Objective To compare the application effect of different doses of rivaroxaban on anticoagulation therapy in patients with pulmonary thromboembolism(PTE)during maintenance period,and to evaluate its benefit-risk.Methods The patients with PTE were divided into conventional-dose group and low-dose group according to the cohort method.Conventional-dose group were given of rivaroxaban 15 mg,twice a day and changed to 20 mg once a day after 3 weeks;low-dose group were given rivaroxaban 10 mg twice a day and changed to 15 mg once a day after 3 weeks,and the anticoagulation treatment time in both groups was ≥ 3 months.The clinical efficacy in the two groups was recorded.Serum indicators[D-dimer(D-D),N-terminal pro-brain natriuretic peptide(NT-proBNP),cardiac troponin Ⅰ(cTn Ⅰ)]and liver-kidney function[glutamic-pyruvic transaminase(GPT),glutamic-oxaloacetic transaminase(GOT),blood urea nitrogen(BUN),creatinine(Cr)]were compared before treatment and after 3 months of treatment.The patients were followed up for 3 months after treatment,and the endpoint events such as PTE recurrence and death and the bleeding events were recorded in the two groups.Results There were 42 cases in conventional-dose group,44 cases in low-dose group.After 3 months of treatment,the total effective rates in low-dose group and conventional-dose group were both 100.00％,with no significant difference(P＞0.05).After 3 months of treatment,serum D-D levels in low-dose group and conventional-dose group were(0.31±0.08)and(0.29±0.07)mg·L-1,NT-proBNP levels were(125.49±24.16)and(121.39±22.08)ng·L-1,cTn Ⅰ levels were(0.02±0.00)and(0.02±0.00)μg·L-1,all with significant differences(all P＞0.05).There were no significant changes in GPT,GOT,BUN and Cr in the two groups before and after treatment(all P＞0.05),and there were no statistically significant differences between the two groups(all P＞0.05).The total incidences of bleeding events during follow-up was 6.82％in low-dose group and was 23.81％in conventional-dose group(P＜0.05).Conclusion Compared with conventional-dose rivaroxaban,low-dose rivaroxaban has similar anticoagulant effect,but the latter one can better reduce the risk of bleeding events in patients with PTE.

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

Benzene, as a major indoor pollutant, has received widespread attention. In order to better control indoor benzene pollution and protect people's health, the limit value of benzene in the"Standards for indoor air quality (GB/T 18883-2022)'' was reduced from 0.11 mg/m³ to 0.03 mg/m³. This study reviewed and discussed the relevant technical contents of the determination of benzene limit value, including the exposure status of benzene, health effects, and derivation of the limit value. It also proposed prospects for the future direction of formulating indoor air benzene standards.
Humans ; Air Pollution, Indoor/prevention & control* ; Benzene/analysis* ; Air Pollutants/analysis* ; Environmental Pollutants ; China ; Environmental Monitoring

Benzene, as a major indoor pollutant, has received widespread attention. In order to better control indoor benzene pollution and protect people's health, the limit value of benzene in the"Standards for indoor air quality (GB/T 18883-2022)'' was reduced from 0.11 mg/m³ to 0.03 mg/m³. This study reviewed and discussed the relevant technical contents of the determination of benzene limit value, including the exposure status of benzene, health effects, and derivation of the limit value. It also proposed prospects for the future direction of formulating indoor air benzene standards.
Humans ; Air Pollution, Indoor/prevention & control* ; Benzene/analysis* ; Air Pollutants/analysis* ; Environmental Pollutants ; China ; Environmental Monitoring

Objective: To investigate the functional changes of key gut microbiota (GM) that produce lipopolysaccharide (LPS) in atrial fibrillation (AF) patients and to explore their potential role in the pathogenesis of AF. Methods: This was a prospective cross-sectional study. Patients with AF admitted to Beijing Chaoyang Hospital of Capital Medical University were enrolled from March 2016 to December 2018. Subjects with matched genetic backgrounds undergoing physical examination during the same period were selected as controls. Clinical baseline data and fecal samples were collected. Bacterial DNA was extracted and metagenomic sequencing was performed by using Illumina Novaseq. Based on metagenomic data, the relative abundances of KEGG Orthology (KO), enzymatic genes and species that harbored enzymatic genes were acquired. The key features were selected via the least absolute shrinkage and selection operator (LASSO) analysis. The role of GM-derived LPS biosynthetic feature in the development of AF was assessed by receiver operating characteristic (ROC) curve, partial least squares structural equation modeling (PLS-SEM) and logistic regression analysis. Results: Fifty nonvalvular AF patients (mean age: 66.0 (57.0, 71.3), 32 males(64%)) were enrolled as AF group. Fifty individuals (mean age 55.0 (50.5, 57.5), 41 males(82%)) were recruited as controls. Compared with the controls, AF patients showed a marked difference in the GM genes underlying LPS-biosynthesis, including 20 potential LPS-synthesis KO, 7 LPS-biosynthesis enzymatic genes and 89 species that were assigned as taxa harbored nine LPS-enzymatic genes. LASSO regression analysis showed that 5 KO, 3 enzymatic genes and 9 species could be selected to construct the KO, enzyme and species scoring system. Genes enriched in AF group included 2 KO (K02851 and K00972), 3 enzymatic genes (LpxH, LpxC and LpxK) and 7 species (Intestinibacter bartlettii、Ruminococcus sp. JC304、Coprococcus catus、uncultured Eubacterium sp.、Eubacterium sp. CAG:251、Anaerostipes hadrus、Dorea longicatena). ROC curve analysis revealed the predictive capacity of differential GM-derived LPS signatures to distinguish AF patients in terms of above KO, enzymatic and species scores: area under curve (AUC)=0.957, 95%CI: 0.918-0.995, AUC=0.940, 95%CI 0.889-0.991, AUC=0.972, 95%CI 0.948-0.997. PLS-SEM showed that changes in lipopolysaccharide-producing bacteria could be involved in the pathogenesis of AF. The key KO mediated 35.17% of the total effect of key bacteria on AF. After incorporating the clinical factors of AF, the KO score was positively associated with the significantly increased risk of AF (OR<0.001, 95%CI:<0.001-0.021, P<0.001). Conclusion: Microbes involved in LPS synthesis are enriched in the gut of AF patients, accompanied with up-regulated LPS synthesis function by encoding the LPS-enzymatic biosynthesis gene.
Aged ; Atrial Fibrillation/complications* ; Cross-Sectional Studies ; Gastrointestinal Microbiome ; Humans ; Lipopolysaccharides ; Male ; Middle Aged ; Prospective Studies

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Objective:To evaluate the current situation of comprehensive medical and health services of primary medical institutions in a city under the policy of family doctor contracted service, and explore the influencing factors and put forward improvement strategies, for the reference to improve the medical and health service level of primary medical institutions.Methods:In January 2021, 18 primary medical institutions in 3 counties(cities, districts) of a city in Shandong province were selected by stratified sampling method, and 60-70 contracted residents were selected from each institution for questionnaire survey. The questionnaire covered two dimensions: service provision(19 items) and metion frequency of health problems(12 items). According to the principle of information saturation, qualitative interviews were conducted with 20 family doctors and 15 contracted residents to identify the current service needs and existing problems. Descriptive analysis was used for all data, and single factor analysis of variance and multiple linear regression analysis were used for influencing factors of comprehensive service scores of primary medical institutions.Results:1 098 contracted residents were included in this study, and the comprehensive service score was 3.15±0.42. The vaccination, maternal health care and health education scored higher with 3.80±0.54, 3.70±0.64, 3.78±0.57 respectively; The dermatology, mental health counseling and family sickbed scored lower, with 2.27±1.20, 2.97±1.01 and 1.92±1.18 respectively. Contracted institution, gender, age and marital status were the influencing factors of comprehensive service scores( P<0.05). Residents′ needs for family sickbeds, psychological counseling and fall prevention had not been met. Conclusions:The primary medical institutions of the city had provided better basic public health services, while unmet needs were demand for home sickbeds, psychological counseling and fall prevention. We should take effective measures to increase the service supply based on the needs of residents, and provide more comprehensive medical and health services for residents at primary medical institutions.

AIM: To study the distribution of CYP2C9∗3 and VKORC1-1639G>A gene polymorphism in Han population in Anhui province and their influence on the stable dose of warfarin. METHODS: The blood samples of 1 169 patients from 6 tertiary general hospitals in 5 areas of Anhui province from January 2020 to December 2021 were selected, the genotype of CYP2C9∗3 and VKORC1-1639G>A was detected by fluorescent staining in situ hybridization technique. RESULTS: The distribution of CYP2C9∗3 genotypes in 1 169 patients: the frequencies of AA, AC and CC genes were 90.16%, 9.24% and 0.60%, respectively; The distribution of VKORC1 genotype: the frequencies of AA, AG and GG genes were 84.26%, 14.71% and 1.03% respectively; There was no significant difference between the two genotypes in gender, age and regional distribution (P>0.05). The average daily warfarin dose of CYP2C9∗3 AA genotype in 755 patients with stable warfarin dose was (3.02±0.59) mg/d, which was significantly higher than patients with AC genotype and CC genotype; The average daily warfarin dose of patients with VKORC1-1639AA genotype was (2.72±0.40) mg/d, which was significantly lower than that of patients with AG genotype and GG genotype (P<0.05). And the difference was statistically significant (P<0.05); There are significant differences in gender, age and clinical diagnosis between patients with stable dose of warfarin and those without stable dose (P<0.05). CONCLUSION: CYP2C9 and VKORC1 genotypes are associated with the stable dose of warfarin. Clinical anticoagulation therapy guided by CYP2C9 and VKORC1 genotypes can provide guidance for individualized medication of warfarin.

Although computational approaches have been complementing high-throughput biolog-ical experiments for the identification of functional regions in the human genome,it remains a great challenge to systematically decipher interactions between transcription factors(TFs)and regulatory elements to achieve interpretable annotations of chromatin accessibility across diverse cellular con-texts.To solve this problem,we propose DeepCAGE,a deep learning framework that integrates sequence information and binding statuses of TFs,for the accurate prediction of chromatin acces-sible regions at a genome-wide scale in a variety of cell types.DeepCAGE takes advantage of a den-sely connected deep convolutional neural network architecture to automatically learn sequence signatures of known chromatin accessible regions and then incorporates such features with expres-sion levels and binding activities of human core TFs to predict novel chromatin accessible regions.In a series of systematic comparisons with existing methods,DeepCAGE exhibits superior perfor-mance in not only the classification but also the regression of chromatin accessibility signals.In a detailed analysis of TF activities,DeepCAGE successfully extracts novel binding motifs and mea-sures the contribution of a TF to the regulation with respect to a specific locus in a certain cell type.When applied to whole-genome sequencing data analysis,our method successfully prioritizes puta-tive deleterious variants underlying a human complex trait and thus provides insights into the understanding of disease-associated genetic variants.

OBJECTIVE: To investigate specific technique and clinical effects of closed folding top consolidation maneuver combined with splint fixation maneuver for consolidation and cedar bark external fixation splint for the treatment of double fractures of distal ulna and radius in children. METHODS: From January 2017 to December 2019, 17 children with double fractures of distal ulna and radius were treated with closed folded apex consolidation maneuver, including 13 males and 4 females, aged from 4 to 11 years old with an average of (7.29±2.34) years old. The fractures were fixed with cedar bark splint and followed up for 6 months, and alignment of fracture was evaluated according to the latest X-rays by follow up, and function of the affected limbs was evaluated by Anderson forearm function evaluation criteria. RESULTS: Fifteen of 17 children were successfully reset immediately, and 2 children were successfully reset again. The average fixed time was (25.00±3.35) days. At 6 months of follow up, 12 patients got excellent results, 3 good, 2 fair, and 0 poor according to Anderson forearm function evaluation criteria. The position of all children were larger than 3/4, and 10 children were received anatomical reduction, alignment of 4 children was less than 10°, 3 children was less than 15°. No complications such as fracture displacement, nonunion, compartment syndrome, and forearm rotation dysfunction occurred. CONCLUSION Restoration of distal radius double fracture in children with the combination of the closed folding and top fixation maneuver and splint fixation maneuver has advantages of higher success rate, lower complications, which could reduce operating difficultyand pain of patients.
Aged ; Child ; Child, Preschool ; Female ; Fracture Fixation ; Fracture Fixation, Internal ; Humans ; Male ; Radius ; Radius Fractures/therapy* ; Splints ; Treatment Outcome ; Ulna ; Ulna Fractures