Spatial and temporal distribution characteristics and risk assessment of heavy metals in groundwater of Pingshuo mining area.

Groundwater pollution in the Pingshuo mining area is strongly associated with mining activities, with heavy metals (HMs) representing predominant pollutants. To obtain accurate information about the pollution status and health risks of groundwater, 189 groups of samples were collected from four types of groundwater, during three periods of the year, and analyzed for HMs. The results showed that the concentration of HMs in groundwater was higher near the open pit, waste slag pile, riverfront area, and human settlements. Except for Ordovician groundwater, excessive HMs were found in all investigated groundwater of the mining area, as compared with the standard thresholds. Fe exceeded the threshold in 13-75% of the groundwater samples. Three sources of HMs were identified and quantified by Pearson's correlation analysis and the PMF model, including coal mining activities (68.22%), industrial, agricultural, and residential chemicals residue and leakage (16.91%), and natural sources (14.87%). The Nemerow pollution index revealed that 7.58% and 100% of Quaternary groundwater and mine water samples were polluted. The health risk index for HMs in groundwater showed that the non-carcinogenic health risk ranged from 0.18 to 0.42 for adults, indicating an acceptable level. Additionally, high carcinogenic risks were identified in Quaternary groundwater (95.45%), coal series groundwater (91.67%), and Ordovician groundwater (26.67%). Both carcinogenic and non-carcinogenic risks were greater for children than adults, highlighting their increased vulnerability to HMs in groundwater. This study provides a scientific foundation for managing groundwater quality and ensuring drinking water safety in mining areas.

The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy.

BACKGROUND: Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. RESULTS: In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. CONCLUSION: In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment.

Clinical value of soluble fms-like tyrosine kinase 1 (sFlt-1) in adult secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a syndrome characterized by an excessive systemic inflammatory response, manifested by multiple organ dysfunction, lacking reliable immune biomarkers for predicting their inflammatory status and prognosis. Soluble fms-like tyrosine kinase 1 (sFlt-1) is associated with various inflammation-related diseases, including sepsis and severe organ failure. METHODS: This study retrospectively included 32 adult sHLH patients diagnosed from January 2020 to December 2021. The expression of Flt-1 in peripheral blood CD14 + monocytes was detected by flow cytometry, and the level of plasma sFlt-1 was detected by ELISA. RESULTS: In our study, the results of flow cytometry reveal that the Flt-1 expression on CD14 + monocytes of peripheral blood from sHLH patients was higher than that in normal control. In plasma samples of sHLH patients, sFlt-1 levels were 677.8 (463.2-929.7) pg/mL, significantly higher than in normal controls 377.18 (350.4-424.6) pg/mL and sepsis group 378.3 (257.0-499.1) pg/mL. Besides, a positive correlation was found between sFlt-1 and IL-6 in sHLH patients. The analysis of univariate Cox regression indicated that sFlt-1 >681.5 pg/mL demonstrated unfavorable overall survival ( p = 0.022). Multivariate analysis demonstrated that sFlt-1 >681.5 pg/mL was an independent factor associated with OS ( p = 0.041) after adjustment for confounders. Restricted cubic spline confirmed a linear and positive association between sFlt-1 and mortality risk. CONCLUSION: Retrospective analysis showed that sFlt-1 was a promising prognostic factor.

Prognostic value of the albumin-bilirubin score in patients with non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare life-threatening systemic disease. This study aimed to assess the prognostic value of pretreatment albumin-bilirubin (ALBI). We retrospectively analyzed 168 non-Hodgkin lymphoma-associated secondary hemophagocytic lymphohistiocytosis (NHL-sHLH) patients with hepatic injuries. Multivariable logistic/Cox models and restricted cubic spline models were conducted to evaluate the relationships between the ALBI score and short- and long-term survival. Among 168 adult NHL-sHLH patients, 82 (48.8%) patients died within 30 days after admission, and 144 (85.7%) patients died during the follow-up period. Multivariable logistic/Cox regression model indicated that ALBI grade could be an independent risk factor for predicting the prognosis of patients with 30-day mortality and overall survival (odds ratios [OR]30 days 5.37, 95% confidence interval 2.41-12.64, P < 0.001; hazard ratios [HR]OS 1.52, 95% confidence interval 1.06-2.18, P = 0.023), respectively. The restricted cubic spline curve displayed a linear and positive relationship between the ALBI score and risk of mortality (P for nonlinearity =0.503). Furthermore, receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) for predicting mortality by integrative analysis of the ALBI score and ferritin was significantly improved compared to the ALBI score (AUC 30 days: 0.820 vs 0.693, P = 0.001; AUC1 year: 0.754 vs 0.681, P = 0.043) or ferritin (AUC30 days: 0.820 vs 0.724, P = 0.005; AUC1 year: 0.754 vs 0.658, P = 0.031) alone. The ALBI score could be a useful indicator of short and long-term survival for NHL-sHLH patients with hepatic injuries.

Prognostic value of lipid profile in adult hemophagocytic lymphohistiocytosis.

Background: Adult secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare clinical syndrome with a high mortality rate. Currently, there are no feasible prognostic factors to clinically predict untreated sHLH patients' prognosis. Our objective was to characterize the lipid profile of adult sHLH patients and to determine the relationship with overall survival. Methods: We retrospectively analyzed 247 patients with newly diagnosed sHLH from January 2017 to January 2022 according to the HLH-2004 criteria. Multivariate Cox regression analyses and restricted cubic splines were conducted to evaluate the prognostic value of the lipid profile. Results: The median age of all patients was 52 years, and the commonest cause of sHLH in our cohort was malignancy. During a median follow-up of 88 (interquartile ranges, 22-490) days, 154 deaths occurred. The univariate analysis confirmed total cholesterol (TC) ≤ 3 mmol/L, triglycerides (TG) > 3.08 mmol/L, high-density lipoprotein cholesterol (HDL-c) ≤ 0.52 mmol/L, and low-density lipoprotein cholesterol (LDL-c) ≤ 2.17 mmol/L were associated with an inferior survival. In a multivariate model, HDL-c, hemoglobin, platelet, fibrinogen, and soluble interleukin-2 receptor were considered as independent factors. Additionally, the restricted cubic spline analyses indicated an inverse linear association between HDL-c and the risk of mortality in sHLH. Conclusion: Lipid profiles, which were low-cost and readily available promising biomarkers, were strongly associated with the overall survival in adult sHLH patients.

Genome-Wide Splicing Quantitative Expression Locus Analysis Identifies Causal Risk Variants for Non-Small Cell Lung Cancer.

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies (GWAS) have been linked to expression quantitative trait loci (eQTL) in previous studies, further work is needed to better elucidate the relationship to other genetic regulatory mechanisms, such as splicing QTLs (sQTL). Here, we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non-small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas. The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions, genetic regulatory elements, RNA-binding protein (RBP) binding sites, and known NSCLC risk loci. In addition, target genes affected by sQTLs (sGenes) were involved in multiple processes in cancer, including cell growth, apoptosis, metabolism, immune infiltration, and drug responses, and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform (GSTO2-V1) and lower expression of the truncated GSTO2 isoform (GSTO2-V2), which was induced by RBP quaking (QKI). Mechanistically, compared with GSTO2-V1, GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall, this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential. SIGNIFICANCE: Analysis of sQTL reveals the role of genetically driven mRNA splicing alterations in NSCLC risk and elucidates that rs156697 variant impacts risk by altering GSTO2 splicing.

Defective iron based metal-organic frameworks derived from zero-valent iron for highly efficient fenton-like catalysis.

Introducing crystal defects into iron based metal-organic frameworks (Fe-MOFs) is regarded as a promising strategy to enhance Fenton-like performance. However, developing a facile and effective strategy to construct defective Fe-MOFs as highly efficient Fenton-like catalyst is still a challenge. Herein, MIL-100(Fe) (Def-MIL-100(Fe)) with missing ligands defects was synthesized by a simple heterogeneous reaction using zero-valent iron. The bisphenol A degradation efficiency in the Def-MIL-100(Fe)/H2O2 system reached up to 91.26% within 10 min at pH 4 with a low catalyst dosage of 0.05 g/L, while the perfect MIL-100(Fe) has almost no Fenton-like performance. It was observed that missing ligands defects in the Def-MIL-100(Fe) play a key role in the Fenton-like reaction. The missing ligands defects could increase the Lewis acidity for fast H2O2 adsorption and accelerate the electron transfer between FeII and FeIII cycling, leading to faster and more·OH generation. Moreover, the missing ligands defects could promote the mass transfer for improving·OH utilization efficiency. This work provides a novel strategy to construct defective Fe-MOFs as highly efficient Fenton-like catalyst to degrade organic pollutants in water.

Ischemia and reperfusion injury combined with cisplatin induces immunogenic cell death in lung cancer cells.

A first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), cisplatin (CDDP), fails to induce immunogenic cell death (ICD) because it fails to induce calreticulin (CRT) exposure on the cell surface. We investigated the potential of ischemia and reperfusion injury (I/R) combined with CDDP to induce ICD in lung cancer cells. The in vitro model of I/R, oxygen-glucose deprivation and reperfusion (OGD/R), effectively induced CRT exposure, ATP secretion, high mobility group box 1 (HMGB1) release and eIF2α phosphorylation in both Lewis lung carcinoma (LLC) and A549 cells when combined with CDDP. By using a vaccine assay and coculture with bone marrow-derived dendritic cells (BMDCs), we showed that OGD/R restored the immunogenicity of CDDP by phosphorylating eIF2α and demonstrated that OGD/R + CDDP (O + C) is an ICD inducer. Using the inguinal tumor model, we found that I/R significantly enhanced the tumor-killing effect of CDDP and Mitomycin C, and this effect relied on adaptive antitumor immunity. Consistently, I + C altered the ratio of interferon-gamma-secreting T lymphocytes, thus overcoming the immunosuppressive effect induced by CDDP. In conclusion, our research presents a new combination strategy and indicates that I/R is a potential anticancer immunogenic modality when combined with nonimmunogenic chemotherapy.

Hydrochemical assessments and driving forces of groundwater quality and potential health risks of sulfate in a coalfield, northern Ordos Basin, China.

Groundwater is the primary water source in coalfields under arid and semiarid climates. However, the problem of excessive concentrations of sulfate, which is a constant component in coalfields, and its potential health risks are often neglected in Northwest, China. To determine the groundwater quality, health threats, and driving forces of sulfate in coal mine groundwater, this study performed hydrochemical and isotopic analyses of 61 groundwater samples from a typical coalfield in northwestern China. We found that phreatic groundwater had lower total dissolved solid (TDS) and freshwater hydrochemical types (mainly Ca-HCO3 and Ca-Na + K-HCO3 types). In contrast, confined groundwater showed saline affinity (Na + K-SO4 type) and high TDS values, and the quality was unacceptable for drinking, with EWQI values larger than 100, which could be attributed to its high SO42- concentration. In addition, confined groundwater was also unsuitable for irrigation with high values of electric conductivity (EC), sodium absorption ratio (SAR), and Na%. Combining with isotopic analysis (δD, δ18Owater, δ34S and δ18Osulfate), the sulfate of confined and phreatic groundwater was controlled by gypsum dissolution and irrigation activities. As for public human health, SO42- poses potential non-carcinogenic risks to various populations, especially children. Therefore, the impact of geogenic and anthropogenic factors should be paid attention to, including the reduction of the use of sulfur-containing fertilizers and discharge of sulfur-containing sewage; and the water treatment should be carried out. Importantly, there is a need to adopt a strategy of water supply from multiple sources to ensure human health.

The prevalence and prognosis of hyponatraemia in non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis.

Non-Hodgkin lymphoma associated hemophagocytic lymphohistiocytosis (NHL-HLH) in adult secondary HLH is a common and universally highly lethal critical disorder. Hyponatraemia is the most common electrolyte disorder in the critical illness setting and acts as a negative prognostic factor. The aim of our study was to evaluate the prognostic role of hyponatraemia among patients with NHL-HLH. The results showed that 81 (52.9%) patients had hyponatraemia. After a median follow up 47 (range 14-180) days, there were 72 (88.9%) cumulative deaths in hyponatraemia group while 50 (69.4%) in normonatremia group. After adjustment for confounders, multivariate analysis revealed that hyponatraemia was an independent prognostic factor for OS (HR:1.51, 95% CI: 1.03-2.20; p = 0.033). Restricted cubic spline confirmed a linear and positive association between serum sodium and the risk of mortality. Hyponatraemia is relatively frequent in NHL-HLH. As a readily available biomarker in clinical routine, it was a promising prognostic predictor for NHL-HLH.

Interleukin -1ß Promotes Lung Adenocarcinoma Growth and Invasion Through Promoting Glycolysis via p38 Pathway.

BACKGROUND: There is a close relationship among inflammation, glycolysis, and tumors. The IL-1 family includes important inflammatory cytokines, among which IL-1ß has been widely studied. In this study, we focused on the effect of IL-1ß on glycolysis of lung adenocarcinoma (LUAD) cells in vivo and in vitro and explored its possible mechanisms. METHODS: A bioinformatic database and quantitative real-time PCR were used to analyze the expression of glycolysis-related enzyme genes and their correlations with IL1ß in human LUAD samples. The human LUAD cell line A549 and Lewis lung carcinoma LLC cell line were stimulated with IL-1ß. In vitro treatment effects, including glycolysis level, migration, and invasion were evaluated with a glucose assay kit, lactate assay kit, Western blotting, wound healing, and the transwell method. We established a mouse model of subcutaneous tumors using LLC cells pretreated with IL-1ß and analyzed in vivo treatment effects through positron-emission tomography-computed tomography and staining. Virtual screening and molecular dynamic simulation were used to screen potential inhibitors of IL-1ß. RESULTS: Our results showed that IL1ß was positively correlated with the expression of glycolysis-related enzyme genes in LUAD. Glycolysis, migration, and invasion significantly increased in A549 and LLC stimulated with IL-1ß. In vivo, IL-1ß increased growth, mean standard uptake value, and pulmonary tumor metastasis, which were inhibited by the glycolysis inhibitor 2-deoxy-D-glucose and p38-pathway inhibitors. Small molecular compound ZINC14610053 was suggested being a potential inhibitor of IL-1ß. CONCLUSION: IL-1ß promotes glycolysis of LUAD cells through p38 signaling, further enhancing tumor-cell migration and invasion. These results show that IL-1ß links inflammation to glycolysis in LUAD, and targeting IL-1ß and the glycolysis pathway may be a potential therapeutic strategy for lung cancer.

Clinical features of 47 secondary hemophagocytic lymphohistiocytosis patients complicated with capillary leak syndrome.

The clinical features of patients with secondary hemophagocytic lymphohistiocytosis (sHLH) complicated with capillary leak syndrome (CLS) remain controversial. The data of 259 sHLH patients were retrospectively analyzed. The clinical manifestations, laboratory findings, treatment, and prognosis of the CLS-sHLH group and non-CLS-sHLH group were compared. The levels of fibrinogen, albumin, and serum calcium in the CLS-sHLH group were lower than in the non-CLS-sHLH group, and serum triglycerides in the CLS-sHLH group were higher than in the non-CLS-sHLH group (P < 0.05). Univariate analysis showed that fibrinogen level was an independent prognostic factor in sHLH patients complicated with CLS. The median survival time was significantly shorter in patients with fibrinogen ≤ 1.3 g/L than in patients with fibrinogen > 1.3 g/L (P < 0.05). Patients with improved CLS conditions in the CLS-sHLH group had significantly increased albumin and serum calcium after treatment (P < 0.05); patients without improved conditions in the CLS-sHLH group also had significantly increased albumin after treatment (P < 0.05), but the serum calcium did not change significantly (P > 0.05). sHLH patients complicated with CLS had significantly worse prognosis than without CLS. Significant reduction in fibrinogen may be an independent prognostic factor for poor prognosis in sHLH patients complicated with CLS.

The prognostic role of plasma fibrinogen in adult secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: In adult patients with secondary hemophagocytic lymphohistiocytosis (sHLH), no valid immune biomarker has been available for predicting the prognosis of untreated sHLH patients. METHODS: Circulating plasma levels of fibrinogen (FIB) were measured at diagnosis in 293 cases of adult sHLH. We categorized FIB levels into tertiles. Multivariable Cox proportional hazards models were used to evaluate the relationship between FIB and survival. Restricted cubic spline models and two-piecewise Cox proportional hazards models were used to address the nonlinear association between FIB and mortality. RESULTS: During a median follow-up of 52 (interquartile ranges, 18-221) days, 208 deaths occurred, with 137 deaths in malignancy-associated hemophagocytic lymphohistiocytosis (MHLH) and 71 deaths in non-malignancy-associated hemophagocytic lymphohistiocytosis (non-MHLH). After multivariable adjustment, compared with the highest tertile of FIB, the hazard ratios (HRs) with 95% confidence intervals (CIs) of survival for tertile 2 and tertile 1 were 1.06 (0.90-1.24) and 0.84 (0.71-0.98), respectively. The restricted cubic spline curve displayed a nonlinear and inverse relationship between FIB and mortality. Furthermore, the threshold effect analysis demonstrated that the inflection point for the curve was at an FIB level of 1.76 g/L. The HRs (95% CIs) for survival were 0.68 (0.55-0.83) and 1.08 (0.96-1.21) on the left and right side of the inflection point, respectively. CONCLUSIONS: These results suggest that plasma fibrinogen is nonlinearly and inversely associated with the risk of mortality in adult secondary hemophagocytic lymphohistiocytosis.

Immunoregulatory Roles of Extracellular Vesicles and Associated Therapeutic Applications in Lung Cancer.

Lung cancer represents a fatal condition that has the highest morbidity and mortality among malignancies. The currently available treatments fall short of improving the survival and quality of life of late-stage lung cancer patients. Extracellular vesicles (EVs) secreted by tumors or immune cells transport proteins, lipids, and nucleic acids to other cells, thereby mediating immune regulation in the tumor microenvironment. The cargo carried by EVs vary by cellular state or extracellular milieu. So far, multiple studies have suggested that EVs from lung tumor cells (TEVs) or immune cells promote tumor progression mainly through suppressing antitumor immunity. However, modified or engineered EVs can be used as vaccines to elicit antitumor immunity. In addition, blocking the function of immunosuppressive EVs and using EVs carrying immunogenic medicine or EVs from certain immune cells also shows great potential in lung cancer treatment. To provide information for future studies on the role of EVs in lung cancer immunity, this review focus on the immunoregulatory role of EVs and associated treatment applications in lung cancer.

Is oseltamivir suitable for fighting against COVID-19: In silico assessment, in vitro and retrospective study.

BACKGROUND: Oseltamivir is a first-line antiviral drug, especially in primary hospitals. During the ongoing outbreak of coronavirus disease 2019 (COVID-19), most patients with COVID-19 who are symptomatic have used oseltamivir. Considering its popular and important role as an antiviral drug, it is necessary to evaluate oseltamivir in the treatment of COVID-19. OBJECTIVE: To evaluate the effect of oseltamivir against COVID-19. METHODS: Swiss-model was used to construct the structure of the N-terminal RNA-binding domain (NRBD) of the nucleoprotein (NC), papain-like protease (PLpro), and RNA-directed RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). TM-align program was performed to compare the structure of the viral proteins with the structure of the neuraminidase of influenza A. Molecular docking was used to analyze the theoretical possibility of effective binding of oseltamivir with the active centers of the viral proteins. In vitro study was used to evaluate the antiviral efficiency of oseltamivir against SARS-CoV-2. By clinical case analysis, we statistically evaluated whether the history of oseltamivir use influenced the progression of the disease. RESULTS: The structures of NRBD, PLpro, and RdRp were built successfully. The results from TM-align suggested that the S protein, NRBD, 3C-like protease (3CLpro), PLPrO, and RdRp were structurally similar to the influenza A neuraminidase, with TM-scores of 0.30077, 0.19254, 0.28766, 0.30666, and 0.34047, respectively. Interestingly, the active center of 3CL pro was found to be similar to the active center from the neuraminidase of influenza A. Through an analysis of molecular docking, we discovered that oseltamivir carboxylic acid was more favorable to bind to the active site of 3CLpro effectively, but its inhibitory effect was not strong compared with the positive group. Finally, we used in vitro study and retrospective case analysis to verify our speculations. We found that oseltamivir is ineffective against SARS-CoV-2 in vitro study and the clinical use of oseltamivir did not improve the patients' symptoms and signs and did not slow the disease progression. CONCLUSIONS: We consider that oseltamivir isn't suitable for the treatment of COVID-19. During the outbreak of novel coronavirus, when oseltamivir is not effective for the patients after they take it, health workers should be highly vigilant about the possibility of COVID-19.

Metabolic characteristics of large and small extracellular vesicles from pleural effusion reveal biomarker candidates for the diagnosis of tuberculosis and malignancy.

Pleural effusion is a common respiratory disease worldwide; however, rapid and accurate diagnoses of tuberculosis pleural effusion (TPE) and malignancy pleural effusion (MPE) remain challenging. Although extracellular vesicles (EVs) have been confirmed as promising sources of disease biomarkers, little is known about the metabolite compositions of its subpopulations and their roles in the diagnosis of pleural effusion. Here, we performed metabolomics and lipidomics analysis to investigate the metabolite characteristics of two EV subpopulations derived from pleural effusion by differential ultracentrifugation, namely large EVs (lEVs, pelleted at 20,000 × g) and small EVs (sEVs, pelleted at 110,000 × g), and assessed their metabolite differences between tuberculosis and malignancy. A total of 579 metabolites, including amino acids, acylcarnitines, organic acids, steroids, amides and various lipid species, were detected. The results showed that the metabolic profiles of lEVs and sEVs overlapped with and difference from each other but significantly differed from those of pleural effusion. Additionally, different type of vesicles and pleural effusion showed unique metabolic enrichments. Furthermore, lEVs displayed more significant and larger metabolic alterations between the tuberculosis and malignancy groups, and their differential metabolites were more closely related to clinical parameters than those of sEV. Finally, a panel of four biomarker candidates, including phenylalanine, leucine, phosphatidylcholine 35:0, and sphingomyelin 44:3, in pleural lEVs was defined based on the comprehensive discovery and validation workflow. This panel showed high performance for distinguishing TPE and MPE, particularly in patients with delayed or missed diagnosis, such as the area under the receiver-operating characteristic curve (AUC) >0.95 in both sets. We conducted comprehensive metabolic profiling analysis of EVs, and further explored the metabolic reprogramming of tuberculosis and malignancy at the level of metabolites in lEVs and sEVs, providing insight into the mechanism of pleural effusion, and identifying novel biomarkers for diagnosing TPE and MPE.

Low T3 syndrome is a prognostic marker of poor outcomes in secondary hemophagocytic lymphohistiocytosis.

This study aimed to examine the association between low T3 syndrome and overall survival (OS) in patients with secondary hemophagocytic lymphohistiocytosis (sHLH). The study consisted of 111 consecutive patients hospitalized due to newly diagnosed sHLH with detailed thyroid hormone profiles on admission. Low T3 syndrome was found in 75.7% of the studied sHLH population. After a median follow-up of 83 (interquartile range 25-365) days, there were 60 (71.4%) cumulative deaths in the low T3 syndrome group and 13 (48.1%) in the euthyroid group. Survival analysis showed a lower survival probability for patients with low FT3 than for those with normal FT3 (median OS, 60 vs. 365 days, p = .011). In the multivariate analysis, low T3 syndrome was an independent prognostic factor for OS (HR = 2.474; 95% CI 1.351-4.532, p = .003). Low T3 syndrome is frequently found and associated with worse outcomes in patients with sHLH.

Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study.

AIMS/HYPOTHESIS: Hyperglycaemia is associated with an elevated risk of mortality in community-acquired pneumonia, stroke, acute myocardial infarction, trauma and surgery, among other conditions. In this study, we examined the relationship between fasting blood glucose (FBG) and 28-day mortality in coronavirus disease 2019 (COVID-19) patients not previously diagnosed as having diabetes. METHODS: We conducted a retrospective study involving all consecutive COVID-19 patients with a definitive 28-day outcome and FBG measurement at admission from 24 January 2020 to 10 February 2020 in two hospitals based in Wuhan, China. Demographic and clinical data, 28-day outcomes, in-hospital complications and CRB-65 scores of COVID-19 patients in the two hospitals were analysed. CRB-65 is an effective measure for assessing the severity of pneumonia and is based on four indicators, i.e. confusion, respiratory rate (>30/min), systolic blood pressure (≤90 mmHg) or diastolic blood pressure (≤60 mmHg), and age (≥65 years). RESULTS: Six hundred and five COVID-19 patients were enrolled, including 114 who died in hospital. Multivariable Cox regression analysis showed that age (HR 1.02 [95% CI 1.00, 1.04]), male sex (HR 1.75 [95% CI 1.17, 2.60]), CRB-65 score 1-2 (HR 2.68 [95% CI 1.56, 4.59]), CRB-65 score 3-4 (HR 5.25 [95% CI 2.05, 13.43]) and FBG ≥7.0 mmol/l (HR 2.30 [95% CI 1.49, 3.55]) were independent predictors for 28-day mortality. The OR for 28-day in-hospital complications in those with FBG ≥7.0 mmol/l and 6.1-6.9 mmol/l vs <6.1 mmol/l was 3.99 (95% CI 2.71, 5.88) or 2.61 (95% CI 1.64, 4.41), respectively. CONCLUSIONS/INTERPRETATION: FBG ≥7.0 mmol/l at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes. Glycaemic testing and control are important to all COVID-19 patients even where they have no pre-existing diabetes, as most COVID-19 patients are prone to glucose metabolic disorders. Graphical abstract.

Performances of the beam monitoring system and quality assurance equipment for the HIMM of carbon-ion therapy.

PURPOSE: The heavy-ion medical machine (HIMM), which is the first commercial medical accelerator designed and built independently by the institute of modern physics (IMP) in Wuwei, Gansu Province, China, had officially completed clinical trials at the time of this article's writing. Three types of detector systems were developed based on the ionization-chamber principle to monitor the beam parameters during treatment in real time, quickly verify the beam performance during a routine checkup, and ensure patient safety. METHODS AND MATERIALS: The above-mentioned detector systems were used for beam monitoring and quality assurance in the treatment system. The beam-monitoring system is composed of three integral ionization chambers (ICs) and two multistrip ionization chambers (MSICs) as a redundant design. The irradiation dose, beam position, and homogeneity of a lateral profile are monitored online by the beam-monitoring system, and safety interlocks are established to keep the test results under the predefined tolerance limitation. The quality-assurance equipment was composed of one MSIC and one IC stack. The IC stack was used for energy verification. RESULTS: The off-axis response of ICs is within a tolerance of 2%, and the dose interlock system (DIS) response time is less than 7 ms during the treatment process. The positioning resolution of MSICs reached 73 µm. The IC stack can verify the beam range within one spill and the measurement resolution is less than 0.2 mm. CONCLUSIONS: The beam-monitoring system (BMS) and quality-assurance equipment (QAE) have been installed and run successfully within HIMM for two years and are associated with the HIMM treatment system to deliver the right dose to the correct position precisely. Furthermore, the daily QA task is simplified by it. Above all, the system has passed the performance test of the China Food and Drug Administration (CFDA).