YTHDF3 modulates the progression of breast cancer cells by regulating FGF2 through m6A methylation.

Introduction: Breast cancer (BC) is a prevailing malignancy among women, and its inconspicuous development contributes significantly to mortality. The RNA N6-methyladenosine (m6A) modification represents an emerging mechanism for gene expression regulation, with the active involvement of the YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) in tumor progression across multiple cancer types. Nonetheless, its precise function in breast cancer necessitates further investigation. Methods: The expression of YTHDF3 in both cell lines and patient tissues was examined using Western blotting, reverse transcription quantitative PCR (RT-qPCR), and immunohistochemistry (IHC) techniques. Bioinformatics analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptome RNA sequencing (RNA-seq) data was employed to screen for the target genes of YTHDF3. The main focus of this study was to investigate the in vitro biological functions of YTHDF3. The specific binding of YTHDF3 to its target genes and its correlation with m6A methylation were studied through RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation experiments. The protein regulatory mechanisms of downstream genes of YTHDF3 were assessed using protein stability analysis. Furthermore, the biological functions of YTHDF3 and its target genes in breast cancer cells were validated through CRISPR-Cas9 technology and rescue experiments. Results: By constructing a risk model using the TCGA database, YTHDF3 was identified as a high-risk factor among m6A methylation factors. Subsequent investigations revealed its elevated expression in various subtypes of breast cancer, accompanied by poor prognosis. MeRIP-seq analysis further revealed fibroblast growth factor 2 (FGF2) as a downstream gene of YTHDF3. Knockdown of YTHDF3 in breast cancer cells led to significant inhibition of cell self-renewal, migration, and invasion abilities in vitro. Mechanistically, YTHDF3 specifically recognized the methylated transcript of FGF2 within its coding sequence (CDS) region, leading to the inhibition of FGF2 protein degradation. Moreover, depletion of FGF2 markedly suppressed the biological functions of breast cancer cells, while reducing FGF2 expression in YTHDF3-overexpressing breast cancer cell lines substantially alleviated the malignant progression. Conclusions: In summary, our study elucidates the role of YTHDF3 as an oncogene in maintaining FGF2 expression in BC cells through an m6A-dependent mechanism. Additionally, we provide a potential biomarker panel for prognostic prediction in BC.

Predictive Value of Esophageal Deviation Index for Clinical Outcomes of Patients With Left-Sided Congenital Diaphragmatic Hernia.

PURPOSE: This study aimed to evaluate the prognostic value of postnatal esophageal deviation index (EDI) measured within the first 24 h of life for predicting mortality and morbidity in neonates with left-sided congenital diaphragmatic hernia (L-CDH). METHOD: This retrospective study analyzed clinical data from 133 neonates with L-CDH admitted to Guangzhou Women and Children's Medical Center between January 2016 and January 2024. Patients were categorized into two groups based on outcomes: survivors (n = 108) and non-survivors (n = 27). Risk factors for mortality were identified using both univariate and multivariate analyses. A receiver operating characteristic (ROC) curve was utilized to evaluate the predictive value of EDI for mortality in L-CDH patients. Subsequently, patients were divided into two groups: those with an EDI> 16.1% and those with an EDI≤16.1%. The relationship between EDI and both mortality and morbidity was analyzed using Kaplan-Meier analysis, chi-square test, Fisher's exact test, and multivariate analysis. RESULTS: EDI (adjusted OR: 0.822, 95% CI 0.723-0.935; P = 0.003) was identified as the independent predictor of mortality through both univariate and multivariate logistic regression analysis. The ROC curve demonstrated that the area under the curve (AUC) for predicting the mortality was 0.854 (95%CI: 0.782-0.930) for EDI, with an optimal cut-off value of 16.125%. The cumulative mortality rate through Day 200 was higher in patients with an EDI>16.1% (P＜0.001). Among the 133 neonates with L-CDH, 24.8% had an EDI>16.1%. This was associated with significantly worse CDH characteristics, including a high incidence of intrathoracic stomach and a high occurrence of high-risk defect sizes (type C/D), (P＜0.001), as well as more severe pulmonary hypertension (P＜0.001). An EDI>16.1% was associated with higher mortality and a greater need for ECMO support compared to an EDI≤16.1% (P＜0.001). CONCLUSION: EDI within the first 24 h of life in patients with L-CDH is associated with increased mortality and the need for ECMO, particularly when EDI exceeds 16.1%. LEVEL OF EVIDENCE: III.

Mixed active metabolites of the SNP-6 series of novel compounds mitigate metabolic dysfunction-associated steatohepatitis and fibrosis: promising results from pre-clinical and clinical trials.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with no effective pharmacological treatments. SNP-630, a newly developed synthetic molecule with multiple mechanisms of action, and a mixture of two of its active metabolites (SNP-630-MS) inhibit CYP2E1 expression to prevent reactive oxygen species generation, thereby reducing the accumulation of hepatic triglycerides and lowering chemokine levels. This study investigated the SNP-630's potential to alleviate the liver injury in MASH and its efficacy in both a mouse model and patients with MASH to identify a drug candidate that targets multiple pathways implicated in MASH. METHODS: SNP-630 and SNP-630-MS were separately administered to the MASH mouse model. The tolerability, safety, and efficacy of SNP-630-MS were also evaluated in 35 patients with MASH. The primary endpoint of the study was assessment of the changes in serum alanine aminotransferase (ALT) levels from baseline to week 12, while the secondary endpoints included the evaluation of liver inflammation, steatosis, and fibrosis parameters and markers. RESULTS: SNP-630 treatment in mice improved inflammation, liver steatosis, and fibrosis compared with that in the MASH control group. Both SNP-630 and SNP-630-MS treatments markedly reduced ALT levels, hepatic triglyceride content, and the expression of inflammatory cytokines monocyte chemoattractant protein 1 and fibrotic collagen (i.e., Col1a1, Col3a1, and Timp1) in mice. In the clinical trial, patients treated with SNP-630-MS exhibited significant improvement in ALT levels at week 12 compared with baseline levels, with no reports of severe adverse events. This improvement in ALT levels surpassed that achieved with most other MASH candidates. SNP-630-MS demonstrated potential antifibrotic effects, as evidenced by a significant decrease in the levels of fibrogenesis-related biomarkers such as CCL4, CCL5, and caspase 3. Subgroup analysis using FibroScan measurements further indicated the efficacy of SNP-630-MS in ameliorating liver fibrosis. CONCLUSIONS: SNP-630 and SNP-630-MS demonstrated favorable results in mice. SNP-630-MS showed excellent tolerability in mice and patients with MASH. Efficacy analyses indicated that SNP-630-MS improved liver steatosis and injury in patients with MASH, suggesting that SNP-630 and 630-MS are promising therapeutic options for MASH. Larger scale clinical trials remain warranted to assess the efficacy and safety of SNP-630 in MASH. TRIAL REGISTRATION: ClinicalTrials.gov NCT03868566. Registered 06 March 2019-Retrospectively registered, https://clinicaltrials.gov/study/NCT03868566.

A comprehensive risk assessment of microplastics in soil, water, and atmosphere: Implications for human health and environmental safety.

Microplastics (MPs) are pervasive across ecosystems, likely posing significant environmental and health risks based on more and more evidence. In this study, we searched through the Web of Science Core Collection and obtained 1039 papers for visualization and analysis. In order to discuss the chemical composition, migration, transformation and potential risk of MPs, 135 sets of relevant data in soil, water, and atmosphere were collected in China as a typical region, which is a hotspot region for investigation of MPs. The results showed that the primary polymer categories of MPs in the environment to be polypropylene, polyethylene, and polystyrene. The soil contains a significant quantity of MPs, averaging at 12,107.42 items·kgdw-1, while water contains averaging at 97,271.18 items m-3. The total pollution load indexes for all three environments are at risk level I. Based on current risk assessment methods, the potential ecological risk of MPs is low. However, based on the polymer components, migration and transformation patterns, and especially the complexes with other pollutants, it indicates an increasing indirect risk. Interactions with some other pollutants are likely amplify the ecological and health risks associated with MPs. Aggregative results showed that the present risk assessment models could not assess the risks of MPs well. Thus, we suggested develop a risk assessment methodology for MPs based on relevant research progress. Some factors such as the size and form of MPs, sources and distribution, bioaccumulation, social acceptance and economic costs could be considered adding in the present risk assessment models. Finally, promotion of development and application of green chemically synthesized bioplastics such as using synthetic biology to help degrade plastics would be an alternative and sustainable option to relieve the adverse environmental and health concerns of MPs.

The importance of high total body water/fat free mass ratio and serial changes in body composition for predicting hospital mortality in patients with severe pneumonia: a prospective cohort study.

PURPOSE: This study aimed to investigate the impact of body composition variables on hospital mortality compared to other predictive factors among patients with severe pneumonia. Additionally, we aimed to monitor the dynamic changes in body composition variables over the course on days 1, 3, and 8 after intensive care unit (ICU) admission for each patient. METHODS: We conducted a prospective study, enrolling patients with severe pneumonia admitted to the medical intensive care unit at Kaohsiung Chang Gung Memorial Hospital from February 2020 to April 2022. We collected clinical data from all patients and assessed their body composition at 1, 3, and 8 days post-ICU admission. On day 1, we analyzed clinical and body composition variables to predict in-hospital mortality. RESULTS: Multivariate analysis identified the Modified Nutrition Risk in the Critically Ill (mNUTRIC) score and the ratio of total body water to fat-free mass (TBW/FFM) as independent factors associated with in-hospital mortality in severe pneumonia patients. Receiver operating characteristic analysis determined that the TBW/FFM ratio was the most reliable predictive parameter of in-hospital mortality, with a cutoff value of 0.74. General linear regression with repeated measures analysis showed that hospital non-survivors displayed notable fluctuations in body water, fat, and muscle variables over the course of days 1, 3, and 8 after ICU admission. CONCLUSIONS: The mNUTRIC score and TBW/FFM ratio emerged as independent factors for predicting hospital mortality, with the TBW/FFM ratio demonstrating the highest reliability as a predictive parameter.

Development of an agroinfiltration-based transient hairpin RNA expression system in pak choi leaves (Brassica rapa ssp. chinensis) for RNA interference against Liriomyza sativae.

The vegetable leafminer (Liriomyza sativae) is a devastating invasive pest of many vegetable crops and horticultural plants worldwide, causing serious economic loss. Conventional control strategy against this pest mainly relies on the synthetic chemical pesticides, but widespread use of insecticides easily causes insecticide resistance development and is harmful to beneficial organisms and environment. In this context, a more environmentally friendly pest management strategy based on RNA interference (RNAi) has emerged as a powerful tool to control of insect pests. Here we report a successful oral RNAi in L. sativae after feeding on pak choi (Brassica rapa ssp. chinensis) that transiently express hairpin RNAs targeting vital genes in this pest. First, potentially lethal genes are identified by searching an L. sativae transcriptome for orthologs of the widely used V-ATPase A and actin genes, then expression levels are assessed during different life stages and in different adult tissues. Interestingly, the highest expression levels for V-ATPase A are observed in the adult heads (males and females) and for actin in the abdomens of adult females. We also assessed expression patterns of the target hairpin RNAs in pak choi leaves and found that they reach peak levels 72 h post agroinfiltration. RNAi-mediated knockdown of each target was then assessed by letting adult L. sativae feed on agroinfiltrated pak choi leaves. Relative transcript levels of each target gene exhibit significant reductions over the feeding time, and adversely affect survival of adult L. sativae at 24 h post infestation in genetically unmodified pak choi plants. These results demonstrate that the agroinfiltration-mediated RNAi system has potential for advancing innovative environmentally safe pest management strategies for the control of leaf-mining species.

Advances and future directions of environmental risk research: A bibliometric review.

Environmental risk is one of the world's most significant threats, projected to be the leading risk over the next decade. It has garnered global attention due to increasingly severe environmental issues, such as climate change and ecosystem degradation. Research and technology on environmental risks are gradually developing, and the scope of environmental risk study is also expanding. Here, we developed a tailored bibliometric method, incorporating co-occurrence network analysis, cluster analysis, trend factor analysis, patent primary path analysis, and patent map methods, to explore the status, hotspots, and trends of environment risk research over the past three decades. According to the bibliometric results, the publications and patents related to environmental risk have reached explosive growth since 2018. The primary topics in environmental risk research mainly involve (a) ecotoxicology risk of emerging contaminants (ECs), (b) environmental risk induced by climate change, (c) air pollution and health risk assessment, (d) soil contamination and risk prevention, and (e) environmental risk of heavy metal. Recently, the hotspots of this field have shifted into artificial intelligence (AI) based techniques and environmental risk of climate change and ECs. More research is needed to assess ecological and health risk of ECs, to formulize mitigation and adaptation strategies for climate change risks, and to develop AI-based environmental risk assessment and control technology. This study provides the first comprehensive overview of recent advances in environmental risk research, suggesting future research directions based on current understanding and limitations.

SHP2-Triggered Endothelial Cell Activation Fuels Estradiol-Independent Endometrial Sterile Inflammation.

Sterile inflammation occurs in various chronic diseases due to many nonmicrobe factors. Examples include endometrial hyperplasia (EH), endometriosis, endometrial cancer, and breast cancer, which are all sterile inflammation diseases induced by estrogen imbalances. However, how estrogen-induced sterile inflammation regulates EH remains unclear. Here, a single-cell RNA-Seq is used to show that SHP2 upregulation in endometrial endothelial cells promotes their inflammatory activation and subsequent transendothelial macrophage migration. Independent of the initial estrogen stimulation, IL1ß and TNFα from macrophages then create a feedforward loop that enhances endothelial cell activation and IGF1 secretion. This endothelial cell-macrophage interaction sustains sterile endometrial inflammation and facilitates epithelial cell proliferation, even after estradiol withdrawal. The bulk RNA-Seq results and phosphoproteomic analysis show that endothelial SHP2 mechanistically enhances RIPK1 activity by dephosphorylating RIPK1Tyr380. This event activates downstream activator protein 1 (AP-1) and instigates the inflammation response. Furthermore, targeting SHP2 using SHP099 (an allosteric inhibitor) or endothelial-specific SHP2 deletion alleviates endothelial cell activation, macrophage infiltration, and EH progression in mice. Collectively, the findings demonstrate that SHP2 mediates the transition of endothelial activation from estradiol-driven acute inflammation to macrophage-amplified chronic inflammation. Targeting sterile inflammation mediated by endothelial cell activation is a promising strategy for nonhormonal intervention in estrogen-related diseases.

China's progress in synergetic governance of climate change and multiple environmental issues.

Advancing the synergetic control of climate change and environmental crisis is crucial for achieving global sustainable development goals. This study evaluates synergetic governance levels over climate change and four environmental issues at the provincial level in China from 2009 to 2020. Our findings reveal significant progress in China's coordinated efforts to mitigate carbon emissions, reduce air pollutants, and conserve water resources. However, there remains room for improvement in managing solid waste and protecting ecological systems and overall progress in synergetic governance has slowed since 2015. Employing a random forest model, we identify socio-economic factors with great influence on synergetic climate change and environmental governance, such as energy intensity, service sector development, electronic equipment manufacturing, and transportation. Additionally, we reveal nonlinear relationships between some factors and performance of environmental subsystems, including both plateau effects (e.g. output in the smelting of ferrous metals) and U-shaped patterns (e.g. output in the manufacturing of metal products), possibly attributed to constraints in end-of-pipe treatment capacities and complexities in supply chain networks. Furthermore, through hierarchical clustering analysis, we classify provinces into four groups and provide tailored recommendations for policymakers to enhance synergetic governance levels in their respective regions. The framework established in this study also serves as a valuable reference for countries seeking to develop practical and context-specific solutions to mitigate climate and environmental risks.

circ_SMA4 promotes gastrointestinal stromal tumors malignant progression by sponging miR-494-3p/KIT axis and activating JAK/STAT pathway.

Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are implicated in the development and progression of various tumors. The aim of this study was to investigate the effects of circ_SMA4 in Gastrointestinal Stromal Tumors (GISTs) malignant progression. Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in GISTs. The effect of circ_SMA4 on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo settings. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_SMA4/miR-494-3p/ KIT axis. The results revealed that circ_SMA4 was significantly upregulated in GISTs, and exhibited high diagnostic efficiency with an AUC of 0.9824 (P < 0.01). circ_SMA4 promoted cell proliferation, invasion, migration, while inhibiting apoptosis in GISTs cells, both in vitro and in vivo. Silencing circ_SMA4 partially inhibited GISTs malignant progression. Additionally, circ_SMA4 acted as a competing endogenous RNA (ceRNA) by targeting miR-494-3p, and KIT was identified as a functional gene for miR-494-3p in GISTs. Furthermore, the results confirmed that circ_SMA4/miR-494-3p/ KIT axis plays a role in activating the JAK/STAT signaling pathway in GISTs. Therefore, for the first time, we have identified and emphasized that circ_SMA4 is significantly upregulated and plays an oncogenic role in GISTs by sponging miR-494-3p to activate the KIT/JAK/STAT pathway. These findings underscore circ_SMA4 may serve as a novel diagnostic biomarker and therapeutic target for GISTs.

Microwave Remote Sensing with Hybrid Quantum Receiver.

Detecting a microwave signal that is emitted or reflected by distant targets is a powerful tool in fundamental science and industrial technology. Solid-state spins provide an opportunity to realize quantum-enhanced remote sensing under ambient conditions. However, the weak interaction between the free-space signal and atomic size sensor limits the sensitivity. This hinders the realization of practical quantum remote sensing. Here, we demonstrate active microwave remote sensing with a diamond-based hybrid quantum receiver by combining electromagnetic field localization at nanoscale with quantum spin manipulation. A method of differential spin refocusing (DSR) is developed to overcome the challenge of reducing the impact of inhomogeneities in spin-signal interaction, while the strength of interaction is enhanced by more than 3 orders with nanostructure. It improves the coherent interaction time of quantum receiver by 30-fold, substantially enhancing the sensitivity and stability. By detecting the reflected microwave with picotesla sensitivity, diamond remote sensing monitors the real-time status of a centimeter-sized target at 2 m distance. Our method is general to various solid-state spins. The results will expand the applications of solid-state spin quantum sensors in areas ranging from medical imaging to resource survey.

Migration and availability of Ni and Cd in industrial soils under different leaching conditions: Insights from DGT and DIFS models.

Rainfall runoff can mobilize heavy metals in industrial soils, posing environmental risks. The mobility and distribution of heavy metals in different industrial soil layers are often overlooked. This study employed dynamic leaching experiments in layered soil columns with DGT (the diffusive gradients in thin films) measurements and DIFS (DGT-induced fluxes in soils and sediments) model to describe the migration, availability, and resupply ability of metals at different depths in surface and deep soil columns of industrial soils. Results showed significantly higher available concentrations (CDGT and CSoln) of Ni and Cd in surface soils compared to deep soils, likely due to the differences in soil physiochemical properties (contamination, pH, and soil texture). Continuous leaching promoted the migration of available Ni and Cd in surface soils. Maximum values of RNi (0.79-0.91) and RCd (0.75-0.80) were observed in the top layer (0-4 cm) of the surface soil, consistent with the trends of RFe. Combined DGT and DIFS model analysis implied higher potential availability and resupply of Ni and Cd in surface soil columns. These findings highlight the importance of considering dynamic leaching effects on heavy metal transport, availability, and release in industrial soils.

Paospora carinifang n. gen., n. sp. (Microsporidia: Spragueidae), a parasite of the ridgetail white prawn, Palaemon carinicauda.

A new microsporidian disease of the pond-reared ridgetail white prawn, Palaemon carinicauda, was found in China. Light microscopy, pathology, and scanning electron microscopy showed that the parasite infected the host's skeletal muscle tissue and formed spherical sporophorous vesicles (SPOVs). Electron microscopy revealed that its merogonic life stages developed in direct contact with the host cytoplasm. The sporogonic life stages underwent octosporoblastic sporogony with the formation of eight uninucleate spores in each SPOV. Fresh SPOVs were 5.4 ± 0.55 µm in diameter. The octospores were oval and measured 2.3 × 1.5 µm (fresh) and 1.96 × 1.17 µm (fixed). The isofilar polar filament was coiled with 9-10 turns and arranged in two rows. Phylogenetic analysis based on the SSU rRNA gene suggests that this microsporidium has close affinities with members of the genera Potaspora and Apotaspora, but represents an independent generic taxon. We therefore propose the establishment of a new genus and species (Paospora carinifang n. gen., n. sp.) within the family Spragueidae. We also propose a taxonomic revision to transfer Potaspora macrobrachium to this new genus and reclassify it as Paospora macrobrachium comb. nov.

Measuring climate change perception in China using mental images: A nationwide open-ended survey.

Current knowledge about public climate change perception mainly covers belief, concern, and attitudes. However, how this discourse is interpreted using individuals' own frame of reference remains largely unknown, particularly in many large emitters from non-Annex I countries such as China. This study, for the first time, performs a nationwide open-ended survey covering 4,037 respondents and collected 12,100 textual answers. Using a semiautomated coding method, we find seven mental images that exclusively represent the Chinese interpretation of the climate change issue, including global warming, distant icons, natural disasters, environmental degradation, cause, solution, and weather. Analysis of influencing factors shows that females, those with lower education levels, lower income, and older individuals tend to connect climate change with natural weather phenomena. Younger and well-educated residents in developed cities are more aware of various consequences and anthropogenic causes of climate change. People with stronger climate change beliefs, policy support, and personal experience of extreme weather are more likely to mention disastrous impacts, carbon emission as causes, and potential solutions. Employing the multilevel regression and post-stratification technique, we map the prevalence of mental images in China at the prefecture-city level. The results reveal significant geographical heterogeneity, with estimated national means ranging from a high of 55% (weather) to a low of 11% (solution). Our findings reveal diverse perspectives and a widespread misconception of climate change in China, suggesting the need for tailored clarification strategies to gain public consent.

Serum Uric Acid Levels Associated with Outcomes of Neurodegenerative Disorders and Brain Health: Findings from the UK Biobank.

BACKGROUND: The relationship between serum uric acid (SUA) levels and brain-related health remains uncertain. OBJECTIVES: This study aimed to investigate the relationship between SUA levels and some neurodegenerative disorders and brain structure. DESIGN: A longitudinal study. SETTING AND PARTICIPANTS: 384,517 participants who did not have stroke, dementia, and Parkinsonism, with complete urate testes and covariates were included. MEASUREMENTS: Cox proportional hazards models, competing risk models, and restricted cubic spine models were applied. RESULTS: During the median follow-up time of 12.7 years (interquartile range [IQR]:12.0, 13.5), 7821 (2.0%) participants developed stroke, 5103 (1.3%) participants developed dementia, and 2341 (0.6%) participants developed Parkinsonism. Nonlinear relationships were identified between SUA levels and stroke (J-shaped), dementia, and Parkinsonism (U-shaped). SUA levels of 4.2 mg/dl, 6.4 mg/dl, and 6.6 mg/dl yielded the lowest risk of stroke, dementia, and Parkinsonism, respectively. Besides, we found high SUA levels reduced the volumes of total brain, grey matter, white matter, grey matter in the hippocampus, and hippocampus, but increased lateral-ventricle volume. Inflammation accounted for 9.1% and 10.0% in the association of SUA with stroke and lateral-ventricle volume. CONCLUSIONS: Lower SUA levels increased the risk of Parkinsonism, while both lower and higher SUA levels were positively associated with increased risk of stroke and dementia. Moreover, high SUA levels reduced brain structure volumes. Our findings suggest the association between SUA levels and brain-related disorders and highlight the importance of SUA management.

An ensemble machine learning model to uncover potential sites of hazardous waste illegal dumping based on limited supervision experience.

With the soaring generation of hazardous waste (HW) during industrialization and urbanization, HW illegal dumping continues to be an intractable global issue. Particularly in developing regions with lax regulations, it has become a major source of soil and groundwater contamination. One dominant challenge for HW illegal dumping supervision is the invisibility of dumping sites, which makes HW illegal dumping difficult to be found, thereby causing a long-term adverse impact on the environment. How to utilize the limited historic supervision records to screen the potential dumping sites in the whole region is a key challenge to be addressed. In this study, a novel machine learning model based on the positive-unlabeled (PU) learning algorithm was proposed to resolve this problem through the ensemble method which could iteratively mine the features of limited historic cases. Validation of the random forest-based PU model showed that the predicted top 30% of high-risk areas could cover 68.1% of newly reported cases in the studied region, indicating the reliability of the model prediction. This novel framework will also be promising in other environmental management scenarios to deal with numerous unknown samples based on limited prior experience.

A Deep-Learning-Enabled Electrocardiogram and Chest X-Ray for Detecting Pulmonary Arterial Hypertension.

The diagnosis and treatment of pulmonary hypertension have changed dramatically through the re-defined diagnostic criteria and advanced drug development in the past decade. The application of Artificial Intelligence for the detection of elevated pulmonary arterial pressure (ePAP) was reported recently. Artificial Intelligence (AI) has demonstrated the capability to identify ePAP and its association with hospitalization due to heart failure when analyzing chest X-rays (CXR). An AI model based on electrocardiograms (ECG) has shown promise in not only detecting ePAP but also in predicting future risks related to cardiovascular mortality. We aimed to develop an AI model integrating ECG and CXR to detect ePAP and evaluate their performance. We developed a deep-learning model (DLM) using paired ECG and CXR to detect ePAP (systolic pulmonary artery pressure > 50 mmHg in transthoracic echocardiography). This model was further validated in a community hospital. Additionally, our DLM was evaluated for its ability to predict future occurrences of left ventricular dysfunction (LVD, ejection fraction < 35%) and cardiovascular mortality. The AUCs for detecting ePAP were as follows: 0.8261 with ECG (sensitivity 76.6%, specificity 74.5%), 0.8525 with CXR (sensitivity 82.8%, specificity 72.7%), and 0.8644 with a combination of both (sensitivity 78.6%, specificity 79.2%) in the internal dataset. In the external validation dataset, the AUCs for ePAP detection were 0.8348 with ECG, 0.8605 with CXR, and 0.8734 with the combination. Furthermore, using the combination of ECGs and CXR, the negative predictive value (NPV) was 98% in the internal dataset and 98.1% in the external dataset. Patients with ePAP detected by the DLM using combination had a higher risk of new-onset LVD with a hazard ratio (HR) of 4.51 (95% CI: 3.54-5.76) in the internal dataset and cardiovascular mortality with a HR of 6.08 (95% CI: 4.66-7.95). Similar results were seen in the external validation dataset. The DLM, integrating ECG and CXR, effectively detected ePAP with a strong NPV and forecasted future risks of developing LVD and cardiovascular mortality. This model has the potential to expedite the early identification of pulmonary hypertension in patients, prompting further evaluation through echocardiography and, when necessary, right heart catheterization (RHC), potentially resulting in enhanced cardiovascular outcomes.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial.

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Mediating effect of social support on the relationship between social activity and depressive symptoms among older widows in Taiwan.

The purpose of this study was to investigate the mediating effect of social support on the relationship between social activity and depressive symptoms among older widows in Taiwan. A cross-sectional study was conducted that recruited 256 older widows in southern Taiwan. Data were collected on demographic characteristics, self-rated health, instrumental activities of daily living, social activity, social support, and depression. Multiple linear regressions performed examined whether social activities and social support were significantly associated with depressive symptoms and which types of social activity were significantly related to social support and depressive symptoms. Mediation analyses performed tested the mediation effect of social support between the number of different types of social activities performed (termed "number of activities" in this study) and depression. Overall, 17.2% of the participants reported having at least two depressive symptoms. The total effect of the number of activities on depressive symptoms was significant (p < .001). The direct pathway from the number of activities to depressive symptoms remained significant (p < .001), and the mediation pathway (from the number of activities to depressive symptoms through social support) was also significant (Bootstrap CI = -.072, -.003). These findings demonstrated that older widows had more social support when they participated in more social activities, which could then decrease depressive symptoms. In addition, informal community group activities and religious group activities were the most effective at increasing social support and reducing depressive symptoms among the older Taiwanese widows.