NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

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.

Creating Culturally Adapted Multilingual Materials for Research.

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.

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

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.

Assessing Strengths, Challenges, and Equity Via Pragmatic Evaluation of a Social Care Program.

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.

Mixed Methods Evaluation of the Impact of the COVID-19 Pandemic on Immigrant Families.

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.

Variation over Time in Child and Neighborhood Characteristics Associated with COVID-19.

Introduction: To examine the associations between child and neighborhood characteristics and incidence of COVID-19 infection during the first 19 months of the pandemic. Study Design: We utilized individual electronic health record data and corresponding census tract characteristics for pediatric SARS-CoV-2 cases (age <18 years) from March 23, 2020 to September 30, 2021 with molecular tests resulted at a children's health system in Colorado. We compared associations between individual SARS-CoV-2 cases and census tract SARS-CoV-2 positivity rates over three time periods (TP1: March-September 2020; TP2: October 2020-March 2021; TP3: April-September 2021) using multinomial logistic regression for individual associations and negative binomial regression for census tract associations. Results: We included 7498 pediatric SARS-CoV-2 cases and data from 711 corresponding census tracts. Spanish preferred health care language was associated with SARS-CoV-2 positivity for TP1 (odds ratio [OR] 4.9, 95% confidence interval [CI] 3.7-6.5) and TP2 (OR 2.01, 95% CI 1.6-2.6) compared with TP3. Other non-English preferred health care language was associated with SARS-CoV-2 positivity in TP1 (OR 2.4, 95% CI 1.4-4.2). Increasing percentage internationally born in a census tract was associated with SARS-CoV-2 positivity for TP1 (multivariable incident rate ratio [IRR]=1.040, p<0.0001), TP2 (multivariable IRR=1.028, p<0.0001), and in all TP combined (multivariable IRR=1.024, p<0.0001). Discussion: Our study is notable for the identification of COVID-19 disparities among children in immigrant families and communities, particularly early in the pandemic. Addressing disparities for immigrant communities requires targeted investments in public health infrastructure.

High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Health Care for Children in Immigrant Families: Key Considerations and Addressing Barriers.

One in four US children is a child in an immigrant family. Children in immigrant families (CIF) have distinct health and health care needs that vary by documentation status, countries of origin, and health care and community experience caring for immigrant populations. Health insurance access and language services are fundamental to providing health care to CIF. Promoting health equity for CIF requires a comprehensive approach to both the health and social determinants of health needs of CIF. Child health providers can promote health equity for this population through tailored primary care services and partnerships with immigrant-serving community organizations.

Mixed methods evaluation of pediatric telehealth equity for patients/families who communicate in languages other than English.

Background: Emerging research demonstrates telehealth disparities for patients who communicate in languages other than English. A better understanding of pediatric telehealth use with families who communicate in languages other than English is needed to inform interventions to promote telehealth equity. Methods: We conducted a mixed methods study of telehealth care in a children's hospital health system using electronic health record data for outpatient video telehealth encounters from April 2020 to July 2021 and qualitative interviews with clinical staff and Spanish-speaking parents of telehealth patients. Results: The 16-month study period included 102,387 telehealth encounters; 5% of which were encounters in languages other than English. 83% of languages other than English encounters were with patients/families with a preferred healthcare language of Spanish. 11% of providers conducted ≥10 languages other than English telehealth encounters. This subset of providers conducted 71% of all languages other than English encounters. We conducted 25 interviews with clinical staff (n=13) and parents (n=12). Common themes identified across interviews were: (I) technology barriers affect access to and quality of telehealth; (II) clinical staff and parents are uncertain about the future role of telehealth for patients/families who communicate in languages other than English; (III) the well-known impact of language barriers on in-person healthcare access and quality for patients who communicate in languages other than English is also evident in telehealth. Conclusions: Patients who communicate in languages other than English were underrepresented among telehealth encounters and encounters were concentrated among few providers. Promoting equitable telehealth care requires investment to address technology barriers, increase the readiness of providers and clinics to provide telehealth care in languages other than English, and continued attention to reducing the healthcare impact of language barriers.

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.

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.

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8+ T cells.

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, acetate) in Listeria monocytogenes (Lm)-infected mice, we demonstrate that CD8+ T effector (Teff) cells utilize metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily towards nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support ATP and de novo pyrimidine synthesis. Additionally, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. Importantly, 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 Teff cell function in vivo.

Quality Improvement Campaign Improved Utilization of Rapid Sequence MRI for Diagnosis of Pediatric Appendicitis.

INTRODUCTION: Appendicitis is the most common indication for emergency general surgery in the pediatric population. Computed tomography (CT) or magnetic resonance imaging (MRI) may be used for diagnosis when ultrasound findings are equivocal. However, CT involves unnecessary radiation exposure if MRI is available. After introducing a rapid sequence MRI (rsMRI) appendicitis protocol at our institution, CT was still preferentially used. We therefore implemented a quality improvement (QI) campaign to reduce the rate of CTs and increase the rate of rsMRI. Here, we assess the effectiveness of the QI campaign while evaluating potential barriers to using rsMRI. METHODS: We conducted a mixed methods study, first performing stakeholder interviews which informed the design of a QI campaign initiated in May 2021 and a midway feedback survey in December 2021. A retrospective cohort study was then performed of children evaluated for appendicitis at our institution between January 1, 2016, and April 30, 2022. CT and rsMRI rates were compared before and after QI campaign implementation. RESULTS: There was a significant decrease in rate of CTs and increase in rate of rsMRIs performed following the initiation of the QI campaign (p < 0.0001). The rate of CT scans decreased by a factor of 0.4 while the rate of rsMRI increased by a factor of 9.5. CONCLUSION: A successful QI campaign was initiated at our institution, resulting in decreased utilization of CT and increased use of rsMRI for the evaluation of suspected appendicitis. These results highlight the potential impact of QI projects. LEVEL OF EVIDENCE: III.

LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.

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.

Prior metabolite extraction fully preserves RNAseq quality and enables integrative multi-'omics analysis of the liver metabolic response to viral infection.

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.

Developing a Social Determinants of Health Needs Assessment for Colorado Kids (SNACK) Tool for a School-Based Asthma Program: Findings from a Pilot Study.

Background: School-based asthma programs effectively address poorly controlled asthma and asthma disparities, especially when coupled with screening for and addressing social determinants of health (SDOH) needs. Existing screening tools are tailored to clinical settings; therefore, we sought to develop a community-based SDOH screening tool. Design/Methods: We used a four-phase iterative design process to develop and pilot a community-based screening tool. We used a modified Delphi process to identify screening tool domains, identified validated items for inclusion, and developed an appropriate tool layout for populations with limited health/general literacy. Community advisory boards reviewed and refined a draft tool. Next, we conducted a qualitative pilot test of acceptability to parents and feasibility for staff in a community health center. Results: Six domains are included in our SDOH screening tool: health care access, transportation, food insecurity, public benefits, housing, and utilities. In the pilot test, 41 screenings were completed, and 36 parents (16.7% Spanish speaking) provided feedback. Most families understood the purpose of the screening; felt that the questions were clear, appropriate, and quick to complete; and liked the pictures. The clinic's care coordinator expressed a preference for the pilot tool compared to their existing screening tool and recommended improvements to encourage honest reporting by patients. Conclusion: This community-based screening tool addresses key SDOH needs that impact asthma and is acceptable to families. The next steps are to implement the tool in school-based asthma programs to support improvements in asthma outcomes and disparities by identifying and addressing families' unmet SDOH needs.

Understanding Core Community Needs for School-Based Asthma Programming: A Qualitative Assessment in Colorado Communities.

Objectives: Asthma is one of the most prevalent chronic conditions affecting approximately 8.5% of children in Colorado. Our school-based asthma program (SBAP) has effectively improved asthma control and reduced asthma disparities among children but has been largely limited to the Denver area. We interviewed community stakeholders in 5 regions of Colorado to understand community needs for broader dissemination of SBAPs. Methods: In-depth, semistructured key informant interviews were conducted with school nurses, parents, pediatric healthcare providers, public health professionals, and community resource organization representatives. Inductive and deductive analyses were informed by the practical, robust, implementation, and sustainability model, an implementation science framework. Results: Participants (n=52) identified 6 types of needs for successful future implementation of our SBAP: (1) buy-in from stakeholders; (2) asthma prioritization; (3) improved relationships, communication, and coordination among school nurses, healthcare providers, and community organizations that address social determinants of health (SDOH) and children/families; (4) resources to address healthcare and SDOH needs and awareness of existing resources; (5) asthma education for children/families, school staff, and community members; and (6) improved coordination for School Asthma Care Plan completion. These needs mapped to a 3-tiered, progressive structure of foundational, relational, and functional needs for implementation success. Conclusion: These 6 types of needs illuminate factors that will allow this SBAP to work well and program delivery approaches and implementation strategies that may need modification to be successful. Next steps should include tailoring implementation strategies to variations in local context to support fit, effectiveness, and sustainment.

"All of the things to everyone everywhere": A mixed methods analysis of community perspectives on equitable access to monoclonal antibody treatment for COVID-19.

BACKGROUND: Neutralizing monoclonal antibody (mAb) treatment for COVID-19 prevents hospitalization and death but is underused, especially in racial/ethnic minority and rural populations. Reasons for underuse and inequity may include community member lack of awareness or healthcare access barriers, among others. This study assessed mAbs community awareness and opportunities for improving equitable mAb access. METHODS: A concurrent mixed methods study including surveys and focus groups with adults with high-risk conditions or their proxy decision-makers. Surveys and focus group guides addressed diffusion of innovation theory factors. Descriptive statistics and Fisher's exact method was used to report and compare survey findings by race and ethnicity. Rapid qualitative methods were used for focus group analysis. RESULTS: Surveys from 515 individuals (460 English, 54 Spanish, 1 Amharic), and 8 focus groups (6 English, 2 Spanish) with 69 participants, completed June 2021 to January 2022. Most survey respondents (75%) had heard little or nothing about mAbs, but 95% would consider getting mAb treatment. Hispanic/Latino and Non-Hispanic People of Color (POC) reported less awareness, greater concern about intravenous infusions, and less trust in mAb safety and effectiveness than White, Non-Hispanic respondents. Focus group themes included little awareness but high interest in mAb treatment and concerns about cost and access barriers such as lacking established sources of care and travel from rural communities. Focus groups revealed preferences for broad-reaching but tailored messaging strategies using multiple media and trusted community leaders. CONCLUSIONS: Despite unfamiliarity with mAb treatment, most respondents were open to receiving mAbs or recommending mAbs to others. While mAb messaging should have broad reach "to everyone everywhere," racial and geographic disparities in awareness and trust about mAbs underscore need for tailored messaging to promote equitable access. Care processes should address patient-level barriers like transportation, insurance, or primary care access. COVID-19 treatment dissemination strategies should promote health equity.

"The First Step to Changing Something": Addressing Latinx Childhood Obesity through Photovoice.

BACKGROUND: Latinx children in immigrant families have disproportionately high obesity rates; effective obesity treatment for this subset of Latinx children is critically needed. OBJECTIVES: To inform the development of weight management interventions we explored: 1) community facilitators and barriers to achieving childhood healthy weight through photovoice; and 2) participant reflections on the photovoice process. METHODS: Photovoice was conducted using established methods in a local church. After photovoice, participants completed semi-structured interviews to reflect on their experience. Transcripts were analyzed using a general thematic analysis approach to arrive at preliminary themes, which were presented to participants for validation. Participant input was used to finalize the themes. RESULTS: Six adults and two youth Latinx immigrants identified photograph themes over seven sessions. Four themes emerged regarding community barriers and facilitators to achieving childhood healthy weight: 1) family habits, 2) cultural influences on food, 3) built environment, and 4) food marketing. Participant reflections revealed they were motivated to participate in photovoice to learn more about health, recognized personal growth as a result of group sharing, valued representation as a community, and felt empowered to be role models. CONCLUSIONS: Findings from both photovoice and participant reflections reinforced the need for multi-level approaches to treating childhood obesity. Though participant reflections were gathered to inform continued engagement of Latinx families, they ultimately had a significant impact on our conclusions about priority intervention components.

Carbon source availability drives nutrient utilization in CD8+ T cells.

How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycle. In fact, CD8+ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector T cells.

Applying dissemination and implementation research methods to translate a school-based asthma program.

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.