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Ready-to-use supplemental foods (RUSF) are energy-dense meals formulated to prevent and treat moderate and severe childhood acute malnutrition (MAM and SAM) in high-risk settings. Although lifesaving, the degree and durability of weight recovery with RUSF is unpredictable. We examined whether environmental enteric dysfunction (EED) and gut microbiota perturbations are risk factors for RUSF failure in a birth cohort of 416 rural Pakistani children followed for growth, common childhood illnesses, and biomarkers from blood, urine, and stool. Infants who developed wasting (weight-for-length Z score <-2, n=187, 45%) during surveillance received Acha Mum (a chickpea-based RUSF) daily for eight weeks. Machine learning identified seven biomarkers that predicted RUSF response (n=75) vs. non-response (n=112) with 73% accuracy. Remarkably, gut microbiome composition predicted RUSF response with 93% (pre-supplementation) and 98% (post-supplementation) accuracy. Seven outliers whose microbiome falsely predicted positive response experienced extraordinary burdens of inflammation and illness during supplementation. These findings identify gut microbial signatures and biomarkers of gut and systemic inflammation as robust predictors of RUSF response in infants free from intercurrent illness during recovery, setting the stage for predictive models to guide precision use of RUSF and adjunct therapies in undernourished children.

Background: Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression., Methods: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single-cell neighborhoods from mIF images followed by multivariate discriminant analysis., Results: Spatial quantitation of tumor cell MHC-I expression revealed intratumoral and intertumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56 + cell numbers in patient tumors were positively associated with disease-free survival (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56 + and CD8 + cells (HR=0.199, p<1×10 -3 ). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3 + CD8 + T cells and CD3 - CD56 + NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single-cell neighborhood profiles to delineate the cellular environments of IFNγ +/- NK cells and T cells. We discovered that both IFNγ + NK and CD8 T cells were more frequently associated with other IFNγ + lymphocytes in comparison to IFNγ - NK cells and CD8 T cells (p<1×10 -30 ). Moreover, IFNγ + lymphocytes were most often found clustered near MHC-I + tumor cells., Conclusions: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Coassociation of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent colocalization of IFNγ + NK cells with other IFNγ + lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated., Competing Interests: Competing interests: CLS: Research support to the University of Virginia from Celldex (funding, drug), Merck (funding, drug), Theraclion (device staff support); Funding to the University of Virginia from Polynoma for PI role on the MAVIS Clinical Trial; Funding to the University of Virginia for roles on Scientific Advisory Boards for Immatics and CureVac. CLS also receives licensing fee payments through the UVA Licensing and Ventures Group for patents for peptides used in cancer vaccines. RDG: Research support to the University of Virginia from Pfizer, Amgen, Chugai, Merck, AstraZeneca, Janssen, Daiichi Sankyo, Alliance Foundation, Takeda, ECOG/ACRIN, Jounce Therapeutics, Bristol Myers Squibb, SWOG, Helsinn, Dizal Pharmaceuticals, and Mirati. RDG received payment for service on Scientific Advisory Boards including AstraZeneca, Takeda, Gilead, Janssen, Mirati, Daiichi Sankyo, Sanofi, Oncocyte, Jazz Pharmaceuticals, Blueprint Medicines, and Merus., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression., Methods: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single cell neighborhoods from mIF images followed by multivariate discriminant analysis., Results: Spatial quantitation of tumor cell MHC-I expression revealed intra- and inter-tumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56 + cell numbers in patient tumors were positively associated with disease-free survival (DFS) (HR=0.58, p =0.064) and overall survival (OS) (HR=0.496, p =0.041). The OS association strengthened with high counts of both CD56 + and CD8 + cells (HR=0.199, p <1×10 -3 ). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3 + CD8 + T cells and CD3 - CD56 + NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single cell neighborhood profiles to delineate the cellular environments of IFNγ +/- NK cells and T cells. We discovered that both IFNγ + NK and CD8 T cells were more frequently associated with other IFNγ + lymphocytes in comparison to IFNγ - NK cells and CD8 T cells (p<1×10 -30 ). Moreover, IFNγ + lymphocytes were most often found clustered near MHC-I + tumor cells., Conclusions: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ + NK cells with other IFNγ + lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated., Competing Interests: Competing interests – CLS - Research support to UVA from Celldex (funding, drug), Merck (funding, drug), Theraclion (device staff support); Funding to UVA from Polynoma for PI role on the MAVIS Clinical Trial; Funding to UVA for roles on Scientific Advisory Boards for Immatics and CureVac. CLS receives licensing fee payments through the UVA Licensing and Ventures Group for patents for peptides used in cancer vaccines. RDG – Research support to UVA from Pfizer, Amgen, Chugai, Merck, AstraZeneca, Janssen, Daiichi Sankyo, Alliance Foundation, Takeda, ECOG/ACRIN, Jounce Therapeutics, Bristol Myers Squibb, SWOG, Helsinn, Dizal Pharmaceuticals, and Mirati. RDG received payment for service on Scientific Advisory Boards including AstraZeneca, Takeda, Gilead, Janssen, Mirati, Daiichi Sankyo, Sanofi, Oncocyte, Jazz Pharmaceuticals, Blueprint Medicines, and Merus.

Background: Parenteral nutrition-associated cholestasis (PNAC) in the neonatal intensive care unit (NICU) causes significant morbidity and associated healthcare costs. Laboratory detection of PNAC currently relies on elevated serum conjugated bilirubin levels in the aftermath of impaired bile flow. Here, we sought to identify fecal biomarkers, which when integrated with clinical data, would better predict risk for developing PNAC., Methods: Using untargeted metabolomics in 200 serial stool samples from 60 infants, we applied statistical and machine learning approaches to identify clinical features and metabolic biomarkers with the greatest associative potential for risk of developing PNAC. Stools were collected prospectively from infants receiving PN with soybean oil-based lipid emulsion at a level IV NICU., Results: Low birth weight, extreme prematurity, longer duration of PN, and greater number of antibiotic courses were all risk factors for PNAC (P < 0.05). We identified 78 stool biomarkers with early predictive potential (P < 0.05). From these 78 biomarkers, we further identified 12 sphingomyelin lipids with high association for the development of PNAC in precholestasis stool samples when combined with birth anthropometry., Conclusion: We demonstrate the potential for stool metabolomics to enhance early identification of PNAC risk. Earlier detection of high-risk infants would empower proactive mitigation with alterations to PN for at-risk infants and optimization of energy nutrition with PN for infants at lower risk., (© 2022 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background & Aims: The circadian clock orchestrates ∼24-hour oscillations of gastrointestinal epithelial structure and function that drive diurnal rhythms in gut microbiota. Here, we use experimental and computational approaches in intestinal organoids to reveal reciprocal effects of gut microbial metabolites on epithelial timekeeping by an epigenetic mechanism., Methods: We cultured enteroids in media supplemented with sterile supernatants from the altered Schaedler Flora (ASF), a defined murine microbiota. Circadian oscillations of bioluminescent PER2 and Bmal1 were measured in the presence or absence of individual ASF supernatants. Separately, we applied machine learning to ASF metabolomics to identify phase-shifting metabolites., Results: Sterile filtrates from 3 of 7 ASF species (ASF360 Lactobacillus intestinalis, ASF361 Ligilactobacillus murinus, and ASF502 Clostridium species) induced minimal alterations in circadian rhythms, whereas filtrates from 4 ASF species (ASF356 Clostridium species, ASF492 Eubacterium plexicaudatum, ASF500 Pseudoflavonifactor species, and ASF519 Parabacteroides goldsteinii) induced profound, concentration-dependent phase shifts. Random forest classification identified short-chain fatty acid (SCFA) (butyrate, propionate, acetate, and isovalerate) production as a discriminating feature of ASF "shifters." Experiments with SCFAs confirmed machine learning predictions, with a median phase shift of 6.2 hours in murine enteroids. Pharmacologic or botanical histone deacetylase (HDAC) inhibitors yielded similar findings. Further, mithramycin A, an inhibitor of HDAC inhibition, reduced SCFA-induced phase shifts by 20% (P < .05) and conditional knockout of HDAC3 in enteroids abrogated butyrate effects on Per2 expression. Key findings were reproducible in human Bmal1-luciferase enteroids, colonoids, and Per2-luciferase Caco-2 cells., Conclusions: Gut microbe-generated SCFAs entrain intestinal epithelial circadian rhythms by an HDACi-dependent mechanism, with critical implications for understanding microbial and circadian network regulation of intestinal epithelial homeostasis., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

In Ceará, Brazil, seasonal influenza transmission begins before national annual vaccination campaigns commence. To assess the perinatal consequences of this misalignment, we tracked severe acute respiratory infection (SARI), influenza, and influenza immunizations during 2013-2018. Among 3,297 SARI cases, 145 (4.4%) occurred in pregnant women. Statewide vaccination coverage was >80%; however, national vaccination campaigns began during or after peak influenza season. Thirty to forty weeks after peak influenza season, birthweights decreased by 40 g, and rates of prematurity increased from 10.7% to 15.5%. We identified 61 children born to mothers with SARI during pregnancy; they weighed 10% less at birth and were more likely to be premature than 122 newborn controls. Mistiming of influenza vaccination campaigns adversely effects perinatal outcomes in Ceará. Because Ceará is the presumptive starting point for north-to-south seasonal influenza transmission in Brazil, earlier national immunization campaigns would provide greater protection for pregnant women and their fetuses in Ceará and beyond.

Nurses often have difficulty applying theory to clinical practice. The author explores ways to which nurse educators can facilitate the transfer of theory to practice using the nursing skills laboratory.