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Background/aims No information is available regarding the influence of besifovir (BSV) on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to assess the reduced risk of HCC in patients undergoing BSV treatment. Methods Overall, 188 patients with CHB were treated with BSV for up to 8 years. We assessed the incidence of HCC during follow-up and compared it with the predictive numbers of HCC using models developed from untreated CHB patients. Additionally, we compared the performance of various HCC prediction models developed for patients with CHB receiving antiviral therapy. Results During the follow-up period of 8 years, five patients developed HCC; one of 139 patients with non-cirrhotic CHB, and four of 49 patients with liver cirrhosis. We compared the HCC incidence in non-cirrhotic patients with the predicted number derived from the REACH-B model. The standardized incidence ratio (SIR) was 0.128 (P = 0.039) at 7 years, suggesting a significant decrease in HCC incidence in non-cirrhotic CHB patients. The incidence of HCC in patients with cirrhosis was compared using the GAG-HCC model, and the SIR was 0.371 (P = 0.047) at 7.5 years, suggesting a significantly decreased HCC incidence. When we compared several HCC prediction models developed for CHB patients under antiviral therapy, the HCC-RESCUE model showed the highest area under the curve (0.924). Conclusions BSV decreases the risk of HCC in patients with CHB, with or without liver cirrhosis. HCC prediction was available for BSV-treated patients using the existing prediction models. Clinical trial registry website and trial number: ClinicalTrials.gov no: NCT01937806.

Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml−1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg (P = 0.001), but not for the bepirovirsen 150 mg group (P = 0.245) or participants receiving stable NA therapy (P = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n = 3) or day 36 (n = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population., A first-in-human study of an antisense oligonucleotide targeting hepatitis B virus (HBV) RNA provides initial insights into this potential new therapeutic modality for individuals with chronic HBV infection.

Background Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins. Methods We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Groups 1, 2, and 3 received loading doses of bepirovirsen. The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication. Results The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4). Conclusions In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HBV infection. Larger and longer trials are required to assess the efficacy and safety of bepirovirsen. (Funded by GSK; B-Clear ClinicalTrials.gov number, NCT04449029.)

Acinar cell cystadenoma, also known as an acinar cystic transformation of the pancreas, is an exceedingly rare but benign pancreatic lesion. A 51-year-old woman was transferred to Inje University Busan Paik Hospital because of an 8 cm-sized calcified, multiseptated, and multilocular cystic mass in the pancreatic tail observed during abdominal CT performed at another hospital. The patient did not complain of abdominal pain or other symptoms, and her laboratory findings were normal. MRI showed that the cyst was not connected to the main pancreatic duct. A pancreatic serous cystadenoma was suspected, and a laparoscopic distal pancreatectomy was performed. The resected mass was composed of variable sized multilocular cysts with incomplete septa and focally lined by epithelium with acinar differentiation. The patient was diagnosed with acinar cell cystadenoma and is currently being followed up regularly. No complications or recurrences have been observed.

Purpose The establishment of a preclinical model of the abscopal effect on hepatocellular carcinoma (HCC) and evaluation of whether the hypofractionated radiation therapy (RT) multitumor Hepa1-6 mouse HCC model could be used to suppress nonradiated tumor mass was performed in this study. Methods and Materials Hepa1-6 mouse liver cancer cell lines were used to form tumors. Immunogenicity was analyzed using ELISpot and immune cell labeled antibody. Interferon (IFN) β expression was confirmed through polymerase chain reaction. Results After investigation, the intratumoral transcription of type Ⅰ IFN increased by 2-fold. The antitumor immune response to Hepa 1-6 cells induced by radiation was increased. Moreover, the influx of activated CD8+ T cells was increased in nonirradiated tumors. The number of dendritic cells and activation status were evaluated by flow cytometry on the second day after irradiation. Flow cytometry revealed a significantly increased dendritic cell population expressing the CD11c molecule in tumor-draining lymph nodes. Furthermore, because irradiation leads to adaptation of immune resistance of tumor cells against RT, we sought to elucidate a potent tool to overcome the resistance and confirm the ability of PD-L1 antibody to survive late RT resistance. Conclusions The immunologic mechanism of the abscopal effect was revealed and the application of PD-L1 inhibitor successfully performed as a breakthrough in late RT resistance in the Hepa1-6 tumor model.

Background/aims Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, shows potent antiviral activity against hepatitis B virus (HBV). Our previous 48-week trial revealed that BSV has comparable antiviral efficacy to tenofovir disoproxil fumarate (TDF) and better safety profiles in terms of improved renal and bone safety. This extension study evaluated the prolonged efficacy and safety of BSV in treatment-naive chronic hepatitis B patients. Methods Patients continued to participate in an open-label BSV study after an initial 48-week double-blind comparison of BSV and TDF treatment. The antiviral efficacy and drug safety was evaluated up to 192 weeks in two groups: patients continuing BSV treatment (BSV-BSV) and patients switching from TDF to BSV after 48 weeks (TDF-BSV). Results Among 197 patients receiving randomized treatments, 170 (86%) entered the open-label phase and 152 (77%) entered the 192-week extension study. Virological response rates over 192 weeks were 92.50% and 93.06% in the BSV-BSV and TDF-BSV groups, respectively (p = 0.90). Hepatitis B envelop antigen seroconversion and alanine aminotransferase normalization rates were similar between the groups (p = 0.75 and p = 0.36, respectively). There were no drug-resistant mutations to BSV. Bone mineral density and renal function were well preserved in the BSV-BSV group, whereas these initially worsened then recovered after switching therapy in the TDF-BSV group. Conclusions BSV maintained potent antiviral efficacy after 192 weeks and showed no evidence of drug resistance. BSV was safe, well tolerated, and effective in patients who switched from TDF to BSV. Trial Registration Number: NCT01937806 (Date: September 10, 2013).

INTRODUCTION: Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV). METHODS: After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL). RESULTS: Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients. DISCUSSION: This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.

Tax authorities in developed countries agree that their governments should take action to eliminate treaty shopping, but disagree on what such action should be. Cancellation or renegotiation of existing tax treaties is two obvious alternatives. However, in order to determine which treaty network is most effective to block, the effects of blocking the treaty shopping routes should be calculated. In this paper, we measure the effects of blocking certain routes of treaty shopping in the tax treaty network. The basic model used in our research is the optimal treaty shopping route model established in a previous study. We ran the model using a few route blocking scenarios: Scenario I involves blocking tax haven routes, Scenario II involves blocking routes where the treaty tax rate is zero, and Scenario III involves blocking routes including countries with zero domestic withholding tax rates. We then compared the effectiveness of these blocking measures by assessing the results of changes in the network due to blocking in each of these scenarios. Scenario II proved to be the most effective, and blocking multiplex routes turned out to be more effective than blocking single routes. We also confirmed that blocking tax haven routes is not adequate to prevent tax avoidance. In addition, we discovered that the interests of developed nations and developing nations differ regarding tax revenue. However, not all developed countries share common interests. Our research quantifying the effectiveness of ways of blocking treaty shopping routes and differences in interest relations among nations provides useful information.JEL Classification E62·F21·F23·F53·H25·H26·H73·H87·K34

Background Dysbiosis of ulcerative colitis (UC) has been frequently investigated using readily accessible stool samples. However, stool samples might insufficiently represent the mucosa-associated microbiome status. We hypothesized that luminal contents including loosely adherent luminal bacteria after bowel preparation may be suitable for diagnosing the dysbiosis of UC. Methods This study included 16 patients with UC (9 men and 7 women, mean age: 52.13 ± 14.09 years) and 15 sex- and age-matched healthy individuals (8 men and 7 women, mean age: 50.93 ± 14.11 years). They donated stool samples before colonoscopy and underwent luminal content aspiration and endoscopic biopsy during the colonoscopy. Then, the composition of each microbiome sample was analyzed by 16S rRNA-based next-generation sequencing. Results The microbiome between stool, luminal contents, and biopsy was significantly different in alpha and beta diversities. However, a correlation existed between stool and luminal contents in the Procrustes test (p = 0.001) and Mantel test (p = 0.0001). The stool microbiome was different between patients with UC and the healthy controls. Conversely, no difference was found in the microbiome of luminal content and biopsy samples between the two subject groups. The microbiome of stool and lavage predicted UC, with AUC values of 0.85 and 0.81, respectively. Conclusion The microbiome of stool, luminal contents, and biopsy was significantly different. However, the microbiome of luminal contents during colonoscopy can predict UC, with AUC values of 0.81. Colonoscopic luminal content aspiration analysis could determine microbiome differences between patients with UC and the healthy control, thereby beneficial in screening dysbiosis via endoscopy. Trial registration: This trial was registered at http://cris.nih.go.kr. Registration No.: KCT0003352), Date: 2018–11-13.

Due to antimicrobial resistance and the adverse health effects that follow broad and inappropriate use of antibacterial agents, new classes of antibacterials with broad and strong bactericidal activity and safety for human use are urgently required globally, increasingly so with the onset of climate change. However, R&D in this field is known to be rarely profitable, unless a cost-effective, flexible, and convenient platform that ensures the production of workable candidate antibacterials can be developed. To address this issue, inorganic nanomaterials have been considered for their bactericidal activities, yet further investigations of composition crystalline modifications and/or surface biomaterial coatings are still required to provide effective and safe antibacterial nanoparticles. In this study, we developed a plug-in system comprising a spark plasma reactor and a flow heater under nitrogen gas flow to supply precursor inorganic nanoparticles (Cu-Te configuration) that can be modulated in-flight at different temperatures. From antibacterial and toxicological assays in both in vitro and in vivo models, bactericidal and toxicological profiles showed that the plug-in system-based platform can be used to identify key parameters for producing safe-by-design agents with antibacterial activity [>88% (in vitro) and >80% (in vivo) in antibacterial efficiency] and safety (>65% in in vitro viability and >60% in in vivo survival rate).

Background/Aims To examine whether visceral adiposity serves as a risk factor for colorectal cancer (CRC) and colorectal adenomas. Methods Two hundred healthy subjects, 200 patients with colorectal adenoma, and 151 patients with CRC (46 with early-stage and 105 with advanced-stage cancers) were enrolled at a tertiary referral hospital. All subjects underwent colonoscopy, and had laboratory data, and computed tomography (CT) scan available for abdominal fat measurement. An abdominal CT scan taken 1 to 4 years (mean interval, 20.6 months) before the diagnosis of CRC was also available in the 42 CRC patients. Results The mean areas of visceral adipose tissue (VAT) areas in the control, adenoma, early- and advanced-stage CRC groups were 94.6, 116.8, 110.4, and 99.7 cm2, respectively (P0.05). The risk of both adenoma and CRC positively correlated with fasting plasma glucose levels (P for trend

Pigment epithelium-derived factor (PEDF)–derived 34-mer peptide (PEDF34, Asp44-Asn77) has anti-angiogenic activity but has limitations in clinical application because of an inverted bell–shaped dose-effect relationship and a short half-life. In this study, we attempted to mitigate these problems by mixing PEDF34 with type I collagen. The anti-angiogenic activity of the PEDF34/atelocollagen mixture was evaluated by HUVEC tube formation assay and in a laser-induced choroidal neovascular (CNV) mouse model. PEDF34 and/or collagen were administrated using intravitreal injections or eye drops. CNV lesion size was quantified using FITC-dextran-perfused retinal whole mounts. Western blot analysis and inhibitor assays were used to define the action mechanisms of PEDF34 and the mixture. Collagen broadened the effective dose range of PEDF34 in the tube formation assay by > 250 times (from 0.2 to 50 nM). In the CNV model, five intravitreal injections of PEDF34 were required for therapeutic effect, whereas the mixture had a significant therapeutic effect following a single injection. Eye drops of the mixture showed significantly stronger CNV-suppressive effects than drops of PEDF34 alone. The anti-angiogenic activity of PEDF34 might be mediated by inhibition of ERK and JNK activation by VEGF, and collagen potentiated these effects. Collagen can serve as a carrier and reservoir of PEDF34. PEDF peptide/collagen mixture is easy to prepare than conventional methods for maintaining the therapeutic effect of PEDF peptide.

The Janus tyrosine kinase and signal transducers and activators of transcription (JAK/STAT) pathway is involved in vascular endothelial growth factor (VEGF) expression, but the role of this pathway in diabetic retinopathy (DR) remains unclear. We investigated the role of the JAK/STAT pathway on DR and VEGF expression using a streptozotocin (STZ)-induced DR mouse model.Cultured ARPE-19 cells were exposed to high-glucose conditions and treated with JAK/STAT inhibitors (JAK inhibitor I [JAKiI], tofacitinib, STAT3 inhibitor [STAT3i]) for 48 h. Reverse-transcription polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to investigate p-JAK/STAT and VEGF expression. Diabetes was induced by intraperitoneal injection of STZ (50 mg/kg) in C57BL/6 mice for 5 days. DR development was evaluated every 4 weeks. JAK/STAT inhibitors were administered for 8 weeks. Immunofluorescence was used to measure the activation status of the JAK/STAT pathway and VEGF production in the retinal tissue.In ARPE-19 cells exposed to high-glucose conditions, the mRNA and secretory protein levels of VEGF, p-JAK1, p-JAK2, p-STAT3, and p-STAT5 levels were significantly increased. Treatment with JAKiI, tofacitinib, and STAT3i significantly suppressed VEGF to basal levels at both the mRNA and secretory levels in vitro. In STZ-induced mice, retinal vascular leakage, p-JAK1, p-JAK2, p-JAK3, p-STAT3, and VEGF were significantly increased after diabetes induction. Diabetes-induced retinal vascular leakage was significantly reduced by treatment with JAKiI and tofacitinib. Increased p-JAK1 and VEGF in STZ-induced mice were significantly reduced by JAKiI (p 0.05, p 0.001) and tofacitinib (p 0.001, respectively).JAK1 may be more involved in VEGF production and DR progression in mice than JAK2, JAK3, and STAT3.

Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection.This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 logParts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 logGSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified.NCT03020745.Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.

Background: Dysbiosis of ulcerative colitis (UC) has been frequently investigated using readily accessible stool samples. However, stool samples might insufficiently represent the mucosa-associated microbiome status. We hypothesized that luminal contents including loosely adherent luminal bacteria after bowel preparation may be suitable for diagnosing the dysbiosis of UC.Methods: This study included 16 patients with UC (9 men and 7 women, mean age: 52.13 ± 14.09 years) and 15 sex- and age-matched healthy individuals (8 men and 7 women, mean age: 50.93 ± 14.11 years). They donated stool samples before colonoscopy and underwent luminal content aspiration and endoscopic biopsy during the colonoscopy. Then, the composition of each microbiome sample was analyzed by 16S rRNA-based next-generation sequencing.Results: The microbiome between stool, luminal contents, and biopsy was significantly different in alpha and beta diversities. However, a correlation existed between stool and luminal contents in the Procrustes test (p = 0.001) and Mantel test (p = 0.0001). The stool microbiome was different between patients with UC and the healthy controls. Conversely, no difference was found in the microbiome of luminal content and biopsy samples between the two subject groups. The microbiome of stool and lavage predicted UC, with AUC values of 0.85 and 0.81, respectively.Conclusion: The microbiome of stool, luminal contents, and biopsy was significantly different. However, the microbiome of luminal contents during colonoscopy can predict UC, with AUC values of 0.81. Colonoscopic luminal content aspiration analysis could determine microbiome differences between patients with UC and the healthy control, thereby beneficial in screening dysbiosis via endoscopy. Trial registration: This trial was registered at http://cris.nih.go.kr.Registration No.: KCT0003352), Date : 2018-11-13

Conventional RGB sub-pixel layout for displays has low geometric fill factor, which show limitations in application for high resolution and efficiency improvement. Color-tunable pixel, which can reproduce various colors with a single pixel, can be an innovative approach to improve the fill factor issue. The bilayered emission layer (EML) structure is a method to implement the color-tunable pixels. However, a simple bilayer structure exhibit limited color-tuning range. Thus, color-modulation layer (CML) insertion between EMLs is essential to control the carrier distribution. CML materials are usually dissolved in organic solvent for solution process. Here, a process issue occurs as organic solvents can damage the previous QD layer. In this research, we analyze the effects of various organic solvents on the QD layer and suggest the most suitable solvent that minimizes the damage. The bilayer QD-LED structure is ITO/PEDOT:PSS/PVK/green QD(CdSe@ZnS)/organic solvents/red QD(CdSe@ZnS)/ZnO/Al. Toluene, chlorobenzene, 1,4-dioxane, and n-octane are used for organic solvent process and deposited on the QD layer. The current density and the luminance of the device without solvent process and with toluene, 1,4-dioxane, and n-octane process are (99.5 mA/cm2 and 908 cd/m2), (63.7 mA/cm2 and 490 cd/m2), (63.1 mA/cm2 and 304 cd/m2), and (43 mA/cm2 and 200 cd/m2), respectively, at 9.5V. These results indicate that toluene, 1,4-dioxane, and n-octane process caused severe damage on the green QD layer. However, current density and luminance of chlorobenzene process are 208.8 mA/cm2, 934 cd/m2, respectively, at 8V. Moreover, chlorobenzene treated device showed even wider color-tuning range than the one without solvent process. Therefore, chlorobenzene is the most suitable solvent for the CML..

Widely tunable color emission from a single pixel is a promising but challenging technology for quantum-dot light-emitting diodes (QD-LEDs). Even a QD-LED pixel with stacked multi-QD layers having different colors is likely to emit a monotonic color because the exciton recombination mostly occurs in 1 or 1.5 QD layers with better charge balance. In this study, an all-solution-processed QD-LED with electrically tunable color emission over a wide color range by introducing a charge modulation layer (CML) is developed. Specifically, the CML acted as a high and narrow energy barrier for electrons between two QD layers, and the electron drift is sensitively controlled via the field-dependent tunneling effect. Therefore, the charge distribution and balance in the two QD layers re-electrically tunable, which enhanced the color tunability. The color tuning range and quantum efficiency are effectively controlled depending on the CML material and thickness. In addition, the color change caused by the solvent effect in a QD-LED with dual QD layers is thoroughly investigated. The proposed method may advance the understanding of QD emission behavior with the use of CML and provide a practical approach for the actual application of color-tunable pixel technology.

Background The advancement of treatment with direct-acting antiviral (DAA) agents has improved the cure rate of hepatitis C virus (HCV) infection close to 100%. The aim of our study was to assess the real-world effectiveness and safety of DAA regimens for the treatment of patients with chronic HCV genotype 2. Methods We retrospectively analyzed the clinical data of patients treated with sofosbuvir plus ribavirin (SOF + RBV) or glecaprevir/pibrentasvir (G/P) for chronic HCV genotype 2 infection at seven university hospitals in the Korean southeast region. Results SOF + RBV therapy produced an 89% and 98.3% sustained virologic response 12 week (SVR12) after treatment completion in the full analysis set and per-protocol set, respectively, and the corresponding values for G/P therapy were 89.5% and 99.2%, respectively. The difference between the treatments was probably because 6.2% (59/953) of patients in the SOF + RBV group did not complete the treatment and 9.8% (14/143) in the G/P group did not test HCV RNA after treatment completion. Adverse events (A/Es) were reported in 59.7% (569/953) and 25.9% (37/143) of the SOF + RBV and G/P groups, respectively. In the SOF + RBV group, 12 (1.26%) patients discontinued treatment owing to A/Es, whereas no patients discontinued treatment because of A/Es in the G/P group. Conclusion In both treatment groups, SVR was high when treatment was completed. However, there was a high dropout rate in the SOF + RBV group, and the dropout analysis showed that these were patients with liver cirrhosis (LC; 43/285, 15.1%), especially those with decompensated LC (12/32, 37.5%). Therefore, an early initiation of antiviral therapy is recommended for a successful outcome before liver function declines. Furthermore, patients with decompensated LC who are considered candidates for SOF + RBV treatment should be carefully monitored to ensure that their treatment is completed, especially those with low hemoglobin and high alanine transaminase., Graphical Abstract

We demonstrate a novel structure for a quantum-dot light-emitting diode (QD-LED) with wide-range colour-tuneable pixels, fabricated via full solution processing. The proposed device has a symmetrical structure produced via stacking of an inverted-structure diode with a green QD emission layer (EML) and normal-structure diode with a red QD EML. It is an electron-only device; however, a charge generation layer in the middle of the device generates holes for the formation of excitons. Depending on the polarity of the applied voltage, either the bottom inverted unit or the top normal unit is operated, thereby emitting green or red light, respectively. The working mechanism of the device is investigated via analysis of the charge generation mechanism and carrier transport path. In addition, the colour tunability is verified using a simple alternating current (AC) driving scheme; the duty cycle modulation of the AC signal enables fine colour adjustment over a broad range, from pure green to pure red. Thus, our colour-tuneable QD-LED with vertically stacked independently operated sub-pixels can open a promising pathway towards cost-effective ultra-high-resolution displays.

Safe-by-design principles, such as optimum balance of material function and safety, have received much recent attention. On-demand production is also receiving great interest in the realization of nanotechnologies that meet unpredictable demands of reconfiguration and modification to maximize the efficacy of materials processing. Antimicrobial nanomaterials are representative subjects of these approaches, because they require built-to-order configurations with safe-by-design principles for practical applications. However, few studies have achieved biosafety with original material function using economically feasible production platforms. In this regard, we developed a safe-by-design plug-and-play approach for continuous gas flow production of silver (or copper)-doped tellurium (Ag- or Cu–Te) nanoparticles with safer antimicrobial activity. Using this approach, we achieved precise modulation of dopant contents (5–8% atomic Ag and Cu) in nanoparticles without using batch hydrothermal chemistry. We also suggest the use of ratios between biocompatibility and antimicrobial activity as safety indices (SIs) for evaluations of nanoparticle applications. Approximately 6% atomic Ag in Ag–Te particles exhibited an optimal SI and significantly reduced the minimum inhibitory concentration of individual Te nanoparticles.

Background/Aims: Sessile serrated adenomas (SSAs) are known to be precursors of colorectal cancer (CRC). The proper interval of follow-up colonoscopy for SSAs is still being debated. We sought to determine the proper interval of colonoscopy surveillance in patients diagnosed with SSAs in South Korea. Methods: We retrospectively reviewed the medical records of patients diagnosed with SSAs who received 1 or more follow-up colonoscopies. The information reviewed included patient baseline characteristics, SSA characteristics, and colonoscopy information. Results: From January 2007 to December 2011, 152 SSAs and 8 synchronous adenocarcinomas were identified in 138 patients. The mean age of the patients was 62.2 years and 60.1% patients were men. SSAs were located in the right colon (i.e., from the cecum to the hepatic flexure) in 68.4% patients. At the first follow-up, 27 SSAs were identified in 138 patients (right colon, 66.7%). At the second follow-up, 6 SSAs were identified in 65 patients (right colon, 66.7%). At the 3rd and 4th follow-up, 21 and 11 patients underwent colonoscopy, respectively, and no SSAs were detected. The total mean follow-up duration was 33.9 months. The mean size of SSAs was 8.1±5.0 mm. SSAs were most commonly found in the right colon (126/185, 68.1%). During annual follow-up colonoscopy surveillance, no cancer was detected. Conclusions: Annual colonoscopy surveillance is not necessary for identifying new CRCs in all patients diagnosed with SSAs. In addition, the right colon should be examined more carefully because SSAs occur more frequently in the right colon during initial and follow-up colonoscopies. (Intest Res 2018;16:134-141)

Pulmonary fibrosis, a potentially fatal disease, results from acute and chronic interstitial lung diseases. Fucoxanthin (Fx), a carotenoid found in brown seaweed, shows a wide range of pharmacological activities. In this study, we investigated the antifibrotic effects of fucoxanthin and their underlying molecular mechanisms in transforming growth factor-beta1 (TGF-β1)-stimulated human pulmonary fibroblasts (HPFs). Thus, the effects of Fx on TGF-β1-induced expression of fibrotic factors, such as alpha-smooth muscle actin (α-SMA), type 1 collagen, fibronectin, and interleukin-6 (IL-6), in HPFs were investigated. We performed an enzyme-linked immunosorbent assay (ELISA), and a western blot analysis to elucidate the mechanisms underlying the antifibrotic effects of Fx in TGF-β1-stimulated cells. The contractile activity of HPFs was measured using a collagen gel contraction assay. We also investigated the effects of Fx on inflammation and fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. We observed that Fx inhibited the TGF-β1-induced expression of α-SMA, type 1 collagen, fibronectin, and IL-6 in HPFs. Similarly, markedly inhibition of TGF-β1-induced phosphorylation of p-38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and Smad2/Smad3 (Smad2/3) was observed after Fx treatment. Collagen contraction also significantly decreased on fucoxanthin treatment. Intraperitoneal injection of Fx (10mg/kg) in mice inhibited BLM-induced lung fibrosis and type I collagen protein expression. Overall, our findings suggest that Fx may be effective in the treatment of pulmonary fibrosis owing to its potent antifibrotic activity.

The international tax treaty system is a highly integrated and complex network. In this system, many multinational enterprises (MNEs) explore ways of reducing taxes by choosing optimal detour routes. Treaty abuse by these MNEs causes significant loss of tax revenues for many countries, but there is no systematic way of regulating their actions. However, it may be helpful to find a way of detecting the optimal routes by which MNEs avoid taxes and observe the effects of this behavior. In this paper, we investigate the international tax treaty network system of foreign investment channels based on real data and introduce a novel measure of tax-routing centrality and other centralities via network analysis. Our analysis of tax routing in a multiplex network reveals not only various tax-minimizing routes and their rates, but also new paths which cannot be found by navigating a single network layer. In addition, we identify strongly connected components of the multiplex tax treaty system with minimal tax shopping routes; more than 80 countries are included in this system. This means that there are far more pathways to be observed than can be detected on any given individual single layer. We provide a unified framework for analyzing the international tax treaty system and observing the effects of tax avoidance by MNEs.

We report a new approach to the synthesis of molybdenum disulfide (MoS 2 ) quantum dots (QDs) that uses a single layer MoS 2 grown by chemical vapor deposition (CVD) method as a precursor. The MoS 2 QDs were formed by a thermal annealing process at 500 °C for 70 h to reduce the particle size. The results indicated that CVD-MoS 2 covered almost area of the substrate, which showed a typical single layer thickness and 2H-MoS 2 structure. A blue shift from 682 nm to 548 nm wavelength was observed in the photoluminescence (PL) spectra. It shows a successful formation of QDs with 4–7 nm small size from the large sized layers. This process is relatively easy for defining MoS 2 QDs with a density of 10 11 cm -2 and shows potential advantages for the fabrication of a wide range of electrical optical devices using QDs.