The CD8 T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects.

Peripheral CD8 T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8 T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors.

Characterisation and reproducibility of the HumanMethylationEPIC v2.0 BeadChip for DNA methylation profiling.

Background: The Illumina family of Infinium Methylation BeadChip microarrays has been widely used over the last 15 years for genome-wide DNA methylation profiling, including large-scale and population-based studies, due to their ease of use and cost effectiveness. Succeeding the popular HumanMethylationEPIC BeadChip (EPICv1), the recently released Infinium MethylationEPIC v2.0 BeadChip (EPICv2) claims to extend genomic coverage to more than 935,000 CpG sites.

Isolation and characterisation of PR3-specific B cells and their immunoglobulin sequences.

Background: PR3 autoantibodies are essential to the diagnosis and monitoring of granulomatosus with polyangiitis, but to date no PR3 autoantibody sequences have been published.

Objectives: To identify and characterise PR3-specific B cells from the peripheral blood of patients with PR3 autoantibodies.

Methods: Peripheral blood mononuclear cells from seven patients with PR3 autoantibodies were stained with PR3.

Evaluation of an Advanced Practice Provider Onboarding and Development Program.

Objective: To evaluate the impact of implementing a comprehensive secondary onboarding and development program within a hospital medicine group at a large tertiary academic medical institution.

Methods: This was a mixed-methods study with physician and advanced practice providers (APPs) at an academic medical institution.

Results: For quantitative methods, improvement in competencies was determined using a pre-and posttest for APPs and pre- and postevaluation scores from collaborating physicians.

Identification of human progenitors of exhausted CD8 T cells associated with elevated IFN-γ response in early phase of viral infection.

T cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of individuals with primary infection using single-cell multi-omics to identify the functions and phenotypes of HCV-specific CD8 T cells.

STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2D CD8 T cell dysregulation and accumulation.

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8 T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8 T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules.

Comprehensive methylome sequencing reveals prognostic epigenetic biomarkers for prostate cancer mortality.

Background: Prostate cancer is a clinically heterogeneous disease with a subset of patients rapidly progressing to lethal-metastatic prostate cancer. Current clinicopathological measures are imperfect predictors of disease progression. Epigenetic changes are amongst the earliest molecular changes in tumourigenesis.

Antiviral Pharmacology: A Standardized Patient Case for Preclinical Medical Students.

Introduction: Pharmacology is an important learning topic in preclinical medical education. Simulated patient encounters allow students to apply basic science knowledge in a clinical setting and have been useful in previous studies of pharmacology education. We developed a standardized patient (SP) encounter to reinforce antiviral pharmacology content for first-year medical students.

STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis.

Background: Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown.

A metatranscriptomic approach to explore longitudinal tissue specimens from non-healing diabetes related foot ulcers.

Cellular mechanisms and/or microbiological interactions which contribute to chronic diabetes related foot ulcers (DRFUs) were explored using serially collected tissue specimens from chronic DRFUs and control healthy foot skin. Total RNA was isolated for next-generation sequencing. We found differentially expressed genes (DEGs) and enriched hallmark gene ontology biological processes upregulated in chronic DRFUs which primarily functioned in the host immune response including: (i) Inflammatory response; (ii) TNF signalling via NFKB; (iii) IL6 JAK-STAT3 signalling; (iv) IL2 STAT5 signalling and (v) Reactive oxygen species.

Early Pre-clerkship Clinical Skills Assessments Predict Clerkship Performance.

Introduction: Assessment of medical students' clinical skills (CS) remains a challenge. Little is known about early predictors of future CS performance. This study examines the relationship between students' pre-clerkship clinical skills (PCCS) performance and year 3 clerkship performance measures.

Student, Faculty, and Coach Perspectives on Why Athletes Excel in Medical School: A Qualitative Analysis.

Medical schools are tasked with selecting applicants who will excel in a rigorous curriculum and successfully perform as future physicians. While many studies have assessed quantitative prematriculation data for predicting success in medical school, fewer studies have assessed for qualitative prematriculation factors influencing medical school performance. A recent study revealed that medical students with at least one year of varsity level college athletics participation outperformed their peers on United States Medical Licensing board exams and clinical clerkships.

Uncontrolled CD21 age-associated and B1 B cell accumulation caused by failure of an EGR2/3 tolerance checkpoint.

CD21 age-associated or atypical memory B cells are autoantibody enriched and poised for plasma cell differentiation. These cells overaccumulate in chronic infections, autoimmune disease, and immunodeficiency, posing the question of what checkpoints normally oppose their accumulation. Here, we reveal a critical role for paralogous calcium-NFAT-regulated transcription factors EGR2 and EGR3 that are induced in self-reactive B cells.

Host-microbe metatranscriptome reveals differences between acute and chronic infections in diabetes-related foot ulcers.

Virtually all diabetes-related foot ulcers (DRFUs) will become colonized by microorganisms that may increase the risk of developing an infection. The reasons why some ulcerations develop acute clinical infections (AI-DRFUs) whilst others develop chronic infection (CI-DRFUs) and the preceding host-microbe interactions in vivo remain largely unknown. Establishing that acute and chronic infections are distinct processes requires demonstrating that these are two different strategies employed by microbes when interacting with a host.

Simulation: an Innovative Approach to Engaging Preclinical Medical Students with Bioethics.

Background: Integrating bioethical concepts into preclinical medical school curriculum and engaging early medical learners in bioethics are a challenge.

Activity: A total of 140 medical students participated in a 2-h simulation activity consisting of a series of standardized patient (SP) encounters.

Results: A total of 41 of 140 students (29%) completed the learner evaluation survey.

Calling differentially methylated regions from whole genome bisulphite sequencing with DMRcate.

Whole genome bisulphite sequencing (WGBS) permits the genome-wide study of single molecule methylation patterns. One of the key goals of mammalian cell-type identity studies, in both normal differentiation and disease, is to locate differential methylation patterns across the genome. We discuss the most desirable characteristics for DML (differentially methylated locus) and DMR (differentially methylated region) detection tools in a genome-wide context and choose a set of statistical methods that fully or partially satisfy these considerations to compare for benchmarking.

Antigen-driven EGR2 expression is required for exhausted CD8 T cell stability and maintenance.

Chronic stimulation of CD8 T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets.

A multiomics approach to identify host-microbe alterations associated with infection severity in diabetic foot infections: a pilot study.

Diabetic foot infections (DFIs) are a major cause of hospitalization and can lead to lower extremity amputation. In this pilot study, we used a multiomics approach to explore the host-microbe complex within DFIs. We observed minimal differences in the overall microbial composition between PEDIS infection severities, however Staphylococcus aureus and Streptococcus genera were abundant and highly active in most mild to moderate DFIs.

The Zombie Virus Pandemic: An Innovative Simulation Integrating Virology, Population Health, and Bioethics for Preclinical Medical Students.

Introduction: Understanding population health in the context of infectious disease outbreaks is an important physician competency. However, identifying effective ways to engage early medical students in this content remains a challenge. We designed an innovative pandemic simulation for first-year medical students utilizing the pop culture theme of zombies.

Development and implementation of a COVID-19 near real-time traffic light system in an acute hospital setting.

Common causes of death in COVID-19 due to SARS-CoV-2 include thromboembolic disease, cytokine storm and adult respiratory distress syndrome (ARDS). Our aim was to develop a system for early detection of disease pattern in the emergency department (ED) that would enhance opportunities for personalised accelerated care to prevent disease progression. A single Trust's COVID-19 response control command was established, and a reporting team with bioinformaticians was deployed to develop a real-time traffic light system to support clinical and operational teams.

The Simulated Virology Clinic: A Standardized Patient Exercise for Preclinical Medical Students Supporting Basic and Clinical Science Integration.

Introduction: Virology is inherently challenging due to the sheer volume of information medical students are responsible for learning. Cognitive integration of this content is critical for early medical students to practice applying this knowledge to diagnostic problem-solving. Simulation offers learners engaging opportunities to practice cognitive integration.

Temporal ordering of omics and multiomic events inferred from time-series data.

Temporal changes in omics events can now be routinely measured; however, current analysis methods are often inadequate, especially for multiomics experiments. We report a novel analysis method that can infer event ordering at better temporal resolution than the experiment, and integrates omic events into two concise visualizations (event maps and sparklines). Testing our method gave results well-correlated with prior knowledge and indicated it streamlines analysis of time-series data.

Transient exposure to miR-203 enhances the differentiation capacity of established pluripotent stem cells.

Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs.

COVID-19: a primer for healthcare providers.

According to the World Health Organization (WHO) the China office was first notified of cases of atypical pneumonia in Wuhan City on 31 December 2019. A viral genome sequence of a novel coronavirus, currently termed SARS-CoV‑2, with a disease process called COVID-19 was released 1 week later via online resources to obtain public health support in control of spread. Since then, the virus rapidly evolved into a global pandemic.