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Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are manifestations of the post-acute sequelae of SARS-CoV-2. Our understanding of metabolic decline after acute COVID-19 remains unclear due to the lack of animal models. Here, we report a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 using SARS-CoV-2 infected African green monkeys. Using this model, we identify a dysregulated blood chemokine signature during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. Hyperglycemia also correlates with liver glycogen levels, but there is no evidence of substantial long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the African green monkey model exhibits important similarities to humans and can be utilized to assess therapeutic candidates to combat COVID-related metabolic defects.
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COVID-19 , Modelos Animais de Doenças , Hiperglicemia , Fígado , SARS-CoV-2 , Animais , Hiperglicemia/imunologia , COVID-19/imunologia , COVID-19/virologia , COVID-19/sangue , Chlorocebus aethiops , SARS-CoV-2/imunologia , Fígado/virologia , Fígado/metabolismo , Fígado/imunologia , Glicogênio/metabolismo , Glicemia/metabolismo , Humanos , Masculino , Pâncreas/virologia , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/metabolismo , Quimiocinas/metabolismo , Quimiocinas/sangue , Feminino , Replicação ViralRESUMO
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.
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ATP Citrato (pro-S)-Liase , Acetatos , Acetilcoenzima A , Linfócitos T CD8-Positivos , Cromatina , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Cromatina/metabolismo , Acetilcoenzima A/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , ATP Citrato (pro-S)-Liase/genética , Camundongos , Acetatos/metabolismo , Acetato-CoA Ligase/metabolismo , Acetato-CoA Ligase/genética , Acetilação , Camundongos Knockout , Citosol/metabolismo , Histonas/metabolismoRESUMO
INTS11 and CPSF73 are metal-dependent endonucleases for Integrator and pre-mRNA 3'-end processing, respectively. Here, we show that the INTS11 binding partner BRAT1/CG7044, a factor important for neuronal fitness, stabilizes INTS11 in the cytoplasm and is required for Integrator function in the nucleus. Loss of BRAT1 in neural organoids leads to transcriptomic disruption and precocious expression of neurogenesis-driving transcription factors. The structures of the human INTS9-INTS11-BRAT1 and Drosophila dIntS11-CG7044 complexes reveal that the conserved C terminus of BRAT1/CG7044 is captured in the active site of INTS11, with a cysteine residue directly coordinating the metal ions. Inspired by these observations, we find that UBE3D is a binding partner for CPSF73, and UBE3D likely also uses a conserved cysteine residue to directly coordinate the active site metal ions. Our studies have revealed binding partners for INTS11 and CPSF73 that behave like cytoplasmic chaperones with a conserved impact on the nuclear functions of these enzymes.
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Núcleo Celular , Citoplasma , Proteínas de Drosophila , Ligação Proteica , Humanos , Animais , Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Citoplasma/metabolismo , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Endonucleases/metabolismo , Endonucleases/genética , Células HEK293 , Neurogênese/genética , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/genética , Domínio CatalíticoRESUMO
The effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. In this pilot study, we exposed two pigtail macaques (PTMs) chronically infected with SIVmac239, exhibiting from very low to no CD4 T cells across all compartments, to SARS-CoV-2. We monitored the disease progression, viral replication, and evolution, and compared these outcomes with SIV-naïve PTMs infected with SARS-CoV-2. No overt signs of COVID-19 disease were observed in either animal, and the SARS-CoV-2 viral kinetics and evolution in the SIVmac239 PTMs were indistinguishable from those in the SIV-naïve PTMs in all sampled mucosal sites. However, the single-cell RNA sequencing of bronchoalveolar lavage cells revealed an infiltration of functionally inert monocytes after SARS-CoV-2 infection. Critically, neither of the SIV-infected PTMs mounted detectable anti-SARS-CoV-2 T-cell responses nor anti-SARS-CoV-2 binding or neutralizing antibodies. Thus, HIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants but may remove the ability of infected individuals to mount adaptive immune responses against SARS-CoV-2.
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COVID-19 , Coinfecção , Modelos Animais de Doenças , SARS-CoV-2 , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Vírus da Imunodeficiência Símia/imunologia , COVID-19/imunologia , COVID-19/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , SARS-CoV-2/imunologia , Coinfecção/imunologia , Coinfecção/virologia , Replicação Viral , Macaca nemestrina , Projetos Piloto , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Carga Viral , Linfócitos T CD4-Positivos/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangueRESUMO
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.
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Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.
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Metabolômica , Proteoma , Proteômica , Proteoma/metabolismo , Metabolômica/métodos , Proteômica/métodos , Humanos , Animais , Glutationa/metabolismo , Metaboloma , Transaminases/metabolismoRESUMO
OBJECTIVES: To evaluate carbapenem prescribing rates for initial definitive treatment of urinary tract infections and clinical outcomes before and after removing ESBL status labels on antibiotic susceptibility reports. METHODS: This was a retrospective cohort study of adult patients treated for at least 48â h for an ESBL-producing/ceftriaxone-resistant Enterobacterales urinary tract infection. ESBL status reporting ceased in September 2022 for a network of seven community hospitals within the USA. The primary endpoint was the rate of carbapenem prescribing for initial definitive treatment of urinary tract infections. Secondary endpoints included total days of therapy for initial definitive treatment with carbapenems, clinical cure rates, time to transition to oral antibiotic therapy for initial definitive treatment, rate of guideline-compliant therapy, rate of relapsed infection within 30â days, 30â day readmission rate, and 30â day all-cause in-hospital mortality. RESULTS: Of 3055 patients screened, 199 were included in the pre group and 153 were included in the post group. The rate of carbapenem prescribing for initial definitive treatment was 156 patients (78%) in the pre group, compared with 93 patients (61%) in the post group (Pâ=â<0.01). Days of therapy for initial definitive therapy with carbapenem was 620 in the pre group compared with 372 in the post group (Pâ<â0.01). There was no difference between other secondary outcomes. CONCLUSIONS: Removing ESBL status labels from laboratory reports reduced carbapenem use for initial definitive treatment of urinary tract infections from 78% to 61% (Pâ<â0.01) without impacting clinical outcomes.
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Antibacterianos , Carbapenêmicos , Infecções por Enterobacteriaceae , Infecções Urinárias , beta-Lactamases , Humanos , Carbapenêmicos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Estudos Retrospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Idoso , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Testes de Sensibilidade Microbiana , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/enzimologia , Enterobacteriaceae/isolamento & purificação , Adulto , Idoso de 80 Anos ou mais , Gestão de AntimicrobianosRESUMO
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.
Assuntos
Acetatos , Linfócitos T CD8-Positivos , Isótopos de Carbono , Glutamina , Glutamina/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Acetatos/metabolismo , Camundongos , Listeriose/metabolismo , Listeriose/imunologia , Listeriose/microbiologia , Listeria monocytogenes , Ciclo do Ácido Cítrico , Glucose/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Many speculated that COVID-19 would severely restrict the delivery of essential health services, including family planning (FP), but evidence of this impact is limited, partly due to data limitations. We use cross-sectional data collected from regional and national samples of health facilities (n = 2,610) offering FP across seven low- and middle-income countries (LMICs) between 2019 and 2021, with longitudinal data from four geographies, to examine reported disruptions to the FP service environment during COVID-19, assess how these disruptions varied according to health system characteristics, and evaluate how disruptions evolved throughout the first two years of the pandemic, relative to a pre-pandemic period. Findings show significant variation in the impact of COVID-19 on facility-based FP services across LMICs, with the largest disruptions to services occurring in Rajasthan, India, where COVID-19 cases were highest among geographies sampled, while in most sub-Saharan African settings there were limited disruptions impacting FP service availability, method provision, and contraceptive supplies. Facility-reported disruptions to care were not reflected in observed changes to the number of FP clients or types of stockouts experienced in the first two years of the pandemic. Public and higher-level facilities were generally less likely to experience COVID-19-related disruptions to FP services, suggesting policy mitigation measures-particularly those implemented among government-operated health facilities-may have been critical to ensuring sustained delivery of reproductive healthcare during the pandemic.
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Early childhood home visiting programs are well positioned to improve equity and reduce health disparities for families headed by caregivers with intellectual disabilities and other learning differences. Early identification of learning differences through screening may help home visiting staff tailor services and thus improve family engagement and outcomes. Using a mixed methods design, this study assessed potential determinants and outcomes related to implementation of a screening tool for learning differences adapted for the home visiting context. Participants were six home visiting staff and nine caregivers from multiple home visiting programs in one state. Staff completed surveys at enrollment and each time they conducted a screen with a caregiver. Staff also completed semi-structured interviews after conducting screens with at least two caregivers. Caregivers completed semi-structured interviews after taking part in a screen. At study enrollment, staff felt it was important to know if caregivers had learning differences, yet some believed caregivers would not like being asked about them. Survey and interview data aligned with theoretical determinants of implementation success, including staff competencies related to screening (e.g., knowledge, skills), perceived fit of screening with staff role and organizational context, and beliefs that the screening would improve engagement of caregivers and service delivery. Staff perceived the tool to be acceptable, feasible, and useful, although some acknowledged that caregivers might feel uncomfortable if the tool was not used carefully. Overall, caregivers found the tool to be acceptable and most believed it was helpful for the home visitor to have information about their learning experiences and needs. Findings lend initial support for the use of an adapted screening tool to identify potential learning differences.
Assuntos
Cuidadores , Estudos de Viabilidade , Humanos , Cuidadores/educação , Feminino , Masculino , Pré-Escolar , Visita Domiciliar , Adulto , Programas de Rastreamento , Inquéritos e Questionários , Lactente , Entrevistas como AssuntoRESUMO
Toll-like receptors (TLRs) are crucial to the innate immune response. They regulate inflammatory reactions by initiating the production of pro-inflammatory cytokines and chemokines. TLRs also play a role in shaping the adaptive immune responses. While this protective response is important for eliminating infectious pathogens, persistent activation of TLRs may result in chronic immune activation, leading to detrimental effects. The role of TLR2 in regulating HIV-1 infection in vivo has yet to be well described. In this study, we used an SIV-infected rhesus macaque model to simulate HIV infection in humans. We evaluated the plasma of the macaques longitudinally and found a significant increase in the soluble TLR2 (sTLR2) level after SIV infection. We also observed an increase in membrane-bound TLR2 (mb-TLR2) in cytotoxic T cells, B cells, and NK cells in PBMC and NK cells in the gut after infection. Our results suggest that sTLR2 regulates the production of various cytokines and chemokines, including IL-18, IL-1RA, IL-15, IL-13, IL-9, TPO, FLT3L, and IL-17F, as well as chemokines, including IP-10, MCP-1, MCP-2, ENA-78, GRO-α, I-TAC, Fractalkine, SDF-1α, and MIP-3α. Interestingly, these cytokines and chemokines were also upregulated after the infection. The positive correlation between SIV copy number and sTLR2 in the plasma indicated the involvement of TLR2 in the regulation of viral replication. These cytokines and chemokines could directly or indirectly regulate viral replication through the TLR2 signaling pathways. When we stimulated PBMC with the TLR2 agonist in vitro, we observed a direct induction of various cytokines and chemokines. Some of these cytokines and chemokines, such as IL-1RA, IL-9, IL-15, GRO-α, and ENA-78, were positively correlated with sTLR2 in vivo, highlighting the direct involvement of TLR2 in the regulation of the production of these factors. Our findings suggest that TLR2 expression may be a target for developing new therapeutic strategies to combat HIV infection.
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Persistent and uncontrolled SARS-CoV-2 replication in immunocompromised individuals has been observed and may be a contributing source of novel viral variants that continue to drive the pandemic. Importantly, the effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. Here we conducted a pilot study wherein two pigtail macaques (PTM) chronically infected with SIVmac239 were exposed to SARS-CoV-2 and monitored for six weeks for clinical disease, viral replication, and viral evolution, and compared to our previously published cohort of SIV-naïve PTM infected with SARS-CoV-2. At the time of SARS-CoV-2 infection, one PTM had minimal to no detectable CD4+ T cells in gut, blood, or bronchoalveolar lavage (BAL), while the other PTM harbored a small population of CD4+ T cells in all compartments. Clinical signs were not observed in either PTM; however, the more immunocompromised PTM exhibited a progressive increase in pulmonary infiltrating monocytes throughout SARS-CoV-2 infection. Single-cell RNA sequencing (scRNAseq) of the infiltrating monocytes revealed a less activated/inert phenotype. Neither SIV-infected PTM mounted detectable anti-SARS-CoV-2 T cell responses in blood or BAL, nor anti-SARS-CoV-2 neutralizing antibodies. Interestingly, despite the diminished cellular and humoral immune responses, SARS-CoV-2 viral kinetics and evolution were indistinguishable from SIV-naïve PTM in all sampled mucosal sites (nasal, oral, and rectal), with clearance of virus by 3-4 weeks post infection. SIV-induced immunodeficiency significantly impacted immune responses to SARS-CoV-2 but did not alter disease progression, viral kinetics or evolution in the PTM model. SIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants.
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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.
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Linfócitos T CD8-Positivos , Histonas , Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Acetilação , Histonas/metabolismo , Corpos Cetônicos , Animais , CamundongosRESUMO
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.
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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.
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Histonas , Proteínas Serina-Treonina Quinases , Humanos , Histonas/genética , Histonas/metabolismo , Acetilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Citocinas/metabolismo , Inflamação/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
There are many cognitive, physical, and social-emotional benefits for youths from participating in outdoor adventure activities. However, youths with visual impairments are not given the same opportunities to participate in outdoor adventure activities as their peers without disabilities. The purpose of this study was to examine the outdoor adventure experiences of youths with visual impairments participating in a week-long sports camp. Thirty-seven youths with visual impairment (ages 9-19 years) attending a one-week sports camp participated in this study. Participants engaged in a variety of outdoor adventure activities throughout the week of camp (e.g., sailing, hiking, rock climbing, biking, kayaking). Participants provided written accounts about their outdoor adventure experiences and were observed throughout the week during each activity to examine instructional strategies and task modifications. Additionally, 10 randomly chosen athletes, their one-on-one coaches, and five outdoor recreation specialists participated in focus group interviews. The data analysis revealed three major themes: (1) Benefits, (2) Support, and (3) Barriers. The subthemes of benefits were enjoyment, independence, and relationships; the subthemes of support were instructional strategies and task modifications; and subthemes for barriers were fear and anxiety, exclusion and low expectations, and lack of equipment. These findings support the inclusion of youths with visual impairments in all outdoor adventure programming with appropriate instruction and modification.
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Esportes , Humanos , Adolescente , Criança , Adulto Jovem , Adulto , Recreação , Emoções , Ciclismo , Transtornos da Visão/epidemiologiaRESUMO
Objective: We sought to determine the value of an audit-and-feedback monitoring method in facilitating meaningful practice changes to improve vancomycin dosing and monitoring. Design: Retrospective, multicenter, before-and-after implementation observational quality assurance initiative. Setting: The study was conducted in 7 not-for-profit, acute-care hospitals within a health system in southern Florida. Methods: The preimplementation period (September 1, 2019, through August 31, 2020) was compared to the postimplementation period (September 1, 2020, through May 31, 2022). All vancomycin serum-level results were screened for inclusion. The primary end point was the rate of fallout, defined as vancomycin serum level ≥25 µg/mL with acute kidney injury (AKI) and off-protocol dosing and monitoring. Secondary end points included the rate of fallout with respect to AKI severity, rate of vancomycin serum levels ≥25 µg/mL, and average number of serum-level evaluations per unique vancomycin patient. Results: In total, 27,611 vancomycin levels were analyzed from 13,910 unique patients. There were 2,209 vancomycin serum levels ≥25 µg/mL (8%) among 1,652 unique patients (11.9%). AKI was identified in 379 unique patients (23%) with a vancomycin levels ≥25 µg/mL. In total, 60 fallouts (35.2%) occurred in the 12-month preimplementation period (â¼5 per month) and 41 fallouts (19.6%) occurred in the 21-month postimplementation period (â¼2 per month; P = .0006). Failure was the most common AKI severity in both periods (risk: 35% vs 24.3%, P = .25; injury: 28.3% vs 19.5%, P = .30; failure: 36.7% vs 56%, P = .053). Overall, the number of evaluations of vancomycin serum levels per unique patient remained consistent throughout both periods (2 vs 2; P = .53). Conclusions: Implementation of a monthly quality assurance tool for elevated outlier vancomycin levels can improve dosing and monitoring practices resulting in enhanced patient safety.
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OBJECTIVES: Studies in several sub-Saharan geographies conducted early in the COVID-19 pandemic suggested little impact on contraceptive behaviours. Initial results may mask widening disparities with rising poverty, and changes to women's pregnancy desires and contraceptive use amid prolonged health service disruptions. This study examined trends in contraceptive behaviours in four sub-Saharan African settings 1 year into the pandemic. DESIGN: Nationally and regionally representative longitudinal surveys. SETTING: Burkina Faso, Kenya, Democratic Republic of Congo (Kinshasa) and Nigeria (Lagos). PARTICIPANTS: Women aged 15-49 years with sample size ranging from 1469 in Nigeria to 9477 in Kenya. OUTCOME MEASURES: Fertility preferences, contraceptive use and unintended pregnancies measured before COVID-19 (November 2019 to January 2020) and during COVID-19 (November 2020 to January 2021). ANALYSIS: We described population-level and individual-level changes by socioeconomic characteristics using generalised equation modelling. We used logistic regression models to identify factors related to contraceptive adoption and discontinuation and to experiencing an unintended pregnancy. RESULTS: At the population level, we found no change in women's exposure to unintended pregnancy risk, alongside 5-9 percentage point increases in contraceptive prevalence in Burkina Faso, Kenya and Lagos. Reliance on provider-dependent methods dropped by 2 and 4 percentage points in Kenya and Burkina Faso, respectively, although these declines were not statistically significant. Between 1.0% and 2.8% of women across sites experienced an unintended pregnancy during COVID-19, with no significant change over time. Individual-level trajectories showed contraceptive adoption was more common than discontinuation in Burkina Faso, Kenya and Lagos, with little difference by sociodemographic characteristics. Women's COVID-19-related economic vulnerability was unrelated to unintended pregnancy across sites. CONCLUSIONS: This study highlights the resilience of African women across diverse settings in sustaining contraceptive practices amid the COVID-19 pandemic. However, with reports of rising poverty in sub-Saharan Africa, there is continued need to monitor access to essential sexual and reproductive health services.
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COVID-19 , Anticoncepcionais , Gravidez , Humanos , Feminino , Serviços de Planejamento Familiar , Intenção , Pandemias , COVID-19/epidemiologia , Nigéria/epidemiologia , República Democrática do Congo , Fertilidade , Serviços de Saúde , Comportamento ContraceptivoRESUMO
Zhang et al. (2022) show that TCR signaling promotes the phosphorylation and activation of glycogen phosphorylase B (PYGB) in CD8+ memory T (Tmem) cells. PYGB-dependent glycogen mobilization provides a carbon source to support glycolysis and early Tmem cell recall responses.
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Glicogênio , Células T de Memória , Glicogênio/metabolismo , Glicólise , Transdução de SinaisRESUMO
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.