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Symbolic numeracy first emerges as children learn the meanings of number words and how to use them to precisely count sets of objects. This development starts before children enter school and forms a foundation for lifelong mathematics achievement. Despite its importance, exactly how children acquire this basic knowledge is unclear. Here we test competing theories of early number learning by measuring event-related brain potentials during a novel number word-quantity comparison task in 3-4-year-old preschool children (N = 128). We find several qualitative differences in neural processing of number by conceptual stage of development. Specifically, we find differences in early attention-related parietal electrophysiology (N1), suggesting that less conceptually advanced children process arrays as individual objects and more advanced children distribute attention over the entire set. Subsequently, we find that only more conceptually advanced children show later-going frontal (N2) sensitivity to the numerical-distance relationship between the number word and visual quantity. The nature of this response suggested that exact rather than approximate numerical meanings were being associated with number words over frontal sites. No evidence of numerical distance effects was observed over posterior scalp sites. Together these results suggest that children may engage parallel individuation of objects to learn the meanings of the first few number words, but, ultimately, create new exact cardinal value representations for number words that cannot be defined in terms of core, nonverbal number systems. More broadly, these results document an interaction between attentional and general cognitive mechanisms in cognitive development.

Abstract Background The optimal timing for administering dual antiplatelet therapy (DAPT) post-coronary artery bypass grafting (CABG) remains a subject of debate. This study aimed to evaluate the safety and efficacy of early DAPT administration within 6 h post-CABG, following the implementation of a new standard operating procedure (SOP). This study was conducted in three phases at the National Heart Institute of Malaysia. Phase 1 involved a clinical audit of 80 isolated CABG patients to evaluate current DAPT practices. Phase 2 was a pilot study involving 320 patients to establish criteria for early DAPT initiation. Phase 3 comprised a prospective cohort analysis comparing outcomes between 939 propensity-matched pairs receiving early/new SOP ( 6 h) DAPT. Results The clinical audit revealed a mean DAPT administration time of 18.3 h post-CABG, highlighting variability in practice. The pilot study demonstrated that early DAPT was associated with a significantly lower chest reopening rate (0.8% vs. 21.6%) under stringent selection criteria. In the follow-up study, early DAPT was linked to reduced rates of postoperative stroke (1.0% vs. 2.5%, p = 0.013), dialysis (5.5% vs. 7.0%, p

Methamphetamine use disorder (MUD) is a substance use disorder. Because MUD has become more prevalent due to the COVID-19 pandemic, alternative ways to help the efficiency of mass screening of MUD are important. Previous studies used electroencephalogram (EEG), heart rate variability (HRV), and galvanic skin response (GSR) aberrations during the virtual reality (VR) induction of drug craving to accurately separate patients with MUD from the healthy controls. However, whether these abnormalities present without induction of drug-cue reactivity to enable separation between patients and healthy subjects remains unclear. Here, we propose a clinically comparable intelligent system using the fusion of 5–channel EEG, HRV, and GSR data during resting state to aid in detecting MUD. Forty-six patients with MUD and 26 healthy controls were recruited and machine learning methods were employed to systematically compare the classification results of different fusion models. The analytic results revealed that the fusion of HRV and GSR features leads to the most accurate separation rate of 79%. The use of EEG, HRV, and GSR features provides more robust information, leading to relatively similar and enhanced accuracy across different classifiers. In conclusion, we demonstrated that a clinically applicable intelligent system using resting-state EEG, ECG, and GSR features without the induction of drug cue reactivity enhances the detection of MUD. This system is easy to implement in the clinical setting and can save a lot of time on setting up and experimenting while maintaining excellent accuracy to assist in mass screening of MUD.

Abstracts: Objective: Mature extragonadal teratomas, particularly at the pelvic extraperitoneal site, are rare. Herein, we report a case of paravaginal teratoma and fistula formation five years post-operation. Case Report: A 23-year-old woman (G4P3A1) presented with a left paravaginal cystic tumor. After transvaginal tumor excision, histopathology revealed a paravaginal dermoid cyst. Five years post-operation, she returned with recurrent symptoms, including fever and perineal pain. Pelvic magnetic resonance imaging showed abscess at the surgical site, with tract-like extensions through the levator ani and vaginal wall. Treatment was administered without surgical intervention. Seven years post-operation, the patient underwent debridement of the left paravaginal abscess via the left perineal route. The patient was diagnosed with an abscess and an epidermal keratinous cyst with a vaginoperineal fistula. No recurrent abscess or fistula formation was encountered four years after debridement and fistulectomy. Conclusion: Preoperative and postoperative counseling should be conducted with long-term follow-up for such patients.

Abstract Background High-risk pregnancy leads to uncertainty and stress in pregnant women due to the threatened of mother and fetus health. The Uncertainty Stress Scale High-Risk Pregnancy Version, a 54-item Chinese version (USS-HRPV-C), has been widely used to assess the uncertainty and stress that women experience during pregnancy. However, the length of the scale may result in a burden for respondents. Thus, a brief version of the USS-HRPV-C is needed for a concise and vigorous assessment. The aim of this study was to shorten the USS-HRPV-C and validate the brief version. Methods This study used a cross-sectional design. A convenience sample of 200 women with high-risk pregnancies completed the 54-item USS-HRPV- C. Confirmatory factor analysis (CFA) and Rasch model to examine the construct validity of the short version of the USS-HRPV-C. Rasch analysis was used with a stepwise approach to select items with better goodness-of-fit and no differential item functioning (DIF). Additionally, Cronbachs’ α and Pearson correlations to evaluate the internal consistency of the original and brief versions. Test analysis modules (TAM) and Lavaan packages in R were used for data analyses. Results The results of CFA supported a two-factor structure of the HRPV-C. Using the Rasch analysis, we reduced the USS-HRPV-C scale from 54 to 17 items. The selected 17 items were robust without displaying differential item functioning. Further, the 17-item short version exhibited satisfactory fit statistics that infit and outfit mean square ranged between 0.71 and 1.35, respectively. Internal consistency of Cronbach’s α for the short version of the USS-HRPV-C scale ranged was 0.90 and 0.92 for the subscales of uncertainty and stress respectively. Both subscales of the brief version were significantly related to the original version of USS-HRPV-C. Conclusions This study developed a 17-item brief version of the USS-HRPV-C scale, which has demonstrated its satisfactory psychometric properties. Healthcare providers can use the validated brief version of the USS-HRPV-C to proficiently assess women’s psychosocial stress and uncertainty during pregnancy.

Abstract The randomness and volatility of existing clean energy sources have increased the complexity of grid scheduling. To address this issue, this work proposes an artificial intelligence (AI) empowered method based on the Environmental, Social, and Governance (ESG) big data platform, focusing on multi-objective scheduling optimization for clean energy. This work employs a combination of Particle Swarm Optimization (PSO) and Deep Q-Network (DQN) to enhance grid scheduling efficiency and clean energy utilization. First, the work analyzes the complexity and uncertainty challenges faced in clean energy scheduling within the current power system, highlighting the limitations of traditional methods in handling multi-objective optimization and real-time response. Consequently, the work introduces the ESG big data platform and leverages its abundant data resources and computational power to improve the scheduling decision-making process. Next, PSO is used for initial scheduling optimization and a mathematical model for clean energy scheduling optimization is constructed. To further enhance the dynamic response capability of the scheduling process, this work designs a dual-layer architecture. Among this architecture, DQN is responsible for adjusting the PSO initially optimized scheduling plan based on real-time data during the actual scheduling process, adapting it to the instantaneous change demand and renewable energy output characteristics. Finally, to verify the model’s effectiveness, this work conducts simulation analyses using real data from the state grid ESG big data platform. The results indicate that this method significantly improves clean energy utilization, increasing it from 62.4% (with traditional methods) to 87.7%, while reducing scheduling costs by 22%. With the increase in communication delay, the generation time of scheduling instruction increases significantly. This is because the algorithm needs to wait longer to receive the complete grid status information, which affects the generation speed of scheduling instructions. Moreover, this method demonstrates good adaptability and stability under different load demands and clean energy supply conditions. This work introduces a novel and efficient method for clean energy scheduling optimization by integrating PSO and DQN. It contributes to the overall improvement of clean energy utilization within the State Grid and provides a theoretical and empirical foundation for further research in related fields.

Abstract Kidney Chromophobe (KICH) is the third most prevalent renal malignancy, with research challenges due to a dearth of cell lines and clinical samples. There is no specific treatment regimen tailored exclusively for KICH. This study employed gene expression analysis, immunohistochemistry (IHC), Spearman’s correlation, immune cell infiltration assessment, and molecular network construction to investigate the autophagy gene ATG10 in KICH. ATG10 was uniquely downregulated in KICH, predominantly regulated by RNA m6A methylation. This downregulation correlated with patient survival, suggesting a potential tumor-regulatory role. ATG10’s involvement in the protein lipidation pathway, essential for cuproptosis, was identified. B cells and CD8 + T cells were key immune cells in KICH tumorigenesis associated with ATG10. Examination of molecular networks identified several key molecules and mechanisms, including ceRNA, interplaying proteins, and transcription factors. Additionally, drug targeting analysis pointed to specific amino acids and metabolites as potential therapeutic agents. This study elucidates the significance of ATG10 in KICH, implicating m6A methylation and cuproptosis as novel targets for therapeutic intervention. The identification of B cells and CD8 + T cells as key immune components, along with specific amino acids, suggests that a combination of targeted immune therapies and dietary interventions could provide a multifaceted approach to KICH treatment. Given the limited understanding of KICH pathogenesis, our analysis has unveiled new theoretical insights and potential clinical significances for KICH, expected to broaden the research horizon in this field.

Hemophilic articular cartilage damage presents a significant challenge for surgeons, characterized by recurrent intraarticular bleeding, a severe inflammatory microenvironment, and limited self-repair capability of cartilage tissue. Currently, there is a lack of tissue engineering-based integrated therapies that address both early hemostasis, anti-inflammation, and long-lasting chondrogenesis for hemophilic articular cartilage defects. Herein, we developed an adhesive hydrogel using oxidized chondroitin sulfate and gelatin, loaded with exosomes derived from bone marrow stem cells (BMSCs) (Hydrogel-Exos). This hydrogel demonstrated favorable injectability, self-healing, biocompatibility, biodegradability, swelling, frictional and mechanical properties, providing a comprehensive approach to treating hemophilic articular cartilage defects. The adhesive hydrogel, featuring dynamic Schiff base bonds and hydrogen bonds, exhibited excellent wet tissue adhesiveness and hemostatic properties. In a pig model, the hydrogel could be smoothly injected into the knee joint cartilage defect site and gelled in situ under fluid-irrigated arthroscopic conditions. Our in vitro and in vivo experiments confirmed that the sustained release of exosomes yielded anti-inflammatory effects by modulating macrophage M2 polarization through the NF-κB pathway. This immunoregulatory effect, coupled with the extracellular matrix components provided by the adhesive hydrogel, enhanced chondrogenesis, promoted the cartilage repair and joint function restoration after hemophilic articular cartilage defects. In conclusion, our results highlight the significant application potential of Hydrogel-Exos for early hemostasis, immunoregulation, and long-term chondrogenesis in hemophilic patients with cartilage injuries. This innovative approach is well-suited for application during arthroscopic procedures, offering a promising solution for addressing the complex challenges associated with hemophilic articular cartilage damage.

Abstract Lung cancer is one of the most critical global health threats, as the second most common cancer and leading cause of cancer deaths globally. While smoking is the primary risk factor, an increasing number of cases occur in nonsmokers, with lung cancer in nonsmokers (LCNS) now recognized as the fifth leading cause of cancer mortality worldwide. Recent evidence identifies air pollution, particularly fine particulate matter (PM2.5), as a significant risk factor in LCNS. PM2.5 can increase oxidative stress and inflammation, induce genetic alterations and activation of oncogenes (including the epidermal growth factor receptor, EGFR), and contribute to lung cancer progression. This review summarizes the current understanding of how exposure to PM2.5 induces lung carcinogenesis and accelerates lung cancer development. It underscores the importance of prevention and early detection while calling for targeted therapies to combat the detrimental effects of air pollution. An integrated approach that combines research, public health policy, and clinical practice is essential to reduce the lung cancer burden and improve outcomes for those affected by PM2.5 exposurrre.

Abstract Background With the rising prevalence of abdominal radical hysterectomy, the need for perioperative blood transfusion has emerged as a significant clinical challenge. Independent risk factors for blood transfusion during abdominal radical hysterectomy remains limited, and identifying these factors is needed. Methods A retrospective analysis of data was performed using the Nationwide Inpatient Sample (NIS), focusing on patients who underwent abdominal radical hysterectomy between 2010 and 2019. Patients were categorized into two groups based on whether they received a blood transfusion. The analysis encompassed various demographic factors, including race, sex, and age, as well as length of stay (LOS), total hospitalization charges, hospital characteristics (admission type, insurance type, bed size, teaching status, geographic location, and hospital region), hospital mortality rates, comorbidities, and perioperative complications. Subsequently, both univariate and multivariate logistic regression analyses were employed to ascertain factors associated with abdominal radical hysterectomy patients requiring blood transfusions. Results Blood transfusions occurred in 14.84% of patients between 2010 and 2019, with a downward trend over time. Receiving a transfusion was associated with several negative outcomes, including a longer length of stay, higher total charges, and complications like thrombocytopenia, acute myocardial infarction, pneumonia, and so on. Additionally, patients who received transfusions were more likely to experience postoperative delirium, deep vein thrombosis, and wound infection. Independent risk factors for blood transfusion include Black race, Asian or Pacific Islander race, non-elective surgery, hospitalization in a rural setting, pre-existing medical conditions like coagulopathy, chronic blood loss anemia, deficiency anemia and others. Conversely, patients with private insurance, residing in the West, or Midwest/North Central regions were less likely to require a blood transfusion. Conclusion Our study highlights the concern of perioperative blood transfusion in radical hysterectomy, linked to significant complications. Reducing intraoperative blood loss and optimizing care based on patient factors are crucial for improving outcomes.

Root system architecture plays an essential role in water and nutrient acquisition in plants, and it is significantly involved in plant adaptations to various environmental stresses. In this study, a panel of 242 cotton accessions was collected to investigate six root morphological traits at the seedling stage, including main root length (MRL), root fresh weight (RFW), total root length (TRL), root surface area (RSA), root volume (RV), and root average diameter (AvgD). The correlation analysis of the six root morphological traits revealed strong positive correlations of TRL with RSA, as well as RV with RSA and AvgD, whereas a significant negative correlation was found between TRL and AvgD. Subsequently, a genome-wide association study (GWAS) was performed using the root phenotypic and genotypic data reported previously for the 242 accessions using 56,010 single nucleotide polymorphisms (SNPs) from the CottonSNP80K array. A total of 41 quantitative trait loci (QTLs) were identified, including nine for MRL, six for RFW, nine for TRL, 12 for RSA, 12 for RV and two for AvgD. Among them, eight QTLs were repeatedly detected in two or more traits. Integrating these results with a transcriptome analysis, we identified 17 candidate genes with high transcript values of transcripts per million (TPM)≥30 in the roots. Furthermore, we functionally verified the candidate gene GH_D05G2106, which encodes a WPP domain protein 2 in root development. A virus-induced gene silencing (VIGS) assay showed that knocking down GH_D05G2106 significantly inhibited root development in cotton, indicating its positive role in root system architecture formation. Collectively, these results provide a theoretical basis and candidate genes for future studies on cotton root developmental biology and root-related cotton breeding.

Abstract Three-dimensional Spatial Transcriptomics has revolutionized our understanding of tissue regionalization, organogenesis, and development. However, existing approaches overlook either spatial information or experiment-induced distortions, leading to significant discrepancies between reconstruction results and in vivo cell locations, causing unreliable downstream analysis. To address these challenges, we propose ST-GEARS (Spatial Transcriptomics GEospatial profile recovery system through AnchoRS). By employing innovative Distributive Constraints into the Optimization scheme, ST-GEARS retrieves anchors with exceeding precision that connect closest spots across sections in vivo. Guided by the anchors, it first rigidly aligns sections, next solves and denoises Elastic Fields to counteract distortions. Through mathematically proved Bi-sectional Fields Application, it eventually recovers the original spatial profile. Studying ST-GEARS across number of sections, sectional distances and sequencing platforms, we observed its outstanding performance on tissue, cell, and gene levels. ST-GEARS provides precise and well-explainable ‘gears’ between in vivo situations and in vitro analysis, powerfully fueling potential of biological discoveries.

Abstract Background Lifelong learning is essential for cultivating conscientious nurses. Because self-directed learning is significantly correlated with lifelong learning, it is necessary to enhance nursing students’ self-directed learning skills after graduation. This study examined the effectiveness of an integrated team-based learning and empathy mapping teaching strategy in a Psychiatric Nursing course for enhancing students’ self-directed learning skills and academic performance. Methods A quasi-experimental design was used. The subjects of the study were 89 third-year nursing students who enrolled in a course on Psychiatric Nursing. Data were collected from September 22, 2021 to January 31, 2022. The participants were recruited using purposive sampling and divided into experimental group and control group. The pre- and post-test learning outcomes of nursing students were evaluated with the Self-Directed Learning Instrument (SDLI). Results The experimental group performed significantly better than the control group on the dimensions of “identifying learning resources,” “monitoring learning progress,” and “interpersonal communication,” (p

Abstract To evaluate the necessity of performing whole spine magnetic resonance imaging (MRI) as opposed to solely lumbosacral MRI for detecting high-level spinal lesions (in the brain, cervical, or thoracic spine) in patients with anorectal malformations (ARM). This retrospective cohort study included 69 patients treated for ARM at a medical center between January 2011 and January 2022. Before March 2021, lumbosacral MRI was used for patients with ARM. Since March 2021, anomalies in the posterior cranial fossa and whole spine were assessed using routine MRI. Both male (n = 30, 43.4%) and female patients were included in the study. Out of the 69 patients, 19 (27.5%) underwent whole spine MRI, and 50 (72.5%) underwent lumbosacral MRI. In the whole spine group, 4 patients had anomalies beyond the lumbosacral area. In the lumbosacral group, 4 patients subsequently underwent whole spine MRI due to symptoms, with 3 revealing higher-level anomalies.High-level spinal and brain anomalies, although infrequent, are present in patients with ARM. The findings suggest considering routine whole spine MRI in screening ARM patients to avoid missing high-level anomalies.

Abstract Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells.

This study aims to explore how e-textbooks with emotional design affect students' emotion, cognitive load and learning achievement. There were 147 freshman students in total: the experimental group I, II and control group consisted of 49, 47 and 51 students, using e-textbooks with emotional design, without emotional design and traditional paper textbooks. The results reveal the following: Students' emotion after using e-textbooks with emotional design is more positive than those using e-textbooks without emotional design and paper textbooks. Students' cognitive load after using e-textbooks with emotional design is significantly lower than those using etextbooks without emotional design. Students' learning achievement after using two types of e-textbooks is better than after using paper textbooks. Comparing all types of textbooks altogether, emotion has a significantly positive correlation with learning achievement, and both emotion and learnng achievement are significantly and negatively correlated with cognitive load. For the three types of textbooks, the relationship between emotion and learning achievement all becomes not significantly correlated. For two types of e-textbooks, cognitive load and learning achievement become not significantly correlated, disturbed by the digitalization of textbooks. Instructors are suggested to firstly adopt e-textbooks with emotional design, those without emotional design secondly, and paper textbooks rank last.

Leptomeningeal metastasis (LM) is a significant complication of advanced non-small cell lung cancer (NSCLC), occurring in only 3-5% of patients and exceedingly rare in newly diagnosed NSCLC patients. This also indicates that the tumor is highly malignant and aggressive, which brings great challenges to treatment. Here we present a case report of an EGFR-mutated NSCLC patient who presented with LM as the primary clinical manifestation, and review the latest advances in existing studies on LM-related treatment. The patient underwent multiple cycles of high-dose aumolertinib in combination with intrathecal pemetrexed administered via Ommaya reservoir. As of the submission date, the patient achieved significant remission and a LM Progression-Free Survival (PFS) exceeding 20 months. This case highlights the positive impact of high-dose aumolertinib combined with intrathecal pemetrexed on NSCLC patients presenting with severe meningeal symptoms as the initial manifestation, offering a viable therapeutic approach for managing severe meningeal symptoms associated with LM, such as headache, nausea, neck stiffness, and vomiting.

Objective Despite revascularization has been proven to be the optimal choice of moyamoya disease (MMD), many complications may occur in this context.. This study aimed to analyse the risk factors for new or expanded symptomatic infarctions of patients with MMD after revascularization.Methods Patients with MMD who received revascularization in our department were retrospectively enrolled, new or expanded cerebral infarction within a month after revascularization was the main concern. Basic and clinical information, and intraoperative conditions were evaluated. Univariate and multivariate analyses were performed to evaluate the risk factors. Receiver operating characteristic curve analysis was conducted to evaluate the efficiency of the risk factors.Results Eventually, 108 consecutive patients received 174 surgeries were enrolled, experienced new or expanded infarction occured in 13 (7.47%) surgeries, which showed higher Suzuki stage on the non-operative side, more posterior cerebral artery (PCA) involvement, and more intraoperative hypotension compared to those without infarction(p

Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety of other solid tumors, including pancreatic adenocarcinoma and renal cell carcinoma. Here, we identified a novel fully human PSCA antibody using phage display methodology. The structure-based affinity maturation yielded a high-affinity binder, F12, which is highly specific and does not bind to 6,000 human membrane proteins based on a membrane proteome array assay. F12 targets PSCA amino acids 63–69 as tested by the peptide scanning microarray, and it cross-reacts with the murine PSCA. IgG1 F12 efficiently internalizes into PSCA-expressing tumor cells. The antimitotic reagent monomethyl auristatin E (MMAE)-conjugated IgG1 F12 (ADC, F12-MMAE) exhibits dose-dependent efficacy and specificity in a human prostate cancer PC-3-PSCA xenograft NSG mouse model. This is a first reported ADC based on a fully human PSCA antibody and MMAE that is characterized in a xenograft murine model, which warrants further optimizations and investigations in additional preclinical tumor models, including prostate and other solid tumors.

Background and purpose The triglyceride-glucose (TyG) index, a novel reliable biomarker for IR that incorporates blood glucose and triglyceride, is linked to intracranial atherosclerotic stenosis (ICAS). In this study, we aimed to further investigate the association between the TyG index and the outcomes of ICAS patients following extracranial-to-intracranial (EC-IC) bypass grafting.Methods 489 ICAS patients who underwent EC-IC bypass between Jan 2009 and Jan 2022 at our hospital were retrospectively collected. The major adverse cardiac and cerebrovascular events (MACCEs), and anastomotic restenosis, both of which are critical factors leading to poor prognosis of ICAS patients after EC-IC bypass, were mainly recorded and analyzed. Kaplan–Meier survival curve and Log-rank tests were sequentially conducted. Cox regression model was used to investigate the association between the TyG index and MACCEs & anastomotic stenosis. C-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI) evaluated the incremental predictive value of the TyG index.Results A higher incidence of MACCEs and anastomotic stenosis was found in higher-tertile TyG index group. The TyG index was significantly associated with an increased risk of MACCEs and anastomotic stenosis, independent of confounding factors, with a value of HR (1.30, 95%CI 1.10-1.51, p

Background: Intravenous immune checkpoint inhibitors (ICIs) have shown efficacy in treating locally advanced rectal cancer (LARC), but concerns about systemic toxicity persist. This study developed a unique approach termed chemo-immuno-embolization with transcatheter rectal arterial intervention (CIETAI), aiming to enhance the anti-tumor response while minimizing systemic toxicity. Method: This is a prospective, single-arm, phase II clinical trial conducted in Daping hospital. Patients with previously untreated stage II/III LARC underwent preoperative CIETAI combined with PD-1 inhibitor tislelizumab plus oxaliplatin, followed by standard concomitant chemoradiotherapy (capecitabine and 50.4 Gy radiation). Intravenous tislelizumab was administered for an additional two cycles. Results: Between January 2023 and December 2023, a total of 38 patients were enrolled. As the primary endpoint, 17 (44.74 %) patients achieved pathological complete response (TRG0), with a major pathologic response (MPR) rate of 65.79 %. The anal preservation rate was 84.21 % (32/38), and importantly, 15 of 21 patients with low rectal cancer achieved organ preservation with functional maintenance. Eight patients experienced grade 3–4 adverse events (AEs). All immune-related AEs were grade 1–2, with the most common being endocrine toxicity (5/6, 83.33 %). No grade 5 AEs occurred. Conclusion: This study provides preliminary evidence supporting the safety and efficacy of intraarterial tislelizumab delivery in the neoadjuvant setting for LARC. These promising results encourage further exploration in larger cohorts to validate the clinical impact of this novel CIETAI strategy. Trial registration: ClinicalTrials.gov Identifier: NCT05957016.

Abstract Protein complexes are fundamental to all cellular processes, so understanding their evolutionary history and assembly processes is important. Gene duplication followed by divergence is considered a primary mechanism for diversifying protein complexes. Nonetheless, to what extent assembly of present-day paralogous complexes has been constrained by their long evolutionary pathways and how cross-complex interference is avoided remain unanswered questions. Subunits of protein complexes are often stabilized upon complex formation, whereas unincorporated subunits are degraded. How such cooperative stability influences protein complex assembly also remains unclear. Here, we demonstrate that subcomplexes determined by cooperative stabilization interactions serve as building blocks for protein complex assembly. We further develop a protein stability-guided method to compare the assembly processes of paralogous complexes in cellulo. Our findings support that oligomeric state and the structural organization of paralogous complexes can be maintained even if their assembly processes are rearranged. Our results indicate that divergent assembly processes by paralogous complexes not only enable the complexes to evolve new functions, but also reinforce their segregation by establishing incompatibility against deleterious hybrid assemblies.

Abstract Background Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. Methods Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. Results Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). Conclusions Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient’s quality of life.

Abstract Purpose To apply an independent GPU-accelerated Monte Carlo (MC) dose verification for CyberKnife M6 with Iris collimator and evaluate the dose calculation accuracy of RayTracing (TPS-RT) algorithm and Monte Carlo (TPS-MC) algorithm in the Precision treatment planning system (TPS). Methods GPU-accelerated MC algorithm (ArcherQA-CK) was integrated into a commercial dose verification system, ArcherQA, to implement the patient-specific quality assurance in the CyberKnife M6 system. 30 clinical cases (10 cases in head, and 10 cases in chest, and 10 cases in abdomen) were collected in this study. For each case, three different dose calculation methods (TPS-MC, TPS-RT and ArcherQA-CK) were implemented based on the same treatment plan and compared with each other. For evaluation, the 3D global gamma analysis and dose parameters of the target volume and organs at risk (OARs) were analyzed comparatively. Results For gamma pass rates at the criterion of 2%/2 mm, the results were over 98.0% for TPS-MC vs.TPS-RT, TPS-MC vs. ArcherQA-CK and TPS-RT vs. ArcherQA-CK in head cases, 84.9% for TPS-MC vs.TPS-RT, 98.0% for TPS-MC vs. ArcherQA-CK and 83.3% for TPS-RT vs. ArcherQA-CK in chest cases, 98.2% for TPS-MC vs.TPS-RT, 99.4% for TPS-MC vs. ArcherQA-CK and 94.5% for TPS-RT vs. ArcherQA-CK in abdomen cases. For dose parameters of planning target volume (PTV) in chest cases, the deviations of TPS-RT vs. TPS-MC and ArcherQA-CK vs. TPS-MC had significant difference (P 0.05). ArcherQA-CK had less calculation time compared with TPS-MC (1.66 min vs. 65.11 min). Conclusions Our proposed MC dose engine (ArcherQA-CK) has a high degree of consistency with the Precision TPS-MC algorithm, which can quickly identify the calculation errors of TPS-RT algorithm for some chest cases. ArcherQA-CK can provide accurate patient-specific quality assurance in clinical practice.

Abstract The canonical non-homologous end joining (c-NHEJ) repair pathway, generally viewed as stochastic, has recently been shown to produce predictable outcomes in CRISPR-Cas9 mutagenesis. This predictability, mainly in 1-bp insertions and small deletions, has led to the development of in-silico prediction programs for various animal species. However, the predictability of CRISPR-induced mutation profiles across species remained elusive. Comparing CRISPR-Cas9 repair outcomes between human and plant species reveals significant differences in 1-bp insertion profiles. The high predictability observed in human cells links to the template-dependent activity of human Polλ. Yet plant Polλ exhibits dual activities, generating 1-bp insertions through both templated and non-templated manners. Polλ knockout in plants leads to deletion-only mutations, while its overexpression enhances 1-bp insertion rates. Two conserved motifs are identified to modulate plant Polλ‘s dual activities. These findings unveil the mechanism behind species-specific CRISPR-Cas9-induced insertion profiles and offer strategies for predictable, precise genome editing through c-NHEJ.

Abstract Background The effectiveness of fish oil in preventing cardiovascular events is still debating. Some studies indicate a correlation between the use of fish oil supplements and reduced mortality or decreased incidence of stroke. However, other studies show no significant association between fish oil intake and stroke prevention, indicating an ongoing debate. This study aimed at exploring which subjects may benefit more from fish oil supplementation. Methods This study utilized the data obtained through face-to-face interview from the Taiwan Longitudinal Study in Aging (TLSA). A total of 3,652 participants were included from the 2003 baseline data, after excluding patients with pre-existing ischemic heart disease or stroke. Participants were divided into two groups based on whether taking fish oil supplement or not. Participants were followed until 2015, estimating and comparing the all-cause mortality and cumulative incidence rate of stroke between both groups. Results The results of the 12-year longitudinal study showed that the cumulative incidence rate of stroke in the fish oil supplementation group was 5.7%, compared to 7.7% in the non-supplemented group (P

Abstract Background This study aims to investigate the benefits of employing a Physical Lifelike Brain (PLB) simulator for training medical students in performing craniotomy for glioblastoma removal and decompressive craniectomy. Methods This prospective study included 30 medical clerks (fifth and sixth years in medical school) at a medical university. Before participating in the innovative lesson, all students had completed a standard gross anatomy course as part of their curriculum. The innovative lesson involved PLB Simulator training, after which participants completed the Learning Satisfaction/Confidence Perception Questionnaire and some received qualitative interviews. Results The average score of students’ overall satisfaction with the innovative lesson was 4.71 out of a maximum of 5 (SD = 0.34). After the lesson, students’ confidence perception level improved significantly (t = 9.38, p

Abstract Background The interplay between diabetes mellitus (DM), glycemic traits, and vascular and valvular calcifications is intricate and multifactorial. Exploring potential mediators may illuminate underlying pathways and identify novel therapeutic targets. Methods We utilized univariable and multivariable Mendelian randomization (MR) analyses to investigate associations and mediation effects. Additionally, the multivariable MR analyses incorporated cardiometabolic risk factors, allowing us to account for potential confounders. Results Type 2 diabetes mellitus (T2DM) and glycated hemoglobin (HbA1c) were positively associated with both coronary artery calcification (CAC) and calcific aortic valvular stenosis (CAVS). However, fasting glucose (FG) was only linked to CAVS and showed no association with CAC. Additionally, CAVS demonstrated a causal effect on FG. Calcium levels partially mediated the impact of T2DM on both types of calcifications. Specifically, serum calcium was positively associated with both CAC and CAVS. The mediation effects of calcium levels on the impact of T2DM on CAC and CAVS were 6.063% and 3.939%, respectively. The associations between T2DM and HbA1c with calcifications were influenced by body mass index (BMI) and smoking status. However, these associations were generally reduced after adjusting for hypertension. Conclusion Our findings suggest a genetically supported causal relationship between DM, glycemic traits, and vascular and valvular calcifications, with serum calcium playing a critical mediating role.

Abstract Neoadjuvant immunochemotherapy (NAIC) achieves superior clinical benefits over neoadjuvant chemotherapy (NAC) in multiple types of human cancers, including gastric adenocarcinoma (GAC). However, it is poorly understood how the malignant epithelial cells and tumor immune microenvironment (TIME) might respond distinctly to NAIC and NAC that underlies therapeutic efficacy. Here treatment‐naive and paired tumor tissues from multiple centers were subjected to pathological, immunological, and transcriptomic analysis. NAIC demonstrated significantly increased rate of pathological complete response compared to NAC (pCR: 25% vs. 4%, p

Background: Microbiota manipulation through preoperative probiotic supplementation to reduce surgical site infection has shown promising results in recent years. However, the changes in gut microbiota resulting from this manipulation remain unclear. In eastern Asia, Clostridium butyricum (CBM588) has been demonstrated to have antimicrobial ability. This study aimed to explore postoperative outcomes associated with microbiota changes in a murine colonic anastomosis model. Materials and Methods: C57BL/6 mice were divided into four groups. All mice, including group A as the control, received standard oral neomycin and metronidazole before surgery. Group B received CBM588 before surgery. Group C received the antibiotic cocktail therapy before surgery. Group D received the antibiotic cocktail therapy followed by CBM588 supplementation before surgery. A 16S rRNA amplicon with SMS was used to show the impact of different treatments on the murine gut microbiota. Results: The implementation of the antibiotic cocktail therapy resulted in improved postoperative performance, significantly better anastomotic healing scores, and reduced areas of anastomotic necrosis in both group C and D, but particularly prominently in group D. Metagenomic analysis revealed that group D was enriched with the order Clostridiales, the family Clostridiaceae, and the genus Clostridium, with low bacterial diversity and distinct bacterial composition. Conclusions: A preoperative antibiotic cocktail therapy followed by CBM588 supplementation modulates bacterial diversity and composition, resulting in an increased percentage of Clostridiaceae in a murine colonic anastomosis model. The associated outcomes include lower intra-abdominal adhesion scores, improved postoperative performance, improved anastomotic healing scores, and reduced areas of anastomotic necrosis.

IntroductionWhile nutrition's critical role in enhancing respiratory health is acknowledged, the specific impacts of vitamins A and K on lung function remain largely unexplored. The study aimed to evaluate the relationships between vitamins A and K intake and lung function.MethodsThe cross-sectional study focused on adults aged 20–79 with utilizing data from US National Health and Nutrition Examination Survey (NHANES) 2007–2012. Lung function was assessed by measuring forced expiratory volume (FEV1), forced vital capacity (FVC), and the ratio of these two values (FEV1/FVC). Regression model was performed to determine the associations between intake of vitamins A and K and outcomes.ResultsData of 10,034 participants (representing 142,965,892 adults in the US) were analyzed. After adjusting for relevant confounders, multivariable analysis revealed 1 μg/day increase of vitamin A intake was significantly associated with 0.03 ml increased FEV1 (p = 0.004) and 0.04 ml increased forced vital capacity (FVC) (p < 0.001). In addition, 1 μg/day increase in vitamin K intake was significantly associated with 0.11 ml increased FEV1 (p = 0.022). Neither vitamin A and K intake was associated with FEV1/FVC or presence of airway obstruction.ConclusionsIn relatively healthy population of the US, greater vitamin A or K intake was independently associated with better lung function assessed by spirometry. Benefits of such vitamins for pulmonary health should be confirmed in future randomized controlled trials.