RESUMO
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.
Assuntos
Biologia Computacional , Citometria de Fluxo , Imunofenotipagem , Software , Humanos , Imunofenotipagem/métodos , Citometria de Fluxo/métodos , Biologia Computacional/métodos , Aprendizado de MáquinaRESUMO
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.
Assuntos
Receptores de Antígenos de Linfócitos T gama-delta , Humanos , Criança , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Adulto , Pré-Escolar , Adolescente , Adulto Jovem , Feminino , Lactente , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Idoso , Recém-NascidoRESUMO
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.
RESUMO
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.
Assuntos
Tomada de Decisões , Demência , Casas de Saúde , Humanos , Masculino , Feminino , Demência/psicologia , Idoso de 80 Anos ou mais , Idoso , Inquéritos e Questionários , Atividades Cotidianas/psicologia , Qualidade de Vida/psicologia , Preferência do Paciente/psicologiaRESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Animais , Humanos , Sistema Imunitário , MicrogliaRESUMO
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.
Assuntos
Diálise Renal , Humanos , Diálise Renal/instrumentação , Diálise Renal/métodos , Diálise Renal/normas , Criança , Desenho de Equipamento , Cateteres Venosos Centrais/normas , Falência Renal Crônica/terapiaRESUMO
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.
Assuntos
United States Department of Veterans Affairs , Estados Unidos , United States Department of Veterans Affairs/organização & administração , Humanos , Prestação Integrada de Cuidados de Saúde/organização & administração , Veteranos , Ciência da ImplementaçãoRESUMO
The purpose of the current study was to evaluate treatment fidelity (i.e., the extent to which an intervention is provided as intended) in the Family-Centered Function-Focused Care (Fam-FFC) intervention. This was a descriptive study using data collected during intervention activities throughout the course of the Fam-FFC study. Specific measures included Environment and Policy Assessments, Fam-FFC Knowledge Test, Goal Attainment Scale, Function-Focused Care Behavior Checklist, and completion of the FamPath Audit. Delivery was provided as intended. Staff demonstrated intervention skills with only one Fam-FFC research nurse needing retraining. Receipt was based on Fam-FFC Knowledge Test scores >80%, with the majority of participants reporting goal achievement as expected or higher than expected and slight improvement in environments and policies to better support Fam-FFC. Lastly, enactment was based on evidence that in 67% of observations staff provided at least one function-focused care intervention. Findings from this study will be used to adapt the intervention to reach all staff, increase ways to change environments and policies, consider ways to more comprehensively evaluate enactment of function-focused care during real-world interactions, and consider the characteristics of nursing staff and whether a relationship exists between staff characteristics and providing function-focused care. [Research in Gerontological Nursing, 16(4), 165-171.].
Assuntos
Enfermagem Geriátrica , Recursos Humanos de Enfermagem , Humanos , Idoso , Atividades Cotidianas , MotivaçãoRESUMO
Nursing homes (NHs) are challenged to consistently deliver person-centered care (PCC), or care based on residents' values and preferences. NH staff associate certain resident preferences with risk. However, there are limited evidence-based person-centered risk management strategies to assist NH staff with risky resident preferences. The purpose of the current study was to explore NH staff perceptions of health and safety outcomes associated with honoring NH residents' risky preferences to inform intervention development. This descriptive, qualitative study used sequential focus groups and content analysis, revealing that nursing staff perceive negative and positive outcomes for staff and residents when seeking to honor residents' risky preferences. This finding is supported by three themes: Potential Harms to Staff, Potential Harms to Residents, and Positive Shared Outcomes. These results contribute a set of nurse-driven quality of life and quality of care outcomes for NH staff and residents associated with PCC delivery in NHs. [Research in Gerontological Nursing, 15(6), 271-281.].
Assuntos
Enfermagem Geriátrica , Recursos Humanos de Enfermagem , Humanos , Idoso , Assistência Centrada no Paciente , Qualidade de Vida , Casas de SaúdeRESUMO
OBJECTIVE: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response - measured by change in magnetisation transfer ratio - is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values). METHODS: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level. RESULTS: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores. INTERPRETATION: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes.
Assuntos
Esclerose Múltipla , Remielinização , Bexaroteno/farmacologia , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologiaRESUMO
BACKGROUND: Nursing education influences medication administration practices, which involve clinical decision making and risk perceptions. METHOD: This mixed-methods concurrent nested study explored the relationship among knowledge, personality traits, and self-efficacy related to medication administration error in fourth-year, prelicen-sure nursing students (n = 60) who were recruited from three campuses of a large university. RESULTS: Results indicated low mean knowledge (70.75) and neuroticism (2.44) scores, and high mean self-efficacy and confidence (5.78) and conscientiousness (4.51) scores. Conscientiousness was correlated with both knowledge (r = .271, p = .036) and neuroticism (r = -.313, p = .015). Thematic analysis yielded four themes: nature of risk perceptions, more opportunities to learn, experiences with medication administration error, and intrinsic characteristics influence errors. Convergence was evident in both knowledge and personality data; self-efficacy/confidence and risk perceptions data diverged. CONCLUSION: Knowledge, personality traits, and self-efficacy appear to influence nursing students' risk perceptions of medication administration error, indicating an area for future research. [J Nurs Educ. 2022;61(7):367-374.].
Assuntos
Bacharelado em Enfermagem , Estudantes de Enfermagem , Humanos , Conhecimento , Personalidade , AutoeficáciaRESUMO
Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Alemtuzumab/efeitos adversos , Autoimunidade , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Marketing , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológicoRESUMO
AIM: The purpose of this study was to explore and describe pre-licensure nursing students' perceptions of risk for medication administration errors in fourth-year baccalaureate student nurses from three campuses at a large central Pennsylvania university. BACKGROUND: Medication administration errors continue to be a significant safety concern in healthcare settings. Pre-licensure nursing education is a critical time period during which to have an impact on future medication administration practices. Perception of risk influences decision making and behavior, including nursing clinical decision making. DESIGN: This descriptive, exploratory study involved a qualitative design. METHODS: A thematic analysis of the qualitative data resulting from 60 individual, in-depth semi-structured interviews was conducted. RESULTS: The participants offered rich, detailed narratives which revealed the following themes: (1) the nature of risk perceptions, (2) more opportunities to learn, (3) experiences with medication administration error, and (4) intrinsic characteristics influence errors. CONCLUSIONS: The findings provide a broad description of the nature of student nurse risk perceptions for future medication administration errors. Recommendations for nursing education practice and pedagogy include additional clinical experiences, modified pharmacology curricula and instruction, and expanded simulations involving medication administration error.
Assuntos
Bacharelado em Enfermagem , Educação em Enfermagem , Estudantes de Enfermagem , Humanos , Aprendizagem , Pesquisa QualitativaRESUMO
The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.
Assuntos
5'-Nucleotidase/genética , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linfócitos T Reguladores/metabolismo , 5'-Nucleotidase/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MasculinoRESUMO
Dopaminergic (DA) cell replacement therapies are a promising experimental treatment for Parkinson's disease (PD) and a number of different types of DA cell-based therapies have already been trialled in patients. To date, the most successful have been allotransplants of foetal ventral midbrain but even then, the results have been inconsistent. This coupled to the ethical and logistical problems with using this tissue has meant that an alternative cell source has been sought of which human pluripotent stem cells (hPSCs) sources have proven very attractive. Robust protocols for making mesencephalic DA (mesDA) progenitor cells from hPSCs now exist and the first in-human clinical trials have or are about to start. However, while their safety and efficacy are well understood, relatively little is known about their immunogenicity and in this review, we briefly summarise this with reference mainly to the limited literature on human foetal DA cells.
RESUMO
The retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (atRA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation in vitro. By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of atRA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive in vitro. Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.
Assuntos
Bexaroteno/farmacologia , Linfopoese/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Receptores X de Retinoides/agonistas , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Alitretinoína/farmacologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Células Cultivadas , Ensaios Clínicos como Assunto , Ácidos Graxos Insaturados/farmacologia , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Pessoa de Meia-Idade , Receptores X de Retinoides/fisiologia , Linfócitos T Reguladores/imunologia , Tetra-Hidronaftalenos/farmacologia , Células Th17/citologiaRESUMO
Hospitalized persons with dementia are at higher risk for functional decline and cognitive loss related to delirium. Family-centered, function-focused care (Fam-FFC) engages the family care partner in education and active participation in function-focused goal setting, implementation, and evaluation to support delirium prevention and abatement and return to baseline physical function. The purpose of the current study was to examine the association of function-focused goal attainment with two discharge outcomes, return to baseline physical function and delirium severity at discharge, in hospitalized persons with dementia. In the ongoing Fam-FFC clinical trial, the majority of goals (N = 433) developed by 134 care partner/patient dyads and nurses address mobility, cognitive stimulation, and self-care. Regression techniques demonstrated that goal attainment was significantly associated with return to baseline function (B = 0.826, Wald = 4.17 [1], p = 0.041) and lower delirium severity at discharge (B = 0.175, t = 2.239, p = 0.027). Results support the contribution of family engagement in promoting functional recovery of hospitalized persons with dementia. [Journal of Gerontological Nursing, 47(9), 13-20.].