephthalate) (PET/PBT) waste represents an increasing fraction of heterogeneous polyester streams with limited compatibility with mechanical recycling within municipal material recovery facilities. This study evaluates a continuous neutral-hydrolysis process for a nominal 70/30 PET/PBT feed using Aspen Plus simulation, techno-economic analysis, and cradle-to-gate life-cycle assessment (LCA). The framework integrates literature-based reaction kinetics with simulated separation, economic, and environmental inventories to assess the system-level implications of mixed PET/PBT neutral hydrolysis. At 270 °C, 60 bar, and 30 min residence time, the simulation predicted 80.75 kg/h terephthalic acid (TPA) in the recovered solid cake from 100 kg/h mixed PET/PBT feed, corresponding to 97.1 % of the stoichiometric maximum. The recovered cake contained 96.45 wt% TPA prior to product polishing. Thermal demand is concentrated in hydrolysis and downstream separation, with the base-case simulation used to quantify external utility requirements. A separate pinch-based utility-displacement analysis indicates that recovering roughly 40 % of the available hot-cold overlap could reduce external utility demand; this value represents a thermodynamic integration target, not demonstrated heat-exchanger-network performance. With glycol coproduct credits included, the estimated minimum selling price was $3.66/kg TPA, while LCA estimated a greenhouse-gas intensity of 2.68 kg CO2-eq/kg TPA. Within the modeled system boundary, neutral hydrolysis may complement mechanical recycling for PET/PBT-rich waste streams. Pilot-scale validation with representative mixed PET/PBT feedstocks and assessment of contaminant partitioning, solids handling, and recycle-water stability remain essential next steps.