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Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

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World Journal of Hepatology 2024年第3期16卷 331-343页

作者： Robert Lam Joseph K Lim Section of Digestive Diseases Yale University School of MedicineNew HavenCT 06520United States

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United *** is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver *** therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver ***,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver *** investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV *** we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

关键词： Hepatitis B virus Treatment Clinical trials RNA interference Entry inhibitors Core inhibitors Immunomodulators

Recipient functional status impacts on short and long-term intestinal transplant outcomes in United States adults

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World Journal of Transplantation 2024年第3期14卷 80-94页

作者： Sarpong Boateng Prince Ameyaw Solomon Gyabaah Yaw Adjepong Basile Njei Department of Medicine Yale New Haven HealthBridgeport HospitalBridgeportCT 06610United States Department of Epidemiology and Biostatistics University of North TexasFort WorthTX 76107United States Department of Medicine Komfo Anokye Teaching HospitalKumasi KS 1934Ghana Yale University School of Medicine New HavenCT 06520United States Section of Digestive Diseases Yale University School of MedicineNew HavenCT 06520United States

BACKGROUND Recipient functional status prior to transplantation has been found to impact post-transplant outcomes in heart,liver and kidney ***,information on how functional status,before and after transplant impacts post-transplant survival outcomes is *** To investigate the impact of recipient functional status on short and long term intestinal transplant outcomes in United States *** We conducted a retrospective cohort study on 1254 adults who underwent first-time intestinal transplantation from 2005 to *** primary outcome was *** the Karnofsky Performance Status,functional impairment was categorized as severe,moderate and *** were conducted using Kaplan-Meier curves and multivariable Cox *** The median age was 41 years,majority(53.4%)were *** impairment was present in 28.3%of *** median survival time was 906.6 *** median survival time was 1331 and 560 days for patients with normal and severe functional impairment *** with severe impairment had a 56%higher risk of mortality at one year[Hazard ratio(HR)=1.56;95%CI:1.23–1.98;Pctional *** with worse functional status after transplant also had poor survival *** Pre-and post-transplant recipient functional status is an important prognostic indicator for short-and long-term intestinal transplant outcomes.

关键词： Intestinal transplantation Functional status Karnofsky performance status Post-transplant outcomes Survival analysis Transplant outcome

Capturing Plateau-Rayleigh instability in silver nanowires via ultrafast electron microscopy

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Nano Research 2024年第9期17卷 8402-8407页

作者： Shuai Jiang Volkan Ortalan Department of Materials Science and Engineering University of ConnecticutStorrsCT 06269USA

Understanding the structural stability of nanomaterials such as nanowires is imperative for their practical ***,using single-shot ultrafast transmission electron microscopy,we captured the Plateau-Rayleigh instability behavior of silver nanowires decomposing into silver nanoparticles upon laser irradiation on nanosecond time *** found that this dynamic process can be accelerated by a factor of 10 through increasing the peak laser fluence from 6.03 to 14.60 mJ/cm^(2).Moreover,by comparing the laser fluence required to initiate the Plateau-Rayleigh instability in silver nanowires on carbon and Formvar membranes,it was found that the main driving force for the Plateau-Rayleigh instability in this study was substrate *** element analysis and molecular dynamics simulations are also applied to estimate the temperature jump of the nanowires and atomistic behavior,*** addition,the complex motions of silver nanowires under laser irradiation were systematically investigated by combining the results of ultrafast transmission electron microscopy with scanning electron microscopy characterizations and were determined to be related to nanowire-membrane interactions or pre-existing stresses on the nanowires,which in turn demonstrated the potential of ultrafast transmission electron microscopy for the characterization of nanomaterials and devices under extreme conditions.

关键词： silver nanowire Plateau-Rayleigh instability ultrafast transmission electron microscopy molecular dynamics simulation

Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review

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Journal of Clinical and Translational Hepatology 2024年第3期12卷 316-326页

作者： Christopher J.Costa Minh Thu T.Nguyen Haleh Vaziri George Y.Wu Department of Medicine University of Connecticut Health CenterFarmingtonCTUSA Division of Gastroenterology and Hepatology University of Connecticut Health CenterFarmingtonCTUSA

Gallstone(GS)disease is common and arises from a combination of genetic and environmental *** genetic abnormalities specifically leading to cholesterol GSs are rare,there are clinically significant gene variants associated with cholesterol *** contrast,most bilirubin GSs can be attributed to genetic *** pathogenesis of cholesterol and bilirubin GSs differs *** GSs are notably influenced by genetic variants within the ABC protein superfamily,including ABCG8,ABCG5,ABCB4,and ABCB11,as well as genes from the apolipoprotein family such as ApoB100 and ApoE(especially the E3/E3 and E3/E4 variants),and members of the MUC ***,bilirubin GSs are associated with genetic variants in highly expressed hepatic genes,notably UGT1A1,ABCC2(MRP2),ABCC3(MRP3),CFTR,and MUC,alongside genetic defects linked to hemolytic anemias and conditions impacting *** genetic cases constitute a small portion of GS disease,recognizing genetic predisposition is essential for proper diagnosis,treatment,and genetic counseling.

关键词： Gallstones Cholelithiasis ATP-binding cassette transporters ABCG8 protein Human UDP-glucuronosyltransferase A1

Unique Genetic Features of Lean NAFLD: A Review of Mechanisms and Clinical Implications

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Journal of Clinical and Translational Hepatology 2024年第1期12卷 70-78页

作者： Jasmine Tidwell George Y.Wu Department of Medicine University of Connecticut Health CenterFarmingtonCTUSA Division of Gastroenterology-Hepatology University of Connecticut Health CenterFarmingtonCTUSA

Non-alcoholic fatty liver disease(NAFLD)affects 25%of the global *** 20%have a normal body mass index(BMI)and a variant known as lean *** typical NAFLD cases associated with obesity and diabetes,lean NAFLD causes liver disease by mechanisms not related to excess weight or insulin *** disorders are among the major factors in developing lean NAFLD,and genome-wide association studies have identified several genes associated with the *** review aims to increase awareness by describing the genetic markers linked to NAFLD and the defects involved in developing lean NAFLD.

关键词： Lean nonalcoholic fatty liver disease Palatine-like phospholipase domain-containing-3 Transmembrane 6 superfamily member 2 Familial hypobetalipoproteinemia Abetalipoproteinemia

Etiologies of Splenic Venous Hypertension:A Review

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Journal of Clinical and Translational Hepatology 2024年第6期12卷 594-606页

作者： Jasmine Tidwell Bianca Thakkar George Y.Wu Department of Medicine University of Connecticut Health CenterFarmingtonCTUSA Division of Gastroenterology-Hepatology University of Connecticut Health CenterFarmingtonCTUSA

Splenic venous hypertension or left-sided portal hypertension is a rare condition caused by an obstruction of the splenic ***,it presents with upper gastrointestinal bleeding in the absence of liver *** can be classified based on the mechanism of development of splenic vein hypertension:compression,stenosis,inflammation,thrombosis,and surgically decreased splenic venous *** is established by various imaging modalities and should be suspected in patients with gastric varices in the absence of esophageal varices,splenomegaly,or *** management and prognosis vary depending on the underlying etiology but generally involve reducing splenic venous *** aim of this review was to summarize the etiologies of splenic venous hypertension according to the mechanism of development.

关键词： Splenic venous hypertension Left-sided portal hypertension Sinistral portal hypertension Splenic vein thrombosis Gastric varices Hematemesis Upper gastrointestinal bleeding

Heritable Chronic Cholestatic Liver Diseases:A Review

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Journal of Clinical and Translational Hepatology 2024年第8期12卷 726-738页

Chronic cholestasis due to heritable causes is usually diagnosedin ***,many cases can present andsurvive into *** time course varies considerablydepending on the underlying *** data usuallyreveal elevated conjugated hyperbilirubinemia,alkalinephosphatase,and gamma-glutamyl *** be asymptomatic;however,when present,the typicalsymptoms are pruritus,jaundice,fatigue,and *** diagnostic methods and management requireddepend on the underlying *** development of genome-wide associated studies has allowed the identificationof specific genetic mutations related to the pathophysiologyof cholestatic liver *** aim of this review was tohighlight the genetics,clinical pathophysiology,presentation,diagnosis,and treatment of heritable etiologies of chroniccholestatic liver disease.

关键词： Chronic cholestasis Cholestatic liver disease Congenital hepatic fibrosis Caroli disease Caroli syndrome Alagille syndrome Biliary atresia

Integrating mRNA Decay Information into Co-Regulation Study

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Journal of Computer Science & Technology 2005年第4期20卷 434-438页

作者：陈亮赵宏宇 DepartmentofMolecular CellularandDevelopmentalBiologyYaleUniversityNewHavenCT06520U.S.A. DepartmentofEpidemiologyandPublicHealth YaleUniversityNewHavenCT06520U.S.A.

Absolute or relative transcript amounts measured through high-throughput technologies (e.g., microarrays)are now commonly used in bioinformatics analysis, such as gene clustering and DNA binding motif finding. However,transcription rates that represent mRNA synthesis may be more relevant in these analyses. Because transcription rates are not equivalent to transcript amounts unless the mRNA degradation rates as well as other factors that affect transcript amount are identical across different genes, the use of transcription rates in bioinformatics analysis may lead to a better description of the relationships among genes and better identification of genomic signals. In this article, we propose to use experimentally measured mRNA decay rates and mRNA transcript amounts to jointly infer transcription rates, and then use the inferred transcription rates in downstream analyses. For gene expression similarity analysis, we find that there tends to be higher correlations among co-regulated genes when transcription-rate-based correlations are used compared to those based on transcript amounts. In the context of identifying DNA binding motifs, using inferred transcription rates leads to more significant findings than those based on transcript amounts. These analyses suggest that the incorporation of mRNA decay rates and the use of the inferred transcription rates can facilitate the study of gene regulations and the reconstruction of transcriptional regulatory networks.

关键词： DNA 脱氧核糖核酸 mRNA 实验

Applying Machine Learning Approach to Explore Childhood Circumstances and Self-Rated Health in Old Age-China and the US,2020-2021

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China CDC weekly 2024年第11期6卷 213-218,I0008-I0013页

作者： Shutong Huo Derek Feng Thomas M.Gill Xi Chen Department of Health Society&BehaviorPublic HealthUniversity of CaliforniaIrvineCAUSA Department of Statistics and Data Science Yale UniversityNew HavenCTUS Department of Internal Medicine Yale School of MedicineNew HavenCTUS Department of Health Policy and Management Yale School of Public HealthNew HavenCTUS Department of Economics Yale UniversityNew HavenCTUS.

Introduction:Childhood circumstances impact senior health,prompting the introduction of machine learning methods to assess their individual and collective contributions to senior ***:Using health and retirement study(HRS)and China Health and Retirement Longitudinal Study(CHARLS),we analyzed 2,434 American and 5,612 Chinese participants aged 60 and *** inference trees and forests were employed to estimate the influence of childhood circumstances on self-rated health(SRH).Results:The conventional method estimated higher inequality of opportunity(IOP)values in both China(0.039,accounting for 22.67%of the total Gini coefficient 0.172)and the US(0.067,accounting for 35.08%of the total Gini coefficient 0.191).In contrast,the conditional inference tree yielded lower estimates(China:0.022,accounting for 12.79%of 0.172;US:0.044,accounting for 23.04%of 0.191),as did the forest(China:0.035,accounting for 20.35%of 0.172;US:0.054,accounting for 28.27%of 0.191).Childhood health,financial status,and regional differences were key determinants of senior *** conditional inference forest consistently outperformed others in predictive accuracy,as demonstrated by lower out-of-sample mean squared error(MSE).Discussion:The findings emphasize the need for early-life interventions to promote health equity in aging *** learning showcases the potential in identifying contributing factors.

关键词： collective inequality estimates