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Gut microbiology is associated with liver disease due to gut-liver circulation via the gut microbial-liver axis. There is a paucity of data regarding the effects of treatment to cure hepatitis C virus (HCV) infection on the gut microbiota. The aim of this study was to evaluate the fecal microbiota before and after treatment with direct antiviral agents (DAA) in patients with HCV infection.This prospective study was conducted at Kaohsiung Chung-Gung Memorial Hospital, Taiwan, between December 2019 and November 2020. We recruited patients with chronic hepatitis C (CHC) receiving DAA treatment. Fecal samples were collected twice: at baseline (before DAA treatment; CHC group) and 24 weeks after the end of treatment (EOT; SVR24 group), and once from healthy controls at baseline (control group). The taxonomic composition of the gut microbiota was determined using 16 S ribosomal RNA gene sequencing of stool samples.A total of 60 patients with CHC and 60 healthy controls matched by age and gender were enrolled. All patients achieved a sustained virologic response (SVR). Alpha diversity was not significantly difference between any groups. Analysis of similarities (ANOSIM) revealed minor differences in the microbial community structure between the control group and CHC group (R = 0.0146, P = 0.098) and less significant differences between the CHC group and SVR24 group (R = -0.0139; P = 0.94). Three phyla and eight genera were differentially abundant between the control group and CHC group.Individuals with CHC do not exhibit significant gut microbiota alterations and eradication of HCV by DAA is not associated with significant modification of the gut microbiota.

We aimed to compare the one-year retreatment efficacy and renal safety of entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) after HBV relapse in patients who discontinued entecavir or TDF.This retrospective study included 289 chronic hepatitis B (CHB) patients without cirrhosis who received entecavir (n = 93), TDF (n = 103), or TAF (n = 86) retreatment for at least 12 months after entecavir or TDF cessation.The rate of virological response (HBV DNA 20 IU/mL) at 12 months of retreatment was 79/93 (84.9%) in the entecavir group, 92/103 (89.3%) in the TDF group, and 72/86 (83.7%) in the TAF group. The rate of ALT normalization (ALT ≤ 40 U/L) after 12 months of retreatment was 76/93 (81.7%) in the entecavir group, 77/103 (74.7%) in the TDF group , and 73/86 (84.9%) in the TAF group. There was no significant difference in the rates of virological response (p = 0.495) and ALT normalization (p = 0.198) among the three groups. Multivariate analysis showed that lower HBV DNA and HBsAg levels at baseline were independently associated with virological response at 12 months of retreatment. The TDF group (37.8 ± 34.8 U/L) had higher ALT levels at 12 months of retreatment than the TAF (27. ± 17.9 U/L, p = 0.015) and entecavir (28.3 ± 19.3 U/L, p = 0.022) groups. In patients with eGFR 60-90 mL/min/1.73 mTAF could be one of the retreatment options for retreatment of HBV relapse after entecavir or TDF cessation.

Tenofovir disoproxil fumarate (TDF) and Entecavir (ETV) are commonly used for patients with chronic hepatitis B (CHB), and renal or bone toxicity are possible concerns. This study is to evaluate the renal and bone effect of TDF compared with ETV in CHB patients. This is a retrospective study at Kaohsiung Chung-Gung memorial hospital, Taiwan, from June 2013 to December 2018. Patients with CHB were prescribed with TDF or ETV for 3 years or above. Renal function was assessed at 12-week intervals. Dual-energy X-ray absorptiometry scans of the spine and femurs were performed at 48-week intervals. The propensity score analysis was conducted to balance the baseline characteristics of patients in both treatment groups. A total of 258 patients were included in this study: TDF (n = 135) and ETV (n = 123). The prevalence of osteopenia was much higher in the TDF group at week 48 and week 96. The TDF group showed significant mean percentage decrease from baseline in bone mineral density throughout the treatment course. Logistic regression analysis adjusted for the propensity score demonstrated that the use of TDF was the only predictive factor of significant bone density loss at week 144. The mean percentage decline of estimated glomerular filtration rate was significant in the TDF group at all time points. Renal threshold phosphate concentration was similar among both treatment groups. This study suggested CHB patients treated with TDF may experience increased risks of bone loss and renal deficits compared to those treated with ETV.

Background and aim Tenofovir disoproxil fumarate (TDF) and entecavir are effective antiviral medications that are recommended as first-line monotherapies for the treatment of chronic hepatitis B (CHB) infection, including decompensated liver cirrhosis with ascites. Acute kidney injury (AKI) commonly occurs in patients with cirrhosis and ascites. The aim of this study was to compare the development of AKI during TDF and entecavir treatment of CHB patients with cirrhotic refractory ascites. Methods From January 2011 to April 2017, we identified patients who were diagnosed with cirrhosis with refractory ascites and received TDF or entecavir treatments at Kaohsiung Chang Gung Memorial Hospital. AKI was defined as an increase in serum creatinine of more than 0.3 mg/dL or 1.5-fold from baseline. All episodes of AKI were recorded and compared between those who received TDF and entecavir. Results A total of 111 patients were enrolled in this retrospective study, of which 22 patients were treated with TDF and 89 were treated with entecavir. Patients with AKI episodes had a higher proportion of TDF treatment (P = 0.01), male (P = 0.023), hepatocellular carcinoma (P = 0.007), admission (P = 0.045), and mortality (P = 0.018). Logistic regression analysis illustrated that TDF treatment of patients with comorbidity was an independent risk factor for the development of AKI [odds ratio (OR), 3.756; 95% confidence interval (CI), 1.293-10.912; P = 0.015] and hepatorenal syndrome (OR, 7.651; 95% CI, 1.697-34.508; P = 0.008). Conclusions TDF treatment is a risk factor for AKI and HRS development in cirrhotic patients with refractory ascites in comparison with entecavir treatment, especially in patients with comorbidity.

Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP) is a novel marker for evaluating fibrosis and predicting the development of hepatocellular carcinoma (HCC). However, the role of WFA(+)-M2BP in the prognosis of HCC patients after curative surgery remains unknown. In this study, we aimed to evaluate the prognostic role of serum WFA(+)-M2BP in HCC patients after curative resection and liver transplantation. We enrolled 460 HCC patients (357 resection and 103 transplantation) to analyze the risk factors for HCC recurrence and patient’s survival. We employed time-to-event models using univariate and multivariable Cox proportional hazards regression analyses and calculated the hazard ratios (HRs) and adjusted HRs with their corresponding 95% confidence intervals (CIs). The levels of WFA(+)-M2BP were 0.19-14.51 COI (median 1.08) in patients of hepatectomy and 0.47-19.90 COI (median 6.0) in transplant patients. The levels of WFA(+)-M2BP in liver transplant patients is much higher than that of hepatectomy patients. Overall, liver fibrotic stage was positively correlated to WFA(+)-M2BP levels (P

When designing headlights using optical software LightTools, we found that the maximum illuminance and facula diameter of the initial headlamp lighting system design were less than 20000 lux (maximum illuminance) and 40mm (facula diameter), which did not meet the minimum performance requirements. However, if we increase the maximum illuminance value, the facula diameter value will become smaller and may not meet the minimum performance requirements. In order to obtain the best value of maximum illuminance and facula diameter at the same time, we used a multi-objective optimization method (combination of Taguchi method and robust multiple criterion optimization approach (RMCO)) to solve maximum illuminance and facula diameter optimization problem. It is effective and helpful increase the maximum illuminance and facula diameter of the headlamp lighting system (The maximum illuminance increased from 9580 lux to 22900 lux, the facula diameter increased from 40mm to 50mm). In this method, the concept of statistical analysis is used to obtain a set of diversified Pareto-optimal solutions. The set of diversified Pareto-optimal solutions can obtain for energy optimized design of headlamp lighting system. This study is the first attempt to use the RMCO method to optimize the multi-objective problem in a headlamp lighting system.

Renal toxicity of direct-acting antivirals (DAAs) in chronic hepatitis C (CHC) patients has not been well-characterized. The aim of this study was to assess renal safety of DAAs in an Asian CHC patient cohort. Data from CHC patients (n = 1536) treated with DAAs were used in this retrospective study. Serial estimated glomerular filtration rate (eGFR) at pretreatment (1-year prior to treatment), baseline, end of treatment (EOT), and 12 weeks after treatment (SVR12 ) was evaluated. While a significant decrease in eGFR from baseline to EOT (84.8 → 81.8 mL/min/1.73 m2 , P 65 years (OR = 1.862, P = .011), baseline eGFR ≥ 60 mL/min/1.73 m2 (OR = 2.684, P = .023), and liver transplant (OR = 3.894, P = .001) were independent risk factors for deteriorating renal function. In conclusion, DAA treatment led to a significant decline in eGFR at EOT but was followed by a slight rise at 12 weeks after treatment. A similar trend was observed with PrOD, DCV/ASV and GZP/EBV, but not in SOF-based regimens. As age >65 years, baseline eGFR ≥ 60 mL/min/1.73 m2 and liver transplantation are significant risk factors for deterioration in renal function, we strongly advice close monitoring of renal function in these populations.

Background Diabetes is a risk factor of fibrosis progression in chronic hepatitis C (CHC). However, only one longitudinal study exploring whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in CHC patients has been conducted. Aims We investigated whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients. Methods A cohort consisting of 976 non-genotype 3 patients histologically proven to have CHC was studied. After excluding patients with biopsy-proven or ultrasound-identified cirrhosis, there were 684 patients without cirrhosis. All 684 patients underwent hepatocellular carcinoma surveillance using ultrasound every 6 months, with a median duration of follow-up evaluation of 102.4 months. During the follow-up period, 60 patients developed cirrhosis according to ultrasound findings. Results For the subgroup of 684 patients without cirrhosis, Kaplan–Meier survival analyses showed no significantly different cumulative incidences of cirrhosis (log-rank test; P = 0.71) among the patients with diabetes as compared to those without. However, after making adjustments for age, gender, fibrosis, steatosis, sustained virological response status, and obesity using Cox’s proportional hazard model, diabetes was found to be an independent predictor for cirrhosis (HR = 1.9; 95% CI = 1.05–3.43, P = 0.03). Conclusions Diabetes is associated with progression from non-cirrhotic liver to cirrhosis in non-genotype 3 CHC patients.

Hepatic steatosis (HS) can cause substantial problems for both donors and recipients in living donor liver transplantation. The controlled attenuation parameter (CAP) is a noninvasive method of measuring HS using a process based on transient elastography.To evaluate the accuracy of CAP in quantifying HS during living donor liver transplantation.A total of 54 liver donors who received CAP and intraoperative liver biopsy (LB) were enrolled in this study. The performance of CAP compared with LB for diagnosing HS was assessed using areas under receiver operating characteristic curves. HS was defined by the presence of steatosis in5% of hepatocytes.No HS was found in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Using CAP, the area under receiver operating characteristic curve was 0.96 (95% CI, 0.91-1; P .001) for HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%). Among the 42 candidates with CAP 257 dB/m, none had HS, while of the 12 candidates with CAP ≥257 dB/m, 7 had HS. In a multivariate linear regression analyses, body mass index (β = 0.71, P .001) was found to be independently associated with CAP in those without HS.CAP might be a promising tool to exclude HS in East Asian living liver donors. Body mass index was found to be independently associated with CAP values in those without HS.

Background and importance Clinical decision support systems (CDSSs) are frequently adopted in hospitals to increase prescription accuracy in patients with renal impairment, but the alerts from CDSSs are usually overridden in clinical practice. Therefore, an intensified CDSS with more detailed information should be developed and its effectiveness with regard to prescribing errors determined. Aim and objectives To evaluate the effectiveness of an intensified CDSS with regard to prescribing errors for inappropriate drugs in cases of renal dysfunction. Material and methods We conducted a pre- and post-intervention study in an inpatient setting in the largest medical centre in Taiwan in 2019. Previously, the CDSS only reminded clinicians to adjust drugs according to the patient’s renal function. After May 2019, we initiated an intensified CDSS directly providing clinicians with the precise drug dosage or alternative drug recommendations for patients with renal impairment. The study outcome was the rate of prescribing errors, as identified by pharmacists after prescribing by clinicians. We used interrupted time series analysis to estimate the trend in prescribing error rate before (January 2019 to May 2019) and after (June 2019 to December 2019) implementing the intensified CDSS. As a control, we conducted similar analyses in another hospital with the same healthcare systems but without an intensified CDSS. We hypothesised there would be a reduction in the rate of prescribing errors for inappropriate drugs in cases of renal dysfunction after the intensification of CDSS in the study hospital, compared with the control hospital. Results The mean prescribing error rates due to inappropriate drugs in patients with renal dysfunction were 1.70 and 1.59 per 1000 inpatient beds before and after the introduction of the intensified CDSS, respectively, which did not constitute a significant change between the pre- and post- intervention (β=0.01; 95% CI −0.32 to 0.35). However, we observed a non-significantly increased prescribing error rate between the study hospital and the control hospital (β=0.04; 95% CI −0.51 to 0.59) after the introduction of the intensified CDSS. Conclusion and relevance The deployment of an intensified CDSS providing detailed information on how to prescribe drugs for patients with renal impairment may inhibit the increase in prescribing error rate due to inappropriate drugs in patients with renal dysfunction. References and/or acknowledgements Conflict of interest No conflict of interest

Background and importance Pan-genotypic direct acting antiviral agents (ie, glecaprevir/pibrentasvir (GLE/PIB)), have been proven in clinical trials to be effective and safe in the treatment of chronic hepatitis C (CHC) infection. However, CHC genotypes may vary in different populations and limited evidence is available regarding the effects of GLE/PIB in patients with different genotypes. Aim and objectives To compare the effectiveness and safety of GLE/PIB in CHC patients with different genotypes in Taiwan. Material and methods We retrospectively identified a cohort of CHC patients newly initiating GLE/PIB between August 2018 and June 2019 from the Chang Gung Research Database, a multi-institutional electronic medical records database covering approximately 1.3 million individuals (6% of the Taiwan population). We classified patients by genotype who were followed up for 12 weeks from completion of GLE/PIB therapy. Sustained virological response at 12 weeks (SVR12) was observed as the primary outcome. The safety outcome included elevation of alanine aminotransferase (ALT) or total bilirubin by three times the upper limit of normal (ULN), which was taken as an indicator of liver related adverse events. We calculated the rate of study outcomes among CHC patients with different genotypes. Results We identified 1589 CHC patients newly initiating GLE/PIB. Mean age was 61.7 (SD 12.6) years and 53% were women. The major CHC genotype was type 2 (60.2%), followed by type 1b (16.5%) and mixed type (5.7%). We found the rate of SVR12 was relatively lower among patients with genotype type 6 (91.1%), type 2 (91.4%) and type 3 (92.2%) compared with genotype type 1 (100%), type 5 (100%), mixed type (96.7%) and unknown type (93.8%). Furthermore, 14.7% of patients were found to have ALT elevation (>3 times the ULN). Most of these were genotype type 2 (8.7%), followed by type 1b (1.8%) and type 3 (1.2%). No patient had total bilirubin levels over three times the ULN. Conclusion and relevance The effectiveness and safety of GLE/PIB in Taiwan may vary in CHC patients with different genotypes. The findings could be strong grounds for future large scale prospective studies to confirm the association between CHC genotypes and treatment outcome with GLE/PIB. References and/or acknowledgements Conflict of interest No conflict of interest

Background Non-invasive techniques for liver fibrosis diagnosis are very important for clinician especially in high-risk patients for liver biopsy. We further explored the diagnostic accuracy of FibroScan, FIB-4 and aminotransferase-to-platelet ratio index (APRI) in identifying liver fibrosis and assess their predictive role for oesophageal varices in patients with hepatocellular carcinoma (HCC). Methods In total, 380 patients who underwent surgery for HCC were included based on retrospective study design. Liver fibrosis was pathologically diagnosed using the Ishak scoring system. Liver stiffness parameters were measured using FibroScan. APRI and FIB-4 were calculated. Among those, 121 patients who received oesophagogastroduodenoscopic examination underwent variceal evaluation. Results For liver cirrhosis diagnosis with FibroScan, the optimal cut-off values for the patients with HCC overall, left HCC and right HCC were 8.85, 11.75 and 8.70 kPa (the accuracy were 78.7%, 78.4% and 79.2%, respectively). They had high areas under the receiver operating characteristic curve of 0.84, 0.84 and 0.85. The combined FibroScan, APRI and FIB-4 had very high specificity (more than 92%) for cirrhosis diagnosis. The optimal cut-off liver stiffness values for the diagnosis of varices were all 11.2 kPa. For predicting varices, the optimal cut-off values of FIB-4 and APRI were 2.64 and 0.71, their accuracy were 64.3%-78.4%, 69.4% and 72.7%, respectively. Conclusions FibroScan, FIB-4 and APRI have moderate accuracy for liver fibrosis diagnosis and oesophageal varices prediction in patients with hepatoma. This is a study of these non-invasive techniques applied in specific hepatoma patients and with inevitable limitations and need future more studies for validation.

Tenofovir disoproxil fumarate (TDF) and Entecavir (ETV) are commonly used for patients with chronic hepatitis B (CHB), and renal or bone toxicity are possible concerns. This study is to evaluate the renal and bone effect of TDF compared with ETV in CHB patients.This is a retrospective study at Kaohsiung Chung-Gung memorial hospital, Taiwan, from June 2013 to December 2018. Patients with CHB were prescribed with TDF or ETV for 3 years or above. Renal function was assessed at 12-week intervals. Dual-energy X-ray absorptiometry scans of the spine and femurs were performed at 48-week intervals. The propensity score analysis was conducted to balance the baseline characteristics of patients in both treatment groups.A total of 258 patients were included in this study: TDF (n = 135) and ETV (n = 123). The prevalence of osteopenia was much higher in the TDF group at week 48 and week 96. The TDF group showed significant mean percentage decrease from baseline in bone mineral density throughout the treatment course. Logistic regression analysis adjusted for the propensity score demonstrated that the use of TDF was the only predictive factor of significant bone density loss at week 144. The mean percentage decline of estimated glomerular filtration rate was significant in the TDF group at all time points. Renal threshold phosphate concentration was similar among both treatment groups.This study suggested CHB patients treated with TDF may experience increased risks of bone loss and renal deficits compared to those treated with ETV.

Comparative long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) for prevention of disease progression to hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis B (CHB)-related compensated cirrhosis is controversial.To compare the long-term efficacy of ETV and TDF in HCC prevention in patients with CHB-related cirrhosis, and to evaluate predictive risk factors for HCC development.From January 2008 to March 2018, 894 treatment-naïve patients with CHB-related compensated cirrhosis on ETV or TDF were enrolled based on the longitudinal cohort study. Data were originally collected for 7.3 years of follow-up or after the launch of TDF in 2011. Only the 5-year cumulative incidence and risk factors of HCC were assessed.Total 678 and 216 patients received ETV and TDF, respectively. The cumulative risk of HCC at 1, 3 and 5 years of follow-up was 1.6%, 11.3% and 18.7%, respectively, in the ETV group; and 0.9%, 6.7% and 10.7%, respectively, in the TDF group (P = 0.0305). Univariate and adjusted-multivariable models revealed that platelet count, alpha-fetoprotein (AFP) levels and upper gastrointestinal (UGI) varices were independent risk factors for HCC development. TDF resulted in risk of HCC development compared to ETV with adjusted hazard ratios (aHRs) of 0.66 (95% confidence interval [CI]:0.40, 1.08; P = 0.0971), 0.69 (95% CI: 0.42, 1.14; P = 0.1488) and 0.66 (95% CI: 0.38, 1.14; P = 0.1407) under stepwise selection, propensity score adjustment, and propensity score matching multivariable models, respectively.For treatment-naïve patients with CHB-related compensated cirrhosis with 5-year follow-up, after variable adjustments, propensity score approaches and subgroup analyses, TDF showed a lower rate of HCC development that did not reach statistical significance, compared to the ETV.

Background/Purpose: Prdevious meta-analyses assess whether or not patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C > G) was associated with increased risk of hepatocellular carcinoma (HCC) in Caucasians patients with hepatitis C virus (HCV)-related cirrhosis, these meta-analyses did not provide firm conclusions. Only one cross-sectional study involving Asian patients has previously been conducted to explore this issue. We aim to investigate this in a longitudinal cohort of Asian chronic hepatitis C (CHC) patients. Methods: We consecutively enrolled 1011 CHC patients who underwent liver biopsy before initiating interferon-based therapy. These patients were followed-up and screened for HCC up to a median of 6.9 years. The influence of rs738409 (GG) genotype on the occurrence of HCC was assessed using the Kaplan–Meier method, then according to the multivariate Cox model. Results: During follow-up, 143 (14.1%) patients developed HCC. rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.634). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.12). Among 261 patients with liver cirrhosis, rs738409 (GG) genotype was not associated with time-to-HCC development on multivariate Cox regression (P = 0.737). When considering the occurrence of these events over time, rs738409 (GG) genotype did not influence the risk of HCC development (log-rank = 0.72). Conclusion: In this longitudinal study with liver biopsy to stage liver fibrosis, we affirm there is no influence of the rs738409 (GG) genotype on the occurrence of HCC in Asian CHC patients, including cirrhotic patients. Keywords: Patatin-like phospholipase domain containing 3, Hepatocellular carcinoma, Hepatitis C virus

Background Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease that is involved in the invasiveness and progression of cancer. There is good evidence that uPA expression is a clinically relevant biomarker in some solid tumors, but its role in hepatocellulcar carcinoma (HCC) is uncertain. We evaluated the prognostic value of serum uPA before surgery in HCC patients receiving curative resection. Methods Serum uPA levels were determined by enzyme-linked immunosorbent assay in 282 HCC patients who received complete liver resections at Kaohsiung Chang Gung Memorial Hospital. Overall survival (OS) curves were constructed using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional -hazards regression model was used to identify independent prognostic factors. The median follow-up time was 52 months. Results Patients with higher pretreatment serum uPA (≥1 ng/ml) had significantly shorter OS (p = 0.002). Patients with liver cirrhosis, hypoalbuminemia, and thrombocytopenia were significantly more likely to present with elevated uPA levels. Multivariate Cox regression analyses indicated that high pretreatment serum uPA [hazard ratio (HR), 1.848, p = 0.006], vascular invasion (HR, 2.940, p p Conclusions We conclude that uPA is a clinically relevant biomarker in HCC patients receiving curative resection, with higher expression of uPA being associated with higher mortality. This also highlights the potential utility of uPA as a therapeutic target for improved treatment strategies.

BACKGROUND AND AIM This study investigated whether hepatitis B surface antigen (HBsAg) could predict hepatitis B virus (HBV) relapse after cessation of entecavir or tenofovir disoproxil fumarate (TDF) prophylaxis for chronic hepatitis B cancer patients who are undergoing chemotherapy. METHODS The study enrolled 122 hepatitis B e-antigen-negative cancer patients who underwent chemotherapy with entecavir or TDF for antiviral prophylaxis and posttreatment follow-up for at least 6 months. RESULTS Of the 122 patients, 52 and 18 experienced virological and clinical relapse, which had 3-year cumulative incidences of 46.6% and 18.6%, respectively. Multivariate analysis showed that end-of-treatment HBsAg levels and baseline HBV-DNA ≥ 2000 IU/mL were independent predictors of virological relapse. The best HBsAg cutoff value was 500 IU/mL. An end-of-treatment HBsAg of 500 IU/mL was useful for predicting virological relapse in patients with baseline HBV-DNA

Background/Purpose: Metabolic risk factors are associated with liver fibrosis. Whether or not metabolic risk factors affect the severity of liver fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), or risk factors associated with non-alcoholic fatty liver disease (NAFLD) remains unclear. We aimed to investigate this by transient elastography. Methods: In this cross-sectional study, we enrolled 1513 patients who presented with chronic liver disease (CLD) at a tertiary hospital. Liver stiffness measurement (LSM) >13 kPa was used as a cutoff suggesting possible liver cirrhosis (LC). Results: Possible LC was noted in 7.8% of the CHB patients, 19.9% of the CHC patients, and 11.9% of the patients with risk factors associated with NAFLD. After adjustments for biochemical and virological factors were made, BMI (per 1 kg/m2 increase) (OR: 1.17, 95% CI: 1.06–1.29, P = 0.002) was found to be an independent factor associated with possible LC in CHB patients; BMI (per 1 kg/m2 increase) (OR: 1.15, 95% CI: 1.07–1.24, P

Background and Aim. Liver fibrosis is associated with the prognosis of patients with hepatocellular carcinoma (HCC) after resection. The fibrosis-4 (FIB-4) index is an accurate and noninvasive marker to determine the degree of liver fibrosis. Here, we evaluated the effect of pre- and postoperative FIB-4 index in predicting the outcomes after resection of HCC in patients who have chronic hepatitis B (CHB) infection. Methods. A total of 534 CHB patients with HCC who received curative hepatectomy between 2001 and 2016 at Kaohsiung Chang Gung Memorial Hospital, Taiwan, were enrolled in this study. The impact of the FIB-4 index (preoperative and the 1st year after operation) on overall survival (OS) and recurrence-free survival (RFS) was evaluated. Results. There was a significant association between the preoperative FIB-4 index and Metavir fibrosis stage (p<0.01). The multivariate analysis showed that preoperative FIB‐4>2 is an independent risk factor for RFS and OS after HCC curative resection [hazard ratio (HR), 1.902; 95% CI, 1.491–2.460; p<0.001, and HR, 2.207; 95% CI, 1.420–3.429; p<0.001, respectively]. Notably, preoperative FIB-4 is also an independent risk factor for RFS (HR, 1.219; p=0.035) in noncirrhotic patients. Furthermore, patients had deteriorated FIB-4 1 year after operation [definition: the value the 1st year FIB‐4 after operation minus preoperative FIB‐4>1] and had an adverse outcome in RFS and OS (p<0.001, both). Conclusion. The pre and postoperative FIB-4 indexes are useful clinical markers to predict the prognosis in HBV-HCC patients after curative hepatectomy.

This study was done to elucidate the influence of direct-acting antiviral (DAA) agents on the recurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC (HCV-HCC) after curative therapies. HCV-HCC patients who received curative therapies and obtained a complete response were analyzed. From January 2017 to September 2017, 112 HCV-HCC patients received DAA and obtained a sustained virological response (SVR). From January 2006 to December 2014, another 345 HCV-HCC patients received peg-interferon-based treatment and 118 obtained SVR. From January 2012 to December 2016, 248 HCV-HCC patients had complete HCC response and did not receive antiviral treatment. Patients were divided into DAA, IFN, and Untreated groups based on what antiviral treatment they received. There were 82 patients in the DAA group, 80 patients in the IFN group, and 160 patients in the Untreated group. During the follow-up period, the DAA group had 22 (26.8%) recurrent cases, whereas the IFN group had 46 (56.8%) cases after antiviral treatment. Among the 22 recurrent cases in the DAA group, 19 (86.9%) experienced HCC recurrence during 1 year after DAA initiation. Compared with the IFN group, the DAA group had poorer one-year recurrence-free survival (75.4% vs. 95%, p 0.001), even after adjustment with propensity score matching (81.4% vs. 93.9%, p = 0.034). However, DAA was an improving factor for HCC recurrence compared with the Untreated group in the multivariate analysis. Among HCV-HCC patients with complete treatment, those with DAA-induced SVR had a higher one-year recurrence rate than those who received IFN-based antiviral therapy, but DAA did not seem to increase HCC recurrence compared to untreated patients.

WLCSP packaging is wildly use in portable electronic products such as phone, watch, and intelligent bracelet. The advantages of WLCSP package are parasitic inductance minimized, reduced package size, and enhanced thermal conduction characteristics. To enable these benefits regardless of the die's functional complexity, we adopted Cu with ELK (extreme Low-K) material as inter-metal-dielectric native to advanced silicon fabrication technology, and WLCSP packing with large die size, thus fulfilling requirements for high speed & low power consumption. To investigate wafer WLCSP board level reliability performance is essential and critical for successful product launch and preventing field return risk. Test vehicles were used with combinations in PBO2 opening, PCB thickness, and PCB metal gradient, to understand stress on ELK behavior and potential impact on board level reliability. A quick stress test methodology using 75 cycles of -650C~1500C liquid-to-liquid thermal shock (LLTS), showing ~acceleration factor of 1.9 compared with TCB stress, was validated and used for shortening experiment cycle time. A 6x6 mm2 test vehicle was used for different WLCSP package PBO2 opening, PCB thickness and PCB metal design to assess board level reliability impact. LLTS 75cycles result showed larger PBO2 opening will get die edge ELK delamination defects. Higher PCB metal gradient board (more than 50%) & more thick (1mm) also got higher fail rate. For better WLCSP board level reliability structure, smaller WLCSP package PBO2 opening, thinner PCB thickness and uniform PCB metal distribution are recommended.

Flip chip packages with Cu bump have been introduced in recent years to address the needs of advanced packaging for reducing bump pitch and increasing I/O density, which can also enhance performance and offer a cost effective solution with smaller form factor. Moreover, Cu interconnect with extra low-k (ELK) dielectric material was also applied to reduce power consumption and further enhance device performance, especially for advanced silicon nodes. Due to the nature of ELK dielectric material characteristics, it is more sensitive while a flip chip package using Cu bump with ELK dielectric, and subjected to thermal loading conditions. Thermal stresses are induced in Si/package due to the coefficients of thermal expansion (CTE) mismatch among different packaging materials under thermal loading. ELK dielectric delamination/cracking during chip-package-interaction (CPI) related reliability tests, is a primary concern in the advanced Si packaging development and quick thermal cycling (QTC) test has been widely used to assess the CPI reliability performance for newly developed packages. From the past experience, "white bump" issue, which is related to ELK delamination, is mainly caused by excessive ELK stresses, and appeared within 1~3 bump pitches range from die edge or corner due to CTE mismatch between die (~2.8 ppm/oC) and organic substrate (~17 ppm/oC). The previously proposed solutions include die/substrate co-design, substrate selection, underfill/TIM/adhesive materials selection, and heat spreader design. However, more and more QTC test results indicate that the configuration of top metal layout and bump pattern can also affect the ELK reliability significantly. This work investigated advanced Si package ELK reliability performance from die attach (using conventional reflow process) to subsequent QTC tests. A three-dimensional (3-D) nonlinear finite element method is applied, and a two-level of specified boundary condition (SBC) of global-local technique are adopted to achieve more accurate resolution. Meanwhile, modeling results were calibrated with experimental package warpage measurements. The modeling predictions were also compared with QTC test data and obtained good agreements. Based on collected modeling and test data, it was revealed that higher density and more uniform pattern in both top metal and bump layouts could relieve ELK thermal stresses significantly. The proposed methodology in this paper had been validated and design guideline will be proposed upon the findings of this study, which product / package designers can benefit from the superior device / package performance provided from the integration of Cu interconnect and ELK dielectric, meanwhile, alleviate potential CPI related risks while using advanced Si packaging.