Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity

BACKGROUND: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)-expressing (c-Met+) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans. METHODS: In-depth phenotyping of peripheral blood T cells, including c-Met+ T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation. RESULTS: We show that c-Met+ T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met+ T cells are distinct from those of c-Met-negative (c-Met-) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met+ T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met+ T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met+ T cells. CONCLUSIONS: Our study demonstrates that the detection of circulating c-Met+ T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury

Measurement of Situation Awareness Effects of Adaptive Automation of Air Traffic Control Information Processing Functions

The goal of this research was to define a measure of situation awareness (SA) in an air traffic control (ATC) task and to investigate the effect of adaptive automation (AA) of various information processing functions on SA. An ATC simulation was used that was capable of presenting four different modes of control, including information acquisition, information analysis, decision making and action implementation automation, and a manual mode. Eight subjects completed two trials under each mode of control. Operator workload, assessed using a secondary task, was used to trigger automation of the primary ATC task. The SA measure was an adaptation of the Situation Awareness Global Assessment Technique (SAGAT), involving cueing of aircraft positions as well as objective weighting of the relevance of aircraft to controllers for queries. The SA response measure revealed a significant effect of AA on subject perception and overall SA, with superior SA under the information acquisition mode of automation. ATC performance was significantly superior (p\u3c0.05) when automation was applied to lower-order sensory processing functions, including information acquisition and action implementation, as compared to higher-order functions, specifically information analysis. During manual control periods as part of AA trials, ATC performance was significantly superior when following automation of information acquisition and information analysis functions. Secondary task performance was significantly worse under information analysis and decision making automation

Situation Awareness Implications of Adaptive Automation of Air Traffic Controller Information Processing Functions

The goal of this research was to define a measure of situation awareness (SA) in an air traffic control (ATC) task and to assess the influence of adaptive automation (AA) of various information processing functions on controller perception, comprehension and projection. The measure was also to serve as a basis for defining and developing an approach to triggering dynamic control allocations, as part of AA, based on controller SA. To achieve these objectives, an enhanced version of an ATC simulation (Multitask (copyright)) was developed for use in two human factors experiments. The simulation captured the basic functions of Terminal Radar Approach Control (TRACON) and was capable of presenting to operators four different modes of control, including information acquisition, information analysis, decision making and action implementation automation, as well as a completely manual control mode. The SA measure that was developed as part of the research was based on the Situation Awareness Global Assessment Technique (SAGAT), previous goal-directed task analyses of enroute control and TRACON, and a separate cognitive task analysis on the ATC simulation. The results of the analysis on Multitask were used as a basis for formulating SA queries as part of the SAGAT-based approach to measuring controller SA, which was used in the experiments. A total of 16 subjects were recruited for both experiments. Half the subjects were used in Experiment #1, which focused on assessing the sensitivity and reliability of the SA measurement approach in the ATC simulation. Comparisons were made of manual versus automated control. The remaining subjects were used in the second experiment, which was intended to more completely describe the SA implications of AA applied to specific controller information processing functions, and to describe how the measure could ultimately serve as a trigger of dynamic function allocations in the application of AA to ATC. Comparisons were made of the sensitivity of the SA measure to automation manipulations impacting both higher-order information processing functions, such as information analysis and decision making, versus lower-order functions, including information acquisition and action implementation. All subjects were exposed to all forms of AA of the ATC task and the manual control condition. The approach to AA used in both experiments was to match operator workload, assessed using a secondary task, to dynamic control allocations in the primary task. In total, the subjects in each experiment participated in 10 trials with each lasting between 45 minutes and 1 hour. In both experiments, ATC performance was measured in terms of aircraft cleared, conflicting, and collided. Secondary task (gauge monitoring) performance was assessed in terms of a hit-to-signal ratio. As part of the SA measure, three simulation freezes were conducted during each trial to administer queries on Level 1, 2, and 3 SA

Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity

BACKGROUND: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)-expressing (c-Met+) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans. METHODS: In-depth phenotyping of peripheral blood T cells, including c-Met+ T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation. RESULTS: We show that c-Met+ T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met+ T cells are distinct from those of c-Met-negative (c-Met-) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met+ T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met+ T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met+ T cells. CONCLUSIONS: Our study demonstrates that the detection of circulating c-Met+ T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury

Study protocol for Attachment & Child Health (ATTACHTM) program: promoting vulnerable Children’s health at scale

Background Children’s exposure to toxic stress (e.g., parental depression, violence, poverty) predicts developmental and physical health problems resulting in health care system burden. Supporting parents to develop parenting skills can buffer the effects of toxic stress, leading to healthier outcomes for those children. Parenting interventions that focus on promoting parental reflective function (RF), i.e., parents’ capacity for insight into their child’s and their own thoughts, feelings, and mental states, may understand help reduce societal health inequities stemming from childhood stress exposures. The Attachment and Child Health (ATTACHTM) program has been implemented and tested in seven rapid-cycling pilot studies (n = 64) and found to significantly improve parents’ RF in the domains of attachment, parenting quality, immune function, and children’s cognitive and motor development. The purpose of the study is to conduct an effectiveness-implementation hybrid (EIH) Type II study of ATTACHTM to assess its impacts in naturalistic, real-world settings delivered by community agencies rather than researchers under more controlled conditions. Methods The study is comprised of a quantitative pre/post-test quasi-experimental evaluation of the ATTACHTM program, and a qualitative examination of implementation feasibility using thematic analysis via Normalization Process Theory (NPT). We will work with 100 families and their children (birth to 36-months-old). Study outcomes include: the Parent Child Interaction Teaching Scale to assess parent-child interaction; the Parental Reflective Function and Reflective Function Questionnaires to assess RF; and the Ages and Stages Questionnaire – 3rd edition to examine child development, all administered pre-, post-, and 3-month-delayed post-assessment. Blood samples will be collected pre- and post- assessment to assess immune biomarkers. Further, we will conduct one-on-one interviews with study participants, health and social service providers, and administrators (total n = 60) from each collaborating agency, using NPT to explore perceptions and experiences of intervention uptake, the fidelity assessment tool and e-learning training as well as the benefits, barriers, and challenges to ATTACHTM implementation. Discussion The proposed study will assess effectiveness and implementation to help understand the delivery of ATTACHTM in community agencies. Trial registration Name of registry: https://clinicaltrials.gov/. Registration number: NCT04853888 . Date of registration: April 22, 2021.Medicine, Faculty ofNon UBCMedical Genetics, Department ofReviewedFacultyResearcherOthe