Search

Abstract Accurate treatment response assessment using serial CT scans is essential in oncological clinical trials. However, oncologists’ assessment following the Response Evaluation Criteria in Solid Tumors (RECIST) guideline is subjective, time-consuming, and sometimes fallible. Advanced liver cancer often presents multifocal hepatic lesions on CT imaging, making accurate characterization more challenging than with other malignancies. In this work, we developed a tumor volume guided comprehensive objective response evaluation based on deep learning (RECORD) for liver cancer. RECORD performs liver tumor segmentation, followed by sum of the volume (SOV)-based treatment response classification and new lesion assessment. Then, it can provide treatment evaluations of response, stability, and progression, and calculates progression-free survival (PFS) and response time. The RECORD pipeline was developed with both CNN and ViT backbones. Its performance was evaluated in three longitudinal cohorts involving 60 multi-national centers, 206 patients, 891 CT scans, using internal five-fold cross-validation and external validations. RECORD with the most effective backbone achieved an average AUC-response of 0.981, AUC-stable of 0.929, and AUC-progression of 0.969 for SOV-based disease status classification, F1-score of 0.887 for new lesion identification, and accuracy of 0.889 for final treatment outcome assessments across all cohorts. RECORD’s PFS and response time predictions strongly correlated with clinician’s assessments (P

Abstract Customer perception is an important consideration factor in evaluating the quality of human-computer interaction services. Sustainable user experiences and marketing strategies can be created by analyzing customer perception. By understanding consumer satisfaction with product services in the customer perception area, appropriate product service failure prevention strategies can be formulated. A service failure evaluation model is proposed in this study, which considers the customer tolerance area to accurately evaluate consumers’ behavioral experiences from purchasing to using products. The concept of tolerance area is introduced, and a combination of the fuzzy Failure Mode and Effect Analysis (FMEA) method and the Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) method is used to construct a human-computer interaction service failure evaluation model. Potential service failure factors of smart speakers are accurately evaluated by this model, and these service failure factors are ranked within the tolerance area. The research identifies voice misinterpretation and signal connectivity issues as the primary risk factors impacting the quality of human-computer interaction for smart speakers. The application of this method not only enhances the evaluation of smart speaker human-computer interaction services quality but also aids in the precise identification and prioritization of critical failure modes. The proposed service failure prevention strategies can reduce consumer dissatisfaction and provide innovative references for smart product design and marketing. The findings bolster empirical evidence for service failure prevention strategies in smart products and pave the way for novel perspectives on enhancing the quality of human-computer interaction services.

Abstract Sepsis-induced cardiomyopathy (SIC) is described as a reversible myocardial depression that occurs in patients with septic shock. Increasing evidence shows that microRNA-194-5p (miR-194-5p) participates in the regulation of oxidative stress, mitochondrial dysfunction, and apoptosis and its expression is associated with the occurrence and progression of cardiovascular disease; however, the effects of miR-194-5p in SIC are still unclear. This study explores whether miR-194-5p could modulate SIC by affecting oxidative stress, mitochondrial function, and apoptosis. Experimental septic mice were induced by intraperitoneal injection of lipopolysaccharide (LPS) in C57BL/6J mice. The biological role of miR-194-5p in SIC in vivo was investigated using cardiac echocardiography, ELISA, western blot, qRT-PCR, transmission electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, bioinformatics analysis, and dual-luciferase reporter gene assay. Our major finding is that miR-194-5p antagomir mitigates sepsis-induced cardiac dysfunction, inflammation, oxidative stress, apoptosis and mitochondrial dysfunction in the hearts of septic mice, while miR-194-5p agomir triggers the opposite effects. Furthermore, dual-specificity phosphatase 9 (DUSP9) is a direct target of miR-194-5p and the cardioprotective effects of miR-194-5p antagomir on cardiac dysfunction, inflammation, apoptosis, mitochondrial dysfunction and oxidative stress are abolished through inhibiting DUSP9. Therefore, miR-194-5p inhibition could mitigate SIC via DUSP9 in vivo and the novel miR-194-5p/DUSP9 axis might be the potential treatment targets for SIC patients.

Abstract Background Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. Methods Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. Results We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. Conclusions Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Abstract Objectives To develop a deep learning model combining CT scans and clinical information to predict overall survival in advanced hepatocellular carcinoma (HCC). Methods This retrospective study included immunotherapy-treated advanced HCC patients from 52 multi-national in-house centers between 2018 and 2022. A multi-modal prognostic model using baseline and the first follow-up CT images and 7 clinical variables was proposed. A convolutional-recurrent neural network (CRNN) was developed to extract spatial-temporal information from automatically selected representative 2D CT slices to provide a radiological score, then fused with a Cox-based clinical score to provide the survival risk. The model’s effectiveness was assessed using a time-dependent area under the receiver operating curve (AUC), and risk group stratification using the log-rank test. Prognostic performances of multi-modal inputs were compared to models of missing modality, and the size-based RECIST criteria. Results Two-hundred seven patients (mean age, 61 years ± 12 [SD], 180 men) were included. The multi-modal CRNN model reached the AUC of 0.777 and 0.704 of 1-year overall survival predictions in the validation and test sets. The model achieved significant risk stratification in validation (hazard ratio [HR] = 3.330, p = 0.008), and test sets (HR = 2.024, p = 0.047) based on the median risk score of the training set. Models with missing modalities (the single-modal imaging-based model and the model incorporating only baseline scans) can still achieve favorable risk stratification performance (all p

Abstract Clostridium septicum infections are highly predictive of certain malignancies in human patients. To initiate infections, C. septicum spores must first germinate and regain vegetative growth. Yet, what triggers the germination of C. septicum spores is still unknown. Here, we observe that C. septicum germinates in response to specific bile salts. Putative bile salt recognition genes are identified in C. septicum based on their similarity in sequence and organization to bile salt-responsive csp genes in Clostridioides difficile. Inactivating two of these csp orthologs (cspC-82 and cspC-1718) results in mutant spores that no longer germinate in the presence of their respective cognate bile salts. Additionally, inactivating the putative cspBA or sleC genes in C. septicum abrogates the germination response to all bile salt germinants, suggesting that both act at a convergent point downstream of cspC-82 and cspC-1718. Molecular dynamics simulations show that both CspC-82 and CspC-1718 bear a strong structural congruence with C. difficile’s CspC. The existence of functional bile salt germination sensors in C. septicum may be relevant to the association between infection and malignancy.

Abstract Aim Exercise stress ECG is a common diagnostic test for stable coronary artery disease, but its sensitivity and specificity need to be further improved. In this paper, we construct a machine learning model for the prediction of angiographic coronary artery disease by HFQRS analysis of cycling exercise ECG. Methods and results This study prospectively included 140 inpatients and 59 healthy volunteers undergoing cycling exercise ECG. The CHD group (N=104) and non-CHD group (N=95) were determined by coronary angiography gold standard. Automated HF QRS analysis was performed by the blinded method. The coronary group was predominantly male, with a higher prevalence of age, BMI, hypertension, and diabetes than the non-coronary group ( $$P

Abstract Identifying spatially variable genes (SVGs) is crucial for understanding the spatiotemporal characteristics of diseases and tissue structures, posing a distinctive challenge in spatial transcriptomics research. We propose HEARTSVG, a distribution-free, test-based method for fast and accurately identifying spatially variable genes in large-scale spatial transcriptomic data. Extensive simulations demonstrate that HEARTSVG outperforms state-of-the-art methods with higher $${F}_{1}$$ F 1 scores (average $${F}_{1}$$ F 1 Score=0.948), improved computational efficiency, scalability, and reduced false positives (FPs). Through analysis of twelve real datasets from various spatial transcriptomic technologies, HEARTSVG identifies a greater number of biologically significant SVGs (average AUC = 0.792) than other comparative methods without prespecifying spatial patterns. Furthermore, by clustering SVGs, we uncover two distinct tumor spatial domains characterized by unique spatial expression patterns, spatial-temporal locations, and biological functions in human colorectal cancer data, unraveling the complexity of tumors.

Abstract The objective of this umbrella review was to investigate comprehensive and synthesized evidence of the association between ambient air pollution and obesity based on the current systematic reviews and meta-analyses. Related studies from databases including PubMed, EMBASE, Web of Science, and the Cochrane Library, published before July 16, 2023, were considered in the analysis. All selected systematic reviews and meta-analyses were included in accordance with PRISMA guidelines. The risk of bias and the methodological quality were evaluated using the AMSTAR 2 tool. The protocol for this umbrella review was documented in PROSPERO with the registration number: CRD42023450191. This umbrella review identified 7 studies, including 5 meta-analyses and 2 systematic reviews, to assess the impacts of air pollutants on obesity. Commonly examined air pollutants included PM1, PM2.5, PM10, NO2, SO2, O3. Most of the included studies presented that air pollution exposure was positively associated with the increased risk of obesity. The impact of air pollution on obesity varied by different ambient air pollutants. This study provided compelling evidence that exposure to air pollution had a positive association with the risk of obesity. These findings further indicate the importance of strengthening air pollution prevention and control. Future studies should elucidate the possible mechanisms and pathways linking air pollution to obesity.

Abstract Recent studies have shifted the spotlight from adult disease to gametogenesis and embryo developmental events, and these are greatly affected by various environmental chemicals, such as drugs, metabolites, pollutants, and others. Growing research has highlighted the critical importance of identifying and understanding the roles of chemicals in reproductive biology. However, the functions and mechanisms of chemicals in reproductive processes remain incomplete. We developed a comprehensive database called the Reproductive Chemical Database (RCDB) ( https://yu.life.sjtu.edu.cn/ChenLab/RCDB ) to facilitate research on chemicals in reproductive biology. This resource is founded on rigorous manual literature extraction and precise protein target prediction methodologies. This database focuses on the delineation of chemicals associated with phenotypes, diseases, or endpoints intricately associated with four important reproductive processes: female and male gamete generation, fertilization, and embryo development in human and mouse. The RCDB encompasses 93 sub-GO processes, and it revealed 1447 intricate chemical–biological process interactions. To date, the RCDB has meticulously cataloged and annotated 830 distinct chemicals, while also predicting 614 target proteins from a selection of 3800 potential candidates. Additionally, the RCDB offers an online predictive tool that empowers researchers to ascertain whether specific chemicals play discernible functional roles in these reproductive processes. The RCDB is an exhaustive, cross-platform, manually curated database, which provides a user-friendly interface to search, browse, and use reproductive processes modulators and their comprehensive related information. The RCDB will help researchers to understand the whole reproductive process and related diseases and it has the potential to promote reproduction research in the pharmacological and pathophysiological areas. Graphical Abstract

IntroductionTo investigate the ultrasound characteristics of recurrent laryngeal nerves (RLNs) during radical surgery for thyroid cancer and to enhance the understanding of RLN ultrasound features.MethodsFrom October 2021 to December 2022, a prospective study was conducted involving 24 patients scheduled for bilateral thyroid surgery. Near the conclusion of the surgery, intraoperative ultrasonography of the RLN within the tracheoesophageal groove was performed using a 15-7 MHz transducer. The thickness and width of the RLN were measured during the procedure.ResultsThe internal architecture of the RLN was observed to consist of multiple hypoechoic, parallel, but discontinuous linear hyperechoic areas separated by bands. In the normal RLN group, the diameter of the RLN was relatively consistent, with thickness ranging from 2.20 to 2.71 mm (mean: 2.48 ± 0.14 mm) and width from 1.25 to 1.70 mm (mean: 1.45 ± 0.11 mm). Both weight and the body mass index (BMI) showed a statistically significant correlation with RLN thickness (Weight: r=0.544, P=0.001; BMI: r=0.605, P=0.001). The BMI also showed a statistically significant correlation with the RLN width (r=0.377, P=0.033). In the RLN invasion group, the width of invaded RLNs ranged from 1.9 to 2.3 mm (mean: 2.10 ± 0.11 mm), while the width of non-invaded RLNs ranged from 2.6 to 3.2 mm (mean: 2.93 ± 0.20 mm).ConclusionsUltrasound effectively reveals the structural features of the RLN and enhances sonographers’ understanding of RLN characteristics.

Abstract Background The neutrophil-lymphocyte ratio (NLR) is a novel hematological parameter to assess systemic inflammation. Prior investigations have indicated that an increased NLR may serve as a potential marker for pathological states such as cancer and atherosclerosis. However, there exists a dearth of research investigating the correlation between NLR levels and mortality in individuals with diabetes and prediabetes. Consequently, this study aims to examine the connection between NLR and all-cause as well as cardiovascular mortality in the population of the United States (US) with hyperglycemia status. Methods Data were collected from a total of 20,270 eligible individuals enrolled for analysis, spanning ten cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. The subjects were categorized into three groups based on tertiles of NLR levels. The association of NLR with both all-cause and cardiovascular mortality was evaluated using Kaplan-Meier curves and Cox proportional hazards regression models. Restricted cubic splines were used to visualize the nonlinear relationship between NLR levels and all-cause and cardiovascular mortality in subjects with diabetes after accounting for all relevant factors. Results Over a median follow-up period of 8.6 years, a total of 1909 subjects with diabetes died, with 671 deaths attributed to cardiovascular disease (CVD). And over a period of 8.46 years, 1974 subjects with prediabetes died, with 616 cases due to CVD. The multivariable-adjusted hazard ratios (HRs) comparing high to low tertile of NLR in diabetes subjects were found to be 1.37 (95% CI, 1.19–1.58) for all-cause mortality and 1.63 (95% CI, 1.29–2.05) for CVD mortality. And the correlation between high to low NLR tertile and heightened susceptibility to mortality from any cause (HR, 1.21; 95% CI, 1.03–1.43) and CVD mortality (HR, 1.49; 95% CI, 1.08–2.04) remained statistically significant (both p-values for trend

Plastic film mulching has been widely used to increase maize yield in the semiarid area of China. However, whether long-term plastic film mulching is conducive to agricultural sustainability in this region remains controversial. A field experiment was initiated in 2013 with five different film mulching methods: (i) control method, flat planting without mulching (CK), (ii) flat planting with half film mulching (P), (iii) film mulching on ridges and planting in narrow furrows (S), (iv) full film mulching on double ridges (D), and (v) film mulching on ridges and planting in wide furrows (R). The effects on soil organic carbon (SOC) content, storage, and fractions, and on the carbon management index (CMI) were evaluated after nine consecutive years of plastic film mulching. The results showed that long-term plastic film mulching generally maintained the initial SOC level. Compared with no mulching, plastic film mulching increased the average crop yield, biomass yield, and root biomass by 48.38, 35.06, and 37.32%, respectively, which led to the improvement of SOC sequestration. Specifically, plastic film mulching significantly improved CMI, and increased the SOC content by 13.59%, SOC storage by 7.47% and easily oxidizable organic carbon (EOC) by 13.78% on average, but it reduced the other labile fractions. SOC sequestration and CMI were improved by refining the plastic film mulching methods. The S treatment had the best effect among the four mulching methods, so it can be used as a reasonable film mulching method for sustainable agricultural development in the semiarid area.

The study aims to characterize the immune cell landscape in convalescent Asian seabass (Lates calcarifer) blood samples after exposure to scale-drop disease virus (SDDV). Traditional immunophenotyping approaches used in human and mouse studies are impractical for non-model organisms like the Asian seabass due to the lack of specific antibody-based reagents. To overcome this challenge, 10x Genomics single-cell RNA sequencing was employed. The analysis of blood samples revealed 24 distinct leukocyte clusters, with elevated proportions of B cells, granulocytes, and T cells in the convalescent group compared to the uninfected group. While distinguishing granulocyte and macrophage subsets was challenging, the analysis of differential gene expression in the macrophage population indicated that the upregulated genes were linked to inflammatory processes. Specific T cell clusters showed notable expressions of cd4-1, cd8a, perforin-1 and il-2rβ, suggesting the presence of CD4+ T helper (Th), CD8+ cytotoxic T (Tc) cells, immature T cells, and naive T cells. Attempts to categorize CD4+ T cells into Th subtypes lacked clear distinctions, while CD8+ T cells exhibited three clusters, predominantly Tc1 cells. Furthermore, comparisons between convalescent and uninfected groups revealed increased percentages of activated and antibody-secreting B cells in the convalescent group. This single-cell analysis provides vital insights into the immune cell dynamics in convalescent and uninfected Asian seabass, providing valuable information on potential immune responses to SDDV infection.

With the continuous innovation of genomics, proteomics and molecular biological detection technology, the treatment of non-small cell lung cancer (NSCLC) has changed from traditional chemotherapy to immunotherapy and targeted therapy. Among them, molecular tumor markers targeting tyrosine kinase pathways play more important roles in clinical practice. For advanced NSCLC patients with positive epidermal growth factor receptor (EGFR) mutations, there are many first-line drugs on the market and they could bring significant efficacy, thus completely subverting the treatment pattern of advanced NSCLC. Common mutations of EGFR in Chinese patients are located on exons 19, 20 and 21, of which exons 19 and 21 mutations are the more common types. Besides, there is also a subtype of EGFR mutations, known as EGFR 20 exon insertion (EGFR 20ins) mutation. The authors summarized the treatment of a lung adenocarcinoma patient with EGFR 20ins mutation accepting Furmonertinib mesylate, in order to provide effective references for clinical diagnosis and treatment.

Abstract Regulatory T cells (Tregs) expressing the transcription factor FoxP3 are essential for maintaining immunological balance and are a significant component of the immunosuppressive tumor microenvironment (TME). Single-cell RNA sequencing (ScRNA-seq) technology has shown that Tregs exhibit significant plasticity and functional diversity in various tumors within the TME. This results in Tregs playing a dual role in the TME, which is not always centered around supporting tumor progression as typically believed. Abundant data confirms the anti-tumor activities of Tregs and their correlation with enhanced patient prognosis in specific types of malignancies. In this review, we summarize the potential anti-tumor actions of Tregs, including suppressing tumor-promoting inflammatory responses and boosting anti-tumor immunity. In addition, this study outlines the spatial and temporal variations in Tregs function to emphasize that their predictive significance in malignancies may change. It is essential to comprehend the functional diversity and potential anti-tumor effects of Tregs to improve tumor therapy strategies.

Abstract Background Identifying individuals with mild cognitive impairment (MCI) at risk of progressing to Alzheimer’s disease (AD) provides a unique opportunity for early interventions. Therefore, accurate and long-term prediction of the conversion from MCI to AD is desired but, to date, remains challenging. Here, we developed an interpretable deep learning model featuring a novel design that incorporates interaction effects and multimodality to improve the prediction accuracy and horizon for MCI-to-AD progression. Methods This multi-center, multi-cohort retrospective study collected structural magnetic resonance imaging (sMRI), clinical assessments, and genetic polymorphism data of 252 patients with MCI at baseline from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Our deep learning model was cross-validated on the ADNI-1 and ADNI-2/GO cohorts and further generalized in the ongoing ADNI-3 cohort. We evaluated the model performance using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and F1 score. Results On the cross-validation set, our model achieved superior results for predicting MCI conversion within 4 years (AUC, 0.962; accuracy, 92.92%; sensitivity, 88.89%; specificity, 95.33%) compared to all existing studies. In the independent test, our model exhibited consistent performance with an AUC of 0.939 and an accuracy of 92.86%. Integrating interaction effects and multimodal data into the model significantly increased prediction accuracy by 4.76% (P = 0.01) and 4.29% (P = 0.03), respectively. Furthermore, our model demonstrated robustness to inter-center and inter-scanner variability, while generating interpretable predictions by quantifying the contribution of multimodal biomarkers. Conclusions The proposed deep learning model presents a novel perspective by combining interaction effects and multimodality, leading to more accurate and longer-term predictions of AD progression, which promises to improve pre-dementia patient care.

Linear alkylbenzene sulfonate (LAS) can be thoroughly mineralized within sufficient oxygen (O2), but which is energy intensive and may causes serious foaming problem. Although cometabolism can achieve efficient LAS removal within a wide range of O2 dosages, how O2 dosage systematically affects LAS metabolic pathway is still unclear. Here, membrane aerated biofilm reactor (MABR) enabled accurate O2 delivery and bulk dissolved oxygen (DO) control. MABR achieved efficient removal of LAS (>96.4 %), nitrate (>97.8 %) and total nitrogen (>96.2 %) at the three target DO conditions. At high DO condition (0.6 mg/L), LAS was efficiently removed by aerobic mineralization (predominant) coupled with aerobic denitrification biodegradation with the related functional enzymes. Pseudomonas, Flavobacterium, Hydrogenophaga, and Pseudoxanthomonas were dominant genus contributing to four possible LAS aerobic metabolic pathways. As O2 dosage reduced to only 29.7 % of the demand for LAS mineralization, O2 facilitated LAS activation, benzene-ring cleavage and a portion of respiration. NO3--N respiration-induced anaerobic denitrification also contributed to ring-opening and organics mineralization. Desulfomicrobium and Desulfonema related two possible anaerobic metabolic pathways also contributed to LAS removal. The findings provide a promising strategy for achieving low-cost high LAS-containing greywater treatment.

AbstractObjective: To evaluate the efficacy and feasibility of ultrasound-guided percutaneous thermal ablation (TA) for treating benign parotid tumors.Methods: Patients with benign parotid tumors who underwent ultrasound-guided microwave ablation (MWA) or radiofrequency ablation (RFA) between January 2020 and March 2023 were included in this retrospective study. Change in tumor size (maximum diameter, tumor volume(V), volume reduction rate (VRR)) and cosmetic score (CS) were evaluated during a one-year follow-up period. We also recorded the incidence of any complications associated with TA.Results: A total of 23 patients (13 males and 10 females; median age 65 years, range 5–91 years) were included. The mean VRR at 1, 3, 6, and 12 months after TA was 37.03%±10.23%, 56.52%±8.76%, 82.28%±7.89%, and 89.39%±6.45%, respectively. Mean CS also changed from 3.39 ± 0.66 to 1.75 ± 0.93 (p

AimA growing body of evidence has shown that attachment styles and death attitudes have a significant impact on empathy. This study aimed to explore the precise role of death attitudes in the relationship between attachment styles and empathy levels among trainee nurses.MethodsA total of 626 Chinese trainee nurses with different attachment types were enrolled, and their attachment styles, death attitudes, and empathy levels were assessed using the Revised Adult Attachment Scale, the Death Attitude Profile-Revised, and the Jefferson Scale of Empathy-Healthy Professionals, and finally, data from 566 participants were included for statistical analysis.ResultsWe found that among trainee nurses with secure attachment type, fear of death, approach acceptance, escape acceptance, and neutral acceptance (−) mediated the relationships between attachment-related avoidance/anxiety and their overall empathy levels and all its dimensions; in the preoccupied type, only neutral acceptance (−) mediated the relationships between attachment-related avoidance and their overall empathy levels and compassionate care; and in the fearful type, only fear of death mediated the relationship between attachment-related avoidance and compassionate care. Furthermore, in the secure type, neutral acceptance attenuated the negative predictions of attachment-related avoidance on overall empathy level and perspective taking.ConclusionAttitudes toward death played different mediating and moderating roles in the relationship between attachment styles and empathy among trainee nurses with different attachment types. In addition to acculturated empathy-specific training, targeted education related to death for trainee nurses with different attachment types is needed to prevent their compassion fatigue.

Abstract Transdermal drug delivery has been regarded as an alternative to oral delivery and subcutaneous injection. However, needleless transdermal delivery of biomacromolecules remains a challenge. Herein, a transdermal delivery platform based on biocompatible fluorocarbon modified chitosan (FCS) is developed to achieve highly efficient non-invasive delivery of biomacromolecules including antibodies and antigens. The formed nanocomplexes exhibits effective transdermal penetration ability via both intercellular and transappendageal routes. Non-invasive transdermal delivery of immune checkpoint blockade antibodies induces stronger immune responses for melanoma in female mice and reduces systemic toxicity compared to intravenous injection. Moreover, transdermal delivery of a SARS-CoV-2 vaccine in female mice results in comparable humoral immunity as well as improved cellular immunity and immune memory compared to that achieved with subcutaneous vaccine injection. Additionally, FCS-based protein delivery systems demonstrate transdermal ability for rabbit and porcine skins. Thus, FCS-based transdermal delivery systems may provide a compelling opportunity to overcome the skin barrier for efficient transdermal delivery of bio-therapeutics.

Abstract As single‐cell RNA sequencing enables the detailed clustering of T‐cell subpopulations and facilitates the analysis of T‐cell metabolic states and metabolite dynamics, it has gained prominence as the preferred tool for understanding heterogeneous cellular metabolism. Furthermore, the synergistic or inhibitory effects of various metabolic pathways within T cells in the tumour microenvironment are coordinated, and increased activity of specific metabolic pathways generally corresponds to increased functional activity, leading to diverse T‐cell behaviours related to the effects of tumour immune cells, which shows the potential of tumour‐specific T cells to induce persistent immune responses. A holistic understanding of how metabolic heterogeneity governs the immune function of specific T‐cell subsets is key to obtaining field‐level insights into immunometabolism. Therefore, exploring the mechanisms underlying the interplay between T‐cell metabolism and immune functions will pave the way for precise immunotherapy approaches in the future, which will empower us to explore new methods for combating tumours with enhanced efficacy.

Functional data analysis has significantly enriched the landscape of existing data analysis methodologies, providing a new framework for comprehending data structures and extracting valuable insights. This paper is dedicated to addressing functional data clustering—a pivotal challenge within functional data analysis. Our contribution to this field manifests through the introduction of innovative clustering methodologies tailored specifically to functional curves. Initially, we present a proximity measure algorithm designed for functional curve clustering. This innovative clustering approach offers the flexibility to redefine measurement points on continuous functions, adapting to either equidistant or nonuniform arrangements, as dictated by the demands of the proximity measure. Central to this method is the “proximity threshold”, a critical parameter that governs the cluster count, and its selection is thoroughly explored. Subsequently, we propose a time-shift clustering algorithm designed for time-series data. This approach identifies historical data segments that share patterns similar to those observed in the present. To evaluate the effectiveness of our methodologies, we conduct comparisons with the classic K-means clustering method and apply them to simulated data, yielding encouraging simulation results. Moving beyond simulation, we apply the proposed proximity measure algorithm to COVID-19 data, yielding notable clustering accuracy. Additionally, the time-shift clustering algorithm is employed to analyse NASDAQ Composite data, successfully revealing underlying economic cycles.

Macrophage differentiation is closely associated with idiopathic pulmonary fibrosis (IPF) initiation. Herein, we show that EZY-1, a novel peptide derived from Eucheuma, regulates macrophage differentiation to inhibit IPF. Macrophage differentiation was detected by analyzing the surface antigens of the macrophages using flow cytometry. The effect of EZY-1 on cell proliferation was assessed. Signaling molecules involved in macrophage differentiation and fibrosis were detected by Western blot and enzyme-linked immunosorbent assays. The results showed that EZY-1 suppressed BLM-induced pulmonary fibrosis, with a decrease in type M2 macrophages. Simultaneously, EZY-1 reduced the amount of TGF-β1 secreted by M2 macrophages. In addition, EZY-1 downregulated COL1A1, TGF-β, and p-Smad3 and upregulated p-β-catenin in fibroblasts induced by M2 macrophages. Our results confirmed that EZY-1 inhibits IPF by inhibiting type M2 macrophage differentiation, which may be associated with the expression of Rictor and SHP2. Thus, EZY-1 can potentially be used as a drug for treating IPF.

Abstract Objective To systematically evaluate several factors of persistent human papillomavirus (HPV) infection following conization in patients with cervical intraepithelial neoplasia (CIN). Methods PubMed, EMBASE and the Cochrane Library were searched from January 1, 1998 to September 10, 2021. Random-effects models for meta-analyses were used and pooled relative risks with 95% confidence intervals were reported. Literature screening, data extraction, and assessment of the risk of bias in the included studies were conducted independently by two researchers. Data analysis was performed with Stata software, version 12.0. Results A total of 28 studies were included in this study. Meta-analysis revealed that surgical margin and residual disease were positively correlated with persistent HPV infection after conization. Compared with patients infected with other types of HPV, CIN patients with HPV 16 had a higher persistent infection rate (OR = 1.967, 95% CI (1.232–3.140), P

Abstract Background The two most common methods for ultrasound-guided arterial cannulation are the long-axis in-plane (LA-IP) and short-axis out-of-plane (SA-OOP) approaches. However, it is uncertain which method is more advantageous. We conducted a meta-analysis of reported randomized clinical trials (RCTs) comparing the two techniques in terms of success rate, cannulation time, and complications. Methods We systematically searched PubMed, Embase, and the Cochrane Library database for RCTs comparing the LA-IP and SA-OOP techniques for ultrasound-guided arterial cannulation published from inception through April 31, 2022. The Cochrane Collaboration’s Risk of Bias Tool was used to evaluate the methodological quality of each RCT. Review Manager 5.4 and Stata/SE 17.0 were used to analyze the two primary outcome measures (first-attempt success rate and total success rate) and two secondary outcome measures (cannulation time and complications). Results A total of 13 RCTs with 1,377 patients were included. There were no significant differences in first-attempt success rate (risk ratio [RR], 0.93; 95% confidence interval [CI], 0.78–1.12; P = 0.45; I2 = 84%) and overall success rate (RR, 0.99; 95% CI, 0.95–1.02; P = 0.48; I2 = 57%). When compared with the LA-IP technique, the SA-OOP technique was associated with an increased incidence of posterior wall puncture (RR, 3.01; 95% CI, 1.27–7.14; P = 0.01; I2 = 79%) and hematoma (RR, 2.15; 95% CI, 1.05–4.37; P = 0.04; I2 = 63%). There was no significant difference in the incidence of vasospasm between techniques (RR, 1.26; 95% CI, 0.37–4.23; P = 0.07; I2 = 53%). Conclusions The present results suggest that the SA-OOP technique is associated with a higher incidence of posterior wall puncture and hematoma than the LA-IP technique, whereas success rates are similar for the two ultrasound-guided arterial cannulation techniques. These findings should be experimentally evaluated in a more rigorous manner due to high inter-RCT heterogeneity.

Abstract Background Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Although most patients are initially sensitive to first-line combination chemotherapy with cisplatin and etoposide, chemotherapy drug resistance easily develops and quickly leads to tumour progression. Therefore, understanding the mechanisms of chemotherapy drug resistance and how to reverse it is key to improving the prognosis of patients with SCLC. Moreover, N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalysed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Methods The effects of METTL3 on chemoresistance in SCLC cells were determined using qRT–PCR, Western blotting, immunohistochemistry, cell counting kit (CCK-8) assays, flow cytometry, and tumorigenicity experiments. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP qPCR, immunofluorescence, and drug inhibitor experiments were performed to confirm the molecular mechanism of Decapping Protein 2 (DCP2), which is involved in the chemoresistance of SCLC. Results In the present study, we found that METTL3 is a marker for poor SCLC prognosis, and it is highly expressed in chemoresistant SCLC cells. METTL3 promotes SCLC chemoresistance by positively regulating mitophagy. METTL3 induces m6A methylation of DCP2 and causes the degradation of DCP2, which promotes mitochondrial autophagy through the Pink1-Parkin pathway, leading to chemotherapy resistance. We also found that STM2457, a novel METTL3 inhibitor, can reverse SCLC chemoresistance. Conclusions The m6A methyltransferase METTL3 regulates Pink1-Parkin pathway-mediated mitophagy and mitochondrial damage in SCLC cells by targeting DCP2, thereby promoting chemotherapy resistance in patients with SCLC.

A 65-year-old woman presented to our hospital with 5 days of chest tightness, dyspnoea, and lower abdominal distension. Echocardiography revealed a mass in the right atrium. An emergency operation was carried out to prevent tumour shedding. The patient was discharged on the 4th day of tumour resection, without any complications At the 18 months follow-up, she suffered from kidney and lung tumours. She refused any treatment and passed away. scRNA-seq was applied to analyse the nature of the tumour. The cellular components of benign tumours include chondrocytes, smooth muscle cells, fibroblasts, mesenchymal stromal cells, and osteoblasts. Additionally, the cyclic guanosine monophosphate (cGMP-PKG) signalling pathway, transcriptional misregulation in cancer, and the p53 signalling pathway may be related to the growth of this tumour. scRNA-seq is a good approach to analyse growth patterns of cardiac tumours and helpful for distinguishing the nature of the tumour. Keywords: Sequence Analysis, RNA, Cardiac tumour.

Toxic and major elements, such as As and Fe, in watersheds can significantly impact the surrounding water environment and ecosystem. Thus, in this study, we conducted an investigation into the origins and spatial distribution of typical toxic trace elements (As and Mn) and crustal major elements (Al, Fe, and Ti) in suspended particulate matter (SPM) across various glacial watersheds located at different elevations in the northeastern Tibetan Plateau (NETP) from June to July in 2017. The results revealed that the mean value of each element followed the order of abundance in the samples, with Al having the highest mean value at 21307 µg/L, followed by Fe at 13366 µg/L, Ti at 1520 µg/L, Mn at 245 µg/L, and As at 66.6 µg/L. Moreover, our study identified high content of these elements from the Dabanshan Snowpack, Laohugou Glacier No.12, and Yuzhufeng Glacier in the upper reaches of the basin, which were found to be 9.9, 10.2, and 19.4 times higher, respectively, than that of the upper reaches of the Heihe River. We found that As and Mn exhibited clear indications of anthropogenic influence on a local and regional scale. The calculated enrichment factor (EF) demonstrated a significant As enrichment (EF>100) in the Qiyi and Lenglongling Glaciers, possibly resulting in the release of upstream glacier melt and anthropogenic-derived As deposition. Our findings suggested that the upstream region was primarily linked to glacier meltwater discharge. In contrast, the middle and lower reaches of the basin exhibited a more pronounced influence from local human activities. Based on the findings, the water environment of the glacier watershed appears to be in good condition overall. However, the presence of elevated levels of As element in the water system can be traced back to both anthropogenic and natural factors. As a result, ensuring the safety of the water supply for nearby residents is a matter of utmost concern. This study provides a comprehensive examination of hydrochemical variations and the overall water environment of high-altitude glacier basins in the NETP, offering valuable insights into the topic.

Abstract Extracranial arteriovenous malformations (AVMs) are characterized by anomalous arterial-to-venous connections, aberrant angiogenesis, local inflammation and hypoxia, and disorganized histological architecture; however, the precise molecular perturbations leading to this phenotype remain elusive. We hypothesized that extracranial AVM tissue would demonstrate deregulation of the TGF-β/BMP signaling pathway, which may serve as a potential target in the development of molecular-based therapies for AVMs. AVM tissue was harvested during resection from 10 patients with AVMs and compared to control tissue. Blood was collected from 14 AVM patients and 10 patients without AVMs as controls. Expression of TGF-β/BMP pathway components was analyzed using RT-PCR, western blotting, and immunohistochemistry. Circulating levels of TGF-β1 were analyzed by ELISA. Paired t tests were utilized to perform statistical analysis. The mRNA levels of TGF-β1, ALK1, Endoglin (ENG), Smad6, Smad7, and Smad8 were significantly elevated in AVM tissue when compared to controls. Protein levels of TGF-β1 and Smad3 were elevated in AVM tissue while protein levels of BMP-9, ALK1, Smad1, Smad6, and Smad8 were significantly decreased in AVMs. Immunohistochemistry demonstrated increased TGF-β1 in the perivascular cells of AVMs compared to normal controls, and circulating levels of TGF-β1 were significantly higher in AVM patients. Patients with AVMs demonstrate aberrant TGF-β/BMP expression in AVM tissue and blood compared to controls. Targeting aberrantly expressed components of the TGF-β/BMP pathway in extracranial AVMs may be a viable approach in the development of novel molecular therapies, and monitoring circulating TGF-β1 levels may be a useful indicator of treatment success.

Asian dust comprises a large portion of the northern hemisphere atmospheric dust load, thereby exerting substantial influence on the Earth's climate, global biogeochemistry and hydrological cycle through accelerated snow and ice melt. Dust deposited on alpine glaciers encodes information on broad scale atmospheric-environmental processes. The (234U/238U) values of dust fine particulates can reflect the comminuting time and intermediate processes; thus, it provides a new method for the provenance of aeolian dust in the glacial snowpack/cryoconite. Here we present results from a comprehensive survey of uranium isotopic concentrations in dust collected from cryoconites on the glaciers of the northern Tibetan Plateau (TP). These results indicate significant spatial heterogeneity in the (234U/238U) values associated with snowpack/cryoconite dust over a broad range of glaciers in the northern TP. The values of the (234U/238U) ratio in the glaciers of western Qilian Mountains (Qiyi Glacier, Shiyi Glacier, Laohugou Glacier No.12) were the highest, followed by the Tanggula (Dunkemadi Glacier) and Kunlun Mountains (Yuzhufeng Glacier), whereas these values were the lowest in the eastern Qilian Mountains (Jingyangling Snowpack, Dabanshan Snowpack, Lenglongling Glacier). By including the analysis of Sr-Nd isotopic compositions, we find the spatial isotopic distribution reflects a combination of local dust, which is associated with short comminuting times, and dust transported over long ranges. Meteorological data indicate that the dust production in the west and north TP, Alxa arid lands and Gobi Deserts, may have a significant impact on the TP glaciers. Moreover, U-Sr-Nd isotopic composition and end-member mixing models (EMMA) were used in our study to find out the relative contribution of distinct Asian dust sources to the dust budget in the TP glaciers. The results reveal that snowpack/cryoconite dust is derived from both local sources (low comminution signatures) as well as other dust sources in the Asian region. Our study demonstrates the potential of U isotope composition as a dust tracing method. In particular, by investigating this composition on dust collected from glacier snowpack and cryoconite holes, we arrive at a map of the distribution characteristics of (234U/238U) values in different regions of the TP. Our study is the first to deploy uranium comminution age for Tibetan dust source tracing, and the results are important to elucidate the multiple origins and dynamics of dust in the Tibetan Plateau.

Abstract Current strategies to improve the throughput of continuous directed evolution technologies often involve complex mechanical fluid‐controlling system or robotic platforms, which limits their popularization and application in general laboratories. Inspired by our previous study on bacterial range expansion, in this study, we report a system termed SPACE for rapid and extensively parallelizable evolution of biomolecules by introducing spatial dimensions into the landmark phage‐assisted continuous evolution system. Specifically, M13 phages and chemotactic Escherichia coli cells were closely inoculated onto a semisolid agar. The phages came into contact with the expanding front of the bacterial range, and then comigrated with the bacteria. This system leverages competition over space, wherein evolutionary progress is closely associated with the production of spatial patterns, allowing the emergence of improved or new protein functions. In a prototypical problem, SPACE remarkably simplified the process and evolved the promoter recognition of T7 RNA polymerase (RNAP) to a library of 96 random sequences in parallel. These results establish SPACE as a simple, easy to implement, and massively parallelizable platform for continuous directed evolution in general laboratories.

Carbon dioxide removal (CDR) is proposed to limit the level of global warming and minimize the impacts of climate crises. However, how permafrost may respond to negative carbon emissions remains unknown. Here, the response of near-surface permafrost in the Northern Hemisphere is investigated based on idealized carbon dioxide (CO _2 ) ramp-up (284.7–1138.8 ppm) and symmetric ramp-down model experiments. The results demonstrate that the timing of the minimum permafrost area lags the maximum CO _2 concentration for decades, which is also observed in soil temperatures at different depths and active layer thicknesses (ALTs). When the CO _2 concentration is reversed to the preindustrial level, the permafrost area decreases by ∼12% relative to the initial conditions, together with additional warming in the ground temperature at the top of the permafrost, indicating the hysteresis of permafrost to CO _2 removal. The most profound hysteretic responses occur at high latitudes for soil temperatures owing to Arctic amplification and at the southern margins of the permafrost zones for permafrost and ALT that largely linked to the climate state. Moreover, the sensitivity of permafrost and the associated thermodynamic factors to CO _2 change is generally lower during the CO _2 ramp-down phase than during the ramp-up phase, likely due to the release of stored heat on land. The results reveal the behaviour of permafrost in response to negative carbon emissions, which is informative for the projections of permafrost towards carbon neutral targets. In addition, the results may provide a reference for permafrost-related tipping points (e.g. releasing long-term stored greenhouse gases and destabilising recalcitrant soil carbon) and risk management in the future.

Developing wheat that acquires and uses phosphorus (P) more efficiently is a promising and low-cost solution for increasing grain yield and reducing P-related environmental impacts. The present study identified agronomic and physiological traits that contribute to genetic variation in the P acquisition, remobilization, and utilization efficiency of 11 wheat cultivars from southwest China grown in P-deficient purple lithomorphic soil (Olsen P = 4.7) with balanced (75 kg P ha−1) and excess P (120 kg P ha−1) supplies. On average, soil P deficiency (–P) reduced root P uptake (17.0%–60.8%), P remobilization (33.9%–52.8%), dry mass yield (11.5%–39.2%), and grain yield (17.7%–54.4%). Balanced P (+P) increased grain yield via increased plant biomass rather than increased HI. –P increased phosphorus uptake efficiency (PUpE, 4.5-fold), phosphorus utilization efficiency (PUtE, 1.25-fold), and phosphorus use efficiency (PUE, 5.4-fold) compared with those under +P, and PUtE explained most (58.1%–60.8%) of the genetic variation in PUE under both –P and +P. The high root P uptake of P-efficient cultivars under –P was regulated by root surface area and root length density in the 0–10 cm soil layer but not in the 10–20 and 20–40 cm soil layers, suggesting that a topsoil foraging strategy is a more economical approach than deeper root exploration for increasing P uptake. Root P uptake before anthesis and P remobilization after anthesis were critical for increasing the PUtE of wheat, given that P-efficient cultivars showed higher Pn (net photosynthetic rate) and sucrose levels than P-inefficient cultivars. Pn reduction by –P resulted from decreased Gs and Ci, and high evapotranspiration under +P increased shoot P% by increasing root P uptake. Genetic variation in the source-to-sink ratio was observed in consequence of a +P-induced allometric increase in sucrose in leaves and kernels. Owing to these beneficial effects, +P increased the kernel N and P yields of the 11 cultivars by 9.9%–52.4% and 12.3%–48.8%, respectively. The findings of this study could help improve wheat in future breeding efforts and P management by identifying desirable P-efficient phenotypes in P-deficient farming systems.

Triple-negative breast cancer (TNBC) is characterized by a high degree of malignancy, early metastasis, limited treatment, and poor prognosis. Immunotherapy, as a new and most promising treatment for cancer, has limited efficacy in TNBC because of the immunosuppressive tumor microenvironment (TME). Inducing pyroptosis and activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway to upregulate innate immunity have become an emerging strategy for enhancing tumor immunotherapy. In this study, albumin nanospheres were constructed with photosensitizer-IR780 encapsulated in the core and cGAS–STING agonists/H2S producer-ZnS loaded on the shell (named IR780-ZnS@HSA). In vitro, IR780-ZnS@HSA produced photothermal therapy (PTT) and photodynamic therapy (PDT) effects. In addition, it stimulated immunogenic cell death (ICD) and activated pyroptosis in tumor cells via the caspase-3–GSDME signaling pathway. IR780-ZnS@HSA also activated the cGAS–STING signaling pathway. The two pathways synergistically boost immune response. In vivo, IR780-ZnS@HSA + laser significantly inhibited tumor growth in 4T1 tumor-bearing mice and triggered an immune response, improving the efficacy of the anti-APD-L1 antibody (aPD-L1). In conclusion, IR780-ZnS@HSA, as a novel inducer of pyroptosis, can significantly inhibit tumor growth and improve the efficacy of aPD-L1.

For a long-distance open-channel water transfer project, the correctness of the hydrological state study and hydrodynamic numerical simulation is impacted directly by the spatiotemporal and consistency of the flow monitoring data along the project. Reported here is an inverted data cleaning model for flow monitoring stations based on the principle of water dynamic balance and the longest sequence method of interval flow, targeting the abnormal phenomenon of unequal flow at monitoring stations in the dispatching operation and using the middle route of the South-to-North Water Diversion Project in China as the research object. As an example, a hydrodynamic model is built for verification using flow and water level data after model cleaning as the upper and lower boundaries, respectively, for the middle-route project from the Baihe River to Huangjin River. The findings indicate that the cleaning model enhances the accuracy of flow monitoring data and reduces both the mean absolute error of the water level in front of the gate and the root-mean-square error by 0.0757 and 0.0895 m, respectively. In terms of data spatial consistency and logic, the cleaned flow data are superior to the measured flow data.

Abstract Immune checkpoint inhibitors (ICIs) have made important breakthrough in anti-tumor therapy, however, no single biomarker can accurately predict their efficacy. Studies have found that tumor microenvironment is a key factor for determining the response to ICI therapy. Cytokine receptor 3 (C-X-C Motif Chemokine Receptor 3, CXCR3) pathway has been reported to play an important role in the migration, activation, and response of immune cells. We analyzed survival data, genomics, and clinical data from patients with metastatic urothelial carcinoma (mUC) who received ICI treatment to explore the relationship between CXCR3 pathway activation and the effectiveness of ICIs. The Cancer Genome Atlas Bladder Urothelial Carcinoma cohort and six other cohorts receiving ICI treatment were used for mechanism exploration and validation. In the ICI cohort, we performed univariate and multivariate COX analyses and discovered that patients in the CXCR3-high group were more sensitive to ICI treatment. A Kaplan–Meier analysis demonstrated that patients in the high CXCR3-high group had a better prognosis than those in the CXCR3-low group (P = 0.0001, Hazard Ratio = 0.56; 95% CI 0.42−0.75). CIBERSORT analysis found that mUC patients in the CXCR3-high group had higher levels of activated CD8+ T cells, M1 macrophages, and activated NK cells and less regulatory T cell (Treg) infiltration. Immunogenicity analysis showed the CXCR3-high group had higher tumor neoantigen burden (TNB). Our study suggests that CXCR3 pathway activation may be a novel predictive biomarker for the effectiveness of immunotherapy in mUC patients.

Abstract The characterization of immunological and genomic differences in small-cell lung cancer (SCLC) between East Asian (EA) and Caucasian patients can reveal important clinical therapies for EA patients with SCLC. By sequencing and analyzing a molecular and immunological dataset of 98-SCLC patients of EA ancestry, immunogenicity, including DNA damage repair alterations and tumor mutation burden (TMB), was found to be significantly higher in the EA cohort than in the Caucasian cohort. The epithelial-mesenchymal transition (EMT) was the signaling signature with the predominant frequency of mutations across all patients in the EA cohort. Analysis of tumor-infiltrated immune cells revealed that resting lymphocytes were significantly enriched in the EA cohort. Compound-targeting analysis showed that topoisomerase inhibitors might be capable of targeting TP53 and RB1 comutations in EA SCLC patients. EA SCLC patients who harbored COL6A6 mutations had poor survival, while Caucasian SCLC patients with OTOF, ANKRD30B, and TECPR2 mutations were identified to have a shorter survival.

Abstract Background Ultrasound (US) guided transoral biopsy is a novel and safe procedure for obtaining tissue in patients with oral masses. However, this procedure is less commonly used in comparison to US guided transcutaneous biopsy. The aim of this study is to compare the efficacy and safety of US-guided transoral and transcutaneous core needle biopsy (CNB) in patients with oral masses. Methods From November 2019 to March 2021, consecutive patients with oral masses were randomly assigned to undergo US-guided transoral CNB (transoral group) and US-guided transcutaneous CNB from a submental approach (transcutaneous group). During the operation, procedure time, intra‑operative blood loss volume, diagnostic performance, rate of complications and pain level were recorded and compared. Results There were 112 patients (62 in the transoral group and 50 in the transcutaneous group) evaluated in this study. The postprocedural complication rate of the transcutaneous group was significantly higher than the transoral group (24% vs. 0%, P = 0.000). There was no significant difference in accuracy (95.2% vs. 88%, P = 0.30), biopsy time (76 ± 12 s vs. 80 ± 13 s, p = 0.09), blood losses (2.6 ± 0.5 mL vs. 2.7 ± 0.4 mL, p = 0.17) and visual analogue score (p = 0.327 and p = 0.444 before and after the sampling procedure) between the two groups. Conclusion US-guided transoral CNB results in high rates of technical success and lower rates of postprocedural complications.

Abstract Background In October 2015, China’s one-child policy was universally replaced by a so-called two-child policy. This study investigated the association between the enactment of the new policy and changes in the number of births, and health-related birth outcomes. Methods We used difference-in-difference model to analyse the birth record data in Pudong New Area, Shanghai.The design is descriptive before-and-after comparative study. Results The data covered three policy periods: the one-child policy period (January 2008 to November 2014); the partial two-child policy period (December 2014 to June 2016); the universal two-child policy period (July 2016 to December 2017). There was an estimate of 7656 additional births during the 18 months of the implementation of the universal two-child policy. The trend of monthly percentage of births to mothers aged ≥35 increased by 0.24 percentage points (95% confidence interval 0.19 to 0.28, p

Background/purpose: The scanning accuracy of intraoral scanners’ data collection plays a key role in the success of the final treatment. However, few studies start from scanning technology itself to directly evaluate it. The aim of this study was to evaluate the scanning accuracy of three intraoral scanners, to provide a reference for relevant research and clinical applications. Materials and methods: Six types of resin models containing different numbers of crown-prepared abutments were three-dimensionally printed, and a model scanner, as well as three intraoral scanners, were used to digitally scan the six models. The obtained data were uploaded to three-dimensional reverse software for registration and comparison, and the accuracy of the models were analyzed. Results: When scanning the six groups of models, the Omnicam outperformed both the TRIOS and iTero in terms of accuracy in all groups except the second molar group. The TRIOS and iTero scanners also exhibited decreased degrees of accuracy when scanning the long dental arch. The accuracy decreased as the scanning scope increased; however, the Omnicam scanner exhibited a relatively high degree of accuracy when scanning the three-unit fixed bridge and anterior areas. All scanners exhibited the lowest degree of accuracy when scanning the full-arch model. Certain deviations were observed, and the scanning areas at the incisal edges of the anterior teeth and end of the dental arch exhibited relatively large deviations. Conclusion: With the model scanner data as reference, the scanning accuracy of the three scanners exhibited differences and certain deviations, which were within clinical tolerance.

RNA Polymerase I (Pol I) has recently been recognized as a cancer therapeutic target. The activity of this enzyme is essential for ribosome biogenesis and is universally activated in cancers. The enzymatic activity of this multi-subunit complex resides in its catalytic core composed of RPA194, RPA135, and RPA12, a subunit with functions in RNA cleavage, transcription initiation and elongation. Here we explore whether RPA12 influences the regulation of RPA194 in human cancer cells. We use a specific small-molecule Pol I inhibitor BMH-21 that inhibits transcription initiation, elongation and ultimately activates the degradation of Pol I catalytic subunit RPA194. We show that silencing RPA12 causes alterations in the expression and localization of Pol I subunits RPA194 and RPA135. Furthermore, we find that despite these alterations not only does the Pol I core complex between RPA194 and RPA135 remain intact upon RPA12 knockdown, but the transcription of Pol I and its engagement with chromatin remain unaffected. The BMH-21-mediated degradation of RPA194 was independent of RPA12 suggesting that RPA12 affects the basal expression, but not the drug-inducible turnover of RPA194. These studies add to knowledge defining regulatory factors for the expression of this Pol I catalytic subunit.

ObjectiveTo investigate the diagnostic role of heart rate variability in breast cancer and its relationship with Carcinoembryonic antigen (CEA) in peripheral serum.MethodsWe reviewed the electronic medical records of patients who attended Zhujiang Hospital of Southern Medical University between October 2016 and May 2019. The patients were grouped based on breast cancer history and were divided into two groups: breast cancer group(n = 19) and control group(n = 18). All women were invited for risk factor screening, including 24-hour ambulatory ECG monitoring and blood biochemistry after admission. The difference and correlation between the breast cancer group and control group were performed by comparing the heart rate variability and serum CEA levels. Additionally, diagnostic efficacy analysis of breast cancer was calculated by combining heart rate variability and serum CEA.ResultsIn total, 37 patients were eligible for analysis, with 19 and 18 patients in the breast cancer group and control groups, respectively. Women with breast cancer had a significantly lower level of total LF, awake TP, and awake LF, and a significantly higher level of serum CEA compared with women with no breast cancer. Total LF, awake TP, and awake LF were negatively correlated with the CEA index (P < 0.05). The receiver operating characteristic (ROC) curves indicated the highest area under the curve (AUC) scores and specificity of the combination of awake TP, awake LF, and serum CEA (P < 0.05), while sensitivity was highest for total LF, awake TP, and awake LF (P < 0.05).ConclusionsWomen with history of breast cancer had abnormalities in autonomic function. The combined analysis of heart rate variability and serum CEA analysis may have a predictive effect on the development of breast cancer and provide more basis for clinical diagnosis and treatment.

IntroductionThe prevalence of suicidal ideation among medical students is high. Evidence indicates that feelings of entrapment are a predictor of suicidal ideation. In this study, we aimed to (1) investigate the prevalence of first-onset suicidal ideation among Chinese medical students and (2) explore the predictive effects of perceived entrapment on first-onset suicidal ideation.MethodsThis longitudinal study was conducted between 2018 and 2019 among 211 newly enrolled medical students in Shanghai. Using an anonymous questionnaire, we collected information on sociodemographic (sex, major, parents' income, and academic performance) and psychological (entrapment, depression, loneliness, defeat, social support, and interpersonal needs) variables as well as suicidal ideation. Participants were divided into four subgroups based on their exposure to entrapment (control, new-onset, reduced, and persistent). The primary outcome, first-onset suicidal ideation, was defined as suicidal ideation absent at baseline but present at follow-up.ResultsIn total, 54.98% of participants (116/211) were women, and 76.78% (162/211) majored in clinical medicine. In the follow-up survey, 6.16% of participants (16/211) reported first-onset suicidal ideation, 17.54% (37/211) reported new-onset entrapment, and 12.80% (27/211) reported persistent entrapment during follow-up. Compared with the control group who reported no perceived entrapment at baseline and follow-up, participants who reported new-onset entrapment had the highest risk of new-onset suicidal ideation [odds ratio (OR) = 14.700, 95% confidence interval (CI) = 2.906–74.364; adjusted OR = 8.798; 95% CI = 1.588–48.757; multivariate OR = 8.238, 95% CI = 1.394–48.693).ConclusionNew-onset entrapment can significantly predict suicidal ideation. Therefore, greater attention is needed for new-onset entrapment, such as intervention for suicidal ideation.

Due to the temperature of shallow aquifers being affected by atmospheric temperature, groundwater source heat pumps (GWSHPs) become unstable and the operation efficiency of GWSHP is constrained. In the study, the coupling numerical simulation model of the groundwater flow field and temperature field is established based on the continuous monitoring results in an actual experimental site, and the water and thermal migration of shallow aquifer is simulated under the influence of the atmospheric environment. The influence of the dynamic change in ground temperature is analyzed on a GWSHP. The results indicated that the temperature of the shallow aquifer is affected by the external temperature, and the recharge temperature in the summer cooling period was 33°C, and that in the winter heating period was 6°C in the actual site, to avoid the occurrence of thermal penetration when there is a gap between the actual situation and the design situation, the single cooler can balance the insufficient cooling capacity in summer under the most unfavorable situation. The research results can also provide a reference for the development and utilization of geothermal energy resources in shallow aquifers.

Abstract Investigation of the genetic basis of traits or clinical outcomes heavily relies on identifying relevant variables in molecular data. However, characteristics such as high dimensionality and complex correlation structures of these data hinder the development of related methods, resulting in the inclusion of false positives and negatives. We developed a variable importance measure method, termed the ECAR scores, that evaluates the importance of variables in the dataset. Based on this score, ranking and selection of variables can be achieved simultaneously. Unlike most current approaches, the ECAR scores aim to rank the influential variables as high as possible while maintaining the grouping property, instead of selecting the ones that are merely predictive. The ECAR scores’ performance is tested and compared to other methods on simulated, semi-synthetic, and real datasets. Results showed that the ECAR scores improve the CAR scores in terms of accuracy of variable selection and high-rank variables’ predictive power. It also outperforms other classic methods such as lasso and stability selection when there is a high degree of correlation among influential variables. As an application, we used the ECAR scores to analyze genes associated with forced expiratory volume in the first second in patients with lung cancer and reported six associated genes.

Abstract Background The majority of patients with small‐cell lung cancer (SCLC) show a good response in the early stages of treatment, but more than 90% of patients will develop drug resistance. Therefore, biomarkers are urgently needed to identify patients who can benefit from systemic treatment. Methods We prospectively enrolled 52 extensive‐stage SCLC patients before treatment from a local hospital to identify mutations related to patient prognosis, and verified them in the published Jiang's cohort and George's cohort. Results We found that patients with high mutations (mut‐high) in the fatty acid (FA) metabolism pathway had a longer progression‐free survival (PFS) in the local hospital cohort (HR = 0.446, 95% CI, 0.207–0.959, p = 0.0387) and a longer overall survival (OS) in Jiang's cohort (HR = 0.549, 95% CI, 0.314–0.960, p = 0.0351) than patients with low mutations (mut‐low). Multivariate analysis suggested that mut‐high status was an independent prognostic factor in both cohorts. George's cohort verified that mut‐high status was associated with a longer OS than mut‐low status (HR = 0.730, 95% CI 0.440–1.220, p = 0.2277). The possible mechanisms were as follows: the frequency of mutated FA synthase (FASN) in the mut‐high group was greater than that in the mut‐low group, and pathways related to the cell cycle, DNA repair, and oxidative phosphorylation were enriched in the mut‐high group. Conclusions The prognosis of SCLC patients treated with chemotherapy was better among patients with more mutations in the FA metabolism pathway, and the underlying mechanisms could be found at the genome and transcriptome levels.

Abstract Aims Pulmonary artery pulsatility index (PAPi), defined as [(pulmonary artery systolic pressure − diastolic pulmonary artery pressure)/mean right atrial pressure], is a novel haemodynamic index that predicts right ventricular failure after myocardial infarction and left ventricular assist device implantation. We analysed if a low PAPi is associated with death in our 14 ‐ ​year pulmonary arterial hypertension (PAH) registry. Methods Consecutive patients with newly diagnosed PAH and complete haemodynamic data were prospectively enrolled into our standing registry between January 2003 and December 2016. PAPi was calculated from baseline invasive right heart catheterization data. A prognostic cut‐off value was determined with a decision tree. Baseline characteristics of ‘high’ and ‘low’ PAPi groups based on this cut‐off were compared, as well as odds of death and time‐to‐death. Results One hundred and two patients were included. Mean age was 53 years, and 77% were women. Our multi‐ethnic cohort was 64% Chinese, 23% Malay, and 10% Indian. The aetiologies were idiopathic (33%), connective tissue disease (31%), congenital heart disease (24%), and others (12%). The low PAPi group (