Changes in the Prevalence, Incidence, and Disability-Adjusted Life Years of Non-alcoholic Fatty Liver Disease in the United States Between 1990 and 2019.

INTRODUCTION: This study aimed to determine trends in the prevalence, incidence, and disability-adjusted life years (DALYs) of Non-alcoholic Fatty Liver Disease (NAFLD) in the US across different states and age groups between 1990 and 2019. METHODS: Using the Global Burden of Disease database, this study analyzed the prevalence, incidence, and DALYs of NAFLD in the US between 1990 and 2019. We computed relative percentage changes, performed Joinpoint regression analyses of trends, and compared these between states and age groups (5-19, 20-55, and more than 55 years old). RESULTS: In the United States, the prevalence of NAFLD increased more than the global average over the study period (+ 30.7% vs. + 24.5%), especially in the 5-19-year-old age group. Among all states, Kansas, Washington, and California had the highest increase in prevalence and the District of Columbia followed by Massachusetts and North Carolina had the lowest increase in prevalence. The increase in incidence was greater in the US than the global average (+ 37.18% vs. + 7.28%). West Virginia, Ohio, and Kentucky had the highest increase in incidence. The increase in DALYs was greater in the US compared to the global average (+ 57.15% vs. + 12.65%). Alaska, West Virginia, and Kentucky had the highest increase in DALYs. The increased incidence and DALYs were found in all states except in the District of Columbia. CONCLUSION: The prevalence of NAFLD in the US has increased more rapidly than the global average, especially in the pediatric population. South and Midwest states have the highest increase in prevalence, incidence, and DALYs of NAFLD. The District of Columbia was the only state that has decreased incidence and DALYs.

Asynchronous online lecture may not be an effective method in teaching cardiovascular physiology during the COVID-19 pandemic.

BACKGROUND: Asynchronous online lecture has become a common teaching method in medical education, especially during the COVID-19 pandemic. However, the effectiveness and students' attitudes towards this method under this special circumstance have not been exclusively studied. Hence, we aimed to evaluate these aspects of cardiovascular physiology teaching in an undergraduate medical curriculum. METHODS: We analysed and compared the academic achievement and attitudes of 613 medical students on cardiovascular physiology between pre-COVID-19 and COVID-19 years in which different teaching methods were implemented. In addition, we also explored the importance of teaching methods and teachers by subgroup analysis to evaluate whether they influenced the academic achievement and attitudes of students. RESULTS: Overall students' academic achievement was significantly higher when lectures were taught by the traditional method than by the asynchronous online method. Moreover, subgroup analysis revealed that teachers were also a factor influencing students' academic achievement. Although most students had positive attitudes towards asynchronous online lectures, overall satisfaction was slightly higher when all lectures were taught by the traditional method than by the asynchronous online method. CONCLUSIONS: Asynchronous online lectures might not be an effective teaching method especially during the abrupt change in education. Under the 'new normal' medical education, not only teaching methods but also teachers are the essential keys to the success in academic achievement and attitudes of undergraduate medical students.

The presence of non-hepatic malignancy and its implication in pursuing liver transplantation.

BACKGROUND: Primary extrahepatic malignancy and chronic liver disease co-exist in a considerable number of patients, creating a dilemma both in the aspects of liver transplant candidacy and cancer therapy. In this review, we will explore several aspects and controversies of liver transplantation in patients with non-hepatocellular carcinoma malignancy including risks of cancer recurrence after liver transplantation and the ethical dilemma of the selection of liver transplantation candidates with non-hepatic malignancy. METHODS: We performed a search in several online databases and reviewed published articles and ongoing clinical trials in the topics of transplantation and pre-existing malignancies. RESULTS AND DISCUSSION: Liver transplantation can be safely performed in selected patients with pre-existing extrahepatic malignancies with low recurrence rate if they have an expected 5-year survival rate of at least 50%. The cancer-free period before transplantation depends on the type, stage, and location of cancer. A shorter or no wait-time may be considered in an early stage cancer or carcinoma in situ. The urgency and benefits of liver transplantation should also be taken into consideration when determining a reasonable wait-time. This is particularly important in patients with decompensated cirrhosis who cannot afford to wait a few years before they can undergo liver transplantation.

Novel viral markers and the prediction of off-treatment relapse in chronic hepatitis B patients: A systematic review.

BACKGROUND AND AIM: Hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) are novel markers that reflect intrahepatic cccDNA and could be useful in the prediction of relapse after nucleos(t)ide analogues (NA) discontinuation. The aim of the study is to perform a systematic review on this issue. METHODS: Medline/Pubmed database was searched using text terms related to HBcrAg, RNA, NAs, discontinuation, and relapse. Included studies were those that enrolled adult patients who had been on NAs for more than 6 months with available information on end-of-treatment (EOT) HBcrAg and/or HBV RNA and relapse rates. RESULTS: Sixteen studies were included. Virological and clinical relapse rates ranged from 11% to 100% and 11% to 73%, respectively. Low or undetectable EOT HBcrAg levels were associated with low off-treatment relapse rates in most studies with area under the receiver operating characteristic curve (AUROC) of 0.69-0.70 for predicting virological relapse (VR) and 0.61-0.77 for predicting clinical relapse (CR). Undetectable EOT HBV RNA was associated with a lower risk of off-treatment relapse with AUROC of 0.65-0.76 for predicting VR and 0.66-0.73 for predicting CR. Combined EOT HBcrAg and HBV RNA performed better in predicting off-treatment relapse than either test alone with AUROC of 0.816-0.846 for predicting CR. None of the patients with double-negative HBV RNA and HBcrAg developed CR. CONCLUSION: Combining HBcrAg with HBV RNA or HBsAg improved the discriminating abilities in the prediction of off-treatment relapse of each test. Patients with double-negative HBcrAg and HBV RNA at EOT had low risks of relapse and could be considered for NA discontinuation.

Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome.

BACKGROUND AND AIM: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). METHODS: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. RESULTS: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P < 0.001) and seropositive for anti-mitochondrial antibodies (88% vs 84%, P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8% vs 43.6%, P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76 vs 1.98 × upper limit of normal [ULN], P = 0.006), aspartate aminotransferase (1.29 vs 1.50 × ULN, P < 0.001), and total bilirubin (0.53 vs 0.58 × ULN, P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3% vs 16.1%, P = 0.07) and Paris II response (71.4% vs 69.4%, P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8% vs 90.7%, P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjögren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. CONCLUSIONS: Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.

Two-dimensional integration approach to teaching cardiovascular physiology: effectiveness and students' perspectives.

BACKGROUND: Pre-clerkship medical curriculums consist of a series of organ system-based courses and lectures but often lack an integration between organ systems. Such integration could be beneficial for clerkship years and students' future career. Hence, we aimed to share our process of organising an integrative teaching approach in a large class of pre-clerkship medical students and to reflect the students' perspective toward the teaching process in this observational study. In addition, we tested effectiveness of this integrative approach compared with the traditional teaching (lecture). METHODS: We organised a two-dimensional (2D)-integrative teaching for 309 students in selected topics of cardiovascular physiology of the medical curriculum of the Faculty of Medicine, Chulalongkorn University, Thailand. The first dimension of integration is the incorporation of physiology of other organ systems into the cardiovascular physiology class. The second is the integration of multiple teaching methods and strategies, including small group discussion, student presentation, wrap-up, quiz, and question-and-answer sessions. Unless opting out, students evaluated this integrative teaching by filling in a questionnaire. The summative scores were also used to determine their comprehensive understandings of the content. RESULTS: The course evaluation showed that most students (81.9-91.2%) had positive attitudes toward all organised sessions, i.e. this teaching method helps promote their basic and applied physiology knowledge, critical thinking, information searching, presentation, and teamwork skills. In general, students at all performance levels attained higher scores in the summative exam for the 2D-integrative-class-relevant questions (74.4±16.1%) than for the lecture-pertinent questions (65.2±13.6%). CONCLUSIONS: In a large class size of pre-clerkship students, 2D-integrative teaching strategies with careful planning and preparation can be successfully implemented, based on positive attitudes and relatively high summative scores of students in this study. Hence, this comprehensive teaching could be incorporated in current medical curriculums, particularly for the complex learning topics.

The clinical characteristics, pre- and post-liver transplantation outcomes in patients having autoimmune overlap syndromes.

BACKGROUND: There are little data on the pre- and post-liver transplantation (LT) outcomes of patients having autoimmune hepatitis-primary biliary cholangitis (AIH-PBC), AIH-primary sclerosing cholangitis (AIH-PSC), and AIH-small-duct PSC (AIH-SDPSC). The aim of this study was to analyze pre- and post-LT outcomes and survival of patients having different overlap syndromes (OS) undergoing LT. METHODS: Patients with compatible clinical and pathologic features of AIH-PBC (n = 86), AIH-PSC (n = 22), and AIH-SDPSC (n = 9) were included in the study. Demographic, laboratory, clinical, and survival data were analyzed. Multivariable analyses were performed to determine factors predicting transplant-free survival. RESULTS: AIH-primary sclerosing cholangitis patients were less treatment-responsive and were more likely to undergo LT than other OS. No survival difference was noted among the 3 groups. Liver decompensation was independently associated with higher mortality (HR 21.78; 95% CI 2.50-190.01). Thirteen patients with OS underwent LT. One-year survival post-LT was 91.7%. Overall recurrence rate for OS post-LT was 8%. CONCLUSIONS: AIH-primary sclerosing cholangitis patients were more likely to require LT compared with patients having AIH-PBC. Transplant-free survival was similar among the three AIH-overlap syndromes. Allograft recurrence of OS occurred in about 10% of cases. Patients with OS appear to have good short- and medium-term post-LT outcomes in terms of graft function and overall survival.

Genistein attenuated gastric inflammation and apoptosis in Helicobacter pylori-induced gastropathy in rats.

BACKGROUND: Helicobacter pylori (H. pylori) infection is a major cause of chronic gastritis, peptic ulcer diseases and cancer. Genistein (4',5,7-trihydroxyisoflavone), a tyrosine-specific-protein kinase inhibitor, has been shown to exert an anti-inflammatory property. The aim of this study was to examine the treatment effects of genistein and its mechanisms in rats with H. pylori infection. METHODS: Eighteen male Sprague-Dawley rats were divided into three groups (6 rats per group): (1) control group (Con); (2) H. pylori infected group (HP): the rats were inoculated with H. pylori (108- 1010 CFU/mL; 1 mL/rat.) for 3 consecutive days; and (3) HP + genistein group (HP + Gen): the rats were inoculated with H. pylori as above. Then, they were gavaged with genistein (16 mg/kg BW) for 14 days. Gastric tissue was used for the determination of nuclear factor (NF)-κB expression by immunohistochemistry (IHC), degree of apoptosis by the terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling (TUNEL) reaction, and histopathology. Serum samples were used to measure the levels of tumor necrosis factor-alpha (TNF-α) and cytokine-induced neutrophil chemoattractant-1 (CINC-1). RESULTS: Rats in the HP group had significantly higher levels of pro-inflammatory mediators, NF-κB expression and apoptotic cells when compared with the Con group, and these markers significantly decreased in HP + Gen group when compared with the HP group. The histopathology of HP group showed moderate gastric inflammation and many HP colonization. Gastric pathology in HP + Gen group demonstrated the attenuation of inflammatory cell infiltration and H. pylori colonization. CONCLUSION: Genistein exerted its gastroprotective effects through the reduction of pro-inflammatory mediators, nuclear receptor NF-κB expression and gastric mucosal apoptosis in rats with H. pylori-induced gastropathy.

Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease.

BACKGROUND & AIMS: There are limited data on the risk of hepatocellular cancer (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to estimate the risk of incident HCC among patients with NAFLD. METHODS: We conducted a retrospective cohort study from a total of 130 facilities in the Veterans Health Administration. Patients with NAFLD diagnosed between January 1, 2004 and December 31, 2008 were included and followed until HCC diagnosis, death, or December 31, 2015. We also identified a sex- and age-matched control cohort without NAFLD. We ascertained all new HCC cases from the Central Cancer Registry and manual chart reviews. We calculated incidence rates for HCC by NAFLD status, as well as in subgroups of NAFLD patients. We used competing risk models to compare the risk of HCC in patients with NAFLD vs those without NAFLD. We reviewed electronic medical records of all HCC cases that developed in NAFLD patients without cirrhosis. RESULTS: We compared 296,707 NAFLD patients with 296,707 matched controls. During 2,382,289 person-years [PYs] of follow-up, 490 NAFLD patients developed HCC (0.21/1000 PYs). HCC incidence was significantly higher among NAFLD patients vs controls (0.02/1000 PYs; hazard ratio, 7.62; 95% confidence interval, 5.76-10.09). Among patients with NAFLD, those with cirrhosis had the highest annual incidence of HCC (10.6/1000 PYs). Among patients with NAFLD cirrhosis, HCC risk ranged from 1.6 to 23.7 per 1000 PYs based on other demographic characteristics; risk of HCC was the highest in older Hispanics with cirrhosis. In medical record reviews, 20% of NAFLD patients with HCC had no evidence of cirrhosis. CONCLUSIONS: Risk of HCC was higher in NAFLD patients than that observed in general clinical population. Most HCC cases in NAFLD developed in patients with cirrhosis. The absolute risk of HCC was higher than the accepted thresholds for HCC surveillance for most patients with NAFLD cirrhosis.

Validation of Risk Scoring Systems in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis.

INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.

Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents.

BACKGROUND AND AIMS: The risk of hepatocellular cancer (HCC) after sustained virological response (SVR) with direct-acting antivirals (DAA) is unclear. Our aim was to examine the risk and determinants of HCC in patients cured with DAA. METHODS: We conducted a retrospective cohort study of hepatitis C virus patients who were treated with DAA in any of the 129 Veterans Health Administration hospitals between January 1, 2015 and December 31, 2015. We calculated the annual incidence rates of HCC by SVR. We used Cox regression models to compare the risk of HCC in patients with vs those without SVR and to identify factors associated with incident HCC among patients with SVR. We reviewed a sample of HCC patients for tumor size and stage at diagnosis. RESULTS: Among 22,500 patients treated with DAA (19,518 with SVR; 2982 without SVR), the mean (standard deviation) age was 61.6 (6.1) years, and 39.0% had cirrhosis. There were 271 new cases of HCC, including 183 in patients with SVR. Compared with patients without SVR, those with SVR had a significantly reduced risk of HCC (0.90 vs 3.45 HCC/100 person-years; adjusted hazard ratio, 0.28, 95% CI=0.22-0.36). Patients with cirrhosis had the highest annual incidence of HCC after SVR (1.82 vs 0.34/100 person-years in patients without cirrhosis; adjusted hazard ratio, 4.73. 95% CI, 3.34-6.68). Most (>44.8%) HCC were classified as stage I. Maximum size of the largest lesion was ≤5 cm in over 75% of cases. CONCLUSIONS: Among patients treated with DAA, SVR was associated with a considerable reduction in the risk of HCC. We did not find any evidence to suggest that DAAs promote HCC. However, in patients with SVR, the absolute risk of HCC remained high in patients with established cirrhosis. These patients should be considered for ongoing HCC surveillance.

Role of Age and Race in the Risk of Hepatocellular Carcinoma in Veterans With Hepatitis B Virus Infection.

BACKGROUND & AIMS: Hepatocellular (HCC) surveillance guidelines for patients with chronic hepatitis B virus (HBV) infection are based on race- and age-specific estimates of HCC risk, derived from studies conducted in areas in which HBV is endemic. METHODS: We conducted a retrospective cohort study using the national Veterans Administration data to identify patients with chronic HBV infection from 2001 through 2013. We examined the effect of race and age on HCC risk while adjusting for baseline clinical characteristics. RESULTS: The study cohort had 8329 patients; 3498 patients (42.0%) were white, 3248 (39%) were African Americans, and 659 (7.9%) were Asian Pacific Islanders. The annual HCC incidence was highest in Asian Pacific Islanders (0.65%), followed by whites (0.57%) and African Americans (0.40%). After adjusting for clinical and viral factors, the risk of HCC was significantly higher in Asian Pacific Islanders compared with whites (adjusted hazard ratio [HR] = 2.04; 95% CI, 1.31-3.17). There was no difference in HCC risk between African Americans and whites (adjusted HR, 0.77; 95% CI, 0.58-1.02). HCC risk increased with age: adjusted HR was 1.97 (95% CI, 0.99-3.87) for 40-49 years; adjusted HR was 3.00 (95% CI, 1.55-5.81) for 50-59 years; and adjusted HR was 4.02 (95% CI, 2.03-7.94) for more than 60 years vs less than 40 years. Patients with cirrhosis had higher risk of HCC than patients without cirrhosis (adjusted HR = 3.69; 95% CI, 2.82-4.83). However, even among patients without cirrhosis, the annual incidence of HCC was more than 0.2% for all patients older than 40 years with high levels of alanine aminotransferase-regardless of race. CONCLUSIONS: In a sample of male veterans with chronic HBV infection, risk of HCC is highest among Asian Pacific Islanders, followed by whites and African Americans. Cirrhosis increased HCC risk. Among patients without cirrhosis, male patients who are older than 40 years and have increased levels of alanine aminotransferase might benefit from HCC surveillance, regardless of race.

Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Cirrhosis related to chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). The extent to which HCC occurs in U.S. in the absence of cirrhosis in CHB remains unclear. METHODS: We identified CHB patients who were diagnosed with HCC in the national Veterans Administration (VA) between 2001 and 2013. We defined presence and absence of cirrhosis at the time of HCC diagnosis using explicit histological, radiological, endoscopic, and laboratory criteria. We used multivariable regression analysis to identify demographic and clinical characteristics associated with CHB-related HCC in the absence of cirrhosis. We also examined liver transplant-free survival in CHB-HCC patients with and without cirrhosis. RESULTS: Among 8539 CHB patients, 317 developed HCC of whom 30 (9.5%) did not have any evidence of cirrhosis at the time of HCC diagnosis. Compared to HCC patients with cirrhosis, HCC patients without cirrhosis were more likely to be non-white (African American, OR=6.78; 95% CI 2.05-22.4; Asian, OR 11.6, 95% CI 2.63-50.8), have a family history of HCC (OR 32.9, 95% CI 3.76-288), and hypertension (OR 3.15, 95% CI 1.02-9.75). There was no significant difference in the transplant-free survival between CHB-HCC patients with and without cirrhosis (hazard ratio 0.68, 95% CI 0.43-1.09). CONCLUSIONS: Fewer than 10% of U.S. based CHB-related HCC patients did not have cirrhosis. Race and family history of HCC were the main risk factors for HCC in the absence of cirrhosis in CHB. These factors may help guide the decision to initiate HCC surveillance in CHB patients without cirrhosis. LAY SUMMARY: Patients with chronic hepatitis B who are African American, or Asian, older than 40years of age with family members with liver cancer or high blood pressure are at a higher risk of developing liver cancer in the absence of cirrhosis. These patients should be included in the screening program for liver cancer.

The Validity of HCC Diagnosis Codes in Chronic Hepatitis B Patients in the Veterans Health Administration.

BACKGROUND: Administrative databases that include diagnostic codes are valuable sources of information for research purposes. AIM: To validate diagnostic codes for hepatocellular carcinoma (HCC) in chronic hepatitis B patients. METHODS: We conducted a retrospective study of patients with chronic HBV seen in the national Veterans Administration (VA). HCC cases were identified by the presence of ICD-9 code 155.0. We randomly selected 200 HBV controls without this code as controls. We manually reviewed the electronic medical record (EMR) of all cases and controls to determine HCC status. We calculated the positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity for the HCC code. We conducted an implicit review of the false-positive cases to determine possible reasons for the miscoding. RESULTS: Of the 8350 patients with HBV, 416 had an ICD-9 code for HCC. Of these 416, 332 patients had confirmed HCC and 61 did not; HCC status was indeterminate for 23 patients. Of the 200 controls, none had HCC confirmed in the EMR. The PPV ranged from 85.3 to 80.0% and specificity ranged from 99.2 to 99.0% based on classification of indeterminate cases as true versus false positives, respectively. The NPV, sensitivity, and specificity were 100%. Two-thirds of false-positive cases were diagnosed with HCC prematurely as a workup of liver mass and latter imaging and/or biopsy were not diagnostic for HCC. CONCLUSION: The diagnostic code of HCC in chronic HBV patients in the VHA data is predictive of the presence of HCC in medical records and can be used for epidemiological and clinical research.

Bridging the gap between clinicians and systems biologists: from network biology to translational biomedical research.

With the wealth of data accumulated from completely sequenced genomes and other high-throughput experiments, global studies of biological systems, by simultaneously investigating multiple biological entities (e.g. genes, transcripts, proteins), has become a routine. Network representation is frequently used to capture the presence of these molecules as well as their relationship. Network biology has been widely used in molecular biology and genetics, where several network properties have been shown to be functionally important. Here, we discuss how such methodology can be useful to translational biomedical research, where scientists traditionally focus on one or a small set of genes, diseases, and drug candidates at any one time. We first give an overview of network representation frequently used in biology: what nodes and edges represent, and review its application in preclinical research to date. Using cancer as an example, we review how network biology can facilitate system-wide approaches to identify targeted small molecule inhibitors. These types of inhibitors have the potential to be more specific, resulting in high efficacy treatments with less side effects, compared to the conventional treatments such as chemotherapy. Global analysis may provide better insight into the overall picture of human diseases, as well as identify previously overlooked problems, leading to rapid advances in medicine. From the clinicians' point of view, it is necessary to bridge the gap between theoretical network biology and practical biomedical research, in order to improve the diagnosis, prevention, and treatment of the world's major diseases.

Simplified Chronic Hepatitis B Antiviral Initiation Criteria in Thailand: An Economic Evaluation.

OBJECTIVES: Criteria for antiviral treatment initiation in Thailand were complex and difficult to implement. This study determined the cost-effectiveness of 2 simplified antiviral treatment initiation criteria among patients with chronic hepatitis B in Thailand. METHODS: A hybrid model of the decision tree and Markov model was developed. Two simplified antiviral treatment initiation criteria were the expanded criteria, treating patients with hepatitis B surface antigen positive and viral load (hepatitis B virus deoxyribonucleic acid) >2000 IU/mL or cirrhosis by tenofovir alafenamide (TAF), and the test-and-treat criteria, treating patients with hepatitis B surface antigen positive and viral load >10 IU/mL or cirrhosis by TAF. PubMed was searched from its inception to July 2023 to identify input parameters. Best supportive care was chosen for patients who were ineligible for TAF. Incremental cost-effectiveness ratio per quality-adjusted life-year (QALY) was calculated. RESULTS: The expanded criteria and the test-and-treat could reduce the occurrence of patients progressing to hepatocellular carcinoma. In particular, both criteria could reduce 4846 new cases of hepatocellular carcinoma per 100 000 patients. The incremental cost-effectiveness ratios for the expanded criteria and the test-and-treat criteria were 24 838 Thai baht (THB)/QALY and 163 060 THB/QALY, respectively. CONCLUSIONS: At the current willingness to pay of 160 000 THB/QALY, the expanded criteria were cost-effective, but the test-and-treat criteria were not cost-effective to be the simplified antiviral treatment initiation criteria for patients with chronic hepatitis B in Thailand.

Genistein and sex hormone treatment alleviated hepatic fat accumulation and inflammation in orchidectomized rats with nonalcoholic steatohepatitis.

Testosterone deficiency has been reported to accelerate nonalcoholic fatty liver disease (NAFLD). However, there are minimal data on the risk of NAFLD in transgender women and the treatment of NAFLD in this population. This study aimed to investigate the treatment effects and the mechanisms of action of genistein and sex hormones in orchiectomized (ORX) rats with nonalcoholic steatohepatitis (NASH) induced by a high fat high fructose diet (HFHF). Seven-week old male Sprague-Dawley rats were randomly divided into 7 groups (n = 6 each group); 1) control group, 2) ORX + standard diet group, 3) HFHF group, 4) ORX + HFHF group, 5) ORX + HFHF diet + testosterone group (50 mg/kg body weight (BW) once weekly), 6) ORX + HFHF diet + estradiol group (1.6 mg/kg BW daily), and 7) ORX + HFHF diet + genistein group (16 mg/kg BW daily). The duration of treatment was 6 weeks. Liver tissue was used for histological examination by hematoxylin and eosin staining and hepatic fat measurement by Oil Red O staining. Protein expression levels of histone deacetylase3 (HDAC3) and peroxisome proliferator-activated receptor delta (PPARδ) were analyzed by immunoblotting. Hepatic nuclear factor (NF)-ĸB expression was evaluated by immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, hepatocyte ballooning and the highest percentage of positive Oil Red O staining area among all groups. The expression of HDAC3 and PPARδ was downregulated, while NF-ĸB expression was upregulated in the ORX + HFHF group when compared with control and ORX + standard diet groups. Testosterone, estradiol and genistein treatment improved histological features of NASH together with the reversal of HDAC3, PPARδ and NF-ĸB protein expression comparing with the ORX + HFHF group. In summary, genistein and sex hormone treatment could alleviate NASH through the up-regulation of HDAC3 and PPARδ, and the suppression of NF-ĸB expression.

Genistein and Sex Hormone Supplementation Modulated Hepatic PPARα, δ, and γ Subtypes and STAT1 Expressions in a NASH Rat Model with Bilateral Orchidectomy.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic inflammation and steatosis. Currently, limited data exist regarding the risk of NASH in transgender women and the treatment options for this particular population. The use of testosterone supplementation is unfavorable for transgender women, and estrogen supplementation is linked to an increased risk of breast cancer; thus, an isoflavone derivative compound known as "genistein" could serve as a viable substitute for a hormone supplement in this context. The purpose of this study was to investigate the treatment effects and mechanisms of actions of genistein and sex hormones in orchidectomized (ORX) rats with nonalcoholic steatohepatitis induced via a high-fat high-fructose diet (HFHF) model. Male Sprague-Dawley rats (n = 42) were randomly assigned into seven groups; control, ORX + standard diet, HFHF, ORX + HFHF, ORX + HFHF diet + testosterone (50 mg/kg body weight (BW) once weekly), ORX + HFHF diet + estradiol (1.6 mg/kg BW daily), and ORX + HFHF diet + genistein (16 mg/kg BW daily). The duration of the study was 6 weeks. Some parts of liver tissue were used for histological examination by H&E staining. The determination of fat accumulation was performed using Oil Red O staining. SREBP1c and FAS gene expression were quantified using real-time PCR technique. The levels of all types of peroxisome proliferator-activated receptors (PPARs; α, δ, γ), proteins, and signal transducer and activator of transcription 1 (STAT1) signaling pathway were determined by both immunoblotting and immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, and hepatocyte ballooning, and showed higher levels of genes related to de novo lipogenesis, including SREBP1c and FAS. The expression of PPARγ and STAT1 were upregulated, while the expression of PPARα and PPARδ were downregulated in the ORX + HFHF group. Testosterone, estradiol and genistein treatments improved NASH histopathology together with the reversal of all types of PPAR protein expressions. Interestingly, genistein decreased the levels of STAT1 protein expression more than those of testosterone and estradiol treatment. Genistein and sex hormone treatment could ameliorate NASH through the upregulation of PPARα, and PPARδ, and the suppression of PPARγ and STAT1 expression.

Risk prediction algorithms in guiding antiviral therapy initiation among patients with chronic hepatitis B in Thailand: an economic evaluation and budget impact analysis.

OBJECTIVE: Several risk prediction algorithms have been developed to guide antiviral therapy initiation among patients with chronic hepatitis B (CHB). This study assessed the cost-effectiveness and budget impact of three risk prediction algorithms among patients with CHB in Thailand. METHODS: A decision tree with a Markov model was constructed. Three risk prediction algorithms were compared with current practices including HePAA, TREAT-B and REACH-B. PubMed was searched from its inception to December 2022 to identify inputs. Tenofovir alafenamide and best supportive care were selected for antiviral-eligible patients, and incremental cost-effectiveness ratios per quality-adjusted life year (QALY) were calculated. RESULTS: Our base case analysis showed that HePAA and REACH-B could provide better QALY (0.098 for HePAA and 0.921 for REACH-B) with decreased total healthcare costs (-10909 THB for HePAA and -8,637 THB for REACH-B). TREAT-B provided worse QALY (-0.144) with increased total healthcare costs (10,435 THB). The budget impacts for HePAA and REACH-B were 387 million THB and 3,653 million THB, respectively. CONCLUSION: HePAA and REACH-B algorithms are cost-effective in guiding antiviral therapy initiation. REACH-B is the most cost-effective option, but has a high budget impact. Policymakers should consider both cost-effectiveness and budget impact findings when deciding which algorithm should be implemented.