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Abstract Background Estimating the economic burden of modifiable risk factors is crucial for allocating scarce healthcare resources to improve population health. We quantified the economic burden attributable to modifiable risk factors in an urban area of China. Methods Our Shanghai Municipal Health Commission dataset covered 2.2 million inpatient admissions for adults (age ≥ 20) in public and private hospitals in 2015 (1,327,187 admissions) and 2020 (837,482 admissions). We used a prevalence-based cost-of-illness approach by applying population attributable fraction (PAF) estimates for each modifiable risk factor from the Global Burden of Diseases Study (GBD) to estimate attributable costs. We adopted a societal perspective for cost estimates, comprising direct healthcare costs and productivity losses from absenteeism and premature mortality. Future costs were discounted at 3% and adjusted to 2020 prices. Results In 2020, the total societal cost attributable to modifiable risk factors in Shanghai was US$7.9 billion (95% uncertainty interval [UI]: 4.6–12.4b), mostly from productivity losses (67.9%). Two health conditions constituted most of the attributable societal cost: cancer (51.6% [30.2–60.2]) and cardiovascular disease (31.2% [24.6–50.7]). Three modifiable risk factors accounted for half of the total attributable societal cost: tobacco (23.7% [16.4–30.5]), alcohol (13.3% [8.2–19.7]), and dietary risks (12.2% [7.5–17.7]). The economic burden varied by age and sex; most of the societal costs were from males (77.7%), primarily driven by their tobacco and alcohol use. The largest contributor to societal costs was alcohol for age 20–44, and tobacco for age 45 + . Despite the COVID-19 pandemic, the pattern of major modifiable risk factors remained stable from 2015 to 2020 albeit with notable increases in attributable healthcare costs from cancers and productivity losses from cardiovascular diseases. Conclusions The substantial economic burden of diseases attributable to modifiable risk factors necessitates targeted policy interventions. Priority areas are reducing tobacco and alcohol consumption and improving dietary habits that together constitute half of the total attributable costs. Tailored interventions targeting specific age and sex groups are crucial; namely tobacco in middle-aged/older males and alcohol in younger males.

BackgroundChina’s National Essential Medicines Policy (NEMP) has been implemented for over 15 years; yet empirical evidence on its long-term impacts is lacking, particularly in remote and rural regions. This study aims to assess the short-and long-term effects of NEMP on the drug availability, price, and usage in a deprived rural county in southwestern China.MethodsA quasi-experimental design was employed, featuring a single-group pre-and-post comparison. We gathered 74,436 procurement records spanning from 2009 to 2016 from the drug warehouses of local medical institutions. Pharmaceutical data were analyzed quarterly, considering various policy and therapeutic attributes. Fisher’s Drug Price Index (DPI-F) was calibrated for the retail and wholesale prices of a consistent collection of 405 medications. We conducted interrupted time-series analysis to examine the immediate and enduring impacts of NEMP’s initial (commencing in January 2011) and second (starting from December 2015) stages.ResultsAfter initiation of NEMP, the number of available essential medicines surged by 115 but subsequently faced a steady quarterly decline (−9.1) in township healthcare centers (THCs, primary care). Conversely, county hospitals (secondary care) initially saw a reduction of 40 in drug availability but later exhibited a steady increase (+4.2 per quarter) up to the second-stage NEMP. Regarding price, THCs encountered abrupt (−26.1%/−15.9% in retail/wholesale price) and sustained (−0.2%/−0.3% per quarter) price drops after NEMP. The immediate price change after NEMP in county hospitals were milder but significant in non-essential medicines, and long-term declines were also observed in all drugs. As for total sales, a significant long-term disparity emerged between THCs (+0.9% per quarter) and county hospitals (+3.3% per quarter). Following the second-stage NEMP, retail prices in county hospitals further decreased, although wholesale prices did not; however, following price upward trends were observed in both THCs and county hospitals. Lastly, the influences of NEMP varied across different therapeutical categories of medicines.ConclusionNEMP has successfully regulated drug prices in primary and secondary healthcare facilities in remote and rural areas, both short-term and long-term. However, a remarkable disparity in medicine availability and utilization was observed between different levels of facilities over time. Continuous monitoring is essential, with increased attention needed on the uneven impacts of the policy on diverse drugs, facilities, regions, and demographics.

China’s approach to air pollution control has been shown successful in East Asian countries and even elsewhere in the world. The analysis of the evolution and control of air pollution in China over the past 75 years can be used as a reference for developing countries suffering from air pollution resulting from urbanization. Based on the sorting and mining of relevant indicators, data and policy texts from the areas of population, economy, space and social urbanization, the findings suggest that the presence of air pollution and its changing forms indeed have complex interactive relationships with the process of urbanization. Specifically: (1) the feature of air pollution has changed from “single pollutant and pollution source to multiple pollutants and pollution source, local pollution to regional pollution, light pollution to heavy compound pollution” as a result of urbanization, the emphasizing of construction and the neglect of governance, the emphasizing of economics and the neglect of ecology, and the emphasizing of immediate interests over long-term interests; (2) the interactive relationship between air pollution and urbanization has also gone through three stages from being irrelevant each other to “urbanization determines air pollution” and then “air pollution restricts urbanization”; (3) this has forced air pollution control to shift from the traditional “treating symptoms” to “high-quality urbanization”, thus promoting air pollution and urbanization to move “from confrontation to unification”. Therefore, air pollution control is not a simple technical issue; one of the keys lies in exploring how to adjust the urbanization model, so as to achieve the “win–win” of urbanization and air pollution control.

ObjectiveChronic subdural hematoma (CSDH) is a neurological condition with high recurrence rates, primarily observed in the elderly population. Although several risk factors have been identified, predicting CSDH recurrence remains a challenge. Given the potential of machine learning (ML) to extract meaningful insights from complex data sets, our study aims to develop and validate ML models capable of accurately predicting postoperative CSDH recurrence.MethodsData from 447 CSDH patients treated with consecutive burr-hole irrigations at Wenzhou Medical University’s First Affiliated Hospital (December 2014-April 2019) were studied. 312 patients formed the development cohort, while 135 comprised the test cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) method was employed to select crucial features associated with recurrence. Eight machine learning algorithms were used to construct prediction models for hematoma recurrence, using demographic, laboratory, and radiological features. The Border-line Synthetic Minority Over-sampling Technique (SMOTE) was applied to address data imbalance, and Shapley Additive Explanation (SHAP) analysis was utilized to improve model visualization and interpretability. Model performance was assessed using metrics such as AUROC, sensitivity, specificity, F1 score, calibration plots, and decision curve analysis (DCA).ResultsOur optimized ML models exhibited prediction accuracies ranging from 61.0% to 86.2% for hematoma recurrence in the validation set. Notably, the Random Forest (RF) model surpassed other algorithms, achieving an accuracy of 86.2%. SHAP analysis confirmed these results, highlighting key clinical predictors for CSDH recurrence risk, including age, alanine aminotransferase level, fibrinogen level, thrombin time, and maximum hematoma diameter. The RF model yielded an accuracy of 92.6% with an AUC value of 0.834 in the test dataset.ConclusionOur findings underscore the efficacy of machine learning algorithms, notably the integration of the RF model with SMOTE, in forecasting the recurrence of postoperative chronic subdural hematoma. Leveraging the RF model, we devised an online calculator that may serve as a pivotal instrument in tailoring therapeutic strategies and implementing timely preventive interventions for high-risk patients.

Background Dual‐layer spectral‐detector dual‐energy computed tomography angiography (DLCTA) can distinguish components of carotid plaques. Data on identifying symptomatic carotid plaques in patients using DLCTA are not available. Methods and Results In this prospective observational study, patients with carotid plaques were enrolled and received DLCTA. The attenuation for both polyenergetic image and virtual monoenergetic images (40, 70, 100, and 140 keV), as well as Z‐effective value, were recorded in the noncalcified regions of plaques. Logistic regression models were used to assess the association between attenuations of DLCTA and the presence of symptomatic carotid plaques. In total, 100 participants (mean±SD age, 64.37±8.31 years; 82.0% were men) were included, and 36% of the cases were identified with the symptomatic group. DLCTA parameters were different between 2 groups (symptomatic versus asymptomatic: computed tomography [CT] 40 keV, 152.63 [interquartile range (IQR), 70.22–259.78] versus 256.78 [IQR, 150.34–408.13]; CT 70 keV, 81.28 [IQR, 50.13–119.33] versus 108.87 [IQR, 77.01–165.88]; slope40–140 keV, 0.91 [IQR, 0.35–1.87] versus 1.92 [IQR, 0.96–3.00]; Z‐effective value, 7.92 [IQR, 7.53–8.46] versus 8.41 [IQR, 7.94–8.92]), whereas no difference was found in conventional polyenergetic images. The risk of symptomatic plaque was lower in the highest tertiles of attenuations in CT 40 keV (adjusted odds ratio [OR], 0.243 [95% CI, 0.078–0.754]), CT 70 keV (adjusted OR, 0.313 [95% CI, 0.104–0.940]), Z‐effective values (adjusted OR, 0.138 [95% CI, 0.039–0.490]), and slope40–140 keV (adjusted OR, 0.157 [95% CI, 0.046–0.539]), with all P values and P trends

The J-TEXT capability is enhanced compared to two years ago with several upgrades of its diagnostics and the increase of electron cyclotron resonance heating (ECRH) power to 1 MW. With the application of electron cyclotron wave (ECW), the ECW assisted plasma startup is achieved; the tearing mode is suppressed; the toroidal injection of 300 kW ECW drives around 24 kA current; fast electrons are generated with toroidal injected ECW and the runaway current conversion efficiency increases with ECRH power. The mode coupling between 2/1 and 3/1 modes are extensively studied. The coupled 2/1 and 3/1 modes usually lead to major disruption. Their coupling can be either suppressed or avoided by external resonant magnetic perturbation fields and hence avoids the major disruption. It is also found that the 2/1 threshold of external field is significantly reduced by a pre-excited 3/1 mode, which can be either a locked island or an external kink mode. The disruption control is studied by developing prediction methods capable of cross tokamak application and by new mitigation methods, such as the biased electrode or electromagnetic pellet injector. The high-density operation and related disruptions are studied from various aspects. Approaching the density limit, the collapse of the edge shear layer is observed and such collapse can be prevented by applying edge biasing, leading to an increased density limit. The density limit is also observed to increase, if the plasma is operated in the poloidal divertor configuration or the plasma purity is increased by increasing the pre-filled gas pressure or ECRH power during the start-up phase.

Deep pellet fueling depth is necessary to achieve a high-density high confinement operation and to conduct some pellet-related researches in current devices, such as trigger of internal transport barrier, and to achieve high fusion power and tritium burn-up fraction in future fusion devices. The newly developed PAM code which can make a fast evaluation on pellet ablation and deposition is applied to optimize injection parameters to achieve deep pellet fueling. Systematic scans on pellet injection parameters including pellet injection positions, injection angles, sizes and speeds are performed for optimization purpose, while at the same time demonstrating flexibility and time efficiency of the PAM code. Dependences of the pellet fueling depth on these injection parameters are revealed by simulation results and analyzed. Simulation results indicate that pellet penetration contributes more to the deep pellet deposition than the $\nabla B$ -induced plasmoid drifts in low temperature plasmas, while deep pellet fueling in reactor relevant high temperature plasmas has to rely on plasmoid drifts. Though a shallow penetration is expected in high temperature plasmas, the $\nabla B$ -induced plasmoid drift is expected to be larger than that in relatively low temperature plasmas.

Background Type 2 diabetes mellitus (T2DM) is a common chronic disease that is strongly associated with cardiovascular risk. Long-term high blood glucose levels may induce cardiomyocyte apoptosis, cardiac dysfunction and suppress fetal cardiomyocyte proliferation. Recent epidemiological studies have shown a link between antioxidant carotenoids and T2DM, but a comprehensive longitudinal study of this association has not yet been conducted. Methods We included participants with biological measurements for both serum cis-β-carotene and fasting glucose from NHANES (2001–2006). We divided the participants into quartiles according to serum cis-β-carotene levels and determined the association between these levels and glucose metabolism by using multivariable regression models adjusted for confounding factors. The mechanism through which β-carotene levels regulate plasma glucose levels was further investigated in vivo and in vitro. In addition, we performed a preliminary exploration of the effects of β-carotene on diabetic rats and primary cardiomyocytes. Results Higher cis-β-carotene (quartile 4) was associated with higher LDL-cholesterol levels but lower fasting blood glucose levels. However, T2DM rats subjected to β-carotene treatment showed diminished total triglycerides and LDL-cholesterol, and their β-carotene levels were associated with better cardiac function than that in the T2DM group (P

Background E-health has the potential to promote health accessibility, performance and cost-saving. However, the adoption and penetration of e-health in underprivileged areas remains insufficient. We aim to investigate patients’ and doctors’ perception, acceptance, and utilization of e-health in a rural, spatially isolated and poverty-stricken county in southwestern China. Methods A retrospective analysis based on a cross-sectional survey of patients and doctors in 2016 was conducted. Participants were recruited through convenience and purposive sampling, and questionnaires were self-designed and validated by investigators. The utilization, intention to use and preference of four e-health services were evaluated, including e-appointment, e-consultation, online drug purchase, and telemedicine. Predictors of utilization and intention to use e-health services were investigated by multivariable logistic regression. Results A total of 485 patients were included. The utilization rate of any type of e-health services was 29.9%, ranging from 6% in telemedicine to 18% in e-consultation. Additionally, 13.9%-30.3% of respondents as non-users revealed their willingness to use such services. Users and potential users of e-health services were inclined to specialized care from county, city or province hospitals, and they were most concerned with the quality, ease of use and price of e-health service. Patients’ utilization and intention to use e-health could be associated with education and income level, cohabitants, working location, previous medical utilization, and access to digital device and internet. There remained 53.9%-78.3% of respondents reluctant to use e-health services, mainly due to perceived inability to use them. Of 212 doctors, 58% and 28% had provided online consultation and telemedicine before, and over 80% of county-hospital doctors (including actual providers) indicated their willingness to provide such services. Reliability, quality and ease of use were doctors’ major concerns regarding e-health. Doctors’ actual provision of e-health was predicted by their professional title, number of years in work, satisfaction with the wage incentive system, and self-rated health. Nevertheless, their willingness to adopt was only associated with the possession of smartphone. Conclusions E-health is still in its infancy in western and rural China, where health resources are most scarce, and where e-health could prove most beneficial. Our study reveals the wide gaps between patients’ low usage and their certain willingness to use e-health, as well as gaps between patients’ moderate attention to use and physician’s high preparedness to adopt e-health. Patients’ and doctors’ perceptions, needs, expectations, and concerns should be recognized and considered to promote the development of e-health in these underprivileged regions.

Abstract Lung cancer is one of the most common malignant tumors worldwide. Early detection is the most important factor that affects the prognosis of lung cancer patients. The distal phalanx is a highly unusual metastatic site of lung cancer, and is often misdiagnosed, especially when accompanied by trauma. Herein, we present the case of a 68‐year‐old male patient who injured his right little finger. We hope this rare case will help clinicians to better diagnosis acral metastases of lung cancer to prolong patient survival.

High-power, high-purity, nanosecond (ns) one-dimensional HG0n laser beams are proposed and demonstrated by using Nd:YAG cascaded slabs with a large aspect ratio. The HG0n laser beams are generated by adjusting the pump distribution, the intracavity apertures, and the tilt angle of the output coupler (OC). By controlling the gain and loss of HG0n modes of different orders, the high-purity, one-dimensional, high-order HG0n laser beams with orders 1 to 9 (HG01 to HG09) are produced, and their beam quality factors M2 align well with the theoretical predictions. Meanwhile, the large aspect ratio slab provides an ideal amplifier for the strip-shaped HG0n laser beams, and further power scaling is achieved by seeding the generated HG0n laser beams into an amplifier with an identical slab module. For the HG09 mode, the average power is amplified from 289 mW to 4.73 W with 294 ns pulse width, corresponding to a peak power of 32 kW. Moreover, above 5 W average power is achieved for all HG01 to HG08 modes. Hopefully, this scheme provides a solution for high-power and high-purity HG0n laser beam generation based on the slab-shaped configuration.

Absorbing aerosols have significant influences on tropospheric photochemistry and regional climate change. Here, the direct radiative effects of absorbing aerosols at the major AERONET sites in East Asia and corresponding impacts on near-surface photochemical processes were quantified by employing a radiation transfer model. The average annual aerosol optical depth (AOD) of sites in China, Korea, and Japan was 1.15, 1.02 and 0.94, respectively, and the corresponding proportion of absorbing aerosol optical depth (AAOD) was 8.61%, 6.69%, and 6.49%, respectively. The influence of absorbing aerosol on ultraviolet (UV) radiation mainly focused on UV-A band (315–400 nm). Under the influence of such radiative effect, the annual mean near-surface J[NO2] (J[O1D]) of sites in China, Korea, and Japan decreased by 16.95% (22.42%), 9.61% (13.55%), and 9.63% (13.79%), respectively. In Beijing–Tianjin–Hebei (BTH) and Yangtze River Delta (YRD) region, the annual average AOD was 1.48 and 1.29, and the AAOD was 0.14 and 0.13, respectively. The UV radiative forcing caused by aerosols dominated by black carbon (BC-dominated aerosols) on the surface was −3.19 and −2.98 W m−2, respectively, accounting for about 40% of the total aerosol radiative forcing, indicating that the reduction efficiency of BC-dominated aerosols on solar radiation was higher than that of other types of aerosols. The annual mean J[NO2] (J[O1D]) decreased by 14.90% (20.53%) and 13.71% (18.20%) due to the BC-dominated aerosols. The daily maximum photolysis rate usually occurred near noon due to the diurnal variation of solar zenith angle and, thus, the daily average photolysis rate decreased by 2–3% higher than that average during 10:00–14:00.

Glioma is one of the most common primary tumors in the central nervous system. Circular RNAs (circRNAs) may serve as novel biomarkers of various cancers. The purpose of this study is to reveal the diagnostic value of hsa_circ_0004214 for glioma and to predict its molecular interaction network. The expression of hsa_circ_0004214 was evaluated by RT-qPCR. The vector and siRNAs changed the expression of hsa_circ_0004214 to judge its influence on the migration degree of glioma cells. hsa_circ_0004214 can be stably expressed at a high level in high-grade glioma tissue (WHO III/IV). The area under the ROC curve of hsa_circ_0000745 in glioma tissue was 0.88, suggesting good diagnostic value. While used to distinguish high-grade glioma, AUC value can be increased to 0.931. The multi-factor correlation analysis found that the expression of hsa_circ_0004214 was correlated with GFAP (+) and Ki67 (+) in immunohistochemistry. In addition, the migration capacity of U87 was enhanced by overexpression of hsa_circ_0004214. Through miRNA microarray analysis and database screening, we finally identified 4 miRNAs and 9 RBPs that were most likely to interact with hsa_circ_0004214 and regulate the biological functions of glioma. Hsa_circ_0004 214 plays an important role in glioma, its expression level is a promising diagnostic marker for this malignancy.

This study was performed to elucidate the potential influence of He Qi San (HQS) on glucose and lipid metabolism in type 2 diabetes mellitus (T2DM) patients with phlegm-blood stasis syndrome (PBSS), and to determine DNA methylation changes. Sixty T2DM patients with PBSS were randomly divided into control and HQS groups. The control group received conventional treatments, and the HQS group received conventional treatments plus HQS. Glucose metabolism (FPG, 2hPG, FINS, and HbA1c) and lipid metabolism indexes (TG, TC and LDL-C) were determined. Genes with differential DNA methylation were subjected to GO and KEGG analyses. Glucose and lipid metabolism indexes in both groups were reduced, but were much more pronounced in the HQS group. Differential promoter CpG methylation regions were identified in 682 genes, including 426 genes with high-CpG promoters, 150 genes with intermediate CpG promoters, and 106 genes with low CpG promoters. Genes with differential DNA methylation were mainly enriched in the AMPK and insulin signaling pathways, terpenoid backbone biosynthesis, and renin secretion. We concluded that HQS remarkably improved indexes of glucose and lipid metabolism in T2DM patients with PBSS through regulating the DNA methylation of genes in the AMPK and insulin signaling pathways and terpenoid backbone biosynthesis.

The Chinese economy has developed rapidly since the reform and opening up, but economic growth in Northeast China has declined dramatically after the 21st century. In this context, exploring the characteristics of economic and industrial fluctuations in the northeast of China and their relationship is beneficial to alleviating economic fluctuations and promoting stable economic development from the perspective of industrial development. The relationship between economic and industrial fluctuations in the three provinces of Northeast China was reexamined from the angle of fluctuation components with the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) algorithm. The results obtained are as follows: (1) In the three northeastern provinces of China, economic fluctuations were almost free from the influence of the primary industry, most affected by the secondary industry, and gradually influenced by the tertiary industry after the 21st century. (2) Regarding the short-term business cycle of each province, economic development was the most stable when the market and government participated in the development of the secondary industry simultaneously. (3) The midterm business cycle of Jilin Province was affected by the investment of equipment in secondary and tertiary industries, while that of Liaoning Province was affected by the investment of equipment in the secondary industry. (4) Investment in the equipment of the secondary industry and the construction of secondary and tertiary industries was the key to maintaining the stability of long-term business cycle in Heilongjiang Province, and that in the construction of secondary and tertiary industries was the key to maintaining the stability of long-term business cycles in Jilin and Liaoning Provinces.

We examined the feasibility of estimating the spatial distribution of urban populations based on first-aid calls based on one high-density place, the Shanghai urban area and one low-density place, the Nanhai District of Foshan City in Guangdong Province. We aggregated the population and the total number of first-aid calls on digital maps divided by grids based on a Geographic Information System (GIS). Geographically weighted regression was applied to test the correlation between the population distribution simulated by first-aid call data and the actual residency. The impact of different population densities, different grid cell sizes and different types of first-aid calls on simulation correlation were tested. We found that the use of first-aid call data could explain 60-95% of the actual population distribution in Shanghai using a grid with 1000*1000 m cell size, while the Nanhai experience was that first-aid calls could only explain 4-76% of the actual population distribution using a grid with 2000*2000 m cell size. Thus, the higher the population density, the better the simulation effect. For a high-population density area, the overall accuracy of simulation can reach as high as 0.878 at the 1-km2 resolution. However, there are different kinds of first-aid calls and for the best estimation of the population distribution in densely populated areas, we suggest using first-aid calls from people requiring acute medical care rather than all first-aid call data.

Community health centres (CHCs) are the health gatekeepers of the local population. Location and numbers of the CHCs affect fairness and effectiveness with regard to access to primary health care. In the past, the distribution of the CHCs was solely empiric-based. The goal of this study was to devise a method for CHC distribution based on the principle of improving equity as well as ensuring efficiency. We tested the effectiveness and operability of the method through a process of revision and simulation using Guangdong Province, China as sample district. A methodology based on literature review and expert consultation was repeatedly applied until an ideal result had been reached. A hexagonal, mesh-based method was developed and used to find a solution where the CHCs could be distributed where their location would be the most needed and total number suitable. Testing the effectiveness of the proposed plan, we found the proportion of area covered to be 52.8% and the proportion of the population covered 80.7%, which is 15.4% and 14.7%, respectively, better than before. It was concluded that the hexagonal mesh-based, distribution method can effectively define the location as well as the number or required CHCs, not only improving the accessibility for residents to primary health care services but also maximizing cost-effectiveness. Management of the city by grid is a new idea in urban management, which improves rationality of planning and also may be applied for many different purposes in addition to CHC localization.

OBJECTIVE:To develop a set of structure and process indicators to evaluate tertiary hospitals' performance in the Healthcare Improvement Initiative, a national program with a goal to improve quality of patient-centered care. METHODS:A modified Delphi technique, including literature review, multidisciplinary panel meeting and anonymous rating, was used to generate a set of indicators. A practice test involving both general and special hospitals was conducted to ensure the feasibility of data collection for these indicators. RESULTS:62 indicators were generated by literature review. The panel review procedure involving 39 panelists with diverse backgrounds resulted in a total of 59 indicators, which included 40 qualitative indicators and 19 quantitative indicators. In the practice test, six quantitative indicators were found unfeasible. According to the suggestion of the experts in the hospital evaluation committee, three of those indicators were kept by adjusting their data collection methods, while other three ones were discarded. DISCUSSION:A set of 56 structure and process indicators was developed to evaluate hospitals' performance in the implementation of the Healthcare Improvement Initiative, which could be used in both general and special tertiary hospitals. Results of the indicator measurement could present a panorama of the quality of patient-centered care in tertiary hospitals nation-wide, and inform health administrators of the ways to attain the goal of the Initiative.

Despite rapid advances in chemotherapy and surgical resection strategies, pancreatic cancer remains the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 5%. Therefore, novel therapeutic agents for the prevention and treatment of pancreatic cancer are urgently needed. The aim of this study was to investigate the effect of pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, on inhibition of cell proliferation and induction of apoptosis in three pancreatic cancer cells, BxPC-3, PANC-1 and AsPC-1, in both monotherapy and in combination with gemcitabine. Treatment with pristimerin decreased the cell proliferation of all three pancreatic cancer cells in a dose- and time-dependent manner. Treatment of pancreatic cancer cells with pristimerin also resulted in G1-phase arrest which was strongly associated with a marked decrease in the level of cyclins (D1 and E) and cyclin-dependent kinases (cdk2, cdk4 and cdk6 ) with concomitant induction of WAF1/p21 and KIP1/p27. Pristimerin treatment also resulted in apoptotic cell death, cleavage of caspase-3, modulation in the expressions of Bcl-2 family proteins, inhibition of the translocation and DNA-binding activity of NF-κB. In addition, pristimerin potentiated the growth inhibition and apoptosis inducing effects of gemcitabine in all three pancreatic cancer cells, at least in part, by inhibiting constitutive as well as gemcitabine-induced activation of NF-κB in both its DNA-binding activity and transcriptional activity. Taken together, these data provide the first evidence that pristimerin has strong potential for development as a novel agent against pancreatic cancer.

Seasonal spermatogenesis in fish is driven by spermatogonial stem cells (SSCs), which undergo a complex cellular process to differentiate into mature sperm. In this study, we characterized spermatogenesis in the large yellow croaker (Larimichthys crocea), a marine fish of significant commercial value, based on a highresolution single-cell RNA-sequencing atlas of testicular cells from three distinct developmental stages: juvenile, adult differentiating and regressed testes. We detailed a continuous developmental trajectory of spermatogenic cells, from spermatogonia to spermatids, elucidating the molecular events involved in spermatogenesis. We uncovered dynamic heterogeneity in cellular compositions throughout the annual reproductive cycle, accompanied by strongmolecular signatures within specific testicular cells. Notably, we identified a distinct population of SSCs and observed a critical metabolic transition from glycolysis to oxidative phosphorylation, enhancing our understanding of the biochemical and molecular characteristics of SSCs. Additionally, we elucidated the interactions between somatic cells and spermatogonia, illuminating the mechanisms that regulate SSC development. Overall, this work enhances our understanding of spermatogenesis in seasonal breeding teleosts and provides essential insights for the further conservation and culture of SSCs. [ABSTRACT FROM AUTHOR]