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1.
Immunity ; 56(9): 2021-2035.e8, 2023 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-37516105

RESUMEN

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including ß-hydroxybutyrate (ßOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. ßOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, ßOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.


Asunto(s)
Linfocitos T CD8-positivos , Histonas , Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/farmacología , Acetilación , Histonas/metabolismo , Cuerpos Cetónicos , Animales , Ratones
2.
Mol Cell ; 83(11): 1872-1886.e5, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37172591

RESUMEN

Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.


Asunto(s)
Histonas , Proteínas Serina-Treonina Quinasas , Humanos , Histonas/genética , Histonas/metabolismo , Acetilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Citocinas/metabolismo , Inflamación/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
RNA Biol ; 20(1): 186-197, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-37095747

RESUMEN

Here, we provide an in-depth analysis of the usefulness of single-sample metabolite/RNA extraction for multi-'omics readout. Using pulverized frozen livers of mice injected with lymphocytic choriomeningitis virus (LCMV) or vehicle (Veh), we isolated RNA prior (RNA) or following metabolite extraction (MetRNA). RNA sequencing (RNAseq) data were evaluated for differential expression analysis and dispersion, and differential metabolite abundance was determined. Both RNA and MetRNA clustered together by principal component analysis, indicating that inter-individual differences were the largest source of variance. Over 85% of LCMV versus Veh differentially expressed genes were shared between extraction methods, with the remaining 15% evenly and randomly divided between groups. Differentially expressed genes unique to the extraction method were attributed to randomness around the 0.05 FDR cut-off and stochastic changes in variance and mean expression. In addition, analysis using the mean absolute difference showed no difference in the dispersion of transcripts between extraction methods. Altogether, our data show that prior metabolite extraction preserves RNAseq data quality, which enables us to confidently perform integrated pathway enrichment analysis on metabolomics and RNAseq data from a single sample. This analysis revealed pyrimidine metabolism as the most LCMV-impacted pathway. Combined analysis of genes and metabolites in the pathway exposed a pattern in the degradation of pyrimidine nucleotides leading to uracil generation. In support of this, uracil was among the most differentially abundant metabolites in serum upon LCMV infection. Our data suggest that hepatic uracil export is a novel phenotypic feature of acute infection and highlight the usefulness of our integrated single-sample multi-'omics approach.


Asunto(s)
Metabolómica , Virosis , Animales , Ratones , Análisis de Secuencia de ARN , Hígado , ARN
4.
J Allergy Clin Immunol ; 150(3): 535-548, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35569568

RESUMEN

Our school-based asthma program has reduced asthma exacerbations for youth with health disparities in the Denver metropolitan area, due partly to addressing social determinants of health, such as access to health care and medications. Dissemination and implementation (D&I) science approaches accelerate the translation of evidence-based programs into routine practice. D&I methods are being applied more commonly to improve health equity. The purpose of this publication was to give an overview of D&I research methods, using our school-based asthma program as an example. To successfully scale out our program across the state of Colorado, we are applying a D&I framework that guides the adaptation of our existing implementation approach to better meet our stakeholders' local context-the Exploration, Preparation, Implementation, Sustainment framework. In a pragmatic trial design, we will evaluate the outcomes of implementing the program across 5 Colorado regions, with attention to health equity, using a second commonly used D&I framework-Reach, Effectiveness, Adoption, Implementation, and Maintenance. Our central hypothesis is that our program will have broad and equitable reach to eligible students (primary outcome) and will reduce asthma attacks and symptoms. This D&I approach accelerates dissemination of our program and is an applicable process for translating other effective allergy/asthma programs to address asthma and allergy-related disparities.


Asunto(s)
Asma , Adolescente , Asma/terapia , Atención a la Salud , Humanos , Proyectos de Investigación , Instituciones Académicas
5.
Matern Child Health J ; 26(1): 139-148, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34845572

RESUMEN

OBJECTIVES: To characterize contraceptive method use and satisfaction among Spanish-speaking Latina immigrants who attend their child's well care visit. METHODS: Spanish-speaking women whose youngest child was ≤ 4 years old completed an orally-administered Spanish-language survey in a pediatric clinic (N = 194). Survey items were based on previously published contraceptive use assessments among diverse populations. We used chi-square and Fisher exact test to describe maternal characteristics by contraceptive method effectiveness categories: Tier 1, most effective methods (hormonal implant, intrauterine device, tubal ligation, and vasectomy); Tier 2, very effective methods (hormonal injection, oral contraceptive pill, hormonal patch, and hormonal ring); Tier 3, effective methods (condoms), and no method. RESULTS: 34% of women were using a Tier 1 method, 40% were using a Tier 2 method, and 17% had unmet contraceptive need (no pregnancy intention, no birth control); 84% were satisfied with their current method and 82% of women were uninsured. Tier 2 method or no method users were more likely than women using a Tier 1 method to have children < 9 months old (X2 (6, N = 190) = 20.4, p = .002). CONCLUSIONS: Latina immigrants with young children who attend their child's pediatric visit are mostly using effective contraceptives and are satisfied with their method. A culturally supportive medical home and access to no-cost long-acting reversible contraceptives through a temporary private grant likely contributed to high contraceptive use and satisfaction in our study. Describing maternal contraceptive use among Latina immigrant mothers can inform future equitable, culturally tailored, approaches to pediatric maternal contraceptive need screening.


Asunto(s)
Anticonceptivos , Madres , Niño , Preescolar , Anticoncepción , Femenino , Hispánicos o Latinos , Humanos , Lactante , Lenguaje
6.
Health Promot Pract ; 23(3): 518-529, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-33666103

RESUMEN

BACKGROUND: The U.S. Preventive Services Task Force recommends referral of all obese children to intensive weight management programs. When available, programs are limited to clinical settings and do not address social determinants of health barriers to healthy weight among Latinx immigrant families. Active and Healthy Families, a Spanish-language, culturally tailored group visit intervention has demonstrated effectiveness in decreasing child body mass index but does not address barriers to frequent engagement with the health care system nor social determinants other than immigration. Adapting the intervention for community-based delivery, and to address additional social determinants, may facilitate participation and increase acceptability and engagement among Latinx immigrant families. PURPOSE: To engage a stakeholder network in planning adaptations of an evidence-based weight management intervention for community-based implementation. METHOD: Guided by the intervention mapping-adapt process, we solicited feedback from a stakeholder network from August 2018 to March 2020. The stakeholder network assessed fit, planned adaptations and identified essential intervention components using photovoice, a Participatory Action Research method, and meetings incorporating user-centered design approaches. RESULTS: The stakeholder network membership included Latinx immigrant families, community leaders, health care delivery experts, and researchers. Planned adaptations included curriculum changes to discuss social determinants barriers to behavior change and goal setting to mitigate them. CONCLUSIONS: We successfully engaged a stakeholder network and, using a systematic process, identified adaptations of an evidence-based weight management intervention to allow for community-based implementation. Sustainably addressing obesity disparities for Latinx children also requires addressing structural factors to reduce social determinants of health barriers at the population level.


Asunto(s)
Emigrantes e Inmigrantes , Obesidad Infantil , Índice de Masa Corporal , Niño , Humanos , Sobrepeso/prevención & control , Obesidad Infantil/prevención & control , Determinantes Sociales de la Salud
7.
Matern Child Health J ; 25(12): 1807-1813, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34687401

RESUMEN

INTRODUCTION: Development of mHealth interventions to address health disparities for Latino children in immigrant families requires understanding access to and use of information and communication technology. METHODS: We examined access to information and communication technology and use of common applications/programs by low-income immigrant Latino parents of infants to inform development of mHealth interventions for this population. Latino immigrant parents reported technology use and access of common applications/software via survey. RESULTS: Of the 157 participants, we found nearly all parents owned a smartphone and that 60% accessed the internet only via their smartphone. Around one-quarter of participants had access to unlimited data. Frequent use of text messaging was common, but frequent email use was less common. Less than 10% of participants frequently used health-oriented applications. DISCUSSION: Our findings suggest that mHealth interventions that use data, email, or an application interface may not have the intended reach or effectiveness among low-income immigrant Latino parents. Consideration of these findings is important in guiding the development of future mHealth programs for the low-income Latino population. This study was registered at clinicaltrials.gov (NCT02647814).


Asunto(s)
Emigrantes e Inmigrantes , Telemedicina , Acceso a la Información , Hispánicos o Latinos , Humanos , Padres , Tecnología
8.
Public Health Nurs ; 38(2): 288-295, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33586139

RESUMEN

Latino children have disproportionately high childhood obesity rates, and U.S.-born Latino children of immigrant parents experience higher overweight/obesity rates than other Latino children. Community-based participatory research (CBPR) to engage Latino immigrant families and Latino-serving community organizations is one mechanism to address the lack of effective and practical interventions addressing childhood obesity disparities among Latino children. We present lessons learned from applying CBPR methods to a partnership focused on developing a child obesity treatment program for Latino immigrant families in an emerging Latino immigrant destination to inform the use of CBPR methods in other partnerships in emerging immigrant communities. We encountered challenges working within the partnership related to entrenched sociopolitical hierarchies that were not inclusive of immigrant community leaders, capacity building for partners with limited literacy and administrative experience, and how best to use complementary methods and frameworks to support a community-engaged research process. This work is one way to promote shared learning among the community of researchers using CBPR and other engagement methods to partner with emerging immigrant communities. Together with our community partners, we can identify strategies to more effectively partner to promote health equity and work toward social justice for all members of our communities.


Asunto(s)
Emigrantes e Inmigrantes , Obesidad Infantil , Niño , Investigación Participativa Basada en la Comunidad , Promoción de la Salud , Hispánicos o Latinos , Humanos , Obesidad Infantil/prevención & control
9.
Matern Child Health J ; 19(6): 1354-63, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25430802

RESUMEN

To compare the association between neighborhood Latino immigrant concentration and infant mortality by maternal nativity among singleton births to Mexican-origin women in Los Angeles County. Information about births, infant deaths, and infant and maternal characteristics were obtained from geocoded Los Angeles County vital statistics records (2002-2005). Linked data on neighborhood characteristics (census tracts) were obtained from the 2000 census. Logistic regression models were used to predict infant mortality while accounting for spatial clustering by census tract. Two-thirds of births to Mexican-origin mothers were to foreign-born women. Foreign-born mothers were older, had less education, and were more likely to have delivery costs paid by Medicaid than US-born mothers. Infants born to foreign-born women had a lower infant mortality rates than infants born to US-born women (3.8/1,000 live births vs. 4.6, p = .002). Among infants of foreign-born mothers, the odds of infant mortality increased with increasing immigrant concentration (OR 1.29; 95 % CI 1.01-1.66). There was a similar pattern of association between immigrant concentration and mortality for infants of US-born mothers (OR 1.29; 95 % CI 0.99-1.67). In Los Angeles County, the odds of infant mortality among foreign-born Mexican-origin Latina were higher in higher-density immigrant neighborhoods, with a similar trend among US-born mothers. Thus, living in immigrant enclaves likely does not help to explain the lower than expected infant mortality rate among infants born to Latina women. Instead, higher neighborhood Latino immigrant concentration may indicate a neighborhood with characteristics that negatively impact maternal and infant health for Latinos.


Asunto(s)
Emigrantes e Inmigrantes/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Mortalidad Infantil/etnología , Americanos Mexicanos/estadística & datos numéricos , Características de la Residencia/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Escolaridad , Femenino , Humanos , Lactante , Modelos Logísticos , Los Angeles/epidemiología , Adulto Joven
10.
Acad Pediatr ; 24(1): 23-32, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37024078

RESUMEN

OBJECTIVE: Models of pragmatic social care program evaluations are needed as many are clinical services programs and are not focused on research, limiting the ability to address key evidence gaps. We describe the use of the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework to conduct a pragmatic evaluation of a pediatric ambulatory social care program. METHODS: Our evaluation was based on automated electronic health record data on clinics, community partners, social care program processes, and social needs screen data linked to patient sociodemographic characteristics from February 2020 to September 2021. Two Reach outcomes were assessed: 1) the proportion of eligible patients that completed social needs screening and 2) the proportion of positive screens that receive social care program follow-up. The Effectiveness outcome was meeting families' resource need(s). RESULTS: Reach among eligible patients who completed screening was 79.2%. Reach for positive screens receiving social care program referrals demonstrated a higher proportion of referrals among patients with a preferred healthcare language (PHL) of Spanish (45.1%) compared to English (31.2%, P < .001). Effectiveness analyses demonstrated that overall, 75.1% of social care program referrals had all social resource needs met, 17.5% had some needs met, and 7.4% had no needs met. The percent of patients with all resource needs met was higher for patients with PHL of Spanish or Non-English, Non-Spanish (79% for each respectively) compared to English (73%, P = .023). CONCLUSIONS: Maximizing automated data collection is likely the most feasible way for social care programs to complete evaluation activities outside of the research context.


Asunto(s)
Atención Ambulatoria , Apoyo Social , Niño , Humanos , Evaluación de Programas y Proyectos de Salud
11.
Hisp Health Care Int ; 22(1): 11-24, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37981744

RESUMEN

Introduction: Little is known about the experiences of immigrant families with COVID-19 illness. This mixed methods study compared child and household experiences at the time of a child's COVID-19 diagnosis between immigrant and US-born parents and explored immigrant Latino perspectives on underlying causes of COVID-19 disparities between immigrant and US-born families. Methods: Study data includes surveys of parents of a child with a positive SARS-CoV2 test resulting at Children's Hospital Colorado and focus groups with Latino immigrant adults. We compared household COVID-19 experiences, use of mitigation measures, vaccine intention and sociodemographic information between survey participants stratified by nativity and completed thematic qualitative data analysis. Results: Findings from quantitative data were reinforced by qualitative data including: lower socio-economic status and higher employment in essential services increased infections and spread in immigrant families and higher risk of limited information access related to language barriers and prevalent misinformation. Survey results showed no difference in COVID-19 vaccine intention by nativity. Focus group participants reported limited access to non-English language culturally-tailored vaccine information and competing work demands decreased uptake. Conclusion: Avoiding exacerbating disparities in the face of another public health emergency requires focused investments in policies and approaches specifically directed at immigrant communities.


Asunto(s)
COVID-19 , Emigrantes e Inmigrantes , Niño , Adulto , Femenino , Humanos , Vacunas contra la COVID-19 , Prueba de COVID-19 , Pandemias , ARN Viral , COVID-19/epidemiología , SARS-CoV-2
12.
J Health Care Poor Underserved ; 35(3): 790-801, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39129602

RESUMEN

Addressing housing insecurity contributes to health care programs as stable housing has positive health benefits. Home environmental hazards may reduce these potential health benefits and could increase morbidity for conditions such as asthma. This study examined housing and indoor air quality among urban low-income households in Colorado to inform housing-insecurity interventions. We conducted a community-engaged study among residents of motels, mobile homes, apartments, and single-family homes that included a survey on the home environment, health, and sociodemographic factors, spirometry, and indoor air quality measurement. We enrolled 60 households: 50% single-family homes, 37% apartments, and 13% residential motels. Perceived stress and depression were higher among motel residents compared with other housing types. We did not find differences in lung function by housing type. Indoor fine particulate matter (PM2.5) and black carbon concentrations were higher in motels than in other housing types. The differential health impacts of housing type support housing programs that jointly address security and quality.


Asunto(s)
Contaminación del Aire Interior , Vivienda , Pobreza , Humanos , Femenino , Masculino , Vivienda/estadística & datos numéricos , Contaminación del Aire Interior/análisis , Adulto , Persona de Mediana Edad , Colorado , Material Particulado/análisis , Estado de Salud , Estrés Psicológico
13.
Implement Sci ; 19(1): 60, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39148094

RESUMEN

BACKGROUND: Asthma is a leading cause of children's hospitalizations, emergency department visits, and missed school days. Our school-based asthma intervention has reduced asthma exacerbations for children experiencing health disparities in the Denver Metropolitan Area, due partly to addressing care coordination for asthma and social determinants of health (SDOH), such as access to healthcare and medications. Limited dissemination of school-based asthma programs has occurred in other metropolitan and rural areas of Colorado. We formed and engaged community advisory boards in socioeconomically diverse regions of Colorado to develop two implementation strategy packages for delivering our school-based asthma intervention - now termed "Better Asthma Control for Kids (BACK)" - with tailoring to regional priorities, needs and resources. METHODS: In this proposed type 2 hybrid implementation-effectiveness trial, where the primary goal is equitable reach to families to reduce asthma disparities, we will compare two different packages of implementation strategies to deliver BACK across four Colorado regions. The two implementation packages to be compared are: 1) standard set of implementation strategies including Tailor and Adapt to context, Facilitation and Training termed, BACK-Standard (BACK-S); 2) BACK-S plus an enhanced implementation strategy, that incorporates network weaving with community partners and consumer engagement with school families, termed BACK-Enhanced (BACK-E). Our evaluation will be guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, including its Pragmatic Robust Implementation Sustainability Model (PRISM) determinants of implementation outcomes. Our central hypothesis is that our BACK-E implementation strategy will have significantly greater reach to eligible children/families than BACK-S (primary outcome) and that both BACK-E and BACK-S groups will have significantly reduced asthma exacerbation rates ("attacks") and improved asthma control as compared to usual care. DISCUSSION: We expect both the BACK-S and BACK-E strategy packages will accelerate dissemination of our BACK program across the state - the comparative impact of BACK-S vs. BACK-E on reach and other RE-AIM outcomes may inform strategy selection for scaling BACK and other effective school-based programs to address chronic illness disparities. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT06003569, registered on August 22, 2023, https://classic. CLINICALTRIALS: gov/ct2/show/NCT06003569 .


Asunto(s)
Asma , Servicios de Salud Escolar , Humanos , Asma/terapia , Asma/prevención & control , Niño , Colorado , Servicios de Salud Escolar/organización & administración , Adolescente , Poblaciones Vulnerables , Ciencia de la Implementación , Femenino
14.
Cell Rep ; 43(8): 114506, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39052479

RESUMEN

Functional and phenotypic heterogeneity of dendritic cells (DCs) play crucial roles in facilitating the development of diverse immune responses essential for host protection. Here, we report that KDM5C, a histone lysine demethylase, regulates conventional or classical DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs have increased proportions of cDC2Bs and cDC1s, which is partly dependent on type I interferon (IFN) and pDCs. Loss of KDM5C results in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I IFN and more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and decreased function. In response to Listeria infection, KDM5C-deficient mice mount reduced CD8 T cell responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and critical driver of the functional properties of DCs.


Asunto(s)
Linfocitos T CD8-positivos , Células Dendríticas , Histona Demetilasas , Células Dendríticas/metabolismo , Células Dendríticas/inmunología , Animales , Ratones , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones Endogámicos C57BL , Transcripción Genética , Interferón Tipo I/metabolismo , Presentación de Antígeno
15.
bioRxiv ; 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38979360

RESUMEN

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.

16.
Pediatrics ; 154(1)2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38860305

RESUMEN

Patients who speak languages other than English are frequently excluded from research. This exclusion exacerbates inequities, biases results, and may violate federal regulations and research ethics. Language justice is the right to communicate in an individual's preferred language to address power imbalances and promote equity. To promote language justice in research, we propose a method to translate and culturally-adapt multifaceted research materials into multiple languages simultaneously. Our method involves a multistep approach, including professional translation, review by bilingual expert panels to refine and reach consensus, and piloting or cognitive interviews with patients and families. Key differences from other translation approaches (eg, the World Health Organization) include omitting back-translation, given its limited utility in identifying translation challenges, and limiting expert panelist and piloting-participant numbers for feasibility. We detail a step-by-step approach to operationalizing this method and outline key considerations learned after utilizing this method to translate materials into 8 languages other than English for an ongoing multicenter pediatric research study on family safety-reporting. Materials included family brochures, surveys, and intervention materials. This approach took ∼6 months overall at a cost of <$2000 per language (not including study personnel costs). Key themes across the project included (1) tailor scope to timeline, budget, and resources, (2) thoughtfully design English source materials, (3) identify and apply guiding principles throughout the translation and editing process, and (4) carefully review content and formatting to account for nuances across multiple languages. This method balances feasibility and rigor in translating participant-facing materials into multiple languages simultaneously, advancing language justice in research.


Asunto(s)
Multilingüismo , Humanos , Traducción , Investigación Biomédica/ética , Niño
17.
bioRxiv ; 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39464161

RESUMEN

Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8+ T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8+ T cell responses in vivo.

18.
Sci Adv ; 10(22): eadj1431, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38809979

RESUMEN

Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.


Asunto(s)
Acetatos , Linfocitos T CD8-positivos , Isótopos de Carbono , Glutamina , Glutamina/metabolismo , Animales , Linfocitos T CD8-positivos/metabolismo , Acetatos/metabolismo , Ratones , Listeriosis/metabolismo , Listeriosis/inmunología , Listeriosis/microbiología , Listeria monocytogenes , Ciclo del Ácido Cítrico , Glucosa/metabolismo , Ratones Endogámicos C57BL
19.
J Exp Med ; 221(9)2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39150482

RESUMEN

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.


Asunto(s)
ATP Citrato (pro-S)-Liasa , Acetatos , Acetilcoenzima A , Linfocitos T CD8-positivos , Cromatina , Ratones Endogámicos C57BL , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Animales , Cromatina/metabolismo , Acetilcoenzima A/metabolismo , ATP Citrato (pro-S)-Liasa/metabolismo , ATP Citrato (pro-S)-Liasa/genética , Ratones , Acetatos/metabolismo , Acetato CoA Ligasa/metabolismo , Acetato CoA Ligasa/genética , Acetilación , Ratones Noqueados , Citosol/metabolismo , Histonas/metabolismo
20.
J Pediatr ; 163(5): 1389-95.e1-6, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23759421

RESUMEN

OBJECTIVES: To measure the prevalence of enhanced access services in pediatric primary care and to assess whether enhanced access services are associated with lower emergency department (ED) utilization. STUDY DESIGN: Internet-based survey of a national sample of parents (n = 820, response rate 41%). We estimated the prevalence of reported enhanced access services and ED use in the prior 12 months. We then used multivariable negative binomial regression to assess associations between enhanced access services and ED use. RESULTS: The majority of parents reported access to advice by telephone during office hours (80%), same-day sick visits (79%), and advice by telephone outside office hours (54%). Less than one-half of parents reported access to their child's primary care office on weekends (47%), after 5:00 p.m. on any night (23%), or by email (13%). Substantial proportions of parents reported that they did not know if these services were available (7%-56%, depending on service). Office hours after 5:00 p.m. on ≥ 5 nights a week was the only service significantly associated with ED utilization in multivariable analysis (adjusted incidence rate ratio: 0.51 [95% CI 0.28-0.92]). CONCLUSIONS: The majority of parents report enhanced access to their child's primary care office during office hours, but many parents do not have access or do not know if they have access outside of regular office hours. Extended office hours may be the most effective practice change to reduce ED use. Primary care practices should prioritize the most effective enhanced access services and communicate existing services to families.


Asunto(s)
Servicios Médicos de Urgencia/organización & administración , Servicio de Urgencia en Hospital/organización & administración , Padres , Pediatría/organización & administración , Atención Primaria de Salud/organización & administración , Adolescente , Adulto , Servicios Médicos de Urgencia/estadística & datos numéricos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Accesibilidad a los Servicios de Salud , Humanos , Internet , Persona de Mediana Edad , Análisis Multivariante , Satisfacción del Paciente , Prevalencia , Análisis de Regresión , Encuestas y Cuestionarios , Adulto Joven
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