Dual trigger or hCG alone: A retrospective analysis on patients with diminished ovarian reserve under in vitro fertilization and embryo transfer (IVF-ET) treatment.

OBJECTIVE: With remarkable deficiency in both oocyte stock and competence, the prognosis of IVF-ET in diminished ovarian reserve (DOR) is obstinately poor, underscoring warranted optimization to current procedures. We compared the efficacy of dual-trigger (hCG plus GnRH-a) and hCG alone on the outcomes for DOR patients. STUDY DESIGN: A total of 381 couples and 857 controlled ovarian stimulation (COS) cycles, and 222 couples and 366 frozen embryo transfer (FET) ones were included. The intermediate outcomes during oocyte retrieval and in vitro culture were compared based on COS dataset, while outcomes after embryo transfer analyzed based on FET dataset. The marginal effect of all study factors and covariates were evaluated with a cluster-weighted GEE model. RESULTS AND CONCLUSION: Neither the intermediate nor implantation outcomes were improved by dual-trigger. The OR values were 1.08 (95 % CI: 0.41-2.78) for retrieval cancellation, 1.33 (95 % CI: 0.89-2.00) for oocyte harvest, 1.04(95 %CI: 0.94-1.15) for viable embryo and 1.03(95 %CI: 0.88-1.19) for top-quality embryo. Similarly, the ORs were 0.90 (95 %CI: 0.62-1.30) for implantation and 0.97 (95 %CI: 0.56-1.69) for clinical pregnancy. This equivalence remained unchanged after adjusting for the covariates such as age, BMI, controlled ovarian stimulation protocols, etc. Thus, dual-trigger cannot provide significant advantage over hCG in related to immediate or clinical outcomes of IVF-ET treatments in DOR patients.

APEX1 in intestinal epithelium triggers neutrophil infiltration and intestinal barrier damage in Ulcerative colitis.

Ulcerative colitis (UC) can lead to the generation of large amounts of reactive oxygen species and DNA damage. DNA repair caused by base excision repair (BER) enzymes is an important mechanism for maintaining genomic integrity. However, the specific relationship between the function of BER enzymes and UC remains unclear. To address this, we conducted a study on non-cancerous colon tissue from patients with UC, focusing on the role of apurinic/apyrimidinic endonuclease 1 (APEX1) in BER to explore its significance in the progression of UC. Our research found that the expression of APEX1 in epithelium cells was significantly correlated to the severity of inflammatory bowel disease (IBD) and the infiltration and function of neutrophils in human UC and mouse models, particularly in relation to neutrophil extracellular traps (NETs) and the degranulation processes. APEX1 deficiency resulted in decreased production of the chemokines CXCL1 by the NF-κB pathway in epithelium cells, leading to reduced accumulation and activation of neutrophils associated with colitis in colon tissue, as well as decreased levels of IL-1ß. Furthermore, APEX1 deficiency reduced symptoms of colitis by decreasing epithelial cell apoptosis and altering the gut microbiome. Studies related to the redox activity of APEX1 have shown that the combination of the redox inhibitor E3330 with 5-aminosalicylic acid (5-ASA) can effectively alleviate colitis, indicating that APEX1 has promising prospects for clinical treatment of IBD. APEX1 is required for interactions between neutrophil and intestinal epithelial cells. This study provided a mechanism demonstrating that APEX1 protein triggered the risk of UC by promoting neutrophil infiltration and compromising intestinal epithelial barrier function.

Association of residential air pollution and green space with all-cause and cause-specific mortality in individuals with diabetes: an 11-year prospective cohort study.

BACKGROUND: To assess the long-term impact of residential air pollution and green space exposure on cause-specific mortality in individuals with type 2 diabetes mellitus (T2DM). METHODS: This study includes 174,063 participants newly diagnosed with T2DM from a prospective cohort in Shanghai, China, enrolled between 2011 and 2013. Residential annual levels of air pollutants, including fine (PM2.5) and coarse (PM2.5-10) particulate matter, nitrogen dioxide (NO2), along with the normalized difference vegetation index (NDVI), were derived from satellite-based exposure models. FINDINGS: During a median follow-up of 7.9 years (equivalent to 1,333,343 person-years), this study recorded 22,205 deaths. Higher exposure to PM2.5 was significantly associated with increased risks for all mortality outcomes, whilst PM2.5-10 showed no significant impacts. The strongest associations of PM2.5 were observed for diabetes with peripheral vascular diseases [hazard ratio (HR): 2.70; per 10 µg/m3 increase] and gastrointestinal cancer (2.44). Effects of NO2 became significant at concentrations exceeding approximately 45 µg/m³, with the highest associations for lung cancer (1.20) and gastrointestinal cancer (1.19). Conversely, each interquartile range increase in NDVI (0.10) was linked to reduced mortality risks across different causes, with HRs ranging from 0.76 to 1.00. The association between greenness and mortality was partly and significantly mediated by reduced PM2.5 (23.80%) and NO2 (26.60%). There was a significant and negative interaction between NO2 and greenness, but no interaction was found between PM2.5 and greenness. INTERPRETATION: Our findings highlight the vulnerability of individuals with T2DM to the adverse health effects of air pollution and emphasise the potential protective effects of greenness infrastructure. FUNDING: The 6th Three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWVI-11.1-22), the National Key Research and Development Program (2022YFC3702701), and the National Natural Science Foundation of China (82030103, 82373532).

Predicting 3-month poor functional outcomes of acute ischemic stroke in young patients using machine learning.

BACKGROUND: Prediction of short-term outcomes in young patients with acute ischemic stroke (AIS) may assist in making therapy decisions. Machine learning (ML) is increasingly used in healthcare due to its high accuracy. This study aims to use a ML-based predictive model for poor 3-month functional outcomes in young AIS patients and to compare the predictive performance of ML models with the logistic regression model. METHODS: We enrolled AIS patients aged between 18 and 50 years from the Third Chinese National Stroke Registry (CNSR-III), collected between 2015 and 2018. A modified Rankin Scale (mRS) ≥ 3 was a poor functional outcome at 3 months. Four ML tree models were developed: The extreme Gradient Boosting (XGBoost), Light Gradient Boosted Machine (lightGBM), Random Forest (RF), and The Gradient Boosting Decision Trees (GBDT), compared with logistic regression. We assess the model performance based on both discrimination and calibration. RESULTS: A total of 2268 young patients with a mean age of 44.3 ± 5.5 years were included. Among them, (9%) had poor functional outcomes. The mRS at admission, living alone conditions, and high National Institutes of Health Stroke Scale (NIHSS) at discharge remained independent predictors of poor 3-month outcomes. The best AUC in the test group was XGBoost (AUC = 0.801), followed by GBDT, RF, and lightGBM (AUCs of 0.795, 0, 794, and 0.792, respectively). The XGBoost, RF, and lightGBM models were significantly better than logistic regression (P < 0.05). CONCLUSIONS: ML outperformed logistic regression, where XGBoost the boost was the best model for predicting poor functional outcomes in young AIS patients. It is important to consider living alone conditions with high severity scores to improve stroke prognosis.

Predicting functional outcome in ischemic stroke patients using genetic, environmental, and clinical factors: a machine learning analysis of population-based prospective cohort study.

Ischemic stroke (IS) is a leading cause of adult disability that can severely compromise the quality of life for patients. Accurately predicting the IS functional outcome is crucial for precise risk stratification and effective therapeutic interventions. We developed a predictive model integrating genetic, environmental, and clinical factors using data from 7819 IS patients in the Third China National Stroke Registry. Employing an 80:20 split, we randomly divided the dataset into development and internal validation cohorts. The discrimination and calibration performance of models were evaluated using the area under the receiver operating characteristic curves (AUC) for discrimination and Brier score with calibration curve in the internal validation cohort. We conducted genome-wide association studies (GWAS) in the development cohort, identifying rs11109607 (ANKS1B) as the most significant variant associated with IS functional outcome. We employed principal component analysis to reduce dimensionality on the top 100 significant variants identified by the GWAS, incorporating them as genetic factors in the predictive model. We employed a machine learning algorithm capable of identifying nonlinear relationships to establish predictive models for IS patient functional outcome. The optimal model was the XGBoost model, which outperformed the logistic regression model (AUC 0.818 versus 0.756, P < .05) and significantly improved reclassification efficiency. Our study innovatively incorporated genetic, environmental, and clinical factors for predicting the IS functional outcome in East Asian populations, thereby offering novel insights into IS functional outcome.

Efficacy and Safety of Intravenous Tenecteplase Versus Alteplase in Treating Acute Ischemic Stroke With Diabetes and Admission Hyperglycemia.

BACKGROUND: The aim of this study was to investigate the efficacy and safety of tenecteplase versus alteplase in patients with acute ischemic stroke, considering their diabetes history and admission hyperglycemia status. METHODS AND RESULTS: This was a post hoc analysis of the TRACE-2 (Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-2) randomized clinical trial that enrolled patients in China between June 2021 and May 2022. Eligible patients with acute ischemic stroke for standard intravenous thrombolysis, but ineligible for endovascular thrombectomy, were randomly assigned (1:1) to tenecteplase or alteplase within 4.5 hours of symptom onset. Admission hyperglycemia was defined as plasma glucose >7.8 mmol/L. The primary efficacy and safety outcome were excellent functional outcome at 90 days (modified Rankin Scale score of 0-1) and symptomatic intracranial hemorrhage within 36 hours, respectively. The Cochran-Mantel-Haenszel χ2 test was used for the outcomes. Of the 1382 patients included, 369 (26.7%) had a history of diabetes, and 482 (34.9%) experienced admission hyperglycemia. The primary efficacy outcome, comparing tenecteplase to alteplase, was achieved in 93 (56.7%) versus 97 (48.3%) among patients with a history of diabetes (P=0.11) and 335 (64.6%) versus 300 (62.2%) among those without diabetes (P=0.45), respectively. The primary efficacy outcome for tenecteplase versus alteplase was comparable among patients with and without admission hyperglycemia (57.5% versus 53.9%, P = 0.44; 65.4% versus 60.4%, P=0.12, respectively). No significant difference in the risk of symptomatic intracranial hemorrhage within 36 hours was observed between tenecteplase and alteplase, regardless of diabetes history or admission hyperglycemia. CONCLUSIONS: This study demonstrated that intravenous tenecteplase exhibits similar clinical outcomes compared with alteplase, irrespective of the patient's glucose metabolism status. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04797013.

Parathyroid hormone mediates the adverse impact of air pollution exposure on serum 25-hydroxyvitamin D: A nationwide cross-sectional study in China.

BACKGROUND: Maintaining normal levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) is crucial for preserving skeletal health. However, evidence regarding the associations of exposure to air pollution with serum 25(OH)D and PTH were limited and ambiguous. Hence, the objective of this cross-sectional study was to systematically evaluate the association between air pollution [particulate matter ≤ 2.5 µm (PM2.5) and ozone (O3)] exposure and serum 25(OH)D and PTH levels in males aged 50 and above and postmenopausal female. MATERIALS AND METHODS: This study is multicenter, cross-sectional study within the framework of the ongoing China Community-based Cohort of Osteoporosis. The 1-year-average PM2.5 and O3 exposures prior to the baseline survey were estimated using random forest models with relatively high accuracy. Multiple linear regression models were employed to assess the associations between PM2.5 and O3 concentrations with the serum levels of 25(OH)D and PTH. Furthermore, mediation analysis was performed to scrutinize the potential mediating role of PTH in the interplay between PM2.5, O3, and serum 25(OH)D. RESULTS: A total of 13194 participants were included. Our analysis showed that every 10 µg/m3 increase in the 1-year average PM2.5, were associated with -0.32 units (95% CI: 0.48, -0.17) of change in the 25(OH)D and 0.15 units (95% CI: 0.11, 0.19) of change in the PTH, respectively. Every 10 µg/m3 increase in the 1-year average O3, were associated with -0.78 units (95% CI: 1.05, -0.51) of change in the 25(OH)D and 0.50 units (95% CI: 0.43, 0.57) of change in the PTH, respectively. Estimates of the mediation ratio indicated that increased PTH mediated a 50.48% negative correlation between PM2.5 exposure and circulating 25(OH)D level. Increased PTH mediated 69.61% of the negative effects of O3 exposure on circulating 25(OH)D level. CONCLUSIONS: Exposure to PM2.5 and O3 significantly diminished 25(OH)D while elevating PTH levels. Notably, the elevated PTH concentration partially mediates the associations between PM2.5 and O3 exposure and 25(OH)D level.

Selenium suppressed the LPS-induced oxidative stress of bovine endometrial stromal cells through Nrf2 pathway with high cortisol background.

Stress and infection seriously threaten the reproductive performance and health of dairy cows. Various perinatal stresses increase plasma cortisol concentrations in cows, and chronically high cortisol levels may increase the incidence and severity of the uterine diseases. Selenium (Se) enhances antioxidant capacity of cows. The aim of this study was to explore how Se affects the oxidative stress of primary bovine endometrial stromal cells (BESC) with high cortisol background. The levels of reactive oxygen species (ROS) and other biomarkers of oxidative stress were measured using flow cytometry and assay kits. The changes in nuclear NF-E2-related factor 2 (Nrf2) pathway were detected by Western blot, qPCR, and immunofluorescence. The result showed that lipopolysaccharide (LPS) increased (P < 0.01) ROS and malondialdehyde (MDA) content and reduced (P < 0.01) superoxide dismutase (SOD) concentration, provoking BESC oxidative stress. The elevated levels of cortisol resulted in the accumulation (P < 0.05) of ROS and MDA and inhibition (P < 0.05) of SOD in unstimulated BESC but demonstrated an antioxidative effect in LPS-stimulated cells. Pretreatment with Se reduced (P < 0.01) the levels of ROS and MDA, while increasing (P < 0.05) the antioxidant capacities and the relative abundance of gene transcripts and proteins related to the Nrf2 pathway in BESC. This antioxidant effect was more pronounced in the presence of high cortisol level. In conclusion, cortisol alone induced the oxidative damage but provided an antioxidant protection in the presence of LPS. Se alleviated the LPS-induced cellular oxidative stress, which is probably achieved through activating Nrf2 pathway. At high cortisol levels, Se supplement has a more significant protective effect on BESC oxidative stress. This study provided evidence for the protective role of Se in bovine endometrial oxidative damage of stressed animals and suggested the potential regulatory mechanism in vitro.

The postpartum uterine infections seriously threaten the productive and reproductive performance of dairy cows. The elevated cortisol level after delivery can worsen infections. Selenium (Se) enhances disease resistance of dairy cows. In this study, we observed the changes in the oxidative stress of the primary bovine endometrial stromal cells (BESC) with Se supplement in high cortisol background. First, we found that cortisol alone induced oxidative stress in quiescent BESC, but provided an antioxidant effect in BESC with oxidative stress. Second, Se sustained a global antioxidant ability in BESC oxidative stress and elicited a more significant protective effect in the presence of high cortisol than Se alone.

Glycated albumin levels are associated with adverse stroke outcomes in patients with acute ischemic stroke in China.

BACKGROUND AND AIM: Glycated albumin (GA) is a biomarker monitoring glycemia 2-4 weeks before stroke onset. This study was designed to explore the association between GA levels with poststroke outcomes in patients with acute ischemic stroke or transient ischemic attack (TIA). METHOD: Participants with ischemic stroke or TIA who had a baseline GA measurement were included in the Third China National Stroke Registry study. The effect of GA on stroke recurrence, poor functional outcomes, and combined vascular events was examined during the 1-year follow-up period. Multivariate Cox and logistic regression models were performed to evaluate the association. Discrimination tests were used to examine the incremental predictive value of GA when incorporating it into the conventional model. RESULTS: A total of 3861 participants were enrolled. At the 3-month follow-up, the elevated GA level was associated with an increased risk of poor functional outcomes (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.01-2.09). A similar increase was observed for stroke recurrence (adjusted hazard ratio [HR], 1.56; 95% CI, 1.09-2.24), poor functional outcomes (adjusted OR, 1.62; 95% CI, 1.07-2.45), and combined vascular events (adjusted HR, 1.55; 95% CI, 1.09-2.20) at the 1-year follow-up. In nondiabetic patients, the association between GA and poor functional outcomes was more pronounced (adjusted OR, 1.62; 95% CI, 1.05-2.50). Adding GA into the conventional model resulted in slight improvements in predicting poor functional outcomes (net reclassification improvement [NRI]: 12.30% at 1 year). CONCLUSION: This study demonstrated that elevated GA levels in serum were associated with stroke adverse outcomes, including stroke recurrence, poor functional outcomes, and combined vascular events, in patients with ischemic stroke or TIA.

An artificial intelligence powered study of enlarged facial pore prevalence on one million Chinese from different age groups and its correlation with environmental factors.

BACKGROUND: Enlarged pores are amidst one of the top cosmetic concerns, especially among Chinese. Many small-group studies have been conducted in understanding their prevalence and beauty relevance. Nonetheless, population-level investigations are still lacking because of gaps in data collection and processing of large-scale studies. Owing to the recent technological advancement enabled by artificial intelligence, databases on the scale of millions can be processed and analyzed readily. MATERIALS AND METHODS: Powered by big data capabilities, revealed a number of novel trends on pore conditions among over-a-million Chinese participants recruited via the "You Look Great Today" mobile application. A scoring model was constructed, which demonstrated high consistency with conventional grading method from dermatologists. Environmental data (weather, air pollution, light at night satellite) were applied to correlate with pore severity. RESULTS: Intraclass correlations between the two scoring systems were strong, with coefficients ranging from 0.79 to 0.92 for different facial areas. Statistical differences in pore severity among all four facial areas (cheek, forehead, nose, and overall) were observed, with the cheek exhibiting the most severe pore condition. Interestingly, Chinese men suffer from more severe pore condition than females. Multiple environmental factors exhibited strong correlations with cheek pore severity and were statistically fitted into linear regressions. Specifically, incremental risk with Each Low Temperature, Low Humidity, And High Solar Exposure correlate to worse cheek pore conditions. Although the Pearson correlation was low between cheek pore severity and light at night, comparison between representative cities demonstrated that in geologically similar cities, higher light at night corresponds to more severe cheek pore conditions. CONCLUSION: Our study is showcasing a robust and reliable AI model in facial pore evaluation. More importantly, insights uncovered using this facile approach also bear significant cosmetic ramifications in treatment of pore enlargement.

Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial.

Importance: Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited. Objective: To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset. Design, Setting, and Participants: The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement. Interventions: Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg). Main Outcomes and Measures: The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality. Results: Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23]). Conclusions and Relevance: In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04915729.

NLRP3 targets HMGB1 to exacerbate the pyroptosis of canine corneal epithelial cells infected with Staphylococcus pseudintermedius.

PURPOSE: This study focused on the mechanisms of pyroptosis and oxidative damage exacerbation by NOD-like receptor thermal protein domain associated protein 3 (NLRP3) during the infection of canine corneal epithelial cells (CCECs) with Staphylococcus pseudintermedius. METHODS: The CCECs treated with dimethyl fumarate (DMF), recombinant high mobility group protein 1 (HMGB1), or N-acetylcysteine (NAC). The gasdermin (GSDM) family and HMGB1 mRNA expression levels were detected using quantitative reverse transcription polymerase chain reaction. Lactate dehydrogenase activity, bacterial counts, the pyroptosis rate, reactive oxygen species (ROS) content, and antioxidant enzyme activity were used to reflect pyroptosis and oxidation level. RESULTS: Regulation of NLRP3 significantly affected the pyroptosis rate and GSDMD-N expression levels during S. pseudintermedius infection. Inhibition of GSDMD-N protein activation by DMF reversed the exacerbation of pyroptosis induced by NLRP3 overexpression and reduced the levels of cleaved interleukin-1ß (IL-1ß), cleaved cysteinyl aspartate-specific protease-1, and NLRP3. In addition, NLRP3 was found to target the HMGB1 promoter and regulate its protein expression, to increase ROS accumulation and GSDMD-N expression levels, and activate the NLRP3-HMGB1-ROS-GSDMD signaling axis to aggravate pyroptosis during infection. CONCLUSIONS: NLRP3 aggravates pyroptosis and oxidative damage associated with the activation of NLRP3-GSDMD and NLRP3-HMGB1-ROS-GSDMD signaling pathways during the infection of CCECs with S. pseudintermedius.

Relationships between brain structure-function coupling in normal aging and cognition: A cross-ethnicity population-based study.

Increased efforts in neuroscience seek to understand how macro-anatomical and physiological connectomes cooperatively work to generate cognitive behaviors. However, the structure-function coupling characteristics in normal aging individuals remain unclear. Here, we developed an index, the Coupling in Brain Structural connectome and Functional connectome (C-BSF) index, to quantify regional structure-function coupling in a large community-based cohort. C-BSF used diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (fMRI) data from the Polyvascular Evaluation for Cognitive Impairment and Vascular Events study (PRECISE) cohort (2007 individuals, age: 61.15 ± 6.49 years) and the Sydney Memory and Ageing Study (MAS) cohort (254 individuals, age: 83.45 ± 4.33 years). We observed that structure-function coupling was the strongest in the visual network and the weakest in the ventral attention network. We also observed that the weaker structure-function coupling was associated with increased age and worse cognitive level of the participant. Meanwhile, the structure-function coupling in the visual network was associated with the visuospatial performance and partially mediated the connections between age and the visuospatial function. This work contributes to our understanding of the underlying brain mechanisms by which aging affects cognition and also help establish early diagnosis and treatment approaches for neurological diseases in the elderly.

Ambient particulate matter and chronic obstructive pulmonary disease mortality: a nationwide, individual-level, case-crossover study in China.

BACKGROUND: Short-term exposure to particulate matter air pollution has been associated with the exacerbations of COPD, but its association with COPD mortality was not fully elucidated. We aimed to assess the association between short-term particulate matter exposure and the risk of COPD mortality in China using individual-level data. METHODS: We derived 2.26 million COPD deaths from a national death registry database in Chinese mainland between 2013 and 2019. Exposures to fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) were assessed by satellite-based models of a 1 × 1 km resolution and assigned to each individual based on residential address. The associations of PM2.5 and PM2.5-10 with COPD mortality were examined using a time-stratified case-crossover design and conditional logistic regressions with distributed lag models. We further conducted stratified analyses by age, sex, education level, and season. FINDINGS: Short-term exposures to both PM2.5 and PM2.5-10 were associated with increased risks of COPD mortality. These associations appeared and peaked on the concurrent day, attenuated and became nonsignificant after 5 or 7 days, respectively. The exposure-response curves were approximately linear without discernible thresholds. An interquartile range increase in PM2.5 and PM2.5-10 concentrations was associated with 4.23% (95% CI: 3.75%, 4.72%) and 2.67% (95% CI: 2.18%, 3.16%) higher risks of COPD mortality over lag 0-7 d, respectively. The associations of PM2.5 and PM2.5-10 attenuated slightly but were still significant in the mutual-adjustment models. A larger association of PM2.5-10 was observed in the warm season. INTERPRETATION: This individual-level, nationwide, case-crossover study suggests that short-term exposure to PM2.5 and PM2.5-10 might act as one of the environmental risk factors for COPD mortality. FUNDING: This study is supported by the National Key Research and Development Program of China (2023YFC3708304 and 2022YFC3702701), the National Natural Science Foundation of China (82304090 and 82030103), the 3-year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.2-YQ31), and the Science and Technology Commission of Shanghai Municipality (21TQ015).

A Perspective on Evaluating Life Stage Differences in Drug Dosages for Drug Labeling and Instructions.

Drug labeling and instructions provide essential information for patients regarding the usage of drugs. Instructions for the dosage of drug usage are critical for the effectiveness of the drug and the safety of patients. The dosage of many drugs varies depending on the patient's age. However, as our understanding of human biology deepens, we believe that these instructions need to be modified to incorporate different life stages. This is because human biology and metabolism differ significantly among different life stages, and their responses to drugs also vary. Additionally, the same age of different persons may fall into different life stages. Therefore, our group from multiple institutes and countries proposes a reexamination of whether incorporating life stages in all or any drug instructions will greatly enhance drug efficiency and patients' health.

Plant-based diet indices and their interaction with ambient air pollution on the ovarian cancer survival: A prospective cohort study.

BACKGROUND: Ambient air pollution might serve as a prognostic factor for ovarian cancer (OC) survival, yet the relationships between plant-based diet indices (PDIs) and OC survival remain unclear. We aimed to investigate the associations of comprehensive air pollution and PDIs with OC survival and explored the effects of air pollution-diet interactions. METHODS: The present study encompassed 658 patients diagnosed with OC. The overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI) were evaluated by a self-reported validated food frequency questionnaire. In addition, an air pollution score (APS) was formulated by summing the concentrations of particulate matter with a diameter of 2.5 microns or less, ozone, and nitrogen dioxide. Cox proportional hazard models were applied to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). The potential interactions of APS with PDIs in relation to overall survival (OS) were assessed on both multiplicative and additive scales. RESULTS: Throughout a median follow-up of 37.60 (interquartile: 24.77-50.70) months, 123 deaths were confirmed. Comparing to the lowest tertiles, highest uPDI was associated with lower OS of OC (HR = 2.06, 95 % CI = 1.30, 3.28; P-trend < 0.01), whereas no significant associations were found between either overall PDI or hPDI and OC survival. Higher APS (HR for per interquartile range = 1.27, 95 % CI = 1.01, 1.60) was significantly associated with worse OC survival, and the association was exacerbated by adherence to uPDI. Notably, an additive interaction was identified between combined air pollution and uPDI (P < 0.005 for high APS and high uPDI). We also found that adherence to overall PDI aggravated associations of air pollution with OC survival (P-interaction = 0.006). CONCLUSIONS: Joint exposure to various ambient air pollutants was significantly associated with lower survival among patients with OC, particularly for those who predominantly consumed unhealthy plant-based foods.

Selenium elicited an enhanced anti-inflammatory effect in primary bovine endometrial stromal cells with high cortisol background.

BACKGROUND: An elevated endogenous cortisol level due to the peripartum stress is one of the risk factors of postpartum bovine uterine infections. Selenium is a trace element that elicits anti-inflammation and antioxidation properties. This study aimed to reveal the modulatory effect of selenium on the inflammatory response of primary bovine endometrial stromal cells in the presence of high-level cortisol. The cells were subjected to lipopolysaccharide to establish cellular inflammation. The mRNA expression of toll-like receptor 4 (TLR4), proinflammatory factors, and selenoproteins was measured with qPCR. The activation of NF-κB and MAPK signalling pathways was detected with Western blot and immunofluorescence. RESULTS: The pretreatment with sodium selenite (2 and 4 µΜ) resulted in a down-regulation of TLR4 and genes encoding proinflammatory factors, including interleukin (IL)-1ß, IL-6, IL-8, tumour necrosis factor α, cyclooxygenase 2, and inducible nitric oxide synthase. Selenium inhibited the activation of NF-κB and the phosphorylation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38MAPK and c-Jun N-terminal kinase/stress-activated protein kinase. The suppression of those genes and pathways by selenium was more significant in the presence of high cortisol level (30 ng/mL). Meanwhile the gene expression of glutathione peroxidase 1 and 4 was promoted by selenium, and was even higher in the presence of cortisol and selenium. CONCLUSIONS: The anti-inflammatory action of selenium is probably mediated through NF-κB and MAPK, and is augmented by cortisol in primary bovine endometrial stromal cells.

Training on contrast-enhanced ultrasound LI-RADS classification for resident radiologists: a retrospective comparison of performance after training.

OBJECTIVES: To evaluate the effects and benefits of training radiology residents on contrast-enhanced ultrasound (CEUS) according to the Liver Imaging Reporting and Data System (LI-RADS). METHODS: In total, 234 patients at high risk of hepatocellular carcinoma (HCC) who underwent CEUS were enrolled, including 27 lesions in the education set and 207 lesions in the test sets (a-d). Forty-five radiology residents and 4 radiology experts involved in CEUS LI-RADS training individually reviewed the test sets before, immediately after, and 3-months after training. The consistency with kappa values of the description of CEUS features, the classification of focal liver lesions (FLLs), and the diagnostic performance were evaluated. RESULTS: The level of agreement between the radiology experts and residents improved after training (all p < 0.05), while there were no significant differences between the post-training and 3-months post-training results (all p > 0.05). The sensitivity, specificity, positive predictive value, and area under the curve (AUC) based on the CEUS LI-RADS classification of the radiology experts in the diagnosis of HCC were 62.9%, 96.4%, 96.3%, and 0.796, respectively. The diagnostic performance of the radiology residents significantly improved after training (all p < 0.05). Misunderstanding of definitions and subjective interpretation of images were the main reasons for disagreement with multiple responses. CONCLUSION: Dedicated CEUS LI-RADS training improved the performance of radiology residents in diagnosing FLLs and their agreement with radiology experts on CEUS features. Images and videos to explain typical features of the training were essential to improve agreement between the radiology experts and residents. CRITICAL RELEVANCE STATEMENT: Agreement on lesion descriptors between radiology experts and residents can improve with training. KEY POINTS: The diagnostic performance of less experienced radiologists for diagnosing HCC could be improved by training. Images and videos to explain typical features during training were essential. Agreement on lesion descriptors between radiology experts and residents improved after training.

Monocyte Chemoattractant Protein-1, Inflammatory Biomarkers, and Prognosis of Patients With Ischemic Stroke or Transient Ischemic Attack: Fndings From a Nationwide Registry Study.

BACKGROUND: Recent Mendelian randomization and meta-analysis highlight the relevance of MCP-1 (monocyte chemoattractant protein-1) in stroke. We aimed to investigate the associations between MCP-1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships. METHODS AND RESULTS: A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all-cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP-1 level (<337.6 pg/mL) was associated with a reduced risk of all-cause death (hazard ratio [HR], 0.65 [95% CI, 0.51-0.82]) and poor functional outcome (odds ratio, 0.81 [95% CI, 0.70-0.94]) but was not associated with recurrent stroke (HR, 1.10 [95% CI, 0.95-1.27]), compared with high MCP-1 level (≥337.6 pg/mL). The association between MCP-1 and all-cause death was partially mediated by highly sensitive C-reactive protein, interleukin-6, and YKL-40 (Chitinase-3-like protein 1; mediated proportion: 7.4%, 10.5%, and 7.4%, respectively). The corresponding mediated proportion for poor functional outcome was 9.9%, 17.1%, and 7.1%, respectively. Patients with combined high levels of MCP-1 and inflammatory biomarkers had the highest risks of all-cause death and poor functional outcome. CONCLUSIONS: Low plasma MCP-1 level was associated with decreased risks of all-cause mortality and poor functional outcome after ischemic stroke or transient ischemic attack. Inflammation partially mediated and jointly contributed to the associations.

Combined UTMD-Nanoplatform for the Effective Delivery of Drugs to Treat Renal Cell Carcinoma.

Introduction: The effective accumulation of nanoparticles (NPs) in the tumour area is an important goals of current nanotechnology research, and a targeted nanoplatform is an effective solution. So we designed a multifunctional sound-sensitive targeted NP that combines a sonosensitizer to enable precisely targeted, deep-penetration sonodynamic therapy (SDT) in combination with multimodal imaging for the diagnosis and monitoring of renal cell carcinoma (RCC). Methods: ZnPP@PP NPs (ZnPP@PLGA- PFP NPs) were prepared via a double emulsion method, and G250 was covalently attached to the NPs shell via the carbon diimide method. Physicochemical property tests were conducted on the ZnPP@G-PP NPs, including tests of particle size, potential distribution, encapsulation efficiency and drug loading capability. We assessed the targeting ability, the production of reactive oxygen species (ROS) and permeability of the NPs in vitro. Moreover, we evaluated the nanoparticle's multimodal imaging capabilities and therapeutic ability against RCC, both in vitro and in vivo. Results: The Znpp@G-PP NPs were successfully constructed, and their general properties showed uniform particle size, negative potential and good stability. The nanoparticles were successfully loaded with ZnPP and connected with G250, showing tumor-specific targeting ability. Under LIFU irradiation, the nanoparticles produced 1O2 by SDT. For RCC, PA/US multi-modal imaging of Znpp@G-PP NPs provide diagnostic information and monitor therapies in real time in 786-O RCC xenografts, with good biocompatibility. With the UTMD, nanoparticles can be effectively targeted into the tumor cells and penetrate into the tumor interior, significantly improving the SDT effect. Experiments in vitro and in vivo showed that the combination of the nanoparticles and LIFU could suppress the tumor, and the therapeutic effect was confirmed by immunohistochemistry. Conclusion: ZnPP@G-PP NPs provide a promising theranostic strategy for RCC and a platform for further research on improving the efficacy of diagnosis and treatment.