FlowAtlas: an interactive tool for high-dimensional immunophenotyping analysis bridging FlowJo with computational tools in Julia.

As the dimensionality, throughput and complexity of cytometry data increases, so does the demand for user-friendly, interactive analysis tools that leverage high-performance machine learning frameworks. Here we introduce FlowAtlas: an interactive web application that enables dimensionality reduction of cytometry data without down-sampling and that is compatible with datasets stained with non-identical panels. FlowAtlas bridges the user-friendly environment of FlowJo and computational tools in Julia developed by the scientific machine learning community, eliminating the need for coding and bioinformatics expertise. New population discovery and detection of rare populations in FlowAtlas is intuitive and rapid. We demonstrate the capabilities of FlowAtlas using a human multi-tissue, multi-donor immune cell dataset, highlighting key immunological findings. FlowAtlas is available at https://github.com/gszep/FlowAtlas.jl.git.

Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span.

During ontogeny, γδ T cells emerge from the thymus and directly seed peripheral tissues for in situ immunity. However, their functional role in humans has largely been defined from blood. Here, we analyzed the phenotype, transcriptome, function, and repertoire of human γδ T cells in blood and mucosal and lymphoid tissues from 176 donors across the life span, revealing distinct profiles in children compared with adults. In early life, clonally diverse Vδ1 subsets predominate across blood and tissues, comprising naïve and differentiated effector and tissue repair functions, whereas cytolytic Vδ2 subsets populate blood, spleen, and lungs. With age, Vδ1 and Vδ2 subsets exhibit clonal expansions and elevated cytolytic signatures, which are disseminated across sites. In adults, Vδ2 cells predominate in blood, whereas Vδ1 cells are enriched across tissues and express residency profiles. Thus, antigenic exposures over childhood drive the functional evolution and tissue compartmentalization of γδ T cells, leading to age-dependent roles in immunity.

Evaluating the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care: Protocol for the UK-ROX trial.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

" I'm not a risk taker " : Risk Perceptions of Nursing Home Residents With Dementia.

BACKGROUND: Persons living with Alzheimer disease and related dementia (ADRD) in nursing homes (NH) are often excluded from conversations about their health/safety. These omissions impinge on personhood and the rights to have care preferences heard and honored. While persons with ADRD maintain the ability to communicate their preferences long after their decision-making abilities are affected, little is known about how persons with ADRD understand the risks associated with their preferences. METHODS: As part of a larger focused ethnography, in-depth interviews and an adapted risk propensity questionnaire explored the risk perceptions of NH residents with ADRD (N=7) associated with their preferences for care and activities of daily living. RESULTS: Residents generally self-identified as risk avoiders ( M =3.2±1.84) on the risk propensity scale and were able to rate risk associated with preferences described within 5 thematic categories: 1) participation in decision-making, 2) risk awareness, 3) paying attention to safety, 4) reliance on nursing home staff and family, and 5) impacts on quality of life and quality of care. DISCUSSION: Results suggest NH residents with ADRD can express risk surrounding their preferences and should be encouraged to participate in discussions about their health and safety.

Diabetes distress in Veterans with type 2 diabetes mellitus: Qualitative descriptive study.

Diabetes distress (DD) is a negative psychosocial response to living with type 2 diabetes mellitus (T2DM). We sought insight into Veterans' experiences with DD in the context of T2DM self-management. The four domains in the Diabetes Distress Scale (i.e. regimen, emotional, interpersonal, healthcare provider) informed the interview guide and analysis (structural coding using thematic analysis). The mean age of the cohort (n = 36) was 59.1 years (SD 10.4); 8.3% of patients were female and 63.9% were Black or Mixed Race; mean A1C was 8.8% (SD 2.0); and mean DDS score was 2.4 (SD 1.1), indicating moderate distress. Veterans described DD and challenges to T2DM self-management across the four domains in the Diabetes Distress Scale. We found that (1) Veterans' challenges with their T2DM self-management routines influenced DD and (2) Veterans experienced DD across a wide range of domains, indicating that clinical interventions should take a "whole-person" approach.Trial Registration: NCT04587336.

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.

The immune system comprises multiple cell lineages and heterogeneous subsets found in blood and tissues throughout the body. While human immune responses differ between sites and over age, the underlying sources of variation remain unclear as most studies are limited to peripheral blood. Here, we took a systems approach to comprehensively profile RNA and surface protein expression of over 1.25 million immune cells isolated from blood, lymphoid organs, and mucosal tissues of 24 organ donors aged 20-75 years. We applied a multimodal classifier to annotate the major immune cell lineages (T cells, B cells, innate lymphoid cells, and myeloid cells) and their corresponding subsets across the body, leveraging probabilistic modeling to define bases for immune variations across donors, tissue, and age. We identified dominant tissue-specific effects on immune cell composition and function across lineages for lymphoid sites, intestines, and blood-rich tissues. Age-associated effects were intrinsic to both lineage and site as manifested by macrophages in mucosal sites, B cells in lymphoid organs, and T and NK cells in blood-rich sites. Our results reveal tissue-specific signatures of immune homeostasis throughout the body and across different ages. This information provides a basis for defining the transcriptional underpinnings of immune variation and potential associations with disease-associated immune pathologies across the human lifespan.

Modeling the neuroimmune system in Alzheimer's and Parkinson's diseases.

Parkinson's disease (PD) and Alzheimer's disease (AD) are neurodegenerative disorders caused by the interaction of genetic, environmental, and familial factors. These diseases have distinct pathologies and symptoms that are linked to specific cell populations in the brain. Notably, the immune system has been implicated in both diseases, with a particular focus on the dysfunction of microglia, the brain's resident immune cells, contributing to neuronal loss and exacerbating symptoms. Researchers use models of the neuroimmune system to gain a deeper understanding of the physiological and biological aspects of these neurodegenerative diseases and how they progress. Several in vitro and in vivo models, including 2D cultures and animal models, have been utilized. Recently, advancements have been made in optimizing these existing models and developing 3D models and organ-on-a-chip systems, holding tremendous promise in accurately mimicking the intricate intracellular environment. As a result, these models represent a crucial breakthrough in the transformation of current treatments for PD and AD by offering potential for conducting long-term disease-based modeling for therapeutic testing, reducing reliance on animal models, and significantly improving cell viability compared to conventional 2D models. The application of 3D and organ-on-a-chip models in neurodegenerative disease research marks a prosperous step forward, providing a more realistic representation of the complex interactions within the neuroimmune system. Ultimately, these refined models of the neuroimmune system aim to aid in the quest to combat and mitigate the impact of debilitating neuroimmune diseases on patients and their families.

Identifying Barriers and Facilitators to Veterans Affairs Whole Health Integration Using the Updated Consolidated Framework for Implementation Research.

BACKGROUND: Veterans Affairs (VA) implemented the Veteran-centered Whole Health System initiative across VA sites with approaches to implementation varying by site. PURPOSE: Using the Consolidated Framework for Implementation Research (CFIR), we aimed to synthesize systemic barriers and facilitators to Veteran use with the initiative. Relevance to healthcare quality, systematic comparison of implementation procedures across a national healthcare system provides a comprehensive portrait of strengths and opportunities for improvement. METHODS: Advanced fellows from 11 VA Quality Scholars sites performed the initial data collection, and the final report includes CFIR-organized results from six sites. RESULTS: Key innovation findings included cost, complexity, offerings, and accessibility. Inner setting barriers and facilitators included relational connections and communication, compatibility, structure and resources, learning centeredness, and information and knowledge access. Finally, results regarding individuals included innovation deliverers, implementation leaders and team, and individual capability, opportunity, and motivation to implement and deliver whole health care. DISCUSSION AND IMPLICATIONS: Examination of barriers and facilitators suggest that Whole Health coaches are key components of implementation and help to facilitate communication, relationship building, and knowledge access for Veterans and VA employees. Continuous evaluation and improvement of implementation procedures at each site is also recommended.

Technical requirements and devices available for long-term hemodialysis in children-mind the gap!

Children requiring long-term kidney replacement therapy are a "rare disease" cohort. While the basic technical requirements for hemodialysis (HD) are similar in children and adults, key aspects of the child's cardiovascular anatomy and hemodynamic specifications must be considered. In this article, we describe the technical requirements for long-term HD therapy for children and the devices that are currently available around the world. We highlight the characteristics and major technical shortcomings of permanent central venous catheters, dialyzers, dialysis machines, and software available to clinicians who care for children. We show that currently available HD machines are not equipped with appropriately small circuits and sensitive control mechanisms to perform safe and effective HD in the youngest patients. Manufacturers limit their liability, and health regulatory agencies permit the use of devices, only in children according to the manufacturers' pre-specified weight limitations. Although registries show that 6-23% of children starting long-term HD weigh less than 15 kg, currently, there is only one long-term HD device that is cleared for use in children weighing 10 to 15 kg and none is available and labelled for use in children weighing less than 10 kg anywhere in the world. Thus, many children are being treated "off-label" and are subject to interventions delivered by medical devices that lack pediatric safety and efficacy data. Moreover, recent improvements in dialysis technology offered to adult patients are denied to most children. We, in turn, advocate for concerted action by pediatric nephrologists, industry, and health regulatory agencies to increase the development of dedicated HD machines and equipment for children.