Guidewire Impaction in the Main Pancreatic Duct in a Patient with Chronic Pancreatitis: A Case Report.

The guidewire is an essential accessory in ERCP. Although rare, guidewires can cause complications, such as subcapsular hepatic hematoma, perforation, knotting, fracture, and impaction, during ERCP. This report describes a guidewire impaction during the endoscopic treatment of a patient with symptomatic chronic pancreatitis. The methods used to treat guidewire impaction are not well known. In the present case, the impacted guidewire was retrieved by inserting another guidewire and dilating the space adjacent to it. Endoscopists should check for the free movement of the guidewire before stent deployment. Additionally, it is important to ask for help from experienced senior staff to overcome any challenges during the procedure. In conclusion, endoscopists should be aware of the possibility of a guidewire impaction during ERCP.

Gallstone Is Associated with Metabolic Factors and Exercise in Korea.

Gallstone is a common health problem. Cholesterol stone accounts for 90% of stones in the United States and Europe, but East Asia has a high proportion of pigment stone. The aim of this study was to determine the relationship between modifiable metabolic factors and gallstone in a region with a high prevalence of pigment stone. Among 3159 participants who underwent health screening at Ulsan University Hospital from March 2014 to June 2019, 178 patients were diagnosed with gallstone using abdominal ultrasonography; 2860 participants were selected as a control group. Demographic and laboratory data, and a medical questionnaire were obtained. Hypertension and diabetes mellitus were more prevalent in the gallstone group. Age, waist circumference, systolic blood pressure (SBP) ≥ 140 mmHg, fasting blood glucose, HbA1c ≥ 6.5%, visceral fat index, normal-attenuated muscle area index, and engaging in vigorous exercise for ≥2 days per week were associated with gallstone by univariate analysis. Through multivariate logistic regression analysis, HbA1c ≥ 6.5% (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.31-2.98), and 2 or more days of vigorous exercise per week (OR 0.66, 95% CI 0.45-0.95) remained significant. The association persisted after adjusted analysis for age and sex. HbA1c ≥ 6.5% were positively associated with the gallstone. Vigorous exercise for at least 2 days weekly may be related to a lower risk of gallstone formation.

Safety and efficacy of dietary supplement (gintonin-enriched fraction from ginseng) in subjective memory impairment: A randomized placebo-controlled trial.

BACKGROUND: Gintonin inhibits ß-amyloid production, increases acetylcholine level in the brain, and promotes neurogenesis. We evaluated the efficacy of gintonin-enriched fraction (GEF) in improving the cognitive performance in subjective memory impairment. METHODS: In this 8-week, randomized, assessor and participant blinded, placebo-controlled study, participants with subjective memory impairment but preserved cognitive function (Korean Mini-Mental State Examination [K-MMSE] score ≥23) were assigned to GEF 300mg/day or placebo. K-MMSE, Korean versions of the Alzheimer's disease assessment scale, color-word stroop test (K-CWST), clinical dementia rating, and Beck depression inventory-II were evaluated along with the safety profiles. The primary outcome was set as the change in the K-MMSE. RESULTS: Seventy-six participants complete the study protocol. After 8 weeks, there was no inter-group difference in the primary or secondary outcome score changes. However, GEF group showed an improvement in the K-MMSE scores (P= 0.026), and in the number of correct answers in both word reading (P= 0.008) and color reading (P= 0.005) of K-CWST, although only the improvement in the K-CWST scores were higher than the minimum clinically important difference. The frequency of adverse events was comparable between the groups and all were of mild severity. CONCLUSION: GEF is safe but might not be effective in treating subjective memory impairment within the current study setting. However, GEF showed a trend of improving the global cognition and the frontal executive function. Further large-sized studies with longer follow-up period are warranted. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at Clinical Research Information Service of Korea Centers for Disease Control and Prevention: KCT0004636.

Tenofovir alafenamide treatment may not worsen the lipid profile of chronic hepatitis B patients: A propensity score-matched analysis.

BACKGROUND/AIMS: Tenofovir alafenamide (TAF) has shown less favorable effect on lipids compared to tenofovir disoproxil fumarate (TDF) in clinical trials. However, data regarding these outcomes in patients with chronic hepatitis B (CHB) are scarce. Therefore, this study aimed to evaluate the effect of TAF on the lipid in patients with CHB. METHODS: A total of 237 TAF-treated CHB patients compared with TDF, inactive CHB, and non-hepatitis B virus (HBV)-infected control groups using propensity score matching (PSM). RESULTS: Following PSM, each analysis was conducted on cohorts via the matching of 70:140 (TAF:TDF), 89:89 (TAF:inactive CHB), 140:560 (TAF:non-HBV infected control), and 368:1,472 (TDF:non-HBV-infected control). A significant decrease in the total cholesterol (TC) level was noted at 48 weeks in the TDF group compared to the TAF group (176.3±32.9 vs. 156.7±27.7, P<0.001) and the non-HBV-infected control group (175.0±29.5 vs. 156.2±28.3, P<0.001). However, no significant change in TC was observed in the TAF group and inactive CHB or non-HBV-infected control groups at 48 weeks. For the subgroup analyses of TAF vs. non-HBV-infected control subjects and inactive CHB patients whose detailed lipid profile information were available, no between-group differences in TC, low-density lipoprotein (LDL)-cholesterol, highdensity lipoprotein (HDL)-cholesterol, TC/HDL ratio, and LDL/HDL ratio were observed at 48 weeks. CONCLUSION: TDF seems to have a lipid-lowering effect compared to the non-HBV-infected control and TAF-treated groups. However, in real practice, TAF might not worsen the lipid profiles of subjects compared to non-HBV-infected controls and patients with inactive CHB.

Clinical usefulness of noninvasive fibrosis indices for predicting hepatocellular carcinoma in treatment-naïve patients with chronic hepatitis B following entecavir therapy.

AIMS: This study aimed to evaluate the clinical usefulness of the aminotransferase to platelet ratio index (APRI), fibrosis-4 (FIB-4), and modified FIB-4 (mFIB-4) indices in predicting hepatocellular carcinoma (HCC) in patients receiving entecavir (ETV) treatment. METHODS: Among 1955 patients treated with ETV, a total of 857 treatment-naive chronic hepatitis B patients (424 with liver cirrhosis [LC], 433 without cirrhosis) treated with ETV for more than 1 year were analyzed. RESULTS: Of the 857 patients, 85 (9.9%) patients (77 in the LC group and 8 in the non-LC group) developed HCC during the follow-up period. The median observation period was 6.9 years. Multivariate regression analysis of HCC incidence revealed that the initial mFIB-4 index (hazard ratio [HR] 1.058; 95% confidence interval [CI], 1.007-1.112; p = 0.027) and improvement in the FIB-4 index after 1 year of ETV treatment (HR 0.531; 95% CI, 0.339-0.831; p = 0.006) were independent prognostic factors in the entire cohort. In the LC group, the improvement of the FIB-4 index following ETV treatment (HR 0.491; 95% CI, 0.280-0.861; p = 0.013) was negatively correlated with incidence of HCC. However, the area under the receiver operating characteristic curve of specific cut-off values of the FIB-4 index at baseline and 1 year after ETV treatment were 0.572 (95% CI, 0.504-0.640) and 0.615 (95% CI, 0.546-0.684), respectively. In the non-LC group, none of the invasive fibrosis indices could predict HCC incidence. CONCLUSIONS: The specific cut-off value of the FIB-4 index was not suitable for predicting HCC. However, the improvement in the FIB-4 index after 1 year of ETV therapy could be a predictor of HCC development in cirrhotic patients.

Predictors of reoperation for perianal fistula in Crohn's disease.

OBJECTIVE: Treating perianal fistula in cases of Crohn's disease (CD) remains challenging and the postoperative recurrence rate of perianal fistula is 22%-28%. This study aimed to identify the predictive risk factors for reoperation in Korean CD patients with perianal fistula. METHODS: Medical records of the patients with clinically and pathologically confirmed CD who underwent surgical treatment for perianal fistulas at four referral centers in Korea between March 2010 and February 2020 were retrospectively reviewed. The rate of reoperation due to perianal fistula recurrence, which was defined as any subsequent surgery for perianal fistula or abscess, and the potential risk factors for reoperation were analyzed. RESULTS: Fifty-one patients at a mean age of 22 years were included in the study. During a median follow-up period of 26 months (range 2-89 mo), 21 (41.2%) patients underwent reoperation because of recurrent perianal fistula or abscess. The median interval from the first surgery to reoperation was 13 months. A multivariate Cox regression analysis revealed that drug escalation (from 5-aminosalicylic acid [5-ASA] to thiopurine or from 5-ASA or thiopurine to anti-tumor necrosis factor agents) after the first surgery was associated with a reduced likelihood of reoperation (hazard ratio 0.316, 95% confidence interval 0.117-0.858, P = 0.024). CONCLUSIONS: The postoperative recurrence rate was relatively high (41.2%) after the first surgery for perianal fistula in Korean patients with CD. Drug escalation therapy after the first surgery may help reduce the need for reoperation for perianal fistula.

Cognitive improvement effect of gintonin might be associated with blood-brain barrier permeability enhancement: dynamic contrast-enhanced MRI pilot study.

Along with the multiple neuroprotective effect, recent studies suggest that gintonin might increase the blood brain barrier permeability. We evaluated the effect of gintonin on the vascular permeability changes in different brain segments, using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). In this 8-week, randomized, open label pilot study, ten participants with subjective memory impairment but preserved cognitive function assigned to gintonin-enriched fraction (GEF) 300 mg/day or placebo groups. Korean versions of the Alzheimer's disease assessment scale (ADAS-K) and DCE-MRI parameters including Ktrans and Vp in different brain segments were evaluated at baseline and at 8 weeks after treatment. Nine participants completed the study protocol. No adverse events occurred during the observation period for 8 weeks in both groups. Following gintonin administration, increment trends of the brain permeability that did not reach a statistical significance were observed in the left hippocampus (Ktrans and Vp, both, p = 0.062), left thalamus and in left putamen (Ktrans, p = 0.062), and left insula and right amygdala (Vp, p = 0.062), but not in the control placebo group. The increment of the Ktrans value in the left thalamus from the baseline was highly correlated with the change of the ADAS scores (r = -0.900, p = 0.037). Gintonin might enhance the blood-brain barrier (BBB) permeability in the brain structures involved in cognitive functions. Further efficacy exploration for the synergistic effect of gintonin's BBB permeability enhancement to its other cognitive enhancing mechanisms are warranted. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0003418.

Comparable Incidence of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir.

BACKGROUND/AIMS: Adherence to medication and maintained virologic response (MVR) are related to the risk of adverse clinical outcomes. This study aimed to compare the efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in relation to the adverse clinical outcomes among chronic hepatitis B (CHB) patients stratified according to adherence to medication and MVR. METHODS: A total of 1794 treatment-naive CHB patients treated with ETV (n = 894) or TDF (n = 900) for > 1 year were identified. RESULTS: Adherence rates were significantly higher in the TDF than in the ETV (93.4% vs. 89.1%, respectively; P < 0.001). The MVR of ETV and TDF were 64.5% and 71.7%, respectively (P = 0.001). The MVR of ETV and TDF in the good adherence group were 72.1% and 76.4%, respectively (P = 0.083); in the poor adherence group, the MVR of ETV and TDF were 63.0% and 54.0%, respectively (P = 0.384) Multivariate analysis showed that the risk of HCC and death or transplantation was similar between groups (HR 0.826, 95% CI 0.522-1.306; P = 0.413 and HR 0.636, 95% CI 0.258-1.569; P = 0.325, respectively) after adjusting for adherence to medication and MVR. In the 589 propensity-matched pairs of patients, risk of HCC and death or transplantation was similar between treatment groups after stratification according to adherence rates and MVR. CONCLUSIONS: After adjustment for adherence and MVR, ETV, and TDF did not differ in terms of the risk of HCC and death or transplantation in all patients and propensity score-matched cohorts.

Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance.

BACKGROUND: High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer. METHODS: Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice. FINDINGS: Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner. INTERPRETATION: TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.

Non-steroidal anti-inflammatory drug-induced enteropathy as a major risk factor for small bowel bleeding: a retrospective study.

BACKGROUND: Small bowel (SB) bleeding accounts for 5% of all gastrointestinal (GI) bleeding cases and 80% of obscure GI bleeding cases. Although angioectasia is the common etiology of SB bleeding, nonsteroidal anti-inflammatory drug (NSAID)-induced SB lesions are also reported as a major cause in studies from Eastern countries. Herein, we assessed the frequency of occurrence of NSAID-induced SB lesions in Korean patients with obscure GI bleeding. METHODS: We retrospectively analyzed medical records of all consecutive patients aged ≥18 years who underwent capsule endoscopy from March 2018 to February 2019 at Ulsan University Hospital and Kosin University Gospel Hospital. RESULTS: Of the 83 subjects (all Korean; mean age ± standard deviation: 59 ± 18 years; age range: 18-84 years; men: n = 52; women: n = 31), 55 (66.2%) had stool with clear blood and 28 (33.8%) had normal stool with iron deficiency anemia. The detection rate of SB bleeding and lesions using capsule endoscopy was 72.3% (60 of 83 patients). A significantly higher frequency (40 of 51) of ulcerative/erosive lesions than other causes was observed in patients with inactive bleeding but visible SB lesions. As a result, NSAID-induced enteropathy accounted for 30.1% of 83 patients with obscure GI bleeding (25 of the all 60 SB bleeding cases). CONCLUSIONS: Contrary to what is reported for patients in Western countries, this study in Korean patients showed an improved diagnostic yield of capsule endoscopy for obscure GI bleeding and that NSAID-induced enteropathy was the most common etiology of SB bleeding. Aggressive small intestine examination is required for patients with unexplained GI bleeding.

Low-level viremia and cirrhotic complications in patients with chronic hepatitis B according to adherence to entecavir.

BACKGROUND/AIMS: Low-level viremia (LLV) after nucleos(t)ide analog treatment was presented as a possible cause of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, detailed information on patients' adherence in the real world was lacking. This study aimed to evaluate the effects of LLV on HCC development, mortality, and cirrhotic complications among patients according to their adherence to entecavir (ETV) treatment. METHODS: We performed a retrospective observational analysis of data from 894 consecutive adult patients with treatment-naïve CHB undergoing ETV treatment. LLV was defined according to either persistent or intermittent episodes of <2,000 IU/mL detectable hepatitis B virus DNA during the follow-up period. Good adherence to medication was defined as a cumulative adherence ≥90% per study period. RESULTS: Without considering adherence in the entire cohort (n=894), multivariate analysis of the HCC incidence showed that LLV was an independent prognostic factor in addition to other traditional risk factors in the entire cohort (P=0.031). Good adherence group comprised 617 patients (69.0%). No significant difference was found between maintained virologic response and LLV groups in terms of the incidence of liver-related death or transplantation, HCC, and hepatic decompensation in good adherence group, according to multivariate analyses. CONCLUSION: In patients with treatment-naïve CHB and good adherence to ETV treatment in the real world, LLV during treatment is not a predictive factor for HCC and cirrhotic complications. It may be unnecessary to adjust their antiviral agent for patients with good adherence who experience LLV during ETV treatment.

Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC. DESIGN: Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription-quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines. RESULTS: TonEBP expression is higher in tumours than in adjacent non-tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX-2 promoter. CONCLUSIONS: TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker.

Panax ginseng as an adjuvant treatment for Alzheimer's disease.

Longevity in medicine can be defined as a long life without mental or physical deficits. This can be prevented by Alzheimer's disease (AD). Current conventional AD treatments only alleviate the symptoms without reversing AD progression. Recent studies demonstrated that Panax ginseng extract improves AD symptoms in patients with AD, and the two main components of ginseng might contribute to AD amelioration. Ginsenosides show various AD-related neuroprotective effects. Gintonin is a newly identified ginseng constituent that contains lysophosphatidic acids and attenuates AD-related brain neuropathies. Ginsenosides decrease amyloid ß-protein (Aß) formation by inhibiting ß- and γ-secretase activity or by activating the nonamyloidogenic pathway, inhibit acetylcholinesterase activity and Aß-induced neurotoxicity, and decrease Aß-induced production of reactive oxygen species and neuroinflammatory reactions. Oral administration of ginsenosides increases the expression levels of enzymes involved in acetylcholine synthesis in the brain and alleviates Aß-induced cholinergic deficits in AD models. Similarly, gintonin inhibits Aß-induced neurotoxicity and activates the nonamyloidogenic pathway to reduce Aß formation and to increase acetylcholine and choline acetyltransferase expression in the brain through lysophosphatidic acid receptors. Oral administration of gintonin attenuates brain amyloid plaque deposits, boosting hippocampal cholinergic systems and neurogenesis, thereby ameliorating learning and memory impairments. It also improves cognitive functions in patients with AD. Ginsenosides and gintonin attenuate AD-related neuropathology through multiple routes. This review focuses research demonstrating that ginseng constituents could be a candidate as an adjuvant for AD treatment. However, clinical investigations including efficacy and tolerability analyses may be necessary for the clinical acceptance of ginseng components in combination with conventional AD drugs.

The risk of hepatocellular carcinoma within and beyond the first 5 years of entecavir in Korean patients with chronic hepatitis B.

BACKGROUND & AIMS: The development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) has decreased due to potent antiviral agents. However, it remains uncertain whether the risk of HCC will diminish after long-term antiviral therapy in Asia, where CHB is endemic and vertical transmission is common. This study aimed to compare the incidence of HCC within and beyond the first 5 years of entecavir (ETV) in treatment-naïve Korean patients with CHB. METHODS: We performed a retrospective observational analysis of data from 894 consecutive, adult patients with CHB undergoing ETV treatment at a tertiary referral hospital in Ulsan, Korea from January 1, 2007 through April 31, 2017. We compared the HCC incidence rates per 100 person-years within and beyond the first 5 years. Univariate and multivariate analyses for factors predictive of HCC were performed. RESULTS: The incidence rate of HCC in patients with CHB did not differ statistically when we compared within and beyond the first 5 years of ETV therapy (2.29% vs 1.66% per person-year, P = 0.217). Failure to achieve maintained virological response (MVR) was a major independent risk factor for HCC in patients at a follow-up of <5 years. In contrast, in patients with a follow-up of ≥5 years, achieving MVR was not significantly associated with HCC development. CONCLUSIONS: The incidence rate of HCC may not change significantly before and after 5 years of ETV therapy in Korean CHB patients. The risk of HCC in Asian CHB patients may remain in the long-term.

Mortality, liver transplantation and hepatic complications in patients with treatment-naïve chronic hepatitis B treated with entecavir vs tenofovir.

Few studies have directly compared the long-term clinical outcomes of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). This study aimed to compare the risk of mortality, liver transplantation and hepatic complications including hepatocellular carcinoma (HCC) and hepatic decompensation between these drugs in treatment-naïve chronic hepatitis B (CHB). We performed a longitudinal observational analysis of data from 1325 consecutive adult CHB patients with a cumulative adherence of ≥80% to treatment with ETV (n = 721) or TDF (n = 604) at a tertiary referral hospital in Ulsan, Korea, from 1 January 2007 through 31 April 2017. Among the patients, 708 were analysed using propensity score matching with a ratio of 1:1. In the follow-up period of up to 5 years, five patients (0.4%) died, three patients (0.2%) underwent liver transplantation (LT) and 54 patients (4.1%) developed HCC. Hepatic decompensation occurred in 24 (1.8%) patients. ETV therapy did not significantly differ from TDF therapy regarding the risk of liver-related death or LT (HR 0.96; 95% CI, 0.23-4.07; log-rank P = 0.955), HCC (HR, 1.36; 95% CI, 0.72-2.56; log-rank P = 0.340) and hepatic decompensation (HR, 1.64; 95% CI, 0.67-4.00; log-rank P = 0.276). In the 708 propensity-matched pairs, ETV and TDF were also not significantly different with respect to the risk of mortality, LT and hepatic complications. In this longitudinal observational study of 1325 patients with CHB, ETV and TDF therapies were not significantly different regarding the risk of mortality, HCC, LT and hepatic decompensation.

Phylogenetic comparison of Epstein-Barr virus genomes.

Technologies used for genome analysis and whole genome sequencing are useful for us to understand genomic characterization and divergence. The Epstein-Barr virus (EBV) is an oncogenic virus that causes diverse diseases such as Burkitt's lymphoma (BL), nasopharyngeal carcinoma (NPC), Hodgkin's lymphoma (HL), and gastric carcinoma (GC). EBV genomes found in these diseases can be classified either by phases of EBV latency (type-I, -II, and -III latency) or types of EBNA2 sequence difference (type-I EBV, type-II EBV or EBV-1, EBV-2). EBV from EBV-transformed lymphoblastoid cell line (LCL) establishes type-III latency, EBV from NPC establishes type-II latency, and EBV from GC establishes type-I latency. However, other important factors play key roles in classifying numerous EBV strains because EBV genomes are highly diverse and not phylogenetically related to types of EBV-associated diseases. Herein, we first reviewed previous studies to describe molecular characteristics of EBV genomes. Then, using comparative and phylogenetic analyses, we phylogenetically analyzed molecular variations of EBV genomes and proteins. The review of previous studies and our phylogenetic analysis showed that EBV genomes and proteins were highly diverse regardless of types of EBV-associated diseases. Other factors should be considered in determining EBV taxonomy. This review will be helpful to understand complicated phylogenetic relationships of EBV genomes.

Medication Nonadherence Increases Hepatocellular Carcinoma, Cirrhotic Complications, and Mortality in Chronic Hepatitis B Patients Treated With Entecavir.

OBJECTIVES: Optimal adherence to nucleoside analogue treatment is necessary to achieve undetectable levels of hepatitis B virus (HBV) DNA in patients with chronic hepatitis B (CHB), and to prevent cirrhotic complications. However, any large long-term follow-up study has not been investigated the effect of adherence to entecavir (ETV) treatment on specific liver-related events (LREs), namely, hepatocellular carcinoma (HCC), cirrhotic complications, and mortality. METHODS: This was a 10-year longitudinal observational study of treatment-naïve patients with CHB who received ETV treatment. The primary outcome was the cumulative probability of LREs. The cumulative level of adherence to medication was categorized as good (≥90%) or poor (<90%). RESULTS: Data from 894 treatment-naïve CHB patients who received ETV were analyzed. Overall mean adherence rates were 89.1%. Patients with poor adherence had a higher risk of virologic breakthrough (VBT) (HR, 22.42; 95% CI, 19.57-52.52; P < 0.001) than those with good adherence. Multivariate analyses showed a higher risk of liver-related (HR, 14.29; 95% CI, 3.49-58.47; P < 0.001) or all-cause (HR, 4.96; 95% CI, 2.19-11.27; P < 0.001) mortality, HCC (HR, 2.86; 95% CI, 1.76-4.64; P < 0.001), and cirrhotic complications (HR, 2.86; 95% CI, 1.93-4.25; P < 0.001) with poor adherence. Medication adherence was further stratified into three groups according to adherence rates of <70%, ≥70 to <90%, and ≥90%. The dose-response analyses of adherence rates showed that the risk of LREs increased progressively as medication adherence declined. In particular, the unfavorable effects of nonadherence were more pronounced in patients with cirrhosis. CONCLUSIONS: Poor adherence to medication was associated with a higher mortality and greater risk of HCC and cirrhotic complications, particularly among patients with liver cirrhosis.

Association between non-alcoholic fatty liver disease and subclinical coronary atherosclerosis: An observational cohort study.

BACKGROUND & AIMS: There are limited data on the association between non-alcoholic fatty liver disease (NAFLD) and subclinical coronary atherosclerosis. This study investigated the influence of NAFLD on subclinical coronary atherosclerosis as detected by coronary computed tomography angiography (CCTA) in an asymptomatic population. METHODS: A total of 5,121 consecutive asymptomatic individuals with no prior history of coronary artery disease or significant alcohol intake voluntarily underwent abdominal ultrasonography and CCTA as part of a general health examination. Fatty liver was assessed by ultrasonography examination. The fatty liver index and NAFLD fibrosis score were also calculated. Coronary atherosclerotic plaques on CCTA were evaluated. The association between NAFLD and subclinical coronary atherosclerosis was determined by logistic regression analysis. RESULTS: Of the study participants, 1,979 (38.6%) had ultrasonography-diagnosed NAFLD. After adjustment for cardiovascular risk factors, there were no statistically significant differences in the adjusted odds ratios of NAFLD for calcified plaque (1.03; 95% CI 0.89-1.20; p = 0.673) and mixed plaque (1.15; 95% CI 0.93-1.42; p = 0.214). However, adjusted odds ratios for any atherosclerotic plaque (1.18; 95% CI 1.03-1.35; p = 0.016) and non-calcified plaque (1.27; 95% CI 1.08-1.48; p = 0.003) were significantly higher in NAFLD. In addition, there was a significant association of fatty liver index ≥30 with non-calcified plaque (1.37; 95% CI 1.14-1.65; p = 0.001) and NAFLD fibrosis score ≥-1.455 with non-calcified plaque (1.20; 95% CI 1.08-1.42; p = 0.030). CONCLUSIONS: In this large cross-sectional study of asymptomatic individuals undergoing CCTA, NAFLD was consistently associated with non-calcified plaque, suggesting an increased cardiovascular risk. LAY SUMMARY: In asymptomatic individuals, non-alcoholic fatty liver disease (NAFLD) was an independent risk factor for non-calcified plaque, which has been known as a vulnerable plaque associated with sudden and unexpected cardiac events. Therefore, appropriate medical therapy for NAFLD was required to reduce future cardiac events.

Clinical Course of Partial Virologic Response with Prolonged Tenofovir Therapy in Nuclos(t)ides-Naïve Patients with Chronic Hepatitis B.

BACKGROUND/AIMS: The clinical course of chronic hepatitis B (CHB) patients with partial virologic response (PVR) during tenofovir disoproxil fumarate (TDF) therapy remains unclear. METHODS: We retrospectively investigated the long-term clinical outcomes of TDF treatment in nucleos(t)ides-naïve CHB patients, particularly in those with PVR. RESULTS: A total of 391 patients treated with TDF therapy for more than 12 months were included. Virologic response (VR) was achieved in 341 patients (87.2%). PVR was evident in 127 (45.3%) of the 391 patients. Multivariate logistic regression analysis using selected baseline factors identified absolute HBV DNA levels at baseline (OR 0.496; 95% CI 1.369-1.969) and HBeAg positivity (OR 0.622; 95% CI 1.096-3.167) as factors significantly associated with PVR. During continuous prolonged TDF therapy, 127 (71.8%) of 177 patients with PVR achieved VR. The cumulative rates of VR in patients with PVR at 12, 24, and 36 months were 42.4, 79.7, and 90.2%, respectively. Serum HBV DNA level at week 24 was significantly associated with VR in patients with PVR. CONCLUSIONS: The vast majority of CHB patients with PVR achieved VR through prolonged TDF therapy, although the time to achieve VR was delayed in those with PVR. This suggests that adjustment of TDF therapy in patients with PVR is unnecessary.

Efficacy of tenofovir-based rescue therapy for chronic hepatitis B patients with resistance to lamivudine and entecavir.

BACKGROUND/AIMS: Tenofovir disoproxil fumarate (TDF) monotherapy for 48 weeks provided a virological response comparable to that of TDF and entecavir (ETV) combination therapy in patients infected with ETV-resistant hepatitis B virus (HBV). Little long-term data in routine clinical practice are available regarding the optimal treatment of patients with ETV-resistant HBV. METHODS: We investigated the long-term antiviral efficacy of combination therapy of TDF+lamivudine (LAM) or TDF+ETV compared to that of TDF monotherapy in 73 patients with resistance to both LAM and ETV. RESULTS: Patients were treated with TDF monotherapy (n=12), TDF+LAM (n=19), or TDF+ETV (n=42) for more than 6 months. The median duration of TDF-based rescue therapy was 37 months. Virologic response (VR) was found in 63 patients (86.3%). The rates of VR among the three groups (TDF monotherapy, TDF+LAM, and TDF+ETV) were not statistically different (log-rank P=0.200) at 12 months (59.3%, 78.9%, and 51.8%, respectively) or at 24 months (88.4%, 94.7%, and 84.2%). In addition, treatment efficacy of TDF-based combination or TDF monotherapy was not statistically different with ETV-resistant strains or exposure to other antiviral agents. In multivariate analysis, only lower baseline HBV DNA level was an independent predictor for VR (hazard ratio, 0.723; 95% confidence interval, 0.627-0.834; P<0.001). CONCLUSIONS: TDF monotherapy was as effective as combination therapy of TDF+LAM or TDF+ETV in maintaining long-term viral suppression in chronic hepatitis B patients with resistance to both LAM and ETV. HBV DNA level at the start of TDF rescue therapy was the only independent predictor of subsequent VR.