Donor Posterior Atrial Flap Rotation for Left Atrial Cuff Reconstruction in Lung Transplantation.

We describe in detail a novel surgical technique for repairing donor anterior left atrial wall defect in vivo by rotating the posterior atrial flap during lung transplantation. This method can safely and effectively address the most common type of donor left atrial cuff defect: the anterior wall defect, with the intact posterior wall, typically retained when the donor heart is also used. During atrial cuff anastomosis in lung transplantation, the excess donor posterior atrial wall is trimmed into an atrial flap. After the posterior wall anastomosis is completed, the atrial flap is rotated 180° and used as a patch for anterior wall reconstruction anastomosis. After restoring blood flow, the flow rate of the pulmonary vein is normal and smooth as confirmed by transesophageal echocardiography. Compared with the traditional patch reconstruction method, the new method effectively reduces the atrial cuff anastomosis time. Our results showed no significant difference in pulmonary vein obstruction after reconstruction. Pulmonary artery systolic blood pressure was significantly lower and pulmonary function improved postoperatively in all groups, with no significant differences among the groups. The new technique provides a feasible strategy for the reconstruction of left atrial cuff defects and can improve the effective utilization rate of donor lungs.

SPP1 induces idiopathic pulmonary fibrosis and NSCLC progression via the PI3K/Akt/mTOR pathway.

BACKGROUND: The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression. METHODS: Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells. RESULTS: Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-ß1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts. CONCLUSIONS: Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.

RRM2 inhibition alters cell cycle through ATM/Rb/E2F1 pathway in atypical teratoid rhabdoid tumor.

BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) is an aggressive brain tumor that mainly affects young children. Our recent study reported a promising therapeutic strategy to trigger DNA damage, impede homologous recombination repair, and induce apoptosis in ATRT cells by targeting ribonucleotide reductase regulatory subunit M2 (RRM2). COH29, an inhibitor of RRM2, effectively reduced tumor growth and prolonged survival in vivo. Herein, we explored the underlying mechanisms controlling these functions to improve the clinical applicability of COH29 in ATRT. METHODS: Molecular profiling of ATRT patients and COH29-treated cells was analyzed to identify the specific signaling pathways, followed by validation using a knockdown system, flow cytometry, q-PCR, and western blot. RESULTS: Elevated E2F1 and its signaling pathway were correlated with poor prognosis. RRM2 inhibition induced DNA damage and activated ATM, which reduced Rb phosphorylation to promote Rb-E2F1 interaction and hindered E2F1 functions. E2F1 activity suppression led to decreased E2F1-dependent target expressions, causing cell cycle arrest in the G1 phase, decreased S phase cells, and blocked DNA damage repair. CONCLUSION: Our study highlights the role of ATM/Rb/E2F1 pathway in controlling cell cycle arrest and apoptosis in response to RRM2 inhibition-induced DNA damage. This provides insight into the therapeutic benefits of COH29 and suggests targeting this pathway as a potential treatment for ATRT.

Continuous serratus anterior plane block for postoperative analgesia following lung transplantation via anterolateral incision: a pilot study.

Background: Unilateral or bilateral anterolateral thoracotomy May lead to severe acute pain in lung transplantation (LTx). Although serratus anterior plane block (SAPB) is apparently effective for pain control after open thoracic surgery, there remains a lack of evidence for the application of SAPB for postoperative analgesia after LTx. Objective: In this case series pilot study, we describe the feasibility of continuous SAPB after lung transplantation and provide a preliminary investigation of its safety and efficacy. Methods: After chest incisions closure was complete, all patients underwent ultrasound-guided SAPB with catheter insertion. Numerical rating scale (NRS), additional opioid consumption, time to endotracheal tube removal, ICU length of stay, and catheter-related adverse events were followed up and recorded for each patient within 1 week after the procedure. Results: A total of 14 patients who received LTx at this center from August 2023 to November 2023 were included. All patients received anterolateral approaches, and 10 (71.4%) of them underwent bilateral LTx. The duration of catheter placement was 2 (2-3) days, and the Resting NRS during catheter placement was equal to or less than 4. A total of 11 patients (78.6%) were supported by extracorporeal membrane oxygenation (ECMO) in LTx, whereas 8 patients (57.1%) removed the tracheal tube on the first day after LTx. Intensive care unit (ICU) stay was 5 (3-6) days, with tracheal intubation retained for 1 (1-2) days, and only one patient was reintubated. The morphine equivalent dose (MED) in the first week after LTx was 11.95 mg, and no catheter-related adverse events were detected. Limitations: We did not assess the sensory loss plane due to the retrospective design. In addition, differences in catheter placement time May lead to bias in pain assessment. Conclusion: Although continuous SAPB May be a safe and effective fascial block technique for relieving acute pain after LTx, it should be confirmed by high-quality clinical studies.

Improved Prognosis in HER2-Low Breast Cancer Patients with Reduced Ki67 Index After Neoadjuvant Chemotherapy: A Multi-Center Retrospective Study.

Background: HER2-low breast cancer represents a distinct subgroup with unique clinical characteristics and treatment challenges. Nevertheless, it remains uncertain whether there exists a distinction in δKi67 between patients with HER2-low and HER2-zero statuses, and whether the prognosis varies among patients with differing HER2 statuses and δKi67. Methods: We conducted a multi-center retrospective study to investigate the correlation between alterations in Ki67 index following NAC and the prognosis among patients with HER2-low or HER2-zero breast cancer. 3 distinct cohorts comprising patients with HER2-negative breast cancer who underwent NAC were included. Comprehensive clinicopathological data were documented, with particular emphasis on evaluating changes in Ki67 index from baseline to post-NAC. These changes were then correlated with disease-free survival (DFS) through rigorous analysis. Results: Three cohorts, comprising 403, 315, and 72 patients respectively, were finally included. The study found that δKi67 did not show significant associations with other variables and were not identified as independent risk factors for survival. Nevertheless, across the three cohorts, following NAC, HER2-low breast cancer patients with δKi67 below the cut-off value demonstrated a better prognosis compared to those with δKi67 above the cut-off value. Additionally, their prognosis was also superior to that of HER2-zero breast cancer patients with δKi67 below the cut-off value. Conclusion: Our study demonstrates that HER2-low breast cancer patients with δKi67 values below the cut-off point after NAC are associated with improved prognosis. Monitoring δKi67 index and HER2 status may help identify patients who are likely to benefit from NAC and guide personalized treatment strategies.

Incorporation of laser-induced graphene with hierarchical NiCo layered double hydroxide nanosheets for electrochemical determination of glucose in food and serum.

Dependable and sensitive glucose (Glu) testing in foodstuff and blood serum is highly desirable to prevent and treat diabetes. Electrochemical quantification of Glu has attracted great interests due to the advantages, including simple operation, higher sensitivity, easy miniaturization, ease of on-site and wearable detection as well as fast response. High costs and environmental dependence of enzymes pose a challenge to the electrochemical enzymatic biosensors. Nonenzymatic electrochemical Glu sensors are urgently needed to aid the Glu detection in human serum and food samples. To fabricate flexible Glu electrochemical sensors, designing suitable electrode substrate and efficient electrocatalyst is of paramount significance. Herein, the porous patterned laser-induced graphene (LIG) was fabricated on polyimide substrates through an efficient laser-inducing technology, and then used directly as the electrode substrate. Electrochemical deposition of NiCo layered double hydroxide (LDH) nanoflakes on the LIG surface was then conducted to achieve NiCo-LDH/LIG electrode as a Glu sensor. Under optimal conditions, this sensor displays a low detection limit of 0.05 µM. Two sets of broad detection linear ranges were found to be from 0.5 to 270 µM and from 0.27 to 3.6 mM, with high sensitivities of 9.750 µA µM-1 cm-2 and 3.760 µA µM-1 cm-2, respectively. The enhanced performance was ascribed to the cooperative action of NiCo-LDH and LIG, in which porous LIG provides extraordinary electroconductibility and a high surface area, while NiCo-LDH offers numerous exposed active sites and outstanding electrocatalytic performance. Practical application was further verified during the Glu detection in human serum and food samples. This research confirms that the NiCo-LDH/LIG composite is a prospective electrode for high-performance Glu sensor and provides a way of developing nonenzymatic electrochemical sensors to analyze the Glu in human serum and food samples, opening new avenues in electrochemical sensing.

Contactless ultrasound droplet manipulation system for mixing chemical reagents.

Green chemistry has been a rising topic in environmental sustainability, with a focus on the waste and consumption reduction of chemical and biomedical industries. Traditional chemical handling processes require tools that contact chemical reagents to produce vast amounts of residues and disposals. This study presents a contactless chemical mixing system that integrates acoustic droplet ejection and levitation techniques. First, the acoustic droplet ejection system creates a droplet in mid-air from a designated liquid reservoir by focusing acoustic energy at the liquid-air junction. The droplet levitation system captures and transports the droplet along a predetermined path by shifting the focal points of the acoustic standing waves. This facilitates contactless mixing of chemicals in a defined ratio. Notably, this study employs piezoelectric discs in an acoustic droplet ejection system to eject droplets from liquids. The relationship between the duration of the driving bursts and height and size of ejected droplets was also investigated. The proposed acoustic standing wave levitation system captures droplets with weights between 2.8 and 5.2 mg. To assess the reliability of the proposed system, 25 droplets were sequentially generated and transported to the mixing well without failure. The root mean square error between the collected and expected liquid weights was only 0.098 mg. The proposed system offers a promising solution for reducing waste and promoting environmentally friendly practices in chemical and biomedical laboratories.

[2-DG improves lung ischemia/reperfusion injury by inhibiting NLRP3-mediated pyroptosis in rats].

The aim of this study was to investigate whether the protective effect of 2-deoxyglucose (2-DG) on lung ischemia/reperfusion (I/R) injury is mediated by inhibiting nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis in rats. Male Sprague-Dawley rats were randomly divided into control group, 2-DG group, lung I/R injury group (I/R group) and 2-DG+I/R group. 2-DG (0.7 g/kg) was intraperitoneally injected 1 h prior to lung ischemia. The tissue structure was measured under light microscope. Lung injury parameters were detected. The contents of malondialdehyde (MDA), myeloperoxidase (MPO) and lactate were determined by commercially available kits. ELISA was used to detect the levels of IL-1ß and IL-18. Western blot, qRT-PCR and immunofluorescence staining were used to measure the expression changes of glycolysis and pyroptosis related indicators. The results showed that there was no significant difference in the parameters between the control group and the 2-DG group. However, the lung injury parameters, oxidative stress response, lactic acid content, IL-1ß, and IL-18 levels were significantly increased in the I/R group. The protein expression levels of glycolysis and pyroptosis related indicators including hexokinase 2 (HK2), pyruvate kinase 2 (PKM2), NLRP3, Gasdermin superfamily member GSDMD-N, cleaved-Caspase1, cleaved-IL-1ß and cleaved-IL-18, and the gene expression levels of HK2, PKM2 and NLRP3 were markedly up-regulated in the I/R group compared with those in the control group. The expression of HK2 and NLRP3 was also increased detected by immunofluorescence staining. Compared with the I/R group, the 2-DG+I/R group exhibited significantly improved alveolar structure and inflammatory infiltration, reduced lung injury parameters, and decreased expression of glycolysis and pyroptosis related indicators. These results suggest that 2-DG protects against lung I/R injury possibly by inhibiting NLRP3-mediated pyroptosis in rats.

How can rural digitalization improve agricultural green total factor productivity: Empirical evidence from counties in China.

Against the backdrop of escalating environmental pollution and resource depletion induced by traditional agricultural industry development, the imperative for agricultural efficiency and ecologically friendly practices has become pivotal for global agricultural sustainability. In the digital era, rural digitalization has substantially amplified agricultural production efficiency while notably reducing environmental pollution. This study is based on panel data from 1602 counties in China spanning from 2011 to 2020, measuring the levels of rural digitalization and agricultural green total factor productivity (AGTFP) across these counties, empirically examining their dynamic correlation. The research findings reveal: (1) A significant enhancement of AGTFP with the elevation of rural digitalization; for every 1 % increase in rural digitalization, AGTFP increases by 1.78 %. Robustness checks, including instrumental variables and quasi-natural experiments, affirm the validity of these conclusions. Furthermore, by comparing regional differences in China, it can be observed that the impact of rural digitalization on AGTFP varies across different areas: in the eastern, central, and western regions, for every 1 % increase in rural digitalization, the AGTFP increases by 2.65 %, 1.53 %, and 0.82 %, respectively. (2) Rural digitalization fosters an increase in AGTFP by stimulating rural entrepreneurial activity, with the mediation effect of rural entrepreneurial activity accounting for 3.34 % of the total effect. (3) Utilizing a threshold model, observations indicate that when rural digitalization surpasses the first threshold of 0.3200, the AGTFP coefficient escalates from 0.0462 to 0.7519. However, when rural digitalization exceeds the second threshold of 0.7118, this coefficient declines to 0.2429, signifying a nonlinear trend in the marginal effect of rural digitalization on AGTFP-initial enhancement followed by attenuation. (4) In the spatial model analysis, the study confirms spatial spillover effects of rural digitalization on AGTFP, indicating variations in spatial effects among different matrices. However, the indirect effects of rural digitalization on AGTFP, mainly influenced by the neighboring counties' digitalization levels, contribute more significantly than the direct effects. Based on these conclusions, this paper proposes augmenting investments in rural digitalization, implementing diversified rural digitalization schemes, invigorating rural entrepreneurial activity, and harmonizing regional digital development as novel approaches to enhance AGTFP, thereby fostering rural economic development.

Automated measurement of lumbar pedicle screw parameters using deep learning algorithm on preoperative CT scans.

Purpose: This study aims to devise and assess an automated measurement framework for lumbar pedicle screw parameters leveraging preoperative computed tomography (CT) scans and a deep learning algorithm. Methods: A deep learning model was constructed employing a dataset comprising 1410 axial preoperative CT images of lumbar pedicles sourced from 282 patients. The model was trained to predict several screw parameters, including the axial angle and width of pedicles, the length of pedicle screw paths, and the interpedicular distance. The mean values of these parameters, as determined by two radiologists and one spinal surgeon, served as the reference standard. Results: The deep learning model achieved high agreement with the reference standard for the axial angle of the left pedicle (ICC = 0.92) and right pedicle (ICC = 0.93), as well as for the length of the left pedicle screw path (ICC = 0.82) and right pedicle (ICC = 0.87). Similarly, high agreement was observed for pedicle width (left ICC = 0.97, right ICC = 0.98) and interpedicular distance (ICC = 0.91). Overall, the model's performance paralleled that of manual determination of lumbar pedicle screw parameters. Conclusion: The developed deep learning-based model demonstrates proficiency in accurately identifying landmarks on preoperative CT scans and autonomously generating parameters relevant to lumbar pedicle screw placement. These findings suggest its potential to offer efficient and precise measurements for clinical applications.

[Study on the Experimental Methodology of Plasma Clot Retraction].

OBJECTIVE: To explore the key factors affecting plasma clot retraction and optimize the experimental method of plasma clot retraction, in order to study the regulation of platelet function and evaluate the modulatory effects of drugs on plasma clot retraction. METHODS: The effects of different concentrations of thrombin, Ca2 + and platelets on plasma clot retraction were studied, and the detection system of plasma clot retraction was optimized. The availability of the detection system was then validated by analyzing the regulatory effects of multiple signaling pathway inhibitors on plasma clot retraction. RESULTS: Through the optimization study of multiple factors, platelet rich plasma (PRP) containing 0.5 mmol/L Ca2 + and 40×109/L platelets was treated with 0.2 U/ml thrombin to perform plasma clot retraction analysis. After treatment with thrombin for 15 min, plasma clot retracted significantly. After treatment with thrombin for 30 min, the percentage of plasma clot retraction was more than 50%. The regulatory effects of multiple signaling pathway inhibitors on plasma clot retraction were studied in this detection system. PKC inhibitor Go 6983 exhibited a significant inhibitory effect on plasma clot retraction, while PI3K inhibitor Ly294002 and p38 MAPK inhibitor SB203580 slightly suppressed plasma clot retraction. CONCLUSION: PRP containing 0.5 mmol/L Ca2 + and 40×109/L platelets can be induced with 0.2 U/ml thrombin to conduct plasma clot retraction analysis, which can be used to study the regulation of platelet function and evaluate the modulatory effects of drugs on plasma clot retraction.

Effectiveness and safety of brucea javanica oil assisted TACE versus TACE in the treatment of liver cancer: a systematic review and meta-analysis of randomized controlled trials.

Background: The effectiveness and safety of using Brucea javanica oil (BJO) in combination with Transarterial Chemoembolization (TACE) for liver cancer treatment are subjects of debate. This study aims to assess the comparative effectiveness and safety of BJO-assisted TACE versus TACE alone and quantifies the differences between these two treatment methods. Methods: A systematic search was conducted in multiple databases including PubMed, Cochrane, CNKI, and Wanfang, until 1 July 2023. Meta-analysis was conducted, and the results were presented as mean difference (MD), risk ratio (RR), and 95% confidence intervals (CI). Results: The search yielded 11 RCTs, with a combined sample size of 1054 patients. Meta-analysis revealed that BJO-assisted TACE exhibited superior outcomes compared to standalone TACE. Specific data revealed that BJO-assisted TACE improves clinical benefit rate by 22% [RR = 1.22, 95% CI (1.15, 1.30)], increases the number of people with improved quality of life by 32%, resulting in an average score improvement of 9.53 points [RR = 1.32, 95% CI (1.22, 1.43); MD = 9.53, 95% CI (6.95, 12.10)]. Furthermore, AFP improvement rate improved significantly by approximately 134% [RR = 2.34, 95% CI (1.58, 3.46)], accompanied by notable improvements in liver function indicators, with an average reduction of 27.19 U/L in AST [MD = -27.19, 95% CI (-40.36, -14.02)], 20.77 U/L in ALT [MD = -20.77, 95% CI (-39.46, -2.08)], 12.17 µmol/L in TBIL [MD = -12.17, 95% CI (-19.38, -4.97)], and a decrease of 43.72 pg/mL in VEGF [MD = -43.72, 95% CI (-63.29, -24.15)]. Most importantly, there was a 29% reduction in the occurrence of adverse reactions [RR = 0.71, 95% CI (0.60, 0.84)]. Conclusion: These findings indicate that BJO-assisted TACE may be considered as a potentially beneficial treatment option for liver cancer patients when compared to standalone TACE. It appears to contribute to improved treatment outcomes, enhanced quality of life, and potentially reduced adverse reactions, suggesting it warrants further investigation as a promising approach for liver cancer treatment. Systematic Review Registration: identifier CRD42023428948.

An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.

Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 Å) and C10-AMP intermediate (2.19 Å) in addition to its apo form (2.53 Å). Apart from our measurements for C10-AMS' Ki value of around 0.6 µM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.

Emulsion-Based Multi-Phase Integrated Microbeads with Inner Multi-Interface Structure Enable Dual-Modal Imaging for Precision Endovascular Embolization.

Microsphere-based embolic agents have gained prominence in transarterial embolization (TAE) treatment, a critical minimally invasive therapy widely applied for a variety of diseases such as hypervascular tumors and acute bleeding. However, the development of microspheres with long-term, real-time, and repeated X-ray imaging as well as ultrasound imaging remains challenging. In this study, emulsion-based dual-modal imaging microbeads with a unique internal multi-interface structure is developed for TAE treatment. The embolic microbeads are fabricated from a solidified oil-in-water (O/W) emulsion composed of crosslinked CaAlg-based aqueous matrix and dispersed radiopaque iodinated oil (IO) droplets through a droplet-based microfluidic fabrication method. The CaAlg-IO microbeads exhibit superior X-ray imaging visibility due to the incorporation of exceptionally high iodine level up to 221 mgI mL-1, excellent ultrasound imaging capability attributed to the multi-interface structure of the O/W emulsion, great microcatheter deliverability thanks to their appropriate biomechanical properties and optimal microbead density, and extended drug release behavior owing to the biodegradation nature of the embolics. Such an embolic agent presents a promising emulsion-based platform to utilize multi-phased structures for improving endovascular embolization performance and assessment capabilities.

Biodegradable Microembolics with Nanografted Polyanions Enable High-Efficiency Drug Loading and Sustained Deep-Tumor Drug Penetration for Locoregional Chemoembolization Treatment.

Transarterial chemoembolization (TACE), the mainstay treatment of unresectable primary liver cancer that primarily employs nondegradable drug-loaded embolic agents to achieve synergistic vascular embolization and locoregional chemotherapy effects, suffers from an inferior drug burst behavior lacking long-term drug release controllability that severely limits the TACE efficacy. Here we developed gelatin-based drug-eluting microembolics grafted with nanosized poly(acrylic acid) serving as a biodegradable ion-exchange platform that leverages a counterion condensation effect to achieve high-efficiency electrostatic drug loading with electropositive drugs such as doxorubicin (i.e., drug loading capacity >34 mg/mL, encapsulation efficiency >98%, and loading time <10 min) and an enzymatic surface-erosion degradation pattern (∼2 months) to offer sustained locoregional pharmacokinetics with long-lasting deep-tumor retention capability for TACE treatment. The microembolics demonstrated facile microcatheter deliverability in a healthy porcine liver embolization model, superior tumor-killing capacity in a rabbit VX2 liver cancer embolization model, and stabilized extravascular drug penetration depth (>3 mm for 3 months) in a rabbit ear embolization model. Importantly, the microembolics finally exhibited vessel remodeling-induced permanent embolization with minimal inflammation responses after complete degradation. Such a biodegradable ion-exchange drug carrier provides an effective and versatile strategy for enhancing long-term therapeutic responses of various local chemotherapy treatments.

A novel real-time model for predicting acute kidney injury in critically ill patients within 12 hours.

BACKGROUND: A major challenge in prevention and early treatment of acute kidney injury (AKI) is the lack of high-performance predictors in critically ill patients. Therefore, we innovatively constructed U-AKIpredTM for predicting AKI in critically ill patients within 12 h of panel measurement. METHODS: The prospective cohort study included 680 patients in the training set and 249 patients in the validation set. After performing inclusion and exclusion criteria, 417 patients were enrolled in the training set and 164 patients were enrolled in the validation set finally. AKI was diagnosed by Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: Twelve urinary kidney injury biomarkers (mALB, IgG, TRF, α1MG, NAG, NGAL, KIM-1, L-FABP, TIMP2, IGFBP7, CAF22 and IL-18) exhibited good predictive performance for AKI within 12 h in critically ill patients. U-AKIpredTM, combined with three crucial biomarkers (α1MG, L-FABP and IGFBP7) by multivariate logistic regression analysis, exhibited better predictive performance for AKI in critically ill patients within 12 h than the other twelve kidney injury biomarkers. The area under the curve (AUC) of the U-AKIpredTM, as a predictor of AKI within 12 h, was 0.802 (95% CI: 0.771-0.833, P < 0.001) in the training set and 0.844 (95% CI: 0.792-0.896, P < 0.001) in validation cohort. A nomogram based on the results of the training and validation sets of U-AKIpredTM was developed which showed optimal predictive performance for AKI. The fitting effect and prediction accuracy of U-AKIpredTM was evaluated by multiple statistical indicators. To provide a more flexible predictive tool, the dynamic nomogram (https://www.xsmartanalysis.com/model/U-AKIpredTM) was constructed using a web-calculator. Decision curve analysis (DCA) and a clinical impact curve were used to reveal that U-AKIpredTM with the three crucial biomarkers had a higher net benefit than these twelve kidney injury biomarkers respectively. The net reclassification index (NRI) and integrated discrimination index (IDI) were used to improve the significant risk reclassification of AKI compared with the 12 kidney injury biomarkers. The predictive efficiency of U-AKIpredTM was better than the NephroCheck® when testing for AKI and severe AKI. CONCLUSION: U-AKIpredTM is an excellent predictive model of AKI in critically ill patients within 12 h and would assist clinicians in identifying those at high risk of AKI.

Genetic causal association between gut microbiota and sepsis: Evidence from a two-sample bidirectional Mendelian randomization analysis.

Background: Sepsis is a severe and potentially life-threatening condition characterized by a dysregulated host response and organ dysfunction. The causal relationship between intestinal microbiota and sepsis is unclear. Methods: A two-sample Mendelian randomization (MR) study was performed to proxy the causal association between gut microbiota and sepsis. The genome-wide association study (GWAS) data of sepsis and gut microbiome were collected from the Integrative Epidemiology Unit (IEU) OpenGWAS, with summary-level data obtained from the UK Biobank. Five traditional methods were used to estimate the potential causal relationships between gut microbiota and sepsis, including the inverse-variance weighted method, weighted median method, MR-Egger regression, simple mode, and weighted mode. Reverse MR analysis was performed on the bacteria that were found to be causally associated with sepsis in forward MR analysis. Cochran's Q statistic was used to quantify the heterogeneity of instrumental variables. Results: The inverse-variance weighted estimate suggested that class Lentisphaeria (odds ratio [OR]=0.86, 95% confidence interval [CI]: 0.78 to 0.94, P=0.0017, q=0.1596) and order Victivallales (OR=0.86, 95% CI: 0.78 to 0.94, P=0.0017, q=0.1596) have a protective effect on sepsis. The genus Eubacterium eligens group (OR=1.34, 95% CI: 1.11 to 1.63, P=0.0029, q=0.1881) was positively associated with the risk of sepsis. Sepsis may be a significant risk factor for genus Odoribacter (OR=1.18, 95% CI: 1.10 to 1.39, P=0.0415, q=0.9849) and Phascolarctobacterium (OR=1.21, 95% CI: 1.00 to 1.46, P=0.0471, q=0.9849), but this effect was not statistically significant after false discovery rate correction. There was a suggestive association between sepsis and Faecalibacterium (OR=0.85, 95% CI: 0.73 to 0.98, P=0.0278) and Ruminococcus 1 (OR=0.85, 95% CI: 0.73 to 1.00, P=0.0439), which were not significant after false discovery rate correction (q>0.2). Conclusions: This study found that class Lentisphaeria, order Victivallales, and genus Eubacterium eligens group may have a causal relationship with the risk of sepsis.

Changes in visual performance after implantation of different intraocular lenses.

AIM: To evaluate the trending visual performance of different intraocular lenses (IOLs) over time after implantation. METHODS: Ninety-one patients received cataract surgery with implantations of monofocal (Mon) IOLs, segmental refractive (SegRef) IOLs, diffractive (Dif) IOLs, and extended-depth-of-focus (EDoF) IOLs were included. The aberrations and optical quality collected with iTrace and OQAS within postoperative 6mo were followed and compared. RESULTS: Most of the visual parameters improved over the postoperative 6mo. The postoperative visual acuity (POVA) of the Mon IOL, SegRef IOL, and EDoF IOL groups achieved relative stability in earlier states compared with the Dif IOL group. Nevertheless, the overall visual performance of the 3 IOLs continued to upturn in small extents within the postoperative 6mo. The optical quality initially improved in the EDoF IOL group, then in the Mon IOL, SegRef IOL, and Dif IOL groups. POVA and objective visual performance of the Mon IOL and EDoF IOL groups, as well as POVA and visual quality of the Dif IOL group, improved in the postoperative 1mo and stabilized. Within the postoperative 6mo, gradual improvements were observed in the visual acuity and objective visual performance of the SegRef IOL group, as well as in the postoperative optical quality of the Dif IOL group. CONCLUSION: The visual performance is different among eyes implanted with different IOLs. The findings of the current study provide a potential reference for ophthalmologists to choose suitable IOLs for cataract patients in a personalized solution.

SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer.

Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.