Design optimization of groundwater circulation well based on numerical simulation and machine learning.

The optimal design of groundwater circulation wells (GCWs) is challenging. The key to purifying groundwater using this technique is its proficiency and productivity. However, traditional numerical simulation methods are limited by long modeling times, random optimization schemes, and optimization results that are not comprehensive. To address these issues, this study introduced an innovative approach for the optimal design of a GCW using machine learning methods. The FloPy package was used to create and implement the MODFLOW and MODPATH models. Subsequently, the formulated models were employed to calculate the characteristic indicators of the effectiveness of the GCW operation, including the radius of influence (R) and the ratio of particle recovery (Pr). A detailed collection of 3000 datasets, including measures of operational efficiency and key elements in machine learning, was meticulously compiled into documents through model execution. The optimization models were trained and evaluated using multiple linear regression (MLR), artificial neural networks (ANN), and support vector machines (SVM). The models produced by the three approaches exhibited notable correlations between anticipated outcomes and datasets. For the optimal design of circulating well parameters, machine learning methods not only improve the optimization speed, but also expand the scope of parameter optimization. Consequently, these models were applied to optimize the configuration of the GCW at a site in Xi'an. The optimal scheme for R (Q = 293.17 m3/d, a = 6.09 m, L = 7.28 m) and optimal scheme for Pr (Q = 300 m3/d, a = 3.64 m, L = 1 m) were obtained. The combination of numerical simulations and machine learning is an effective tool for optimizing and predicting the GCW remediation effect.

Precursor exhausted CD8+T cells in colorectal cancer tissues associated with patient's survival and immunotherapy responsiveness.

Exhausted CD8+T cells represent a distinct cellular lineage that emerges during both chronic infections and cancers. Recent studies have shown that persistent antigen exposure can drive the differentiation of precursor exhausted CD8+T cells, termed Tpex cells, which are characterized as TCF-1+PD-1+CD8+T cells. Elevated Tpex cell frequencies in the tumor microenvironment (TME) are associated with improved overall survival (OS) in cancer patients and heightened responsiveness to anti-PD-1 therapy. In our present study, we utilized multi-color immunohistochemistry (mIHC) to determine the localization and clinical implications of tumor-infiltrating Tpex cells within the TME of human colorectal cancer (CRC) tissues. We also conducted a multi-omics integrative analysis using single-cell RNA sequencing (scRNA-seq) data derived from both the murine MC38 tumor model and human CRC tissues. This analysis helped delineate the transcriptional and functional attributes of Tpex cells within the CRC TME. Furthermore, we employed spatial transcriptome sequencing data from CRC patients to investigate the interactions between Tpex cells and other immune cell subsets within the TME. In conclusion, our study not only established a method for Tpex cell detection using mIHC technology but also confirmed that assessing Tpex cells within the CRC TME could be indicative of patients' survival. We further uncovered the transcriptional and functional characteristics of Tpex cells in the TME and ascertained their pivotal role in the efficacy of immunotherapy against CRC.

Epigallocatechin-3-gallate protects sepsis-induced myocardial dysfunction by inhibiting the nuclear factor-κB signaling pathway.

Sepsis-induced myocardial dysfunction (SIMD) has become one of the most lethal complications of sepsis, while the treatment was limited by a shortage of pertinent drugs. Epigallocatechin-3-gallate (EGCG) is the highest content of active substances in green tea, and its application in cardiovascular diseases has broad prospects. This study was conducted to test the hypothesis that EGCG was able to inhibit lipopolysaccharide (LPS) induced myocardial dysfunction and investigate the underlying molecular mechanisms. The cardiac systolic function was assessed by echocardiography. The cardiomyocyte apoptosis was determined by TUNEL staining. The expression of inflammatory factors and apoptosis-related protein, cardiac markers were examined by Western Blot and qRT-PCR. EGCG effectively improve LPS-induced cardiac function damage, enhance left ventricular systolic function, and restore myocardial cell vitality. It can effectively inhibit the upregulation of TLR4 expression induced by LPS and inhibit IκB α/NF- κB/p65 signaling pathway, thereby inhibiting cardiomyocyte apoptosis and improving myocarditis. In conclusion, EGCG protects against SIMD through anti-inflammatory and anti-apoptosis effects; it was mediated by the inhibition of the TLR4/NF-κB signal pathway. Our results demonstrated that EGCG might be a possible medicine for SIMD prevention and treatment.

Fine particulate matter contributes to COPD-like pathophysiology: experimental evidence from rats exposed to diesel exhaust particles.

BACKGROUND: Ambient fine particulate matter (PM2.5) is considered a plausible contributor to the onset of chronic obstructive pulmonary disease (COPD). Mechanistic studies are needed to augment the causality of epidemiologic findings. In this study, we aimed to test the hypothesis that repeated exposure to diesel exhaust particles (DEP), a model PM2.5, causes COPD-like pathophysiologic alterations, consequently leading to the development of specific disease phenotypes. Sprague Dawley rats, representing healthy lungs, were randomly assigned to inhale filtered clean air or DEP at a steady-state concentration of 1.03 mg/m3 (mass concentration), 4 h per day, consecutively for 2, 4, and 8 weeks, respectively. Pulmonary inflammation, morphologies and function were examined. RESULTS: Black carbon (a component of DEP) loading in bronchoalveolar lavage macrophages demonstrated a dose-dependent increase in rats following DEP exposures of different durations, indicating that DEP deposited and accumulated in the peripheral lung. Total wall areas (WAt) of small airways, but not of large airways, were significantly increased following DEP exposures, compared to those following filtered air exposures. Consistently, the expression of α-smooth muscle actin (α-SMA) in peripheral lung was elevated following DEP exposures. Fibrosis areas surrounding the small airways and content of hydroxyproline in lung tissue increased significantly following 4-week and 8-week DEP exposure as compared to the filtered air controls. In addition, goblet cell hyperplasia and mucus hypersecretions were evident in small airways following 4-week and 8-week DEP exposures. Lung resistance and total lung capacity were significantly increased following DEP exposures. Serum levels of two oxidative stress biomarkers (MDA and 8-OHdG) were significantly increased. A dramatical recruitment of eosinophils (14.0-fold increase over the control) and macrophages (3.2-fold increase) to the submucosa area of small airways was observed following DEP exposures. CONCLUSIONS: DEP exposures over the courses of 2 to 8 weeks induced COPD-like pathophysiology in rats, with characteristic small airway remodeling, mucus hypersecretion, and eosinophilic inflammation. The results provide insights on the pathophysiologic mechanisms by which PM2.5 exposures cause COPD especially the eosinophilic phenotype.

Causal relationship between aspirin consumption and heart failure: a Mendelian randomization study.

AIMS: This study aimed to investigate the causal association of aspirin consumption with the risk of heart failure. METHODS: Our study included a total of 218 208 individuals, with 23 397 cases of heart failure. Genetic summary data on the association between single-nucleotide polymorphisms (SNPs) and aspirin consumption were obtained from a large-scale genome-wide association study involving 462 933 individuals, of which 61 702 people were taking aspirin. After the exclusion of critical confounding factors, we assessed the final and independent association between the aspirin consumption and the risk of heart failure using 3 two-sample Mendelian randomization (MR) methods-inverse variance weighted (IVW), weighted-median, and MR-Egger regression. Sensitivity analyses and directionality test were employed to further validate the stability of the results. RESULTS: After excluding the SNPs that exhibited associations with potential confounders and harmonizing the data, a total of 32 SNPs were finally selected for MR analysis from the initially identified 60 SNPs that displayed strong associations with the exposure. The results of the main method (IVW) showed a significant positive association between aspirin use and the occurrence of heart failure (OR [odds ratio]: 1.085; 95% CI [confidence interval]: 1.015-1.161; P = 0.017), although other methods did not showed statistically significant results (MR-Egger, OR: 1.211, 95% CI: 0.842-1.21, P = 0.896; weighted-median, OR: 1.087, 95% CI: 0.983-1.202, P = 0.105). Heterogeneity test, the MR-Egger intercept, and the funnel plot did not reveal any evidence of heterogeneity (Cochran's Q statistic = 29.263; P = 0.556) or horizontal pleiotropy (intercept = 0.007; P = 0.319). The 'leave-one-out' analysis indicated that no individual SNP exerted a dominant influence on the main estimate. Directionality test confirmed the accuracy of the causal relationship between exposure and outcome direction in our data. CONCLUSIONS: Our results support a potential positive causal relationship between aspirin consumption and the occurrence of heart failure.

Relationship Among Fungal Diversity at Different Levels of Root System of Stellaria dichotoma var. lanceolata， Soil Properties， and Main Components of Medicinal Materials in Lithosol Habitats / 中国实验方剂学杂志

ObjectiveTo explore the interaction among root fungi of Stellaria dichotoma var. lanceolata， soil factors， and main components of medicinal materials in lithosol habitats. MethodHigh-throughput sequencing technology was employed to determine the fungal community of the root system of S. dichotoma var. lanceolata at different levels （bulk soil， rhizosphere soil， rhizoplane soil， and root interior） and the soil properties of the root system （bulk and rhizosphere）， and the relationship among the fungal community， soil properties， and the main components of medicinal materials was analyzed. ResultThe total phosphorus， available phosphorus， alkaline nitrogen， dissolved organic carbon， and soil water content in the rhizosphere soil of S. dichotoma var. lanceolata were slightly higher than those in the rhizosphere， but the difference was not significant. Ascomycota is the dominant phylum of root fungi in S. dichotoma var. lanceolata. In the progressive level of bulk-rhizosphere-rhizoplane-root interior system， although the fungal diversity gradually decreased， the abundance of Hypocreales， a new phylum （unclassified_ k_ Fungi）， Helotiales， and Natipusilales gradually increased， among which Hypocreales is the most important fungal group in the root system of S. dichotoma var. lanceolata. The structural equation model （SEM） shows that the physicochemical factors of the root-soil play an important regulatory role in the fungal community and the main components of medicinal herbs， with soil total nitrogen， alkaline nitrogen， soil water content， and pH being the main regulatory factors. Soil nitrogen content is the key to promoting the main components of the medicinal herbs， and Penicillium fungi are the key fungal group to regulate the main components of the medicinal herbs. ConclusionIt highlights that the physicochemical properties of the soil of S. dichotoma var. lanceolata play a crucial role in the fungal community and the components of medicinal materials. Hypocreales fungi in the root of S. dichotoma var. lanceolata were an important group， and Penicillium fungi had a certain role in mediating the components of medicinal materials.

Clinicopathological features of intravascular large B-cell lymphoma and collision tumors of five cases / 中华病理学杂志

Objective: To investigate the clinicopathological characteristics, diagnosis and differential diagnosis of intravascular large B-cell lymphoma (IVLBCL) and its collision tumors. Methods: Five cases of IVLBCL were collected, including 2 cases of collision tumors, and 1 case complicated with liver cirrhosis. The morphology and immunophenotype were analyzed. The related literature was reviewed. Results: There were 2 females and 3 males, aged from 53 to 73 years, with a median age of 65 years. The tumors were located in the lower extremities, right cerebellar hemisphere, left kidney, bilateral nasal cavity, and liver, respectively. Cases 2 and 3 were incidentally found in meningioma and renal cell carcinoma tissues, respectively. Case 5 had a background of liver cirrhosis. Morphologically, atypical large lymphoid cells were located in small blood vessels and capillary lumen, with little cytoplasm, hyperchromasia, prominent nucleoli, and obvious mitotic figures. Immunohistochemically, the IVLBCL tumor cells expressed CD20 and PAX5; 2 cases were CD5 positive. One of the 5 cases was GCB phenotype, and 4 cases were non-GCB phenotype. All cases expressed C-MYC (positive rate was 10%-40%). PD-L1 was positive in 4 cases (positive rate was 60%-90%). Ki-67 proliferation index was 70%-90%. CKpan, CD3, TDT, and CD34 were negative. In case 2, meningioma cells were positive for PR, EMA, and vimentin, but negative for CKpan and PD-L1. In case 3, renal carcinoma cells were positive for CKpan, PAX8, EMA, vimentin, CAⅨ and CD10, while PD-L1 was negative. No EBER expression (by in situ hybridization) or C-MYC gene translocation (FISH, break-apart probe) was detected in any of the 5 cases. Three patients were followed up, and all died within 1-13 months. Conclusions: IVLBCL is a highly aggressive lymphoma, with occult clinical manifestations and poor prognosis. Collision tumors of IVLBCL are extremely rare. A better understanding of IVLBCL would help pathologists avoid misdiagnoses.

Clinical characteristics and prognosis of children with perianal fistulizing Crohn's disease / 中国当代儿科杂志

OBJECTIVES@#To investigate the clinical characteristics, treatment, and prognosis of children with perianal fistulizing Crohn's disease (pfCD).@*METHODS@#A retrospective analysis was conducted on the children, aged 6-17 years, who were diagnosed with Crohn's disease (CD) from April 2015 to April 2023. According to the presence or absence of perianal fistulizing lesions, they were divided into two groups: pfCD (n=60) and non-pfCD (n=82). The two groups were compared in terms of clinical characteristics, treatment, and prognosis.@*RESULTS@#The incidence of pfCD was 42.3% (60/142). The proportion of males in the pfCD group was higher than that in the non-pfCD group. Compared with the non-pfCD group, the pfCD group had a significantly higher proportion of children with involvement of the colon and small intestine or those with upper gastrointestinal lesions (P<0.05). Compared with the non-pfCD group, the pfCD group had a significantly higher rate of use of infliximab during both induction and maintenance treatment (P<0.05). In the pfCD group, the children with complex anal fistula accounted for 62% (37/60), among whom the children receiving non-cutting suspended line drainage accounted for 62% (23/37), which was significantly higher than the proportion among the children with simple anal fistula patients (4%, 1/23) (P<0.05). There were no significant differences between the two groups in mucosal healing rate and clinical remission rate at week 54 of treatment (P>0.05). The pfCD group achieved a fistula healing rate of 57% (34/60) at week 54, and the children with simple anal fistula had a significantly higher rate than those with complex anal fistula (P<0.05).@*CONCLUSIONS@#There is a high incidence rate of pfCD in children with CD, and among the children with pfCD, there is a high proportion of children with the use of biological agents. There is a high proportion of children receiving non-cutting suspended line drainage among the children with complex anal fistula. The occurrence of pfCD should be closely monitored during the follow-up in children with CD.

Preliminary application of foldable pedicled latissimus dorsi myocutaneous flap for repairing soft tissue defects in shoulder and back / 中国修复重建外科杂志

OBJECTIVE@#To explore the feasibility and effectiveness of a foldable pedicled latissimus dorsi myocutaneous flap to repair soft tissue defects in the shoulder and back.@*METHODS@#Between August 2018 and January 2023, the foldable pedicled latissimus dorsi myocutaneous flaps were used to repair soft tissue defects in the shoulder and back of 8 patients. There were 5 males and 3 females with the age ranged from 21 to 56 years (mean, 35.4 years). Wounds were located in the shoulder in 2 cases and in the shoulder and back in 6 cases. The causes of injury were chronic infection of skin and bone exposure in 2 cases, secondary wound after extensive resection of skin and soft tissue tumor in 4 cases, and wound formation caused by traffic accident in 2 cases. Skin defect areas ranged from 14 cm×13 cm to 20 cm×16 cm. The disease duration ranged from 12 days to 1 year (median, 6.6 months). A pedicled latissimus dorsi myocutaneous flap was designed and harvested. The flap was divided into A/B flap and then were folded to repair the wound, with the donor area of the flap being pulled and sutured in one stage.@*RESULTS@#All 7 flaps survived, with primary wound healing. One patient suffered from distal flap necrosis and delayed healing was achieved after dressing change. The incisions of all donor sites healed by first intention. All patients were followed up 6 months to 4 years (mean, 24.7 months). The skin flap has a good appearance with no swelling in the pedicle. At last follow-up, 6 patients had no significant difference in bilateral shoulder joint motion, and 2 patients had a slight decrease in abduction range of motion compared with the healthy side. The patients' daily life were not affected, and linear scar was left in the donor site.@*CONCLUSION@#The foldable pedicled latissimus dorsi myocutaneous flap is an ideal method to repair the soft tissue defect of shoulder and back with simple operation, less damage to the donor site, and quick recovery after operation.

Maimendong decoction regulates M2 macrophage polarization to suppress pulmonary fibrosis via PI3K/Akt/FOXO3a signalling pathway-mediated fibroblast activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Mai Men Dong decoction (MMDD), a traditional Chinese medicine formula, is relevant to ethnopharmacology due to its constituents and therapeutic properties. The formula contains herbs like Ophiopogon japonicus (Thunb.) Ker Gawl., Pinellia ternata (Thunb.) Makino, Panax ginseng C.A.Mey, Glycyrrhiza uralensis Fisch, and Ziziphus jujuba Mill, Oryza sativa L., which have been used for centuries in Chinese medicine. These herbs provide a comprehensive approach to treating respiratory conditions by addressing dryness, cough, and phlegm. Ethnopharmacological studies have explored the scientific basis of these herbs and identified active compounds that contribute to their medicinal effects. The traditional usage of MMDD by different ethnic groups reflects their knowledge and experiences. Examining this formula contributes to the understanding and development of ethnopharmacology. AIM OF THE STUDY: In the case of pulmonary fibrosis (PF), treating it can be challenging due to the limited treatment options available. This study aimed to assess the potential of MMDD as a treatment for PF by targeting macrophages and the PI3K/Akt/FOXO3a signaling pathway. MATERIALS AND METHODS: In a mouse model of PF, we investigated the effects of MMDD on inflammation, fibrosis, and M2 macrophage infiltration in lung tissue. Additionally, we examined the modulation of pro-fibrotic factors and key proteins in the PI3K/Akt/FOXO3a pathway. In vitro experiments involved inducing M2-type macrophages and assessing the impact of MMDD on fibroblast activation and the PI3K/Akt/FOXO3a pathway. RESULTS: Results demonstrated that MMDD improved weight, reduced inflammation, and inhibited M2 macrophage infiltration in mouse lung tissue. It downregulated pro-fibrotic factors, such as TGF-ß1 and PDGF-RB, as well as markers of fibroblast activation. MMDD also exhibited regulatory effects on key proteins in the PI3K/Akt/FOXO3a signaling pathway. CONCLUSIONS: MMDD inhibited M2 macrophage polarization and released profibrotic factors that inhibited pulmonary fibrosis. As a result, the PI3K/Akt/FOXO3a signaling pathway is suppressed. MMDD is proving to be a successful treatment for PF. However, further research is needed to validate its effectiveness in clinical practice.

Interleukin-1 receptor antagonist: An alternative therapy for cancer treatment.

The interleukin-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and a naturally occurring antagonist of the IL-1 receptor. It effectively counteracts the IL-1 signaling pathway mediated by IL-1α/ß. Over the past few decades, accumulating evidence has suggested that IL-1 signaling plays an essential role in tumor formation, growth, and metastasis. Significantly, anakinra, the first United States Food and Drug Administration (FDA)-approved IL-1Ra drug, has demonstrated promising antitumor effects in animal studies. Numerous clinical trials have subsequently incorporated anakinra into their cancer treatment protocols. In this review, we comprehensively discuss the research progress on the role of IL-1 in tumors and summarize the significant contribution of IL-1Ra (anakinra) to tumor immunity. Additionally, we analyze the potential value of IL-1Ra as a biomarker from a clinical perspective. This review is aimed to highlight the important link between inflammation and cancer and provide potential drug targets for future cancer therapy.

Citrus peel extract protects against diesel exhaust particle-induced chronic obstructive pulmonary disease-like lung lesions and oxidative stress.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and characterized by emphysema, small airway remodeling and mucus hypersecretion. Citrus peels have been widely used as food spices and in traditional Chinese medicine for chronic lung disease. Given that citrus peels are known for containing antioxidants and anti-inflammatory compounds, we hypothesize that citrus peel intake can suppress oxidative stress and inflammatory response to air pollution exposure, thereby alleviating COPD-like pathologies. This study aimed to investigate the efficacy of citrus peel extract, namely Guang Chenpi (GC), in preventing the development of COPD induced by diesel exhaust particles (DEPs) and its potential mechanism. DEP-induced COPD-like lung pathologies, inflammatory responses and oxidative stress with or without GC treatment were examined in vivo and in vitro. Our in vivo study showed that GC was effective in decreasing inflammatory cell counts and inflammatory mediator (IL-17A and TNF-α) concentrations in bronchoalveolar lavage fluid (BALF). Pretreatment with GC extract also significantly decreased oxidative stress in the serum and lung tissue of DEP-induced COPD rats. Furthermore, GC pretreatment effectively reduced goblet cell hyperplasia (PAS positive cells) and fibrosis of the small airways, decreased macrophage infiltration as well as carbon loading in the peripheral lungs, and facilitated the resolution of emphysema and small airway remodeling in DEP-induced COPD rats. An in vitro free radical scavenging assay revealed robust antioxidant potential of GC in scavenging DPPH free radicals. Moreover, GC demonstrated potent capacities in reducing ROS production and enhancing SOD activity in BEAS-2B cells stimulated by DEPs. GC treatment significantly attenuated the increased level of IL-8 and MUC5AC from DEP-treated BEAS-2B cells. Mechanistically, GC treatment upregulated the protein level of Nrf-2 and could function via MAPK/NF-κB signaling pathways by suppressing the phosphorylation of p38, JNK and p65. Citrus peel extract is effective in decreasing oxidative stress and inflammatory responses of the peripheral lungs to DEP exposure. These protective effects further contributed to the resolution of COPD-like pathologies.

Biological function and research progress of N6-methyladenosine binding protein heterogeneous nuclear ribonucleoprotein A2B1 in human cancers.

N6-methyladenosine (m6A) is the most prevalent internal modification found in both mRNA and lncRNA. It exerts reversible regulation over RNA function and affects RNA processing and metabolism in various diseases, especially tumors. The m6A binding protein, hnRNPA2B1, is extensively studied as a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) protein family. It is frequently dysregulated and holds significant importance in multiple types of tumors. By recognizing m6A sites for variable splicing, maintaining RNA stability, and regulating translation and transport, hnRNPA2B1 plays a vital role in various aspects of tumor development, metabolism, and regulation of the immune microenvironment. In this review, we summarized the latest research on the functional roles and underlying molecular mechanisms of hnRNPA2B1. Moreover, we discussed its potential as a target for tumor therapy.

Association between CZT­SPECT myocardial blood flow and coronary stenosis: A cross­sectional study.

The association between the quantitative and semi-quantitative parameters of myocardial blood flow obtained using cadmium-zinc-telluride single photon emission computed tomography (CZT-SPECT) and coronary stenosis remains unclear. Therefore, the objective of the present study was to evaluate the diagnostic value of two parameters obtained using CZT-SPECT in patients with suspected or known coronary artery disease. A total of 24 consecutive patients who underwent CZT-SPECT and coronary angiography within 3 months of each other were included in the study. To evaluate the predictive ability of the regional difference score (DS), coronary flow reserve (CFR), and the combination thereof for positive coronary stenosis at the vascular level, receiver operating characteristic (ROC) curves were plotted and the area under the curves (AUCs) were calculated. Comparisons of the reclassification ability for coronary stenosis between different parameters were assessed by calculating the net reclassification index (NRI) and the integrated discrimination improvement (IDI). The 24 participants (median age: 65 years; range: 46-79 years; 79.2% male) included in this study had a total of 72 major coronary arteries. When stenosis ≥50% was defined as the criteria for positive coronary stenosis, the AUCs and the 95% confidence interval (CI) for regional DS, CFR, and the combination of the two indices were 0.653 (CI, 0.541-0.766), 0.731 (CI, 0.610-0.852) and 0.757 (CI, 0.645-0.869), respectively. Compared with single DS, the combination of DS and CFR increased the predictive ability for positive stenosis, with an NRI of 0.197-1.060 (P<0.01) and an IDI of 0.0150-0.1391 (P<0.05). When stenosis ≥75% was considered as the criteria, the AUCs were 0.760 (CI, 0.614-0.906), 0.703 (CI, 0.550-0.855), and 0.811 (CI, 0.676-0.947), respectively. Compared with DS, CFR had an IDI of -0.3392 to -02860 (P<0.05) and the combination of DS and CFR also enhanced the predictive ability, with an NRI of 0.0313-1.0758 (P<0.01). In conclusion, both regional DS and CFR had diagnostic values for coronary stenosis, but the diagnostic abilities differed in distinguishing between different degrees of stenosis, and the efficiency was improved with a combination of DS and CFR.

Value of frontal QRS axis for risk stratification of individuals with prolonged PR interval.

BACKGROUND: There is ongoing controversy regarding the prognostic value of PR prolongation among individuals free of cardiovascular diseases. It is necessary to risk-stratify this population according to other electrocardiographic parameters. METHODS: This study is based on the Third National Health and Nutrition Examination Survey. Cox proportional hazard models were constructed and Kaplan-Meier method was used. RESULTS: A total of 6188 participants (58.1 ± 13.1 years; 55% women) were included. The median frontal QRS axis of the entire study population was 37° (IQR: 11-60°). PR prolongation was present in 7.6% of the participants, of whom 61.2% had QRS axis ≤37°. In a multivariable-adjusted model, mortality risk was highest in the group with concomitant prolonged PR interval and QRS axis ≤37° (hazard ratio [HR]: 1.20; 95% confidence interval [CI]: 1.04-1.39). In models with similar adjustment where population were reclassified depending on PR prolongation and QRS axis, prolonged PR interval and QRS axis ≤37° was still associated with increased risk of mortality (HR: 1.18; 95% CI: 1.03-1.36) compared with normal PR interval. CONCLUSIONS: QRS axis is an important factor for risk stratification in population with PR prolongation. The extent to which this population with PR prolongation and QRS axis ≤37° is at higher risk of death compared with the population without PR prolongation.

Valproate-induced hyperammonemic encephalopathy treated by L-ornithine-L-aspartate: a case report.

A 63-year-old man developed reduced consciousness and dysphagia progressively. Examination and parameters were normal, except for a Glasgow Coma Scale score of seven, and his grading on the swallow water test increased from grade 1 to grade 5. Brain imaging and blood tests were unexplainable except by high plasma ammonia. His past medical history included cerebral infarction, hypertension and epilepsy induced by cerebral hyperperfusion syndrome. He was rceiving antiepileptic treatment of continuously intravenously pumped sodium valproate of 64 mg/h for 4 days, which overlapped for 12 hours with taking 500 mg sustained release tablets. Sodium valproate was stopped; testing demonstrated normal plasma concentrations of sodium valproate and elevated concentrations of ammonia. Ornithine aspartate was administrated. The patient's level of responsiveness and ammonia levels gradually improved. The patient was also being treated with ceftriaxone sodium for a hypostatic pneumonia and with desmopressin for diabetes insipidus. There is an association between sodium valproate and hyperammonaemia and encephalopathy. Immediate recognition of the serious but uncommon adverse effects is essential. To our knowledge this is the first report of ornithine aspartate being used in this disorder.

Prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

BACKGROUND: Tissue-resident CD8+T cells (CD103+CD8+T cells) are the essential effector cell population of anti-tumor immune response in tissue regional immunity. And we have reported that IL-33 can promote the proliferation and effector function of tissue-resident CD103+CD8+T cells. As of now, the immunolocalization and the prognostic values of tissue-resident CD8+T cells in human hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) still remain to be illustrated. METHODS: In our present study, we used the tissue microarrays of HCC and ICC, the multicolor immunohistochemistry (mIHC), and imaging analysis to characterize the tissue-resident CD8+T cells in HCC and ICC tissues. The prognostic values and clinical associations were also analyzed. We also studied the biological functions and the cell-cell communication between tumor-infiltrating CD103+CD8+T cells and other cell types in HCC and ICC based on the published single-cell RNA sequencing (scRNA-seq) data. RESULTS: Our work unveiled the expressions of CD8 and CD103 and immunolocalization of tissue-resident CD8+T cells in human HCC and ICC. Elevated CD8+T cells indicated a better overall survival (OS) rate, implying that tumor-infiltrating CD8+T cells in HCC and ICC could serve as an independent prognostic factor. Moreover, the number of CD103+CD8+T cells was increased in HCC and ICC tissues compared with adjacent normal tissues. HCC patients defined as CD8highCD103high had a better OS, and the CD8lowCD103low group tended to have a poorer prognosis in ICC. Evaluation of the CD103+CD8+T-cell ratio in CD8+T cells could also be a prognostic predictor for HCC and ICC patients. A higher ratio of CD103+CD8+T cells over total CD8+T cells in HCC tissues was negatively and significantly associated with the advanced pathological stage. The percentage of higher numbers of CD103+CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In contrast, the higher ratio of CD103+CD8+T cells over total CD8+T cells in ICC tissues was negatively and significantly associated with the advanced pathological stage. In addition, single-cell transcriptomics revealed that CD103+CD8+T cells were enriched in genes associated with T-cell activation, proliferation, cytokine function, and T-cell exhaustion. CONCLUSION: The CD103+ tumor-specific T cells signified an important prognostic marker with improved OS, and the evaluation of the tissue-resident CD103+CD8+T cells might be helpful in assessing the on-treatment response of liver cancer.

Influence of preoperative simulation on the reduction quality and clinical outcomes of open reduction and internal fixation for complex proximal humerus fractures.

PURPOSE: Proximal humerus fractures (PHFs) are common. With the development of locking plates, open reduction and internal fixation (ORIF) of the proximal humerus can provide excellent clinical outcomes. The quality of fracture reduction is crucial in the locking plate fixation of proximal humeral fractures. The purpose of this study was to determine the impact of 3-dimensional (3D) printing technology and computer virtual technology assisted preoperative simulation on the reduction quality and clinical outcomes of 3-part and 4-part proximal humeral fractures. METHOD: A retrospective comparative analysis of 3-part and 4-part PHFs undergoing open reduction internal fixation was performed. Patients were divided into 2 groups according to whether computer virtual technology and 3D printed technology were used for preoperative simulation: the simulation group and the conventional group. Operative time, intraoperative bleeding, hospital stay, quality of fracture reduction, Constant scores, American Society for Shoulder and Elbow Surgery (ASES) scores, shoulder range of motion, complications, and revision surgeries were assessed. RESULTS: This study included 67 patients (58.3%) in the conventional group and 48 patients (41.7%) in the simulation group. The patient demographics and fracture characteristics were comparable in these groups. Compared with the conventional group, the simulation group had shorter operation time and less intraoperative bleeding (P < 0.001, both). Immediate postoperative assessment of fracture reduction showed a higher incidence of greater tuberosity cranialization of < 5 mm, neck-shaft angle of 120° to 150°, and head shaft displacement of < 5 mm in the simulation group. The incidence of good reduction was 2.6 times higher in the simulation group than in the conventional group (95% CI, 1.2-5.8). At the final follow-up, the chance of forward flexion > 120° (OR 5.8, 95% CI 1.8-18.0) and mean constant score of > 65 (OR 3.4, 95% CI 1.5-7.4) was higher in the simulation group than the conventional group, as well as a lower incidence of complications in the simulation group was obtained (OR 0.2, 95% CI 0.1-0.6). CONCLUSIONS: This study identified that preoperative simulation assisted by computer virtual technology and 3D printed technology can improve reduction quality and clinical outcomes in treatment of 3-part and 4-part PHFs.

Erythropoietin promotes myocardial infarction repair in mice by improving the function of Sca-1+ stem cells / 生理学报

Myocardial infarction (MI) is one of the leading causes of death in the world. With the improvement of clinical therapy, the mortality of acute MI has been significantly reduced. However, as for the long-term impact of MI on cardiac remodeling and cardiac function, there is no effective prevention and treatment measures. Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has anti-apoptotic and pro-angiogenetic effects. Studies have shown that EPO plays a protective role in cardiomyocytes in cardiovascular diseases, such as cardiac ischemia injury and heart failure. EPO has been demonstrated to protect ischemic myocardium and improve MI repair by promoting the activation of cardiac progenitor cells (CPCs). This study aimed to investigate whether EPO can promote MI repair by enhancing the activity of stem cell antigen 1 positive stem cells (Sca-1+ SCs). Darbepoetin alpha (a long-acting EPO analog, EPOanlg) was injected into the border zone of MI in adult mice. Infarct size, cardiac remodeling and performance, cardiomyocyte apoptosis and microvessel density were measured. Lin- Sca-1+ SCs were isolated from neonatal and adult mouse hearts by magnetic sorting technology, and were used to identify the colony forming ability and the effect of EPO, respectively. The results showed that, compared to MI alone, EPOanlg reduced the infarct percentage, cardiomyocyte apoptosis ratio and left ventricular (LV) chamber dilatation, improved cardiac performance, and increased the numbers of coronary microvessels in vivo. In vitro, EPO increased the proliferation, migration and clone formation of Lin- Sca-1+ SCs likely via the EPO receptor and downstream STAT-5/p38 MAPK signaling pathways. These results suggest that EPO participates in the repair process of MI by activating Sca-1+ SCs.

Clinical Observation on Herb-partitioned Moxibustion on Navel Combined with Yishen Tongluo Prescription in Treatment of Infertility Induced by Idiopathic Asthenozoospermia with Kidney-Yang Deficiency and Collateral Obstruction Syndrome / 中国实验方剂学杂志

ObjectiveTo observe the clinical efficacy of herb-partitioned moxibustion on the navel combined with Yishen Tongluo prescription in the treatment of infertility induced by idiopathic asthenozoospermia （iAZS） with kidney-Yang deficiency and collateral obstruction syndrome and its effect on sperm DNA damage and superoxide dismutase （SOD） in the seminal plasma. MethodsA total of 112 eligible patients who met the inclusion criteria were randomly divided into an observation group （56 cases） and a control group （56 cases）. The patients in the observation group were treated with herb-partitioned moxibustion on the navel combined with Yishen Tongluo prescription，while those in the control group received levocarnitine oral liquid. The primary observation indicators included spouse pregnancy rate，progressive motility （PR），and total sperm motility，and the secondary observation indicators included sperm DNA fragmentation index （DFI），SOD in the seminal plasma， and improvement of TCM syndromes. The treatment cycle was 12 weeks. Before and after treatment，the PR，total sperm motility，sperm DFI，SOD in the seminal plasma， and TCM syndrome scores were recorded. The patients were followed up for 12 weeks and the pregnancy status of spouses within 24 weeks （half a year） was recorded. The clinical efficacy of the two groups was evaluated. ResultThe pregnancy rate of spouses in the observation group was 15.69% （8/51）， higher than 3.85% （2/52） in the control group （χ2=4.118，P<0.05）. The total effective rate of the observation group was 88.24%（45/51）， superior to 69.23% （36/52）in the control group （Z=-3.402，P<0.01）. After treatment， PR， total sperm motility，sperm DFI， SOD in the seminal plasma， and TCM syndromes of the two groups were improved compared with those before treatment （P<0.05）， and the observation group was superior to the control group （P<0.05）. ConclusionHerb-partitioned moxibustion on the navel combined with Yishen Tongluo prescription in the treatment of iAZS-induced infertility patients with kidney-Yang deficiency and collateral obstruction syndrome can increase PR，total sperm motility， and SOD level in the seminal plasma， reduce sperm DFI，improve the TCM symptoms of patients， and improve the pregnancy rate of spouses. The mechanism may be attributed to the fact that this treatment can increase the SOD level in the seminal plasma of patients，enhance the body's antioxidant function，protect sperm from oxidative stress damage，and reduce sperm DFI.