Age and hepatic fibrosis are the factors that increase the risk of hepatocellular carcinoma over time. We aimed to explore their impact at the initiation of antiviral therapy on hepatocellular ...carcinoma among chronic hepatitis C (CHC) patients.
A total of 1,281 biopsy-proven CHC patients receiving IFN-based therapy were followed for a mean period of 5.5 years.
The 5-year cumulative incidence of hepatocellular carcinoma did not differ between non-sustained virological response (SVR) and SVR patients who were <40 years old (7.7% vs. 0.5%,
= 0.1) but was significantly higher in non-SVR patients between 40 and 55 years old (18.0% vs. 1.3%,
< 0.001) and >55 years old (15.1% vs. 7.9%,
= 0.03). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patients 40 to 55 years old HR/95% confidence intervals (CI), 10.92/3.78-31.56;
< 0.001 and >55 years old (HR/CI, 1.96/1.06-3.63;
= 0.03) but not in patients <40 years old (HR/CI, 2.76/0.41-18.84;
= 0.3). The 5-year cumulative incidence of hepatocellular carcinoma did not differ between non-SVR and SVR patients whose fibrosis stage was F0-1 (4.6% vs. 1.9%,
= 0.25) but was higher in non-SVR patients with F2-3 (21.4% vs. 4.3%,
< 0.001) or F4 (33.5% vs. 8.4%,
= 0.002). Compared with SVR, non-SVR was independently predictive of hepatocellular carcinoma in patients with F2-3 (HR/CI, 4.36/2.10-9.03;
< 0.001) and F4 (HR/CI, 3.84/1.59-9.30;
= 0.03) but not in those with F0-1 (HR/CI, 1.53/0.49-4.74;
= 0.47).
Delayed hepatitis C virus clearance for patients with CHC >40 years old or with a fibrosis stage >2 increases the risk of hepatocellular carcinoma over time.
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Following myocardial infarction (MI), necrotic cardiomyocytes (CMs) are replaced by fibroblasts and collagen tissue, causing abnormal electrical signal propagation, desynchronizing cardiac ...contraction, resulting in cardiac arrhythmia. In this work, a conductive polymer, poly-3-amino-4-methoxybenzoic acid (PAMB), is synthesized and grafted onto non-conductive gelatin. The as-synthesized PAMB-G copolymer is self-doped in physiological pH environments, making it an electrically active material in biological tissues. This copolymer is cross-linked by carbodiimide to form an injectable conductive hydrogel (PAMB-G hydrogel). The un-grafted gelatin hydrogel is prepared in a similar manner as a control. Both test hydrogels not only provide an optimal matrix for CM adhesion and growth but also maintain CM morphology and functional proteins. The conductivity of PAMB-G hydrogel is ca. 12 times higher than that of gelatin hydrogel. Microelectrode array analyses reveal that a heart placed on the PAMB-G hydrogel has a higher field potential amplitude than that placed on the gelatin hydrogel and can pass current from one heart to excite another heart at a distance. The injection of PAMB-G hydrogel into the scar zone following an MI in a rat heart improves electrical impulse propagation over that in a heart that has been treated with gelatin hydrogel, and synchronizes heart contraction, leading to preservation of the ventricular function and reduction of cardiac arrhythmia, demonstrating its potential for use in treating MI.
Cardiac tissue engineering is of particular importance in the combination of contracting cells with a biomaterial scaffold, which serves as a cell-delivery construct, to replace cardiomyocytes (CMs) ...that are lost as a result of an infarction, to restore heart function. However, most biomaterial scaffolds are nonconductive and may delay regional conduction, potentially causing arrhythmias. In this study, a conductive CM-delivery construct that consists of a gelatin-based gelfoam that is conjugated with a self-doped conductive polymer (poly-3-amino-4-methoxybenzoic acid, PAMB) is proposed as a cardiac patch (PAMB-Gel patch) to repair an infarcted heart. A nonconductive plain gelfoam (Gel patch) is used as a control. The electrical conductivity of the PAMB-Gel patch is approximately 30 times higher than that of the Gel patch; as a result, the conductive PAMB-Gel patch can substantially increase electrical conduction between distinct clusters of beating CMs, facilitating their synchronous contraction. In vivo epicardial implantation of the PAMB-Gel patch that is seeded with CMs (the bioengineered patch) in infarcted rat hearts can significantly enhance electrical activity in the fibrotic tissue, improving electrical impulse propagation and synchronizing CM contraction across the scar region, markedly reducing its susceptibility to cardiac arrhythmias. Echocardiography shows that the bioengineered conductive patch has an important role in the restoration of cardiac function, perhaps owing to the synergistic effects of its conductive construct and the synchronously beating CMs. These experimental results reveal that the as-proposed bioengineered conductive patch has great potential for repairing injured cardiac tissues.
Implantation of the bioengineered conductive patch in infarcted hearts improves electrical impulse propagation and synchronizes cardiomyocyte contraction across the scar region, reducing susceptibility such hearts to cardiac arrhythmias and restoring heart function. Display omitted
Abstract In this paper, we revisit some common recommendations regarding the analysis of matched‐pair and stratified experimental designs in the presence of attrition. Our main objective is to ...clarify a number of well‐known claims about the practice of dropping pairs with an attrited unit when analyzing matched‐pair designs. Contradictory advice appears in the literature about whether or not dropping pairs is beneficial or harmful, and stratifying into larger groups has been recommended as a resolution to the issue. To address these claims, we derive the estimands obtained from the difference‐in‐means estimator in a matched‐pair design both when the observations from pairs with an attrited unit are retained and when they are dropped. We find limited evidence to support the claims that dropping pairs helps recover the average treatment effect, but we find that it may potentially help in recovering a convex‐weighted average of conditional average treatment effects. We report similar findings for stratified designs when studying the estimands obtained from a regression of outcomes on treatment with and without strata fixed effects.
Background and Aim
Hepatitis B virus (HBV) may reactivate when treating chronic hepatitis C (CHC) with direct acting antivirals (DAA). We aim to investigate the risk of HBV reactivation during DAA ...therapy.
Methods
Chronic hepatitis C patients receiving pan‐oral DAA therapy from December 2013 to August 2016 were evaluated. Fifty‐seven patients that had a past HBV infection (negative hepatitis B surface antigen HBsAg and positive hepatitis B core antibody) and seven patients that had a current HBV infection (positive HBsAg) were enrolled. Serum HBV and hepatitis C virus (HCV) markers were regularly measured. The endpoints were the HCV sustained virological response (SVR) and the HBV virological/clinical reactivation.
Results
The overall SVR12 rate was 96.9%, and two patients, one with positive HBsAg, had a relapse of HCV. No episodes of HBV virological reactivation were observed among the patients with a past HBV infection. For the seven patients with a current HBV infection, HBV virological reactivation was found in four (57.1%) of the seven patients. Clinical reactivation of HBV was observed in one patient with pretreatment detectable HBV DNA and recovered after entecavir administration. For the other three patients with HBV virological reactivation, the reappearance of low level HBV DNA without clinical reactivation was observed. HBsAg levels demonstrated only small fluctuations in all the patients.
Conclusions
There was a minimal impact of hepatitis B core antibody seropositivity on HCV efficacy and safety. For CHC patients with current HBV infection, the risk of HBV reactivation was present, and monitoring the HBV DNA level during therapy is warranted.
The outcome of HBV infection, including the dynamics of HBsAg and HBV virological reactivation, among patients coinfected with HCV receiving direct-acting antivirals (DAAs) remains unclear. Thus, we ...aimed to analyze HBV-related outcomes in these patients.
Serial HBsAg and HBV DNA levels were measured in 79 HBV/HCV-coinfected patients receiving DAAs (13 receiving anti-HBV nucleot(s)ide analog NUC therapy simultaneously). The endpoints included HBsAg dynamics and seroclearance, HBV reactivation (HBV DNA >1 log increase or >100 IU/ml if undetectable at baseline) and HBV-related clinical reactivation.
HBsAg levels declined from a median of 73.3 IU/ml at baseline to 16.2 IU/ml at the end-of-DAA treatment and increased to 94.1 IU/ml at 12 months post-treatment. During a mean 11.1-months of follow-up, 8 (10.1%) patients experienced HBsAg seroclearance and 30 (38.0%) HBV reactivation (12-month cumulative incidence, 10.3% and 40.4%, respectively). Patients with pre-treatment HBsAg ≤10 IU/ml had a significantly higher rate of HBsAg seroclearance (hazard ratio HR 8.52; 95% CI 1.048–69.312) and lower risk of HBV reactivation than those with pre-treatment HBsAg >10 IU/ml (HR 2.88; 95% CI 1.057–7.844) in multivariate analyses. Six patients (4 cirrhotics) not receiving NUC therapy experienced HBV-related clinical reactivation; 3 of the 4 cirrhotics developed liver failure and 2 died despite immediate NUC therapy. Compared to untreated HBV-monoinfected patients, HBV/HCV-coinfected patients without NUC prophylaxis had a similar rate of HBsAg seroclearance, but a significantly higher risk of HBV reactivation following DAA therapy (HR 6.59; 95% CI 2.488–17.432).
DAA-treated HBV/HCV-coinfected patients had significantly higher rates of HBV seroclearance, particularly among those with low pre-treatment HBsAg titer, but were at higher risk of HBV reactivation, particularly among those with higher pre-treatment HBsAg titer. Prophylactic anti-HBV therapy is essential for cirrhotic patients, irrespective of baseline HBV DNA levels.
We studied outcomes relating to hepatitis B virus (HBV) in patients coinfected with both hepatitis B and C. Patients receiving direct-acting antiviral treatment for hepatitis C were more likely to experience seroclearance (or functional cure of HBV), but were also more likely to experience HBV reactivation, which can lead to hepatitis, liver failure and death. In coinfected cirrhotic patients being treated for HCV, prophylactic treatment for HBV is mandatory.
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•HBsAg levels decline during DAA therapy and rebound post-DAA therapy in HBV/HCV coinfected patients.•HBsAg loss can occur in HBV/HCV coinfected patients on DAA therapy at a frequency seen in HBV monoinfection.•HBV/HCV-coinfected patients are at risk of HBV reactivation after DAA, especially in those with higher HBsAg levels.•HBV/HCV coinfected cirrhotic patients on DAAs should undergo HBV prophylaxis to reduce risk of hepatic failure and death.•Quantitative HBsAg measurement could guide decision-making in HBV/HCV coinfected patients on DAA therapy.
Background and Aim
Hepatitis B virus (HBV) surface antigen (HBsAg) seroreversion usually occurs during immunosuppressive therapy. The risk and factors of HBsAg seroreversion from resolved HBV ...infection in the general population remained unclear.
Methods
This retrospective study enrolled subjects with resolved HBV infection and who had received at least two times of screening in a longitudinal community screening program. HBsAg, hepatitis B surface antibody (anti‐HBs), and hepatitis C virus antibody (anti‐HCV) were tested every time in all subjects. The primary endpoint was HBsAg seroreversion.
Results
Of the 7630 subjects enrolled, 5158 (67.6%) subjects had positive anti‐HBs at baseline. HBsAg seroreversion occurred in 84 subjects during 42 815‐person‐year follow‐up with an annual incidence of 0.2% and a 10‐year cumulative risk of 1.9%. Anti‐HBV treatment‐experienced subjects had a significantly higher risk of HBsAg seroreversion than anti‐HBV treatment‐naive subjects (83/310 26.8% vs 1/7320 0.01%, P < 0.001). Lower rates of positive anti‐HBs and anti‐HCV were observed in anti‐HBV treatment‐experienced subjects who developed HBsAg seroreversion. Both positive anti‐HBs (hazard ratio/95% confidence interval: 0.56/0.348–0.903, P = 0.017) and positive anti‐HCV (hazard ratio/95% confidence interval: 0.08/0.030–0.234, P < 0.001) were independent factors of HBsAg seroreversion in anti‐HBV treatment‐experienced subjects. Less than 5% of the HBsAg seroreverters had clinical hepatitis flare at HBsAg seroreversion. The HBsAg titer was low, and only transient reappeared in most of the HBsAg seroreverters.
Conclusions
Subjects with resolved HBV infection were at a minimal risk of HBsAg seroreversion, unless with prior anti‐HBV treatment experience. Fortunately, even with a reappearance of HBsAg, it was transient and clinically non‐relevant.
Diabetes mellitus (DM) is a major risk factor for tuberculosis (TB). Evidence has linked the DM-related dysbiosis of gut microbiota to modifiable host immunity to Mycobacterium tuberculosis ...infection. However, the crosslinks between gut microbiota composition and immunological effects on the development of latent TB infection (LTBI) in DM patients remain uncertain.
We prospectively obtained stool, blood samples, and medical records from 130 patients with poorly-controlled DM (pDM), defined as ever having an HbA1c > 9.0% within previous 1 year. Among them, 43 had LTBI, as determined by QuantiFERON-TB Gold in-Tube assay. The differences in the taxonomic diversity of gut microbiota between LTBI and non-LTBI groups were investigated using 16S ribosomal RNA sequencing, and a predictive algorithm was established using a random forest model. Serum cytokine levels were measured to determine their correlations with gut microbiota.
Compared with non-LTBI group, the microbiota in LTBI group displayed a similar alpha-diversity but different beta-diversity, featuring decrease of Prevotella_9, Streptococcus, and Actinomyces and increase of Bacteroides, Alistipes, and Blautia at the genus level. The accuracy was 0.872 for the LTBI prediction model using the aforementioned 6 microbiome-based biomarkers. Compared with the non-LTBI group, the LTBI group had a significantly lower serum levels of IL-17F (p = 0.025) and TNF-α (p = 0.038), which were correlated with the abundance of the aforementioned 6 taxa.
The study results suggest that gut microbiome composition maybe associated with host immunity relevant to TB status, and gut microbial signature might be helpful for the diagnosis of LTBI.
Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by ...regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5 mg/kg) and treated with CCM (25 mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff–Van Gieson, Picro sirius red, and Masson’s trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.
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•Curcumin mitigates pulmonary fibrosis.•Regulation of miR-29a-3p/DNMT3A axis.•Attenuates ECM remodeling & mitochondrial dysfunction.•Promising therapeutic approach for IPF.
Osteosarcoma (OSA) is the most common type of cancer that originates in the bone and usually occurs in young children. OSA patients were treated with neoadjuvant chemotherapy and surgery, and the ...results were disappointing. Marine antimicrobial peptides (AMPs) have been the focus of antibiotic research because they are resistant to pathogen infection. Piscidin-1 is an AMP from the hybrid striped bass (Morone saxatilis × M. chrysops) and has approximately 22 amino acids. Research has shown that piscidin-1 can inhibit bacterial infections and has antinociception and anti-cancer properties; however, the regulatory effects of piscidin-1 on mitochondrial dysfunction in cancer cells are still unknown. We aimed to identify the effects of piscidin-1 on mitochondrial reactive oxygen species (mtROS) and apoptosis in OSA cells. Our analyses indicated that piscidin-1 has more cytotoxic effects against OSA cells than against lung and ovarian cancer cells; however, it has no effect on non-cancer cells. Piscidin-1 induces apoptosis in OSA cells, regulates mtROS, reduces mitochondrial antioxidant manganese superoxide dismutase and mitochondrial transmembrane potential, and decreases adenosine 5'-triphosphate production, thus leading to mitochondrial dysfunction and apoptosis. The mitochondrial antioxidant, mitoTempo, reduces the apoptosis induced by piscidin-1. Results suggest that piscidin-1 has potential for use in OSA treatment.
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