A triad of somatic mutagenesis converges in self-reactive B cells to cause a virus-induced autoimmune disease.

The unexplained association between infection and autoimmune disease is strongest for hepatitis C virus-induced cryoglobulinemic vasculitis (HCV-cryovas). To analyze its origins, we traced the evolution of pathogenic rheumatoid factor (RF) autoantibodies in four HCV-cryovas patients by deep single-cell multi-omic analysis, revealing three sources of B cell somatic mutation converged to drive the accumulation of a large disease-causing clone. A method for quantifying low-affinity binding revealed recurring antibody variable domain combinations created by V(D)J recombination that bound self-immunoglobulin G (IgG) but not viral E2 antigen.

Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies.

The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the "up" conformation of the SARS-CoV-2 spike trimer.

Bivalent Omicron BA.1 vaccine booster increases memory B cell breadth and neutralising antibodies against emerging SARS-CoV-2 variants.

Background: Current literature informs us that bivalent vaccines will generate a broader serum neutralizing antibody response to multiple SARS-CoV-2 variants, but studies on how this breadth relates to the memory B cell (MBC) and T cell responses are sparse. This study compared breadth of neutralising antibody, and memory B and T cell responses to monovalent or a bivalent ancestral/Omicron BA.1 COVID-19 booster vaccine.

Next-Generation Sequencing Methods for Near-Real-Time Molecular Epidemiology of HIV and HCV.

The World Health Organisation has set targets of reducing the transmission of new hepatitis C (HCV) infections by 90%, and ending human immunodeficiency virus-1 (HIV) as a public health threat, by 2030. To achieve this, efficient and timely viral surveillance, and effective public health interventions, are required. Traditional epidemiological methods are largely dependent on the recognition of incident cases with symptomatic illness; acute HIV and HCV infections are commonly asymptomatic, which may lead to delays in the recognition of such new infections.

Rationale and Design of SCOT-HEART 2 Trial: CT Angiography for the Prevention of Myocardial Infarction.

Coronary artery disease continues to be the leading cause of death globally. Identifying patients who are at risk of coronary artery disease remains a public health priority. At present, the focus of cardiovascular disease prevention relies heavily on probabilistic risk scoring despite no randomized controlled trials demonstrating their efficacy.

Discovery of a monoclonal, high-affinity CD8 T-cell clone following natural hepatitis C virus infection.

CD8 T cells recognizing their cognate antigen are typically recruited as a polyclonal population consisting of multiple clonotypes with varying T-cell receptor (TCR) affinity to the target peptide-major histocompatibility complex (pMHC) complex. Advances in single-cell sequencing have increased accessibility toward identifying TCRs with matched antigens. Here we present the discovery of a monoclonal CD8 T-cell population with specificity for a hepatitis C virus (HCV)-derived human leukocyte antigen (HLA) class I epitope (HLA-B*07:02 GPRLGVRAT) which was isolated directly ex vivo from an individual with an episode of acutely resolved HCV infection.

The development of number line estimation in children at risk of mathematics learning difficulties: A longitudinal study.

Children with mathematics learning difficulties (MLD) show poorer performance on the number line task, but how performance on this task relates to other mathematical skills is unclear. This study examined the association between performance on the number line task and mathematical skills during the first 2 years of school for children at risk of MLD. Children (N = 100; M = 83.

B-cell characteristics define HCV reinfection outcome.

Background & Aims: In individuals highly exposed to HCV, reinfection is common, suggesting that natural development of sterilising immunity is difficult. In those that are reinfected, some will develop a persistent infection, while a small proportion repeatedly clear the virus, suggesting natural protection is possible. The aim of this study was to characterise immune responses associated with rapid natural clearance of HCV reinfection.

HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies.

The Hepatitis C virus (HCV) envelope glycoprotein E1 forms a non-covalent heterodimer with E2, the main target of neutralizing antibodies. How E1-E2 interactions influence viral fitness and contribute to resistance to E2-specific antibodies remain largely unknown. We investigate this problem using a combination of fitness landscape and evolutionary modeling.

The APPRISE Virtual Biobank for Infectious Diseases.

The Australian Partnership for Preparedness Research on InfectiouS disease Emergencies (APPRISE) has developed a virtual biobank to support infectious disease research in Australia. The virtual biobank (https://apprise.biogrid.

Developmental dyscalculia is not associated with atypical brain activation: A univariate fMRI study of arithmetic, magnitude processing, and visuospatial working memory.

Functional neuroimaging serves as a tool to better understand the cerebral correlates of atypical behaviors, such as learning difficulties. While significant advances have been made in characterizing the neural correlates of reading difficulties (developmental dyslexia), comparatively little is known about the neurobiological correlates of mathematical learning difficulties, such as developmental dyscalculia (DD). Furthermore, the available neuroimaging studies of DD are characterized by small sample sizes and variable inclusion criteria, which make it problematic to compare across studies.

Wang-Landau sampling of lattice multiblock copolymers.

Synthetic multiblock copolymers are an interesting class of polymeric chains and have emerged as promising materials to mimic the function of complex biomolecules. In this work, we use Wang-Landau sampling to study sequences of multiblock (AnBn)m copolymers on the simple cubic lattice, where n represents the block length and m represents the number of blocks. We first compare to the thermodynamic and structural properties of four sequences previously studied in the continuum [W.

A unique cytotoxic CD4 T cell-signature defines critical COVID-19.

Objectives: SARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T-cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T-cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines.

Comparative Longitudinal Serological Study of Anti-SARS-CoV-2 Antibody Profiles in People with COVID-19.

Serological diagnostic assays are essential tools for determining an individual's protection against viruses like SARS-CoV-2, tracking the spread of the virus in the community, and evaluating population immunity. To assess the diversity and quality of the anti-SARS-CoV-2 antibody response, we have compared the antibody profiles of people with mild, moderate, and severe COVID-19 using a dot blot assay. The test targeted the four major structural proteins of SARS-CoV-2, namely the nucleocapsid (N), spike (S) protein domains S1 and S2, and receptor-binding domain (RBD).

Challenge Inoculum for Hepatitis C Virus Controlled Human Infection Model.

For any controlled human infection model (CHIM), a safe, standardized, and biologically relevant challenge inoculum is necessary. For hepatitis C virus (HCV) CHIM, we propose that human-derived high-titer inocula of several viral genotypes with extensive virologic, serologic, and molecular characterizations should be the most appropriate approach. These inocula should first be tested in human volunteers in a step-wise manner to ensure safety, reproducibility, and curability prior to using them for testing the efficacy of candidate vaccines.

A Novel Randomized Trial Protocol for Evaluating Wound Healing Interventions.

Randomized controlled trials using complete healing as an endpoint suffer from poor statistical power, owing to the heterogeneity of wounds and their healing trajectories. The Food and Drug Administration (FDA) has recently consulted with expert groups to consider percentage area reduction (PAR) of the wound over a 4-week period as a valid intermediate endpoint, creating the opportunity for more powerful study designs. A within-subject controlled study design comparing the PAR of venous leg ulcers (VLU) in patients over 4 weeks receiving different interventions.

Readability and beyond - Health literacy and numeracy and COVID-19 communications in early childhood education: Are we communicating effectively?

Objective: Analyse the linguistic and numerical complexity of COVID-19-related health information communicated from Australian national and state governments and health agencies to national and local early childhood education (ECE) settings.

Methods: Publicly available health information (n = 630) was collected from Australian national and state governments and health agencies, and ECE agencies and service providers. A purposive sample of documents (n = 33) from 2020 to 2021 was analysed inductively and deductively combining readability, health numeracy and linguistic analyses and focusing on the most frequent actionable health advice topics.

Stakeholder perspectives on navigating the pediatric concussion experience: Exploring the needs for improved communication across the care continuum.

Background: For children, the post-concussion return to school process is a critical step towards achieving positive health outcomes. The process requires integration between healthcare professionals, parents, and school personnel.

Objective: This research team conducted focus groups with stakeholders including parents, education personnel, school nurses, external healthcare providers (nurses) and athletic trainers to identify communication patterns between healthcare providers outside of the school setting and school personnel.