SIRT1 inhibits apoptosis of human lens epithelial cells through suppressing endoplasmic reticulum stress in vitro and in vivo

AIM:To explore the effect of silent information regulator factor 2-related enzyme 1(SIRT1)on modulating apoptosis of human lens epithelial cells(HLECs)and alleviating lens opacification of rats through suppressing endoplasmic reticulum(ER)stress.METHODS:HLECs(SRA01/04)were treated with varying concentrations of tunicamycin(TM)for 24h,and the expression of SIRT1 and C/EBP homologous protein(CHOP)was assessed using real-time quantitative polymerase chain reaction(RT-PCR),Western blotting,and immunofluorescence.Cell morphology and proliferation was evaluated using an inverted microscope and cell counting kit-8(CCK-8)assay,respectively.In the SRA01/04 cell apoptosis model,which underwent siRNA transfection for SIRT1 knockdown and SRT1720 treatment for its activation,the expression levels of SIRT1,CHOP,glucose regulated protein 78(GRP78),and activating transcription factor 4(ATF4)were examined.The potential reversal of SIRT1 knockdown effects by 4-phenyl butyric acid(4-PBA;an ER stress inhibitor)was investigated.In vivo,age-related cataract(ARC)rat models were induced by sodium selenite injection,and the protective role of SIRT1,activated by SRT1720 intraperitoneal injections,was evaluated through morphology observation,hematoxylin and eosin(H&E)staining,Western blotting,and RT-PCR.RESULTS:SIRT1 expression was downregulated in TMinduced SRA01/04 cells.Besides,in SRA01/04 cells,both cell apoptosis and CHOP expression increased with the rising doses of TM.ER stress was stimulated by TM,as evidenced by the increased GRP78 and ATF4 in the SRA01/04 cell apoptosis model.Inhibition of SIRT1 by siRNA knockdown increased ER stress activation,whereas SRT1720 treatment had opposite results.4-PBA partly reverse the adverse effect of SIRT1 knockdown on apoptosis.In vivo,SRT1720 attenuated the lens opacification and weakened the ER stress activation in ARC rat models.CONCLUSION:SIRT1 plays a protective role against TM-induced apoptosis in HLECs and slows the progression of cataract in rats by inhibiting ER stress.These findings suggest a novel strategy for cataract treatment focused on targeting ER stress,highlighting the therapeutic potential of SIRT1 modulation in ARC development.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

Postoperative efficacy,safety,predictability,and visual quality of implantable collamer lens implantation versus small incision lenticule extraction in myopic eyes:a Meta-analysis

AIM:To compare the postoperative efficacy,safety,predictability,and visual quality of implantable collamer lens(ICL)implantation versus small incision lenticule extraction(SMILE)in myopia eyes.METHODS:Pub Med,EMBASE,Web of Science,Cochrane Library and several Chinese databases were searched at May 2021 to select relevant studies in comparison of clinical outcomes between ICL implantation and SMILE for myopia.The primary outcomes were efficacy,safety,and predictability.And the secondary outcomes were postoperative higher-order ocular aberrations(HOAs),modulation transfer function cutoff frequency(MTF),objective scatter index(OSI),contrast sensitivity and a quality of vision(Qo V)questionnaire.RESULTS:A total of 1036 eyes from 10 studies,of which 503 eyes underwent ICL implantation and 533 eyes underwent SMILE,were enrolled in this Meta-analysis.Pooled results revealed that ICL group had a better safety index and post-corrected distance visual acuity(CDVA)(P=0.007,<0.00001,respectively),and a lower percentage of eyes with a postoperative CDVA lost 1 line(P=0.007)than the SMILE group.No significant differences were found in comparison of the other primary outcomes.In the longterm follow-up(>6mo),ICL group had a lower total HOA,coma,and spherical aberration than SMILE group(P=0.003,<0.00001,0.04).Yet higher trefoil was found in ICL group at 6mo after surgery(P=0.003).Additionally,ICL group also had a higher MTF value(P=0.02),and a higher contrast sensitivity score for spatial frequencies of 1.5,6,and 12 cpds(P=0.02,0.005,0.02,respectively).And it also had a lower score of bothersome in Qo V questionnaire than SMILE group(P=0.003).CONCLUSION:ICL implantation and SMILE have similar and comparable outcomes in term of the efficacy and predictability for correcting high myopia.However,ICL group is relatively safer and also has better visual quality in comparison of SMILE group.

Plasma exosomal hsa_circ_0079439 as a novel biomarker for early detection of gastric cancer

BACKGROUND Due to the poor prognosis of gastric cancer(GC),early detection methods are urgently needed.Plasma exosomal circular RNAs(circRNAs)have been suggested as novel biomarkers for GC.AIM To identify a novel biomarker for early detection of GC.METHODS Healthy donors(HDs)and GC patients diagnosed by pathology were recruited.Nine GC patients and three HDs were selected for exosomal whole-transcriptome RNA sequencing.The expression profiles of circRNAs were analyzed by bioinformatics methods and validated by droplet digital polymerase chain reaction.The expression levels and area under receiver operating characteristic curve values of plasma exosomal circRNAs and standard serum biomarkers were used to compare their diagnostic efficiency.RESULTS There were 303 participants,including 240 GC patients and 63 HDs,involved in the study.The expression levels of exosomal hsa_circ_0079439 were significantly higher in GC patients than in HDs(P<0.0001).However,the levels of standard serum biomarkers were similar between the two groups.The area under the curve value of exosomal hsa_circ_0079439 was higher than those of standard biomarkers,including carcinoembryonic antigen,carbohydrate antigen(CA)19-9,CA72-4,alpha-fetoprotein,and CA125(0.8595 vs 0.5862,0.5660,0.5360,0.5082,and 0.5018,respectively).The expression levels of exosomal hsa_circ_0079439 were significantly decreased after treatment(P<0.05).Moreover,the expression levels of exosomal hsa_circ_0079439 were obviously higher in early GC(EGC)patients than in HDs(P<0.0001).CONCLUSION Our results suggest that plasma exosomal hsa_circ_0079439 is upregulated in GC patients.Moreover,the levels of exosomal hsa_circ_0079439 could distinguish EGC and advanced GC patients from HDs.Therefore,plasma exosomal hsa_circ_0079439 might be a potential biomarker for the diagnosis of GC during both the early and late stages.

Evaluation of metoprolol standard dosing pathway in Chinese patients with acute coronary syndrome:a prospective multicenter single-arm interventional study

OBJECTIVE To evaluate the feasibility and tolerability of metoprolol standard dosing pathway(MSDP)in Chinese patients with acute coronary syndrome(ACS).METHODS In this multicenter,prospective,open label,single-arm and interventional study that was conducted from February 2018 to April 2019 in fifteen Chinese hospitals.A total of 998 hospitalized patients aged≥18 years and diagnosed with ACS were included.The MSDP was applied to all eligible ACS patients based on the standard treatment recommended by international guidelines.The primary endpoint was the percentage of patients achieving the target dose at discharge(V2).The secondary endpoints included the heart rate and blood pressure at V2 and four weeks after discharge(V4),and percentage of patients experiencing bradycardia(heart rate<50 beats/min),hypotension(blood pressure<90/60 mmHg)and transient cardiac dysfunction at V2 and V4.RESULTS Of the 998 patients,29.46%of patients achieved the target dose(≥95 mg/d)at V2.The total population was divided into two groups:target group(patients achieving the target dose at V2)and non-target group(patients not achieving the target dose at V2).There was significant difference in the reduction of heart rate from baseline to discharge in the two groups(-4.97±11.90beats/min vs.-2.70±9.47 beats/min,P=0.034).There was no significant difference in the proportion of bradycardia that occurred in the two groups at V2(0 vs.0,P=1.000)and V4(0.81%vs.0.33%,P=0.715).There was no significant difference in the proportion of hypotension between the two groups at V2(0.004%vs.0.004%,P=1.000)and V4(0 vs.0.005%,P=0.560).No transient cardiac dysfunction occurred in two groups during the study.A total of five adverse events(1.70%)and one serious adverse event(0.34%)were related to the pathway in target group.CONCLUSIONS In Chinese ACS patients,the feasibility and tolerability of the MSDP have been proved to be acceptable.

In vivo imaging of the neuronal response to spinal cord injury:a narrative review

Deciphering the neuronal response to injury in the spinal cord is essential for exploring treatment strategies for spinal cord injury(SCI).However,this subject has been neglected in part because appropriate tools are lacking.Emerging in vivo imaging and labeling methods offer great potential for observing dynamic neural processes in the central nervous system in conditions of health and disease.This review first discusses in vivo imaging of the mouse spinal cord with a focus on the latest imaging techniques,and then analyzes the dynamic biological response of spinal cord sensory and motor neurons to SCI.We then summarize and compare the techniques behind these studies and clarify the advantages of in vivo imaging compared with traditional neuroscience examinations.Finally,we identify the challenges and possible solutions for spinal cord neuron imaging.

Artificial intelligence in the anterior segment of eye diseases

Ophthalmology is a subject that highly depends on imaging examination.Artificial intelligence(AI)technology has great potential in medical imaging analysis,including image diagnosis,classification,grading,guiding treatment and evaluating prognosis.The combination of the two can realize mass screening of grass-roots eye health,making it possible to seek medical treatment in the mode of“first treatment at the grass-roots level,two-way referral,emergency and slow treatment,and linkage between the upper and lower levels”.On the basis of summarizing the AI technology carried out by scholars and their teams all over the world in the field of ophthalmology,quite a lot of studies have confirmed that machine learning can assist in diagnosis,grading,providing optimal treatment plans and evaluating prognosis in corneal and conjunctival diseases,ametropia,lens diseases,glaucoma,iris diseases,etc.This paper systematically shows the application and progress of AI technology in common anterior segment ocular diseases,the current limitations,and prospects for the future.

Analysis of metabolic characteristics of metabolic syndrome in elderly patients with gastric cancer by non-targeted metabolomics

BACKGROUND The relationship between metabolic syndrome(MetS)and gastric cancer(GC),which is a common metabolic disease,has attracted much attention.However,the specific metabolic characteristics of MetS in elderly patients with GC remain unclear.AIM To investigate the differentially abundant metabolites and metabolic pathways between preoperative frailty and MetS in elderly patients with GC based on nontargeted metabolomics techniques.METHODS In this study,125 patients with nonfrail nonmeal GC were selected as the control group,and 50 patients with GC in the frail group were selected as the frail group.Sixty-five patients with GC combined with MetS alone were included in the MetS group,and 50 patients with GC combined with MetS were included in the MetS group.Nontargeted metabolomics techniques were used to measure plasma metabolite levels by ultrahigh-performance liquid chromatography-mass spectrometry.Multivariate statistical analysis was performed by principal component analysis,orthogonal partial least squares,pattern recognition analysis,cluster analysis,and metabolic pathway annotation.RESULTS A total of 125 different metabolites,including amino acids,glycerophospholipids,sphingolipids,fatty acids,sugars,nucleosides and nucleotides,and acidic compounds,were identified via nontargeted metabolomics techniques.Compared with those in the control group,there were 41,32,and 52 different metabolites in the MetS group,the debilitated group,and the combined group,respectively.Lipid metabolites were significantly increased in the MetS group.In the weak group,amino acids and most glycerol phospholipid metabolites decreased significantly,and fatty acids and sphingosine increased significantly.The combined group was characterized by significantly increased levels of nucleotide metabolites and acidic compounds.The alanine,aspartic acid,and glutamate metabolic pathways were obviously enriched in the asthenic group,and the glycerol and phospholipid metabolic pathways were obviously enriched in the combined group.CONCLUSION Elderly GC patients with simple frailty,simple combined MetS,and frailty combined with MetS have different metabolic characteristics,among which amino acid and glycerophospholipid metabolite levels are significantly lower in frail elderly GC patients,and comprehensive supplementation of fat and protein should be considered.Many kinds of metabolites,such as amino acids,lipids,nucleotides,and acidic compounds,are abnormally abundant in patients with MetS combined with fthenia,which may be related to tumor-related metabolic disorders.

Anti-PD1 antibody and not anti-LAG-3 antibody improves the antitumor effect of photodynamic therapy for treating metastatic breast cancer

Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

Association of preoperative antiviral treatment with incidences of post-hepatectomy liver failure in hepatitis B virus-related hepatocellular carcinoma

BACKGROUND Post-hepatectomy liver failure(PHLF)is a common consequence of radical partial hepatectomy in hepatocellular carcinoma(HCC).AIMS To investigate the relationship between preoperative antiviral therapy and PHLF,as well as assess the potential efficacy of hepatitis B virus(HBV)DNA level in predicting PHLF.METHODS A retrospective study was performed involving 1301 HCC patients with HBV who underwent radical hepatectomy.Receiver operating characteristic(ROC)analysis was used to assess the capacity of HBV DNA to predict PHLF and establish the optimal cutoff value for subsequent analyses.Logistic regression analyses were performed to assess the independent risk factors of PHLF.The increase in the area under the ROC curve,categorical net reclassification improvement(NRI),and integrated discrimination improvement(IDI)were used to quantify the efficacy of HBV DNA level for predicting PHLF.The P<0.05 was considered statistically significant.RESULTS Logistic regression analyses showed that preoperative antiviral therapy was independently associated with a reduced risk of PHLF(P<0.05).HBV DNA level with an optimal cutoff value of 269 IU/mL(P<0.001)was an independent risk factor of PHLF.All the reference models by adding the variable of HBV DNA level had an improvement in area under the curve,categorical NRI,and IDI,particularly for the fibrosis-4 model,with values of 0.729(95%CI:0.705-0.754),1.382(95%CI:1.341-1.423),and 0.112(95%CI:0.110-0.114),respectively.All the above findings were statistically significant.CONCLUSION In summary,preoperative antiviral treatment can reduce the incidence of PHLF,whereas an increased preoperative HBV DNA level has a correlative relationship with an increased susceptibility to PHLF.

Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.

Prevalence of pulmonary embolism at autopsy among elderly patients in a Chinese general hospital

Objectives To investigate the prevalence and characteristics of pulmonary embolism （PE） at autopsy in a Chinese general hospital over a period of 10 years, and to evaluate the antemortem achievement of the prophylaxis, diagnosis, and treatment of PE. Methods All medical records of deaths from the West Branch of the Chinese People＇s Liberation Army （PLA） General Hospital were retrospectively re- viewed, for the period of January 1, 2006 to December 31, 2015. Cases in which autopsies had been performed were identified and further analyzed. The numbers and detailed characteristics of patients who had PEs were noted. Prophylactic measures, along with diagnosis and treatment of PE, were recorded, if performed. Results During the 10-year period, 1057 patients died in the study hospital and 278 necrop- sies were performed （autopsy rate： 26.3%）. Nine patients were found to have PE （3.2%）, and in seven of these patients （2.5%）, the PE was considered to be fatal. Embolisms were found in the trunk and bilateral main branches of the pulmonary artery tree in all seven of the fatal PE cases. Right intracardiac thrombosis was detected in five of the nine PE patients （55.6%）. All patients with PE had been hospitalized in medical departments, and only one had undergone surgery during hospitalization. Antemortem prophylaxis was performed in two of the nine PE cases （22.2%）. None of the 9 patients had received a clinical diagnosis of PE before death. Conclusions The incidence of and death rate associated with PE may vary among different races and regions. Continuous monitoring of PE by means of necropsy in certain representative medical institutions is necessary.

Prediction of early recurrence of hepatocellular carcinoma after liver transplantation based on computed tomography radiomics nomogram

Background:Early recurrence results in poor prognosis of patients with hepatocellular carcinoma(HCC)after liver transplantation(LT).This study aimed to explore the value of computed tomography(CT)-based radiomics nomogram in predicting early recurrence of patients with HCC after LT.Methods:A cohort of 151 patients with HCC who underwent LT between December 2013 and July 2019 were retrospectively enrolled.A total of 1218 features were extracted from enhanced CT images.The least absolute shrinkage and selection operator algorithm(LASSO)logistic regression was used for dimension reduction and radiomics signature building.The clinical model was constructed after the analysis of clin-ical factors,and the nomogram was constructed by introducing the radiomics signature into the clinical model.The predictive performance and clinical usefulness of the three models were evaluated using re-ceiver operating characteristic(ROC)curve analysis and decision curve analysis(DCA),respectively.Cali-bration curves were plotted to assess the calibration of the nomogram.Results:There were significant differences in radiomics signature among early recurrence patients and non-early recurrence patients in the training cohort(P<0.001)and validation cohort(P<0.001).The nomogram showed the best predictive performance,with the largest area under the ROC curve in the training(0.882)and validation(0.917)cohorts.Hosmer-Lemeshow testing confirmed that the nomogram showed good calibration in the training(P=0.138)and validation(P=0.396)cohorts.DCA showed if the threshold probability is within 0.06-1,the nomogram had better clinical usefulness than the clinical model.Conclusions:Our CT-based radiomics nomogram can preoperatively predict the risk of early recurrence in patients with HCC after LT.

Oral administration of asparagine and 3-indolepropionic acid prolongs survival time of rats with traumatic colon injury

Background: Traumatic colon injury(TCI) is a common disease during wartime. Prolongation of posttraumatic survival time is an effective approach to patient outcome improvement. However, there is a lack of basic research in this field.This study aimed to elucidate the mechanisms underlying TCI progression and to develop novel regimens to buy time for TCI patients on the battlefield.Methods: A total of 669 Sprague–Dawley rats were used in this study. Surgical colon incision was performed to generate the TCI rat model. The landscape of colon microbiota compositions was depicted using 16S rRNA sequencing and metabolites in the intestinal contents were detected by metabolomics profiling. The signaling transduction in the intestinal epithelium was investigated using antibody microarrays and Western blotting. The enzyme-linked immunosorbent assay(ELISA) was conducted to measure the levels of interleukin-6 and tumor necrosis factor-α in intestines and plasma for the detection of inflammatory responses. Diamine oxidase, D-lactate and endotoxin in plasma and protein expression of zonula occludens 1 and occludin were selected as the indicators of intestinal barrier permeability. To investigate alterations of microbiota symbiosis, the relative abundances of specific bacterial genera were detected using quantitative real-time PCR(qRT-PCR).Results: As a type of lethal injury, TCI induced acute disruption of intestinal homeostasis, characterized by inflammatory responses, intestinal barrier hyperpermeability and microbiota dysbiosis(P<0.05). Significant alterations in bacterial metabolic patterns were detected with decreases in many metabolites. After a series of screenings,we found that oral administration of asparagine(Asn) and 3-indolepropionic acid(IPA) effectively prolonged posttraumatic survival time [Asn plus IPA vs. Vehicle: hazard ratio(HR)=0.105, 95%CI 0.031–0.356, P=0.0003] and restored intestinal homeostasis in TCI rats(P<0.05). Mechanistically, this combinational strategy protected the rats against TCI through synergistic activation of Akt signaling in the intestinal epithelium(P<0.05).Conclusions: Abrupt dysregulation of intestinal homeostasis plays a critical role in the progression toward TCI induced death. Oral administration of Asn plus IPA may serve as an effective regimen to restore intestinal functions and prolong the posttraumatic survival time.

Causal effects of circulating vitamin levels on the risk of heart failure:a Mendelian randomization study

BACKGROUND Observational studies suggest inverse associations between serum vitamin levels and the risk of heart failure(HF). However, the causal effects of vitamins on HF have not been fully elucidated. Here, we conducted a Mendelian randomization(MR) study to investigate the causal associations between genetically determined vitamin levels and HF.METHODS Genetic instrumental variables for circulating vitamin levels, including vitamins A, B, C, D, and E, which were assessed as either absolute or metabolite levels were obtained from public genome-wide association studies. Summary statistics for single-nucleotide-polymorphisms and HF associations were retrieved from the HERMES Consortium(47,309 cases and 930,014controls) and FinnGen Study(30,098 cases and 229,612 controls). Two-sample MR analyses were implemented to assess the causality between vitamin levels and HF per outcome database, and the results were subsequently combined by meta-analysis.RESULTS Our MR study did not find significant associations between genetically determined circulating vitamin levels and HF risk. For absolute vitamin levels, the odds ratio for HF ranged from 0.97(95% confidence interval [CI]: 0.85–1.09, P = 0.41) for vitamin C to 1.05(95% CI: 0.61–1.82, P = 0.85) for vitamin A. For vitamin metabolites, the odds ratio ranged between 0.94(95% CI:0.75–1.19, P = 0.62) for α-tocopherol and 1.11(95% CI: 0.98–1.26, P = 0.09) for γ-tocopherol.CONCLUSION Evidence from our study does not support the causal effects of circulating vitamin levels on HF. Therefore,there may be no direct beneficial effects of vitamin intake on the prevention of primary HF.

The first attempt for closure of the patent foramen ovale under guidance of teleoperation ultrasonic robot:a case report

Patent foramen ovale(PFO)is a remnant of normal fetal anatomy,which occurs in about 20%–25%of cases.Patients with PFO are at increased risk for migraine,acute limb ischemia secondary to emboli and cryptogenic(no other identifiable cause)stroke.The traditional approach has been to use a fluoroscopically guided blocking device,but this is contraindicated in patients with severe allergies to contrast media or inability to undergo angiography.With the advancements in technology,ultrasonic robotic systems have become available for medical procedures.In the current study,we reported a case of using the ultrasonic robotic teleoperation system to achieve closure of PFO at the Chinese PLA General Hospital,Beijing,China.

Predictive validation of existing bleeding and thromboembolic scores in elderly patients with comorbid atrial fibrillation and acute coronary syndrome

BACKGROUND The validation of various risk scores in elderly patients with comorbid atrial fibrillation(AF)and acute coron-ary syndrome(ACS)has not been reported.The present study compared the predictive performance of existing risk scores in patients.these METHODS A total of 1252 elderly patients with AF and ACS comorbidities(≥65 years old)were consecutively enrolled from January 2015 to December 2019.All patients were followed up for one year.The predictive performance of risk scores in predict-bleeding and thromboembolic events was calculated and compared.ing RESULTS During the 1-year follow-up,183(14.6%)patients had thromboembolic events,198(15.8%)patients had BARC class≥2 bleeding events,and 61(4.9%)patients had BARC class≥3 bleeding events.For the BARC class≥3 bleeding events,discrimina-tion of the existing risk scores was low to moderate,PRECISE-DAPT(C-statistic:0.638,95%CI:0.611-0.665),ATRIA(C-statistic:0.615,95%CI:0.587-0.642),PARIS-MB(C-statistic:0.612,95%CI:0.584-0.639),HAS-BLED(C-statistic:0.597,95%CI:0.569-0.624)and CRUSADE(C-statistic:0.595,95%CI:0.567-0.622).However,the calibration was good.PRECISE-DAPT showed a higher in-tegrated discrimination improvement(IDI)than PARIS-MB,HAS-BLED,ATRIA,and CRUSADE(P<0.05)and the best decision curve analysis(DCA).For thromboembolic events,the discrimination of GRACE(C-statistic:0.636,95%CI:0.608-0.662)was higher than CHA2DS2-VASc(C-statistic:0.612,95%CI:0.584-0.639),OPT-CAD(C-statistic:0.602,95%CI:0.574-0.629)and PARIS-CTE(C-statistic:0.595,95%CI:0.567-0.622).The calibration was good.Compared to OPT-CAD and PARIS-CTE,the IDI of the GRACE score slightly improved(P<0.05).However,NRI analysis showed no significant difference.DCA showed that the clinical practic-of thromboembolic risk scores was similar.ability CONCLUSIONS The discrimination and calibration of existing risk scores in predicting 1-year thromboembolic and bleeding events were unsatisfactory in elderly patients with comorbid AF and ACS.PRECISE-DAPT showed higher IDI and DCA than other risk scores in predicting BARC class≥3 bleeding events.The GRACE score showed a slight advantage in predicting throm-botic events.

A world's first attempt of mixed-reality system guided inferior vena cava filter implantation under remote guidance of 5G communication

Deep vein thrombosis(DVT)is a manifestation of venous thromboembolism,which can result from long-term bed and lead to pulmonary embolism(PE),stroke,mesenteric artery embolis,etc.Patients after surgery without bed-off activity may prone to thrombosis,but traditional anticoagulant therapy is a contraindication for them because of high risk of postoperative hemorrhage.Inferior vena cava filter(IVCF)implantation is the most effective method to intercept thrombosis from lower limb and to prevent PE.However,radiation and contrast agent limit its application.Our team have successfully performed an IVCF implantation guided by a mixed-reality(MR)system,[1]which is a chance for critically ill patients to allow the IVCF implantation exposed under no Xray and require no contrast agent.5G can help remote holographic projection images between distant range,meeting the needs of experts to guide the operation of critically ill patients.We describe a case of weak woman after neurosurgery who can not tolerate traditional interventional surgery to prevent DVT from falling off.We performed a mixed-reality system guided IVCF implantation under remote guidance of 5G communication.

Malignant melanoma resection and reconstruction with the first manifestation of lumbar metastasis:A case report

BACKGROUND Malignant melanoma(MM)has shown an increasing incidence worldwide,and a potential to metastasize to almost any part of the body.Clinically,MM with bone metastasis as the initial manifestation is extremely rare.Spinal metastatic MM can cause spinal cord or nerve root compression,resulting in severe pain and paralysis.Currently,the primary clinical treatments for MM are surgical resection in conjunction with chemotherapy,radiotherapy,and immunotherapy.CASE SUMMARY Here,we report the case of a 52-year-old male who presented to the clinic with progressive low back pain and limited nerve function.No primary lesion or spinal cord compression was detected from computed tomography and magnetic resonance imaging of the lumbar vertebrae and positron emission tomography scan.A lumbar puncture biopsy confirmed the diagnosis of lumbar spine metastatic MM.Following surgical resection,the patient’s quality of life improved,symptoms were relieved,and comprehensive treatment was initiated,which prevented recurrence.CONCLUSION Spinal metastatic MM is clinically rare,and may cause neurological symptoms,including paraplegia.Currently,the clinical treatment plan consists of surgical resection in combination with chemotherapy,radiotherapy,and immunotherapy.