Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B:Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial

INTRODUCTION:Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn.METHODS:Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA &lt;103IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria.RESULTS:Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (&gt;5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P &lt; 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal.DISCUSSION:Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log10IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss.</p

Entecavir and Peginterferon Alfaâ 2a in Adults With Hepatitis B e Antigenâ Positive Immuneâ Tolerant Chronic Hepatitis B Virus Infection

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149552/1/hep30417_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149552/2/hep30417.pd

Interface Scaling in the Contact Process

Scaling properties of an interface representation of the critical contact process are studied in dimensions 1 - 3. Simulations confirm the scaling relation beta_W = 1 - theta between the interface-width growth exponent beta_W and the exponent theta governing the decay of the order parameter. A scaling property of the height distribution, which serves as the basis for this relation, is also verified. The height-height correlation function shows clear signs of anomalous scaling, in accord with Lopez' analysis [Phys. Rev. Lett. 83, 4594 (1999)], but no evidence of multiscaling.Comment: 10 pages, 9 figure

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

The antiferromagnetic phi4 Model, I. The Mean-field Solution

Certain higher dimensional operators of the lagrangian may render the vacuum inhomogeneous. A rather rich phase structure of the phi4 scalar model in four dimensions is presented by means of the mean-field approximation. One finds para- ferro- ferri- and antiferromagnetic phases and commensurate-incommensurate transitions. There are several particles described by the same quantum field in a manner similar to the species doubling of the lattice fermions. It is pointed out that chiral bosons can be introduced in the lattice regularized theory.Comment: To appear in Phys. Rev.

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy

Search for supersymmetry at √S=8TeV in final states with jets and two same-sign leptons or three leptons with the ATLAS detector

A search for strongly produced supersymmetric particles is conducted using signatures involving multiple energetic jets and either two isolated leptons (e or μ) with the same electric charge, or at least three isolated leptons. The search also utilises jets originating from b-quarks, missing transverse momentum and other observables to extend its sensitivity. The analysis uses a data sample corresponding to a total integrated luminosity of 20.3 fb−1 of √s = 8 TeV proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider in 2012. No deviation from the Standard Model expectation is observed. New or significantly improved exclusion limits are set on a wide variety of supersymmetric models in which the lightest squark can be of the first, second or third generations, and in which R-parity can be conserved or violated