OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Objective To investigate the distribution and antimicrobial resistance profiles of clinically isolated Haemophilus influenzae and Moraxella catarrhalis in hospitals across China from 2015 to 2021,and provide evidence for rational use of antimicrobial agents.Methods Data of H.influenzae and M.catarrhalis strains isolated from 2015 to 2021 in CHINET program were collected for analysis,and antimicrobial susceptibility testing was performed by disc diffusion method or automated systems according to the uniform protocol of CHINET.The results were interpreted according to the CLSI breakpoints in 2022.Beta-lactamases was detected by using nitrocefin disk.Results From 2015 to 2021,a total of 43 642 strains of Haemophilus species were isolated,accounting for 2.91％of the total clinical isolates and 4.07％of Gram-negative bacteria in CHINET program.Among the 40 437 strains of H.influenzae,66.89％were isolated from children and 33.11％were isolated from adults.More than 90％of the H.influenzae strains were isolated from respiratory tract specimens.The prevalence of β-lactamase was 53.79％in H.influenzae strains.The H.influenzae strains isolated from children showed higher resistance rate than the strains isolated from adults.Overall,779 strains of H.influenzae did not produce β-lactamase but were resistant to ampicillin(BLNAR).Beta-lactamase-producing strains showed significantly higher resistance rates to these antimicrobial agents than the β-lactamase-nonproducing strains.Of the 16 191 M.catarrhalis strains,80.06％were isolated from children and 19.94％isolated from adults.M.catarrhalis strains were mostly susceptible to both amoxicillin-clavulanic acid and cefuroxime,evidenced by resistance rate lower than 2.0％.Conclusions The emergence of antibiotic-resistant H.influenzae due to β-lactamase production poses a challenge for clinical anti-infective treatment.Therefore,it is very important to implement antibiotic resistance surveillance for H.influenzae and guide rational antibiotic use.All local clinical microbiology laboratories should actively improve antibiotic susceptibility testing and strengthen antibiotic resistance surveillance for H.influenzae.

Objective:To investigate the differences between high-frequency ultrasound-guided manual detorsion combined with surgery(MD+S)and surgery alone in the treatment of testicular torsion,and to provide some new evidence for the timely diagno-sis and treatment of the disease.Methods:We retrospectively analyzed the clinical data on 134 cases of unilateral testicular torsion within 48 hours treated in our hospital by MD+S or by surgery alone from January 2015 to May 2022.We statistically analyzed the age distribution,and duration and degrees of testicular torsion,followed by comparison between the two groups.Results:In the 134 ca-ses,the median age of onset was 15(13-19)years old,the median onset-to-visit time was 15(8-25)hours,and the median de-gree of torsion was 360°(180°-1080°).Of the total number of patients,21 underwent testicular excision and the other 113 were treated with the testis preserved,with no statistically significant difference in age distribution between the two groups(P＞0.05),and a higher rate of testis resection in those with longer duration and greater angle of torsion(P＜0.05).Totally,33 of the patients were assigned to the MD+S group and 101 to the surgery alone group.According to the actual clinical conditions and excluding those with torsion time longer than 24 hours and torsion angle greater than 720 °,28 of the patients underwent ultrasound-guided MD+S(with 1 case of testis resection,3.6％),and 68 received surgery alone(with 7 cases of testis resection,10.3％).The rate of testis resection was higher in the surgery alone than that in the MD+S group,but with no statistically significant difference between the two groups(P＞0.05),which was considered to be related to the small sample size in this study.Conclusion:The popularization of testicular torsion knowledge can shorten the onset-to-visit time,and reasonable manual detorsion before emergency surgery can reduce the rate of testis resection.

Objective To systematically analyze the changes in clinical indicators including blood leukocytes and neutrophils,liver and kidney functions,coagulation function,lipids,and levels of thyroid hormones and antibodies in Graves'ophthalmopathy(GO)patients who had undergone effective treatment with tocilizumab(TCZ)and to explore their clinical significance.Methods Eighty-five patients with moderately or severely active GO who were effectively treated with TCZ were enrolled.Early morning fasting blood was collected and tested for routine blood,biochemical routine,coagulation function,thyroid hormone and antibodies,and basic information such as gender,age,duration of the disease,history of smoking,comorbidities,and medications were also collected from all patients,so changes in the clinical indicators before and after the treatment could be analyzed and correlation analyses could be carried out.Results Patients with moderately to severely active GO treated with TCZ showed a significant decrease in absolute blood leukocyte and neutrophil values compared with before,and a significant decrease in liver function(alanine transaminase,aspartate aminotransferase,creatinine),cholesterol(total cholesterol,high-density lipoprotein and low-density lipoprotein)levels were significantly higher than before,and concentrations of coagulation parameters[prothrombin time,activated partial thromboplastin time,fibrinogen(FIB)and D-dimer]were significantly decreased.The concentrations of thyroid hormone and thyroid-stimulating hormone levels increased significantly,and the antibody titer of thyrotropin receptor antibody(TRAB)was significantly down-regulated after treatment.TRAB levels were significantly correlated with FIB before treatment.Conclusion Thyroid function and antibody levels improved after TCZ treatment in patients with moderately to severely active GO,but blood leukocytes,liver function and coagulation function changed significantly compared with before.The results of this study confirm the therapeutic effect of TCZ on immune disorders in GO ophthalmopathy,while underscoring the importance of monitoring potential adverse effects in clinical treatment.

Systemic lupus erythematosus(SLE)complicated refractory immune thrombocytopenia(ITP)is mainly characterized by persistent severe thrombocytopenia and bleeding.Currently,there are no guidelines for treating such ITP.Hereby we reported a patient diagnosed with SLE with more than 10 years history of anemia and thrombocytopenia.This patient had been treated by various immunity inhibitors,such as corticosteroids,cyclosporine,mycophenolate mofetil,azathioprine,tofacitinib and telitacicept,but there was no obvious effect.The platelet count continued to be below 50×109/L.However,when serum cyclosporine trough level between 100 and 150 ng/mL,the clinical efficacy was improved and the platelet count was above 100×109/L.The patient was followed up for more than 6 months,and no recurrence of disease was found.Cyclosporine combined with low-dose glucocorticoid is safe and effective for SLE associated ITP.Therapeutic drug monitoring is a powerful tool for improving clinical efficacy and ensuring drug safety.

Aim To observe the mechanism of salvian-olic acid B(SalB)against oxygen glucose deprivation/re-oxygenation(OGD/R)injury in H9c2 cardiomyo-cytes.Methods The protective concentration of SalB against OGD/R-injured H9c2 cardiomyocytes was screened by CCK-8 assay.The levels of lactate dehy-drogenase(LDH),aspartate transaminase(AST)and creatine kinase(CK)were detected by ELISA kit.The mechanism of action of SalB on OGD/R-injured H9c2 cardiomyocytes was explored using high-through-put sequencing of the transcriptome.The binding of SalB to differential proteins was assessed using molecu-lar docking assays.Fatty acid content was determined using free fatty acid kits.The relative expressions of mRNA and protein of differential genes were verified by RT-qPCR and Western blot.The causal relationship between the target of action of SalB and heart failure was examined by Mendelian randomization experiment.Results SalB protected OGD/R-injured H9c2 cardio-myocytes and significantly reduced the levels of CK,LDH and AST compared with the blank control group.One hundred differential genes were screened by tran-scriptome sequencing,which were mainly involved in fatty acid elongation,central carbon metabolism of cancer,tryptophan metabolism pathways.Molecular docking showed that SalB had good binding energy to differential proteins.The mRNA and protein expression of core differential genes Elovl6,Echs1 and Acot1 were consistent with the transcriptome sequencing results.SalB reduced fatty acidsafter OGD/R injury.Mende-lian randomization experiments suggested that SalB might reduce the risk of heart failure through fatty acid metabolism,thereby reducing the risk of heart failure.Conclusion SalB can protect H9c2 cardiomyocytes after OGD/R injury by down-regulating Elovl6,Echs1 and Acot1 expression through the fatty acid metabolism pathway.

Objective To screen and analyze biomarkers of comorbidity in nonalcoholic fatty liver disease(NAFLD)and colorectal cancer(CRC)based on bioinformatics so as to explore the mechanism of comorbidity.Methods After data related to NAFLD and CRC were downloaded from the public database(GEO),gene set enrichment analysis(GSEA)was performed for all genes to screen the expression pathways,and the common differentially expressed genes of both genes were annotated by GO and KEGG functions.Subsequently,PPI protein interaction network was constructed using STRING online database to screen key genes,and transcription factor-gene regulatory network was constructed based on key genes,and biomarker genes were identified using LASSO regression.Finally,the transcription factor prediction analysis of key genes and SCD was conducted through Network Analyst database,and the transcription factor network was constructed.Results GSEA analysis revealed that signaling pathways such as TNF-α and IL-6-JAK-STAT3 were activated in NAFLD patients.The 17 common differentially expressed genes were mainly enriched in biological processes such as bivalent inorganic cation homeostasis and neutrophil chemotaxis in GO analysis.KEGG pathway analysis showed that common differentially expressed genes were mainly concentrated in IL-17 signaling pathway.The protein interaction network screened out five key genes:TREM1,FPR1,IL1RN,S100A9,and S100A8.IL1RN and SCD,identified by LASSO regression,were validated as biomarker genes using external datasets and immunohistochemistry data from the human protein atlas(HPA)database,showing high expression in CRC tissues.A transcription factor-key comorbidity gene regulatory network was constructed using Network Analyst.Conclusion The genes for comorbidities between NAFLD and colorectal cancer discovered by bioinformatics reveal the potential pathogenesis of comorbidities,and provide ideas for cancer screening and early diagnosis of colorectal cancer in NAFLD patients.

Objective:To explore the clinical characteristics of biliary system diseases complicated by severe acute pancreatitis(SAP) and the risk factors.Methods:This is a retrospective cohort study. A retrospective analysis was conducted on the clinical data of 159 SAP patients admitted to the Department of Pancreatic and Biliary Surgery,the First Affiliated Hospital of Harbin Medical University from January 2019 to October 2024. There were 105 male cases, 54 female cases;aged (42.3±10.8)years (range:20 to 71 years). Grouping was performed according to the presence or absence of concurrent acute acalculous cholecystitis (AAC) and biliary stricture. There were 58 cases in the AAC group,including 40 males and 18 females;aged (43.8±10.6) years (range:28 to 71 years);101 cases in the non-AAC group,including 64 males and 37 females;aged (41.5±10.8) years (range:20 to 64 years);there were statistically significant differences between the two groups in terms of admission total bilirubin,Balthazar-CTSI score,fasting time,and the proportions of concurrent shock and sepsis (all P<0.05);the time from onset of SAP to diagnosis of AAC( M (IQR)) was 10.5 (13.3) days (range: 3 to 34 days). There were 15 cases in the biliary stricture group,including 13 males and 2 females;age (46.5±10.0) years (range:33 to 63 years);141 cases in the non-biliary stricture group,including 89 males and 52 females;age (41.9±10.8) years (range: 20 to 71 years); there were statistically significant differences between the two groups in the proportions of infected pancreatic necrosis,pancreatic head necrosis,and lower extremity venous thrombosis (all P<0.05);the time from the onset of SAP to the diagnosis of biliary stenosis in patients with biliary stenosis was 2.0 (3.0) months (range: 1 to 19 months). Univariate analysis was performed using independent sample t-test, Mann-Whitney U test, χ 2 test,or Fisher′s exact probability method,and variables with P<0.05 in univariate analysis were included in multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic and predictive value of the multivariate logistic regression model for AAC and biliary stricture. Results:There were statistically significant differences in fasting time,Balthazar-CTSI score,admission total bilirubin,and the proportions of concurrent shock and sepsis between the AAC group and non-AAC group ( P<0.05). Multivariate logistic analysis showed that admission total bilirubin ( OR=1.033,95% CI: 1.010 to 1.058, P=0.004),Balthazar-CTSI score ( OR=1.276,95% CI: 1.036 to 1.572, P=0.022),fasting time ( OR=1.127,95% CI: 1.044 to 1.216, P=0.002), and sepsis ( OR=4.033, 95% CI: 1.419 to 11.462, P=0.009) were independent risk factors for AAC complicated by SAP. The area under the curve (AUC) of the ROC curve was 0.820 (95% CI: 0.752 to 0.888). There were statistically significant differences in the proportions of infected pancreatic necrosis,pancreatic head necrosis,and lower extremity venous thrombosis between the biliary stricture group and non-biliary stricture group ( P<0.05). Multivariate logistic analysis showed that infected pancreatic necrosis ( OR=7.376,95% CI:1.566 to 37.750, P=0.012) and pancreatic head necrosis ( OR=3.898,95% CI:1.180 to 12.877, P=0.026) were independent risk factors for biliary stricture complicated by SAP. The AUC of the ROC curve was 0.806 (95% CI:0.715 to 0.898). Conclusions:AAC typically occurs in the early stage of SAP,and biliary stricture usually occurs in the late stage of SAP. Admission total bilirubin,Balthazar-CTSI score,fasting duration,and concurrent sepsis are independent risk factors for AAC complicating SAP. Infected pancreatic necrosis and pancreatic head necrosis are independent risk factors for biliary stricture complicating SAP.

Background and purpose:The resistance of pancreatic cancer to albumin-bound paclitaxel affects the therapeutic effect and prognosis.Signal transducer and activator of transcription 3(STAT3)is one of the important molecules regulating the chemotherapy sensitivity of cancer cells.The liposome BP1003 targeting the antisense oligonucleotide of STAT3 mRNA can inhibit the expression of STAT3 and increase the chemotherapy sensitivity.However,the effect of BP1003 on the sensitivity of pancreatic cancer cells to albumin-bound paclitaxel remains unclear.The purpose of this study was to investigate the effects of liposome binding antisense oligonucleotide BP1003 on albumin-bound paclitaxel sensitivity in pancreatic cancer cells by inhibiting STAT3.Methods:Pancreatic cancer cell lines PANC-1 and ASPC-1 were cultured.They were divided into control group(without drugs),BP1003 group(200 μg/mL BP1003 intervention),different concentrations of albumin-bound paclitaxel group(5,10,20 nmol/L albumin-bound paclitaxel intervention),BP1003+different concentrations of albumin-bound paclitaxel group(200 μg/mL BP1003 combined with 5,10,20 nmol/L albumin-bound paclitaxel intervention).The proliferation viability,apoptotic rate and the protein expression levels of STAT3,STAT4,STAT6,Bcl-2,Bax and c-Myc were detected.The transplanted tumor model was established by subcutaneous injection of PANC-1 and ASPC-1 cell suspension in nude mice,which were divided into control group(normal saline intervention),BP1003 group(25 mg/kg BP1003 intervention,once every 2 weeks)and albumin-bound paclitaxel group(10 mg/kg albumin-bound paclitaxel,once a week),BP1003+albumin-bound paclitaxel group(25 mg/kg BP1003 intervention,once every 2 weeks combined with 10 mg/kg albumin-bound paclitaxel,once a week).Four weeks later,the graft volume and mass were measured,and the protein expression levels of STAT3,Bcl-2,Bax and c-Myc were detected.Results:The apoptotic rate and the protein expression levels of Bax of PANC-1 and ASPC-1 cells in BP1003 group and albumin-bound paclitaxel group were higher than those in the control group,while the proliferation viability and protein expression levels of STAT3,Bcl-2 and c-Myc were lower than those in control group(P＜0.05).There was no significant difference in the expression levels of STAT4 and STAT6 in PANC-1 and ASPC-1 cells between BP1003 group and the control group(P＞0.05).The apoptotic rate and the protein expression levels of Bax of PANC-1 and ASPC-1 cells in BP1003+different concentrations of albumin-bound paclitaxel groups were higher than those in different concentrations of albumin-bound paclitaxel groups,and the proliferation viability and protein expression levels of STAT3,Bcl-2 and c-Myc were lower than those in different concentrations of albumin-bound paclitaxel groups(P＜0.05).The volume and mass of transplanted tumor and the protein expression levels of STAT3,Bcl-2 and c-Myc of nude mice in BP1003 group,albumin-bound paclitaxel group and BP1003+albumin-bound paclitaxel group were all lower compared with the control group,the protein expression level of Bax was higher compared with the control group(P＜0.05),and the above changes in BP1003+albumin-bound paclitaxel group were more significant compared with BP1003 and albumin-bound paclitaxel group.Conclusion:BP1003 increases the sensitivity of pancreatic cancer cells to albumin-bound paclitaxel by inhibiting the expression of STAT3.