AIM：To investigate retrospectively the long-term efficacy of various treatment strategies using adefovir dipivoxil（adefovir） in patients with lamivudine-resistant chronic hepatitis B.METHODS：We ...included 154 consecutive patients in two treatment groups：the ＂add-on＂ group（n = 79）,in which adefovir was added to ongoing lamivudine treatment due to lamivudine resistance,and the ＂switch/combination＂ group（n = 75）,in which lamivudine was first switched to adefovir and then re-added later as needed.The ＂switch/combination＂ group was then divided into two subgroups depending on whether participants followed（group A,n = 30） or violated（group B,n = 45） a proposed treatment strategy that determined whether to add lamivudine based on the serum hepatitis B virus（HBV） DNA levels（ 60 IU/mL or not） after 6 mo of treatment（roadmap concept）.RESULTS：The cumulative probability of virologic response（HBV DNA 60 IU/mL） was higher in group A than in the ＂add-on＂ group and in group B（P 0.001）.In contrast,the cumulative probability of virologic breakthrough was lower in the ＂add-on＂ group than in group B（P = 0.002）.Furthermore,the risk of virologic breakthrough in the multivariate analysis was significantly lower in the ＂add-on＂ group than in group A（hazard ratio = 0.096;95%CI,0.015-0.629;P = 0.015）.CONCLUSION：The selective combination of adefovir with lamivudine based upon early treatment responses increased the odds of virologic breakthrough relative to the use of uniform combination therapy from the beginning of treatment.
AIM: To evaluate the long-term efficacy adefovir(ADV)-based combination therapies in entecavir(ETV)-resistant chronic hepatitis B(CHB) patients. METHODS: F i fty CHB pat ient s wi t h genotypic ...resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV(ADV/ETV,n = 23) or ADV plus lamivudine(LMV)(ADV/LMV,n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus(HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response(VR; HBV DNA < 20 IU/m L) were calculated using the Kaplan-Meier method,and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR,respectively.RESULTS: Baseline median HBV DNA levels were 5.53(2.81-7.63) log10 IU/m L. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27(12-45) mo. Overall,cumulative VR rates at 6,12,24,and 36 mo were 26%,36%,45%,and 68%,respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates(35%,43%,65%,and 76%,respectively) than those with the ADV/LAM combination(18%,30%,30%,and 62%,respectively; P = 0.048). In the multivariate analysis,low baseline HBV DNA levels(< 5.2 log10 IU/m L) and initial virologic response at 3 mo(IVR-3; HBV DNA < 3.3 log10 IU/m L after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period,the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.CONCLUSION: If tenofovir is not available,ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers,and may becontinued if IVR-3 is achieved.
According to the American Association for the Study of Liver Diseases (AASLD) treatment guidelines for hepatocellular carcinoma (HCC), the role of surgery has been expanded beyond the Barcelona ...Clinic Liver Cancer (BCLC) algorithm. We compared primary hepatectomy (PH) with transarterial chemoembolization (TACE) in patients with intermediate‐ to advanced‐stage (BCLC stage B/C) HCC to determine the current evidence. Through a database search, we included 18 high‐quality studies (one randomized controlled trial RCT, five propensity‐score matching nonrandomized comparative trials NRCTs, and 12 NRCTs) that compared survival outcomes of 5,986 patients after PH and TACE. We found significant survival benefits for PH over TACE in BCLC stage B/C patients (hazard ratio HR, 0.59; 95% confidence interval CI, 0.51‐0.67; P < 0.00001; I2 = 84%). According to the BCLC, both stage B and stage C patients showed significantly better overall survival (OS) for PH compared to TACE (HR, 0.53; 95% CI, 0.43‐0.65; P < 0.00001; I2 = 77%; HR, 0.67; 95% CI, 0.59‐0.77; P < 0.00001; I2 = 79%, respectively). Five‐year survival rates for PH were significantly higher than those for TACE in BCLC stage B/C, stage B, and BCLC stage C patients (odds ratio OR, 2.71, 2.77, and 3.03, respectively; all P < 0.00001). Survival benefits persisted across subgroup, sensitivity, and metaregression analyses; interstudy heterogeneity remained constant. Conclusion: This meta‐analysis suggests that surgical resection provides survival benefits in patients with intermediate‐ to advanced‐stage HCC. The evidence found herein may assist in the choice of treatment modality based on diverse definitions of operability. (Hepatology 2018).
Non-alcoholic fatty liver disease (NAFLD) is a dominant cause of chronic liver disease, but the exact mechanism of progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains ...unknown. Here, we investigated the role of exosomes in NAFLD progression. Exosomes were isolated from a human hepatoma cell line treated with palmitic acid (PA) and their miRNA profiles examined by microarray. The human hepatic stellate cell (HSC) line (LX-2) was then treated with exosome isolated from hepatocytes. Compared with controls, PA-treated hepatocytes displayed significantly increased CD36 and exosome production. The microarray analysis showed there to be distinctive miRNA expression patterns between exosomes from vehicle- and PA-treated hepatocytes. When LX-2 cells were cultured with exosomes from PA-treated hepatocytes, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with exosomes from vehicle-treated hepatocytes. In conclusion, PA treatment enhanced the production of exosomes in these hepatocytes and changed their exosomal miRNA profile. Moreover, exosomes derived from PA-treated hepatocytes caused an increase in the expression levels of fibrotic genes in HSCs. Therefore, exosomes may have important roles in the crosstalk between hepatocytes and HSCs in the progression from simple steatosis to NASH.
Despite of extremely high theoretical capacity of Si (3579 mAh g−1), Si anodes suffer from pulverization and delamination of the electrodes induced by large volume change during charge/discharge ...cycles. To address those issues, herein, self‐healable and highly stretchable multifunctional binders, polydioxythiophene:polyacrylic acid:phytic acid (PEDOT:PAA: PA, PDPP) that provide Si anodes with self‐healability and excellent structural integrity is designed. By utilizing the self‐healing binder, Si anodes self‐repair cracks and damages of Si anodes generated during cycling. For the first time, it is demonstrated that Si anodes autonomously self‐heal artificially created cracks in electrolytes under practical battery operating conditions. Consequently, this self‐healable Si anode can still deliver a reversible capacity of 2312 mAh g−1 after 100 cycles with remarkable initial Coulombic efficiency of 94%, which is superior to other reported Si anodes. Moreover, the self‐healing binder possesses enhanced Li‐ion diffusivity with additional electronic conductivity, providing excellent rate capability with a capacity of 2084 mAh g−1 at a very high C‐rate of 5 C.
Here, we developed a multifunctional self‐healing binder that extends the cycle life of Si anodes by self‐repairing cracks of Si anodes. Furthermore, our self‐healing binder provides enhanced electrokinetics, resulting in exceptional rate capability. For the first time, we also quantified the self‐healing efficiency of Si anodes, which can be widely employed for self‐healing devices.
Kidney organoids derived from human pluripotent stem cells (hPSCs) have extensive potential for disease modelling and regenerative medicine. However, the limited vascularization and immaturity of ...kidney organoids have been still remained to overcome. Extracellular matrix (ECM) can provide mechanical support and a biochemical microenvironment for cell growth and differentiation. Here in vitro methods using a kidney decellularized extracellular matrix (dECM) hydrogel to culture hPSC‐derived kidney organoids, which have extensive vascular network and their own endothelial cells, are reported. Single‐cell transcriptomics reveal that the vascularized kidney organoids cultured using the kidney dECM have more mature patterns of glomerular development and higher similarity to human kidney than those cultured without the kidney dECM. Differentiation of α‐galactosidase A (GLA)‐knock‐out hPSCs generated using CRISPR/Cas9 into kidney organoids by the culture method using kidney dECM efficiently recapitulate Fabry nephropathy with vasculopathy. Transplantation of kidney organoids with kidney dECM into kidney of mouse accelerates the recruitment of endothelial cells from the host mouse kidney and maintains vascular integrity with the more organized slit diaphragm‐like structures than those without kidney dECM. The kidney dECM methodology for inducing extensive vascularization and maturation of kidney organoids can be applied to studies for kidney development, disease modeling, and regenerative medicine.
The limited vascularization and immaturity of kidney organoids are still to be overcome. Here in vitro methods using a kidney dECM hydrogel to culture hPSC‐derived kidney organoids, which have extensive vascular network with their own endothelial cells and matured nephron‐like structures, are reported. This methodology can be applied to studies for kidney development, disease modeling, and regenerative medicine.
Surface modification is one of the important steps for synthesizing hydrophobic silica aerogels by ambient pressure drying in which silylating agent plays a vital role. Trimethylchlorosilane and many ...kinds of methoxysilanes like trimethylmethoxysilane, dimethyldimethoxysilane, and methyltrimethoxysilane have been used as the silylating agents. In this work, silylation effects were investigated with different molar ratios of silylating agent/n-hexane mixture. In addition, the mechanism of the silylation reaction is explained based on the molecular structures by considering the number of methoxy/methyl groups. The silylation extent was characterized by using optical imaging, bulk density and porosity analyses, Fourier-transform infrared spectroscopy, scanning electron microscopy, and Brunauer-Emmett-Teller, Barrett-Joyner-Halenda, and contact angle measurements. It has been found that the methoxysilane-based silylating agents can be used as a replacement without producing the harmful hydrochloric acid and retaining the similar tendency to trimethylchlorosilane in surface modification. This research approach seeks to an alternative silylating agent by investigating the impact on the surface modification based on the molecular structural parameters and reaction mechanisms.
Highlights
Sodium silicate-based silica aerogels were formed by using various silylating agents.
Silylation ability depends on the molecular structure of the methoxysilane.
Silylation could be evaluated from pore structure and electron distribution degree.
DMDMS was found to be excellent silylating agent among the methoxysilanes studied.
Increased serum levels of immunoglobulin E (IgE) is a risk factor for various diseases, including allergy and anaphylaxis. However, the source and ontogeny of B cells producing IgE under steady state ...conditions are not well defined. Here, we show plasma cells that develop in the thymus and potently secrete IgE and other immunoglobulins, including IgM, IgA, and IgG. The development of these IgE-secreting plasma cells are induced by IL-4 produced by invariant Natural Killer T cells, independent of CD1d-mediated interaction. Single-cell transcriptomics suggest the developmental landscape of thymic B cells, and the thymus supports development of transitional, mature, and memory B cells in addition to plasma cells. Furthermore, thymic plasma cells produce polyclonal antibodies without somatic hypermutation, indicating they develop via the extra-follicular pathway. Physiologically, thymic-derived IgEs increase the number of mast cells in the gut and skin, which correlates with the severity of anaphylaxis. Collectively, we define the ontogeny of thymic plasma cells and show that steady state thymus-derived IgEs regulate mast cell homeostasis, opening up new avenues for studying the genetic causes of allergic disorders.
: Besifovir dipivoxil maleate (BSV) and tenofovir alafenamide fumarate (TAF) have been recently approved in Korea as the initial antiviral agents for chronic hepatitis B (CHB). However, the ...real-world outcome data for these drugs remain limited. Therefore, we conducted a noninferiority analysis using real-world data to compare the clinical outcomes of the two nucleotide analogs in treatment-naïve patients with CHB.
: We retrospectively investigated a cohort of patients with CHB who received BSV or TAF as first-line antiviral agents. The endpoints were virological response (VR) and liver-related clinical outcomes.
: A total of 537 patients, consisting of 202 and 335 patients administered BSV and TAF, respectively, were followed up for 42 months. No significant difference was observed between the VRs of the patients from the two groups. The rates of biochemical response, virologic breakthrough, and incidence rates of hepatocellular carcinoma did not differ between the groups. However, the hepatitis B e antigen seroclearance rate was higher and the renal function declined less in the BSV group. Multivariable analysis indicated older age, alcohol abuse, cirrhosis and ascites, and lower serum HBV DNA level to be independently associated with increased hepatocellular carcinoma risk. The 1:1 propensity score-matched analysis with 400 patients showed VR rates of 85.0% and 88.7% in the BSV and TAF group patients, respectively, at 2 years. The absolute value of the 95% confidence interval for the difference (-0.04 to 0.12) satisfied the a priori limit of a noninferiority of 0.15.
: BSV is noninferior to TAF in terms of VR, and their clinical outcomes are comparable to CHB.
Bacterial colonization is an essential aspect of bronchiectasis. Although Haemophilus influenzae is a frequent colonizer in some regions, its clinical impacts are poorly understood. This study aimed ...to elucidate the impact of H. influenzae colonization in patients with bronchiectasis.
This retrospective study screened adult patients diagnosed with bronchiectasis at a tertiary referral center between April 1, 2003, and May 16, 2021, in South Korea. Propensity score matching was used to match patients with and without H. influenzae colonization. We assessed the severity of bronchiectasis as per the bronchiectasis severity index, the incidence of exacerbation, differences in lung function, and all-cause mortality.
Out of the 4,453 patients with bronchiectasis, 79 (1.8%) were colonized by H. influenzae. After 1:2 propensity score matching, 78 and 154 patients were selected from the H. influenzae colonizer and non-colonizer groups, respectively. Although there were no significant differences between the groups regarding baseline demographics, patients colonized with H. influenzae had a higher bronchiectasis severity index (median 6 interquartile range 4-8 vs. 4 2-7, p = 0.002), associated with extensive radiographic involvement (52.2% vs. 37.2%, p = 0.045) and mild exacerbation without hospitalization (adjusted incidence rate ratio 0.15; 95% confidence interval 0.12-0.24). Lung function and mortality rates did not reveal significant differences, regardless of H. influenzae colonization.
H. influenzae colonization in bronchiectasis was associated with more severe disease and greater incidence of mild exacerbation, but not lung function and mortality. Attention should be paid to patients with bronchiectasis with H. influenzae colonization.
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