Burden of gallstone disease in the United States population:Prepandemic rates and trends

BACKGROUND Gallstone disease is one of the most common digestive disorders in the United States and leads to significant morbidity,mortality,and health care utilization.AIM To expand on earlier findings and investigate prepandemic rates and trends in the gallstone disease burden in the United States using national survey and claims databases.METHODS The National Ambulatory Medical Care Survey,National Inpatient Sample,Nationwide Emergency Department Sample,Nationwide Ambulatory Surgery Sample,Vital Statistics of the United States,Optum Clinformatics®Data Mart,and Centers for Medicare and Medicaid Services Medicare 5%Sample and Medicaid files were used to estimate claims-based prevalence,medical care including cholecystectomy,and mortality with a primary or other gallstone diagnosis.Rates were age-adjusted(for national databases)and shown per 100000 population.RESULTS Gallstone disease prevalence(claims-based,2019)was 0.70%among commercial insurance enrollees,1.03%among Medicaid beneficiaries,and 2.09%among Medicare beneficiaries and rose over the previous decade.Recently,in the United States population,gallstone disease contributed to approximately 2.2 million ambulatory care visits,1.2 million emergency department visits,625000 hospital discharges,and 2000 deaths annually.Women had higher medical care rates with a gallstone disease diagnosis,but mortality rates were higher among men.Hispanics had higher ambulatory care visit and hospital discharge rates compared with Whites,but not mortality rates.Blacks had lower ambulatory care visit and mortality rates,but similar hospital discharge rates compared with whites.During the study period,ambulatory care and emergency department visit rates with a gallstone disease diagnosis rose,while hospital discharge and mortality rates declined.Among commercial insurance enrollees,rates were higher compared with national data for ambulatory care visits and hospitalizations,but lower for emergency department visits.Cholecystectomies performed in the United States included 605000 ambulatory laparoscopic,280000 inpatient laparoscopic,and 49000 inpatient open procedures annually.Among commercial insurance enrollees,rates were higher compared with national data for laparoscopic procedures.CONCLUSION The gallstone disease burden in the United States is substantial and increasing,particularly among women,Hispanics,and older adults with laparoscopic cholecystectomy as the mainstay treatment.Current practice patterns should be monitored for better health care access.

Prevalence of hypothyroidism and effect of thyroid hormone replacement therapy in patients with non-alcoholic fatty liver disease:A population-based study

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is currently considered as the most common cause of chronic liver disease worldwide.Risk factors for NAFLD have been well-described,including obesity,type 2 diabetes mellites(T2DM),dyslipidemia(DLP)and metabolic syndrome.Hypothyroidism has been identified as an independent risk factor for the development of NAFLD,although the literature is inconsistent AIM To evaluate the prevalence of hypothyroidism in patients with NAFLD,assess if it is an independent risk factor and explore the effect of thyroxine replacement therapy.METHODS Our cohort’s data was obtained using a validated,large,multicenter database(Explorys Inc,Cleveland,OH,United States)aggregated from pooled outpatient and inpatient records of 26 different healthcare systems,consisting of a total of 360 hospitals in the United States,and utilizing Systematized Nomenclature of Medicine-Clinical Terms for coding.We evaluated a cohort of patients with hypothyroidism and NAFLD.Multivariate analysis was performed to adjust for confounding risk factors including hypertension(HTN),T2DM,DLP,obesity and metabolic syndrome.SPSS version 25,IBM Corp was used for statistical analysis,and for all analyses,a 2-sided P value of<0.05 was considered statistically significant.Exclusion criteria were limited to age<18 years.RESULTS Among the 37648180 included individuals in this database who are above the age of 18 years,there were a total of 2320 patients with NAFLD(6.16 per 100000)in the last five years(2015-2020),amongst which 520 patients(22.4%)had hypothyroidism.Baseline characteristics of patients in this database are described in Table 1.Patients with NAFLD were also more likely to have obesity,T2DM,DLP,HTN,and metabolic syndrome(Table 2).While males and females were equally affected,patients in the age group 18-65 years as well as Caucasians seem to be at a higher risk.There was an increased risk of NAFLD among patients with hypothyroidism(OR=1.587).Furthermore,thyroid hormone replacement was not associated with a decreased risk for developing NAFLD(OR=1.106,C=0.952-1.285,P=0.303).CONCLUSION Hypothyroidism seems to be an independent risk factor for the development of NAFLD.Thyroid hormone replacement did not provide a statistically significant risk reduction.Further studies are needed to evaluate the effect of thyroid hormone replacement and assess if being euthyroid while on thyroid replacement therapy affects development and/or progression of NAFLD.

Chronic hepatitis delta: A state-of-the-art review and new therapies

Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide.Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma.Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans.Infection can occur in the form of a co-infection with hepatitis B,which can be self-limiting,vs superinfection in a patient with established hepatitis B infection,which often leads to chronicity in majority of cases.Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis.Guidelines recommend treatment with pegylated interferon,but this is limited to patients with compensated disease and is efficacious in about 30%of those treated.Due to limited treatment options,novel agents are being investigated and include entry,assembly and export inhibitors of viral particles in addition to stimulators of the host immune response.Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other.Also,surrogate markers of treatment efficacy have been proposed.

Research progress on the drug action and resistance mechanism in Mycobacterium tuberculosis

Tuberculosis(TB)is a chronic infectious disease caused by Mycobacterium Tuberculosis(MTB).It is the second largest single cause of death besides novel coronavirus pneumonia.Along with the abuse of antibiotics and extensive use of anti-tuberculosis drugs,multidrug-resistant(MDR)TB,drug-resistant(XDR)TB and totally drug-resistant(TDR)TB became obstacles to the tuberculosis eradication worldwide.According to the World Health Organization(WHO)statistics,China is not only a high burden tuberculosis country in the world,but also a country with a serious epidemic of MDR.Traditional drugs fail to meet the needs of tuberculosis control.Therefore,it is urgent to find new targets of anti-tuberculosis drugs and develop new anti-tuberculosis drugs.Hence,this paper systematically summarizes the mechanism of traditional and newly developed anti-tuberculosis drugs,in which stressing the research progress of drug resistance mechanisms.This work provides us with new insights of new anti-tuberculosis drug developments,and may contribute to a reduction in the harm that tuberculosis brings to society.

Identification of key genes responsible for cytokine-induced erythroid and myeloid differentiation and switching of hematopoietic stem cells by RAGE

We utilized a unique culture system to analyze the expression patterns of gene, protein, and cell surface antigen, and the biological process of the related genes in erythroid and myeloid differentiation and switching of hematopoietic stem cells （HSCs） in response to cytokine alterations. Gene-specific fragments （266） identified from five populations of cytokine-stimulated HSCs were categorized into three groups： （1） expressed specifically in a single cell population; （2） expressed in two cell populations, and （3） expressed in three or more populations. Of 145 defined cDNAs, three （2%） were novel genes. Protein two-dimensional gel electrophoresis and flow cytometry analyses showed overlapped and distinguished protein expression profiles in the cell populations studied. Biological process mapping of mRNAs expressed in erythroid and myeloid lineages indicated that mRNAs shared by both lineages attended ＇core processes,＇ whereas genes specifically expressed in either lineage alone were related to specific processes or cellular maturation. Data from this study support the hypothesis that committed HSCs （El4 or G14） cells can still be redirected to develop into myeloid or erythroid cells when erythropoietin （EPO） is replaced with granulocyte-colony stimulating factor （G-CSF） under erythroid-cultured condition or G-CSF with EPO in myeloid-cultured environment, respectively. Our results suggest that genes or proteins co-expressed in erythroid and myeloid lineages may be essential for the lineage maintenance and switching in hematopoiesis.

POSSIBLE CLINICAL USES OF GASTROINTESTINAL HORMONE RECEPTOR AGONISTS AND ANTAGONISTS

The structure and pharmacologic effectsof more than 50 gastrointestinal peptideshave been described. However,their physic-logical roles in normal processes or roles inpathological processes are largely unknown.This is primarily due to the lack of re-ceptor-specific agonists or antagonists. How-ever,this is change rapidly at present for anumber of reasons.The receptor

Structure and mechanism for DNA lesion recognition

A fundamental question in DNA repair is how a lesion is detected when embedded in millions to billions of normal base pairs. Extensive structural and functional studies reveal atomic details of DNA repair protein and nucleic acid interactions. This review summarizes seemingly diverse structural motifs used in lesion recognition and suggests a general mechanism to recognize DNA lesion by the poor base stacking. After initial recognition of this shared structural feature of lesions, different DNA repair pathways use unique verification mechanisms to ensure correct lesion identification and removal.

Identifying who best tolerates moderate sedation:Results from a national database of gastrointestinal endoscopic outcomes

BACKGROUND With increasing volume and cost of gastrointestinal endoscopic procedures,the proper selection of patients for moderate sedation becomes increasingly relevant.The current literature lacks consistent findings that allow for appropriate selection of patients for moderate sedation.AIM To analyze a nationwide registry of patients to identify patient and procedural factors associated with lower sedation requirements for endoscopy.METHODS The Clinical Outcomes Research Initiative National Endoscopic Database was queried to assess adult patients undergoing moderate sedation for esophagogastroduodenoscopy(EGD)and colonoscopy from 2008 to 2014.Patients were stratified into two groups[low dose(LD)and high dose sedation]based on sedation requirements.Anthropometric,procedural,and anesthesia data were compared,and multivariable analysis was performed to identify factors associated with LD sedation.RESULTS Of the 371102 patients included in the study,63137 where stratified into the LD sedation group and 307965 were in the high dose group.Moderate sedation was managed primarily by endoscopists(50%)and anesthesia providers(47%).Patients undergoing EGDs and procedures performed in the inpatient setting,in ambulatory surgery centers,intensive care units or hospital wards,required less sedation than colonoscopies,outpatient procedures and procedures done in endoscopy suites,respectively(P<0.0001 for all).On multivariable analysis,factors predictive of tolerance with lower sedation requirements for EGDs and colonoscopies were female gender,age≥50,non-White race,Hispanic descent,body mass index≤25 kg/m^(2),and higher American Society of Anesthesia Class(P<0.0001 for all).CONCLUSION Clinicians should consider these patient profiles in determining which patients will better tolerate moderate sedation vs those better suited for alternative sedation methods.

Immunological mechanisms and therapeutic targets of fatty liver diseases

Alcoholic liver disease(ALD)and nonalcoholic fatty liver disease(NAFLD)are the two major types of chronic liver disease worldwide.Inflammatory processes play key roles in the pathogeneses of fatty liver diseases,and continuous inflammation promotes the progression of alcoholic steatohepatitis(ASH)and nonalcoholic steatohepatitis(NASH).Although both ALD and NAFLD are closely related to inflammation,their respective developmental mechanisms differ to some extent.Here,we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH.Multiple cell types in the liver,including macrophages,neutrophils,other immune cell types and hepatocytes,are involved in fatty liver disease inflammation.In addition,microRNAs(miRNAs),extracellular vesicles(EVs),and complement also contribute to the inflammatory process,as does intertissue crosstalk between the liver and the intestine,adipose tissue,and the nervous system.We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections.Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

Characteristics of Clostridium difficile infection in patients hospitalized with myelodysplastic syndrome or acute myelogenous leukemia

AIM To evaluate factors associated with Clostridium difficile infection (CDI) and outcomes of CDI in the myelodysplastic syndrome(MDS) and acute myeloid leukemia (AML) population.METHODS After IRB approval,all MDS/AML patients hospitalized at the University of Maryland Greenebaum Comprehensive Cancer Center between August 2011 and December 2013 were identified.Medical charts were reviewed for demographics,clinical information,development of CDI,complications of CDI,and mortality.Patients with CDI,defined as having a positive stool PCR done for clinical suspicion of CDI,were compared to those without CDI in order to identify predictors of disease.A t-test was used for comparison of continuous variables and chisquare or Fisher's exact tests were used for categorical variables,as appropriate.RESULTS Two hundred and twenty-three patients (60.1% male,mean age 61.3 years,13% MDS,87% AML) had 594 unique hospitalizations during the study period.Thirtyfour patients (15.2%) were diagnosed with CDI.Factors significantly associated with CDI included lower albumin at time of hospitalization (P < 0.0001),prior diagnosis of CDI (P < 0.0001),receipt of cytarabine-based chemotherapy (P = 0.015),total days of neutropenia (P = 0.014),and total days of hospitalization (P = 0.005).Gender (P = 0.10),age (P = 0.77),proton-pump inhibitor use (P = 0.73),receipt of antibiotics (P = 0.66),and receipt of DNA hypomethylating agent-based chemotherapy (P = 0.92) were not significantly associated with CDI.CONCLUSION CDI is common in the MDS/AML population.Factors significantly associated with CDI in this population include low albumin,prior CDI,use of cytarabine-based chemotherapy,and prolonged neutropenia.In this study,we have identified a subset of patients in which prophylaxis studies could be targeted.

Screening Helicobacter pylori genes induced during infection of mouse stomachs

AIM:To investigate the effect of in vivo environment on gene expression in Helicobacter pylori(H.pylori) as it relates to its survival in the host.METHODS:In vivo expression technology(IVET) systems are used to identify microbial virulence genes.We modified the IVET-transcriptional fusion vector,pIVET8,which uses antibiotic resistance as the basis for selection of candidate genes in host tissues to develop two unique IVET-promoter-screening vectors,pIVET11 and pIVET12.Our novel IVET systems were developed by the fusion of random Sau3A DNA fragments of H.pylori and a tandem-reporter system of chloramphenicol acetyltransferase and beta-galactosidase.Additionally,each vector contains a kanamycin resistance gene.We used a mouse macrophage cell line,RAW 264.7 and mice,as selective media to identify specific genes that H.pylori expresses in vivo.Gene expression studies were conducted by infecting RAW 264.7 cells with H.pylori.This was followed by real time polymerase chain reaction(PCR) analysis to determine the relative expression levels of in vivo induced genes.RESULTS:In this study,we have identified 31 in vivo induced(ivi) genes in the initial screens.These 31 genes belong to several functional gene families,including several well-known virulence factors that are expressed by the bacterium in infected mouse stomachs.Virulence factors,vacA and cagA,were found in this screen and are known to play important roles in H.pylori infection,colonization and pathogenesis.Their detection validates the efficacy of these screening systems.Some of the identified ivi genes have already been implicated to play an important role in the pathogenesis of H.pylori and other bacterial pathogens such as Escherichia coli and Vibrio cholerae.Transcription profiles of allivi genes were confirmed by real time PCR analysis of H.pylori RNA isolated from H.pylori infected RAW 264.7 macrophages.We compared the expression profile of H.pylori and RAW 264.7 coculture with that of H.pylori only.Some genes such as cag A,vac A,lpx C,mur I,tlp C,trx B,sod B,tnp B,pgi,rbf A and inf B showed a 2-20 fold upregulation.Statistically significant upregulation was obtained for all the above mentioned genes(P < 0.05).tlp C,cag A,vac A,sod B,rbf A,inf B,tnp B,lpx C and mur I were also significantly upregulated(P < 0.01).These data suggest a strong correlation between results obtained in vitro in the macrophage cell line and in the intact animal.CONCLUSION:The positive identification of these genes demonstrates that our IVET systems are powerful tools for studying H.pylori gene expression in the host environment.

Mechanisms of Steatosis-Derived Hepatocarcinogenesis:Lessons from HCV Core Gene Transgenic Mice

Hepatitis C virus(HCV)is a major cause of chronic hepatitis,liver cirrhosis,and hepatocellular carcinoma(HCC)worldwide.Among the structural proteins of HCV,the HCV core protein has the ability to regulate gene transcription,lipid metabolism,cell proliferation,apoptosis,and autophagy,all of which are closely related to the development of HCC.Transgenic mice carrying the HCV core gene exhibited age-dependent insulin resistance,hepatic steatosis,and HCC that resembled the clinical characteristics of chronic hepatitis C patients.Several dietary modifications,including calorie restriction and diets rich in saturated fatty acids,trans fatty acids,or cholesterol,were found to influence hepatic steatogenesis and tumorigenesis in HCV core gene transgenic mice.These strategies modulated hepatocellular stress and proliferation,in addition to hepatic fibrotic processes and the microenvironment,thereby corroborating a close interconnection between dietary habits and steatosis-related hepatocarcinogenesis.In this review,we summarize the findings obtained from mouse models transgenic for the HCV genome,with a special focus on HCV core gene transgenic mice,and discuss the mechanisms of steatogenesis and hepatocarcinogenesis induced by the HCV core protein and the impact of dietary habits on steatosis-derived HCC development.

Chowing down:diet considerations in rodent models of metabolic disease

Diet plays a substantial role in the etiology, progression, and treatment of chronic disease and is best considered as a multifacetedset of modifiable input variables with pleiotropic effects on a variety of biological pathways spanning multiple organ systems. Thisbrief review discusses key issues related to the design and conduct of diet interventions in rodent models of metabolic disease andtheir implications for interpreting experiments. We also make specific recommendations to improve rodent diet studies to help betterunderstand the role of diet on metabolic physiology and thereby improve our understanding of metabolic disease.

Impact of Proteinuria on Liver Enzyme Levels

Dear Editors,We read with great interest the recently published article“Subnormal Serum Liver Enzyme Levels:A Review of Pathophysiology and Clinical Significance”by Youssef and colleagues.1 While much attention is given to elevations of liver enzymes,the authors highlight clinically important,often unrecognized reasons leading to low liver enzyme levels.For example,chronic kidney disease was cited as a cause of low serum aspartate aminotransferase(AST)proportional to the progression of the disease,but the cause(s)are not well defined.Little is known about the possible influence of nephrotic syndrome(NS)on liver enzymes.

Alterations of chromosome 3p in 24 cases of gastrinomas and their correlations with clinicopathological and prognostic features

Purpose::The pathogenesis of gastrinomas is largely unknown,and there is a lack of reliable genetic determinants that are useful to distinguish malignant and benign forms of this tumor or predict the prognosis of patients with this disease.Loss of heterozygosity(LOH)on chromosome 3p is reported to occur in pancreatic neuroendocrine tumors(PNETs)as well as in non-PNETs and its presence is reported to correlate with tumor prognosis in non-endocrine tumors.However,little data are available from prospective studies on gastrinomas.Experimental design::We assessed occurrence of 3p LOH in 24 gastrinomas and correlated its presence with tumor biological behavior and other clinicopathological features of gastrinomas.Results::Either 3p LOH or microsatellite instability involving 3p occurred in 11 of 24 tumors(46%).Seven(29%)gastrinomas had 3p LOH.Of the 7 gastrinomas with 3p LOH,5(71%)had 3p12 LOH with the marker D3S2406,which was the shortest region of highest overlap(SRO).Chromosome 3p LOH was not associated with aggressive biological behavior of gastrinomas or with poor prognosis of patients with gastrinoma.Similarly,3p12 LOH(SRO)was not correlated with aggressive growth of tumors and/or liver metastases.Conclusion::Gastrinomas have a relative high frequency of 3p12 LOH suggesting this area may harbor putative tumor suppressor gene(s),which may play a role in the tumorigenesis,but not aggressiveness,of a subset of these tumors.

Erythropoietin modulates bone marrow stromal cell differentiation

Erythropoietin is essential for bone marrow erythropoiesis and erythropoietin receptor on non-erythroid cells including bone marrow stromal cells suggests systemic effects of erythropoietin. Tg6 mice with chronic erythropoietin overexpression have a high hematocrit, reduced trabecular and cortical bone and bone marrow adipocytes, and decreased bone morphogenic protein 2 driven ectopic bone and adipocyte formation. Erythropoietin treatment(1 200 IU·kg–1) for 10 days similarly exhibit increased hematocrit,reduced bone and bone marrow adipocytes without increased osteoclasts, and reduced bone morphogenic protein signaling in the bone marrow. Interestingly, endogenous erythropoietin is required for normal differentiation of bone marrow stromal cells to osteoblasts and bone marrow adipocytes.ΔEpoR_E mice with erythroid restricted erythropoietin receptor exhibit reduced trabecular bone, increased bone marrow adipocytes, and decreased bone morphogenic protein 2 ectopic bone formation. Erythropoietin treated ΔEpoR_E mice achieved hematocrit similar to wild-type mice without reduced bone, suggesting that bone reduction with erythropoietin treatment is associated with non-erythropoietic erythropoietin response. Bone marrow stromal cells from wild-type,Tg6, and ΔEpoR_E-mice were transplanted into immunodeficient mice to assess development into a bone/marrow organ. Like endogenous bone formation, Tg6 bone marrow cells exhibited reduced differentiation to bone and adipocytes indicating that high erythropoietin inhibits osteogenesis and adipogenesis, while ΔEpoR_E bone marrow cells formed ectopic bones with reduced trabecular regions and increased adipocytes, indicating that loss of erythropoietin signaling favors adipogenesis at the expense of osteogenesis. In summary, endogenous erythropoietin signaling regulates bone marrow stromal cell fate and aberrant erythropoietin levels result in their impaired differentiation.

Neutralizing antibodies in hepatitis C virus infection

Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodiesfor control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.

Glia Maturation Factor Gamma (GMFG): A Cytokine-Responsive Protein During Hematopoietic Lineage Development and Its Func-tional Genomics Analysis

Human hematopoiesis was evaluated using the techniques of controlled stem cell differentiation, two-dimensional gel electrophoresis-based proteomics, and functional genomics. We provide the first report that glia maturation factor gamma （GMFG） is a cytokine-responsive protein in erythropoietin-induced and granulocyte-colony stimulating factor-induced hematopoietic lineage development. Results from global functional genomics analysis indicate that GMFG possesses several other features： hematopoietic tissue-specific gene expression, a promoter concentrated with high-score hematopoiesis-specific transcription factors, and possible molecular coevolution with a rudimentary blood/immune system. On the basis of our findings, we hypothesize that GMFG is a hematopoietic-specific protein that may mediate the pluripotentiality and lineage commitment of human hematopoietic stem cells.