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BackgroundRefractory gastroesophageal reflux disease (refractory GERD) is a heterogeneous disease characterized by unresponsiveness or poor efficacy to proton-pump inhibitors (PPIs). This chronic disorder substantially weakens patients’ mental wellbeing and quality of life, increasing the financial burden on society. Multiple articles have been reported in this area. However, literature involving scientometric analysis of refractory GERD is absent. Therefore, it is necessary to understand the evolution of research themes and the main hotspots of refractory GERD through bibliometric methods.MethodsAll documents related to refractory GERD based on the WOS Core Collection from January 2000 to November 2023 were selected for analysis. Citespace V 6.1 R6, VOSviewer V 1.6.20, and Scimago Graphica V 1.0.38 were used to perform bibliometric analysis.ResultsWe collected a total of 241 research articles from 36 countries and 322 institutions, contributed by over 1,000 authors. Over the last 20 years, the number of articles in this field has increased year by year, and since 2011, the number of publications has increased dramatically, with 85.89% of the papers. These countries are led by the United States and Japan. GUT had the highest number of citations and DIGESTION had the highest number of publications. Research on standardized diagnosis and management, mechanisms, novel monitoring methods, and innovative drugs and procedures for refractory GERD are the main topics and hotspots in this field. This study also found that neuroimmune interaction is closely related to refractory GERD, which may be a new direction for future mechanism research.ConclusionOur study is the first bibliometric analysis of the global literature on refractory GERD. This research provides valuable insights for researchers, enabling them to quickly understand the research frontier and hot topics of this field.

To investigate the importance of magnetic resonance diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) for distinguishing between prostate cancer (PCa) and prostate hyperplasia (BPH). A total of 78 patients with prostate disorders and 20 individuals without prostate disorders (control group) treated between June 2020 and June 2023 were examined. Among them, 30 were pathologically diagnosed with BPH and 48 with PCa. (Magnetic Resonance Imaging-diffusion weighted imaging) MRI-DWI and PWI parameters, specifically the apparent diffusion coefficient (ADC), maximum slope of perfusion curve (SSmax) and quasi-T2 relaxation rate (ΔR2*peak), were compared among the three groups. Microvessel density (MVD) of vascular endothelial growth factor (VEGF) and PCa were quantified through immunohistochemistry. No statistically significant differences were observed in ADC values within the transition zone of the prostate among the control group, BPH and PCa patients (p > 0.05), while significant differences in ADC values were observed within the peripheral zone of the three groups (p < 0.05). The ADC and T2 values of BPH lesions were significantly higher than those of PCa tissue (p < 0.05). Moreover, SSmax and ΔR2*peak values were significantly different in BPH lesions (p < 0.05). MVD levels were significantly lower in BPH lesions compared to PCa lesions, and the positive expression rate of VEGF was also significantly lower in BPH lesions (p < 0.05). Correlation analysis revealed a positive association between SSmax and ΔR2*peak levels in PCa lesions and their MVD and VEGF levels (p < 0.05). Both MRI-PWI and DWI imaging demonstrate substantial value in distinguishing between PCa and BPH. Furthermore, a significant correlation was observed between PWI scan parameters, such as SSmax, ΔR2*peak and VEGF and MVD levels in tumor tissues, offering a promising non-invasive option for assessing tumor neovascularization.

Abstract Diabetic cardiomyopathy (DCM) is a condition characterized by myocardial dysfunction that occurs in individuals with diabetes, in the absence of coronary artery disease, valve disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. It is considered a significant and consequential complication of diabetes in the field of cardiovascular medicine. The primary pathological manifestations include myocardial hypertrophy, myocardial fibrosis, and impaired ventricular function, which can lead to widespread myocardial necrosis. Ultimately, this can progress to the development of heart failure, arrhythmias, and cardiogenic shock, with severe cases even resulting in sudden cardiac death. Despite several decades of both fundamental and clinical research conducted globally, there are currently no specific targeted therapies available for DCM in clinical practice, and the incidence and mortality rates of heart failure remain persistently high. Thus, this article provides an overview of the current treatment modalities and novel techniques pertaining to DCM, aiming to offer valuable insights and support to researchers dedicated to investigating this complex condition.

Abstract Background To compare the survival rates of four timing of treatment initiation for people living with HIV/AIDS provided in China in 2006, 2011, 2015, and 2018, and to investigate the factors impacting survival time. Methods A people living with HIV/AIDS retrospective cohort study was in Liuzhou City from April 2006 to December 2020. The information was obtained from the National Comprehensive AIDS Prevention and Control Information System. Life tables and the Kaplan–Meier method were used to calculate participant survival rates and time. The univariate and multivariate Cox regression models were used to investigate the factors related to survival. Results 18,543 participants were included in this study. In four periods, the 1-year survival rates were 81%, 87%, 95%, and 95%. The 2-year survival rates were 76%, 85%, 93%, and 94%. The 3-year survival rates were 73%, 84%, 92%, and 94%. Results of multivariate Cox regression showed that sex, age of HIV diagnosis, ethnicity, household registration, occupation, marital status, the timing of treatment, education level, route of HIV transmission, whether receiving antiretroviral therapy (ART), and the count of CD4+T cells at baseline (count of CD4+T cells at HIV diagnosis) were factors that are significantly correlated with mortality caused by HIV infection. Conclusions With the Guidelines updated from 2006 to 2020, the 1-, 2-, and 3-year survival rates of people living with HIV/AIDS in four periods tended to increase. The timing of treatment initiation of the updated edition of the AIDS Diagnostic and Treatment Guidelines (Guidelines) significantly prolonged the survival time of people living with HIV/AIDS.

A case of immune checkpoint inhibitors (ICIs)-associated myocarditis with reversible advanced atrioventricular block (AVB) was reported. We innovatively used active fixation lead connected to an external device for prolonged temporary pacing until atrioventricular conduction recovered. Invasive electrophysiology studies were performed to evaluate atrioventricular conduction in detail. Long-term follow-up for nearly 120-days and repeated long-term electrocardiography was conducted to ensure the conduction system was truly recovered.

IntroductionAmyloid light-chain cardiac amyloidosis is a progressive infiltrative disease characterized by the deposition of amyloid fibrils in the cardiac tissue, which can cause serious atrioventricular block requiring pacemaker implantation. Left bundle branch pacing has emerged as an alternative method for delivering physiological pacing to achieve electrical synchrony of the left ventricle. However, left bundle branch pacing in patients with amyloid light-chain cardiac amyloidosis has not been studied in detail. Therefore, in this study, we present a case of left bundle branch pacing in a patient with amyloid light-chain cardiac amyloidosis.Case summaryA 66-year-old male patient with amyloid light-chain cardiac amyloidosis presented with syncope for 1 month. Holter monitoring revealed intermittent third-degree atrioventricular block. Left bundle branch pacing was performed successfully. During the 1-year follow-up, it was observed that the left bundle branch capture threshold remained stable without any pacemaker-related complications or left ventricle systolic dysfunction, and there was no recurrence of syncope.ConclusionLeft bundle branch pacing appears to be a safe and feasible option for patients with amyloid light-chain cardiac amyloidosis experiencing atrioventricular block.

Accurate air traffic flow prediction assists controllers formulate control strategies in advance and alleviate air traffic congestion, which is important to flight safety. While existing works have made significant efforts in exploring the high dynamics and heterogeneous interactions of historical air traffic flow, two key challenges still remain. (1) The transfer patterns of air traffic are intricate, subject to numerous constraints and limitations such as controllers, flight regulations, and other regulatory factors. Relying solely on mining historical traffic evolution patterns makes it difficult to accurately predict the constrained air traffic flow. (2) Weather conditions exert a substantial influence on air traffic, making it exceptionally difficult to simulate the impact of external factors (such as thunderstorms) on the evolution of air traffic flow patterns. To address these two challenges, we propose a Spatiotemporal Knowledge Distillation Network (ST-KDN) for air traffic flow prediction. Firstly, recognizing the inherent future insights embedded within flight plans, we develop a “teacher-student” distillation model. This model leverages the prior knowledge of upstream-downstream migration patterns and future air traffic trends inherent in flight plans. Subsequently, to model the influence of external factors and predict air traffic flow disturbed by thunderstorm weather, we propose a student network based on the “parallel-fusion” structure. Finally, employing a feature-based knowledge distillation approach to integrate prior knowledge from flight plans and extract meteorological features, our method can accurately capture complex and constrained spatiotemporal dependencies in air traffic and explicitly model the impact of weather on air traffic flow. Experimental results on real-world flight data demonstrate that our method can achieve better prediction performance than other state-of-the-art comparison methods, and the advantages of the proposed method are particularly prominent in modeling the complicated transfer pattern of air traffic and inferring nonrecurrent flow patterns.

Abstract Objective The optimal treatment for vitreoretinal lymphoma (VRL) remains a challenge, as central nervous system (CNS) relapse occurs frequently, leading to the worst impact on survival. We previously proposed combined intravitreal methotrexate and systemic high‐dose methotrexate therapy for this disease. This study aimed to report the long‐term outcomes of patients with VRL using this combination treatment. Methods We conducted a retrospective cohort study on patients with VRL at a tertiary referral center between 2003 and 2018. Results Thirty‐two patients were included, of whom 23 had primary VRL (PVRL) and nine had concurrent intraocular and CNS diseases. The treatment was well tolerated. Twenty‐six (81.3%) patients achieved complete response (CR). After a median follow‐up time of 103.5 months, the 5‐year survival rate was 73.3%, whereas the 5‐year progression‐free survival (PFS) rate was 29.9%. Twenty‐four (75%) patients relapsed, including 12 with isolated intraocular relapses at first relapse and a total of 17 with CNS/systemic relapses. The development of CNS/systemic relapse negatively affected survival, but intraocular relapse did not. The median CNS/systemic PFS was 69.5 months, but the risk of CNS/systemic relapse increased steadily with a cumulative incidence rate at 2, 5, and 10 years being 22.6%, 44.2%, and 65%, respectively. Multivariate analysis identified concurrent CNS disease at diagnosis as the only poor‐risk factor for CNS/systemic relapse. Conclusions This study confirms good efficacy and acceptable toxicities of the combination approach. However, incorporation of further intensive consolidation strategies into the treatment protocol to effectively prevent subsequent CNS/systemic relapse deserves to be considered.

Objective To investigate the relationship between metabolomic profiles, genome-wide polygenic risk scores (PRSs) and risk of rheumatoid arthritis (RA).Methods 143 nuclear magnetic resonance-based plasma metabolic biomarkers were measured among 93 800 participants in the UK Biobank. The Cox regression model was used to assess the associations between these metabolic biomarkers and RA risk, and genetic correlation and Mendelian randomisation analyses were performed to reveal their causal relationships. Subsequently, a metabolic risk score (MRS) comprised of the weighted sum of 17 clinically validated metabolic markers was constructed. A PRS was derived by assigning weights to genetic variants that exhibited significant associations with RA at a genome-wide level.Results A total of 620 incident RA cases were recorded during a median follow-up time of 8.2 years. We determined that 30 metabolic biomarkers were potentially associated with RA, while no further significant causal associations were found. Individuals in the top decile of MRS had an increased risk of RA (HR 3.52, 95% CI: 2.80 to 4.43) compared with those below the median of MRS. Further, significant gradient associations between MRS and RA risk were observed across genetic risk strata. Specifically, compared with the low genetic risk and favourable MRS group, the risk of incident RA in the high genetic risk and unfavourable MRS group has almost elevated by fivefold (HR 6.10, 95% CI: 4.06 to 9.14).Conclusion Our findings suggested the metabolic profiles comprising multiple metabolic biomarkers contribute to capturing an elevated risk of RA, and the integration of genome-wide PRSs further improved risk stratification.

Background: Myocardial infarction is associated with the autophagy and apoptosis of cardiomyocytes, and the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway plays a crucial role in this mechanism. Methods: Acute myocardial infarction rat models were assessed 0.5, 2, 4, and 6 hours after the induction of the myocardial infarction using hematoxylin and eosin staining, triphenyl tetrazolium chloride staining, myocardial enzyme measurements, and levels of autophagic activity. Additionally, diazoxide, 5-hydroxydecanoate, and LY294002 were intraperitoneally administered to rat models at peak myocardial injury to assess their effects on cardiac injury. The expression levels of autophagy-related and apoptosis-related proteins, as well as p-AKT and p-mTOR, were measured. Electron microscopy was used to assess the ultrastructure and the number of autophagosomes in the cardiac tissue. Results: We demonstrated that the degree of myocardial injury and the level of autophagy were significantly elevated in the experimental cohort compared with the control cohort. In addition, the myocardial infarct size was significantly smaller in diazoxide-treated acute myocardial infarction rats compared with untreated rats. Diazoxide also decreased the levels of myocardial injury markers, autophagy, and apoptosis, while it also induced the levels of AKT and mTOR phosphorylation, decreased the number of autophagosomes, and improved the myocardial ultrastructure of the acute myocardial infarction rats. 5-Hydroxydecanoate treatment resulted in an opposite effect to those observed upon diazoxide treatment. LY294002 was also able to reverse diazoxide treatment effects. Conclusion: Peak levels of myocardial tissue injury and autophagy were observed 2 hours post-acute myocardial infarction induction in rats. Diazoxide treatment inhibited myocardial autophagy and apoptosis while protecting cardiac tissue from ischemic injury, which is likely to have proceeded through activation of the AKT/mTOR pathway.

Background: Low-voltage zones (LVZ) are surrogate markers for cardiac fibrosis, which contribute to the maintenance of atrial fibrillation (AF). The aim of this study was to investigate the effect of the distribution of left atrial (LA) LVZ on the outcome following catheter ablation. Methods: This retrospective study enrolled patients with AF who underwent initial catheter ablation. LVZ were defined as areas with bipolar voltage amplitude 30 s after the initial catheter ablation. Results: Altogether, 148 patients were included, with a mean age of 61 ± 11 years, of which 53 (35.8%) had persistent AF. During a mean follow-up of 14 ± 3 months post-ablation, AA recurrence occurred in 25 (16.9%) patients after the initial catheter ablation. Kaplan–Meier analysis showed that patients without roof LVZ had a higher AA-free survival rate than those with roof LVZ (P = 0.047). In the multivariate Cox regression analysis, the proportion of LA LVZ ≥6% [hazard ratio (HR) 2.315, 95% confidence interval (CI) 1.048–5.114; P = 0.038] and a longer AF duration (HR 1.008, 95% CI 1.002–1.014; P = 0.006) were independent predictors of AA recurrence. Conclusions: In patients with AF, LA roof LVZ may increase the risk of AA recurrence after initial catheter ablation.

University campuses, as small and isolated areas of rapidly growing urban areas, can provide a unique opportunity for urban biodiversity research, conservation, education, and citizen science by monitoring assemblages of butterflies within their areas. We surveyed butterfly biodiversity in a rapidly developing urban area represented by the Chenggong Campus of Yunnan University in southwestern China using the Pollard walk method. In total, 3625 butterfly individuals belonging to 50 species, 35 genera, and six families were recorded in this survey. The results showed that the families Pieridae and Nymphalidae are the families with the highest species richness on the campus, and that the family Riodinidae contained the fewest species. Pieris rapae was the most common species, and seven species assessed by the IUCN Red List were recorded. Butterfly community structure varied across habitats and seasons on campus, and butterfly diversity was higher in spring and autumn than it was in summer and winter, as well as being higher in road habitats than in scenic habitats. Unavoidable urbanisation activities (construction, green space planning, etc.) may have influenced the composition and diversity of butterflies, and conserving urban butterfly diversity requires a balance between urban planning and habitat diversity. Finally, we encourage universities and research institutions to develop butterfly monitoring platforms for citizen scientists to participate in.

Abstract Background This study aimed to evaluate the presence of symptoms of Internet Gaming Disorder (IGD) and examined associations between IGD and depressive symptoms, family and peer support among male college students in Nanchong, China. Methods A cross-sectional study was conducted among 2533 male students in three colleges. Background characteristics, depressive symptoms, family and peer support and IGD information were collected. Binary logistic regression was performed to access the relationship between variables and IGD. PROCESS macro was used to examine the mediation analysis of family and peer support on the relationship between depressive symptoms and IGD. Results The estimated presence of symptoms of IGD was 11.6%. The most commonly endorsed items were escapism, continuation and preoccupation both among total participates and the IGD group. In the binary logistic regression, general expenditure per month, depressive symptoms, and family and peer support revealed their significance in associations with IGD. Adjusted for the significant background variable, depressive symptoms and family and peer support remained significance. Additionally, family and peer support would attenuate the relationship between depressive symptoms and IGD. Conclusions This study found that one in ten male college students reported clinically significant IGD symptoms, which indicate that IGD is an important public health problem in Nanchong, China.

The burden of colorectal cancer (CRC) varies substantially across different geographical locations. However, there was no further quantitative analysis of regional social development and the disease burden of CRC. In addition, the incidence of early- and late-onset CRC has increased rapidly in developed and developing regions. The main purpose of this study was to investigate the trends in CRC burden across different regions, in addition to the epidemiological differences between early and late-onset CRC and their risk factors. In this study, estimated annual percentage change (EAPC) was employed to quantify trends in age-standardized incidence rate (ASIR), mortality rate, and disability-adjusted life-years. Restricted cubic spline models were fitted to quantitatively analyze the relationship between trends in ASIR and Human Development Index (HDI). In addition, the epidemiological characteristics of early- and late-onset CRC were investigated using analyses stratified by age groups and regions. Specifically, meat consumption and antibiotic use were included to explore the differences in the risk factors for early- and late-onset CRC. The quantitative analysis showed that the ASIR of CRC was exponentially and positively correlated with the 2019 HDI in different regions. In addition, the growing trend of ASIR in recent years varied substantially across HDI regions. Specifically, the ASIR of CRC showed a significant increase in developing countries, while it remained stable or decreased in developed countries. Moreover, a linear correlation was found between the ASIR of CRC and meat consumption in different regions, especially in developing countries. Furthermore, a similar correlation was found between the ASIR and antibiotic use in all age groups, with different correlation coefficients for early-onset and late-onset CRC. It is worth mentioning that the early onset of CRC could be attributable to the unrestrained use of antibiotics among young people in developed countries. In summary, for better prevention and control of CRC, governments should pay attention to advocate self-testing and hospital visits among all age groups, especially among young people at high risk of CRC, and strictly control meat consumption and the usage of antibiotics.

Abstract Aberrant DNA modifications affect the tumorigenesis and progression of lung cancer. However, the global methylation status of tumor cells and the heterogeneous methylation status of cells within the same tumor need further study. We used publicly available single-cell RNAseq data to investigate the impact and diversity of global methylation status on lung adenocarcinoma. Clustering cells into subgroups and cell differentiation pseudotime analysis, based on expression profile, demonstrated that the global methylation status was crucial to lung adenocarcinoma function and progression. Hypermethylated tumor cells had increased activity related to the hypoxia response. Hyper- and hypomethylated cells indicated upregulation in pathways involving focal adhesion and cell junctions. Pseudotime analysis showed that cell clusters with unique methylation activities were located at the ends of the putative trajectories, suggesting that DNA methylation and demethylation activities were essential to tumor cell progression. Expression of SPP1 was associated with the global methylation status of tumor cells and with patient prognosis. Our study identified the importance and diversity of global DNA methylation status by analysis at the single-cell level. Our findings provide new information about the global DNA methylation status of tumor cells and suggest new approaches for precision medical treatments for lung adenocarcinoma.

Abstract In solid tumors, hypoxia facilitates malignant progression of cancer cells by triggering epithelial-mesenchymal transition (EMT) and cancer stemness. Fascin-1, an actin-bundling protein, takes part in the formation of many actin-based cellular structures. In the present study, we explored the potential functions of hypoxia-induced upregulation of Fascin-1 in liver cancer. Transcriptome RNA-sequencing was conducted to identify hypoxia-related genes. The potential functions of Fascin-1 were evaluated by western blot, transwell migration and invasion assays, sphere-formation assay, tumor xenograft growth, gelatin zymography analysis, immunofluorescence, cell viability assay, soft agar assay, and flow cytometry. We found that Fascin-1 was upregulated by hypoxia in liver cancer cell lines, elevated in liver cancer patients and correlated with larger tumor size, lymph node metastasis, distant metastasis, and shorter overall survival. Knockdown of Fascin-1 suppressed migration, invasion, EMT, stemness, and tumor xenograft growth of liver cancer cells under both normoxia and hypoxia conditions, while forced Fascin-1 expression showed opposite effects. Moreover, hypoxia-induced upregulation of Fascin-1 was regulated by the Akt/Rac1 signaling, and inhibition of Akt/Rac1 signaling by EHop-016 and MK-2206 restrained migration, invasion, EMT, and stemness of liver cancer cells under hypoxia. Furthermore, Fascin-1 knockdown suppressed MMP-2 and MMP-9 expression, impaired actin cytoskeleton rearrangement, inactivated Hippo/YAP signaling, and increased Sorafenib sensitivity in liver cancer cells. Our study provided a novel insight of Fascin-1 in regulating migration, invasion, EMT, and stemness of liver cancer cells under normoxia and hypoxia conditions.

IntroductionPsoriasis is a common skin disease that seriously affects patients' quality of life. The association of air pollutants with psoriasis, and the extent of their effects remains unclear.MethodsBased on a distributed lag non-linear model, this study explored the short-term effects of air pollutants on outpatients with psoriasis in Hefei, China, between 2015 and 2019 by analyzing the exposure–lag–response relationship, after controlling for confounding influences such as meteorological factors, long-term trends, day of the week, and holidays. Stratified analyses were performed for patients of different ages and genders.ResultsThe maximum relative risks of psoriasis outpatients' exposure to SO2, NO2, and O3 were 1.023 (95% confidence intervals (CI): 1.004–1.043), 1.170 (95% CI: 1.046–1.307), and 1.059 (95% CI: 1.030–1.090), respectively. An increase of 10 μg/m3 of NO2 was associated with a 2.1% (95% CI: 0.7–3.5%) increase in outpatients with psoriasis, and a decrease of 10 μg/m3 of O3 was associated with an 0.8% (95% CI: 0.4–1.2%) increase in outpatients with psoriasis. Stratified analyses showed that male subjects were more sensitive to a change in meteorological factors, while female subjects and outpatients with psoriasis aged 0–17 years old were more sensitive to a change in air pollutants.DiscussionShort-term air pollutant exposures were associated with outpatients having psoriasis, suggesting that patients and high-risk people with psoriasis should reduce their time spent outside and improve their skin protection gear when air quality is poor.

Abstract. Percutaneous endomyocardial biopsy (EMB) is a technique that biopsy samples are obtained using bioptome through peripheral blood vessel. This technique has been used and refined more than 50 years in clinical application. Now EMB has become an important diagnostic tool in the diagnosis of myocarditis and cardiomyopathy. Department of cardiology, Peking Union Medical College Hospital (PUMCH) has performed more than 500 cases of EMB and accumulated abundant practical experience. The clinical practice guideline of percutaneous EMB in PUMCH was also established, including indications, contradictions, operation key points, sample handling and processing, post-procedure monitoring, and treatment strategy for potential complications, etc. Due to the limitation of EMB, cardiologists should collaborate with experts in echocardiography, cardiac magnetic resonance and cardiac pathology to avoid missed diagnosis and misdiagnosis. Cardiologists should pay more attention to the value of EMB and actively perform EMB to improve the diagnosis level for myocarditis and cardiomyopathy in China.

Background: Breast reconstruction is an effective technique to rebuild the appearance of the breasts in patients after mastectomy and improves the prognosis. The current study aimed to compare and analyze willingness for breast reconstruction after breast cancer between populations in China and the United States, from the perspective of social concern, using big data analysis. We also aimed to explore factors affecting surgical selection and to identify methods that can improve social cognition and acceptance of breast reconstruction. Methods: Using Baidu and Google, two representative Internet search engines in China and the United States as research tools, and using big data search volume as the benchmark, we compared and analyzed breast reconstruction willingness and attention characteristics between Chinese and American people, based on search heat, geographical distribution, age and sex, keyword distribution, ethnic group, and social development degree. Results: In both the long-term and short-term, Chinese people paid more attention towards searching about breast cancer, but less attention to breast reconstruction after breast cancer surgery. However, in both the short-term and long-term, people from the United States paid more attention towards breast cancer and breast reconstruction with the help of the Internet, showing a synchronous change relationship. There was a large regional difference in the search volume for breast cancer among the Chinese population, while no significant regional differences were noted in the search volume for breast cancer in the United States. However, a large regional difference was observed in the search volume for breast reconstruction between the two countries; people in the coastal and economically developed areas paid more attention to it. Most people who paid attention to breast reconstruction in China were women aged 20–39 years, while the attention among men was low. Search keywords were also limited to breast cancer-related information. However, between Asians and European Americans, Americans paid more attention to breast cancer and were affected by regional development, religious beliefs, and health facilities. Conclusion: Attention towards breast reconstruction after breast cancer was lower in the Chinese population than in the American population, and this difference was closely related to the level of regional development. There is insufficient information on breast reconstruction after breast cancer in recent Internet media. In addition to strengthening communication in clinics, media education is important to improve the cognitive level and social awareness of patients and their families, which is conducive to breast reconstruction.

Abstract Hepatocellular carcinoma (HCC) is a common malignancy. CD8+ T cell-mediated immune response is critical for the inhibition of HCC progression. M2 macrophages participate in HCC progression. This study set out to investigate the effect of M2 macrophage-derived extracellular vesicles (EVs) on CD8+ T cell exhaustion in HCC. M2 macrophage-derived EVs were isolated and identified. The murine model of primary HCC was established through DEN/CCl4 induction, and model mice were injected with EVs. Peripheral blood mononuclear cells (PBMCs) were isolated from the mouse liver and CD8+ T cells were sorted. The expressions of immune checkpoint inhibitory receptors and effector cytokines on CD8+ T cells were detected, followed by the evaluation of CD8+ T cell proliferation and killing function. miR-21-5p expression in M2 macrophage-derived EVs was detected. The binding relationship between miR-21-5p and YOD1 was verified. The activation of the YAP/β-catenin pathway was detected. Consequently, M2 macrophage-derived EVs promoted CD8+ T cell exhaustion in HCC mice. miR-21-5p expression was upregulated in M2 macrophage-derived EVs, and EVs carried miR-21-5p into HCC tissues. miR-21-5p targeted YOD1. Inhibition of miR-21-5p or overexpression of YOD1 annulled the promoting effect of EVs on CD8+ T cell exhaustion. YOD1 inactivated the YAP/β-catenin pathway. In conclusion, M2 macrophage-derived EVs facilitated CD8+ T cell exhaustion via the miR-21-5p/YOD1/YAP/β-catenin axis. This study may confer novel insights into the immunotherapy of HCC.

Syncope may have many different causes, requiring careful identification. Recurrent syncope is uncommon as an initial symptom of neck lymphoma. Head and neck tumors involving the carotid artery cause syncope associate with carotid sinus syndrome. We report the case of a 72-year-old man who suffered from recurrent syncope due to compression of the right carotid sinus by diffuse large B-cell lymphoma and was successfully treated with immunochemotherapy. Syncope may be an early or sole sign of a neck or head tumor. We should be aware of the possibility of an underlying malignancy in patients with unexplained syncope after initial evaluation.

Right ventricular failure (RVF) is the independent and strongest predictor of mortality in pulmonary arterial hypertension (PAH), but, at present, there are no preventive and therapeutic strategies directly targeting the failing right ventricle (RV). The underlying mechanism of RV hypertrophy (RVH) and dysfunction needs to be explored in depth. In this study, we used myocardial proteomics combined with metabolomics to elucidate potential pathophysiological changes of RV remodeling in a monocrotaline (MCT)-induced PAH rat model. The proteins and metabolites extracted from the RV myocardium were identified using label-free liquid chromatography–tandem mass spectrometry (LC-MS/MS). The bioinformatic analysis indicated that elevated intracellular Ca2+ concentrations and inflammation may contribute to myocardial proliferation and contraction, which may be beneficial for maintaining the compensated state of the RV. In the RVF stage, ferroptosis, mitochondrial metabolic shift, and insulin resistance are significantly involved. Dysregulated iron homeostasis, glutathione metabolism, and lipid peroxidation related to ferroptosis may contribute to RV decompensation. In conclusion, we depicted a proteomic and metabolomic profile of the RV myocardium during the progression of MCT-induced PAH, and also provided the insights for potential therapeutic targets facilitating the retardation or reversal of RV dysfunction in PAH.

In cancer genomics research, gene expressions provide clues to gene regulations implicating patients’ risk of survival. Gene expressions, however, fluctuate due to noises arising internally and externally, making their use to infer gene associations, hence regulation mechanisms, problematic. Here, we develop a new regression approach to model gene association networks while considering uncertain biological noises. In a series of simulation experiments accounting for varying levels of biological noises, the new method was shown to be robust and perform better than conventional regression methods, as judged by a number of statistical measures on unbiasedness, consistency and accuracy. Application to infer gene associations in germinal-center B cells led to the discovery of a three-by-two regulatory motif gene expression and a three-gene prognostic signature for diffuse large B-cell lymphoma.

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Abstract Early acute kidney injury (AKI) contributes to severe morbidity and mortality in critically burned patients. Renal inflammation plays a vital role in the progression of early AKI, acting as a therapeutic target. Astaxanthin (ATX) is a strong antioxidant widely distributed in marine organisms that exerts many biological effects in trauma and disease. ATX is also suggested to have anti-inflammatory activity. Hence, we attempted to explore the role of ATX in protecting against early postburn AKI via its anti-inflammatory effects and the related mechanisms. A severely burned model was established for histological and biochemical assessments based on adult male rats. We found that oxidative stress-induced tissue inflammation participated in the development of early AKI after burn injury and that the MyD88-dependent TLR4/NF-κB pathway was activated to regulate renal inflammation. The TLR4 and NF-κB inhibitors TAK242 and PDTC showed similar effects in attenuating burn-induced renal inflammation and early AKI. Upon ATX treatment, the release of inflammatory mediators in the kidneys was downregulated, while the TLR4/MyD88/NF-κB axis was inhibited in a dose-related manner. TAK242 and PDTC could enhance the anti-inflammatory effect of high-dose ATX, whereas lipopolysaccharide (LPS) reversed its action. Furthermore, the expression of heme oxygenase (HO)-1 was upregulated by ATX in a dose-related manner. Collectively, the above data suggest that ATX protects against renal inflammation in a dose-related manner by regulating the TLR4/MyD88/NF-κB axis and HO-1 and ultimately prevents early AKI following severe burns.

Abstract Aims This study aims to investigate the current status of biventricular pacemaker and defibrillator implantation in chronic heart failure (CHF) patients with indications for primary prevention of sudden cardiac death (SCD) in China and the effects of cardiac resynchronization therapy (CRT)‐pacemaker (P) and CRT‐defibrillator (D) implantation on the clinical prognosis of CHF among patients undergoing CRT. Methods and results Overall, 798 consecutive patients who had devices implanted (implantable cardioverter defibrillator: 199, CRT‐D: 362, and CRT‐P: 237) from May 2012 to July 2013 in POSCD‐China, a multicentric prospective cohort study, were enrolled. The primary endpoint was all‐cause death, and the secondary endpoint was SCD. In total, 71.3% of patients had non‐ischaemic CHF. The mean follow‐up time was 27.7 ± 12.0 months, and death occurred in 158 cases, with 35 cases of SCD. CHF was the main cause of death (68.4%), followed by sudden death (22.2%). In the CRT‐P group, the SCD rate was 8.0%, which was much higher than that in the CRT‐D (3.3%) and implantable cardioverter defibrillator (2.0%) groups. No significant differences were identified in the all‐cause death rate between the CRT‐D and CRT‐P groups (CRT‐D vs. CRT‐P, 20.4% vs. 19.4%, P = 0.840). Conclusions In China, among CHF patients with indications for primary prevention of SCD who received device implantation, non‐ischaemic CHF was the main aetiology, and the most important cause of death was heart failure. No differences in all‐cause death were observed between the CRT‐D and CRT‐P groups, but the CRT‐D group had a lower SCD rate than the CRT‐P group.

Objectives To analyse the current curative expenditure (CCE) of NCDs in China from 2017 to 2019.Design A cross-sectional study. Medical institutions were collected by multistage stratified random sampling from 2017 to 2019.Setting Dalian, ChinaParticipants 408 institutions and 8 104 233 valid items were included in the study. NCDs patients were selected according to International Classification of Diseases-10.Primary and secondary outcome measures CCE for NCDs was measured based on the System of Health Accounts 2011. Influenced factors were analysed by linear regression. All analyses and calculations were performed by STATA V.15.0.Results The CCE of NCDs was ¥14.929 billion in 2017, ¥16.377 billion in 2018 and ¥18.055 billion in 2019, which accounted for more than 65% of total expenditure spent each year. More than 60% came from public financing. The proportion of family health financing continued to decline, reaching 31.16% in 2019. The expenditures were mainly in general hospitals, above 70%. Elderly patients account for the majority. Diseases of the circulatory system, diseases of the digestive system and neoplasms were the main NCDs. Year, age, gender, length of stay, surgery, insurance and institution level affected hospitalisation expenses.Conclusions NCDs are the main CCE of diseases in China, and their resources are not allocated reasonably. To reduce the CCE of NCDs, the government needs to optimise resource allocation and rationalise institutional flows and functions.

Objectives To study the medical expenditure and influencing factors of patients with hypertension in Shanxi Province, China.Design A cross-sectional study.Setting 1088 medical institutions, including general hospitals, traditional Chinese medicine hospitals, special hospitals, basic medical institutions and public health institutions.Participants 180 441 hypertensive outpatients and 14 763 inpatients from 1 January to 31 December 2017.Primary and secondary outcome measures Curative care expenditure for hypertension (CCEht) was measured based on System of Health Accounts 2011. Influenced factors were analysed by univariate analysis and multiple layer perceptron neural network.Results In 2017, CCEht was US$307.71 million, accounting for 3.63% of total CCE and 0.14% of gross domestic product (GDP) in Shanxi Province of China. CCE of hypertensive outpatients (CCEht-out) and inpatients (CCEht-in) accounted for 44.49% and 55.51% of CCEht. Drug fee accounted for 81.55% of CCEht-out and 22.50% of CCEht-in, respectively. The top three influencing factors were drug fee, surgical fee and hospitalisation days for inpatients, and drug fee, examination fee and test fee for outpatients.Conclusions The medical expenditure of hypertension is still heavy for individuals and society. The diagnosis and treatment capacities of primary healthcare system has been enhanced. New rural cooperation medical insurance and urban employee basic medical insurance have a trend of overusing, and the burden of family healthcare expenditure is still heavy. To ease the economic burden of patients with hypertension and improve the efficiency of social resources utilisation, policymakers should pay more attention to key groups, further increase support for primary healthcare system, standardise the treatment and reimbursement of hypertension and incline the reimbursement policy to outpatient service.

Abstract is missing (Short communication)

[This corrects the article DOI: 10.1371/journal.pone.0053831.].

Pulmonary arterial hypertension (PAH) is a rare but fatal cardiovascular disorder with high morbidity and mortality. Diagnosis and treatment of this disease at an early stage would greatly improve outcomes. The molecular indicators of PAH are mostly nonspecific, and diagnostic and prognostic biomarkers are urgently needed. A more comprehensive understanding of the molecular mechanisms underlying this complex disease is crucial for the development of new and more effective therapeutics to improve patient outcomes. In this article, we review published literature on proteomic biomarkers and underlying molecular mechanisms in PAH and their value for disease management, aiming to deepen our understanding of the disease and, ultimately, pave the way for clinical application.

The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor was shown to initiate coronavirus entry into host cells and lead to their infection. The receptor-binding motif (RBM, 438–506) is a region that directly interacts with ACE2 receptor in the RBD and plays a crucial role in determining affinity. To unravel how mutations in the non-RBM regions impact the interaction between RBD and ACE2, we selected three non-RBM mutant systems (N354D, D364Y, and V367F) from the documented clinical cases, and the Q498A mutant system located in the RBM region served as the control. Molecular dynamics simulation was conducted on the mutant systems and the wild-type (WT) system, and verified experiments also performed. Non-RBM mutations have been shown not only to change conformation of the RBM region but also to significantly influence its hydrogen bonding and hydrophobic interactions. In particular, the D364Y and V367F systems showed a higher affinity for ACE2 owing to their electrostatic interactions and polar solvation energy changes. In addition, although the binding free energy at this point increased after the mutation of N354D, the conformation of the random coil (Pro384-Asp389) was looser than that of other systems, and the combined effect weakened the binding free energy between RBD and ACE2. Interestingly, we also found a random coil (Ala475-Gly485). This random coil is very sensitive to mutations, and both types of mutations increase the binding free energy of residues in this region. We found that the binding loop (Tyr495-Tyr505) in the RBD domain strongly binds to Lys353, an important residue of the ACE2 domain previously identified. The binding free energy of the non-RBM mutant group at the binding loop had positive and negative changes, and these changes were more obvious than that of the Q498A system. The results of this study elucidate the effect of non-RBM mutation on ACE2-RBD binding, and provide new insights for SARS-CoV-2 mutation research.

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents. [ABSTRACT FROM AUTHOR]

Abstract Background Bletilla striata is a traditional Chinese medicine used to treat hemorrhage, scald, gastric ulcer, pulmonary diseases and inflammations. In this study, we investigated bioactivity of the effective fraction of B. striata (EFB) in reducing the inflammatory cytokine production induced by water or organic extracts of PM2.5. Methods PM2.5 extracts were collected and analyzed by chromatographic system and inductively coupled plasma mass spectrometer. Cell viability was measured using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, and cell supernatant was analyzed by flow cytometry, ELISA, and qRT-PCR in cultured mouse macrophage cell line RAW264.7 treated with EFB and PM2.5 extracts. Expressions of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway were measured by Western blot. Results PM2.5 composition is complex and the toxicity of PM2.5 extracts were not noticeable. The treatment of EFB at a wide dose-range of 0–40 μg/mL did not cause significant change of RAW264.7 cell proliferation. EFB pretreatment decreased the inflammatory cytokines in the macrophage. Further analysis showed that EFB significantly attenuated PM2.5-induced proinflammatory protein expression and downregulated the levels of phosphorylated NF-κBp65, inhibitor of kappa B (IκB)-α, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38. Conclusions Our study demonstrated the potential effectiveness of B. striata extracts for treating PM2.5-triggered pulmonary inflammation.

Abstract Background Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized progressive cardiomyopathy with heterogenous clinical manifestations that lead to its misdiagnosis and poor prognosis. This study was performed to describe the clinical characteristics and natural history of Chinese patients to improve clinical awareness of this condition. Methods In this study, we retrospectively investigated 23 patients with a confirmed diagnosis of hereditary ATTR-CM in Peking Union Medical College hospital from From January 1, 2000 to December 31, 2018. Results In all, 16 patients (69.6%) were males, the median age at disease onset was 45 (33,55) years old. The median duration from symptom onset to diagnosis was 30 (18,46) months. Phenotypes were classified as exclusively cardiac (n = 1, 4.3%) and mixed type (n = 22, 95.6%). The common mutations were Gly47Arg (7 patients [30.4%]) and Val30Ala (3 patients [13%]). Ventricular hypertrophy was observed in 23 (100%) patients, the mean thickness of the ventricular septum was 16.1 ± 3.9 mm, the mean thickness of the left ventricular posterior wall was 15.1 ± 2.8 mm. The mean left ventricle ejection fraction (LVEF) was 57.3 ± 11.9% and only 5 patients (21.7%) had LVEF 50% have better survival. Clinicians should be more aware of the complex clinical profile of ATTR amyloidosis to avoid misdiagnosis in practice.

IntroductionHepatic sarcomatoid carcinoma (HSC) is a rare type of liver cancer with a high malignant grade and poor prognosis. This study compared the clinical characteristics and magnetic resonance imaging (MRI) features of HSCs with those of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), aiming to identify valuable features for HSC diagnosis.MethodsIn total, 17 pathologically confirmed HSC cases, 50 HCC cases and 50 common ICC cases were enrolled from two hospitals. The clinical characteristics and MRI features of all cases were summarized and statistically analyzed.ResultsOn the one hand, the incidence rates of elevated carbohydrate antigen (CA) 19-9 and elevated carcinoembryonic antigen (CEA) were significantly higher in the HSC cases than in the HCC cases (29.4% vs. 0%; 17.6% vs. 0%). The HSC enhancement patterns, primarily including progressive enhancement, were also significantly different from HCC cases. The incidence rates of heterogeneous signals on T2-weighted imaging and during the arterial phase were significantly higher in the HSC cases than in the HCC cases (94.1% vs. 66.0%; 100.0% vs. 72.0%). The diameter of HSCs was significantly larger than that in the HCC cases (6.12 cm vs. 4.21 cm), and the incidence rates of adjacent cholangiectasis, intrahepatic metastasis and lymph node enlargement were considerably higher in the HSC cases than in the HCC cases (52.9% vs. 6.0%; 47.1% vs. 12.0%; 41.2% vs. 2.0%). On the other hand, the incidence rate of elevated CA199 was significantly lower in the HSC cases than in the ICC cases (29.4% vs. 60.0%). The incidence rates of intratumoral necrosis and pseudocapsules were significantly higher in the HSC cases than in the HCC cases (35.3% vs. 8.0%; 47.1% vs. 12.0%). However, the incidence rates of target signs were significantly lower in the HSC cases than in the HCC cases (11.8% vs. 42.0%). In addition, there was no significant difference in the enhancement patterns between HSC cases and ICC cases.ConclusionsHSCs were frequently seen in elderly men with clinical symptoms and elevated CA199 levels. The MRI features, including large size, obvious heterogeneity, hemorrhage, progressive enhancement, pseudocapsule and lymph node enlargement, contributed to the diagnosis of HSC.

Human carboxylesterase 2 (CES2), one of the most abundant hydrolases distributed in the small intestine, has been validated as a key therapeutic target to ameliorate the intestinal toxicity caused by irinotecan. This study aims to discover efficacious CES2 inhibitors from natural products and to characterize the inhibition potentials and inhibitory mechanisms of the newly identified CES2 inhibitors. Following high-throughput screening and evaluation of the inhibition potency of more than 100 natural products against CES2, it was found that the biflavones isolated from Ginkgo biloba displayed extremely potent CES2 inhibition activities and high specificity over CES1 (>1000-fold). Further investigation showed that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed hydrolysis of various substrates, including the CES2 substrate-drug irinotecan. Notably, the inhibition potentials of four biflavones against CES2 were more potent than that of loperamide, a marketed anti-diarrhea agent used for alleviating irinotecan-induced intestinal toxicity. Inhibition kinetic analyses demonstrated that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed fluorescein diacetate hydrolysis via a reversible and mixed inhibition manner, with Ki values of less than 100 nM. Ensemble docking and molecular dynamics revealed that these biflavones could tightly and stably bind on the catalytic cavity of CES2 via hydrogen bonding and π-π stacking interactions, while the interactions with CES1 were awfully poor. Collectively, this study reports that the biflavones isolated from Ginkgo biloba are potent and highly specific CES2 inhibitors, which offers several promising lead compounds for developing novel anti-diarrhea agent to alleviate irinotecan-induced diarrhea.

Aims: Systemic light-chain (AL) amyloidosis is a multisystemic disorder leading to multiple organ dysfunction and mortality that is often caused by cardiac involvement. Soluble suppression of tumorigenicity 2 (sST2) is a novel biomarker identified for risk stratification of heart disease. The aim of this study was to investigate the value of circulating sST2 levels in prognosis and mortality risk assessments for the AL amyloidosis population.Methods and Results: A total of 56 patients diagnosed with AL amyloidosis were enrolled in Peking Union Medical College Hospital (PUMCH) from January 2015 to May 2018. The relationships between the clinical parameters and overall survival (OS) and risk factors for disease progression were assessed. Additionally, receiver operating characteristic (ROC) curves, Kaplan–Meier analysis, and Cox hazard models were performed to explore the predictive value of sST2 in mortality rates. We found that the median OS of all patients was 7.3 [interquartile range (IQR) 4.4, 15.9] months. The median baseline sST2 level was 12.2 (IQR 5.1, 31.1) ng/ml, and the sST2 high group had more severe patients with a higher Mayo stage. In the ROC analysis, the area under the curve (AUC) was 0.728 [95% confidence interval (CI) 0.603–0.853] for sST2 to predict the outcomes of AL amyloidosis patients, and the optimal cutoff value was 12.34 ng/ml (sensitivity 80.2%, specificity 61.1%). Moreover, in multivariate Cox proportional hazards regression analysis, sST2 acted as an independent predictor of poor functional outcome in patients with AL amyloidosis.Conclusion: In AL amyloidosis patients, sST2 was a strong and independent prognostic biomarker for all-cause mortality, providing complementary prognostic information of a novel scoring system for risk stratification.

Ceramide sphingolipids are major components of membranes. C2 and C6 ceramides induce programmed cell death (PCD) in animals and plants, and we previously showed that C2 and C6 ceramides induce PCD in rice (Oryza sativa) protoplasts. However, the mechanistic link between sphingolipids and PCD in rice remains unclear. Here, we observed that calcium levels increased rapidly after ceramide treatment. Moreover, the calcium channel inhibitor LaCl3 and the intracellular calcium chelator acetoxymethyl-1, 2-bis (2-aminophenoxy) ethic acid (BAPTA-AM) inhibited this calcium increase and prevented ceramide-induced PCD. Moreover, caspase-3-like protease activity increased significantly in C6 ceramide-treated protoplasts, and a caspase-specific inhibitor prevented C6 ceramide-induced cell death. We also detected the other typical PCD events including ATP loss. DIDS (4, 49-diisothiocyanatostilbene- 2, 29-disulfonic acid), an inhibitor of voltage-dependent anion channels (VDACs), decreased C6 ceramide-induced cell death. Together, this evidence suggests that mitochondria played an important role in C6 ceramide-induced PCD.

Background. Acute kidney injury (AKI) has long been recognized as a common and important complication of acute pancreatitis (AP). In the study, machine learning (ML) techniques were used to establish predictive models for AKI in AP patients during hospitalization. This is a retrospective review of prospectively collected data of AP patients admitted within one week after the onset of abdominal pain to our department from January 2014 to January 2019. Eighty patients developed AKI after admission (AKI group) and 254 patients did not (non-AKI group) in the hospital. With the provision of additional information such as demographic characteristics or laboratory data, support vector machine (SVM), random forest (RF), classification and regression tree (CART), and extreme gradient boosting (XGBoost) were used to build models of AKI prediction and compared to the predictive performance of the classic model using logistic regression (LR). XGBoost performed best in predicting AKI with an AUC of 91.93% among the machine learning models. The AUC of logistic regression analysis was 87.28%. Present findings suggest that compared to the classical logistic regression model, machine learning models using features that can be easily obtained at admission had a better performance in predicting AKI in the AP patients.

Abstract Background Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain. Methods The anti-allodynic activities of preemptive intrathecal administration of endomorphin-1 and endomorphin-2 were investigated in complete Freund’s adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining. Results Preemptive intrathecal injection of endomorphins dose-dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation. Conclusions Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation.

Background/Aims: Activated hepatic stellate cells (HSCs) are the major source of extracellular matrix (ECM). Therefore inhibiting HSC activation is considered as an effective strategy to inhibit the process of liver fibrosis. This study aimed to investigate the underlying mechanism of methyl helicterate (MH) isolated from Helicteres angustifolia on the activation of HSCs. Methods: HSC-T6 cells were treated with various concentration of MH and autophagy was inhibited by 3-Methyl adenine (3-MA) or RNA interference. Cell viability was observed by MTT assay and cell colony assay. Cell cycle and apoptosis were analyzed using flow cytometry. Autophagic vacuoles were observed by transmission electron microscopy and monodansyl cadaverine (MDC) staining. Moreover, autophagy-related genes and proteins were detected using real-time PCR and Western blot assays, respectively. Results: MH significantly inhibited HSC activation, as evidenced by the inhibition of cell viability, colony formation and the expression of α-SMA and collagen I. MH caused cell cycle arrest in G2/M phase. Moreover, MH significantly induced apoptosis through regulating the mitochondria-dependent pathway and the activity of caspases. MH treatment significantly increased lysosomes and autophagosomes, and enhanced the formation of autophagic vacuoles and autophagic flux. Interestingly, inhibiting autophagy by 3-MA or RNA interference abolished the ability of MH in inhibiting HSC activation. On the other hand, induction of autophagy promoted MH-induced HSC apoptosis. Further study showed that MH-induced HSC apoptosis and autophagy was mediated by the JNK and PI3K/Akt/mTOR pathways. Conclusion: Our results demonstrate that MH-induced HSC apoptosis and autophagy may be one of the important mechanisms for its anti-fibrosis effect.