Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models

BACKGROUND Acute pancreatitis(AP)encompasses a spectrum of pancreatic inflammatory conditions,ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure.Given the challenges associated with obtaining human pancreatic samples,research on AP predominantly relies on animal models.In this study,we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models.AIM To investigate the shared molecular changes underlying the development of AP across varying severity levels.METHODS AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide(LPS).Additionally,using Ptf1αto drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J-hM3/Ptf1α(cre)mice were administered Clozapine N-oxide to induce AP.Subsequently,we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus(GEO)database.RESULTS Caerulein-induced AP showed severe inflammation and edema,which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis.Compared with the control group,RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model.Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD-like receptor signaling pathway,TLR signaling pathway,and NF-κB signaling pathway,alongside elevated levels of apoptosis-related pathways,such as apoptosis,P53 pathway,and phagosome pathway.The significantly elevated genes in the TLR and NOD-like receptor signaling pathways,as well as in the apoptosis pathway,were validated through quantitative real-time PCR experiments in animal models.Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood,while TLR1,TLR7,RIPK3,and OAS2 genes exhibited marked elevation in human AP.The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP.The transgenic mouse model hM3/Ptf1α(cre)successfully validated significant differential genes in the TLR and NOD-like receptor signaling pathways as well as the apoptosis pathway,indicating that these pathways represent shared pathological processes in AP across different models.CONCLUSION The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP,notably the MYD88 gene.Apoptosis holds a central position in the necrotic processes of AP,with TUBA1A and GADD45A genes exhibiting prominence in human AP.

Prediction model establishment and validation for enteral nutrition aspiration during hospitalization in patients with acute pancreatitis

BACKGROUND Acute pancreatitis(AP)is a disease caused by abnormal activation of pancreatic enzymes and can lead to self-digestion of pancreatic tissues and dysfunction of other organs.Enteral nutrition plays a vital role in the treatment of AP because it can meet the nutritional needs of patients,promote the recovery of intestinal function,and maintain the barrier and immune functions of the intestine.However,the risk of aspiration during enteral nutrition is high;once aspiration occurs,it may cause serious complications,such as aspiration pneumonia,and suffocation,posing a threat to the patient’s life.This study aims to establish and validate a prediction model for enteral nutrition aspiration during hospitalization in patients with AP.AIM To establish and validate a predictive model for enteral nutrition aspiration during hospitalization in patients with AP.METHODS A retrospective review was conducted on 200 patients with AP admitted to Chengdu Shangjin Nanfu Hospital,West China Hospital of Sichuan University from January 2020 to February 2024.Clinical data were collected from the electronic medical record system.Patients were randomly divided into a validation group(n=40)and a modeling group(n=160)in a 1:4 ratio,matched with 200 patients from the same time period.The modeling group was further categorized into an aspiration group(n=25)and a non-aspiration group(n=175)based on the occurrence of enteral nutrition aspiration during hospitalization.Univariate and multivariate logistic regression analyses were performed to identify factors influencing enteral nutrition aspiration in patients with AP during hospitalization.A prediction model for enteral nutrition aspiration during hospitalization was constructed,and calibration curves were used for validation.Receiver operating characteristic curve analysis was conducted to evaluate the predictive value of the model.RESULTS There was no statistically significant difference in general data between the validation and modeling groups(P>0.05).The comparison of age,gender,body mass index,smoking history,hypertension history,and diabetes history showed no statistically significant difference between the two groups(P>0.05).However,patient position,consciousness status,nutritional risk,Acute Physiology and Chronic Health Evaluation(APACHE-II)score,and length of nasogastric tube placement showed statistically significant differences(P<0.05)between the two groups.Multivariate logistic regression analysis showed that patient position,consciousness status,nutritional risk,APACHE-II score,and length of nasogastric tube placement were independent factors influencing enteral nutrition aspiration in patients with AP during hospitalization(P<0.05).These factors were incorporated into the prediction model,which showed good consistency between the predicted and actual risks,as indicated by calibration curves with slopes close to 1 in the training and validation sets.Receiver operating characteristic analysis revealed an area under the curve(AUC)of 0.926(95%CI:0.8889-0.9675)in the training set.The optimal cutoff value is 0.73,with a sensitivity of 88.4 and specificity of 85.2.In the validation set,the AUC of the model for predicting enteral nutrition aspiration in patients with AP patients during hospitalization was 0.902,with a standard error of 0.040(95%CI:0.8284-0.9858),and the best cutoff value was 0.73,with a sensitivity of 91.9 and specificity of 81.8.CONCLUSION A prediction model for enteral nutrition aspiration during hospitalization in patients with AP was established and demonstrated high predictive value.Further clinical application of the model is warranted.

Identification of risk factors and construction of a nomogram predictive model for post-stroke infection in patients with acute ischemic stroke

BACKGROUND Post-stroke infection is the most common complication of stroke and poses a huge threat to patients.In addition to prolonging the hospitalization time and increasing the medical burden,post-stroke infection also significantly increases the risk of disease and death.Clarifying the risk factors for post-stroke infection in patients with acute ischemic stroke(AIS)is of great significance.It can guide clinical practice to perform corresponding prevention and control work early,minimizing the risk of stroke-related infections and ensuring favorable disease outcomes.AIM To explore the risk factors for post-stroke infection in patients with AIS and to construct a nomogram predictive model.METHODS The clinical data of 206 patients with AIS admitted to our hospital between April 2020 and April 2023 were retrospectively collected.Baseline data and post-stroke infection status of all study subjects were assessed,and the risk factors for poststroke infection in patients with AIS were analyzed.RESULTS Totally,48 patients with AIS developed stroke,with an infection rate of 23.3%.Age,diabetes,disturbance of consciousness,high National Institutes of Health Stroke Scale(NIHSS)score at admission,invasive operation,and chronic obstructive pulmonary disease(COPD)were risk factors for post-stroke infection in patients with AIS(P<0.05).A nomogram prediction model was constructed with a C-index of 0.891,reflecting the good potential clinical efficacy of the nomogram prediction model.The calibration curve also showed good consistency between the actual observations and nomogram predictions.The area under the receiver operating characteristic curve was 0.891(95%confidence interval:0.839–0.942),showing predictive value for post-stroke infection.When the optimal cutoff value was selected,the sensitivity and specificity were 87.5%and 79.7%,respectively.CONCLUSION Age,diabetes,disturbance of consciousness,NIHSS score at admission,invasive surgery,and COPD are risk factors for post-stroke infection following AIS.The nomogram prediction model established based on these factors exhibits high discrimination and accuracy.

Acute liver failure:A systematic review and network meta-analysis of optimal type of stem cells in animal models

BACKGROUND The therapeutic effects of various stem cells in acute liver failure(ALF)have been demonstrated in preclinical studies.However,the specific type of stem cells with the highest therapeutic potential has not been determined.AIM To validate the efficacy of stem cells in ALF model and to identify the most promising stem cells.METHODS A search was conducted on the PubMed,Web of Science,Embase,Scopus,and Cochrane databases from inception to May 3,2022,and updated on November 16,2022 to identify relevant studies.Two independent reviewers performed the literature search,identification,screening,quality assessment,and data extraction.RESULTS A total of 89 animal studies were included in the analysis.The results of traditional meta-analysis showed that stem cell therapy could significantly reduce the serum levels of alanine aminotransferase[weighted mean difference(WMD)=-181.05(-191.71,-170.39)],aspartate aminotransferase[WMD=-309.04(-328.45,-289.63)],tumor necrosis factor-alpha[WMD=-8.75(-9.93,-7.56)],and interleukin-6[WMD=-10.43(-12.11,-8.76)]in animal models of ALF.Further subgroup analysis and network meta-analysis showed that although mesenchymal stem cells are the current research hotspot,the effect of liver stem cells(LSCs)on improving liver function is significantly better than that of the other five types of stem cells.In addition,the ranking results showed that the possibility of LSCs improving liver function ranked first.This fully proves the great therapeutic potential of LSCs,which needs to be paid more attention in the future.CONCLUSION LSCs may have a higher therapeutic potential.Further high-quality animal experiments are needed to explore the most effective stem cells for ALF.

A meta-analysis of risk factors for epilepsy after acute ischaemic stroke and the development of a predictive model

Objective:To screen risk factors for epilepsy after acute ischaemic stroke based on meta-analysis and cohort study and to establish a predictive model.Methods:Computer searches of MEDLINE,Embase,Cochrane library,Web of Scinence,PubMed,CNKI,and WanFang Data data were conducted to collect literature on epilepsy after in acute ischemic stroke,from database creation to September 1,2022.The RRs and their 95%confidence intervals(CI)for risk factors for post stroke epilepsy were extracted for each study,and pooled estimates of the RRs and 95%CIs for each study were generated using either a random-effects model or a fixed-effects model.Beta coefficients for each risk factor were calculated based on the combined RR and their corresponding 95%CIs.The beta coefficients were multiplied by 10 and rounded.Results:Ten articles were identified for final inclusion in this meta-analysis,with a total of 141948 cases and 3702 cases of post stroke epilepsy.The risk factors included in the final risk prediction model were infarct size(RR 4.67,95%CI 1.41~15.47;P=0.01),stroke recuRRence(RR 2.48,95%CI 2.01~3.05;P<0.00001),stroke etiology(RR 1.70,95%CI 1.34~2.15;P<0.00001),stroke severity(RR 1.70,95%CI 1.34~2.15;P<0.00001),and stroke risk.stroke severity(RR 1.53,95%CI 1.39~1.70;P<0.00001),NIHSS score(RR 2.91,95%CI 1.64~5.61;P=0.0003),early-onset epilepsy(RR 5.62,95%CI 5.08~6.22;P<0.00001),cortical lesions(RR 3.83.95%CI 2.23~6.58;P<0.00001),total anterior circulation infarction(RR 18.94,95%CI 10.38~34.57;P<0.00001),partial anterior circulation infarction(RR 4.39,95%CI 2.29~8.40;P<0.00001),cardiovascular events(RR 1.78,95%CI 1.59~1.99;P<0.00001).Conclusion:Based on a systematic review and meta-analysis,we developed a simple risk prediction model for late epilepsy in baseline ischemic stroke that integrates clinical risk factors,including infarct size,stroke recurrence,stroke etiology,stroke severity,NIHSS score,early onset epilepsy,cortical lesions,stroke subtype,and cardiovascular events.

Prognostic and diagnostic scoring models in acute alcoholassociated hepatitis:A review comparing the performance of different scoring systems

Alcohol-associated hepatitis(AAH)is a severe form of liver disease caused by alcohol consumption.In the absence of confounding factors,clinical features and laboratory markers are sufficient to diagnose AAH,rule out alternative causes of liver injury and assess disease severity.Due to the elevated mortality of AAH,assessing the prognosis is a radical step in management.The Maddrey discriminant function(MDF)is the first established clinical prognostic score for AAH and was commonly used in the earliest AAH clinical trials.A MDF>32 indicates a poor prognosis and a potential benefit of initiating corticosteroids.The model for end stage liver disease(MELD)score has been studied for AAH prognostication and new evidence suggests MELD may predict mortality more accurately than MDF.The Lille score is usually combined to MDF or MELD score after corticosteroid initiation and offers the advantage of assessing response to treatment a 4-7 d into the course.Other commonly used scores include the Glasgow Alcoholic Hepatitis Score and the Age Bilirubin international normalized ratio Creatinine model.Clinical AAH correlate adequately with histologic severity scores and leave little indication for liver biopsy in assessing AAH prognosis.AAH presenting as acute on chronic liver failure(ACLF)is so far prognosticated with ACLF-specific scoring systems.New artificial intelligence-generated prognostic models have emerged and are being studied for use in AAH.Acute kidney injury(AKI)is one possible complication of AAH and is significantly associated with increased AAH mortality.Predicting AKI and alcohol relapse are important steps in the management of AAH.The aim of this review is to discuss the performance and limitations of different scoring models for AAH mortality,emphasize the most useful tools in prognostication and review predictors of recurrence.

Exploring the regulatory mechanism of tRNA-derived fragments 36 in acute pancreatitis based on small RNA sequencing and experiments

BACKGROUND Acute pancreatitis(AP)is a disease featuring acute inflammation of the pancreas and histological destruction of acinar cells.Approximately 20%of AP patients progress to moderately severe or severe pancreatitis,with a case fatality rate of up to 30%.However,a single indicator that can serve as the gold standard for prognostic prediction has not been discovered.Therefore,gaining deeper insights into the underlying mechanism of AP progression and the evolution of the disease and exploring effective biomarkers are important for early diagnosis,progression evaluation,and precise treatment of AP.AIM To determine the regulatory mechanisms of tRNA-derived fragments(tRFs)in AP based on small RNA sequencing and experiments.METHODS Small RNA sequencing and functional enrichment analyses were performed to identify key tRFs and the potential mechanisms in AP.Reverse transcription quantitative polymerase chain reaction(RT-qPCR)was conducted to determine tRF expression.AP cell and mouse models were created to investigate the role of tRF36 in AP progression.Lipase,amylase,and cytokine levels were assayed to examine AP progression.Ferritin expression,reactive oxygen species,malondialdehyde,and ferric ion levels were assayed to evaluate cellular ferroptosis.RNA pull down assays and methylated RNA immunoprecipitation were performed to explore the molecular mechanisms.RESULTS RT-qPCR results showed that tRF36 was significantly upregulated in the serum of AP patients,compared to healthy controls.Functional enrichment analysis indicated that target genes of tRF36 were involved in ferroptosisrelated pathways,including the Hippo signaling pathway and ion transport.Moreover,the occurrence of pancreatic cell ferroptosis was detected in AP cells and mouse models.The results of interference experiments and AP cell models suggested that tRF-36 could promote AP progression through the regulation of ferroptosis.Furthermore,ferroptosis gene microarray,database prediction,and immunoprecipitation suggested that tRF-36 accelerated the progression of AP by recruiting insulin-like growth factor 2 mRNA binding protein 3(IGF2BP3)to the p53 mRNA m6A modification site by binding to IGF2BP3,which enhanced p53 mRNA stability and promoted the ferroptosis of pancreatic follicle cells.CONCLUSION In conclusion,regulation of nuclear pre-mRNA domain-containing protein 1B promoted AP development by regulating the ferroptosis of pancreatic cells,thereby acting as a prospective therapeutic target for AP.In addition,this study provided a basis for understanding the regulatory mechanisms of tRFs in AP.

Fecal cytolysin does not predict disease severity in acutely decompensated cirrhosis and acute-on-chronic liver failure

Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with mortality in alcohol-associated hepatitis(AH).It is unclear whether cytolysin also contributes to disease severity in AD and ACLF.Methods:We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF.Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction(PCR)was performed.The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed.Results:Fecal cytolysin and E.faecalis abundance did not predict chronic liver failure(CLIF-C)AD and ACLF scores.Presence of fecal cytolysin was not associated with other liver disease markers,including Fibrosis-4(FIB-4)index,‘Age,serum Bilirubin,INR,and serum Creatinine(ABIC)’score,Child-Pugh score,model for end-stage liver disease(MELD)nor MELD-Na scores in AD or ACLF patients.Conclusions:Fecal cytolysin does not predict disease severity in AD and ACLF patients.The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.

An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure

Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

Prognostic models for acute liver failure

BACKGROUND: Acute liver failure (ALF) remains a dramatic and unpredictable disease with high morbidity and mortality. Early and accurate prognostic assessment of patients with ALF is critically important for optimum clinical pathway. DATA SOURCES: Five English-language medical databases, MEDLINE, Science Direct, OVID, Springer Link and Wiley Interscience were searched for articles on 'acute liver failure', 'prognosis', and related topics. RESULTS: Multi-variable prognostic models including the King's College Hospital criteria and the model for end-stage liver disease score have been widely used in determination of the prognosis of ALF, but the results are far from satisfactory. Other prognostic indicators including serum Gc-globulin, arterial blood lactate, serum phosphate, arterial blood ammonia, and serum alpha-fetoprotein are promising but await further assessement. CONCLUSIONS: A reliable prognostic model to be developed in the future should not only have predictive value for poor outcome but also help to predict the survival of patients without a liver transplantation. Further studies are necessary to assess the prognostic accuracy of any new models. (Hepatobiliary Pancreat Dis Int 2010; 9: 122-128)

Preparation method of an ideal model of multiple organ injury of rat with severe acute pancreatitis

AIM： To establish an ideal model of multiple organ injury of rats with severe acute pancreatitis （SAP）.METHODS： SAP models were induced by retrograde injection of 0.1 mL/100 g 3.5% sodium taurocholate into the biliopancreatic duct of Sprague-Dawley rats. The plasma and samples of multiple organ tissues of rats were collected at 3, 6 and 12 h after modeling. The ascites volume, ascites/body weight ratio, and contents of amylase, endotoxin, endothelin-1 （ET-1）, nitrogen monoxidum （NO）, phospholipase A2 （PLA2）, tumor necrosis factor-α （TNF-α）, interleukin-6 （IL-6） in plasma were determined. The histological changes of multiple organs were observed under light microscope.RESULTS： The ascites volume, ascites/body weight ratio, and contents of various inflammatory mediators in blood were higher in the model group than in the sham operation group at all time points [2.38 （1.10）, 2.58 （0.70）, 2.54 （0.71） vs 0.20 （0.04）, 0.30 （0.30）, 0.22 （0.10） at 3, 6 and 12 h in ascites/body weight ratio; 1582 （284）, 1769 （362）, 1618 （302） （U/L） vs 5303 （1373）, 6276 （1029）, 7538 （2934） （U/L） at 3, 6 and 12 h in Amylase; 0.016 （0.005）, 0.016 （0.010）, 0.014 （0.015） （EU/mL） vs 0,053 （0.029）, 0.059 （0.037）, 0.060 （0.022） （EU/mL） at 3, 6 and 12 h in Endotoxin; 3.900 （3.200）, 4.000 （1.700）, 5.300 （3.000） （ng/L） vs 41.438 （37.721）, 92.151 （23.119）, 65.016 （26.806） （ng/L） at 3, 6 and 12 h in TNF-α, all P 〈 0.01]. Visible congestion, edema and lamellar necrosis and massive leukocytic infiltration were found in the pancreas of rats of model group. There were also pathological changes of lung, liver, kidney, ileum, lymphonode, thymus, myocardium and brain.CONCLUSION： This rat model features reliability, convenience and a high achievement ratio. Complicated with multiple organ injury, it is an ideal animal model of SAR

In vitro and in vivo models of acute alcohol exposure

Alcohol abuse is a global problem due to the financial burden on society and the healthcare system. While the harmful health effects of chronic alcohol abuse are well established, more recent data suggest that acute alcohol consumption also affects human wellbeing. Thus, there is a need for research models in order to fully understand the effect of acute alcohol abuse on different body systems and organs. The present manuscript summarizes the interdisciplinary advantages and disadvantages of currently available human and non-human models of acute alcohol abuse, and identifi es their suitability for biomedical research.

Lipopolysaccharide “Two-hit” Induced Refractory Hypoxemia Acute Respiratory Distress Model in Rats

To establish a stable and reliable model of refractory hypoxemia acute respiratory distress syndrome （ARDS） and examine its pathological mechanisms, a total of 144 healthy male Wistar rats were randomized into 4 groups： group Ⅰ （saline control group）, group Ⅱ （LPS intravenous ＂single-hit＂ group）, group Ⅲ （LPS intratracheal ＂single-hit＂ group） and Group IV （LPS ＂two-hit＂ group）. Rats were intravenously injected or intratracheally instilled with a large dose of LPS （10 mg/kg in 0.5 mL） to simulate a single attack of ARDS, or intraperitoneally injected with a small dose of LPS （1 mg/kg） followed by tracheal instillation with median dose of LPS （5 mg/kg） to establish a ＂two-hit＂ model. Rats in each group were monitored by arterial blood gas analysis and visual inspection for three consecutive days. Arterial blood gas values, lung wet/dry weight ratio and pathological pulmonary changes were analyzed to determine the effects of each ALI/ARDS model. Concentrations of TNF-α, IL-1 and IL-10 in the bronchoalveolar lavage fluid （BALF） and blood plasma were meastired by using enzyme-linked immunosorbent assays （ELISA）. Our resulsts showed that single LPS-stimulation, whether through intravenous injection or tracheal instillation, could only induce ALl and temporary hypoxemia in rats. A two-hit LPS stimulation induces prolonged hypoxemia and specific pulmonary injury in rats, and is therefore a more ideal approximation of ARDS in the animal model. The pathogenesis of LPS two-hit-induced ARDS is associated with an uncontrolled systemic inflammatory response and inflammatory injury. It is concluded that the rat ARDS model produced by our LPS two-hit method is more stable and reliable than previous models, and closer to the diagnostic criteria of ARDS, and better mimics the pathological process of ARDS.

Prediction model of in-hospital mortality in elderly patients with acute heart failure based on retrospective study

Objectives The aim of this study was to develop a clinical risk model that is predictive of in-hospital mortality in elderly patients hos- pitalized with acute heart failure （AHF）. Methods 2486 patients who were 60 years and older from intensive care units of Cardiology De- partment in the hospital were analyzed. Independent risk factors for in-hospital mortality were obtained by binary logistic regression and then used to establish the risk prediction score system （RPSS）. The area under the curve （AUC） of receiver operator characteristic and C-statistic test were adopted to assess the performance of RPSS and to compare with previous get with the guidelines-heart failure （GWTG-HF）. Re- sults By binary logistic regression analysis, heart rate （OR： 1.043, 95% CI： 1.030-1.057, P 〈 0.001）, left ventricular ejection fraction （OR： 0.918, 95% CI： 0.833~）.966, P 〈 0.001）, pH value （OR： 0.001, 95% CI： 0.000-0.002, P 〈 0.001）, renal dysfunction （OR： 0.120, 95% CI： 0.066M）.220, P 〈 0.001） and NT-pro BNP （OR： 3.463, 95% CI： 1.870-6.413, P 〈 0.001） were independent risk factors of in-hospital mortal- ity for elderly AHF patients. Additionally, RPSS, which was composed of all the above-mentioned parameters, provided a better risk predic- tion than GWTG-THF （AUC： 0.873 vs. 0.818, P = 0.016）. Conclusions Our risk prediction model, RPSS, provided a good prediction for in-hospital mortality in elderly patients with A/IF.

Porcine acute liver failure model established by two-phase surgery and treated with hollow fiber bioartificial liver support system

AIM： To establish a highly reproducible animal model of acute liver failure （ALF）, for assessing the effect of bioartificial liver support system （BALSS）. METHODS： A two-phase complete liver devascularization procedure was performed in eight Ioco-hybrid pigs. Blood biochemical index and liver biopsy were studied every 2 h after surgery, and survival time was recorded. The BALSS constructed with high volume recirculating technique was a hollow fiber circulating system consisting of a hepatocyte reactor-hollow fiber module inoculated with microcarrieradhering hepatocytes, and a double pump, heparinized, thermostabilized, micro-capsulized activated carbonadsorbing plasmapheresis system. Twelve pigs undergoing two-phase surgery were randomized into： control group （perfused without hepatocytes, n = 6） and treatment group （perfused with hepatocytes, n = 6）. Intergroup liver biochemical indexes, survival time, and liver pathological changes were analyzed at regular intervals. RESULTS： Two-phase surgery was performed in all the experimental pigs, and there was no obvious difference between their biochemical indexes. After 3 h of phase II surgery, ammonia （Amm） increased to （269＋37）μmol/L. After 5 h of the surgery, fibrinogen （Fib） decreased to （1.5±0.2） g/L. After 7 h of the surgery, ALT, AST, Tbil and PT were （7.6±1.8） nka/L, （40±5） nka/L, （55±8）μmol/L and （17.5±1.7） nka/L respectively. After 9 h of surgery, ALB and Cr were （27±4） g/L and （87±9）μmol/L. After 13 h of surgery, BUN was （3.5±0.9） μmol/L. All the above values were different from those determined before surgery. Survival time of pigs averaged 13.5±1.4 h. ALF pigs in the other group were treated with BALSS. The comparison analysis between the treated and control animals showed the changes of Tbil, PT, AIb, BUN, Cr, Fib, and Amm （P〈0.01）, but there was no change of ALT and AST. The survival time was statistically different （P〈0.01）, and there was no significant difference in histological changes.CONCLUSION： The porcine ALF model established by two-phase devascularized surgery is valid and reproducible. The hollow fiber BALSS can meet the needs of life support and is effective in treating ALF.

D-galactosamine based canine acute liver failure model

Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and that is suitable for clinical qualitative and quantitative evaluation of the BAL. A lethal canine liver failure model of acute hepatic failure that re- moves many of the artifacts evidenced in prior canine models is presented. Methods: Six male hounds, 24-30 kg, under isoflu- rane anesthesia, were administered 1.5 g/kg D- galactosamine intravenously. Canine supportive care followed a well-defined management protocol that was guided by electrolyte and invasive monitoring consisting of arterial pressure, central venous pres- sure, extradural intracranial pressure (ICP), pul- monary artery pressure, and end-tidal CO_2. The animals were treated until death-equivalent, defined as inability to sustain systolic blood pressure>80 mmHg for 20 minutes despite maximal fluids and 20 μg·kg^(-1)·min^(-1) dopamine infusion. Results: The mean survival time was 43.7±4.6 hours (mean±SE). All animals showed evidence of progressive liver failure characterized by increasing liver enzymes (aspartate transaminase from 26 to 5977 IU/L; alanine transaminase from 32 to 9740 IU/L), bilirubin (0.25 to 1.30 mg/dl), ammonia (19. 8 to 85. 3 μmol/L), and coagulopathy (pro- thrombin time from 8.7 to 46 s). Increased lability and elevations in intracranial pressures were ob- served. All animals were refractory to maintenance of cerebral perfusion pressure even with only mode- rately elevated intracranial pressure. Severe neuro- logic obtundation, seen in 2 of 6 animals, was associ- ated with elevations of ICP above 50 mmHg. Post- mortem liver histology showed evidence of massive hepatic necrosis. Postmortem blood and ascites mi- crobial growth was consistent with possible transloca- tion of intestinal microbes. Conclusions: The improved lethal canine liver failure model presented here reproduces many of the clinical features of acute liver failure. The model may prove useful for qualitative and quantitative evaluation of BALs.

Development and external validation of models to predict acute respiratory distress syndrome related to severe acute pancreatitis

BACKGROUND Acute respiratory distress syndrome(ARDS)is a major cause of death in patients with severe acute pancreatitis(SAP).Although a series of prediction models have been developed for early identification of such patients,the majority are complicated or lack validation.A simpler and more credible model is required for clinical practice.AIM To develop and validate a predictive model for SAP related ARDS.METHODS Patients diagnosed with AP from four hospitals located at different regions of China were retrospectively grouped into derivation and validation cohorts.Statistically significant variables were identified using the least absolute shrinkage and selection operator regression method.Predictive models with nomograms were further built using multiple logistic regression analysis with these picked predictors.The discriminatory power of new models was compared with some common models.The performance of calibration ability and clinical utility of the predictive models were evaluated.RESULTS Out of 597 patients with AP,139 were diagnosed with SAP(80 in derivation cohort and 59 in validation cohort)and 99 with ARDS(62 in derivation cohort and 37 in validation cohort).Four identical variables were identified as independent risk factors for both SAP and ARDS:heart rate[odds ratio(OR)=1.05;95%CI:1.04-1.07;P<0.001;OR=1.05,95%CI:1.03-1.07,P<0.001],respiratory rate(OR=1.08,95%CI:1.0-1.17,P=0.047;OR=1.10,95%CI:1.02-1.19,P=0.014),serum calcium concentration(OR=0.26,95%CI:0.09-0.73,P=0.011;OR=0.17,95%CI:0.06-0.48,P=0.001)and blood urea nitrogen(OR=1.15,95%CI:1.09-1.23,P<0.001;OR=1.12,95%CI:1.05-1.19,P<0.001).The area under receiver operating characteristic curve was 0.879(95%CI:0.830-0.928)and 0.898(95%CI:0.848-0.949)for SAP prediction in derivation and validation cohorts,respectively.This value was 0.892(95%CI:0.843-0.941)and 0.833(95%CI:0.754-0.912)for ARDS prediction,respectively.The discriminatory power of our models was improved compared with that of other widely used models and the calibration ability and clinical utility of the prediction models performed adequately.CONCLUSION The present study constructed and validated a simple and accurate predictive model for SAPrelated ARDS in patients with AP.

Development and validation of a prediction model for moderately severe and severe acute pancreatitis in pregnancy

BACKGROUND The severity of acute pancreatitis in pregnancy(APIP)is correlated with higher risks of maternal and fetal death.AIM To develop a nomogram that could predict moderately severe and severe acute pancreatitis in pregnancy(MSIP).METHODS Patients with APIP admitted to West China Hospital between January 2012 and December 2018 were included in this study.They were divided into mild acute pancreatitis in pregnancy(MAIP)and MSIP.Characteristic parameters and laboratory results were collected.The training set and test set were randomly divided at a ratio of 7:3.Least absolute shrinkage and selection operator regression was used to select potential prognostic factors.A nomogram was developed by logistic regression.A random forest model was used to validate the stability of the prediction factors.Receiver operating characteristic curves and calibration curves were used to evaluate the model’s predictive performance.RESULTS A total of 190 patients were included in this study.A total of 134 patients(70.5%)and 56 patients(29.5%)were classified as having MAIP and MSIP,respectively.Four independent predictors(lactate dehydrogenase,triglyceride,cholesterol,and albumin levels)were identified for MSIP.A nomogram prediction model based on these factors was established.The model had areas under the curve of 0.865 and 0.853 in the training and validation sets,respectively.The calibration curves showed that the nomogram has a good consistency.CONCLUSION A nomogram including lactate dehydrogenase,triglyceride,cholesterol,and albumin levels as independent predictors was built with good performance for MSIP prediction.

Murine models based on acute myeloid leukemia-initiating stem cells xenografting

Acute myeloid leukemia(AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells(LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to in-troduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models.

Establishment of a Predictive Diagnostic Model for Acute Mycoplasma Pneumoniae Infection in Elderly Patients with Community-acquired Pneumonia

We established a diagnostic model to predict acute Mycoplasma pneumoniae （M. pneumonia） infection in elderly Community-acquired pneumonia （CAP） patients. We divided 456 patients into acute and non-acute M. pneumoniae infection groups. Binary logistic regression and receiver operating characteristic （ROC） curves were used to establish a predictive model. The following independent factors were identified： age 〉 70 years; serum cTNT level 〉 0.0S ng/mL; lobar consolidation; mediastinal lymphadenopathy; and antibody titer in the acute phase 〉 1：40. The area under the ROC curve of the model was 0.923 and a score of 2 7 score predicted acute M. pneumoniae infection in elderly patients with CAP. The predictive model developed in this study has high diagnostic accuracy for the identification of elderly acute M. pneumoniae infection.