Nucleos(t)ide Analog Treatment Discontinuation in Chronic Hepatitis B Virus Infection: A Systematic Literature Review.

Background And Aims: The aim of this systematic literature review (SLR) was to examine outcomes and associated predictors following nucleos(t)ide analog (NA) treatment cessation in adult patients with chronic hepatitis B virus infection.

Methods: The SLR was conducted according to PRISMA methodology. All included studies were quality assessed using appropriate scales or checklists.

Sequential Peg-IFN after bepirovirsen may reduce post-treatment relapse in chronic hepatitis B.

Background & Aims: Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (
Methods: In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 μg once weekly for up to 24 weeks, with up to 36 weeks follow-up.

Flipping the switch: dynamic modulation of membrane transporter activity in bacteria.

The controlled entry and expulsion of small molecules across the bacterial cytoplasmic membrane is essential for efficient cell growth and cellular homeostasis. While much is known about the transcriptional regulation of genes encoding transporters, less is understood about how transporter activity is modulated once the protein is functional in the membrane, a potentially more rapid and dynamic level of control. In this review, we bring together literature from the bacterial transport community exemplifying the extensive and diverse mechanisms that have evolved to rapidly modulate transporter function, predominantly by switching activity off.

B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection.

Introduction: Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection.

Methods: B-Clear is a phase 2b, multicenter, randomized, partial-blind (sponsor/participant-blinded, investigator-unblinded) study in participants with chronic HBV infection receiving stable nucleos(t)ide analogue (On-NA) or not currently receiving NA therapy (Not-on-NA).

Comparison of Pharmacokinetics of the GalNAc-Conjugated Antisense Oligonucleotide GSK3389404 in Participants with Chronic Hepatitis B Infection across the Asia-Pacific Region.

GSK3389404, an N-acetyl galactosamine-conjugated antisense oligonucleotide (ASO), was in clinical development for chronic hepatitis B (CHB) treatment. Few studies have examined ASOs in Asian participants. In this analysis, the plasma pharmacokinetics (PK) of GSK3389404 were characterized and compared in patients with CHB across the Asia-Pacific region (N = 64), including mainland China ( = 16), Hong Kong ( = 8), Japan ( = 21), South Korea ( = 12), Singapore ( = 4), and the Philippines ( = 3), from a phase 2a, multicenter, randomized, double-blind, placebo-controlled study (NCT03020745).

Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection.

Background: Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins.

Methods: We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4).

Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy.

Background & Aims: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection.

Methods: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745).

Hidden Multivalency in Phosphatase Recruitment by a Disordered AKAP Scaffold.

Disordered scaffold proteins provide multivalent landing pads that, via a series of embedded Short Linear Motifs (SLiMs), bring together the components of a complex to orchestrate precise spatial and temporal regulation of cellular processes. One such protein is AKAP5 (previously AKAP79), which contains SLiMs that anchor PKA and Calcineurin, and recruit substrate (the TRPV1 receptor). Calcineurin is anchored to AKAP5 by a well-characterised PxIxIT SLiM.

Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis.

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi-Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish-born individuals were identified.

Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial.

Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins.

Hiding in plain sight: Shellfish-killing phytoplankton in Washington State.

Summer bivalve shellfish mortalities have been observed in Puget Sound for nearly a century and attempts to understand and mitigate these losses have been only partially successful. Likewise, the understanding of the environmental conditions triggering shellfish mortalities and successful strategies for their mitigation are incomplete. In the literature, phytoplankton have played only a cursory role in summer shellfish mortalities in Washington State because spawning stress and bacteria were thought to be the primary causes.

Optimizing surveillance for early disease detection: Expert guidance for Ostreid herpesvirus surveillance design and system sensitivity calculation.

To keep pace with rising opportunities for disease emergence and spread, surveillance in aquaculture must enable the early detection of both known and new pathogens. Conventional surveillance systems (designed to provide proof of disease freedom) may not support detection outside of periodic sampling windows, leaving substantial blind spots to pathogens that emerge in other times and places. To address this problem, we organized an expert panel to envision optimal systems for early disease detection, focusing on Ostreid herpesvirus 1 (OsHV-1), a pathogen of panzootic consequence to oyster industries.

The first detection of a novel OsHV-1 microvariant in San Diego, California, USA.

The spread, emergence, and adaptation of pathogens causing marine disease has been problematic to fisheries and aquaculture industries for the last several decades creating the need for strategic management and biosecurity practices. The Pacific oyster (Crassostrea gigas), a highly productive species globally, has been a target of disease and mortality caused by a viral pathogen, the Ostreid herpesvirus 1 (OsHV-1) and its microvariants (OsHV-1 µvars). During routine surveillance to establish health history at a shellfish aquaculture nursery system in San Diego, California, the presence of OsHV-1 in Pacific oyster juveniles was detected.

Bacteriophages against Vibrio coralliilyticus and Vibrio tubiashii: Isolation, Characterization, and Remediation of Larval Oyster Mortalities.

and are pathogens responsible for high larval oyster mortality rates in shellfish hatcheries. Bacteriophage therapy was evaluated to determine its potential to remediate these mortalities. Sixteen phages against and were isolated and characterized from Hawaiian seawater.

An Accidental Genetic Epidemiologist.

I briefly describe my early life and how, through a series of serendipitous events, I became a genetic epidemiologist. I discuss how the Elston-Stewart algorithm was discovered and its contribution to segregation, linkage, and association analysis. New linkage findings and paternity testing resulted from having a genotyping lab.

Local Ancestry Inference in Large Pedigrees.

Local ancestry, defined as the genetic ancestry at a genomic location of an admixed individual, is widely used as a genetic marker in genetic association and evolutionary genetics studies. Many methods have been developed to infer the local ancestries in a set of unrelated individuals, a few of them have been extended to small nuclear families, but none can be applied to large (e.g.

A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects.

GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo.

Fisher's influence on me.

This is the 100th year anniversary of Fisher's 1918 paper "The correlation between relatives on the supposition of Mendelian inheritance" (Transactions of the Royal Society of Edinburgh 1918, 52 pp 899-438). Fisher's work has had a strong influence on today's genetic epidemiology and this brief autobiographical note highlights a few of the ways his influence on me has affected the field. Although I once took a course of lectures from Fisher, it was mainly his writings that influenced my statistical thinking.

Adjustment for covariates using summary statistics of genome-wide association studies.

Linear regression is a standard approach to identify genetic variants associated with continuous traits in genome-wide association studies (GWAS). In a standard epidemiology study, linear regression is often performed with adjustment for covariates to estimate the independent effect of a predictor variable or to improve statistical power by reducing residual variability. However, it is problematic to adjust for heritable covariates in genetic association analysis.