Comparison of fungal vs bacterial infections in the medical intensive liver unit:Cause or corollary for high mortality?

BACKGROUND Due to development of an immune-dysregulated phenotype,advanced liver disease in all forms predisposes patients to sepsis acquisition,including by opportunistic pathogens such as fungi.Little data exists on fungal infection within a medical intensive liver unit(MILU),particularly in relation to acute on chronic liver failure.AIM To investigate the impact of fungal infections among critically ill patients with advanced liver disease,and compare outcomes to those of patients with bacterial infections.METHODS From our prospective registry of MILU patients from 2018-2022,we included 27 patients with culture-positive fungal infections and 183 with bacterial infections.We compared outcomes between patients admitted to the MILU with fungal infections to bacterial counterparts.Data was extracted through chart review.RESULTS All fungal infections were due to Candida species,and were most frequently blood isolates.Mortality among patients with fungal infections was significantly worse relative to the bacterial cohort(93%vs 52%,P<0.001).The majority of the fungal cohort developed grade 2 or 3 acute on chronic liver failure(ACLF)(90%vs 64%,P=0.02).Patients in the fungal cohort had increased use of vasopressors(96%vs 70%,P=0.04),mechanical ventilation(96%vs 65%,P<0.001),and dialysis due to acute kidney injury(78%vs 52%,P=0.014).On MILU admission,the fungal cohort had significantly higher Acute Physiology and Chronic Health Evaluation(108 vs 91,P=0.003),Acute Physiology Score(86 vs 65,P=0.003),and Model for End-Stage Liver Disease-Sodium scores(86 vs 65,P=0.041).There was no significant difference in the rate of central line use preceding culture(52%vs 40%,P=0.2).Patients with fungal infection had higher rate of transplant hold placement,and lower rates of transplant;however,differences did not achieve statistical significance.CONCLUSION Mortality was worse among patients with fungal infections,likely attributable to severe ACLF development.Prospective studies examining empiric antifungals in severe ACLF and associations between fungal infections and transplant outcomes are critical.

Histological abnormalities of the small bowel mucosa in cirrhosis and portal hypertension

AIM: To study the small bowel (SB) mucosa on biopsy in cirrhotic patients with portal hypertension and in non-cirrhotic controls and grade fi ndings according to the Marsh criteria. METHODS: We prospectively enrolled 51 consecutive patients undergoing an upper endoscopy for their routine medical care. Twenty f ive patients with cirrhosis and portal hypertension were compared to 26 controls. We obtained coeliac serology and multiple upper small bowel biopsies on all 51 patients. A GI pathologist interpreted biopsies and graded fi ndings according to the Marsh criteria. We assessed equivalence in Marsh grade between cirrhotic and non-cirrhotic controls using the Mann-Whitney test for equivalence. RESULTS: Gender, ethnicity and age were similar between both groups. Marsh grades were equivalent between the groups. Grade of 0 was present in 96% and grade of 1 was present in 4% of both groups and there was no villus atrophy or decrease in villus/crypt ratio in patients with portal hypertension. CONCLUSION: This study provides evidence for the lack of villus atrophy in patients with cirrhosis and portal hypertension, and supports the continuous reliance on the Marsh criteria when the diagnosis of coeliac disease is to be made in the presence of cirrhosis.

Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end-stage liver disease

AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study(N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension(ascites,variceal bleeding,thrombocytopenia,or hepatic encephalopathy). A1 ATD was diagnosed using phenotype characterization(MZ or ZZ),liver biopsy detection of PAS-positive diastaseresistant(PAS+) globules,or both. Patients with other causes of liver diseases such as hepatitis C virus(HCV),alcoholic liver disease and non-alcoholic steatohepatitis(NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities,biopsy findings,or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma,or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-tointerval analysis for interval censored data.RESULTS:This study included 675 patients. 7% of subjects had A1ATD(n = 47). Out of all subjects who did not have A1 ATD,46% had HCV,17% had alcoholic liver disease,19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1 ATD,15 had a primary diagnosis of A1ATD(PI*ZZ phenotype and PAS+ globules),8 had a PI*MZ phenotype alone,14 had PAS+ alone,and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4(25th,75 th percentiles:1,5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29%(n = 199). In the A1 ATD group,the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis(P = 0.001). Patients with ESLD due to A1 ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis,1.5% in patients with NASH and 0.9% in alcohol-induced liver disease(P < 0.001).CONCLUSION:Within this group of patients with ESLD,there was no significant association between A1 ATD and increased risk of HCC.

Characterization of patients with both alcoholic and nonalcoholic fatty liver disease in a large United States cohort

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is the hepatic manifestation of the metabolic syndrome(MetS)and is characterized by steatosis in the absence of significant alcohol consumption.However,MetS and significant alcohol intake coexist in certain individuals which may lead to the development of BAFLD.AIM To assess the clinical characteristics of patients with both alcoholic and NAFLD(BAFLD)in a large cohort in the United States.METHODS Adults from the National Health and Nutrition Examination Survey between 2003-2014 were included.NAFLD was diagnosed based on elevated alanine aminotransferase(ALT)and being overweight or obese in the absence of other liver diseases.BAFLD patients met the criteria for NAFLD but also had either MetS or type 2 diabetes and consumed excessive amounts of alcohol.Univariable and multivariable analysis were performed to assess differences between NAFLD and BAFLD and to compare severity based on a validated fibrosis score(FIB4 index).RESULTS The prevalence of NAFLD was at 25.9%(95%CI;25.1-26.8)and that of BAFLD was 0.84%(0.67,1.02)which corresponds to an estimated 1.24 million Americans affected by BAFLD.Compared to NAFLD,patients with BAFLD were more likely to be male,smokers,have higher ALT,aspartate aminotransferase,triglycerides,and lower platelets;P<0.01 for all.More importantly,after adjusting for MetS components,BAFLD patients were significantly more likely to have advanced fibrosis[adjusted OR(95%CI)based on FIB4 index>2.67 was 3.2(1.4,7.0),P=0.004].CONCLUSION A significant percentage of the American general population is afflicted by BAFLD and these patients tend to have more advanced liver fibrosis.

Does serotonin reuptake inhibitor therapy increase the risk of post-sphincterotomy bleeding in patients undergoing endoscopic retrograde cholangio-pancreatography?

AIM To evaluate the risk of immediate and delayed bleeding following sphincterotomy procedure.METHODS This retrospective cohort study was conducted with all patients who underwent endoscopic sphincterotomy during January 2006 to September 2015 at a tertiary academic center. Patients were grouped according to pre procedural usage of serotonin reuptake inhibitors(SRIs). Both groups were matched for demographic and clinical characteristics. Patients with thrombocytopenia,increased international normalized ratio, or a history of bleeding or coagulation disorders, concurrent use of other antiplatelet/anticoagulants were excluded from the study.RESULTS A total of 447 patients were included, of which 219(45.9%) used SRIs and 228(54.1%) cases did not.There was no significant difference in acute or delayed bleeding during endoscopic sphincterotomy between the two groups.(8.2% vs 12.3%, P = 0.16).CONCLUSION The use of SRIs was not associated with an increased risk of post-sphincterotomy bleeding. To our best knowledge, this is the first study to explore this asso-ciation.

High prevalence of chronic viral hepatitis B and C in Minnesota Somalis contributes to rising hepatocellular carcinoma incidence

BACKGROUND Chronic hepatitis B virus(HBV)and hepatitis C virus(HCV)infections are known risk factors for liver disease,cirrhosis and hepatocellular carcinoma(HCC).There is substantial global variation in HBV and HCV prevalence resulting in variations in cirrhosis and HCC.We previously reported high prevalence of HBV and HCV infections in Somali immigrants seen at an academic medical center in Minnesota.AIM To determine the prevalence of chronic viral hepatitis in Somali immigrants in Minnesota through a community-based screening program.METHODS We conducted a prospective community-based participatory research study in the Somali community in Minnesota in partnership with community advisory boards,community clinics and local mosques between November 2010 and December 2015(data was analyzed in 2020).Serum was tested for hepatitis B surface antigen,hepatitis B core antibody,hepatitis B surface antibody and anti-HCV antibody.RESULTS Of 779 participants,15.4%tested positive for chronic HBV infection,50.2%for prior exposure to HBV and 7.6%for chronic HCV infection.Calculated age-adjusted frequencies in males and females for chronic HBV were 12.5%and 11.6%;for prior exposure to HBV were 44.8%and 41.3%;and for chronic HCV were 6.7%and 5.7%,respectively.Seven participants developed incident HCC during follow up.CONCLUSION Chronic HBV and HCV are major risk factors for liver disease and HCC among Somali immigrants,with prevalence of both infections substantially higher than in the general United States population.Community-based screening is essential for identifying and providing health education and linkage to care for diagnosed patients.

Development of a nomogram for predicting a positive repeat prostate biopsy

AIM: To fi nd risk factors of cancer in patients who had a repeat biopsy and to develop the nomogram using our cohort. METHODS: Among 3500 patients who had a prostate biopsy over 11 years between 2000 and 2010 at our hospital, we studied a total of 807 repeat biopsy sessions in 459 patients who had at least 1 initial negative biopsy. At each biopsy session, we recorded patient age, number of previous biopsy sessions, number of biopsy cores, number of previously negative biopsy cores, months from the initial biopsy, months from the previous biopsy, serum PSA, PSA slope, digital rectal examination fi ndings, hypoechoic lesions suspicious for a cancer on transrectal ultrasonography, total prostate volume, transitional zone(TZ) volume, PSA density, PSA TZ density and history of high grade prostatic intraepithelial neoplasia(HGPIN) or atypical small acinar proliferation(ASAP). Clinical and pathological variables were correlated with the outcome of repeat biopsies. A nomogram was developed based on logistic regression analyses and calibration was performed.RESULTS: Overall, 17% of repeat biopsies had a cancer. With receiver operating characteristics analyses, the highest area under the curve(AUC) was obtained based on all available 13 variables, which were age, PSA, digital rectal examination, PSA density, prostate volume, TZ volume, PSA TZ density, cumulative number of biopsy cores, HGPIN, ASAP, months from previous negative biopsy, initial negative biopsy and number of biopsy cores. Based on multivariable logistic regression analysis, a nomogram was constructed with an AUC of 0.74, which was greater than that of any single risk factor. The calibration plot seemed to be good.CONCLUSION: Our nomogram for predicting a positive repeat biopsy can provide probabilities for cancer and may help clinical judgment on whether to do a repeat prostate biopsy.

Impact of recipient functional status on 1-year liver transplant outcomes

BACKGROUND The Karnofsky Performance Status(KPS)scale has been widely validated for clinical practice for over 60 years.AIM To examine the extent to which poor pre-transplant functional status,assessed using the KPS scale,is associated with increased risk of mortality and/or graft failure at 1-year post-transplantation.METHODS This study included 38278 United States adults who underwent first,non-urgent,liver-only transplantation from 2005 to 2014(Scientific Registry of Transplant Recipients).Functional impairment/disability was categorized as severe,moderate,or none/normal.Analyses were conducted using multivariableadjusted Cox survival regression models.RESULTS The median age was 56 years,31%were women,median pre-transplant Model for End-Stage for Liver Disease score was 18.Functional impairment was present in 70%;one-quarter of the sample was severely disabled.After controlling for key recipient and donor factors,moderately and severely disabled patients had a 1-year mortality rate of 1.32[confidence interval(CI):1.21-1.44]and 1.73(95%CI:1.56-1.91)compared to patients with no impairment,respectively.Subjects with moderate and severe disability also had a multivariable-adjusted 1-year graft failure rate of 1.13(CI:1.02-1.24)and 1.16(CI:1.02-1.31),respectively.CONCLUSION Pre-transplant functional status is a useful prognostic indicator for 1-year posttransplant patient and graft survival.

Association of latitude and altitude with adverse outcomes in patients with COVID-19: The VIRUS registry

BACKGROUND The coronavirus disease 2019(COVID-19)course may be affected by environmental factors.Ecological studies previously suggested a link between climatological factors and COVID-19 fatality rates.However,individual-level impact of these factors has not been thoroughly evaluated yet.AIM To study the association of climatological factors related to patient location with unfavorable outcomes in patients.METHODS In this observational analysis of the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study:COVID-19 Registry cohort,the latitudes and altitudes of hospitals were examined as a covariate for mortality within 28 d of admission and the length of hospital stay.Adjusting for baseline parameters and admission date,multivariable regression modeling was utilized.Generalized estimating equations were used to fit the models.RESULTS Twenty-two thousand one hundred eight patients from over 20 countries were evaluated.The median age was 62(interquartile range:49-74)years,and 54%of the included patients were males.The median age increased with increasing latitude as well as the frequency of comorbidities.Contrarily,the percentage of comorbidities was lower in elevated altitudes.Mortality within 28 d of hospital admission was found to be 25%.The median hospital-free days among all included patients was 20 d.Despite the significant linear relationship between mortality and hospital-free days(adjusted odds ratio(aOR)=1.39(1.04,1.86),P=0.025 for mortality within 28 d of admission;aOR=-1.47(-2.60,-0.33),P=0.011 for hospital-free days),suggesting that adverse patient outcomes were more common in locations further away from the Equator;the results were no longer significant when adjusted for baseline differences(aOR=1.32(1.00,1.74),P=0.051 for 28-day mortality;aOR=-1.07(-2.13,-0.01),P=0.050 for hospital-free days).When we looked at the altitude’s effect,we discovered that it demonstrated a non-linear association with mortality within 28 d of hospital admission(aOR=0.96(0.62,1.47),1.04(0.92,1.19),0.49(0.22,0.90),and 0.51(0.27,0.98),for the altitude points of 75 MASL,125 MASL,400 MASL,and 600 MASL,in comparison to the reference altitude of 148 m.a.s.l,respectively.P=0.001).We detected an association between latitude and 28-day mortality as well as hospital-free days in this worldwide study.When the baseline features were taken into account,however,this did not stay significant.CONCLUSION Our findings suggest that differences observed in previous epidemiological studies may be due to ecological fallacy rather than implying a causal relationship at the patient level.

中国人群中动脉硬化性脑小血管病易感基因及预测模型的研究

目的探讨与脑小血管病有关的易感基因及基因预测模型。 方法对共792例4组研究对象的脱氧核糖核酸（deoxyribonucleic acid，DNA）样本应用SNaPshot单核苷酸多态性（single nucleotide polymorphisms，SNP）分型技术进行19个候选基因55个SNP位点分型，在5种遗传模型下对脑小血管病与非卒中对照组个体之间分析，并进行各组之间差异显著性检验及危险因素分析。应用了SAS软件构建预测模型。结果脑小血管病与非卒中对照组个体差异性检验，肌球蛋白轻链激酶基因（myosin light chain kinase，MYLK）SNP位点rs2222823杂合子（A/T）的优势比（odds ratio，OR）为0.52[95%可信区间（confidence interval，CI）（0.35～0.79），P=0.002，校正P=0.031]；细胞周期依赖性激酶抑制基因2A（inhibitor of cdk 4/alternative reading frame，INK4/ARF）SNP位点rs2811712杂合子（C/T）的OR值为1.75[95%CI 1.13～2.71，P=0.004，校正P=0.050]。脑小血管病与高血压性脑出血患者差异性检验， rs2222823位点的P值为0.035。脑小血管病与大动脉硬化性脑血管病患者差异性检验，非糖尿病患者及饮酒患者在rs2222823位点P值分别为0.012和0.018；高脂血症及饮酒患者在rs2811712位点P值分别为0.029和0.04。构建预测模型的基尼指数为0.442。 结论 MYLK和INK4/ARF基因与中国人群中动脉硬化性脑小血管病有相关性，rs2222823杂合子（A/T）有减缓脑小血管病患病率作用，而rs2811712杂合子（C/T）对脑小血管病的患病率具有促进作用。

临床意义上的前列腺癌的预测标准化：可能吗？

近几十年来，对前列腺癌的生物学和流行病学的深入研究已经使前列腺癌的治疗取得了很大进展。很多前列腺癌可以在发病早期被发现，并且有多种有效的治疗手段。然而，仍无明确的数据表明这些早期诊断和治疗能够有效地控制前列腺癌的死亡率。这可能是由于接受治疗的一大部分癌症患者的恶性程度较低，即使不予治疗亦不会对患者的健康和生存期产生影响。基于过度治疗现象的存在，在当代的医疗过程中，积极监测以观后效被认为是一种有效的治疗方式。如何区别不具临床意义的肿瘤与高度恶性、高致死率的肿瘤，对为患者选择积极监测还是立即干预的治疗方案来说至关重要。本章节总结了风险分组和列线图等多种预测模型对于低度恶性肿瘤的预测能力及它们在局限性前列腺癌的治疗中所起的作用。

Medications in type-2 diabetics and their association with liver fibrosis

BACKGROUND The prevalence of nonalcoholic fatty liver disease(NAFLD) is significantly rising worldwide. Type-2 diabetes(T2D) is a major risk factor for NAFLD progression.AIM To assess the association of commonly used medications to advanced fibrosis(AF) in patients with biopsy-proven NAFLD and T2D.METHODS We used the International Classification of Disease 9 th Revision Clinical Modification coding system to identify patients with T2D and included patients who underwent liver biopsy for suspected NAFLD between January 1, 2000 to December 31, 2015. We compared demographics, clinical characteristics, and differences in pattern of medication use in patients who had biopsy-proven AF to those without it. A univariate and multivariate analysis was performed to assess the association of different classes of medication with the presence of AF.RESULTS A total of 1183 patients were included in the final analysis, out of which 32%(n =381) had AF on liver biopsy. Mean age of entire cohort was 52 years and majority were females(65%) and Caucasians(85%). Among patients with AF, 51% were on oral hypoglycemics, 30% were on insulin, 66% were on antihypertensives and 27% were on lipid lowering agents for the median duration of 19 mo, 10 mo, 26 mo, and 24 mo respectively. Medications associated with decreased risk of AF included metformin, liraglutide, lisinopril, hydrochlorothiazide, atorvastatin and simvastatin while the use of furosemide and spironolactone were associated with higher prevalence of AF.CONCLUSION In our cohort of T2D with biopsy proven NAFLD, the patients who were receiving metformin, liraglutide, lisinopril, hydrochlorothiazide, atorvastatin and simvastatin were less likely to have AF on biopsy, while patients who were receiving furosemide and spironolactone had a higher likelihood of having AF when they underwent liver biopsy. Future studies are needed to confirm these findings and to establish measures for prevention of NAFLD progression in patients with T2D.

Metabolomics studies identify novel diagnostic and prognostic indicators in patients with alcoholic hepatitis

AIM: To identify plasma analytes using metabolomics that correlate with the diagnosis and severity of liver disease in patients with alcoholic hepatitis(AH).METHODS: We prospectively recruited patients with cirrhosis from AH(n = 23) and those with cirrhosis with acute decompensation(AD) from etiologies other than alcohol(n = 25). We used mass spectrometry to identify 29 metabolic compounds in plasma samples from fasted subjects. A receiver operating characteristics analysis was performed to assess the utility of biomarkers in distinguishing acute AH from alcoholic cirrhosis. Logistic regression analysis was performed to build a predictive model for AH based on clinical characteristics. A survival analysis was used to construct Kaplan Meier curves evaluating transplant-free survival.RESULTS: A comparison of model for end-stage liver disease(MELD)-adjusted metabolomics levels between cirrhosis patients who had AD or AH showed that patients with AH had significantly higher levels of betaine, and lower creatinine, phenylalanine, homocitrulline, citrulline, tyrosine, octenoyl-carnitine, and symmetric dimethylarginine. When considering combined levels, betaine and citrulline were highly accurate predictors for differentiation between AH and AD(area under receiver operating characteristics curve = 0.84). The plasma levels of carnitine [0.54(0.18, 0.91); P = 0.005], homocitrulline [0.66(0.34, 0.99); P < 0.001] and pentanoyl-carnitine [0.53(0.16, 0.90); P = 0.007] correlated with MELD scores in patients diagnosed with AH. Increased levels of many biomarkers(carnitine P = 0.005, butyrobetaine P = 0.32, homocitrulline P = 0.002, leucine P = 0.027, valine P = 0.024, phenylalanine P = 0.037, tyrosine P = 0.012, acetyl-carnitine P = 0.006, propionyl-carnitine P = 0.03, butyryl-carnitine P = 0.03, trimethyl-lisine P = 0.034, pentanoyl-carnitine P = 0.03, hexanoyl-carnitine P = 0.026) were associated with increased mortality in patients with AH. CONCLUSION: Metabolomics plasma analyte levels might be used to diagnose of AH or help predict patient prognoses.

Microvascular response to transfusion in elective spine surgery

AIM To investigate the microvascular(skeletal muscle tissue oxygenation; SmO_2) response to transfusion in patients undergoing elective complex spine surgery.METHODS After IRB approval and written informed consent, 20 patients aged 18 to 85 years of age undergoing > 3level anterior and posterior spine fusion surgery were enrolled in the study. Patients were followed throughout the operative procedure, and for 12 h postoperatively. In addition to standard American Society of Anesthesiologists monitors, invasive measurements including central venous pressure, continual analysis of stroke volume(SV), cardiac output(CO), cardiac index(CI), and stroke volume variability(SVV) was performed. To measure skeletal muscle oxygen saturation(SmO_2) during the study period, a non-invasive adhesive skin sensor based on Near Infrared Spectroscopy was placed over the deltoid muscle for continuous recording of optical spectra. All administration of fluids and blood products followed standard procedures at the Hospital for Special Surgery, without deviation from usual standards of care at the discretion of the Attending Anesthesiologist based on individual patient comorbidities, hemodynamic status, and laboratory data. Time stamps were collected for administration of colloids and blood products, to allow for analysis of SmO_2 immediately before, during, and after administration of these fluids, and to allow for analysis of hemodynamic data around the same time points. Hemodynamic and oxygenation variables were collected continuously throughout the surgery, including heart rate, blood pressure, mean arterial pressure, SV, CO, CI, SVV, and SmO_2. Bivariate analyses were conducted to examine the potential associations between the outcome of interest, SmO_2, and each hemodynamic parameter measured using Pearson's correlation coeffi-cient, both for the overall cohort and within-patients individually. The association between receipt of packed red blood cells and SmO_2 was performed by running an interrupted time series model, with SmO_2 as our outcome, controlling for the amount of time spent in surgery before and after receipt of PRBC and for the inherent correlation between observations. Our model was fit using PROC AUTOREG in SAS version 9.2. All other analyses were also conducted in SAS version 9.2(SAS Institute Inc., Cary, NC, United States).RESULTS Pearson correlation coefficients varied widely between SmO_2 and each hemodynamic parameter examined. The strongest positive correlations existed between ScvO_2(P = 0.41) and SV(P = 0.31) and SmO_2; the strongest negative correlations were seen between albumin(P =-0.43) and cell saver(P =-0.37) and SmO_2. Correlations for other laboratory parameters studied were weak and only based on a few observations. In the final model we found a small, but significant increase in SmO_2 at the time of PRBC administration by 1.29 units(P = 0.0002). SmO_2 values did not change over time prior to PRBC administration(P = 0.6658) but following PRBC administration, SmO_2 values declined significantly by 0.015 units(P < 0.0001).CONCLUSION Intra-operative measurement of SmO_2 during large volume, yet controlled hemorrhage, does not show a statistically significant correlation with either invasivehemodynamic, or laboratory parameters in patients undergoing elective complex spine surgery.

LIV-4:A novel model for predicting transplant-free survival in critically ill cirrhotics

BACKGROUND Critically ill patients with cirrhosis,particularly those with acute decompensation,have higher mortality rates in the intensive care unit(ICU)than patients without chronic liver disease.Prognostication of short-term mortality is important in order to identify patients at highest risk of death.None of the currently available prognostic models have been widely accepted for use in cirrhotic patients in the ICU,perhaps due to complexity of calculation,or lack of universal variables readily available for these patients.We believe a survival model meeting these requirements can be developed,to guide therapeutic decision-making and contribute to cost-effective healthcare resource utilization.AIM To identify markers that best identify likelihood of survival and to determine the performance of existing survival models.METHODS Consecutive cirrhotic patients admitted to a United States quaternary care center ICU between 2008-2014 were included and comprised the training cohort.Demographic data and clinical laboratory test collected on admission to ICU were analyzed.Area under the curve receiver operator characteristics(AUROC)analysis was performed to assess the value of various scores in predicting inhospital mortality.A new predictive model,the LIV-4 score,was developed using logistic regression analysis and validated in a cohort of patients admitted to the same institution between 2015-2017.RESULTS Of 436 patients,119(27.3%)died in the hospital.In multivariate analysis,a combination of the natural logarithm of the bilirubin,prothrombin time,white blood cell count,and mean arterial pressure was found to most accurately predict in-hospital mortality.Derived from the regression coefficients of the independent variables,a novel model to predict inpatient mortality was developed(the LIV-4 score)and performed with an AUROC of 0.86,compared to the Model for End-Stage Liver Disease,Chronic Liver Failure-Sequential Organ Failure Assessment,and Royal Free Hospital Score,which performed with AUROCs of 0.81,0.80,and 0.77,respectively.Patients in the internal validation cohort were substantially sicker,as evidenced by higher Model for End-Stage Liver Disease,Model for End-Stage Liver Disease-Sodium,Acute Physiology and Chronic Health Evaluation III,SOFA and LIV-4 scores.Despite these differences,the LIV-4 score remained significantly higher in subjects who expired during the hospital stay and exhibited good prognostic values in the validation cohort with an AUROC of 0.80.CONCLUSION LIV-4,a validated model for predicting mortality in cirrhotic patients on admission to the ICU,performs better than alternative liver and ICU-specific survival scores.

Cardiac risk factors limiting survival to liver transplantation in patients with nonalcoholic fatty liver disease

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)describes the hepatic manifestations of metabolic syndrome,which is estimated to affect 25%of adults,and currently represents the second most common indication for liver transplant in the United States.Studies have shown that patients with NAFLD are at an increased risk for heart failure,arrhythmia,and coronary artery disease(CAD),which may impact outcomes of liver transplantation.However,it remains unclear whether the presence of cardiac disease affects survival prior to liver transplant.If so,this would represent an important opportunity to optimize cardiac status and improve outcomes before liver transplant.AIM To identify cardiac factors that impact survival to liver transplantation in patients with NAFLD and on the transplant waitlist.METHODS The aim of this study was to identify cardiac risk factors that limit survival to transplant in patients with NAFLD.We performed a retrospective analysis of patients with NAFLD listed for liver transplant at a tertiary academic medical center in the United States from January 2015 to January 2021,identified through United Network of Organ Sharing registry.Exclusion criteria included a concurrent etiology of liver disease and removal from the transplant list due to chemical dependency,lack of social support,improvement in liver disease,or being lost to followup.We manually reviewed patient charts including electrocardiogram,echocardiogram,and cardiac catheterization reports as well as physician notes to identify cardiac disease states(i.e.,heart failure,arrhythmia,valvular disease and CAD)and other related diagnoses.We performed a survival analysis by Cox proportional hazards regression model to analyze the association between cardiac factors at the time listed for transplant and death or clinical deterioration prior to transplant.RESULTS Between January 2015 and January 2021,265 patients with nonalcoholic fatty liver disease were listed for liver transplant at our institution.Our patient sample had a median age of 63 and an even distribution between sexes.The median Model for End-Stage Liver Disease(MELD)score was 17 and the median body mass index was 31.6.Of these 265 patients,197(74.3%)survived to transplant and 68(25.7%)died or clinically deteriorated prior to transplant.The presence of mild or moderate CAD represented a hazard ratio of 2.013(95%CI 1.078-3.759,P=0.029)for death or clinical deterioration when compared to patients without CAD,after adjustment for age,sex,and MELD.MELD represented an adjusted hazard ratio of 1.188.CONCLUSION Mild or moderate CAD represents a hazard for waitlist mortality prior to liver transplant in patients with NAFLD.Aggressive management of CAD may be needed to improve patient outcomes.

Novel device for monitoring respiratory rate during endoscopy-A thermodynamic sensor

BACKGROUND Monitoring ventilation accurately is an indispensable aspect of patient care in procedural settings.The current gold standard method of monitoring ventilation is by measuring exhaled carbon dioxide concentration,known as capnography.A new device utilizing thermodynamic measurement,the Linshom Respiratory Monitoring Device(LRMD),has been designed to measure respiratory rate(RR)by using the temperature of exhaled breath.We hypothesized that the temperature sensor is at least equivalent in accuracy to capnography in monitoring ventilation.AIM To determine if the temperature sensor is equivalent to capnography in monitoring procedural ventilation.METHODS In this prospective study,participants were individually fitted with a face mask monitored by both LRMD and capnography.The following data were collected:gender,age,body mass index,type of procedure,and doses of medication.For each patient,we report the mean RR for each device as well as the mean difference.All analyses were performed using SAS,and a P<0.05 was considered statistically significant.RESULTS Twelve consecutive patients undergoing endoscopic procedures at our institution were enrolled.Four patients were excluded due to incomplete data,inadequate data,patient cooperation,and capnography failure.Overall,we found that LRMD RR highly correlated to capnography RR(P<0.001);the average capnography RR increases by 0.66 breaths for every one additional breath measured by the LRMD.In addition,apnea rates were 7.4%for the capnography and 6.4%for the LRMD(95%confidence interval:0.92-1.10).CONCLUSION The LRMD correlated with the gold standard capnography with respect to respiratory rate detection and apnea events.The LRMD could be used as an alternative to capnography for measuring respiration in endoscopy.

A New Integrated Fuzzifier Evaluation and Selection (NIFEs) Algorithm for Fuzzy Clustering

Fuzzy C-means (FCM) is simple and widely used for complex data pattern recognition and image analyses. However, selecting an appropriate fuzzifier (m) is crucial in identifying an optimal number of patterns and achieving higher clustering accuracy, which few studies have investigated. Built upon two existing methods on selecting fuzzifier, we developed an integrated fuzzifier evaluation and selection algorithm and tested it using real datasets. Our findings indicate that the consistent optimal number of clusters can be learnt from testing different fuzzifiers for each dataset and the fuzzifier with the lowest value for this consistency should be selected for clustering. Our evaluation also shows that the fuzzifier impacts the clustering accuracy. For longitudinal data with missing values, m = 2 could be an empirical rule to start fuzzy clustering, and the best clustering accuracy was achieved for tested data, especially using our multiple-imputation based fuzzy clustering.

Development of a tRNA-derived small RNA diagnostic and prognostic signature in liver cancer

Liver cancer presents divergent clinical behaviors.There remain opportunities for molecular markers to improve liver cancer diagnosis and prognosis,especially since tRNA-derived small RNAs(tsRNA)have rarely been studied.In this study,a random forests(RF)diagnostic model was built based upon tsRNA profiling of paired tumor and adjacent normal samples and validated by independent validation(IV).A LASSO model was used to developed a seven-tsRNA-based risk score signature for liver cancer prognosis.Model performance was evaluated by a receiver operating characteristic curve(ROC curve)and Precision-Recall curve(PR curve).The five-tsRNA-based RF diagnosis model had area under the receiver operating characteristic curve(AUROC)88%and area under the precision–recall curve(AUPR)87%in the discovery cohort and 87%and 86%in IV-AUROC and IV-AUPR,respectively.The seven-tsRNA-based prognostic model predicts the overall survival of liver cancer patients(Hazard Ratio 2.02,95%CI 1.36–3.00,P<0.001),independent of standard clinicopathological prognostic factors.Moreover,the model successfully categorizes patients into high-low risk groups.Diagnostic and prognostic modeling can be reliably utilized in the diagnosis of liver cancer and high-low risk classification of patients based upon tsRNA characterization.

Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts

Extracellular sulfatase-2(Sulf-2)influences receptor-ligand binding and subsequent signaling by chemokines and growth factors,yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis(RA).In the present study,we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts(RASFs).Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice.RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated~2500 genes compared to scrambled siRNA.Ingenuity Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in RA.Western blot,ELISA,and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1,VCAM1,CAD11,PDPN,CCL5,CX3CL1,CXCL10,and CXCL11.Signaling studies identified the protein kinase C-delta(PKCδ)and c-Jun N-terminal kinase(JNK)pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion.Knockdown of Sulf-2 abrogated TNF-α-induced RASF proliferation.Sulf-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδand JNK,thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human RASFs.Interestingly,Sulf-2 expression positively correlated with the expression of TNF receptor 1,and coimmunoprecipitation assays demonstrated the binding of these two proteins,suggesting they exhibit crosstalk in TNF-αsignaling.This study identified a novel role of Sulf-2 in TNF-αsignaling and the activation of RA synoviocytes,providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.