AIRE expands: new roles in immune tolerance and beyond

More than 15 years ago, mutations in the autoimmune regulator (AIRE) gene were identified as the cause of autoimmune polyglandular syndrome type 1 (APS1). It is now clear that this transcription factor has a crucial role in promoting self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery. In this Review, we highlight many of the recent advances in our understanding of the complex biology that is related to AIRE, with a particular focus on advances in genetics, molecular interactions and the effect of AIRE on thymic selection of regulatory T cells. Furthermore, we highlight new areas of biology that are potentially affected by this key regulator of immune tolerance

Aire and T cell development

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a critical role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified

Epigenome‐wide DNA methylation analysis implicates neuronal and inflammatory signaling pathways in adult murine hepatic tumorigenesis following perinatal exposure to bisphenol A

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133545/1/em22024.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133545/2/em22024_am.pd

A Latent Profile Analysis of Aggression and Victimization across Relationship Types Among Veterans Who Use Substances

Objective: This study examined patterns of violence victimization and aggression in both intimate partner and non-partner relationships among veterans, and used latent profile analysis to identify subtypes of violence involvement. Methods: Participants were 841 substance use treatment-seeking veterans (94% male) from a large VA Medical Center who completed screening measures for a randomized controlled trial. Self-report measures were: substance use, legal problems, depression, and violence involvement. Results: Past year violence involvement, including both intimate partner (IPV) and non-partner (NPV) were common in the sample; although NPV occurred at somewhat higher rates. When including either IPV or NPV aggression or victimization, over 48% reported involvement with physical violence, 31% with violence involving injury and 86% with psychological aggression. Latent profile analysis including both aggression and victimization in partner and non-partner relationships indicated a four profile solution: no-low violence (NLV, n = 701), predominantly IPV (n = 35), predominantly NPV (n = 83), and high general violence (HGV, n = 22). Multinomial logistic regression analyses revealed that compared to the no-low violence group, the remaining three groups differed in demographics, depressive symptoms, alcohol and other drug use, and legal involvement. Individuals within each profile had different patterns of substance use and legal involvement with the participants with an HGV profile reporting the most legal problems. Conclusions: IPV and NPV are relatively common among veterans seeking substance use treatment. Characteristics of violence and associated substance use, mental health, and legal difficulties may be useful in considering how to tailor substance use and mental health services

Modest serum creatinine elevation affects adverse outcome after general surgery

Modest serum creatinine elevation affects adverse outcome after general surgery.BackgroundModest preoperative serum creatinine elevation (1.5 to 3.0 mg/dL) has been recently shown to be independently associated with morbidity and mortality after cardiac surgery. It is important to know if this association can be applied more broadly to general surgery cases.MethodsMultivariable logistic regression analyses of 46 risk variables in 49,081 cases from the Veterans Affairs National Surgical Quality Improvement Program, undergoing major general surgery from 10/1/96 through 9/30/98.ResultsThirty day mortality and several cardiac, respiratory, infectious and hemorrhagic morbidities were significantly (P < 0.001) higher in patients with a serum creatinine>1.5 mg/dL. With multivariable analysis, the adjusted odds ratio for mortality for patients with a serum creatinine of 1.5 to 3.0 mg/dL was 1.44 [95% confidence interval (95% CI) 1.22 to 1.71] and for creatinine>3.0 mg/dL was 1.93 (95% CI 1.51 to 2.46). The adjusted odds ratio for morbidity (one or more postoperative complications) for patients with a serum creatinine of 1.5 to 3.0 mg/dL was 1.18 (95% CI 1.06 to 1.32) and for creatinine>3.0 mg/dL was 1.19 (95% CI 0.99 to 1.43). Further stratification and recursive partitioning of creatinine levels revealed that a serum creatinine level>1.5 mg/dL was the approximate threshold for both increased morbidity and mortality.ConclusionsModest preoperative serum creatinine elevation (>1.5 mg/dL) is a significant predictor of risk-adjusted morbidity and mortality after general surgery. A preoperative serum creatinine of 1.5 mg/dL or higher is a readily available marker for potential adverse outcomes after general surgery

An exploratory cluster randomised controlled trial of knowledge translation strategies to support evidence-informed decision-making in local governments (The KT4LG study)

Background: Childhood overweight and obesity is the most prevalent and, arguably, politically complex child health problem internationally. Governments, communities and industry have important roles to play, and are increasingly expected to deliver an evidence-informed system-wide prevention program. However, efforts are impeded by a lack of organisational access to and use of research evidence. This study aims to identify feasible, acceptable and ideally, effective knowledge translation (KT) strategies to increase evidence-informed decision making in local governments, within the context of childhood obesity prevention as a national policy priority.Methods/Design: This paper describes the methods for KT4LG, a cluster randomised controlled trial which is exploratory in nature, given the limited evidence base and methodological advances. KT4LG aims to examine a program of KT strategies to increase the use of research evidence in informing public health decisions in local governments. KT4LG will also assess the feasibility and acceptability of the intervention. The intervention program comprises a facilitated program of evidence awareness, access to tailored research evidence, critical appraisal skills development, networking and evidence summaries and will be compared to provision of evidence summaries alone in the control program. 28 local governments were randomised to intervention or control, using computer generated numbers, stratified by budget tertile (high, medium or low). Questionnaires will be used to measure impact, costs, and outcomes, and key informant interviews will be used to examine processes, feasibility, and experiences. Policy tracer studies will be included to examine impact of intervention on policies within relevant government policy documents.Discussion: Knowledge translation intervention studies with a focus on public health and prevention are very few in number. Thus, this study will provide essential data on the experience of program implementation and evaluation of a system-integrated intervention program employed within the local government public health context. Standardised programs of system, organisational and individual KT strategies have not been described or rigorously evaluated. As such, the findings will make a significant contribution to understanding whether a facilitated program of KT strategies hold promise for facilitating evidence-informed public health decision making within complex multisectoral government organisations.<br /

Feasibility study to assess the delivery of a lifestyle intervention (TreatWELL) for patients with colorectal cancer undergoing potentially curative treatment

Objectives To assess the feasibility of delivering and evaluating a lifestyle programme for patients with colorectal cancer undergoing potentially curative treatments.Study design Non-randomised feasibility trial.Setting National Health Service (NHS) Tayside.Participants Adults with stage I–III colorectal cancer.Intervention The programme targeted smoking, alcohol, physical activity, diet and weight management. It was delivered in three face-to-face counselling sessions (plus nine phone calls) by lifestyle coaches over three phases (1: presurgery, 2: surgical recovery and 3: post-treatment recovery).Primary outcome Feasibility measures (recruitment, retention, programme implementation, achieved measures, fidelity, factors affecting protocol adherence and acceptability).Secondary outcomes Measured changes in body weight, waist circumference, walking and self-reported physical activity, diet, smoking, alcohol intake, fatigue, bowel function and quality of life.Results Of 84 patients diagnosed, 22 (26%) were recruited and 15 (18%) completed the study. Median time for intervention delivery was 5.5 hours. Coaches reported covering most (>70%) of the intervention components but had difficulties during phase 2. Evaluation measures (except walk test) were achieved by all participants at baseline, and most

Brain Biomarkers and Pre-Injury Cognition are Associated with Long-Term Cognitive Outcome in Children with Traumatic Brain Injury

BACKGROUND: Children with traumatic brain injury (TBI) are frequently at risk of long-term impairments of attention and executive functioning but these problems are difficult to predict. Although deficits have been reported to vary with injury severity, age at injury and sex, prognostication of outcome remains imperfect at a patient-specific level. The objective of this proof of principle study was to evaluate a variety of patient variables, along with six brain-specific and inflammatory serum protein biomarkers, as predictors of long-term cognitive outcome following paediatric TBI. METHOD: Outcome was assessed in 23 patients via parent-rated questionnaires related to attention deficit hyperactivity disorder (ADHD) and executive functioning, using the Conners 3rd Edition Rating Scales (Conners-3) and Behaviour Rating Inventory of Executive Function (BRIEF) at a mean time since injury of 3.1 years. Partial least squares (PLS) analyses were performed to identify factors measured at the time of injury that were most closely associated with outcome on (1) the Conners-3 and (2) the Behavioural Regulation Index (BRI) and (3) Metacognition Index (MI) of the BRIEF. RESULTS: Higher levels of neuron specific enolase (NSE) and lower levels of soluble neuron cell adhesion molecule (sNCAM) were associated with higher scores on the inattention, hyperactivity/impulsivity and executive functioning scales of the Conners-3, as well as working memory and initiate scales of the MI from the BRIEF. Higher levels of NSE only were associated with higher scores on the inhibit scale of the BRI. CONCLUSIONS: NSE and sNCAM show promise as reliable, early predictors of long-term attention-related and executive functioning problems following paediatric TBI

American Society of Hematology 2019 guidelines for management of venous thromboembolism : prevention of venous thromboembolism in surgical hospitalized patients

Background: Venous thromboembolism (VTE) is a common source of perioperative morbidity and mortality. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about preventing VTE in patients undergoing surgery. Methods: ASH formed a multidisciplinary guideline panel balanced to minimize bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic reviews. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 30 recommendations, including for major surgery in general (n = 8), orthopedic surgery (n = 7), major general surgery (n = 3), major neurosurgical procedures (n = 2), urological surgery (n = 4), cardiac surgery and major vascular surgery (n = 2), major trauma (n = 2), and major gynecological surgery (n = 2). Conclusions: For patients undergoing major surgery in general, the panel made conditional recommendations for mechanical prophylaxis over no prophylaxis, for pneumatic compression prophylaxis over graduated compression stockings, and against inferior vena cava filters. In patients undergoing total hip or total knee arthroplasty, conditional recommendations included using either aspirin or anticoagulants, as well as for a direct oral anticoagulant over low-molecular-weight heparin (LMWH). For major general surgery, the panel suggested pharmacological prophylaxis over no prophylaxis, using LMWH or unfractionated heparin. For major neurosurgery, transurethral resection of the prostate, or radical prostatectomy, the panel suggested against pharmacological prophylaxis. For major trauma surgery or major gynecological surgery, the panel suggested pharmacological prophylaxis over no prophylaxis.Peer reviewe

A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4+ T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4+ T cell hybridomas were generated from inflamed tissue–derived CD4+ T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0–specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3–5 wk of age. This abrupt disease was associated with the production of interferon γ by P0-specific T cells and a lack of CD4+ Foxp3+ regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy