Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the ...potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
Abstract
We present a blind time-delay strong lensing (TDSL) cosmographic analysis of the doubly imaged quasar SDSS 1206+4332 . We combine the relative time delay between the quasar images, Hubble ...Space Telescope imaging, the Keck stellar velocity dispersion of the lensing galaxy, and wide-field photometric and spectroscopic data of the field to constrain two angular diameter distance relations. The combined analysis is performed by forward modelling the individual data sets through a Bayesian hierarchical framework, and it is kept blind until the very end to prevent experimenter bias. After unblinding, the inferred distances imply a Hubble constant H0 = 68.8$^{+5.4}_{-5.1}$ km s−1 Mpc−1, assuming a flat Λ cold dark matter cosmology with uniform prior on Ωm in 0.05, 0.5. The precision of our cosmographic measurement with the doubly imaged quasar SDSS 1206+4332 is comparable with those of quadruply imaged quasars and opens the path to perform on selected doubles the same analysis as anticipated for quads. Our analysis is based on a completely independent lensing code than our previous three H0LiCOW systems and the new measurement is fully consistent with those. We provide the analysis scripts paired with the publicly available software to facilitate independent analysis (footnote with link to www.h0licow.org). The consistency between blind measurements with independent codes provides an important sanity check on lens modelling systematics. By combining the likelihoods of the four systems under the same prior, we obtain H0 = 72.5$^{+2.1}_{-2.3}$ km s−1 Mpc−1. This measurement is independent of the distance ladder and other cosmological probes.
Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined.
We completed a comprehensive literature ...search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed.
One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0–12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9–34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4–31.1. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01–16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ2 = 2.12, P = 0.5473).
The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.
Summary
What is known and objective
Febuxostat is recommended as an alternative drug for gouty patients with a history of allopurinol hypersensitivity or carrying the HLA‐B*5801 allele.
Case summary
...An 81‐year‐old man with the medical history of gout presented to our clinic with generalized rashes for 2 days. After taking febuxostat for 2 days, he developed generalized skin rash with high fever. Laboratory tests showed elevated liver enzymes and acute kidney injury.
What is Known and Objective
This is the first identified case of febuxostat‐associated DRESS. Febuxostat should be withdrawn immediately when DRESS is observed to avoid further serious complications.
Time course of liver function tests.
The development of an electronic skin is critical to the realization of artificial intelligence that comes into direct contact with humans, and to biomedical applications such as prosthetic skin. To ...mimic the tactile sensing properties of natural skin, large arrays of pixel pressure sensors on a flexible and stretchable substrate are required. We demonstrate flexible, capacitive pressure sensors with unprecedented sensitivity and very short response times that can be inexpensively fabricated over large areas by microstructuring of thin films of the biocompatible elastomer polydimethylsiloxane. The pressure sensitivity of the microstructured films far surpassed that exhibited by unstructured elastomeric films of similar thickness, and is tunable by using different microstructures. The microstructured films were integrated into organic field-effect transistors as the dielectric layer, forming a new type of active sensor device with similarly excellent sensitivity and response times.
While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant ...tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.
Multiferroics, where (anti-) ferromagnetic, ferroelectric and ferroelastic order parameters coexist, enable manipulation of magnetic ordering by an electric field through switching of the electric ...polarization. It has been shown that realization of magnetoelectric coupling in a single-phase multiferroic such as BiFeO3 requires ferroelastic (71 , 109 ) rather than ferroelectric (180 ) domain switching. However, the control of such ferroelastic switching in a single-phase system has been a significant challenge as elastic interactions tend to destabilize small switched volumes, resulting in subsequent ferroelastic back-switching at zero electric field, and thus the disappearance of non-volatile information storage. Guided by our phase-field simulations, here we report an approach to stabilize ferroelastic switching by eliminating the stress-induced instability responsible for back-switching using isolated monodomain BiFeO3 islands. This work demonstrates a critical step to control and use non-volatile magnetoelectric coupling at the nanoscale. Beyond magnetoelectric coupling, it provides a framework for exploring a route to control multiple order parameters coupled to ferroelastic order in other low-symmetry materials.
Summary Objective To determine whether autophagy contributes to the pathogenesis of degenerative disc disease (DDD) or retards the intervertebral disc (IVD) degeneration, and investigate the possible ...relationship between compression-induced autophagy and intracellular reactive oxygen species (ROS) in nucleus pulposus (NP) cells in vitro. Methods The autophagosome and autophagy-related markers were used to explore the role of autophagy in rat NP cells under compressive stress, which were measured directly by electronic microscopy, monodansylcadaverine (MDC) staining, immunofluorescence, western blot, and indirectly by analyzing the impact of pharmacological inhibitors of autophagy such as 3-methyladenine (3-MA) and chloroquine (CQ). And the relationship between autophagy and apoptosis was investigated by Annexin-V/propidium iodide (PI)-fluorescein staining. In addition, ROS were measured to determine whether these factors are responsible for the development of compression-induced autophagy. Results Our results indicated that rat NP cells activated autophagy in response to the same strong apoptotic stimuli that triggered apoptosis by compression. Autophagy and apoptosis were interconnected and coordinated in rat NP cells exposed to compression stimuli. Compression-induced autophagy was closely related to intracellular ROS production. Conclusions Enhanced degradation of damaged components of NP cells by autophagy may be a crucial survival response against mechanical overload, and extensive autophagy may trigger autophagic cell death. Regulating autophagy and reducing the generation of intracellular ROS may retard IVD degeneration.
BACKGROUND AND PURPOSE Prevention or disease‐modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's ...disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models.
EXPERIMENTAL APPROACH Mesencephalic neuron–glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme‐linked immunosorbent assay and real‐time RT PCR.
KEY RESULTS In mesencephalic neuron–glia cultures, SAHA displayed dose‐ and time‐dependent prolongation of the survival and protection against neurotoxin‐induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation.
CONCLUSION AND IMPLICATIONS The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases.
Biaxial compressive strain has been used to markedly enhance the ferroelectric properties of BaTiO3 thin films. This strain, imposed by coherent epitaxy, can result in a ferroelectric transition ...temperature nearly 500 degrees C higher and a remanent polarization at least 250% higher than bulk BaTiO3 single crystals. This work demonstrates a route to a lead-free ferroelectric for nonvolatile memories and electro-optic devices.
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