AIM To examine the effect of center size on survival differences between simultaneous liver kidney transplantation(SLKT) and liver transplantation alone(LTA) in SLKT-listed patients.METHODS The United Network of Organ...AIM To examine the effect of center size on survival differences between simultaneous liver kidney transplantation(SLKT) and liver transplantation alone(LTA) in SLKT-listed patients.METHODS The United Network of Organ Sharing database was queried for patients ≥ 18 years of age listed for SLKT between February 2002 and December 2015. Posttransplant survival was evaluated using stratified Cox regression with interaction between transplant type(LTA vs SLKT) and center volume.RESULTS During the study period, 393 of 4580 patients(9%) listed for SLKT underwent a LTA. Overall mortality was higher among LTA recipients(180/393, 46%) than SLKT recipients(1107/4187, 26%). The Cox model predicted a significant survival disadvantage for patients receiving LTA vs SLKT [hazard ratio, hazard ratio(HR) = 2.85; 95%CI: 2.21, 3.66; P < 0.001] in centers performing 30 SLKT over the study period. This disadvantage was modestly attenuated as center SLKT volume increased, with a 3% reduction(HR = 0.97; 95%CI: 0.95, 0.99; P = 0.010) for every 10 SLKs performed.CONCLUSION In conclusion, LTA is associated with increased mortality among patients listed for SLKT. This difference is modestly attenuated at more experienced centers and may explain inconsistencies between smaller-center and larger registry-wide studies comparing SLKT and LTA outcomes.展开更多
The presence of human-leukocyte antigen （HLA）-antibodies and blood group incompatibility remain a large barrier to kidney transplantation leading to increased morbidity and mortality on the transplant waiting list. ...The presence of human-leukocyte antigen （HLA）-antibodies and blood group incompatibility remain a large barrier to kidney transplantation leading to increased morbidity and mortality on the transplant waiting list. Over the last decade a number of new approaches were developed to overcome these barriers. Intravenous immunoglobulin （IVIG） remains the backbone of HLA desensitization therapy and has been shown in a prospective, randomized, placebo controlled trial to improve transplantation rates. Excellent outcomes with the addition of rituximab （anti-B cell） to IVIG based desensitization have been achieved. There is limited experience with bortezomib （anti-plasma cell） and eculizumab （complement inhibition） for desensitization. However, these agents may be good adjuncts for patients who are broadly sensitized with strong, complement-fxing HLA antibodies. Excellent short and long-term outcomes have been achieved in ABO incompatible transplantation with the combination of antibody removal, B cell depletion, and pre-transplant immunosuppression. Kidney paired donation has emerged as a reasonable alternative for programs who cannot provide desensitization or in conjunction with desensitization. Future therapies directed toward cytokines that alter B cell proliferation are under investigation.展开更多
Non-alcoholic steatohepatitis(NASH)is the most common chronic liver disease worldwide,and the fastest growing indication for liver transplantation in the United States.NASH is now the leading etiology for liver transp...Non-alcoholic steatohepatitis(NASH)is the most common chronic liver disease worldwide,and the fastest growing indication for liver transplantation in the United States.NASH is now the leading etiology for liver transplantation in women,the second leading indication for men,and the most common cause amongst recipients aged 65 years and older.Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases,including obesity,type 2 diabetes(T2D),and hypertension.These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality.Furthermore,these patients carry considerable risk of morbidity and mortality both before after liver transplantation,with high rates of T2D,cardiovascular disease,chronic kidney disease,poor nutrition,and disease recurrence.Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure.Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation,control of diabetes,nutritional support,and even,potentially,consultation with a bariatric surgeon.This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.展开更多
Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)w...Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.展开更多
Cirrhosis is a major cause of morbidity and mortality worldwide with liver transplantations as it only possible cure.In the face of a significant organ shortage many patients die waiting.A major complication of cirrho...Cirrhosis is a major cause of morbidity and mortality worldwide with liver transplantations as it only possible cure.In the face of a significant organ shortage many patients die waiting.A major complication of cirrhosis is the development of portal hypertension and ascites.The management of ascites has barely evolved over the last hundred years and includes only a few milestones in our treatment approach,but has overall significantly improved patient morbidity and survival.Our mainstay to ascites management includes changes in diet,diuretics,shunt procedures,and large volume paracentesis.The understanding of the pathophysiology of cirrhosis and portal hypertension has significantly improved in the last couple of decades but the changes in ascites management have not seemed to mirror this newer knowledge.We herein review the history of ascites management and discuss some its current limitations.展开更多
AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation param...AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation parameter(CAP) was used to assess hepatic steatosis post-sustained virological response(SVR);the CAP technology was not available in the United States at study initiation.Liver stiffness/fibrosis was measured before and 47 wk after treatment completion.Patients with genotype 3 and patients with cirrhosis were excluded.RESULTS One hundred and one patients were included in the study.Post-SVR there were decreases from baseline in alanine aminotransferase(ALT)(63.1 to 17.8 U/L),aspartate aminotransferase(51.8 to 21.5 U/L) and fibrosis score(7.4 to 6.1 k Pa)(P < 0.05).Post-SVR,48 patients(47.5%) had steatosis on CAP;of these,6.25% had advanced fibrosis.Patients with steatosis had higher body mass index(29.0 vs 26.1 kg/m2),glucose(107.8 vs 96.6 mg/d L),ALT(20.4 vs 15.3 mg/d L),CAP score(296.3 vs 212.4 d B/m) and fibrosis score(7.0 vs 5.3 k Pa);P < 0.05.Interestingly,compared to baseline,both patients with and without steatosis had change in fibrosis score post-SVR(7.7 k Pa vs 7.0 k Pa and 7.0 k Pa vs 5.3 k Pa);alternatively,(P < 0.05) and therefore patients with steatosis continued to have clinically significant stiffness(≥ 7 k Pa).CONCLUSION Fatty liver is very common in hepatitis C virus(HCV) patients post-SVR.These patients continue to have elevated mean fibrosis score(≥ 7 k Pa) compared to those without fatty liver;some have advanced fibrosis.Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.展开更多
BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has...BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies reporting symptoms of depression,two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk,with further improvements observed in some studies after 4 and 8 wk of treatment.展开更多
Endothelial cells(ECs) are essential for pancreas differentiation, endocrine specification, and endocrine function. They are also involved in the physiopathology of type 1 and type 2 diabetes. During embryogenesis, ao...Endothelial cells(ECs) are essential for pancreas differentiation, endocrine specification, and endocrine function. They are also involved in the physiopathology of type 1 and type 2 diabetes. During embryogenesis, aortic ECs provide specific factors that maintain the expression of key genes for pancreas development such as pancreatic and duodenal homeobox-1. Other unknown factors are also important for pancreatic endocrine specification and formation of insulin-producing beta cells. Endocrine precursors proliferate interspersed with ductal cells and exocrine precursors and, at some point of development, these endocrine precursors migrate to pancreatic mesenchyme and start forming the islets of Langerhans. By the end of the gestation and close to birth, these islets contain immature beta cells with the capacity to express vascular endothelial growth factor and therefore to recruit ECs from the surrounding microenvironment. ECs in turn produce factors that are essential to maintain insulin secretion in pancreatic beta cells. Once assembled, a cross talk between endocrine cells and ECs maintain the integrity of islets toward an adequate function during the whole life of the adult individual. This review will focus in the EC role in the differentiation and maturation of pancreatic beta cells during embryogenesis as well as the current knowledge about the involvement of endothelium to derive pancreatic beta cells in vitro from mouse or human pluripotent stem cells.展开更多
Approximately 50% of all heart failure patients in the US are above 75 years of age, which is almost similar to most European countries and the Middle and the Far East. Even though aging is an independent molecular pr...Approximately 50% of all heart failure patients in the US are above 75 years of age, which is almost similar to most European countries and the Middle and the Far East. Even though aging is an independent molecular process with a multitude of genetic predetermination and biochemical mediations, aging itself does not automatically result in cardiac insufficiency. On the other hand, with increasing age, cardioprotective mechanisms in response to stress are lost, and progressive cardiomyocyte degeneration with replace- ment fibrosis is often seen in older hearts, even though the exact triggers are not completely understood. Older patients with heart failure have distinct features that require special attention in diagnosis as well as therapy. The elderly more frequently suffer from multiple co-morbidities and might have atypical clinical presentations. Several precautions are essential in the treatment of heart failure in the elderly due to co-existing morbidities and the pharmacokinetic and pharmacodynamic changes related to increased age. Also, treatment expectations, compliance, mental status and cognitive function might play a major role regarding optimized treatment and monitoring options in the elderly suffering from heart failure. This review summarizes current issues of heart failure management in the elderly.展开更多
Objective Heart failure is an epidemic in the elderly, but there is a striking lack of data in this clinically important patient population. We investigated the demographics, cardiac performance, and medication manage...Objective Heart failure is an epidemic in the elderly, but there is a striking lack of data in this clinically important patient population. We investigated the demographics, cardiac performance, and medication management of a segment of the hospital popula- tion in at least their eighth decade of life. Methods We retrospectively reviewed 75 records of heart failure patients who were 80 years of age or older. Records were reviewed for demographic information, presence or absence of diastolic dysfunction, evaluation of ejection fraction, and medication usage including angiotensin-concerting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARBs), beta-adrenergic blockers, digoxin, and aldosterone antagonists. Assessment for contra-indications to ACE inhibitor or ARBs use was also performed to assess co-morbidities that limit treatment of heart failure. Results The population of very elderly with heart failure is heterogeneous. We found a higher proportion of females as well as higher rates of diastolic dysfunction in patients aged ≥ 90 years compared to patients between the ages of 80-89 years. Usage of ACE inhibitors, ARBs and beta-adrenergic blockers was strikingly low throughout the very elderly population. While co-morbid conditions limited use of agents in many cases, there was a lack of explicit contra-indication in most patients not on an ACE inhibitor or an ARB. Conclusions Heart failure is not a single disease processes, but a continuum of disease processes that vary with age. The elderly with heart failure are an undertreated population, in part due to the multitude of co-morbidities that affect them. Further prospective studies are needed to better understand the physiology and ideal treatment regiment in this growing population.展开更多
Introduction Hepatic sinusoidal obstruction syndrome(HSOS)is a hepatic vascular disease characterized by injury of the endothelial cells in the sinusoidal hepatic and interlobular veins,intra-hepatic congestion,liver ...Introduction Hepatic sinusoidal obstruction syndrome(HSOS)is a hepatic vascular disease characterized by injury of the endothelial cells in the sinusoidal hepatic and interlobular veins,intra-hepatic congestion,liver dysfunction,and portal hypertension[1].In Western countries,HSOS is often associated with myeloablative regimens used for hematopoietic stem-cell transplantation,while,in China,it is often associated with oral intake of Gynura segetum plants that contain pyrrolidine alkaloids[2].In addition,new-onset HSOS after solid-organ transplantation has received increasing attention[3-8].展开更多
Background Most interventions for conditions with a small cohort size,such as transplantation,are unlikely to be part of a clinical trial.When condition-specific evidence is lacking,expert consensus can offer more pre...Background Most interventions for conditions with a small cohort size,such as transplantation,are unlikely to be part of a clinical trial.When condition-specific evidence is lacking,expert consensus can offer more precise guidance to improve care.Management of cardiovascular risk in liver-transplant recipients is one example for which clinicians have,to date,adapted evidence-based guidelines from studies in the general population.However,even when consensus is achieved,implementation of practice guidance is often inadequate and protracted.We report on a novel mixed-methods approach,the Northwestern MethodVC,for the development of clinical-practice guidance when condition-specific evidence is lacking.We illustrate the method through the development of practice guidance for managing cardiovascular risk in liver-transplant recipients.Methods The Northwestern MethodVC consists of(i)adaptation of relevant,existing,evidence-based clinical-practice guidelines for the target population;(ii)consensus by experts of the proposed practice guidance;(iii)identification of barriers to guidance adherence in current practice;and(iv)recommendation for implementation and dissemination of the practice guidance.The method is based on an iterative,user-centered approach in which the needs,wants,and limitations of all end users,including patients,are attended to at each stage of the design and development process.Conclusions The Northwestern MethodVC for clinical-practice-guidance development uses a mixed-methods approach to bring together broad representation from multiple disciplines and practice settings to develop consensus considering the unique needs and preferences of patients,caregivers,and practitioners who are directly impacted by clinical-practice-guidance recommendations.We hypothesize that a priori involvement of end users in the guidance-development process will lead to sustainable implementation of guidance statements into clinical practice.展开更多
The global average life expectancy is projected to rise to 80 years by 2040[1].Since cancer is closely linked to aging,its prevalence is expected to grow as the population ages.Advancements in cancer diagnosis and tre...The global average life expectancy is projected to rise to 80 years by 2040[1].Since cancer is closely linked to aging,its prevalence is expected to grow as the population ages.Advancements in cancer diagnosis and treatment have led to an increasing number of cancer survivors.In a 2021 consensus statement,the International Society for Geriatric Oncology updated its top priorities for improving care for older cancer patients[2,3].According to the Global Burden of Disease(GBD)study,there were over four million deaths from gastrointestinal(GI)cancer in 2021[4].The aging population,advancements in cancer management,and shifting risk factors are undoubtedly influencing the prevalence of GI cancers in older adults[5].While aging has increasingly captured the attention of policymakers and stakeholders,epidemiological data on GI cancers in older adults remains limited.Older patients are also underrepresented in GI-specific clinical trials.This study aimed to estimate the global burden of GI cancers in older adults using the most recent GBD 2021[6].展开更多
Our understanding of immune responses to SARS-CoV-2 and variants of concern(VOCs)has been primarily acquired through analysis of Spike-specific IgG responses.However,a more comprehensive understanding of the breadth a...Our understanding of immune responses to SARS-CoV-2 and variants of concern(VOCs)has been primarily acquired through analysis of Spike-specific IgG responses.However,a more comprehensive understanding of the breadth and longevity of immune responses after infection and vaccination requires analysis of cellular immunity.Herein,we report on T cell immunity in infected and vaccinated individuals,identifying CD4+/CD8+T cell cytokine responses to SARS-CoV-2 and variant peptides(Alpha,B.1.1.7 and Delta,B.1.617.2).展开更多
Large bone defect repair requires biomaterials that promote angiogenesis and osteogenesis.In present work,a nanoclay(Laponite,XLS)-functionalized 3D bioglass(BG)scaffold with hypoxia mimicking property was prepared by...Large bone defect repair requires biomaterials that promote angiogenesis and osteogenesis.In present work,a nanoclay(Laponite,XLS)-functionalized 3D bioglass(BG)scaffold with hypoxia mimicking property was prepared by foam replication coupled with UV photopolymerization methods.Our data revealed that the incorporation of XLS can significantly promote the mechanical property of the scaffold and the osteogenic differentiation of human adipose mesenchymal stem cells(ADSCs)compared to the properties of the neat BG scaffold.Desferoxamine,a hypoxia mimicking agent,encourages bone regeneration via activating hypoxia-inducible factor-1 alpha(HIF-1α)-mediated angiogenesis.GelMA-DFO immobilization onto BG-XLS scaffold achieved sustained DFO release and inhibited DFO degradation.Furthermore,in vitro data demonstrated increased HIF-1αand vascular endothelial growth factor(VEGF)expressions on human adipose mesenchymal stem cells(ADSCs).Moreover,BG-XLS/GelMA-DFO scaffolds also significantly promoted the osteogenic differentiation of ADSCs.Most importantly,our in vivo data indicated BG-XLS/GelMA-DFO scaffolds strongly increased bone healing in a critical-sized mouse cranial bone defect model.Therefore,we developed a novel BG-XLS/GelMA-DFO scaffold which can not only induce the expression of VEGF,but also promote osteogenic differentiation of ADSCs to promote endogenous bone regeneration.展开更多
Chronic hepatitis B is a worldwide disease,with significant burden on health care systems.While universal vaccination programs have led to an overall decrease in incidence of transmission of hepatitis B,unfortunately,...Chronic hepatitis B is a worldwide disease,with significant burden on health care systems.While universal vaccination programs have led to an overall decrease in incidence of transmission of hepatitis B,unfortunately,there remain large areas in the world where vaccination against hepatitis B is not practiced.In addition,vertical transmission of hepatitis B persists as a major concern.Hepatitis B treatment of the pregnant patient requires a thorough assessment of disease activity and close monitoring for flares,regardless of initiation of antiviral therapy.We discuss,in this article,the current and emergent strategies which aim to reduce the rate of transmission of hepatitis B from the pregnant mother to the infant and we review the updated guidelines regarding management of liver disease in pregnant women with hepatitis B.展开更多
Giant cell arteritis(GCA)is a vasculitis of medium and large sized vessels that occurs most often in people>50 years of age with associated symptoms of fever,weight loss,headache and jaw claudication.Polymyalgia rh...Giant cell arteritis(GCA)is a vasculitis of medium and large sized vessels that occurs most often in people>50 years of age with associated symptoms of fever,weight loss,headache and jaw claudication.Polymyalgia rheumatica(PMR),which is characterized by aching and stiffness in the shoulders,hip girdle,neck and torso,is intimately associated with GCA,and evidence suggests that GCA and PMR are two phases of the same disease.The occurrence of liver enzyme abnormalities in either of these conditions is rare.Furthermore,as these conditions occur most commonly in the elderly population who may be subject to polypharmacy,patients with elevated aminotransferases due to underlying GCA/PMR may mistakenly have their abnormal liver function tests attributed to drug-induced liver injury.Given the potential complications of these diseases if left untreated,including ischemic stroke and blindness,early recognition and treatment are critical.We report two patients who developed severe cholestatic liver enzyme elevation,which had been initially attributed to drug toxicity,but was ultimately caused by large vessel vasculitis,specifically GCA and PMR.展开更多
Hepatocellular carcinoma(HCC)is among the leading causes of cancer incidence and mortality worldwide.Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essenti...Hepatocellular carcinoma(HCC)is among the leading causes of cancer incidence and mortality worldwide.Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival.Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance,but it has limited sensitivity in early disease and may be inadequate in certain individuals.This review article will provide a comprehensive overview of the current landscape of HCC surveillance,including the rationale and indications for HCC surveillance,standard methods for HCC surveillance,and their strengths/limitations.Alternative surveillance methods such as the role of cross-sectional imaging,emerging circulating biomarkers,as well as the problem of under-utilization of HCC surveillance and surveillance-related harms will also be discussed in this review.展开更多
Background:Bariatric surgery represents an important treatment option for severely obese patients with nonalcoholic fatty liver disease(NAFLD).However,there remains inadequate data regarding the effects of different b...Background:Bariatric surgery represents an important treatment option for severely obese patients with nonalcoholic fatty liver disease(NAFLD).However,there remains inadequate data regarding the effects of different bariatric procedures on various NAFLD parameters,especially for histological outcomes.Thus,this meta-analysis aimed to compare the effects of restrictive bariatric procedures and foregut bypass on the metabolic,biochemical,and histological parameters for patients with NAFLD.Methods:Medline and Embase were searched for articles relating to bariatric procedures and NAFLD.Pairwise meta-analysis was conducted to compare efficacy of bariatric procedures pre-vs.post-procedure with subgroup analysis to further compare restrictive against foregut bypass procedures.Results:Thirty-one articles involving 3,355 patients who underwent restrictive bariatric procedures(n=1,460)and foregut bypass(n=1,895)were included.Both foregut bypass(P<0.01)and restrictive procedures(P=0.03)significantly increased odds of fibrosis resolution.Compared to restrictive procedures,foregut bypass resulted in a borderline non-significant decrease in fibrosis score(P=0.06)and significantly lower steatosis score(P<0.001).For metabolic parameters,foregut bypass significantly lowered body mass index(P=0.003)and low-density lipoprotein(P=0.008)compared to restrictive procedures.No significant differences were observed between both procedures for aspartate aminotransferase(P=0.17)and alkaline phosphatase(P=0.61).However,foregut bypass resulted in significantly lower gamma-glutamyl transferase than restrictive procedures(P=0.01)while restrictive procedures resulted in significantly lower alanine transaminase than foregut bypass(P=0.02).Conclusions:The significant histological and metabolic advantages and comparable improvements in biochemical outcomes support the choice of foregut bypass over restrictive bariatric procedures in NAFLD management.展开更多
Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)constitute the main subtypes of primary liver cancers(PLCs)as a major cause of cancer-related mortality and incidence.They emerge from varying quan...Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)constitute the main subtypes of primary liver cancers(PLCs)as a major cause of cancer-related mortality and incidence.They emerge from varying quantities and levels of differentiation among major liver cells,comprising hepatocytes,mucin-or non-mucin-producing cholangiocytes,and hepatic progenitor cells(HPCs)with the capability to differentiate into either hepatocytes or cholangiocytes.展开更多
文摘AIM To examine the effect of center size on survival differences between simultaneous liver kidney transplantation(SLKT) and liver transplantation alone(LTA) in SLKT-listed patients.METHODS The United Network of Organ Sharing database was queried for patients ≥ 18 years of age listed for SLKT between February 2002 and December 2015. Posttransplant survival was evaluated using stratified Cox regression with interaction between transplant type(LTA vs SLKT) and center volume.RESULTS During the study period, 393 of 4580 patients(9%) listed for SLKT underwent a LTA. Overall mortality was higher among LTA recipients(180/393, 46%) than SLKT recipients(1107/4187, 26%). The Cox model predicted a significant survival disadvantage for patients receiving LTA vs SLKT [hazard ratio, hazard ratio(HR) = 2.85; 95%CI: 2.21, 3.66; P < 0.001] in centers performing 30 SLKT over the study period. This disadvantage was modestly attenuated as center SLKT volume increased, with a 3% reduction(HR = 0.97; 95%CI: 0.95, 0.99; P = 0.010) for every 10 SLKs performed.CONCLUSION In conclusion, LTA is associated with increased mortality among patients listed for SLKT. This difference is modestly attenuated at more experienced centers and may explain inconsistencies between smaller-center and larger registry-wide studies comparing SLKT and LTA outcomes.
文摘The presence of human-leukocyte antigen （HLA）-antibodies and blood group incompatibility remain a large barrier to kidney transplantation leading to increased morbidity and mortality on the transplant waiting list. Over the last decade a number of new approaches were developed to overcome these barriers. Intravenous immunoglobulin （IVIG） remains the backbone of HLA desensitization therapy and has been shown in a prospective, randomized, placebo controlled trial to improve transplantation rates. Excellent outcomes with the addition of rituximab （anti-B cell） to IVIG based desensitization have been achieved. There is limited experience with bortezomib （anti-plasma cell） and eculizumab （complement inhibition） for desensitization. However, these agents may be good adjuncts for patients who are broadly sensitized with strong, complement-fxing HLA antibodies. Excellent short and long-term outcomes have been achieved in ABO incompatible transplantation with the combination of antibody removal, B cell depletion, and pre-transplant immunosuppression. Kidney paired donation has emerged as a reasonable alternative for programs who cannot provide desensitization or in conjunction with desensitization. Future therapies directed toward cytokines that alter B cell proliferation are under investigation.
文摘Non-alcoholic steatohepatitis(NASH)is the most common chronic liver disease worldwide,and the fastest growing indication for liver transplantation in the United States.NASH is now the leading etiology for liver transplantation in women,the second leading indication for men,and the most common cause amongst recipients aged 65 years and older.Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases,including obesity,type 2 diabetes(T2D),and hypertension.These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality.Furthermore,these patients carry considerable risk of morbidity and mortality both before after liver transplantation,with high rates of T2D,cardiovascular disease,chronic kidney disease,poor nutrition,and disease recurrence.Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure.Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation,control of diabetes,nutritional support,and even,potentially,consultation with a bariatric surgeon.This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.
文摘Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.
文摘Cirrhosis is a major cause of morbidity and mortality worldwide with liver transplantations as it only possible cure.In the face of a significant organ shortage many patients die waiting.A major complication of cirrhosis is the development of portal hypertension and ascites.The management of ascites has barely evolved over the last hundred years and includes only a few milestones in our treatment approach,but has overall significantly improved patient morbidity and survival.Our mainstay to ascites management includes changes in diet,diuretics,shunt procedures,and large volume paracentesis.The understanding of the pathophysiology of cirrhosis and portal hypertension has significantly improved in the last couple of decades but the changes in ascites management have not seemed to mirror this newer knowledge.We herein review the history of ascites management and discuss some its current limitations.
文摘AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation parameter(CAP) was used to assess hepatic steatosis post-sustained virological response(SVR);the CAP technology was not available in the United States at study initiation.Liver stiffness/fibrosis was measured before and 47 wk after treatment completion.Patients with genotype 3 and patients with cirrhosis were excluded.RESULTS One hundred and one patients were included in the study.Post-SVR there were decreases from baseline in alanine aminotransferase(ALT)(63.1 to 17.8 U/L),aspartate aminotransferase(51.8 to 21.5 U/L) and fibrosis score(7.4 to 6.1 k Pa)(P < 0.05).Post-SVR,48 patients(47.5%) had steatosis on CAP;of these,6.25% had advanced fibrosis.Patients with steatosis had higher body mass index(29.0 vs 26.1 kg/m2),glucose(107.8 vs 96.6 mg/d L),ALT(20.4 vs 15.3 mg/d L),CAP score(296.3 vs 212.4 d B/m) and fibrosis score(7.0 vs 5.3 k Pa);P < 0.05.Interestingly,compared to baseline,both patients with and without steatosis had change in fibrosis score post-SVR(7.7 k Pa vs 7.0 k Pa and 7.0 k Pa vs 5.3 k Pa);alternatively,(P < 0.05) and therefore patients with steatosis continued to have clinically significant stiffness(≥ 7 k Pa).CONCLUSION Fatty liver is very common in hepatitis C virus(HCV) patients post-SVR.These patients continue to have elevated mean fibrosis score(≥ 7 k Pa) compared to those without fatty liver;some have advanced fibrosis.Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.
文摘BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies reporting symptoms of depression,two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk,with further improvements observed in some studies after 4 and 8 wk of treatment.
基金Supported by Eris M.Field Endowment for Diabetes Research assigned to Donald C Dafoe
文摘Endothelial cells(ECs) are essential for pancreas differentiation, endocrine specification, and endocrine function. They are also involved in the physiopathology of type 1 and type 2 diabetes. During embryogenesis, aortic ECs provide specific factors that maintain the expression of key genes for pancreas development such as pancreatic and duodenal homeobox-1. Other unknown factors are also important for pancreatic endocrine specification and formation of insulin-producing beta cells. Endocrine precursors proliferate interspersed with ductal cells and exocrine precursors and, at some point of development, these endocrine precursors migrate to pancreatic mesenchyme and start forming the islets of Langerhans. By the end of the gestation and close to birth, these islets contain immature beta cells with the capacity to express vascular endothelial growth factor and therefore to recruit ECs from the surrounding microenvironment. ECs in turn produce factors that are essential to maintain insulin secretion in pancreatic beta cells. Once assembled, a cross talk between endocrine cells and ECs maintain the integrity of islets toward an adequate function during the whole life of the adult individual. This review will focus in the EC role in the differentiation and maturation of pancreatic beta cells during embryogenesis as well as the current knowledge about the involvement of endothelium to derive pancreatic beta cells in vitro from mouse or human pluripotent stem cells.
文摘Approximately 50% of all heart failure patients in the US are above 75 years of age, which is almost similar to most European countries and the Middle and the Far East. Even though aging is an independent molecular process with a multitude of genetic predetermination and biochemical mediations, aging itself does not automatically result in cardiac insufficiency. On the other hand, with increasing age, cardioprotective mechanisms in response to stress are lost, and progressive cardiomyocyte degeneration with replace- ment fibrosis is often seen in older hearts, even though the exact triggers are not completely understood. Older patients with heart failure have distinct features that require special attention in diagnosis as well as therapy. The elderly more frequently suffer from multiple co-morbidities and might have atypical clinical presentations. Several precautions are essential in the treatment of heart failure in the elderly due to co-existing morbidities and the pharmacokinetic and pharmacodynamic changes related to increased age. Also, treatment expectations, compliance, mental status and cognitive function might play a major role regarding optimized treatment and monitoring options in the elderly suffering from heart failure. This review summarizes current issues of heart failure management in the elderly.
文摘Objective Heart failure is an epidemic in the elderly, but there is a striking lack of data in this clinically important patient population. We investigated the demographics, cardiac performance, and medication management of a segment of the hospital popula- tion in at least their eighth decade of life. Methods We retrospectively reviewed 75 records of heart failure patients who were 80 years of age or older. Records were reviewed for demographic information, presence or absence of diastolic dysfunction, evaluation of ejection fraction, and medication usage including angiotensin-concerting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARBs), beta-adrenergic blockers, digoxin, and aldosterone antagonists. Assessment for contra-indications to ACE inhibitor or ARBs use was also performed to assess co-morbidities that limit treatment of heart failure. Results The population of very elderly with heart failure is heterogeneous. We found a higher proportion of females as well as higher rates of diastolic dysfunction in patients aged ≥ 90 years compared to patients between the ages of 80-89 years. Usage of ACE inhibitors, ARBs and beta-adrenergic blockers was strikingly low throughout the very elderly population. While co-morbid conditions limited use of agents in many cases, there was a lack of explicit contra-indication in most patients not on an ACE inhibitor or an ARB. Conclusions Heart failure is not a single disease processes, but a continuum of disease processes that vary with age. The elderly with heart failure are an undertreated population, in part due to the multitude of co-morbidities that affect them. Further prospective studies are needed to better understand the physiology and ideal treatment regiment in this growing population.
基金supported by Beijing Municipal Science and Technology Commission Funding Project[Z161100000116058]302 Military Hospital Project[YNKT 2014006].
文摘Introduction Hepatic sinusoidal obstruction syndrome(HSOS)is a hepatic vascular disease characterized by injury of the endothelial cells in the sinusoidal hepatic and interlobular veins,intra-hepatic congestion,liver dysfunction,and portal hypertension[1].In Western countries,HSOS is often associated with myeloablative regimens used for hematopoietic stem-cell transplantation,while,in China,it is often associated with oral intake of Gynura segetum plants that contain pyrrolidine alkaloids[2].In addition,new-onset HSOS after solid-organ transplantation has received increasing attention[3-8].
基金supported by the National Heart,Lung and Blood Institute at the National Institutes of Health to L.B.V.[grant number,K23 HL136891].
文摘Background Most interventions for conditions with a small cohort size,such as transplantation,are unlikely to be part of a clinical trial.When condition-specific evidence is lacking,expert consensus can offer more precise guidance to improve care.Management of cardiovascular risk in liver-transplant recipients is one example for which clinicians have,to date,adapted evidence-based guidelines from studies in the general population.However,even when consensus is achieved,implementation of practice guidance is often inadequate and protracted.We report on a novel mixed-methods approach,the Northwestern MethodVC,for the development of clinical-practice guidance when condition-specific evidence is lacking.We illustrate the method through the development of practice guidance for managing cardiovascular risk in liver-transplant recipients.Methods The Northwestern MethodVC consists of(i)adaptation of relevant,existing,evidence-based clinical-practice guidelines for the target population;(ii)consensus by experts of the proposed practice guidance;(iii)identification of barriers to guidance adherence in current practice;and(iv)recommendation for implementation and dissemination of the practice guidance.The method is based on an iterative,user-centered approach in which the needs,wants,and limitations of all end users,including patients,are attended to at each stage of the design and development process.Conclusions The Northwestern MethodVC for clinical-practice-guidance development uses a mixed-methods approach to bring together broad representation from multiple disciplines and practice settings to develop consensus considering the unique needs and preferences of patients,caregivers,and practitioners who are directly impacted by clinical-practice-guidance recommendations.We hypothesize that a priori involvement of end users in the guidance-development process will lead to sustainable implementation of guidance statements into clinical practice.
文摘The global average life expectancy is projected to rise to 80 years by 2040[1].Since cancer is closely linked to aging,its prevalence is expected to grow as the population ages.Advancements in cancer diagnosis and treatment have led to an increasing number of cancer survivors.In a 2021 consensus statement,the International Society for Geriatric Oncology updated its top priorities for improving care for older cancer patients[2,3].According to the Global Burden of Disease(GBD)study,there were over four million deaths from gastrointestinal(GI)cancer in 2021[4].The aging population,advancements in cancer management,and shifting risk factors are undoubtedly influencing the prevalence of GI cancers in older adults[5].While aging has increasingly captured the attention of policymakers and stakeholders,epidemiological data on GI cancers in older adults remains limited.Older patients are also underrepresented in GI-specific clinical trials.This study aimed to estimate the global burden of GI cancers in older adults using the most recent GBD 2021[6].
文摘Our understanding of immune responses to SARS-CoV-2 and variants of concern(VOCs)has been primarily acquired through analysis of Spike-specific IgG responses.However,a more comprehensive understanding of the breadth and longevity of immune responses after infection and vaccination requires analysis of cellular immunity.Herein,we report on T cell immunity in infected and vaccinated individuals,identifying CD4+/CD8+T cell cytokine responses to SARS-CoV-2 and variant peptides(Alpha,B.1.1.7 and Delta,B.1.617.2).
基金This work is supported by the Chinese National Natural Science Foundation of China(31600773)Zhejiang Provincial Natural Science Foundation of China(LY18C100002).
文摘Large bone defect repair requires biomaterials that promote angiogenesis and osteogenesis.In present work,a nanoclay(Laponite,XLS)-functionalized 3D bioglass(BG)scaffold with hypoxia mimicking property was prepared by foam replication coupled with UV photopolymerization methods.Our data revealed that the incorporation of XLS can significantly promote the mechanical property of the scaffold and the osteogenic differentiation of human adipose mesenchymal stem cells(ADSCs)compared to the properties of the neat BG scaffold.Desferoxamine,a hypoxia mimicking agent,encourages bone regeneration via activating hypoxia-inducible factor-1 alpha(HIF-1α)-mediated angiogenesis.GelMA-DFO immobilization onto BG-XLS scaffold achieved sustained DFO release and inhibited DFO degradation.Furthermore,in vitro data demonstrated increased HIF-1αand vascular endothelial growth factor(VEGF)expressions on human adipose mesenchymal stem cells(ADSCs).Moreover,BG-XLS/GelMA-DFO scaffolds also significantly promoted the osteogenic differentiation of ADSCs.Most importantly,our in vivo data indicated BG-XLS/GelMA-DFO scaffolds strongly increased bone healing in a critical-sized mouse cranial bone defect model.Therefore,we developed a novel BG-XLS/GelMA-DFO scaffold which can not only induce the expression of VEGF,but also promote osteogenic differentiation of ADSCs to promote endogenous bone regeneration.
文摘Chronic hepatitis B is a worldwide disease,with significant burden on health care systems.While universal vaccination programs have led to an overall decrease in incidence of transmission of hepatitis B,unfortunately,there remain large areas in the world where vaccination against hepatitis B is not practiced.In addition,vertical transmission of hepatitis B persists as a major concern.Hepatitis B treatment of the pregnant patient requires a thorough assessment of disease activity and close monitoring for flares,regardless of initiation of antiviral therapy.We discuss,in this article,the current and emergent strategies which aim to reduce the rate of transmission of hepatitis B from the pregnant mother to the infant and we review the updated guidelines regarding management of liver disease in pregnant women with hepatitis B.
文摘Giant cell arteritis(GCA)is a vasculitis of medium and large sized vessels that occurs most often in people>50 years of age with associated symptoms of fever,weight loss,headache and jaw claudication.Polymyalgia rheumatica(PMR),which is characterized by aching and stiffness in the shoulders,hip girdle,neck and torso,is intimately associated with GCA,and evidence suggests that GCA and PMR are two phases of the same disease.The occurrence of liver enzyme abnormalities in either of these conditions is rare.Furthermore,as these conditions occur most commonly in the elderly population who may be subject to polypharmacy,patients with elevated aminotransferases due to underlying GCA/PMR may mistakenly have their abnormal liver function tests attributed to drug-induced liver injury.Given the potential complications of these diseases if left untreated,including ischemic stroke and blindness,early recognition and treatment are critical.We report two patients who developed severe cholestatic liver enzyme elevation,which had been initially attributed to drug toxicity,but was ultimately caused by large vessel vasculitis,specifically GCA and PMR.
基金funded by the American College of Gastroenterology,grant name“Junior Faculty Development Award”United States Department of Defense,grant number CA191051National Institutes of Health,grant number R01CA246304,R01CA253651,R01CA255727,R21CA235340,and R21CA240887.
文摘Hepatocellular carcinoma(HCC)is among the leading causes of cancer incidence and mortality worldwide.Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival.Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance,but it has limited sensitivity in early disease and may be inadequate in certain individuals.This review article will provide a comprehensive overview of the current landscape of HCC surveillance,including the rationale and indications for HCC surveillance,standard methods for HCC surveillance,and their strengths/limitations.Alternative surveillance methods such as the role of cross-sectional imaging,emerging circulating biomarkers,as well as the problem of under-utilization of HCC surveillance and surveillance-related harms will also be discussed in this review.
文摘Background:Bariatric surgery represents an important treatment option for severely obese patients with nonalcoholic fatty liver disease(NAFLD).However,there remains inadequate data regarding the effects of different bariatric procedures on various NAFLD parameters,especially for histological outcomes.Thus,this meta-analysis aimed to compare the effects of restrictive bariatric procedures and foregut bypass on the metabolic,biochemical,and histological parameters for patients with NAFLD.Methods:Medline and Embase were searched for articles relating to bariatric procedures and NAFLD.Pairwise meta-analysis was conducted to compare efficacy of bariatric procedures pre-vs.post-procedure with subgroup analysis to further compare restrictive against foregut bypass procedures.Results:Thirty-one articles involving 3,355 patients who underwent restrictive bariatric procedures(n=1,460)and foregut bypass(n=1,895)were included.Both foregut bypass(P<0.01)and restrictive procedures(P=0.03)significantly increased odds of fibrosis resolution.Compared to restrictive procedures,foregut bypass resulted in a borderline non-significant decrease in fibrosis score(P=0.06)and significantly lower steatosis score(P<0.001).For metabolic parameters,foregut bypass significantly lowered body mass index(P=0.003)and low-density lipoprotein(P=0.008)compared to restrictive procedures.No significant differences were observed between both procedures for aspartate aminotransferase(P=0.17)and alkaline phosphatase(P=0.61).However,foregut bypass resulted in significantly lower gamma-glutamyl transferase than restrictive procedures(P=0.01)while restrictive procedures resulted in significantly lower alanine transaminase than foregut bypass(P=0.02).Conclusions:The significant histological and metabolic advantages and comparable improvements in biochemical outcomes support the choice of foregut bypass over restrictive bariatric procedures in NAFLD management.
文摘Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)constitute the main subtypes of primary liver cancers(PLCs)as a major cause of cancer-related mortality and incidence.They emerge from varying quantities and levels of differentiation among major liver cells,comprising hepatocytes,mucin-or non-mucin-producing cholangiocytes,and hepatic progenitor cells(HPCs)with the capability to differentiate into either hepatocytes or cholangiocytes.
