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 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.

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.

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.

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.

Effects of probiotics on pancreatic inflammation and intestinal integrity in mice with acute pancreatitis.

BACKGROUND: Severe acute pancreatitis is a potentially life-threatening disease. Despite being a common disorder, acute pancreatitis lacks a specific treatment. The present study aimed to examine the effects of probiotics on pancreatic inflammation and intestinal integrity in mice with acute pancreatitis. METHODS: Male ICR mice were randomly divided into 4 groups (n = 6 per group). The control group received two intraperitoneal (i.p.) injections of normal saline as a vehicle control. The acute pancreatitis (AP) group received two i.p. injections of L-arginine 450 mg/100 g body weight. AP plus probiotics groups received L-arginine to induce acute pancreatitis as above. In the single-strain and mixed-strain groups, mice received 1 mL of Lactobacillus plantarum B7 1 × 108 CFU/mL and 1 mL of Lactobacillus rhamnosus L34 1 × 108 CFU/mL and Lactobacillus paracasei B13 1 × 108 CFU/mL by oral gavage, respectively for 6 days starting 3 days prior to the AP induction. All mice were sacrificed 72 h after L-arginine injection. Pancreatic tissue was obtained for histological evaluation and immunohistochemical studies for myeloperoxidase, whereas ileal tissue was used for immunohistochemical studies for occludin, and claudin-1. Blood samples were collected for amylase analysis. RESULTS: Serum amylase levels and pancreatic myeloperoxidase levels in the AP group were significantly higher than in controls and significantly decreased in probiotic groups compared with the AP group. Ileal occludin and claudin-1 levels were significantly lower in the AP group than in controls. Ileal occludin levels significantly increased, whereas ileal claudin-1 levels did not significantly change in both probiotic groups as compared with the AP group. The pancreatic histopathology showed significantly higher degree of inflammation, edema, and fat necrosis in the AP group, and these changes improved in mixed-strained probiotic groups. CONCLUSIONS: Probiotics, particularly the mixed-strain ones, attenuated AP via the reduction of inflammation and the maintenance of intestinal integrity.

Student academic performance in non-lecture physiology topics following the abrupt change from traditional on-site teaching to online teaching during COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, pre-clerkship medical education, including all physiology classes, was obliged to change to online teaching due to limitations of on-site (face-to-face) classes. However, the effectiveness of online teaching in non-lecture physiology topics during the COVID-19 pandemic has not been thoroughly investigated. METHOD: We conducted a prospective study to evaluate the students' academic achievement and opinions on online teaching during the COVID-19 academic year. Academic achievement of 312 students in the COVID-19 year was compared with that of 299 students in the pre-COVID-19 year. Student opinions regarding social interactions and the preferred learning method were also collected. RESULTS: We found that student academic achievement in the non-lecture physiology topics, assessed by summative scores, was 4.80±0.92 percent higher in the pre-COVID-19 year than in the COVID-19 year (P < 0.01, Cohen's d = 0.42). Students rated that online classes tended to reduce their interactions with peers and teachers; however, students preferred online learning over traditional on-site learning. CONCLUSIONS: This study pointed out that students' academic performance related to the physiology topics taught by online non-lecture methods during the COVID-19 pandemic was lower than their performance when the topics were taught by the traditional (on-site) methods, although students reported that they preferred the online teaching. Hence, we suggest that medical teachers should deliberately plan and utilise a variety of tools and techniques when developing online non-lecture classes to preserve the interactivity of the classes, which might overcome this gap in students' academic performance.

The Efficacy of Oligonol in Nonalcoholic Fatty Liver Disease: A Randomized Double-Blinded Placebo-Controlled Trial.

Introduction: Oligonol, an oligomerized-polyphenol from Litchi chinensis extract, has been shown to alleviate metabolic syndrome. The aim of this study was to evaluate the effects of oligonol in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Adult patients with NAFLD defined by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) ≥11% were enrolled and then randomly assigned to receive either oligonol or placebo capsules. Primary endpoint was ≥30% reduction in MRI-PDFF at 24 weeks. Secondary outcomes were reductions in bodyweight, waist circumference, alanine transaminase, fasting blood sugar, and lipid profiles at week 24. Results: Forty patients were enrolled (n = 20/group). Primary endpoint was achieved in 20% in the oligonol group and 15% in the placebo group (p = 0.50). The authors found a reduction in MRI-PDFF between weeks 0 and 24 in the oligonol group; however, the change was not different from the placebo group. Secondary outcomes were similar between two groups. Discussion: Oligonol has not shown a significant therapeutic effect in NAFLD. Future studies with a longer duration of therapy might be needed to achieve the primary endpoint. Clinical Trial Registration Number: Thai Clinical Trial Registry identification number: TCTR20200814001.

Genistein attenuated oxidative stress, inflammation, and apoptosis in L-arginine induced acute pancreatitis in mice.

AIM: Acute pancreatitis is a common and potentially serious condition. However, a specific treatment for this condition is still lacking. Genistein, with its anti-oxidant and anti-inflammatory effects, could possibly be used to tackle the underlying pathophysiology of acute pancreatitis. Therefore, the aim of this study was to investigate the effects of genistein on oxidative stress, inflammation, and apoptosis in acute pancreatitis induced by L-arginine in mice. METHODS: Twenty-four male ICR mice were equally divided into 4 groups: Control (Con); Acute pancreatitis (AP) group: Two doses of i.p. 350 mg/100 g body weight (BW) of L-arginine were administered 1 h apart; AP and low-dose genistein (LG) group: mice were given i.p. injection of 10 mg/kg genistein 2 h prior to L-arginine injection followed by once-daily dosing for 3 days; and AP and high-dose genistein (HG) group: mice were given 100 mg/kg genistein with the similar protocol as the LG group. Pancreatic tissue was evaluated for histopathological changes and acinar cell apoptosis, malondialdehyde (MDA) levels, immunohistochemical staining for myeloperoxidase (MPO), nuclear factor-kappa beta (NF-kB), and 4-hydroxynonenal (4-HNE). Serum levels of amylase (AMY), c-reactive protein (CRP), and interleukin (IL)-6 were measured. RESULTS: Significant increases in the degree of acinar cell apoptosis, pancreatic MDA, serum IL-6 and amylase, MPO, NF-kB and 4-HNE positivity were observed in the AP group. All these parameters declined after low- and high-dose genistein treatment. Severe pancreatic inflammation, edema, and acinar cell necrosis were observed in the AP group. Significant improvement of histopathological changes was seen in both low- and high-dose genistein groups. There were no significant differences in any parameters between low and high doses of genistein. CONCLUSION: Genistein could attenuate the severity of histopathological changes in acute pancreatitis through its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

Litchi-Derived Polyphenol Alleviates Liver Steatosis and Gut Dysbiosis in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized Double-Blinded, Placebo-Controlled Study.

Preclinical data suggest the role of litchi extract in alleviating non-alcoholic fatty liver disease (NAFLD) by modulating gut microbiota. We aimed at investigating whether oligonol, a litchi-derived polyphenol, could improve liver steatosis and gut dysbiosis in patients with NAFLD. Adults with grade ≥2 steatosis, defined by an MRI proton density fat fraction (MRI-PDFF) of ≥11%, were randomly assigned to receive either oligonol or placebo for 24 weeks. The alteration in the MRI-PDFF and gut microbiota composition assessed by 16S ribosomal RNA sequencing were examined. There were 38 patients enrolled (n = 19 in each group). A significant reduction in the MRI-PDFF between week 0 and week 24 was observed in the oligonol group, while there was a non-significant decrease in the placebo group. A significant improvement in alpha-diversity was demonstrated in both of the groups. The oligonol-induced microbiota changes were characterized by reduced abundance of pathogenic bacteria, including Dorea, Romboutsia, Erysipelotrichaceae UCG-003 and Agathobacter, as well as increased abundance of short-chain fatty acids (SCFAs)-producing bacteria, such as Akkermansia, Lachnospira, Dialister and Faecalibacterium. In summary, this study is the first to provide evidence that supports that oligonol improves steatosis through the modulation of gut bacterial composition. Our results also support the beneficial and complementary role of oligonol in treating NAFLD.

Probiotics and their beneficial effects on alcohol-induced liver injury in a rat model: the role of fecal microbiota.

BACKGROUND: Current therapies for alcohol-induced liver injury are of limited efficacy and associated with significant side effects. With the proposed pathophysiology of alcohol-induced liver injury to be related to deranged gut microbiota, we hypothesized that probiotics would have beneficial effects in attenuating alcohol-induced liver injury. METHODS: Twenty-four male Sprague-Dawley rats were divided into 4 groups: control group, alcohol group, Lactobacillus plantarum group, and mixed-strain probiotics group. After 4 weeks, all rats were sacrificed, and blood samples were analyzed for ALT, lipopolysaccharide level (LPS), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Liver tissues were processed for histopathology, malondialdehyde (MDA) level and immunohistochemistry for toll-like receptors 4 (TLR-4). Stool samples were collected, and 16S rRNA sequencing was used to analyze the fecal microbiota. RESULTS: Liver histopathology showed the presence of significant hepatocyte ballooning in the alcohol group as compared with the control group, and the treatment with L. plantarum or mixed-strain probiotics alleviated these changes. Significant elevation of serum ALT, LPS, IL-6, and TNF-α, hepatic MDA levels, and hepatic TLR-4 expression were observed in alcohol-fed rats as compared with control rats. The administration of L. plantarum or mixed-strain probiotics restored these changes to the levels of control rats. The relative abundance of fecal bacteria at genus level showed a significant reduction in Allobaculum, Romboutsia, Bifidobacterium, and Akkermansia in the alcohol group as compared with the control group. In probiotics-treated rats, significant increases in Allobaculum and Bifidobacterium were observed, while the relative abundance of Romboutsia and Akkermansia was unchanged compared to the alcohol group. A reduction in alpha diversity was observed in alcohol-treated rats, whereas the improvement was noted after probiotic treatment. CONCLUSIONS: The treatment with Lactobacillus, whether as single-, or mixed-strain probiotics, was beneficial in reducing the severity of alcohol-induced liver injury likely through the increase in beneficial bacteria, and the reduction of inflammatory responses, and oxidative stress.

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.

Economic Evaluation of Oral Nucleos(t)ide Analogues for Patients with Chronic Hepatitis B in Thailand.

BACKGROUND: Nucleos(t)ide analogues (NAs) are the main drug category used in the treatment of chronic hepatitis B (CHB). There is a need to update the economic evaluation of CHB treatment. OBJECTIVE: This study aimed to determine the cost effectiveness of NAs for CHB in Thailand. METHOD: We used a lifetime Markov model undertaken from a societal perspective. Tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), entecavir (ETV) with TDF or TAF as rescue medications, and lamivudine (LAM) with TDF or TAF rescue medications were compared with best supportive care (BSC). We performed a network meta-analysis to estimate the treatment effects of each NA on hepatitis B surface antigen (HBsAg) loss in an Asian population and performed an additional literature review to identify inputs. We calculated incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-years (QALYs) and performed sensitivity analyses. RESULTS: Compared with BSC, all NAs could improve patients' QALYs, with results ranging from 4.04 to 4.25 QALYs gained. TAF, TDF, LAM/TAF, and LAM/TDF yielded lower total lifetime costs than BSC, ranging from - $US1387 to - 814, whereas ETV/TAF and ETV/TDF yielded higher total lifetime costs than BSC, ranging from $US4965 to 4971. The ICER was $US1230/QALY for ETV/TDF and $US1228/QALY for ETV/TAF. Full incremental analysis showed that the ICER for LAM/TAF was $US1720/QALY compared with TAF. CONCLUSION: At current prices, TAF, TDF, LAM/TAF, and LAM/TDF are dominant options, and ETV/TAF or ETV/TDF are cost-effective options. LAM/TAF is the most cost-effective option, followed by TAF.

Genistein and exercise treatment reduced NASH related HDAC3, IL-13 and MMP-12 expressions in ovariectomized rats fed with high fat high fructose diet.

BACKGROUND AND AIM: Genistein (GEN) and exercise (Ex) may be regarded as an alternative treatment for non-alcoholic steatohepatitis (NASH). However, the mechanisms behind their therapeutic effects in NASH are not well-understood. EXPERIMENTAL PROCEDURE: This study investigated the roles of histone deacetylase (HDAC)3 and interleukin-(IL-)13 in the NASH model of ovariectomized (OVX) rats fed with high fat high fructose (HFHF) diet. RESULTS AND CONCLUSION: Nine weeks after being fed with HFHF diet, severe NASH pathology with mild fibrosis were seen along with an increase in HDAC3, IL-13 and matrix metalloelastase (MMP-12) expressions in OVX rats. Five weeks of either GEN or Ex treatments abrogated the increase in both HDAC3 and IL-13 expressions in OVX rats fed with HFHF diet and ameliorated NASH features, liver fibrosis and MMP-12 expression. The combination of Gen and Ex, however, did not provide additional benefits on NASH features in OVX rats fed with HFHF diet. These results suggested that GEN and Ex treatments improved HFHF diet induced NASH in OVX rats through the suppression of HDAC3, IL-13 and MMP-12 expression.

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.

Changes of vitamin D receptors (VDR) and MAPK activation in cytoplasmic and nuclear fractions following exposure to cigarette smoke with or without filter in rats.

Cigarette smoke (CS) is a major cause of obstructive lung disease which is associated with significant disability and mortality. Vitamin D receptor (VDR) together with, mitogen activated protein kinases (MAPKs; ERK, JNK and p38) are the cellular transmission signals that mechanistically respond to CS and are recently found to have a role in lung pathogenesis. There are a few in vitro studies on subcellular VDR distribution involved MAPK but in vivo effects of cigarette smoke exposure with and without filter on this complex remain unclear. This study investigated subcellular VDR distribution and MAPK expression at early stages of both types of cigarette smoke exposure (CSE) in a rat model. Male Wistar rats were randomly divided into no-filter, filter and control groups. After 7 and 14 days of CSE, lung tissues were obtained to determine histopathology and protein expression. Cytoplasmic and nuclear VDR distribution significantly decreased on both CSE groups and corresponded with immunohistochemistry detection. The ratio of phosphorylated ERK to total ERK significantly increased in cytoplasm of both CSE on day 7. In particular, nuclear ERK MAPK significantly escalated in the filter group on day 14. In consistent with changes in intracellular markers, histopathological examination in both CSE groups showed significant increases in tracheal and peribronchiolar epithelial proliferation, alveolar macrophages and an increased trend of parenchymal infiltration. In summary, the evidence of lung injuries along with VDR depletion and MAPK activation observed in both CSE types indicated that there was no benefit of using cigarette filter to prevent protein damage or protect cells against cigarette smoke exposure in this model.

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 Utility of Assessing Liver Allograft Fibrosis and Steatosis Post-Liver Transplantation Using Transient Elastography With Controlled Attenuation Parameter.

AIM: Allograft steatosis is an emerging concern after liver transplantation (LT). The use of transient elastography (TE) with controlled attenuation parameter (CAP) may facilitate early detection of and intervention for allograft steatosis. This study aimed to evaluate the prevalence and risk factors of allograft steatosis using TE and CAP. METHODS: The presence of steatosis and severe steatosis were defined by CAP ≥222 and ≥290 dB/m, respectively. Demographics and clinical characteristics were compared between patients with and without severe steatosis. Regression analyses were performed to determine factors associated with severe steatosis. RESULTS: Of 150 patients, 105 (70%) had steatosis while 40% of these had severe steatosis. Thirty-four (81.0%) patients with severe steatosis had normal alanine transaminase at the time of TE. In multivariable analyses, age at LT (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.01-1.08), post-LT obesity (OR 5.34, 95% CI 1.53-18.65), and alcoholic liver disease (OR 12.86, 95% CI 2.24-73.74) were significant predictors of severe steatosis. Five patients underwent liver biopsies as a result of advance fibrosis seen on TE and were later diagnosed with chronic allograft rejection. Two of these patients had normal liver chemistries, and the remaining 3 had mild elevation of alkaline phosphatase. CONCLUSION: Steatosis was present in 70% of patients who underwent TE after LT. Advanced age at LT, post-LT obesity, and alcoholic liver disease were significant predictors for severe steatosis. The majority of patients with severe steatosis had normal liver enzymes. TE should be considered as a screening modality for allograft steatosis and fibrosis even when liver chemistries are normal.

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.