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.

When polymyositis meets Graves' disease: A rare case report.

Polymyositis is rarely associated with Graves' disease. A 22- year-old woman was admitted for progressively worsening proximal muscle weakness of both upper and lower extremities. One month prior to admission, she was diagnosed with thyrotoxicosis and prescribed carbimazole 10mg twice daily. Neurological examination confirmed proximal myopathy and blood investigations revealed marked elevation of muscle enzymes, particularly creatine kinase. Electromyography demonstrated myopathic changes while right quadriceps muscle biopsy showed only traces of inflammatory myopathy. She was treated with pulsed intravenous methylprednisolone followed by tapering doses of oral prednisolone, which was eventually down-titrated to 5mg daily during subsequent clinic visits. The initial clinical improvement that she exhibited did not persist despite being rendered euthyroid. She was readmitted approximately one year later with the same complaint. A second course of intravenous methylprednisolone brought about clinical improvement as well as reduction of creatine kinase levels. A diagnosis of polymyositis was then made, for which she was managed with oral prednisolone 20mg daily in combination with gradual up-titration of azathioprine. She continued to show clinical and biochemical improvements during follow-ups. Polymyositis should be considered in the diagnostic workup of proximal myopathy in a patient with Graves' disease, especially in the setting of markedly raised muscle enzymes.

Impact of ledipasvir/sofosbuvir on the work productivity of genotype 1 chronic hepatitis C patients in Asia.

Chronic, untreated hepatitis C virus (HCV) infection is associated with a poor clinical prognosis and a detrimental impact on patients' lives, including on work productivity. To estimate the value of productivity losses due to genotype 1 (GT1) HCV infection in Hong Kong, Singapore, South Korea and Taiwan and to estimate the potential productivity gains associated with treating patients with ledipasvir/sofosbuvir (LDV/SOF) therapy, an economic model was developed with a time horizon of 1 year. Hepatitis C virus patients entered the model at 12 weeks post-treatment, having achieved or not achieved sustained virological response (SVR). Absenteeism and presenteeism rates were taken from a pooled analysis of data from the ION 1-3 studies. These rates were converted into hours of lost productivity, multiplied by the average wage and applied to the total employed, adult GT1 population in each country. Results were compared assuming no treatment, and assuming all patients were treated with LDV/SOF. Total productivity losses due to untreated HCV were: $11.3 million, $17.1 m, $146.0 m and $349.1 m in Hong Kong, Singapore, South Korea and Taiwan. LDV/SOF treatment resulted in economic gains of $4.5 m, $6.8 m, $58.7 m and $138 m, respectively. These gains were due to reduced presenteeism. The results were sensitive to changes in the prevalence of HCV and the average wage. In conclusion, productivity losses due to untreated HCV infection represent a substantial economic burden. By instituting universal HCV treatment with LDV/SOF (or other therapies with high SVR rates), productivity gains can be achieved.

Higher risk of hepatocellular carcinoma in chronic hepatitis B vs chronic hepatitis C after achievement of virologic response.

It is unclear whether the achievement of virologic response modifies the risk of hepatocellular carcinoma (HCC) differently in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Our aim was to compare the risk of HCC between patients with CHB and CHC who achieved virological response. We analysed data from patients with CHB treated with entecavir (n=2000) or CHC treated with peg-interferon and ribavirin (n=733) at a tertiary hospital from 2004 to 2011. Virological response was defined as serum HBV DNA<15 IU/mL at 1 year of treatment for CHB or the achievement of sustained virologic response for CHC. Virological response was achieved in 1520 patients with CHB (76.0%) and 475 patients with CHC (64.8%). During the median follow-up period of 6 years, 228 patients with CHB (11.4%) and 59 patients with CHC (8.0%) developed HCC. Among patients with virological response, CHB was independently associated with a significantly higher incidence of HCC (hazard ratio, 2.17; 95% CI, 1.30-3.63; P=.003) than CHC. Among patients without virological response, there were no differences in HCC incidence between the two cohorts (P=.52). In patients with cirrhosis at baseline, the incidence of HCC did not differ between the two cohorts even after achieving virological response (P>.99). In conclusion, patients with CHB treated with entecavir were associated with a higher risk of HCC compared to patients with CHC treated with peg-interferon and ribavirin after achieving virological response. However, the risk of HCC did not differ between the two cohorts if the patients had cirrhosis at baseline, even if virological response was achieved.

Tuberous sclerosis and its rare association with macrodactyly and fibrous hamartomas.

Tuberous sclerosis complex is a genetic disease that results in abnormal cellular proliferation and hamartoma growths in multiple organ systems. However, macrodactyly and subcutaneous fibrous harmatomas are very uncommon associations with this disease. We see these rare manifestations in our case report of a 16-year-old female with tuberous sclerosis complex and discuss the imaging findings and pathogenetics of these manifestations. Through this, our report aims to expand the known clinical spectrum of features seen in tuberous sclerosis and aid in its diagnosis.

A phase 3b study of sofosbuvir plus ribavirin in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 2 hepatitis C virus.

In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon-alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon-free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38-46% in Korea. This single-arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12-week duration) in chronic genotype 2 HCV-infected treatment-naive and treatment-experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment-naive and 100% (24/24) of treatment-experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on-treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment-emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all-oral, interferon-free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.

Usage of Traditional and Complementary Medicine (T & CM): Prevalence, Practice and Perception among Post Stroke Patients Attending Conventional Stroke Rehabilitation in A Teaching Hospital in Malaysia.

INTRODUCTION: The lack of evidence that proves the benefit of traditional and complementary medicines (T & CM) in treating chronic medical conditions does not deter its usage among patients worldwide. Prevalence of usage among post-stroke patients in Malaysia especially is unknown. This study aims to determine the prevalence, practice and perception of T & CM use among stroke survivors attending an outpatient rehabilitation program in a teaching hospital. METHODS: A cross-sectional study was conducted among 104 post stroke patients attending an outpatient rehabilitation program. A structured self-administered questionnaire was used to collect data on sociodemographic and clinical profile of patients, as well as types of therapy used and perception on T & CM usage. Descriptive analysis was done, and bivariate analysis was used to determine associations between categorical data. RESULTS: Mean age of patients was 62 years (SD 12.2), 54% were Chinese and 75% of the patients had ischaemic stroke. Mean age of T & CM users was younger compared to non- T & CM users (61 years vs. 66 years, p=0.04). Two-thirds (66%) of patients admitted to concurrent T & CM usage while attending conventional post stroke rehabilitation. Acupuncture (40.4%), massage (40.4%) and traditional Chinese medicine (11.5%) were the most common T & CM used. Positive perception was recorded in terms of ability of T & CM usage to relieve post stroke symptoms (68%), and it was safe to use because it was made from 'natural sources'. Negative perception recorded: T & CM caused significant adverse effects (57.6%) and was not safe to be used in combination with other conventional medicines (62.5%). CONCLUSIONS: Concurrent T & CM usage among post-stroke patients attending structured outpatient rehabilitation program is widely practised especially acupuncture, massage and traditional Chinese medicines. Overall the perception towards its use is favourable.

SUMOylation of nonstructural 5A protein regulates hepatitis C virus replication.

Viruses exploit cellular SUMOylation machinery to favour their own propagation. We show that NS5A is a target protein of small ubiquitin-like modifier (SUMO) and is SUMOylated at lysine residue 348. We demonstrated that SUMOylation increased protein stability of NS5A by inhibiting ubiquitylation, and SUMOylation was also required for protein interaction with NS5B. These data imply that SUMO modification may contribute to HCV replication. Indeed, silencing of UBC9 impaired HCV replication in Jc1-infected cells, and HCV replication level was also significantly reduced in SUMO-defective subgenomic replicon cells. Taken together, these data indicate that HCV replication is regulated by SUMO modification of NS5A protein. We provide evidence for the first time that HCV exploits host cellular SUMO modification system to favour its own replication.

Influence of sintering temperature on the microstructure and thermoelectric properties of polycrystalline Fe1.9925P0.0075O3.

The solution combustion process is used to synthesize Fe1.9925P0.0075O3 nano-powders. The sintered Fe1.9925P0.0075O3 bodies are alpha-Fe2O3-based single phase with the rhombohedral structure. The electrical conductivity increases with an increase in sintering temperature because of an increase in grain size and density. The absolute value of the Seebeck coefficient escalates with an increase in sintering temperature up to 1000 degrees C, and then decreases with a further rise in its sintering temperature. The Fe1.9925P0.0075O3 sintered at 1000 degrees C shows the highest power factor, i.e., 1.39 x 10(-5) W m(-1) K(-2) at 700 degrees C.

Nonstructural 5A protein of hepatitis C virus regulates heat shock protein 72 for its own propagation.

We identified heat shock protein 72 (Hsp72) as a host factor that was differentially expressed in cells expressing nonstructural 5A (NS5A) protein. To investigate how NS5A modulates Hsp72 in hepatitis C virus (HCV) life cycle, we examined the role of Hsp72 in HCV replication and virus production. NS5A specifically interacted with Hsp72. Both Hsp72 and nuclear factor of activated T cells 5 (NFAT5) levels were increased in cells expressing NS5A protein. Treatments of N-acetylcysteine and glutathione markedly reduced protein levels of both NFAT5 and Hsp72. Knockdown of NFAT5 resulted in decrease in Hsp72 level in cells expressing NS5A. Importantly, silencing of Hsp72 expression resulted in decrease in both RNA replication and virus production in HCV-infected cells. These data indicate that NS5A modulates Hsp72 via NFAT5 and reactive oxygen species activation for HCV propagation.

Predicted effect-site concentration of propofol and sufentanil for gynecological laparoscopic surgery.

BACKGROUND: this study was to estimate the predicted effect-site concentration of propofol administered by a target-controlled infusion (TCI) for maintenance of anesthesia based on the bispectral (BIS) index as a measure of hypnosis in laparoscopic surgery. METHOD: one-hundred and sixty unpremedicated patients undergoing gynecologic laparoscopy were assigned randomly to receive one of the target effect-site concentrations of propofol 2.0, 2.5, 3.0, 3.5 and 4.0 microg/ml during TCI with propofol and sufentanil. The dose-response relationship of propofol for the maintenance of adequate anesthesia based on BIS, movement and hemodynamic response was investigated using a fixed effect-site concentration of sufentanil (0.2 ng/ml). The BIS values, hemodynamic variables, time course during emergence and intraoperative awareness were also assessed. RESULTS: the predicted effect-site propofol concentrations for adequate anesthesia at the skin incision in 50% (EC(50) ) and 95% (EC(95) ) of patients undergoing gynecologic laparoscopy were 2.2 and 3.7 microg/ml, respectively. The predicted propofol EC(50) and EC(95) to maintain adequate anesthesia in these patients were 2.6 microg/ml (95% CI 2.3-2.7 microg/ml) and 3.6 microg/ml (95% CI 3.3-4.0 microg/ml), respectively. The BIS values, effect-site concentration of propofol, hemodynamic data and time course during emergence and post-operative adverse events were comparable in each group. There were no reports of intraoperative awareness in the post-anesthetic care unit. CONCLUSION: based on the anesthetic depth assessed by the clinical signs and BIS monitoring, the predicted effect-site propofol concentrations for the maintenance of anesthesia in patients undergoing gynecologic laparoscopy were similar in those administered adequate anesthesia at the skin incision during TCI.

Thermoelectric properties of nanocrystalline Ca(3-x)Cu(x)Co4O9 (0 < or = x < or = 0.32) for power generation.

We successfully synthesized nano-sized Ca(3-x)Cu(x)Co4O9 (0 < or = x < or = 0.32) powders by solution combustion process. Plate-like grains and porous structure were observed in the sintered Ca(3-x)Cu(x)Co4O9 ceramics. The sintered Ca(3-x)Cu(x)Co4O9 showed a monoclinic symmetry. The electrical conductivity of the Ca(3-x)Cu(x)Co4O9 increased with increasing temperature, indicative of a semiconducting behavior. The added Cu led to a significant increase in the electrical conductivity. The Seebeck coefficient of the Cu-added Ca(3-x)Cu(x)Co4O9 was much higher than that of the Cu-free Ca3Co4O9. The highest power factor (9.99 x 10(-4) Wm(-1)K-2) was obtained for Ca2.76Cu0.24Co4O9 at 800 degrees C.

Thermoelectric properties of Ca(1-x-y)Dy(x)CeyMnO3 for power generation.

The sintered Ca(1-x-y)Dy(x)CeyMnO3 bodies were a single phase with a perovskite structure without any impurity phases. The calculated crystallite sizes of the Ca(1-x-y)Dy(x)CeyMnO3 were in the range of 43.3 to 63.3 nm. The composition significantly affected their microstructural and thermoelectric characteristics. The doped Dy led to both an increase in the electrical conductivity as well as the absolute value of the Seebeck coefficient, resulting in an enhanced power factor. The highest power factor (5.1 x 10(-4) Wm(-1) K(-2)) was obtained for Ca(0.8)Dy(0.2)MnO3 at 800 degrees C. In this study, we systematically discussed the thermoelectric properties of the Ca(1-x-y)Dy(x)CeyMnO3, with respect to the substitution of Dy and/or Ce for Ca.

Pretreatment of polyethylene terephthalate substrate for the growth of Ga-doped ZnO thin film.

The effect of the pretreatment of polyethylene terephthalate (PET) substrate on the growth of transparent conducting Ga-doped ZnO (GZO) thin film was investigated. Because of its high gas and moisture absorption and easy gas permeation, PET substrate was annealed at 100 degrees C in a vacuum chamber prior to the sputtering growth of GZO thin film for the outgassing of impurity gases. GZO thin film was deposited on the pretreated PET substrate by rf-magnetron sputtering and significantly improved electrical properties of GZO thin film was achieved. Electrical and structural characterizations of the GZO thin films were carried out by 4-point probe, Hall measurement, and scanning electron microscopy, and the effects of the pretreatment on the improved properties of GZO thin films were discussed. This result is not only useful to PET substrate, but also could be applicable to other plastic substrates which inevitably containing the moisture and impurity gases.

Impact of MELD on waitlist outcome of retransplant candidates.

Under the current allocation system for liver transplantation (LTx), primary and retransplantation (ReTx) are treated identically. The aims of this study were (1) to compare the risk of death between ReTx and primary LTx candidates at a given MELD score and (2) to gauge the impact of the MELD-based allocation system on the waitlist outcome of ReTx candidates. Based on data of all waitlist registrants in the United States between 2000 and 2006, unique adult patients with chronic liver disease were identified and followed forward to determine mortality within six months of registration. There were a total of 45,943 patients waitlisted for primary LTx and 2081 registered for ReTx. In the MELD era (n = 30,175), MELD was significantly higher among ReTx candidates than primary LTx candidates (median, 21 vs. 15). Within a range of MELD scores where most transplantation took place, mortality was comparable between ReTx and primary candidates after adjusting for MELD. The probability for LTx increased significantly following implementation of the MELD-based allocation in both types of candidates. We conclude that by and large, primary and ReTx candidates fare equitably under the current MELD-based allocation system, which has contributed to a significant increase in the probability of LTx.

Local structural and electrical properties of ferroelectric Bi3.25La0.75Ti3O12 thin films on Pt.

Ferroelectric Bi3.25La0.75Ti3O12 (BLT) thin films have been grown by a sol-gel method. Annealing conditions after the drying process have been explored over a wide range of temperature. BLT thin films prepared on Pt/TiO2 coated SiO2/Si(100) were investigated by Raman scattering spectroscopy, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy. Raman spectra reveal the growth route of phase-formation of the BLT films. Ferroelectric domains in the thin films are observed by using AFM, registering the electrostatic force response of the thin films in the presence of a low ac field. It is found that the as-grown domain configuration and switching behavior are strongly dependent on growth temperature. Depth-profiling of the electronic states of Bi, Ti, and La atoms shows the oxidation during the growth.

Anti-viral therapy is associated with improved survival but is underutilised in patients with hepatitis B virus-related hepatocellular carcinoma: real-world east and west experience.

BACKGROUND: Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis. METHODS: This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death. RESULTS: Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P < 0.001) while patients receiving anti-viral therapy had increased 5-year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti-viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001). CONCLUSIONS: Anti-viral therapy improved overall survival in patients with HBV-related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti-viral therapy in HBV-related HCC and better linkage-to-care for HBV patients are needed.

Netrin UNC-6 and the regulation of branching and extension of motoneuron axons from the ventral nerve cord of Caenorhabditis elegans.

In the Caenorhabditis elegans embryo, some ventral midline motoneurons extend a process circumferentially to the dorsal midline and a process longitudinally along ventral nerve cord interneurons. Circumferential migrations are guided by netrin UNC-6, which repels motoneuron axons dorsally. Although the motoneuron cell bodies and the longitudinal axons are positioned along UNC-6-expressing interneurons in the ventral nerve cord, the circumferential processes extend only from the motoneuron cell bodies and from defined locations along some longitudinal axons. This implies a mechanism regulates motoneuron branching of UNC-6-responsive processes. We show that expression of unc-6DeltaC, which encodes UNC-6 without domain C, partially rescues circumferential migration defects in unc-6 null animals. This activity depends on the netrin receptors UNC-5 and UNC-40. These results indicate that UNC-6DeltaC can provide the circumferential guidance functions of UNC-6. Furthermore, we show that expression of unc-6DeltaC causes motoneuron branching and the extension of processes from abnormal positions along the ventral nerve cord. This activity is also UNC-5- and UNC-40-dependent. We propose that local interactions mediated by domain C regulate motoneuron branching and responsiveness to the UNC-6 cue.

Evaluation of In-Stent Restenosis After Stent Implantation in the Vertebral Artery Ostium by Multislice Computed Tomography Angiography: Factors Affecting Accurate Diagnosis.

PURPOSE: Few articles have evaluated vertebral artery ostium stents using multislice computed tomography (CT). The purpose of our study was to evaluate the diagnostic performance of 64- and 16-slice CT for detecting significant in-stent restenosis after vertebral artery ostium stenting, and to identify factors affecting the accurate diagnosis by CT. METHODS: We reviewed 57 stents scanned using 64-slice CT and 34 stents using 16-slice CT. The accuracy of CT for diagnosing significant in-stent restenosis (≥ 50% diameter narrowing) was calculated using conventional angiography as a reference standard. Possible factors influencing the diagnostic performance of CT were analyzed, such as CT scanner, image quality, and stent characteristics. RESULTS: With 64-slice CT, 46 (80.7%) of 57 stents were classified as evaluable, while with 16-slice CT, 28 (82.3%) of 34 stents were classified as evaluable. No stents with diameters ≤ 2.75 mm were evaluable. The respective results for 64- versus 16-slice CT were sensitivity 87.5% (95% confidence interval [CI] 47.3-99.7%) versus 100% (95% CI 15.8-100.0%), specificity 94.7% (95% CI 82.3%-99.4%) versus 96.2% (95% CI 80.4-99.9%). Factors reducing the accurate diagnosis were those associated with poor image quality, a diameter ≤ 2.75 mm, and drug-eluting stent type (p < 0.05). CONCLUSIONS: 64-slice and 16-slice CT scans are adequate in stents with diameters > 2.75 mm for the evaluation of in-stent restenosis after stent implantation in the vertebral artery ostium.