Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Association of gout medications and risk of cataract: a population-based case-control study.

BACKGROUND: The relationship between gout medication use and cataract development is controversial. Moreover, limited clinical studies have evaluated this relationship. AIM: To assess the effects of colchicine, allopurinol and benzbromarone on the risk of cataract in patients with gout. DESIGN: Population-based nested case-control study. METHODS: We enrolled 7900 patients who had received a new diagnosis of cataract >3 years after gout diagnosis into the study group and 33 475 patients who did not receive a diagnosis of cataract into the control group by matching for age, sex and the year of gout diagnosis at a ratio of 1:1. We used World Health Organization's defined daily dose (DDD) as a measure to assess the dosage of colchicine, allopurinol and benzbromarone exposure. Logistic regression was used to estimate crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of cataract. RESULTS: The risk of cataract significantly increased in patients who received colchicine at a cumulative DDD of ≥66.5 (OR = 1.17, 95% CI = 1.01-1.36, P = 0.041). In the age-stratified analysis, patients with gout aged >60 years had a higher risk of cataract (OR = 1.27, 95% CI = 1.06-1.53, P = 0.011) than did patients aged <60 years. Allopurinol and benzbromarone had no association with cataract. CONCLUSIONS: In this population-based nested case-control study, we observed that colchicine use increased the risk of cataract in patients with gout, especially in those aged >60 years who received colchicine at a cumulative DDD of >66.5.

Nasotracheal intubation in patients with limited mouth opening: a comparison between fibreoptic intubation and the Trachway®.

In patients with limited mouth opening, traditional laryngoscopy and videolaryngoscopes are not useful when performing nasotracheal intubation. Eighty patients with limited mouth opening who required nasotracheal intubation were randomly assigned to either fibreoptic intubation (n = 40) or the Trachway(®) (n = 40). Using the modified nasal intubation difficulty scale, 22 (55%) patients who received fibreoptic intubation were categorised as no difficulty compared with 40 (100%) patients in the Trachway group (p < 0.001). Mean (SD) total intubation time was 71.8 (23.3) s in patients who received fibreoptic intubation compared with 35.4 (9.8) s in the Trachway group (p < 0.001). We conclude that the Trachway technique for nasotracheal intubation is quicker and easier compared with fibreoptic intubation in patients with limited mouth opening.

High seroprevalence of human herpesvirus type 8 in patients with hepatocellular carcinoma.

Cirrhosis patients have immunologic insufficiency and a high seroprevalence of human herpesvirus type 8 (HHV-8). Nearly all hepatocellular carcinoma (HCC) patients are cirrhotic and have immunoabnormalities. This study aimed to assess the HHV-8 seroprevalence and hemograms in HCC patients. Blood samples from 95 HCC patients, 95 age-, sex-, and Child-Pugh class-matched cirrhotics, and 95 age- and sex-matched healthy controls were analyzed for anti-HHV-8 antibodies, HHV-8 DNA, and lymphocyte, monocyte, and platelet counts. HCC patients had lower lymphocyte and platelet counts and a higher monocyte count than the healthy controls (each p < 0.0001). HCC patients, and particularly those with a severe Child-Pugh class, had higher platelet counts than the corresponding cirrhosis patients (p = 0.003 and 0.002, respectively). HHV-8 seropositivity and antibody titers in HCC patients were comparable with values in cirrhosis patients and were much higher than in controls (both p < 0.0001). HCC patients, but not cirrhosis patients, had a higher prevalence of high anti-HHV-8 antibody titers (≥ 1:160) than healthy controls (p = 0.003). HCC patients with lymphopenia or thrombocytopenia had lower HHV-8 seropositivity than those without lymphopenia and thrombocytopenia (p = 0.04 and 0.01, respectively). One each of HCC and cirrhosis patients were positive for HHV-8 DNA. HCC patients seemed to suffer from less severe or shorter duration of portal hypertension compared with Child-Pugh class-matched cirrhosis patients. HCC patients had a high HHV-8 seroprevalence, which seemed to be inversely associated with lymphopenia and thrombocytopenia.

CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex.

Converging epidemiological studies indicate that cannabis abuse during adolescence increases the risk of developing psychosis and prefrontal cortex (PFC)-dependent cognitive impairments later in life. However, the mechanisms underlying the adolescent susceptibility to chronic cannabis exposure are poorly understood. Given that the psychoactive constituent of cannabis binds to the CB1 cannabinoid receptor, the present study was designed to determine the impact of a CB1 receptor agonist (WIN) during specific windows of adolescence on the functional maturation of the rat PFC. By means of local field potential recordings and ventral hippocampal stimulation in vivo, we found that a history of WIN exposure during early (postnatal days - P35-40) or mid-(P40-45) adolescence, but not in late adolescence (P50-55) or adulthood (P75-80), is sufficient to yield a state of frequency-dependent prefrontal disinhibition in adulthood comparable to that seen in the juvenile PFC. Remarkably, this prefrontal disinhibition could be normalized following a single acute local infusion of the GABA-Aα1 positive allosteric modulator Indiplon, suggesting that adolescent exposure to WIN causes a functional downregulation of GABAergic transmission in the PFC. Accordingly, in vitro recordings from adult rats exposed to WIN during adolescence demonstrate that local prefrontal GABAergic transmission onto layer V pyramidal neurons is markedly reduced to the level seen in the P30-35 PFC. Together, these results indicate that early and mid-adolescence constitute a critical period during which repeated CB1 receptor stimulation is sufficient to elicit an enduring state of PFC network disinhibition resulting from a developmental impairment of local prefrontal GABAergic transmission.

Left endobronchial intubation with a double-lumen tube using direct laryngoscopy or the Trachway® video stylet.

We compared direct laryngoscopy with a Macintosh blade vs indirect bronchoscopy with a Trachway® stylet, for endobronchial intubation with a left-sided double-lumen tube. We allocated participants scheduled for thoracic surgery and who had normal predicted laryngoscopy, 30 to each group. The mean (SD) intubation times with laryngoscope and Trachway were 48 (11) s vs 28 (4) s, respectively, p < 0.001. The rates of hoarseness on the first postoperative day, categorised as none/mild/moderate/severe, were 10/12/7/1 and 22/6/2/0, respectively, p = 0.008, without differences on subsequent days. Left endobronchial intubation with a double-lumen tube is slower using direct laryngoscopy and causes more hoarseness than indirect bronchoscopy with a Trachway stylet.

HLA-B*15:02 is associated with anemia in patients with chronic hepatitis C treated with pegylated interferon-α and ribavirin.

To investigate the relationship between human leukocyte antigen (HLA) class I and II alleles and treatment-induced anemia in chronic hepatitis C (CHC) patients receiving combination therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV). One hundred six naïve CHC patients (59 females and 47 males; mean age, 53.08 years) who underwent combination treatment were enrolled. The patients were considered positive for hemoglobin (Hb)-related side effects if the Hb concentrations dropped below 10 g/dl during PEG-IFN-α plus RBV treatment. The HLA-A, -B, -C, -DR, and -DQ loci were investigated by sequence-based genotyping. The effects of the clinical characteristics, virologic variables, and the HLA alleles on treatment-induced anemia were evaluated by a logistic regression analysis. Forty patients (37.7%) had Hb levels below 10 g/dl during the treatment course. Low baseline Hb levels and an advanced liver fibrosis stage were associated with decreases in Hb levels to below 10 g/dl. The occurrence of treatment-related anemia (Hb < 10 g/dl) was significantly associated with HLA-B*15:02 as shown by multivariate analysis (adjusted odds ratio, 8.13; 95% confidence interval: 1.19-55.70; P-value after Holm's procedure, 0.03). HLA-B*15:02 is associated with treatment-induced anemia in Taiwanese CHC patients receiving combination therapy with PEG-IFN-α plus RBV.

Comparison of the GlideScope® videolaryngoscope and the Macintosh laryngoscope for double-lumen tube intubation.

Intubation with a double-lumen tube is important for achieving one-lung ventilation and facilitating thoracic surgery. The GlideScope(®) videolaryngoscope (Verathon Inc., Bothell, WA, USA) is designed to assist tracheal intubation for patients with a difficult airway. We wished to compare the GlideScope and direct laryngoscopy for double-lumen tube intubation. Sixty adult patients requiring a double-lumen tube for thoracic surgery and predicted uncomplicated laryngoscopy were randomly assigned to a direct Macintosh laryngoscopy group (n = 30) or a GlideScope group (n = 30). The mean (SD) duration of intubation was longer in the Macintosh group (62.5 (29.7) s) than in the GlideScope group (45.6 (10.7) s; p = 0.007). There was no difference in the success of the first attempt at intubation (26/30 (87%) and 30/30 (100%) for Macintosh and GlideScope groups, respectively; p = 0.112). The incidence of sore throat and hoarseness was higher in the Macintosh group (18 (60%) and 14 (47%), respectively) than in the GlideScope group (6 (20%) and 4 (13%), respectively; p = 0.003 and 0.004). We conclude that double-lumen tube intubation in patients with predicted normal laryngoscopy is easier using the GlideScope videolaryngoscope than the Macintosh laryngoscope.

Chromate removal as influenced by the structural changes of soil components upon carbonization at different temperatures.

Surface fire could induce heat transferring into the soil, creating a carbonized environment, which may alter the chemical compositions of soil organic matters (SOM). In the study, a surface soil was carbonized at up to 600 °C with limited air to simulate soils experiencing a surface fire, and Cr(VI) removal on the carbonized soils was investigated. NMR and FTIR analyses demonstrated a remarkable change of SOM structures at 300-400 °C. TGA-MS spectra indicated that (e.g. C(2)H(4), CH(3)OH and C(3)H(8)) were the major components in the evolved gases from the pyrolyzed soil. A maximum amount of Cr(VI) removal (ca. 4 mg g(-1) soil) occurred for the 200 °C-carbonized soils, attributed mainly to a significant increase of Cr(VI) reduction by 0.1 M KCl extractable organic carbon (EOC) with abundant carboxylic groups. Nonetheless, the formation of aromatic C upon carbonization of the soil at >400 °C may be responsible for Cr(VI) reduction.

Random forest can predict 30-day mortality of spontaneous intracerebral hemorrhage with remarkable discrimination.

BACKGROUND AND PURPOSE: Risk-stratification models based on patient and disease characteristics are useful for aiding clinical decisions and for comparing the quality of care between different physicians or hospitals. In addition, prediction of mortality is beneficial for optimizing resource utilization. We evaluated the accuracy and discriminating power of the random forest (RF) to predict 30-day mortality of spontaneous intracerebral hemorrhage (SICH). METHODS: We retrospectively studied 423 patients admitted to the Taichung Veterans General Hospital who were diagnosed with spontaneous SICH within 24 h of stroke onset. The initial evaluation data of the patients were used to train the RF model. Areas under the receiver operating characteristic curves (AUC) were used to quantify the predictive performance. The performance of the RF model was compared to that of an artificial neural network (ANN), support vector machine (SVM), logistic regression model, and the ICH score. RESULTS: The RF had an overall accuracy of 78.5% for predicting the mortality of patients with SICH. The sensitivity was 79.0%, and the specificity was 78.4%. The AUCs were as follows: RF, 0.87 (0.84-0.90); ANN, 0.81 (0.77-0.85); SVM, 0.79 (0.75-0.83); logistic regression, 0.78 (0.74-0.82); and ICH score, 0.72 (0.68-0.76). The discriminatory power of RF was superior to that of the other prediction models. CONCLUSIONS: The RF provided the best predictive performance amongst all of the tested models. We believe that the RF is a suitable tool for clinicians to use in predicting the 30-day mortality of patients after SICH.

Thymosin beta-4 upregulates anti-oxidative enzymes and protects human cornea epithelial cells against oxidative damage.

BACKGROUND: The ability to scavenge reactive oxygen species (ROS) is crucial for cornea epithelial cells to resist oxidative damage. The authors previously demonstrated that exogenous thymosin beta-4 (T beta(4)) was able to protect human cornea epithelial (HCE-T) cells against H(2)O(2)-induced oxidative damage, and its cellular internalisation was essential. The aim of this study is to further elucidate its protective mechanism. METHODS: HCE-T cells with or without T beta(4) pretreatment were exposed to H(2)O(2), and the differences in caspase activity, intracellular ROS levels, cell viability, and the expression of anti-oxidative enzymes, were measured and compared. RESULTS: Besides reducing caspase-9 activation and intracellular ROS levels induced by H(2)O(2), treatment of T beta(4) could also increase cell viability and stimulate the expression of manganese superoxide dismutase (SOD) and copper/zinc SOD. Moreover, both transcription and translation levels of catalase were also upregulated by T beta(4) in the presence of exogenous H(2)O(2). Furthermore, it was demonstrated that the addition of catalase inhibitor abrogated the protective effect of T beta(4) against H(2)O(2)-induced oxidative damage. CONCLUSION: To the best of the authors' knowledge, this is the first report to show that T beta(4 )was capable of upregulating anti-oxidative enzymes in human corneal epithelial cells, and these findings further support its role in cornea protection.