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Background: Patients with Barcelona clinic liver cancer (BCLC) stage B hepatocellular carcinoma (HCC) are considerably heterogeneous in terms of tumor burden, liver function, and performance status. To improve the poor survival outcomes of these patients, treatment approaches other than transarterial chemoembolization (TACE), which is recommended by HCC guidelines, have been adopted in real-world clinical practice. We hypothesize that this non-adherence to treatment guidelines, particularly with respect to the use of liver resection, improves survival in patients with stage B HCC., Aim: To assess guideline adherence in South Korean patients with stage B HCC and study its impact on survival., Methods: A retrospective analysis was conducted using data from 2008 to 2016 obtained from the Korea Central Cancer Registry. Patients with stage B HCC were categorized into three treatment groups, guideline-adherent, upward, and downward, based on HCC guidelines recommended by the Asian Pacific Association for the Study of the Liver (APASL), the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD). The primary outcome was HCC-related deaths; tumor recurrence served as the secondary outcome. Survival among the groups was compared using the Kaplan-Meier method and the log-rank test. Predictors of survival outcomes were identified using multivariable Cox regression analysis., Results: In South Korea, over the study period from 2008 to 2016, a notable trend was observed in adherence to HCC guidelines. Adherence to the EASL guidelines started relatively high, ranging from 77% to 80% between 2008 and 2012, but it gradually declined to 58.8% to 71.6% from 2013 to 2016. Adherence to the AASLD guidelines began at 71.7% to 75.9% from 2008 to 2010, and then it fluctuated between 49.2% and 73.8% from 2011 to 2016. In contrast, adherence to the APASL guidelines remained consistently high, staying within the range of 90.14% to 94.5% throughout the entire study period. Upward treatment, for example with liver resection, liver transplantation, or radiofrequency ablation, significantly improved the survival of patients with BCLC stage B HCC compared to that of patients treated in adherence to the guidelines (for patients analyzed according to the 2000 EASL guidelines, the 5-year survival rates were 63.4% vs 27.2%, P < 0.001), although results varied depending on the guidelines. Progression-free survival rates were also significantly improved upon the use of upward treatments in certain groups. Patients receiving upward treatments were typically < 70 years old, had platelet counts > 10 5 /μL, and serum albumin levels ≥ 3.5 g/dL., Conclusion: Adherence to guidelines significantly influences survival in South Korean stage B HCC patients. Curative treatments outperform TACE, but liver resection should be selected with caution due to disease heterogeneity., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Directional differentiation of stem cells is a key step in stem cell therapy. In this study, we developed saponin-based nanoparticles (Ad-SNPs) containing dexamethasone (Dex) and alpha-lipoic acid (ALA) to promote osteogenic differentiation of human mesenchymal stem cells (hMSCs) and bone regeneration. The Ad-SNPs can achieve rapid cellular uptake through a pore-forming effect without cytotoxic cationic charges. They also provide extended retention in cell cytosol due to their uptake route. These properties are advantageous in efficiently supplying drugs to the hMSCs. The combination of Dex and ALA facilitated mitochondrial fusion and prevented reactive oxygen species-induced DNA damage. It also helped to preserve mitochondrial dynamics, and the efficient supply of it provided by the Ad-SNPs induced differentiation of hMSCs into osteoblasts. The Ad-SNPs showed outstanding performance in osteoblast differentiation, maturation, and mineralization in 3D culture compared with NPs without saponin and with free drugs. When Ad-SNP-treated hMSCs were tested in a rat femoral bone defect model, they showed the fastest regeneration of bones and complete repair in the shortest period among all groups. To the best of our knowledge, this study is the first application of pore-forming saponin-based NPs with rapid cellular uptake and extended retention to stem cell therapy, and we demonstrated their promising potential in bone regeneration and efficient delivery of Dex and ALA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Heebeom Koo reports financial support was provided by Korea Ministry of Science and ICT. Heebeom Koo reports financial support was provided by Korean Ministry of Health & Welfare. Ji Sun Park reports financial support was provided by Korea Ministry of Science and ICT. Heebeom Koo reports financial support was provided by Catholic Medical Center of the Catholic University of Korea. Heebeom Koo has patent pending to The Catholic University of Korea., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Aims: HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase., Approach and Results: We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log 10 IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively ( p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase

Competing Interests: SGL has received grants from Gilead Sciences, Abbott Diagnostics, and Sysmex; consulting fees for participation on advisory boards from Janssen, Roche, Fibronostics, Gilead, GSK, Sysmex, Assembly, Arbutus, and Grifols; and payments for participation in speakers' bureau from Gilead Sciences, Janssen, Roche, Sysmex, and GSK. SGL is an Asia Pacific regional advisor to AASLD; an ICE-HBV governing board member; an HBV Forum board member; a scientific advisory board member of ANRS; and chairman of Singapore Hepatology Conference and Science of HBV Cure Conference, all of which are unpaid.

Introduction: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population., Methods: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment., Results: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77)., Conclusion: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background & Aims: Antiviral therapy may attenuate the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to explore how tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) affect HCC risk in patients with CHB., Methods: The REACH-B, aMAP, and mPAGE-B models were utilized to assess HCC risk in patients with CHB from two global randomized-controlled trials evaluating the impact of TAF vs. TDF treatment. Standard incidence ratios (SIRs) were calculated using data from the REACH-B model as a ratio of observed HCC cases in the TAF- or TDF-treated patients vs. predicted HCC cases for untreated historical controls. Proportions of treated patients shifting aMAP and mPAGE-B risk categories between baseline and Week 240 were calculated., Results: Of the 1,632 patients (TAF, n = 1,093; TDF, n = 539) followed for up to 300 weeks, 22 HCC cases developed. Those receiving TAF had an SIR that was lower compared to the SIR of individuals receiving TDF: 0.32 ( p <0.001) vs. 0.56 ( p  = 0.06). In the general study population, individuals without cirrhosis at baseline had an SIR that was lower compared to the SIR of individuals with cirrhosis at baseline: 0.37 ( p <0.001) vs. 0.58 ( p  = 0.15). Of the patients at low risk of HCC at baseline, the majority (97%) remained low risk by mPAGE-B and aMAP scoring at Week 240. Among those at medium or high risk at baseline, substantial portions shifted to a lower risk category by Week 240 (mPAGE-B: 22% and 42%; aMAP: 39% and 63%, respectively)., Conclusions: This evaluation provides evidence that treatment with TAF or TDF can reduce HCC risk in patients with CHB, particularly in patients without cirrhosis., Impact and Implications: Despite the substantial impact of HCC on long-term outcomes of patients with CHB, the differential risk of HCC development among those receiving treatment with TAF vs. TDF has not been well elucidated. Using three validated risk prediction models, we found that TAF is at least as effective as TDF in reducing HCC risk in patients with CHB. While TDF is well-studied in the context of HCC risk reduction, our novel findings underscore the effectiveness of TAF as a treatment option for patients with CHB., Clinical Trial Numbers: NCT01940341; NCT02836249; NCT01940471; NCT02836236., Competing Interests: AJH: There are no financial disclosures for this author. CP: Has served as a speaker for Gilead and received research grants from Gilead. DRS: There are no financial disclosures for this author. EG: Member of scientific advisory boards for AbbVie, Abbott Diagnostics, Aligos, Arbutus, Arrowhead, Assembly, Avalia, Clear B Therapeutics, Dicerna, Enanta, Gilead Sciences, GSK, Intellia, Janssen, Merck, Novartis, Genentech-Roche, Vaccitech, Ventorx, Vir Bio and Virion Therapeutics. FA: Gilead Sciences employee and stock ownership. HJ: Received grants from: AbbVie, Gilead Sciences, GSK, Janssen, Roche, Vir Biotechnology Inc. Is a consultant for: Aligos, Antios, Arbutus, Eiger, Gilead Sciences, GSK, Janssen, Merck, Roche, VBI Vaccines, Vir Biotechnology Inc., Viroclinics. HC: Has served as an advisor for Aligos, Arbutus, Hepion, Janssen, Gilead, GSK, Roche, Vaccitech, Vir Biotechnology, Virion Therapeutic, and as a speaker for Gilead, Roche, and Mylan. HW: Employee and stockholder for Gilead. JF: Employee and stockholder for Gilead. JK: Consultant for Abbvie, Abbott, Gilead Sciences, Roche and Sysmex. On speaker’s bureaus for Abbvie, Bristol-Myers Squibb, Gilead Sciences, and Fujirebio. JH: Has received consulting fee from AbbVie, Arbutus, Bristol Myers Squibb, Gilead Sciences, Johnson & Johnson, Roche and received grants from Bristol Myers Squibb and Johnson & Johnson. KA: Aligos, Assembly, Bluejay, BMS, BI, DrugFarm, Gilead, GSK, Janssen, Merck, Roche, Sobi. LJY: Employee of Gilead Sciences and own stock in Gilead Sciences. MB: Has served as an advisor for Abbvie, Arbutus, Assembly, Janssen, Gilead, GSK, Roche, and as a speaker for Gilead and Abbvie. MBr: Speakers Bureau for AbbVie and Gilead. Advisory for AbbVie, Gilead, Janssen, Roche, EISAI-MSD. NI: There are no financial disclosures for this author. QN: Has served as a consultant for BMS, GSK, MSD, and Novartis. SHA: Has acted as advisors and investigator for Gilead, Janssen, AbbVie, Roche, Assembly Biosciences, Arbutus, Brii, Vaccitech, GSK, Inovio, Aligos, Vir Biotechnology, SL Vaxigen, GeneOne Life Science, GreenCross, Yuhan, Samil and Ildong. SF: Has received research support from Gilead. Consultant for Abbvie, Assembly Bio, Janssen, and Gilead. Teacher and speaking for Abbvie and Gilead. SGL: Speakers bureau for Gilead, Janssen, Roche, Sysmex. Advisory board for Gilead, Abbott, Roche, GSK, Janssen, Sysmex, Springbank, Arbutus, Assembly, Grifols, Eisai. Research support from Gilead, Abbott, Roche, Sysmex, Fibronostics, Merck. TTC: There are no financial disclosures for this author. WLC: Member of Advisory Board for Gilead, AbbVie, BMS, Roche, and PharmaEssentia. Speaker for Gilead, AbbVie, BMS, Roche, PharmaEssentia. WKS: Received speaker’s fees from Mylan and AstraZeneca, is an advisory board member of Abbott, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees and research funding from Gilead Sciences. YSL: Advisor/consultant/speaker for AbbVie, Assembly Biosciences, Bayer Healthcare, GlaxoSmithKline, Gilead Sciences, Janssen, Olix Pharmaceuticals, Roche, Vaccitech, and Vir Biotechnology; and received grant/research support from Gilead Sciences. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

HDV is a defective virus that uses the HBV surface antigen to enter hepatocytes. It is associated with an accelerated course of liver fibrosis progression and an increased risk of hepatocellular carcinoma. Negative HDV RNA 24 weeks after the end of therapy has been proposed as an endpoint but late relapses make this endpoint suboptimal, hence HBsAg loss appears to be more appropriate. Current HBV antiviral agents have poor activity against HDV hence the search for improved therapy. Drugs only active against HDV, such as lonafarnib, have shown efficacy in combination with nucleoside analogues and peginterferon, but do not lead to HBsAg loss. HBsAg loss sustained 24 weeks after the end of therapy with negative HBV DNA is termed functional cure. Agents that are being investigated for functional cure include those that inhibit replication such as entry inhibitors, polymerase inhibitors and capsid assembly modulators but seldom lead to functional cure. Agents that reduce HBV antigen load such as RNA interference and inhibitors of HBsAg secretion are promising. Immunomodulators on their own seldom achieve functional cure, hence these agents in combination to assess the optimal combination are being investigated. Consequently, agents leading to functional cure of HBV are ideal for both HBV and HDV., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The sense of spiciness is related to the stimulation of vanilloid compounds contained in the foods. Although, the spiciness is commonly considered as the part of taste, it is more classified to the sense of pain stimulated on a tongue, namely, pungency, which is described as a tingling or burning on the tongue. Herein, first, a reusable electronic tongue based on a transient receptor potential vanilloid 1 (TRPV1) nanodisc conjugated graphene field-effect transistor is fabricated and spiciness-related pain evaluation with reusable electrode is demonstrated. The pungent compound reactive receptor TRPV1 is synthesized in the form of nanodiscs to maintain stability and reusability. The newly developed platform shows highly selective and sensitive performance toward each spiciness related vanilloid compound repeatably: 1 aM capsaicin, 10 aM dihydrocapsaicin, 1 fM piperine, 10 nM allicin, and 1 pM AITC. The binding mechanism is also examined by simulation. Furthermore, the elimination of the burning sensation on the tongue after eating spicy foods is not investigated. Based on the synthesis of micelles composed of casein protein (which is contained in skim milk) that remove pungent compounds bound to TRPV1 nanodisc, the deactivation of TRPV1 is investigated, and the electrode is reusable that mimics electronic tongue., (© 2023 Wiley-VCH GmbH.)

Background: Comparative outcomes of HBV-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. We conducted a large, multiethnic, multicenter study to examine the natural history of LLV versus MVR in compensated cirrhosis., Patients and Methods: We enrolled patients with HBV-infected compensated cirrhosis (n=2316) from 19 hospitals in South Korea, Singapore, and Japan. We defined the LLV group as untreated patients with ≥1 detectable serum HBV-DNA (20-2000 IU/mL), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation., Results: The annual HCC incidence was 2.7/100 person-years (PYs), 2.6/100 PYs, and 3.3/100 PYs for LLV (n=742), Spontaneous-MVR (n=333), and AVT-MVR (n=1241) groups, respectively ( p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6/100 PYs, 1.9/100 PYs, and 1.6/100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively ( p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p >0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p >0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups)., Conclusions: Untreated LLV in HBV-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-MVR and AVT-MVR. These data have important implications for practice and further research., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background & Aims: Hepatitis B core-related antigen (HBcrAg) is a new biomarker for chronic hepatitis B (CHB) whose performance has not been critically or systematically appraised. Herein, we performed a systematic review to determine its clinical utility., Methods: We evaluated the biological pathway of HBcrAg and performed a systematic review of PubMed for clinical trials, cohort studies, and case-control studies that evaluated the clinical utility of HBcrAg. The effectiveness of HBcrAg in predicting HBV-specific clinical events (e.g. HBeAg seroconversion, phases of CHB, HBsAg loss, treatment response, and relapse after stopping therapy) was examined using receiver-operating characteristic curves. The correlation coefficients of HBcrAg with HBV DNA, quantitative HBsAg (qHBsAg), HBV RNA, and cccDNA were summarised from published studies. Median values were used as estimates., Results: HBcrAg consists of three precore/core protein products: HBcAg, HBeAg, and a 22 kDa precore protein. HBcrAg assays have been associated with false-positive rates of 9.3% and false-negative rates of between 12-35% for CHB. The new iTACT-HBcrAg is more sensitive but does not reduce the false-positive rate. A PubMed search found 248 papers on HBcrAg, of which 59 were suitable for analysis. The clinical performance of HBcrAg was evaluated using AUROC analyses, with median AUROCs of 0.860 for HBeAg seroconversion, 0.867 for predicting HBeAg(-) hepatitis, 0.645 for HBsAg loss, 0.757 for treatment response, and 0.688 for relapse after stopping therapy. The median correlation coefficient (r) was 0.630 with HBV DNA, 0.414 with qHBsAg, 0.619 with HBV RNA and 0.550 with cccDNA. Correlation decreased during antiviral therapy, but combined biomarkers improved performance., Conclusions: HBcrAg has a mixed performance and has a poor correlation with HBsAg loss and antiviral therapy, hence HBcrAg results should be interpreted with caution., Impact and Implications: Hepatitis B core-related antigen (HBcrAg) has been used to assess management of patients with chronic hepatitis B (CHB) without a systematic and critical Sreview of its performance. Our finding that HBcrAg had a false-positive rate of 9% and a false-negative rate of 12-35% raises concerns, although larger studies are needed for validation. A systematic review showed that the performance of HBcrAg was variable depending on the CHB endpoint; it was excellent at predicting HBeAg seroconversion and HBeAg-negative chronic hepatitis (vs. chronic infection), which should be its main use, but it was poor for relapse after stopping antiviral therapy and for HBsAg loss. HBcrAg results should be interpreted with considerable caution, particularly by physicians, researchers, guideline committees and agencies that approve diagnostic tests., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available., (© 2023. Springer Nature Limited.)

The long-term effect of Helicobacter pylori eradication on metachronous gastric neoplasm prevention after endoscopic submucosal dissection (ESD) of gastric adenoma is unclear. This study included patients with confirmed H. pylori infection after ESD with curative resection for gastric adenoma. Patients were divided based on the success of H. pylori eradication treatment into two groups: eradication and non-eradication. Patients with any newly detected lesion within 1 year after ESD and recurrence at the ESD site were excluded from the analysis. Further, 1:1 propensity score matching was also performed to eliminate baseline differences between the two groups. H. pylori eradication treatment was administered to 673 patients after ESD (163 in the successful eradication group and 510 in the non-eradication group). During the median follow-up periods of 25 and 39 months in the eradication and non-eradication groups, metachronous gastric neoplasm was identified in 6 (3.7%) and 22 patients (4.3%), respectively. Adjusted Cox analysis revealed that H. pylori eradication was not associated with increased risk of metachronous gastric neoplasm after ESD. Kaplan-Meier analysis in the matched population yielded similar findings ( p = 0.546). H. pylori eradication treatment was not associated with metachronous gastric neoplasm after ESD with curative resection for gastric adenoma.

Semiconducting lead halide perovskite nanocrystals (PNCs) are regarded as promising candidates for next-generation optoelectronic devices due to their solution processability and outstanding optoelectronic properties. While the field of light-emitting diodes (LEDs) and photovoltaics (PVs), two prime examples of optoelectronic devices, has recently seen a multitude of efforts toward high-performance PNC-based devices, realizing both devices with high efficiencies and stabilities through a single PNC processing strategy has remained a challenge.  In this work, diphenylpropylammonium (DPAI) surface ligands, found through a judicious ab-initio-based ligand search, are shown to provide a solution to this problem. The universal PNC ink with DPAI ligands presented here, prepared through a solution-phase ligand-exchange process, simultaneously allows single-step processed LED and PV devices with peak electroluminescence external quantum efficiency of 17.00% and power conversion efficiency of 14.92% (stabilized output 14.00%), respectively. It is revealed that a careful design of the aromatic rings such as in DPAI is the decisive factor in bestowing such high performances, ease of solution processing, and improved phase stability up to 120 days. This work illustrates the power of ligand design in producing PNC ink formulations for high-throughput production of optoelectronic devices; it also paves a path for "dual-mode" devices with both PV and LED functionalities., (© 2022 Wiley-VCH GmbH.)

Introduction: The etiology of liver diseases has changed significantly, but its impact on the comparative burden of cirrhosis between males and females is unclear. We estimated sex differences in the burden of cirrhosis across 204 countries and territories from 2010 to 2019., Methods: We analyzed temporal trends in the burden of cirrhosis using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of cirrhosis incidence, death, and disability-adjusted life-years (DALYs) by sex, region, country, and etiology., Results: In 2019, the frequency of incident cases, deaths, and DALYs due to cirrhosis was 1,206,125, 969,068, and 31,781,079 in males versus 845,429, 502,944, and 14,408,336 in females, respectively. From 2010 to 2019, the frequency of cirrhosis deaths increased by 9% in males and 12% in females. Incidence ASRs remained stable in males but increased in females, while death ASRs declined in both. Death ASRs for both sexes declined in all regions, except in the Americas where they remained stable. In 2019, alcohol was the leading cause of cirrhosis deaths in males, and hepatitis C in females. Death ASRs declined for all etiologies in both sexes, except in nonalcoholic steatohepatitis (NASH). The ratio of female-to-male incidence ASRs in 2019 was lowest in alcohol(0.5), and highest in NASH(1.3), while the ratio of female-to-male death ASRs was lowest in alcohol(0.3) and highest in NASH(0.8)., Conclusion: The global burden of cirrhosis is higher in males. However, incidence and death ASRs from NASH cirrhosis in females are comparable to that of males., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Rationale: Chronic pancreatitis is an ongoing fibroinflammatory disease of the pancreas characterized by irreversible damage to the pancreatic parenchyma and ductal system. Besides, chronic pancreatitis can present with a variety of life-threatening complications., Patient Concerns: The patients visited our hospital due to abdominal pain and anemia, and had chronic pancreatitis as an underlying disease., Diagnoses: Computed tomography showed a large gastroduodenal artery pseudoaneurysm, arterioportal vein fistula, and portal vein stenosis., Interventions: We would like to report the successful use of the coils, and N-butyl cyanoacrylate glue for the therapeutic embolization of the pseudoaneurysm and fistula between the gastroduodenal artery and the portal vein, and stenting for portal vein stenosis., Outcomes: On the day following the endovascular management, the patient reported remission of abdominal pain, and hemoglobin level returned to normal after transfusion. It was confirmed that it was still well maintained in the follow-up examination after 1 month., Lessons: Although chronic pancreatitis causes many vascular complications, simultaneous occurrence of these lesions is extremely rare. Herein, we share our experience with a unique case of an extrahepatic arterioportal fistula induced by the rupture of gastroduodenal artery pseudoaneurysm with concomitant portal vein stenosis. In these complex cases, combined transarterial embolization and transportal stenting can be helpful., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Both entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line therapies for chronic hepatitis B (CHB), but their comparative effectiveness with regards to hepatitis B surface antigen (HBsAg) seroclearance remains unclear., Methods: This international multicenter cohort study enrolled 7697 treatment-naïve CHB patients (median age 50 years; male 66.75%) initiated on either ETV (n = 5430) or TDF (n = 2267) without baseline malignancy or immunosuppression from 23 centers across 10 countries or regions. Patients were observed for HBsAg seroclearance until death, loss to follow-up, or treatment discontinuation or switching. The incidences of HBsAg seroclearance were adjusted for competing mortality and compared between ETV and TDF cohorts with inverse probability of treatment weighting (IPTW) and also by multivariable regression analysis., Results: The study population was followed up for a median duration of 56.1 months with 36,929 11 person-years of observation. HBsAg seroclearance occurred in 70 ETV-treated and 21 TDF-treated patients, yielding 8-year cumulative incidence of 1.69% (95% confidence interval [CI] 1.32-2.17) for ETV and 1.34% (95% CI 0.85-2.10%), for TDF (p = 0.58). In the IPTW analysis with the two study cohorts more balanced in background covariates, the age-adjusted hazard ratio (HR) of TDF versus ETV for HBsAg seroclearance was 0.91 (95% CI 0.50-1.64; p = 0.75). Furthermore, there was no significant difference between the two medications in the multivariable competing risk regression model (adjusted sub-distributional HR 0.92 for TDF vs. ETV; 95% CI 0.56-1.53; p = 0.76)., Conclusions: ETV and TDF did not differ significantly in the incidence of HBsAg seroclearance, which rarely occurred with either regimen., (© 2022. Asian Pacific Association for the Study of the Liver.)

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.)., (Copyright © 2022 Massachusetts Medical Society.)

Percutaneous transhepatic biliary drainage (PTBD) has been an effective treatment to access the biliary tree, especially in case of endoscopically inaccessible biliary tree. In general, PTBD techniques are divided into two methods: fluoroscopy-guided PTBD and ultrasound (US)-guided PTBD. This study aimed to evaluate the effectiveness of US-guided PTBD, focusing on radiation exposure according to intrahepatic duct (IHD) dilatation degree, differences between right- and left-sided approaches and differences between benign and malignant biliary stenosis/obstruction. We evaluated technical success, clinical success, procedural data (the number of liver capsule punctures, procedural time, fluoroscopy time and radiation dose), and procedure-related complications. During the study period, a total of 123 patients with biliary stenosis/obstruction or bile leakage were initially eligible. We excluded 76 patients treated with only ERCP or initially treated with ERCP followed underwent PTBD insertion. Finally, a total of 50 procedures were performed in 47 patients. Of the 47 patients, 8 patients had anatomical alteration due to previous surgery, 6 patients refused ERCP, and 3 patients failed ERCP. For the remaining 30 patients, PTBD was performed on weekend or at night, 11 of whom had poor general condition, 10 patients underwent ERCP 3 to 4 days later after PTBD insertion, 6 patients improved after PTBD insertion without ERCP, 1 patient died, and 1 patient was referred to other hospital. Remaining 1 patient underwent surgery due to Mirizzi syndrome. All procedures were performed by two interventional radiologists. Technical success rate was 100%, clinical success was 94%, and the complication rate was 10%. Fluoroscopy time and the reported radiation dose were significantly lower in patients with dilated bile ducts than in those with non-dilated bile ducts, when biliary puncture under US guidance was performed initially. However, even in patients with non-dilated bile ducts undergoing initial trials of biliary puncture under US guidance, the fluoroscopy time and the reported radiation dose were low, based on current studies. No statistical significant differences were observed in terms of technical and dosimetry results according to right-sided and left-sided procedures and benign and malignant biliary stenosis/obstruction. Thus, US-guided PTBD was found to be a safe and effective technique that significantly reduced fluoroscopy time and radiation doses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hepatitis B Virus (HBV) is a hepadnavirus that is the principal pathogen underlying viral liver disease in human populations. In this study, we describe the isolation and characterization of a fully human monoclonal antibody for HBV. This HuMab was isolated by a combinatorial screen of the memory B-cell repertoire from an acute/recovered HBV-infected patient. Lead candidate selection was based upon strong binding and neutralizing activity for live HBV. We provide a detailed biochemical/biophysical, and subclass characterization of its specificity and affinity against all of the principal HBV genotypes combined with a functional analysis of its in vitro activity. We also demonstrate its potential as a prophylaxis/therapy in vivo using human liver chimeric mouse models for HBV infection. These data have important implications for our understanding of natural human immunity to HBV and suggest that this potentially represents a new antibody-based anti-viral candidate for prophylaxis and/or therapy for HBV infection., (© 2022. The Author(s).)

Transient receptor potential vanilloid 1 (TRPV1) agonists that bind to the vanilloid pocket are being actively studied in the pharmaceutical industry to develop novel treatments for chronic pain and cancer. To discover synthetic vanilloids without the side effect of capsaicin, a time-consuming process of drug candidate selection is essential to a myriad of chemical compounds. Herein, we propose a novel approach to field-effect transistors for the fast and facile screening of lead vanilloid compounds for the development of TRPV1-targeting medications. The graphene field-effect transistor was fabricated with human TRPV1 receptor protein as the bioprobe, and various analyses (SEM, Raman, and FT-IR) were utilized to verify successful manufacture. Simulations of TRPV1 with capsaicin, olvanil, and arvanil were conducted using AutoDock Vina/PyMOL to confirm the binding affinity. The interaction of the ligands with TRPV1 was detected via the fabricated platform, and the collected responses corresponded to the simulation analysis., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background & Aims: 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., Methods: 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 log 10 IU/ml reduction from baseline) rate, safety and pharmacokinetics., Results: Parts 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 log 10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours., Conclusions: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified., Clinical Trial Number: NCT03020745., Lay Summary: 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., Competing Interests: Conflict of interest MFY has been an advisor for and received consulting fees from AbbVie, Arbutus, Bristol-Myers Squibb (BMS), Dicerna, GSK, Gilead, Janssen, Merck Sharp & Dohme (MSD), Clear B Therapeutics, Springbank and Roche; and received grants from Assembly biosciences, Arrowhead, BMS, Fujirebio, Gilead, MSD, Springbank and Sysmex. JHeo, YS, QX, JJ, YK, JLT, WX, ZD, S-JP, RK, Y-OK and HJY report no conflicts of interest. HK has received teaching fees from MSD, Gilead, AbbVie, Eisei and Dainippon Sumitomo. FS has received teaching fees from AbbVie and Gilead. JLHou has received consulting fees from Aligos, Assembly, Gilead Sciences, Johnson & Johnson, Roche; lecturer fees from Gilead, Johnson & Johnson, Roche and grants from BMS. KC has received grants from AbbVie and Dainippon Sumitomo; and has received teaching fees from MSD, BMS and Gilead. MI received grants and teaching fees from BMS. S-GL has been an advisor for and received grants from Abbott Diagnostics, Gilead, Roche and MSD; and has been an advisor for Kaleido Bioscience, Arbutus, Assembly Grifols, Janssen, Fibronostics and GSK. YTanaka received grants from Gilead, Janssen and Chugai; and teaching fees from Gilead and Fujirebio, Inc. J-HY received grants from GSK, Dicerna Pharmaceuticals, Roche, AstraZeneca, Daewoong and Hanmi. MK was an advisor for Gilead and GSK; and received speaking fees from Gilead, AbbVie, MSD, Eisai, Chugai and Bayer. MEL has been an advisor for and received speaking fees for Abbott Diagnostics, Hi-Eisai, Menarini, Mylan and Roche. YTao, JC, RE, MD, SB-B, KH, FMC, MP and DT are employees of GSK and hold GSK stocks/options. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The optimal interval between self-expanding metallic stent (SEMS) insertion and surgery remains controversial in malignant left-sided large-bowel obstruction (MLLO), especially with respect to oncologic aspects., Aims: The aim of this study is to examine whether the time interval to surgery is related to oncologic outcomes., Methods: Prospectively collected database of MLLO between January 2005 and December 2017 were reviewed. They were divided according to established cut-off value of 14 days for the time interval to surgery. The two groups (early and late groups) were compared with respect to disease-free survival (DFS) and overall survival (OS). Additional subgroup analysis was performed using the established cut-off values for patients with stage II and III tumors., Results: A total of 149 patients underwent surgery after SEMS insertion. There were no significant differences between the early and late groups in the 5-year DFS (78.0% vs 72.4%; P = 0.513) and the OS (74.2% vs 75.7%; P = 0.864) rates in all MLLO. Subgroup analysis showed that there were significant differences between the two groups for DFS and OS in stage II MLLO. The multivariate Cox regression analysis in stage II MLLO demonstrated that the time to surgery was a prognostic factor for DFS (HR, 2.051; 95% CI, 1.528-42.136; P = 0.014) and for OS (HR, 4.947; 95% CI, 1.520-16.107; P = 0.008)., Conclusions: The time to surgery was demonstrated not to be a significant prognostic factor in all MLLO. However, it was a prognostic factor for patients with stage II MLLO., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Various Fe-based layered oxide materials have received attention as promising cathode materials for sodium ion batteries because of their low cost and high specific capacity. Only a few P3-type Fe-based oxide materials, however, have been examined as cathodes because the synthesis of highly crystalline P3-type Fe-based oxides is not facile. For this reason, the structural merits of the P3 structure are not yet fully understood. Herein, highly crystalline P3-type Na 0.67 [Li 0.1 (Fe 0.5 Mn 0.5 ) 0.9 ]O 2 heated at 900 °C is introduced to improve the electrochemical performance of Fe-based layered oxides. The structures, reaction mechanisms, and electrochemical performances of P3 Na 0.67 [Li 0.1 (Fe 0.5 Mn 0.5 ) 0.9 ]O 2 , P2 Na 0.57 [Li 0.1 (Fe 0.5 Mn 0.5 ) 0.9 ]O 2 , and P2 Na 0.67 [Fe 0.5 Mn 0.5 ]O 2 are compared to demonstrate the roles of Li + doping in the improved electrochemical performance of P3 Na 0.67 [Li 0.1 (Fe 0.5 Mn 0.5 ) 0.9 ]O 2 , such as stable capacity retention over 100 cycles. P3 Na 0.67 [Li 0.1 (Fe 0.5 Mn 0.5 ) 0.9 ]O 2 significantly suppresses the migration of Fe 3+ ions to tetrahedral sites in the Na layer during cycling because the cation disorder of Li + is more favorable than that of Fe 3+ . As a result, P3 Na 0.67 [Li 0.1 (Fe 0.5 Mn 0.5 ) 0.9 ]O 2 shows better cycle performance than P2 Na 0.67 [Fe 0.5 Mn 0.5 ]O 2 . P3 Na 0.67 [Li 0.1 (Fe 0.5 Mn 0.5 ) 0.9 ]O 2 also exhibits an improved rate performance compared to P2 Na 0.67 [Fe 0.5 Mn 0.5 ]O 2 . This finding provides fundamental insights to improve the electrochemical performance of layered oxide cathode materials for sodium ion batteries.

Adequate serotonin levels are pivotal to human well-being; thus, serotonin can be used as a biomarker because it regulates a wide range of physical and psychological functions. As an imbalance of serotonin is highly likely to initiate the pathogenesis of various disorders, monitoring serotonin levels in real time is in high demand for the early detection of disease. We fabricated a field-effect transistor (FET) biosensor based on aptamer-immobilized conducting polymer nanohybrids, which showed an instantaneous response toward serotonin in solution. The mechanism of serotonin detection was based on aptamer deformation after aptamer-ligand interaction and the consequential decrease in the charge carrier density of the FET template. Docking simulations with AutoDock/Vina and PyMOL were successfully used to investigate the binding site of serotonin in the loop structure of the aptamer. The fabricated FET template showed high sensitivity toward serotonin in the range of 10 fM to 100 nM, and the limit of detection (LOD) was exceptionally low at 10 fM. Moreover, the selectivity toward serotonin was confirmed by observing no signal after the injection of structural analogs, functional analogs and excess physiological biomolecules. The potential clinical application of this sensor was confirmed because it remained consistent when the buffer solution was exchanged for artificial serum or artificial cerebrospinal fluid (CSF).  † S.G.L. and S.E.S. contributed equally to this work., (© 2022. The Author(s).)

Background: A considerable number of surgical residents fail the mandated endoscopy exam despite having completed the required clinical cases. Low-cost endoscopy box trainers (BTs) could democratize training; however, their effectiveness has never been compared with higher-cost virtual reality simulators (VRSs)., Study Design: In this randomized noninferiority trial, endoscopy novices trained either on the VRS used in the Fundamental of Endoscopic Surgery manual skills (FESms) exam or a validated BT-the Basic Endoscopic Skills Training (BEST) box. Trainees were tested at fixed timepoints on the FESms and on standardized ex vivo models. The primary endpoint was FESms improvement at 1 week. Secondary endpoints were FESms improvement at 2 weeks, FESms pass rates, ex vivo tests performance, and trainees' feedback., Results: Seventy-seven trainees completed the study. VRS and BT trainees showed comparable FESms improvements (25.16 ± 14.29 vs 25.58 ± 11.75 FESms points, respectively; p = 0.89), FESms pass rates (76.32% vs 61.54%, respectively; p = 0.16) and total ex vivo tasks completion times (365.76 ± 237.56 vs 322.68 ± 186.04 seconds, respectively; p = 0.55) after 1 week. Performances were comparable also after 2 weeks of training, but FESms pass rates increased significantly only in the first week. Trainees were significantly more satisfied with the BT platform (3.97 ± 1.20 vs 4.81 ± 0.40 points on a 5-point Likert scale for the VRS and the BT, respectively; p < 0.001)., Conclusions: Simulation-based training is an effective means to develop competency in endoscopy, especially at the beginning of the learning curve. Low-cost BTs like the BEST box compare well with high-tech VRSs and could help democratize endoscopy training., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Hepatitis B virus (HBV) infection persists as a major global health problem despite the availability of HBV vaccines for disease prevention. However, vaccination rates remains low in some regions of the world, driving the need for novel strategies to minimise infections and prevent disease progression. Thus, understanding of perturbed molecular signaling events during early phases of HBV infection is required. Phosphosignaling is known to be involved in the HBV infection processes, yet systems-level changes in phosphosignaling pathways in the host during infection remain unclear. To this end, we performed phosphoproteome profiling on HBV-infected HepG2-NTCP cells. Our results showed that HBV infection drastically altered the host phosphoproteome and its associated proteins, including kinases. Computational analysis of this phosphoproteome revealed dysregulation of the pathways involved in immune responses, cell cycle processes, and RNA processing during HBV infection. Kinase Substrate Enrichment Analysis (KSEA) identified the dysregulated activities of important kinases, including those from CMGC (CDK, MAPK, GSK, and CLK), AGC (protein kinase A, G, and C), and TK (Tyrosine Kinase) families. Of note, the inhibition of CLKs significantly reduced HBV infection in HepG2-NTCP cells. In all, our study unravelled the aberrated phosphosignaling pathways and the associated kinases, presenting potential entry points for developing novel therapeutic strategies for HBV treatment.

The relationship between androgen excess and bone health in patients with congenital adrenal hyperplasia (CAH) with 21-hydroxylase (21-OH) deficiency is not fully understood. This study demonstrated positive correlations between androgen hormones and bone mineral density (BMD) in CAH women with 21-OH deficiency., Purpose: This study aims to assess BMD and its association with androgen excess in women with CAH., Methods: We enrolled 92 women with CAH with 21-OH deficiency and retrospectively reviewed their clinical features, hormone concentrations, body composition, glucocorticoid (GC) dose, and BMD., Results: BMD was not different according to the subtypes of CAH. BMD at the lumbar spine was lower in women with CAH with regular menstruation than those with irregular menstruation (1.081 vs. 1.165 g/cm 2 , P < 0.05). BMD was lower in women with CAH with 17-hydroxyprogesterone (17-OHP) < 10 ng/mL than in those with ≥ 10 ng/mL (lumbar spine, 1.019 vs. 1.150 g/cm 2 ; femur neck, 0.806 vs. 0.899 g/cm 2 ; total hip, 0.795 vs. 0.943 g/cm 2 ; all P < 0.05). After adjusting for age and BMI in correlation analyses, testosterone concentrations were positively correlated with lumbar spine, femur neck, and total hip BMD (r = 0.46, r = 0.38, and r = 0.35, respectively; all P < 0.05), while 17-OHP was positively correlated with lumbar spine BMD (r = 0.38, P < 0.01). In subgroup analysis, 17-OHP was positively correlated with BMD (lumbar spine, r = 0.22; femur neck, r = 0.22; total hip, r = 0.24; all P < 0.05) only in the group with a total cumulative dose of GC ≥ 156.0 g/m 2 ., Conclusion: Androgen excess may have a protective effect on BMD in women with classic CAH and high cumulative doses of GC., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Background: The clinical outcomes of endoscopic submucosal dissection (ESD) for undifferentiated (UD) intramucosal early gastric cancer (EGC) compared with those of surgery, regardless of lesion size, are not well known. Furthermore, there is a concern regarding the treatment plan before and after ESD in cases of UD intramucosal EGC within expanded indications., Aim: To evaluate clinical outcomes of ESD compared with those of surgery in UD intramucosal EGC patients regardless of tumor size., Methods: We enrolled patients with UD intramucosal EGC after ESD with complete resection or surgery from January 2005 to August 2020 who met the within or beyond expanded indications with lesion size > 2 cm (the only non-curative factor). Overall, 123 and 562 patients underwent ESD and surgery, respectively. After propensity-score matching, clinical and long-term outcomes, i.e ., recurrence-free survival (RFS) and overall survival (OS), were analyzed. The multivariable Cox proportional hazard model with treatment modality and ESD indication was used to evaluate the recurrence risk., Results: After matching, 119 patients each were finally enrolled in the ESD and surgery groups. The median length of hospital stay was shorter in the ESD group than surgery group (4.0 vs 9.0 days, P < 0.001). Four cases of recurrence after ESD were local recurrences, all of which occurred within 1 year. Total recurrence was seven (5.9%) and two (1.7%) in the ESD and surgery groups, respectively. No difference was observed between the two groups with respect to OS ( P = 0.948). However, the ESD group had inferior RFS compared with the surgery group ( P = 0.031). ESD was associated with the risk of recurrence after initial treatment in all enrolled patients (hazard ratio, 5.2; 95% confidence interval: 1.0-25.8, P = 0.045)., Conclusion: Although OS was similar between the two groups, surveillance endoscopy was important for the ESD than for the surgery group because RFS was inferior and local recurrence was an issue., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest were disclosed., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: We aimed to compare the longitudinal changes in estimated glomerular filtration rate (eGFR) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF)., Methods: This is a retrospective study of 6189 adult treatment-naïve CHB patients initiated therapy with TDF (n = 2482) or ETV (n = 3707) at 25 international centers using multivariable generalized linear modeling (GLM) to determine mean eGFR (mL/min/1.73 m 2 ) and Kaplan-Meier method to estimate incidence of renal impairment (≥ 1 chronic kidney disease [CKD] stage worsening). We also examined above renal changes in matched ETV and TDF patients (via propensity score matching [PSM] on age, sex, diabetes mellitus [DM], hypertension [HTN], cirrhosis, baseline eGFR, and follow-up duration)., Results: In the overall cohort (mean age 49.7 years, 66.2% male), the baseline eGFR was higher for TDF vs. ETV group (75.9 vs. 74.0, p = 0.009). PSM yielded 1871 pairs of ETV or TDF patients with baseline eGFR ≥ 60 and 520 pairs for the eGFR < 60 group. GLM analysis of the overall (unmatched) cohort and PSM cohorts revealed lower adjusted mean eGFRs in TDF (vs. ETV) patients (all p < 0.01) during 10 years of follow-up. Among PSM eGFR ≥ 60 patients, the 5-year cumulative incidences of renal impairment were 42.64% for ETV and 48.03% for TDF (p = 0.0023). In multivariable Cox regression, TDF vs. ETV (adjusted HR 1.26, 95% CI 1.11-1.43) was associated with higher risk of worsening renal function., Conclusion: Over the 10-year study follow-up, compared to ETV, TDF was associated with a lower mean eGFR and higher incidence of renal impairment., (© 2021. Asian Pacific Association for the Study of the Liver.)

Background & Aims: The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA., Methods: We conducted a randomized controlled trial of CHB patients on NA >12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg) >1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg <200 IU/mL, qHBsAg <100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT)., Results: A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P < .0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P < .001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P < .0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy)., Conclusions: ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Complete surface passivation of colloidal quantum dots (CQDs) and their strong electronic coupling are key factors toward high-performance CQD-based photovoltaics (CQDPVs). Also, the CQD matrices must be protected from oxidative environments, such as ambient air and moisture, to guarantee air-stable operation of the CQDPVs. Herein, we devise a complementary and effective approach to reconstruct the oxidized CQD surface using guanidinium and pseudohalide. Unlike conventional halides, thiocyanate anions provide better surface passivation with effective replacement of surface oxygen species and additional filling of defective sites, whereas guanidinium cations promote the construction of epitaxial perovskite bridges within the CQD matrix and augment electronic coupling. Additionally, we replace a defective 1,2-ethanedithiol-treated CQD hole transport layer (HTL) with robust polymeric HTLs, based on a judicious consideration of the energy level alignment established at the CQD/HTL interface. These efforts collectively result in high-performance and stable CQDPVs with photocurrents over 30 mA cm -2 , ∼80% quantum efficiency at excitonic peaks and stable operation under humid and ambient conditions. Elucidation of carrier dynamics further reveals that interfacial recombination associated with band alignment governs both the CQDPV performance and stability.

The effect of glucose-dependent insulinotropic polypeptide (GIP) on cells under oxidative stress induced by glutamate, a neurotransmitter, and the underlying molecular mechanisms were assessed in the present study. We found that in the pre-treatment of HT-22 cells with glutamate in a dose-dependent manner, intracellular ROS were excessively generated, and additional cell damage occurred in the form of lipid peroxidation. The neurotoxicity caused by excessive glutamate was found to be ferroptosis and not apoptosis. Other factors (GPx-4, Nrf2, Nox1 and Hspb1) involved in ferroptosis were also identified. In other words, it was confirmed that GIP increased the activity of sub-signalling molecules in the process of suppressing ferroptosis as an antioxidant and maintained a stable cell cycle even under glutamate-induced neurotoxicity. At the same time, in HT-22 cells exposed to ferroptosis as a result of excessive glutamate accumulation, GIP sustained cell viability by activating the mitogen-activated protein kinase (MAPK) signalling pathway. These results suggest that the overexpression of the GIP gene increases cell viability by regulating mechanisms related to cytotoxicity and reactive oxygen species production in hippocampal neuronal cell lines.

Introduction: Self-expandable metallic stents (SEMSs) are widely used in patients with malignant left-sided large-bowel obstruction (MLLO) to convert an emergency situation into an elective one. However, the effects of endoscopic stenting on oncological outcomes remain unclear. This study aimed to analyze the oncological outcomes of SEMS placement in patients with MLLO stratified by pathological stage., Methods: We reviewed the data of patients with MLLO that were prospectively collected between January 2005 and December 2016. Patients were divided into those who underwent SEMS placement as a bridge to surgery and those who underwent emergency surgery. Disease-free survival (DFS) and overall survival (OS) were compared between groups, and their prognostic factors were determined by pathological stage., Results: SEMS placement and emergency surgery were performed in 130 and 45 patients, respectively. There was no difference in the 5-year DFS and OS rate between two groups. Subgroup analysis revealed a significant difference in the 5-year DFS and OS rate in patients with stage III MLLO, but was not observed in patients with stage II MLLO. Multivariate Cox regression analysis for stage III MLLO revealed endoscopic stenting (hazard ratio [HR], 2.051; 95% confidence interval [CI], 1.018-4.131; p = 0.044) as the only prognostic factor for DFS. Age, tumor differentiation, perineural invasion, and endoscopic stenting (HR, 3.189; 95% CI, 1.346-7.556; p = 0.008) were prognostic factors for OS., Conclusion: In terms of oncologic outcomes, endoscopic stenting might be more beneficial than ES in patients with stage III MLLO., (© 2022 S. Karger AG, Basel.)

Although regular endoscopic screening may help in early detection of gastric cancer, interval cancer remains a problem in the screening program. This study evaluated the association between regular endoscopic screening and interval cancer detection in the Korean National Cancer Screening Program (KNCSP). We defined three groups (regularly, irregularly, and not screened) according to the screening interval, and the trends in the interval cancer rate (ICR) between the groups were tested using the Cochran-Armitage test. The influence of regular endoscopic screening on the risk of interval cancer was evaluated using multivariable logistic regression. Among the 11,642,410 participants who underwent endoscopy, the overall ICR was 0.36 per 1000 negative screenings. The ICR of the not screened group (0.41) was the highest among the three groups and the risk of interval cancer in this group was 1.68 times higher ( p < 0.001) than that in the regularly screened group. Women in their 40s who had regular screening with no history of intestinal metaplasia and gastric polyps would have the lowest probability of having interval cancer (0.005%). Regular participation in endoscopic screening programs for reducing the risk of interval cancer may help to improve the quality of screening programs.

Background/aim: [6]-Gingerol, a compound extracted from ginger, has been studied for its therapeutic potential in various types of cancers. However, its effects on oral cancer remain largely unknown. Here, we aimed to investigate the potential anticancer activity and underlying mechanisms of [6]-gingerol in oral cancer cells., Materials and Methods: We analyzed the antigrowth effects of [6]-gingerol in oral cancer cell lines by cell proliferation, colony formation, migration, and invasion assays. We detected cell cycle and apoptosis with flow cytometry and further explored the mechanisms of action by immunoblotting., Results: [6]-Gingerol significantly inhibited oral cancer cell growth by inducing apoptosis and cell cycle G2/M phase arrest. [6]-Gingerol also inhibited oral cancer cell migration and invasion by up-regulating E-cadherin and down-regulating N-cadherin and vimentin. Moreover, [6]-gingerol induced the activation of AMPK and suppressed the AKT/mTOR signaling pathway in YD10B and Ca9-22 cells., Conclusion: [6]-Gingerol exerts anticancer activity by activating AMPK and suppressing the AKT/mTOR signaling pathway in oral cancer cells. Our findings highlight the potential of [6]-gingerol as a therapeutic drug for oral cancer treatment., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Controversial areas in chronic hepatitis B (CHB) are those where there is uncertainty, or differences of opinion in management, or where evidence may be insufficient. Areas of controversy include whether patients with high viral load but normal liver function tests should be treated to prevent hepatocellular carcinoma (HCC) or liver disease progression to cirrhosis. Another area is whether quantitative hepatitis B surface antigen (qHBsAg) can be used to better characterize phases of CHB and prognosticate. Finally, the utility of qHBsAg in the management of patients on antiviral therapy such as interferon and nucleoside analogues could improve management practices., Competing Interests: Disclosure D.Q. Huang: Advisory board: Eisai; Research support: NMRC Research Training Fellowship, Exxon Mobil-NUS Research Fellowship for Clinicians. G.S. Kew has no disclosures. S.G. Lim: Advisory board: Gilead Sciences, Springbank, Roche, Abbvie, Abbott, Kaleido; Speakers bureau: Gilead Sciences, Abbott, Roche; Research support: Abbott, Merck Sharpe and Dohme, Roche, Gilead Sciences., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: Availability of transient elastography (TE) limits the application of Baveno-VI criteria. In a derivation study, the ABP criteria (Albumin >40 g/l, Bilirubin <22 μmol/l and Platelet >114,000/μl) had been shown to perform well in identifying compensated advanced chronic liver disease (cACLD) patients without high-risk varices (HRV). We aim to externally validate this novel ABP criteria for the exclusion of HRVs among cACLD patients., Methods: Data was retrospectively collected from consecutive cACLD patients with paired TE and esophagogastroduodenoscopy (EGD) performed between 2011 and 2017 in Changi General Hospital, Singapore. We estimate the discriminative ability of ABP criteria in validation cohort using AUROC and calibration-in-the-large. We subsequently compare the performance between ABP and Baveno-VI criteria in the validation cohort., Results: Among 314 patients included in our validation cohort, 32 (10.2%) had HRV on screening EGD. Application of ABP criteria within this validation cohort has increased discriminative ability than the derivation cohort. The AUROC of validation and derivation cohort were 0.68 (0.60-0.76) and 0.66 (0.60-0.76), respectively. The mean and standard error for calibration-in-the-large and calibration slope were -0.08 (0.22) and 0.93 (0.26) respectively. The ABP criteria had excellent performance in excluding HRV and will spare more screening EGDs than the Baveno-VI criteria (39.2% vs 27.4%, p < 0.001), without missing more HRVs., Conclusion: We validated the performance of ABP criteria for the exclusion of HRVs in cACLD patients. ABP criteria is superior to Baveno-VI criteria by sparing more screening EGD without the need of TE., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

To date, there exists no established endoscopic surveillance interval strategy after endoscopic submucosal dissection (ESD) for gastric adenoma. In this study, we suggest a risk factor-based statistical model for optimal surveillance intervals for gastric adenoma after ESD with curative resection. A cox proportional hazard model was applied to identify risk factors for recurrence after ESD. Patients (n = 698) were categorized into groups based on the identified risk factors. The cumulative density of recurrence over time was computed using a cubic splined baseline hazard function, and the customized surveillance interval was modeled for each risk group. The overall cumulative incidence of recurrence was 7.3% (n = 51). Risk factors associated with recurrence were male (hazard ratio [HR], 2.60, P = 0.030), protruded scar (HR, 3.18, P < 0.001), and age ≥ 59 years (HR, 1.05, P < 0.001). The surveillance interval for each group was developed by using the recurrence limit for the generated risk groups. According to the developed schedule, high-risk patients would have a maximum of seven surveillance visits for 5 years, whereas low-risk patients would have biennial surveillance for cancer screening. We proposed a simple and promising strategy for determining a better endoscopic surveillance interval by parameterizing diverse and group-specific recurrence risk factors into a well-known survival model., (© 2021. The Author(s).)

There is a lack of studies regarding the long-term outcomes of Asian adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. We hypothesized that adults with CAH are at higher metabolic risk than their age-, and sex-matched controls. We further investigated the long-term health outcome-related factors in adults with CAH. We compared metabolic risk between adults with CAH (71 men, 93 women) and age-, and sex-matched controls (190 men, 261 women) from the Korean National Health and Nutrition Examination Survey data. The presence of obesity, testicular adrenal rest tumors (TARTs), and menstrual irregularity was assessed. Hormone status and treatment regimens were compared according to the presence of adverse outcomes. The median age was 27.0 y and 28.0 y for men and women, respectively. Adults with CAH had a higher waist circumference (88.0 vs. 82.3 cm in men, and 83.5 vs . 72.3 cm in women), and blood pressure (125.0 vs. 113.0 mmHg in men, and 120.0 vs . 104.0 mmHg in women) than age- and sex-matched controls ( P <0.05 for all). The 2.7-fold increased risk for hypertension (men) and 2.0-fold increased risk for obesity (women) was significant in patients with CAH ( P <0.05 for both). Obese adults with CAH showed significantly higher adrenal limb thicknesses (men) and 17-hydroxyprogesterone and dehydroepiandrosterone sulfate levels (women) ( P <0.05 for both). TARTs occurred in 58.1% of men and did not differ by hormone or treatment regimen. Irregular menstruation was observed in 57.1% of women, with higher dehydroepiandrosterone sulfate levels in those with irregular periods. Adults with CAH had a higher metabolic risk than the general population. Poor disease control may increase their risk of metabolic morbidity and menstrual irregularity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lim, Lee, Jang, Kong, Ahn, Kim, Shin and Kim.)

Detection rates of pancreatic cystic lesions (PCLs) have increased, resulting in greater requirements for regular monitoring using imaging modalities. We aimed to evaluate the capability of ultrasonography (US) for morphological characterization of PCLs as a reference standard using endoscopic ultrasonography (EUS). A retrospective analysis was conducted of 102 PCLs from 92 patients who underwent US immediately prior to EUS between January 2014 and May 2017. The intermodality reliability and agreement of the PCL morphologic findings of the two techniques were analyzed and compared using the intraclass correlation coefficient and κ values. The success rates of US for delineating PCLs in the head, body, and tail of the pancreas were 77.8%, 91.8%, and 70.6%, respectively. The intraclass correlation coefficient for US and the corresponding EUS lesion size showed very good reliability (0.978; p < 0.001). The κ value between modalities was 0.882 for pancreatic duct dilation, indicating good agreement. The κ values for solid components and cystic wall and septal thickening were 0.481 and 0.395, respectively, indicating moderate agreement. US may be useful for monitoring PCL growth and changes in pancreatic duct dilation, but it has limited use in the diagnosis and surveillance of mural nodules or cystic wall thickness changes.

Experiments were conducted to identify different ratios of Bacillus sp. SJ-10 and Lactobacillus plantarum KCCM 11322 mixtures at a concentration of 1 × 10 8  CFU/g diet; the effects on growth and cellular and humoral immune responses and the characteristics of disease protection in olive flounder (Paralichthys olivaceus). Flounder were divided into six groups and fed control diet D-1 (without Bacillus sp. SJ-10 and L. plantarum KCCM 11322), positive control diets D-2 (Bacillus sp. SJ-10 at 1 × 10 8  CFU/g feed) and D-3 (L. plantarum KCCM 11322 at 1 × 10 8  CFU/g feed); or treatment diets D-4 (3:1 Bacillus sp. SJ-10 and L. plantarum KCCM 11322 at 0.75 + 0.25 × 10 8  CFU/g feed), D-5 (1:1 Bacillus sp. SJ-10 and L. plantarum KCCM 11322 at 0.50 + 0.50 × 10 8  CFU/g feed), or D-6 (1:3 Bacillus sp. SJ-10 and L. plantarum KCCM 11322 at 0.25 + 0.75 × 10 8  CFU/g feed) for 8 weeks. Group D-4 demonstrated better growth and feed utilization (P < 0.05) compared with the controls and positive controls. Similar modulation was also observed in respiratory burst for all treatments and in the expression levels of TNF-α, IL-1β, IL-6, and IL-10 in different organs in D-4. D-4 and D-5 increased respiratory burst, superoxide dismutase, lysozyme, and myeloperoxidase activities compared with the controls, and only D-4 increased microvilli length. When challenged with 1 × 10 8  CFU/mL Streptococcus iniae, the fish in the D-4 and D-5 groups survived up to 14 days, whereas the fish in the other groups reached 100% mortality at 11.50 days. Collectively, a ratio-specific Bacillus sp. SJ-10 and L. plantarum KCCM 11322 mixture (3:1) was associated with elevated growth, innate immunity, and streptococcosis resistance (3:1 and 1:1) compared with the control and single probiotic diets., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Recent development of multiple treatments for human hepatocellular carcinoma (HCC) has allowed for the selection of combination therapy to enhance the effectiveness of monotherapy. Optimal selection of therapies is based on both HCC and its microenvironment. Therefore, it is critical to develop and validate preclinical animal models for testing clinical therapeutic solutions., Approach and Results: We established cell line-based or patient-derived xenograft-based humanized-immune-system mouse models with subcutaneous and orthotopic HCC. Mice were injected with human-specific antibodies (Abs) to deplete human immune cells. We analyzed the transcription profiles of HCC cells and human immune cells by using real-time PCR and RNA sequencing. The protein level of HCC tumor cells/tissues or human immune cells was determined by using flow cytometry, western blotting, and immunohistochemistry. The HCC tumor size was measured after single, dual-combination, and triple-combination treatment using N-(1',2-Dihydroxy-1,2'-binaphthalen-4'-yl)-4-methoxybenzenesulfonamide (C188-9), bevacizumab, and pembrolizumab. In this study, human immune cells in the tumor microenvironment were strongly selected and modulated by HCC, which promoted the activation of the IL-6/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in tumor cells and led to augmented HCC proliferation and angiogenesis by releasing angiogenic cytokines in humanized-immune-system mice with HCC. In particular, intratumor human cluster of differentiation-positive (hCD14 + ) cells could produce IL-33 through damage-associated molecular pattern/Toll-like receptor 4/activator protein 1, which up-regulated IL-6 in other intratumor immune cells and activated the JAK2/STAT3 pathway in HCC. Specific knockdown of the CD14 gene in human monocytes could impair IL-33 production induced by cell lysates. Subsequently, we evaluated the in vivo anti-HCC effect of C188-9, bevacizumab, and pembrolizumab. The results showed that the anti-HCC effect of triple-combination therapy was superior to that of single or dual treatments., Conclusions: Humanized-immune-system HCC mouse models are suitable for identifying targets from cancer and immune components and for testing combinational therapies., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Juxtaposed with another zinc finger protein 1 (JAZF1) is associated with metabolic disorders, including type 2 diabetes mellitus (T2DM). Several studies showed that JAZF1 and body fat mass are closely related. We attempted to elucidate the JAZF1 functions on adipose development and related metabolism using in vitro and in vivo models., Results: The JAZF1 expression was precisely regulated during adipocyte differentiation of 3T3-L1 preadipocyte and mouse embryonic fibroblasts (MEFs). Homozygous JAZF1 deletion (JAZF1-KO) resulted in impaired adipocyte differentiation in MEF. The JAZF1 role in adipocyte differentiation was demonstrated by the regulation of PPARγ-a key regulator of adipocyte differentiation. Heterozygous JAZF1 deletion (JAZF1-Het) mice fed a normal diet (ND) or a high-fat diet (HFD) had less adipose tissue mass and impaired glucose homeostasis than the control (JAZF1-Cont) mice. However, other metabolic organs, such as brown adipose tissue and liver, were negligible effect on JAZF1 deficiency., Conclusion: Our findings emphasized the JAZF1 role in adipocyte differentiation and related metabolism through the heterozygous knockout mice. This study provides new insights into the JAZF1 function in adipose development and metabolism, informing strategies for treating obesity and related metabolic disorders., (© 2021. The Author(s).)

Development of colloidal quantum dot (CQD) inks enables single-step spin-coating of compact CQD films of appropriate thickness, enabling the promising performance of CQD photovoltaics (CQDPVs). Today's highest-performing CQD inks rely on volatile n -butylamine (BTA), but it is incompatible with scalable deposition methods since a rapid solvent evaporation results in irregular film thickness with an uneven surface. Here, we present a hybrid solvent system, consisting of BTA and N , N -dimethylformamide, which has a favorable acidity for colloidal stability as well as an appropriate vapor pressure, enabling a stable CQD ink that can be used to fabricate homogeneous, large-area CQD films via spray-coating. CQDPVs fabricated with the CQD ink exhibit suppressed charge recombination as well as fast charge extraction compared with conventional CQD ink-based PVs, achieving an improved power conversion efficiency (PCE) of 12.22% in spin-coated devices and the highest ever reported PCE of 8.84% among spray-coated CQDPVs.