Heterogeneity in Risk and Implications for Hepatitis C Reinfection in People Who Inject Drugs in England.

Chronic hepatitis C virus (HCV) infection is associated with significant morbidity, mortality and health economic burden. Over 90% of HCV cases in England occur in people who inject drugs (PWID). Current treatments for HCV are effective but do not protect against reinfection.

Plasticity of Mouse Dorsal Root Ganglion Neurons by Innate Immune Activation Is Influenced by Electrophysiological Activity.

The complex relationship between inflammation, its effects on neuronal excitability and the ensuing plasticity of dorsal root ganglion (DRG) sensory neurons remains to be fully explored. In this study, we have employed a system of experiments assessing the impact of inflammatory conditioned media derived from activated immune cells on the excitability and activity of DRG neurons and how this relates to subsequent growth responses of these cells. We show here that an early phase of increased neuronal activity in response to inflammatory conditioned media is critical for the engagement of plastic processes and that neuronal excitability profiles are linked through time to the structural phenotype of individual neurons.

SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire.

During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM/SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets.

Preschoolers use probabilistic evidence to flexibly change or maintain expectations on an active search task.

This study investigated 3- to 5-year-olds' (N = 64, 37 girls, 62.5% White, data collected between 2021-2022) ability to use probabilistic information gleaned through active search to appropriately change or maintain expectations. In an online fishing game, children first learned that one of two ponds was good for catching fish.

The Impact of COVID-19 Fear on Mental Health of Community Behavioral Health Providers.

Objective: The COVID-19 pandemic has impacted communities worldwide. Behavioral health providers are at the forefront providing services and are thus vulnerable to psychological sequalae. This study hypothesizes that the fear of COVID-19 predicts depression and anxiety among these providers.

Neuronal maturation and axon regeneration: unfixing circuitry to enable repair.

Mammalian neurons lose the ability to regenerate their central nervous system axons as they mature during embryonic or early postnatal development. Neuronal maturation requires a transformation from a situation in which neuronal components grow and assemble to one in which these components are fixed and involved in the machinery for effective information transmission and computation. To regenerate after injury, neurons need to overcome this fixed state to reactivate their growth programme.

Climate change and public health: An evaluation framework for local government.

Objectives: To develop and pilot an evaluation framework for assessing the engagement of local government public health teams in England on climate change and sustainability. These teams are uniquely positioned to address local health impacts of climate change and promote health co-benefits of mitigation. No statutory framework currently exists to support their engagement in this agenda.

Atypia detected during breast screening and subsequent development of cancer: observational analysis of the Sloane atypia prospective cohort in England.

Objective: To explore how the number and type of breast cancers developed after screen detected atypia compare with the anticipated 11.3 cancers detected per 1000 women screened within one three year screening round in the United Kingdom.

Design: Observational analysis of the Sloane atypia prospective cohort in England.

Evidence-informed recommendations on managing breast screening atypia: perspectives from an expert panel consensus meeting reviewing results from the Sloane atypia project.

Evidence-based clinical guidelines are essential to maximize patient benefit and to reduce clinical uncertainty and inconsistency in clinical practice. Gaps in the evidence base can be addressed by data acquired in routine practice. At present, there is no international consensus on management of women diagnosed with atypical lesions in breast screening programmes.

SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire.

During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets.

Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases.

Purpose: This study aims to assess the diagnostic utility and provide reporting recommendations for clinical DNA methylation episignature testing based on the cohort of patients tested through the EpiSign Clinical Testing Network.

Methods: The EpiSign assay utilized unsupervised clustering techniques and a support vector machine-based classification algorithm to compare each patient's genome-wide DNA methylation profile with the EpiSign Knowledge Database, yielding the result that was reported. An international working group, representing distinct EpiSign Clinical Testing Network health jurisdictions, collaborated to establish recommendations for interpretation and reporting of episignature testing.

Optical Genome Mapping: Integrating Structural Variations for Precise Homologous Recombination Deficiency Score Calculation.

Homologous recombination deficiency (HRD) is characterized by the inability of a cell to repair the double-stranded breaks using the homologous recombination repair (HRR) pathway. The deficiency of the HRR pathway results in defective DNA repair, leading to genomic instability and tumorigenesis. The presence of HRD has been found to make tumors sensitive to ICL-inducing platinum-based therapies and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi).

The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development.

Copy number variants that duplicate distal upstream enhancer elements of the SOX9 gene cause 46,XX testicular differences of sex development (DSD) which is characterized by a 46,XX karyotype in an individual presenting with either ambiguous genitalia or genitalia with varying degrees of virilization, including those resembling typical male genitalia. Reported duplications in this region range in size from 24 to 780 kilobases (kb). Here we report a family with two affected individuals, the proband and his maternal uncle, harboring a 3.

Large Chromosome 2p Duplication-Associated Mechanisms and Clinical Presentations.

Chromosome 2p (chr2p) duplication, also known as trisomy 2p, is a rare chromosome abnormality associated with developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Most of the reported cases involving trisomy 2p include additional copy number variants (CNVs) in other regions of the genome and are usually small in size. Little is known about the clinical outcomes of large duplications of chr2p as the sole cytogenetic abnormality.

17q25.3 copy number changes: association with neurodevelopmental disorders and cardiac malformation.

Copy number variants (CNVs) have been identified as common genomic variants that play a significant role in inter-individual variability. Conversely, rare recurrent CNVs have been found to be causal for many disorders with well-established genotype-phenotype relationships. However, the phenotypic implications of rare non-recurrent CNVs remain poorly understood.

Clinical Utility of Optical Genome Mapping and 523-Gene Next Generation Sequencing Panel for Comprehensive Evaluation of Myeloid Cancers.

The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping/fluorescent in situ hybridization (FISH) (cytogenetic analysis) and targeted gene panels (usually ≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Despite this combinatorial approach, ~50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the molecular etiology of many myeloid tumors. In this study, we evaluated the performance and clinical utility of combinatorial use of optical genome mapping (OGM) and a 523-gene next-generation sequencing (NGS) panel for comprehensive genomic profiling of 30 myeloid tumors and compared it to SOC cytogenetic methods (karyotyping and FISH) and a 54-gene NGS panel.

Fear of COVID-19 among nonsmokers and smokers/former smokers: Implications for health promotion practice.

Introduction: Fear of COVID-19 may differ for individuals with compromised health and those with unhealthy behaviors, placing them at greater risk. Based on previous analysis of academic medical center faculty and staff, the authors predicted that workers who were smokers/previous smokers would express the greater fear of COVID-19 relative to nonsmokers.

Methods: The present study used the Fear of COVID-19 Scale to assess fear among nonsmokers (n = 1,489) and smokers/previous smokers (n = 272) from a larger population of academic medical center members (N = 1,761).

Clinical Validation and Diagnostic Utility of Optical Genome Mapping in Prenatal Diagnostic Testing.

The standard-of-care diagnostic prenatal testing includes a combination of cytogenetic methods, such as karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray (CMA), using either direct or cultured amniocytes or chorionic villi sampling. However, each technology has its limitations: karyotyping has a low resolution (>5 Mb), FISH is targeted, and CMA does not detect balanced structural variations (SVs). These limitations necessitate the use of multiple tests, either simultaneously or sequentially, to reach a genetic diagnosis.

Laboratory diagnosed microbial infection in English UK Biobank participants in comparison to the general population.

Understanding the genetic and environmental risk factors for serious bacterial infections in ageing populations remains incomplete. Utilising the UK Biobank (UKB), a prospective cohort study of 500,000 adults aged 40-69 years at recruitment (2006-2010), can help address this. Partial implementation of such a system helped groups around the world make rapid progress understanding risk factors for SARS-CoV-2 infection and COVID-19, with insights appearing as early as May 2020.

Cohort profile of the Sloane Project: methodology for a prospective UK cohort study of >15 000 women with screen-detected non-invasive breast neoplasia.

Purpose: The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact.

Aerodynamic-induced Effects of Artificial Subglottic Stenosis on Vocal Fold Model Phonatory Response.

Objective: Subglottic stenosis (SGS) is characterized by a narrowing of the trachea near the cricotracheal junction and impairs breathing. SGS may also adversely affect voice quality, but for reasons that are not fully understood. The purpose of this study is to provide experiment-based data concerning the effects on phonation of airway obstruction due to SGS.

The presentation, management and outcome of patients with ductal carcinoma in situ (DCIS) with microinvasion (invasion ≤1 mm in size)-results from the UK Sloane Project.

Background: The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial.

Methods: We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project.

Results: Microinvasion was recorded in 521 of 11,285 patients (4.