Budget impact analysis of introducing fruquintinib for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy and biologics in the United States from the payer perspective.

AIMS: Fruquintinib is a selective small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 recently approved in the United States (US) for the treatment of adult patients with mCRC who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, anti-epidermal growth factor receptor therapy. This study aimed to estimate the 5-year budget impact of fruquintinib from a US payer perspective (commercial and Medicare). MATERIALS AND METHODS: A budget impact model was developed to compare two scenarios: a reference scenario in which patients received regorafenib, trifluridine/tipiracil, or trifluridine/tipiracil with bevacizumab and an alternative scenario in which patients received reference scenario treatments or fruquintinib. Market shares were evenly divided across available options. A 5-year time horizon and a hypothetical health plan of 1 million members was assumed. The model included epidemiological inputs to estimate the eligible population; clinical inputs for treatment duration, progression-free survival, overall survival, and adverse event (AE) frequency; and cost inputs for treatment, AEs, disease management, subsequent therapy, and terminal care costs. Budget impact was reported as total, per member per year (PMPY), and per member per month (PMPM). RESULTS: The model estimated an eligible population of 194 patients (39 per year) over 5 years. In the base case, the estimated 5-year budget impact of fruquintinib was $4,077,073 ($0.82 PMPY and 0.07 PMPM) for a commercial health plan. During the first year, the estimated budget impact was $627,570 ($0.63 PMPY and 0.05 PMPM). Results were robust across sensitivity analyses. PMPM costs from the Medicare perspective were greater than the base-case (commercial) ($0.17 vs. $0.07) due to higher incidence of CRC in that population. CONCLUSIONS: Fruquintinib is associated with a low budget impact for payers based on proposed thresholds in the US.

Fruquintinib is a treatment for metastatic colorectal cancer that has progressed after or not responded to multiple guideline-recommended therapies. This budget impact analysis was conducted to estimate the added costs a health plan would incur over a 5-year period if it chose to cover this therapy. The analysis found that the per plan member per month cost of covering fruquintinib was $0.07 for a United States commercial health plan and $0.17 for Medicare.

The correlation between the level of cellular classification in bronchoalveolar lavage fluid of children with severe Mycoplasma pneumoniae and clinical characteristics.

Mycoplasma pneumoniae pneumonia (MPP) is a common respiratory tract infection disease in children. To date, there have been few studies on the relationship between cytological changes in bronchoalveolar lavage fluid (BALF) and clinical features. The objective of this study is to investigate the correlation between changes in the proportion of cell classifications in BALF and the clinical features in children with severe MPP (SMPP). In total, the study included 64 children with SMPP requiring bronchoalveolar lavage who were admitted to our hospital between March and September 2022 (study group) and 11 children with bronchial foreign bodies without co-infection (control group), who were admitted during the same period. The proportion of cell classifications in BALF was determined by microscopic examination after performing Wright-Giemsa staining. Patients were grouped according to different clinical characteristics, and between-group comparisons were made regarding the variations in the proportion of cell classifications in BALF. The levels of blood routine neutrophil percentage (GRA%), C-reactive protein, D-dimer and lactate dehydrogenase in the study group were higher than those in the control group (P < 0.05). There were differences in the GRA% and macrophage percentage in the BALF between the two groups (P < 0.05). The GRA% and blood lymphocyte percentage were associated with pleural effusion. Multiple indicators correlated with extrapulmonary manifestations (P < 0.05). Moreover, the percentage of lymphocytes in the BALF correlated with pleural effusion, extrapulmonary manifestations and refractory MPP (RMPP) (P < 0.05). Logistic regression showed that BALF lymphocytes were protective factors for RMPP, while serum amyloid A and extrapulmonary manifestations were risk factors (P < 0.05). CONCLUSION: The BALF of children with SMPP is predominantly neutrophilic. A lower percentage of lymphocytes is related to a higher incidence of pleural effusion, extrapulmonary manifestations and progression to RMPP, as well as a longer length of hospitalisation. WHAT IS KNOWN: • Mycoplasma pneumonia in children is relatively common in clinical practice. Bronchoalveolar lavage (BAL) is a routine clinical procedure. WHAT IS NEW: However, there are relatively few studies focusing on the cytomorphological analysis of cells in BAL fluid.

Photoinduced Lignin C α -C ß Bond Cleavage and Chemodivergent Functionalization via Iron Catalysis.

The photocatalytic conversion of lignin into value-added chemicals especially those functionalized molecules represent one of the most important strategies for sustainable and environmental-friendly development. Cleavage of C-C bonds in lignin under mild photocatalytic conditions for refining lignin into useful molecules is meaningful but challenging. Meanwhile, the assembly of diverse functional groups into active lignin fragments during the depolymerization is of great challenging. Herein, using cheap iron catalysts under visible light irradiation, the highly selective and efficient cleavage of Cα-Cß bond in lignin is realized via ligand-to-metal charge transfer (LMCT) and hydrogen atom transfer (HAT) processes. The subsequent divergent functionalization of generated lignin fragment-based radical intermediates enables an efficient formation of diverse functionalized molecules. This method is also effective for cleavage of Cα-Cß bond in native lignin, yielding two identified benzaldehyde monomers in a total yield of 8.7 wt%.

Oxidative stress in the alveolar lavage fluid of children with Mycoplasma pneumoniae pneumonia.

OBJECTIVE: To investigate the correlation between oxidative stress in the bronchoalveolar lavage fluid (BALF) of children with Mycoplasma pneumoniae pneumonia (MPP) and the clinical characteristics of severe MPP (SMPP) and refractory MPP (RMPP). METHODS: Clinical and BALF-related data were collected from 83 patients with MPP, of which 29 had SMPP and 54 had general MPP (GMPP); 37 patients were in the RMPP group and 46 in the non-RMPP group. The levels of malondialdehyde (MDA) and advanced oxidation protein products (AOPP) as well as the activity levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in BALF were detected. Logistic regression analyses were performed on MDA, AOPP, SOD, GSH-PX, gender, heat peak, neutrophil percentage, C-reactive protein, lactate dehydrogenase, d-dimer, lung consolidation, sputum embolus, and pleural effusion. RESULTS: The levels of MDA and AOPP in the BALF of the MPP group were significantly higher than those in the control group (p < .05), whereas SOD and GSH-PX levels were lower than those in the control group (p < .05). The BALF AOPP levels in the RMPP group were higher than those in the non-RMPP group, and the SOD and GSH-PX levels in the BALF were lower than those in the non-RMPP group; the difference was statistically significant (p < .05). The levels of MDA and AOPP in the BALF of children in the SMPP group were higher than those in the GMPP group, and the levels of SOD and GSH-PX were lower than those in the GMPP group, with statistically significant differences (p < .05). The C-index of the logistic regression model was 0.960 (95% confidence interval 0.958-0.963), which indicates that the model has good predictive ability. CONCLUSION: Advanced oxidation protein products may be a marker for predicting the conditions of SMPP and RMPP, and the prediction model can assess the risk of progression in children to RMPP, which is conducive to clinical diagnosis and treatment.

Primary and Orthotopic Murine Models of Nasopharyngeal Carcinoma Reveal Molecular Mechanisms Underlying its Malignant Progression.

Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein-Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV- (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC-associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene-edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV-coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV- and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.

Modulating cell stiffness for improved vascularization: leveraging the MIL-53(fe) for improved interaction of titanium implant and endothelial cell.

Vascularization plays a significant role in promoting the expedited process of bone regeneration while also enhancing the stability and viability of artificial bone implants. Although titanium alloy scaffolds were designed to mimic the porous structure of human bone tissues to facilitate vascularization in bone repair, their biological inertness restricted their broader utilization. The unique attribute of Metal-organic framework (MOF) MIL-53(Fe), known as "breathing", can facilitate the efficient adsorption of extracellular matrix proteins and thus provide the possibility for efficient interaction between scaffolds and cell adhesion molecules, which helps improve the bioactivity of the titanium alloy scaffolds. In this study, MIL-53(Fe) was synthesized in situ on the scaffold after hydrothermal treatment. The MIL-53(Fe) endowed the scaffold with superior protein absorption ability and preferable biocompatibility. The scaffolds have been shown to possess favorable osteogenesis and angiogenesis inducibility. It was indicated that MIL-53(Fe) modulated the mechanotransduction process of endothelial cells and induced increased cell stiffness by promoting the adsorption of adhesion-mediating extracellular matrix proteins to the scaffold, such as laminin, fibronectin, and perlecan et al., which contributed to the activation of the endothelial tip cell phenotype at sprouting angiogenesis. Therefore, this study effectively leveraged the intrinsic "breathing" properties of MIL-53 (Fe) to enhance the interaction between titanium alloy scaffolds and vascular endothelial cells, thereby facilitating the vascularization inducibility of the scaffold, particularly during the sprouting angiogenesis phase. This study indicates that MIL-53(Fe) coating represents a promising strategy to facilitate accelerated and sufficient vascularization and uncovers the scaffold-vessel interaction from a biomechanical perspective.

Study on the Correlation Between the Expression of NF-Ƙb in the Alveolar Lavage Fluid of Children with Severe Mycoplasma Pneumoniae Pneumonia, Its Clinical Characteristics, and Cellular Immunity.

Objective: This study explored the level of nuclear factor-ƙB (NF-ƙB) in the bronchoalveolar lavage fluid (BALF) of children with severe Mycoplasma Pneumoniae pneumonia (SMPP) and the correlation between NF-ƙB, cellular immunity, and clinical characteristics. Methods: A total of 41 hospitalized children diagnosed with SMPP were selected and included in the SMPP group, and 13 bronchial foreign bodies (FB) without infection during the same period were included in the FB group. The NF-ƙB in the BALF of participants was detected by enzyme-linked immunosorbent assay. The correlation between NF-ƙB and laboratory findings, cellular immunity, and the clinical features in children with SMPP was analyzed. The differences in chest imaging and bronchoscopy in children with SMPP were observed. Results: The levels of NF-ƙB were significantly increased in the SMPP group compared with the FB group (P < 0.001). There were correlations between different NF-ƙB pairs in the SMPP group (P < 0.01). Nuclear factor-ƙB (NF-ƙB) correlated with IL-6, the mycoplasma load in BALF, fever peak, length of hospital stay, and sputum suppository (P < 0.05). The higher the intracellular NF-ƙB level in BALF, the lower the CD3+ CD4+ value in peripheral blood (P < 0.05). Intracellular NF-ƙB and total NF-ƙB correlated with pleural effusion, pericardial effusion, and extrapulmonary complications (P < 0.05). Conclusion: NF-ƙB is involved in airway inflammation changes in children with SMPP. The higher the level of NF-ƙB in the airway, the more severe the clinical manifestations, and the longer the length of hospital stay is likely to be.

Sustainable depolymerization of lignin into aromatic compounds using amphiphilic Anderson-type polyoxometalate catalysts.

Lignin serves as a primary abundant source of renewable aromatic compounds. Achieving efficient breakdown of lignin and retaining its aromatic properties is highly desirable but remains a challenging task. To address this challenge, we synthesized Anderson-type polyoxometalate (POM) catalysts, particularly [CTAC]2[CoMo6]. We then investigated the effectiveness of the POM catalysts in the oxidative depolymerization of larch lignin. Under conditions of 160 °C, 1.0 MPa oxygen atmosphere, and a catalyst-to-substrate ratio of 1:5, we achieved a monomer yield of phenolic compounds at 12.43 wt%. The unsaturated coordination sites of Mo5+ within the catalysts were identified as active sites, facilitating enhanced O2 adsorption and activation. The enhanced O2 adsorption significantly influenced the production of aromatic monomers from lignin. We observed that the catalysts effectively cleaved CC bonds in ß-O-4 dimer compounds using lignin dimer model compounds. Notably, the [CTAC]2[CoMo6] catalyst exhibited excellent stability across five cycles, maintaining its high efficiency in lignin depolymerization. This indicates that Anderson-type POM-based catalysts exhibit potential for sustainable conversion of biomass into valuable compounds and for enhancing lignin valorization processes.

Versatile ionic liquid gels formed by dynamic covalent bonding and microphase separated structures.

It is challenging for ionic liquid gels to achieve the combination of rapid self-healing with high toughness. Here, ionic liquid gels (DI-PR) were prepared from readily available materials. A dynamic covalently bonded oxime-carbamate was prepared from polycaprolactone diol, isophorone diisocyanate and dimethylethyleneglyoxime, followed by addition of the "rigid-flexible" cross-linking agent rutin to chemically cross-link the polymer chains and afford the ionic liquid gels, DI-PR. The tensile strength, elongation at break and toughness of the DI-PR gels were as high as 16.5 MPa, 1132.6%, and 52.6 MJ m-3, respectively. The toughness is similar to that of natural silkworm silk (70 MJ m-3) and wool (60 MJ m-3). After stretching, the DI-PR can rebound within 1 s, their room temperature self-healing rate is as high as 92%, they remain functional over the temperature range -50 °C to 140 °C and the interface with a steel plate has an adhesion toughness of >2000 J m-2. These properties mean that the DI-PR gels are particularly suitable for use as anticorrosion coatings for submarine and underground gas and oil pipelines. The use of rutin, which combines rigid quercetin-based structural units with flexible glycoside-based structural units, as a cross-linking agent, provides a new method for improving the toughness of soft materials through its synergistic interaction with hard and soft chain fragments of polyurethanes.

Enhancing osteogenesis and angiogenesis functions for Ti-24Nb-4Zr-8Sn scaffolds with methacrylated gelatin and deferoxamine.

Repair of large bone defects remains challenge for orthopedic clinical treatment. Porous titanium alloys have been widely fabricated by the additive manufacturing, which possess the elastic modulus close to that of human cortical bone, good osteoconductivity and osteointegration. However, insufficient bone regeneration and vascularization inside the porous titanium scaffolds severely limit their capability for repair of large-size bone defects. Therefore, it is crucially important to improve the osteogenic function and vascularization of the titanium scaffolds. Herein, methacrylated gelatin (GelMA) were incorporated with the porous Ti-24Nb-4Zr-8Sn (Ti2448) scaffolds prepared by the electron beam melting (EBM) method (Ti2448-GelMA). Besides, the deferoxamine (DFO) as an angiogenic agent was doped into the Ti2448-GelMA scaffold (Ti2448-GelMA/DFO), in order to promote vascularization. The results indicate that GelMA can fully infiltrate into the pores of Ti2448 scaffolds with porous cross-linked network (average pore size: 120.2 ± 25.1 µm). Ti2448-GelMA scaffolds facilitated the differentiation of MC3T3-E1 cells by promoting the ALP expression and mineralization, with the amount of calcium contents ∼2.5 times at day 14, compared with the Ti2448 scaffolds. Impressively, the number of vascular meshes for the Ti2448-GelMA/DFO group (∼7.2/mm2) was significantly higher than the control group (∼5.3/mm2) after cultivation for 9 h, demonstrating the excellent angiogenesis ability. The Ti2448-GelMA/DFO scaffolds also exhibited sustained release of DFO, with a cumulative release of 82.3% after 28 days. Therefore, Ti2448-GelMA/DFO scaffolds likely provide a new strategy to improve the osteogenesis and angiogenesis for repair of large bone defects.

Transformation of Coherent Twin Boundary into Basal-Prismatic Boundary in HCP-Ti: A Molecular Dynamics Study.

The manufacturing process for wrought Ti alloys with the hexagonal close-packed (HCP) structure introduces a complicated microstructure with abundant intra- and inter-grain boundaries, which greatly influence performance. In the hexagonal close-packed (HCP) structure, two types of grain boundaries are commonly observed between grains with ~90° misorientation: the basal/prismatic boundary (BPB) and the coherent twin boundary (CTB). The mechanical response of the BPB and CTB under external loading was studied through molecular dynamic simulations of HCP-Ti. The results revealed that CTB undergoes transformation into BPB through the accumulation of twin boundary (TB) steps and subsequent emission of Shockley partial dislocations. When the total mismatch vector is close to the Burgers vector of a Shockley partial dislocation, BPB emits partial dislocations and further grows along the stacking faults. When a pair of CTBs are close to each other, severe boundary distortion occurs, facilitating the emission and absorption of partial dislocations, which further assists the CTB-BPB transformation. The present results thus help to explain the frequent observation of coexisting CTB and BPB in HCP alloys and further contribute to the understanding of their microstructure and property regulation.

Exploring the Common Genetic Underpinnings of Chronic Pulmonary Disease and Esophageal Carcinoma Susceptibility.

Background: Pulmonary diseases and esophageal cancer are highly prevalent conditions with rising incidence worldwide. Prior evidence supports shared environmental and behavioral factors, but less is known regarding potential genetic links underlying this comorbidity. This study aimed to elucidate the complex genetic relationship between chronic lung diseases and esophageal cancer risk. Methods: Linkage disequilibrium score regression assessed the genetic correlation between esophageal cancer and asthma, COPD, and idiopathic pulmonary fibrosis leveraging extensive GWAS datasets. Pleiotropic analysis, gene-set enrichment, eQTL mapping, and mendelian randomization causality analyses were then conducted to identify specific shared genetic variants, enriched pathways, causal relationships and gene regulatory mechanisms connecting lung disease and cancer susceptibility. Results: Significant genetic correlations were observed between esophageal cancer and both COPD and asthma, but not idiopathic pulmonary fibrosis. Further analyses identified 13 pleiotropic loci and 6 shared genes including CHRNA4, ERBB3, and SMAD3, as well as pathways related to immune function. eQTL integration highlighted 53 genes like SOCS1, FGF2, and CHRNA5 with tissue-specific regulatory effects on disease risk. Bidirectional relationships were noted, whereby genetic predisposition to asthma and COPD increased esophageal cancer risk, while cancer liability reciprocally raised pulmonary fibrosis risk. Conclusions: These genomic analyses provide initial evidence that shared genetic factors may underpin the comorbidity between lung conditions and esophageal malignancy. The genes and pathways identified offer insights into biological mechanisms linking both diseases, aiding future screening, prevention and therapeutic efforts to mitigate this growing comorbidity burden.

Predictive value of bronchoscopy combined with CT score for refractory mycoplasma pneumoniae pneumonia in children.

INTRODUCTION: Mycoplasma pneumoniae pneumonia (MPP) is prevalent in paediatric patients and can progress to refractory mycoplasma pneumoniae pneumonia (RMPP). OBJECTIVE: To assess the predictive value of bronchoscopy combined with computed tomography (CT) score in identifying RMPP in children. METHODS: A retrospective analysis was conducted on 244 paediatric patients with MP, categorising them into RMPP and general mycoplasma pneumoniae pneumonia (GMPP) groups. A paired t-test compared the bronchitis score (BS) and CT score before and after treatment, supplemented by receiver operating characteristic (ROC) analysis. RESULTS: The RMPP group showed higher incidences of extrapulmonary complications and pleural effusion (58.10% and 40%, respectively) compared with the GMPP group (44.60%, p = 0.037 and 18.71%, p < 0.001, respectively). The CT scores for each lung lobe were statistically significant between the groups, except for the right upper lobe (p < 0.05). Correlation analysis between the total CT score and total BS yielded r = 0.346 and p < 0.001. The ROC for BS combined with CT score, including area under the curve, sensitivity, specificity, and cut-off values, were 0.82, 0.89, 0.64, and 0.53, respectively. CONCLUSION: The combined BS and CT score method is highly valuable in identifying RMPP in children.

Essential role of glycoprotein Ibα in platelet activation.

ABSTRACT: Glycoprotein Ibα (GPIbα), the ligand-binding subunit of platelet GPIb-IX complex, interacts with von Willebrand factor (VWF) exposed at the injured vessel wall, initiating platelet adhesion, activation, hemostasis, and thrombus formation. The cytoplasmic tail of GPIbα interacts with 14-3-3ζ, regulating the VWF-GPIbα-elicited signal transduction and VWF binding function of GPIbα. However, we unexpectedly found that the GPIbα-14-3-3ζ association, beyond VWF-dependent function, is essential for general platelet activation. We found that the myristoylated peptide of GPIbα C-terminus MPαC, a potential GPIbα inhibitor, by itself induced platelet aggregation, integrin αIIbß3 activation, granule secretion, and phosphatidylserine (PS) exposure. Conversely, the deletion of the cytoplasmic tail of GPIbα in mouse platelets (10aa-/-) decreased platelet aggregation, integrin αIIbß3 activation, granule secretion, and PS exposure induced by various physiological agonists. Phosphoproteome-based kinase activity profiling revealed significantly upregulated protein kinase C (PKC) activity in MPαC-treated platelets. MPαC-induced platelet activation was abolished by the pan-PKC inhibitor and PKCα deletion. Decreased PKC activity was observed in both resting and agonist-stimulated 10aa-/- platelets. GPIbα regulates PKCα activity by sequestering 14-3-3ζ from PKCα. In vivo, the deletion of the GPIbα cytoplasmic tail impaired mouse hemostasis and thrombus formation and protected against platelet-dependent pulmonary thromboembolism. Therefore, our findings demonstrate an essential role for the GPIbα cytoplasmic tail in regulating platelet general activation and thrombus formation beyond the VWF-GPIbα axis.

Analytical validation of the DropXpert S6 system for diagnosis of chronic myelocytic leukemia.

Digital PCR is a powerful method for absolute nucleic acid quantification and is widely used in the absolute quantification of viral copy numbers, tumor marker detection, and prenatal diagnosis. However, for most of the existing droplet-based dPCR systems, the droplet generation, PCR reaction, and droplet detection are performed separately using different instruments. Making digital PCR both easy to use and practical by integrating the qPCR workflow into a superior all-in-one walkaway solution is one of the core ideas. A new innovative and integrated digital droplet PCR platform was developed that utilizes cutting-edge microfluidics to integrate dPCR workflows onto a single consumable chip. This makes previously complex workflows fast and simple; the whole process of droplet generation, PCR amplification, and droplet detection is completed on one chip, which meets the clinical requirement of "sample in, result out". It provides high multiplexing capabilities and strong sensitivity while all measurements were within the 95% confidence interval. This study is the first validation of the DropXpert S6 system and focuses primarily on verifying its reliability, repeatability, and consistency. In addition, the accuracy, detection limit, linearity, and precision of the system were evaluated after sample collection. Among them, the accuracy assessment by calculating the absolute bias of each target gene yielded a range from -0.1 to 0.08, all within ±0.5 logarithmic orders of magnitude; the LOB for the assay was set at 0, and the LoD value calculated using probit curves is MR4.7 (0.002%); the linearity evaluation showed that the R2 value of the BCR-ABL was 0.9996, and the R2 value of the ABL metrics calculated using the ERM standard was 0.9999; and the precision evaluation showed that all samples had a CV of less than 4% for intra-day, inter-day, and inter-instrument variation. The CV of inter-batch variation was less than 7%. The total CV was less than 5%. The results of the study demonstrate that dd-PCR can be applied to molecular detection and the clinical evaluation of CML patients and provide more precise personal treatment guidance, and its reproducibility predicts the future development of a wide range of clinical applications.

A nomogram for predicting postoperative delirium in pediatric patients following cardiopulmonary bypass: A prospective observational study.

OBJECTIVES: To create a nomogram for early delirium detection in pediatric patients following cardiopulmonary bypass. RESEARCH METHODOLOGY/DESIGN: This prospective, observational study was conducted in the Cardiac Intensive Care Unit at a Children's Hospital, enrolling 501 pediatric patients from February 2022 to January 2023. Perioperative data were systematically collected through the hospital information system. Postoperative delirium was assessed using the Cornell Assessment of Pediatric Delirium (CAPD). For model development, Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to identify the most relevant predictors. These selected predictors were then incorporated into a multivariable logistic regression model to construct the predictive nomogram. The performance of the model was evaluated by Harrell's concordance index, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis. External validity of the model was confirmed through the C-index and calibration plots. RESULTS: Five independent predictors were identified: age, SpO2 levels, lymphocyte count, diuretic use, and midazolam administration, integrated into a predictive nomogram. This nomogram demonstrated strong predictive capacity (AUC 0.816, concordance index 0.815) with good model fit (Hosmer-Lemeshow test p = 0.826) and high accuracy. Decision curve analysis showed a significant net benefit, and external validation confirmed the nomogram's reliability. CONCLUSIONS: The study successfully developed a precise and effective nomogram for identifying pediatric patients at high risk of post-cardiopulmonary bypass delirium, incorporating age, SpO2 levels, lymphocyte counts, diuretic use, and midazolam medication. IMPLICATIONS FOR CLINICAL PRACTICE: This nomogram aids early delirium detection and prevention in critically ill children, improving clinical decisions and treatment optimization. It enables precise monitoring and tailored medication strategies, significantly contributes to reducing the incidence of delirium, thereby enhancing the overall quality of patient care.

Design, synthesis and biological evaluation of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives as Mnk1/2 inhibitors.

The Mnk-eIF4E axis plays a crucial role in tumor development, and inhibiting Mnk kinases is a promising approach for cancer therapy. Starting with fragment WS23, a series of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives were designed and synthesized. Among these derivatives, compound 15b showed the highest potency with IC50 values of 0.8 and 1.5 nM against Mnk1 and Mnk2, respectively. Additionally, it demonstrated good selectivity among 30 selected kinases. 15b significantly suppressed MOLM-13 and K562 cell lines growth and caused cell cycle arrest. Furthermore, the Western blot assay revealed that 15b effectively downregulated the downstream proteins p-eIF4E, Mcl-1, and c-myc. Additionally, 15b exhibited remarkable stability in rat plasma and rat and human microsomes. In vivo anti-tumor activity study suggested that treatment with 15b suppressed tumor growth in LL/2 syngeneic models. These findings highlight the potential of 15b as a novel and potent Mnks inhibitor, which deserves further investigation.

Comprehensive single-cell transcriptomic profiling reveals molecular subtypes and prognostic biomarkers with implications for targeted therapy in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a genetically heterogeneous disease with poor clinical outcomes. Identification of biomarkers linked to DNA replication stress may enable improved prognostic risk stratification and guide therapeutic decision making. We performed integrated single-cell RNA sequencing and computational analyses to define the molecular determinants and subtypes underlying ESCC heterogeneity. METHODS: Single-cell RNA sequencing was performed on ESCC samples and analyzed using Seurat. Differential gene expression analysis was used to identify esophageal cell phenotypes. DNA replication stress-related genes were intersected with single-cell differential expression data to identify potential prognostic genes, which were used to generate a DNA replication stress (DRS) score. This score and associated genes were evaluated in survival analysis. Putative prognostic biomarkers were evaluated by Cox regression and consensus clustering. Mendelian randomization analyses assessed the causal role of PRKCB. RESULTS: High DRS score associated with poor survival. Four genes (CDKN2A, NUP155, PPP2R2A, PRKCB) displayed prognostic utility. Three molecular subtypes were identified with discrete survival and immune properties. A 12-gene signature displayed robust prognostic performance. PRKCB was overexpressed in ESCC, while PRKCB knockdown reduced ESCC cell migration. CONCLUSIONS: This integrated single-cell sequencing analysis provides new insights into the molecular heterogeneity and prognostic determinants underlying ESCC. The findings identify potential prognostic biomarkers and a gene expression signature that may enable improved patient risk stratification in ESCC. Experimental validation of the role of PRKCB substantiates the potential clinical utility of our results.

Use of Interfacial Interactions and Complexation of Carbon Dots to Construct Ultra-Robust and Efficient Photothermal Film From Micro-Carbonized Polysaccharides.

Solar energy conversion technologies, particularly solar-driven photothermal conversion, are both clean and manageable. Although much progress has been made in designing solar-driven photothermal materials, significant challenges remain, not least the photobleaching of organic dyes. To tackle these issues, micro-carbonized polysaccharide chains, with carbon dots (CDs) suspended from the chains, are conceived, just like grapes or tomatoes hanging from a vine. Carbonization of sodium carboxymethyl cellulose (CMC) produces just such a structure (termed CMC-g-CDs), which is used to produce an ultra-stable, robust, and efficient solar-thermal film by interfacial interactions within the CMC-g-CDs. The introduction of the CDs into the matrix of the photothermal material effectively avoided the problem of photobleaching. Manipulating the interfacial interactions (such as electrostatic interactions, van der Waals interactions, π-π stacking, and hydrogen bonding) between the CDs and the polymer chains markedly enhances the mechanical properties of the photothermal film. The CMC-g-CDs are complexed with Fe3+ to eliminate leakage of the photothermal reagent from the matrix and to solve the problem of poor water resistance. The resulting film (CMC-g-CDs-Fe) has excellent prospects for practical application as a photothermal film.