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Background and aimsDietary quality affects cardiometabolic risk, yet its pathways of influence on regional adipose tissue depots involved in metabolic and diabetes risk are not well established. We aimed to investigate the relationship between dietary quality and regional adiposity.Methods and resultsWe investigated 5079 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) who had food-frequency questionnaires and measurement of pericardial fat and hepatic attenuation at the baseline study visit in MESA, as well as a subgroup with imaging for visceral and subcutaneous fat (N = 1390). A dietary quality score (DietQuality) was constructed to include established food group constituents of a Mediterranean-type diet. Linear models estimated associations of dietary score as well as its constituents with regional adiposity. Baseline mean age was 61 (± 10) years, and approximately half of the participants (47%) were male. Those with a higher DietQuality score were generally older, female, with a lower body mass index, C-reactive protein, and markers of insulin resistance. After adjustment, a higher DietQuality score was associated with lower visceral fat (lowest vs. highest dietary score quartile: 523.6 vs. 460.5 cm(2)/m; P < 0.01 for trend), pericardial fat (47.5 vs. 41.3 cm(3)/m; P < 0.01 for trend), lesser hepatic steatosis (by hepatic attenuation; 58.6 vs. 60.7 Hounsfield units; P < 0.01 for trend), but not subcutaneous fat (P = 0.39). Greater fruits, vegetables, whole grains, seeds/nuts and yogurt intake were associated with decreased adiposity, while red/processed meats were associated with greater regional adiposity.ConclusionA higher quality diet pattern is associated with less regional adiposity, suggesting a potential mechanism of beneficial dietary effects on diabetes, metabolic, and cardiovascular risk.

Objective: To describe the utility of twin studies for attention-deficit/hyperactivity disorder (ADHD) research and demonstrate their potential for the identification of alternative phenotypes suitable for genomewide association, developmental risk assessment, treatment response, and intervention targets.Method: Brief descriptions of the classic twin study and genetic association study methods are provided, with illustrative findings from ADHD research. Biometrical genetics refers to the statistical modeling of data gathered from one or more group of known biological relation; it was apparently coined by Francis Galton in the 1860s and led to the "Biometrical School" at the University of London. Twin studies use genetic correlations between pairs of relatives, derived using this theoretical framework, to parse the individual differences in a trait into latent (unmeasured) genetic and environmental influences. This method enables the estimation of heritability, i.e., the percentage of variance due to genetic influences. It is usually implemented with a method called structural equation modeling, which is a statistical technique for fitting models to data, typically using maximum likelihood estimation. Genetic association studies aim to identify those genetic variants that account for the heritability estimated in twin studies. Measurements other than those used for the clinical diagnosis of the disorder are popular phenotype choices in current ADHD research. It is argued that twin studies have great potential to refine phenotypes relevant to ADHD.Results: Prior studies have consistently found that the majority of the variance in ADHD symptoms is due to genetic factors. To date, genomewide association studies of ADHD have not identified replicable associations that account for the heritable variation. Possibly, the application of genomewide association studies to these alternative phenotypic measurements will assist in identifying the pathways from genetic variants to ADHD.Conclusion: Power to detect associations should be improved by the study of highly heritable endophenotypes for ADHD and by reducing the number of phenotypes to be considered. Therefore, twin studies are an important research tool in the development of endophenotypes, defined as alternative, more highly heritable traits that act at earlier stages of the pathway from genes to behavior. Although genetic variation in liability to ADHD is likely polygenic, the proposed approach should help to identify improved alternative measurements for genetic association studies. [ABSTRACT FROM AUTHOR]

Peptides are important biomarkers for various diseases, however distinguishing specific amino-acid sequences using artificial receptors remains a major challenge in biomedical sensing. This study introduces a new approach for creating highly selective recognition surfaces using phage display biopanning against metal-organic nanosheets (MONs). Three MONs (ZIF-7, ZIF-7-NH 2, and Hf-BTB-NH 2 ) are added to a solution containing every possible combination of seven-residue peptides attached to bacteriophage hosts. The highest affinity peptides for each MON are isolated through successive bio-panning rounds. Comparison of the surface properties of the MONs and high-affinity peptides provide useful insights into the relative importance of electrostatic, hydrophobic, and co-ordination bonding interactions in each system, aiding the design of future MONs. Coating of the Hf-BTB-NH 2 MONs onto a quartz crystal microbalance (QCM) produced a five-fold higher signal for phage with the on-target peptide sequence compared to those with generic sequences. Surface plasmon resonance (SPR) studies produce a 4600-fold higher equilibrium dissociation constant (K D ) for on-target sequences and are comparable to those of antibodies (K D = 4 x 10 -10  m). It is anticipated that insights from the biopanning approach, combined with the highly tunable nature of MONs, will lead to a new generation of highly selective recognition surfaces for use in biomedical sensors., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Background: Maternal periodontal disease is associated with preterm and low-birthweight deliveries, but randomized trials of likely efficacious treatments (e.g., dental scaling and root planing) during pregnancy have not reduced these adverse outcomes. As an alternative, we hypothesized that periconception initiation of xylitol chewing gum would reduce the occurrence of preterm or low-birthweight deliveries among a historical high-prevalence population in Malawi., Methods: We conducted an open-label, parallel-enrollment, matched-pair, cluster-randomized, controlled clinical trial across eight health centers (sites) in and around Lilongwe, Malawi. Sites were paired by anticipated delivery volume and randomized to prenatal and oral health education alone (active control) or with twice-daily xylitol chewing gum (intervention) throughout the periconception and antenatal periods. For the primary prevention of preterm (<37 weeks) and low-birthweight (<2,500 g) deliveries (co-primary outcomes), comparison by allocation group was performed using generalized linear mixed models for each outcome as a fixed factor and the site(s) as a random factor., Findings: 10,069 participants were enrolled (n = 4,549 at intervention sites, n = 5,520 at active control sites), with >95% available for analyses. Initiation of xylitol chewing gum resulted in significant reductions in the co-primary outcomes: preterm birth (12.6% [549/4,349] vs. 16.5% [878/5,321]; relative risk [RR] 0.76, 95% confidence interval [CI] 0.57-0.99) and <2,500-g neonates (8.9% [385/4,305] vs. 12.9% [679/5,260]; RR 0.70, 95% CI 0.49-0.99). Xylitol chewing gum use also led to fewer neonatal demises (0.2% [8/4,305] vs. 0.4% [22/5,260]; RR 0.41, 95% CI 0.19-0.89)., Conclusions: Periconception initiation and ongoing use of xylitol chewing gum significantly reduced the occurrence of preterm and low-birthweight deliveries in Malawi., Funding: E.W. Al Thrasher Foundation (to K.A.) and USAID Saving Lives at Birth Grand Challenges Grant AID-OAA-G-11-00062 (to K.A.). Additional financial and in-kind support was graciously provided by Texas Children's Hospital and Baylor Foundation Malawi., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Although some randomized trials have reported beneficial effects of protein intake on cardiometabolic risk factors, evidence from prospective studies have not supported a strong link between protein intake and cardiovascular disease (CVD) risk. It is also unclear whether diversity in protein intake plays a role in CVD risk., Objective: We investigated prospective associations of (1) protein intake, overall and by food source and (2) diversity of protein sources with risk of CVD, coronary heart disease (CHD), and stroke., Methods: In a multi-ethnic cohort of 5879 U.S. adults (45-84 years), who were free of CVD at baseline, protein intake was assessed at baseline (2000-2002) using a validated 120-item food frequency questionnaire. Two different aspects of protein diversity were assessed including count (number of protein food consumed at least once/week) and dissimilarity (diversity of the attributes of the protein sources consumed). Relationships with incident CVD outcomes through 2019 were assessed using Cox proportional hazards models adjusting for sociodemographic, lifestyle, and comorbidity factors., Results: During 83,430 person-years, 1045 CVD cases were identified, including 668 CHD and 332 stroke cases. In multivariable models, we found no significant associations between protein intake, overall and by food source, with incident CVD, CHD, or stroke. Protein count, but not protein dissimilarity, was weakly associated with CVD risk. We found no significant associations between diversity of consumption of animal or plant food source and CVD outcomes., Conclusions: Our findings suggest protein consumption may not significantly impact CVD risk in middle-aged adults.

Background: Flavonoids may play a role in mitigating atherosclerotic cardiovascular diseases, with evidence suggesting effects may differ between vascular beds. Studies examining associations with subclinical markers of atherosclerosis between subpopulations with different underlying risks of atherosclerosis are lacking., Methods: Among 5599 participants from the MESA (Multi-Ethnic Study of Atherosclerosis), associations between dietary flavonoid intakes (estimated from a food frequency questionnaire) and subclinical measures of atherosclerosis (ankle-brachial index, carotid plaques and intima-media thickness, and coronary artery calcification) were examined using repeated measures models. Exposures and outcomes were measured at exam 1 (2000-2002) and exam 5 (2010-2011). Stratified analyses and interaction terms were used to explore effect modification by time, sex, race/ethnicity, and smoking status., Results: In the analytic population, at baseline, ≈46% were men with a median age of 62 (interquartile range, 53-70) years and total flavonoid intakes of 182 (interquartile range, 98-308) mg/d. After multivariable adjustments, participants with the highest (quartile 4) versus lowest (quartile 1) total flavonoid intakes had 26% lower odds of having an ankle-brachial index <1 (odds ratio, 0.74 [95% CI, 0.60-0.92]) and 18% lower odds of having a carotid plaque (odds ratio, 0.82 [95% CI, 0.69-0.99]), averaged over exams 1 and 5. Moderate (quartile 3) to high (quartile 4) intakes of flavonols, flavanol monomers, and anthocyanins were associated with 19% to 34% lower odds of having an ankle-brachial index <1 and 18% to 20% lower odds of having carotid plaque. Participants with the highest intakes of anthocyanins (quartile 4) at baseline had a marginally slower rate of carotid plaque progression than those with moderate intakes (quartiles 2 and 3). There were no significant associations with intima-media thickness or coronary artery calcification. Observed associations did not differ by sex, race/ethnicity, or smoking status., Conclusions: In this multi-ethnic population, higher dietary flavonoid intakes were associated with lower odds of peripheral and carotid artery atherosclerosis. Increasing intakes of healthy, flavonoid-rich foods may protect against atherosclerosis in the peripheral and carotid arteries., Competing Interests: None.

Background: Inflammation is a feature of coronary heart disease (CHD), but the role of proinflammatory microbial infection in CHD remains understudied., Methods and Results: CHD was defined in the MESA (Multi-Ethnic Study of Atherosclerosis) as myocardial infarction (251 participants), resuscitated arrest (2 participants), and CHD death (80 participants). We analyzed sequencing reads from 4421 MESA participants in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program using the PathSeq workflow of the Genome Analysis Tool Kit and a 65-gigabase microbial reference. Paired reads aligning to 840 microbes were detected in >1% of participants. The association of the presence of microbe reads with incident CHD (follow-up, ~18 years) was examined. First, important variables were ascertained using a single regularized Cox proportional hazard model, examining change of risk as a function of presence of microbe with age, sex, education level, Life's Simple 7, and inflammation. For variables of importance, the hazard ratio (HR) was estimated in separate (unregularized) Cox proportional hazard models including the same covariates (significance threshold Bonferroni corrected P <6×10 -5 , 0.05/840). Reads from 2 microbes were significantly associated with CHD: Gemella morbillorum (HR, 3.14 [95% CI, 1.92-5.12]; P =4.86×10 -6 ) and Pseudomonas species NFACC19-2 (HR, 3.22 [95% CI, 2.03-5.41]; P =1.58×10 -6 )., Conclusions: Metagenomics of whole-genome sequence reads opens a possible frontier for detection of pathogens for chronic diseases. The association of G morbillorum and Pseudomonas species reads with CHD raises the possibilities that microbes may drive atherosclerotic inflammation and that treatments for specific pathogens may provide clinical utility for CHD reduction.

Background and Aims: Calcific aortic valve disease is associated with increased thrombin formation, platelet activation, decreased fibrinolysis, and subclinical brain infarcts. We examined the long-term association of aortic valve calcification (AVC) with newly diagnosed dementia and incident stroke in the Multi-Ethnic Study of Atherosclerosis (MESA)., Methods: AVC was measured using non-contrast cardiac CT at Visit 1. We examined AVC as a continuous (log-transformed) and categorical variable (0, 1-99, 100-299, ≥300). Newly diagnosed dementia was adjudicated using International Classification of Disease codes. Stroke was adjudicated from medical records. We calculated absolute event rates (per 1000 person-years) and multivariable adjusted Cox proportional hazards ratios (HR)., Results: Overall, 6812 participants had AVC quantified with a mean age of 62.1 years old, 52.9 % were women, and the median 10-year estimated atherosclerotic cardiovascular disease (ASCVD) risk was 13.5 %. Participants with AVC >0 were older and less likely to be women compared to those with AVC=0. Over a median 16-year follow-up, there were 535 cases of dementia and 376 cases of stroke. The absolute risk of newly diagnosed dementia increased in a stepwise pattern with higher AVC scores, and stroke increased in a logarithmic pattern. In multivariable analyses, AVC was significantly associated with newly diagnosed dementia as a log-transformed continuous variable (HR 1.09; 95 % CI 1.04-1.14) and persons with AVC ≥300 had nearly a two-fold higher risk (HR 1.77; 95 % CI 1.14-2.76) compared to those with AVC=0. AVC was associated with an increased risk of stroke after adjustment for age, sex, and race/ethnicity, but not after adjustment for ASCVD risk factors., Conclusions: After multivariable adjustment, AVC >0 was significantly associated with an increased risk of newly diagnosed dementia, but not incident stroke. This suggests that AVC may be an important risk factor for the long-term risk of dementia beyond traditional ASCVD risk factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

RUNX1::RUNX1T1 (R::RT1) acute myeloid leukaemia (AML) remains a clinical challenge, and further research is required to model and understand leukaemogenesis. Previous zebrafish R::RT1 models were hampered by embryonic lethality and low penetrance of the malignant phenotype. Here, we overcome this by developing an adult zebrafish model in which the human R::RT1 isoform 9a is co-expressed with the frequently co-occurring oncogenic NRASG12D mutation in haematopoietic stem and progenitor cells (HSPCs), using the Runx1+23 enhancer. Approximately 50% of F0 9a+NRASG12D transgenic zebrafish developed signs of haematological disease between 5 and 14 months, with 27% exhibiting AML-like pathology: myeloid precursor expansion, erythrocyte reduction, kidney marrow hypercellularity and the presence of blasts. Moreover, only 9a+NRASG12D transplant recipients developed leukaemia with high rates of mortality within 40 days, inferring the presence of leukaemia stem cells. These leukaemic features were rare or not observed in animals expressing either the NRAS or 9a oncogenes alone, suggesting 9a and NRAS cooperation drives leukaemogenesis. This novel adult AML zebrafish model provides a powerful new tool for investigating the basis of R::RT1 - NRAS cooperativity with the potential to uncover new therapeutic targets., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Circulating metabolite levels partly reflect the state of human health and diseases, and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single study analyses. Leveraging the rich metabolomics resources generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally-diverse samples. We provided recommendations for outlier and imputation handling to process metabolite data, as well as a general analytical framework. We further performed a pooled analysis following our practical recommendations and discovered 1,778 independent loci associated with 667 metabolites. Among 108 novel locus - metabolite pairs, we detected not only novel loci within previously implicated metabolite associated genes, but also novel genes (such as GAB3 and VSIG4 located in the X chromosome) that have putative roles in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, including well-known metabolic genes such as FADS2 , D2HGDH , SUGP1 , UTG2B17 , strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

Background: An increasing body of evidence suggests that neuroinflammation is one of the key drivers of late-onset Alzheimer's disease (LOAD) pathology. Due to the increased permeability of the blood-brain barrier (BBB) in older adults, peripheral plasma proteins can infiltrate the central nervous system (CNS) and drive neuroinflammation through interactions with neurons and glial cells. Because these inflammatory factors are heritable, a greater understanding of their genetic relationship with LOAD could identify new biomarkers that contribute to LOAD pathology or offer protection against it., Methods: We used a genome-wide association study (GWAS) of 90 different plasma proteins ( n  = 17,747) to create polygenic scores (PGSs) in an independent discovery (cases = 1,852 and controls = 1,990) and replication (cases = 799 and controls = 778) cohort. Multivariate logistic regression was used to associate the plasma protein PGSs with LOAD diagnosis while controlling for age, sex, principal components 1-2, and the number of APOE -e4 alleles as covariates. After meta-analyzing the PGS-LOAD associations between the two cohorts, we then performed a two-sample Mendelian randomization (MR) analysis using the summary statistics of significant plasma protein level PGSs in the meta-analysis as an exposure, and a GWAS of clinically diagnosed LOAD (cases = 21,982, controls = 41,944) as an outcome to explore possible causal relationships between the two., Results: We identified four plasma protein level PGSs that were significantly associated (FDR-adjusted p  < 0.05) with LOAD in a meta-analysis of the discovery and replication cohorts: CX3CL1, hepatocyte growth factor (HGF), TIE2, and matrix metalloproteinase-3 (MMP-3). When these four plasma proteins were used as exposures in MR with LOAD liability as the outcome, plasma levels of HGF were inferred to have a negative causal relationship with the disease when single-nucleotide polymorphisms (SNPs) used as instrumental variables were not restricted to cis-variants (OR/95%CI = 0.945/0.906-0.984, p  = 0.005)., Conclusion: Our results show that plasma HGF has a negative causal relationship with LOAD liability that is driven by pleiotropic SNPs possibly involved in other pathways. These findings suggest a low transferability between PGS and MR approaches, and future research should explore ways in which LOAD and the plasma proteome may interact., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cammann, Lu, Rotter, Wood and Chen.)

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement., Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy., Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses., Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET)., Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02)., Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2 + cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Children with certain congenital anomalies of the kidney and urinary tract and neurogenic bladder (CAKUT/NGB) are at higher risk of treatment failure for urinary tract infections (UTIs) than children with normal genitourinary anatomy, but the literature describing treatment and outcomes is limited. The objectives of this study were to describe the rate of treatment failure in children with CAKUT/NGB and compare duration of antibiotics between those with and without treatment failure., Methods: Multicenter retrospective cohort of children 0 to 17 years old with CAKUT/NGB who presented to the emergency department with fever or hypothermia and were diagnosed with UTI between 2017 and 2018. The outcome of interest was treatment failure, defined as subsequent emergency department visit or hospitalization for UTI because of the same pathogen within 30 days of the index encounter. Descriptive statistics and univariates analyses were used to compare covariates between groups., Results: Of the 2014 patient encounters identified, 482 were included. Twenty-nine (6.0%) of the 482 included encounters had treatment failure. There was no difference in the mean duration of intravenous antibiotics (3.4 ± 2.5 days, 3.5 ± 2.8 days, P = .87) or total antibiotics between children with and without treatment failure (10.2 ± 3.8 days, 10.8 ± 4.0 days, P = .39) Of note, there was a higher rate of bacteremia in children with treatment failure (P = .04)., Conclusions: In children with CAKUT/NGB and UTI, 6.0% of encounters had treatment failure. Duration of antibiotics was not associated with treatment failure. Larger studies are needed to assess whether bacteremia modifies the risk of treatment failure., (Copyright © 2024 by the American Academy of Pediatrics.)

Short-chain fatty acids (SCFAs) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched SCFAs (BSCFAs; isobutyrate, isovalerate, and methylbutyrate) is largely unknown. In a cohort of 219 non-Hispanic White participants and 126 African American participants, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, and lipid traits, and other SCFAs. We observed a bimodal distribution of BSCFAs, with 25 individuals having high levels (H-BSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared with the L-BSCFA group (16% vs. 49%; P = 0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFAs. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose levels were lower and the disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial C-peptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes., (© 2024 by the American Diabetes Association.)

Background: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium., Methods: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction., Results: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions., Conclusions: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD., Competing Interests: Disclosures Dr Murphy reports having worked as a consultant for Pharmavite (until 2021). The remaining authors have reported no relationships relevant to the contents of this article. Dr Psaty serves on the steering committee of the Yale Open Data Access Project, funded by Johnson and Johnson.

Background and Aims: To investigate associations between avocado intake and glycemia in adults with Hispanic/Latino ancestry., Methods and Results: The associations of avocado intake with measures of insulin and glucose homeostasis were evaluated in a cross-sectional analysis of up to 14,591 Hispanic/Latino adults, using measures of: average glucose levels (hemoglobin A1c; HbA1c), fasting glucose and insulin, glucose and insulin levels after an oral glucose tolerance test (OGTT), and calculated measures of insulin resistance (HOMA-IR, and HOMA-%β), and insulinogenic index. Associations were assessed using multivariable linear regression models, which controlled for sociodemographic factors and health behaviors, and which were stratified by dysglycemia status. In those with normoglycemia, avocado intake was associated with a higher insulinogenic index (β = 0.17 ± 0.07, P = 0.02). In those with T2D (treated and untreated), avocado intake was associated with lower hemoglobin A1c (HbA1c; β = -0.36 ± 0.21, P = 0.02), and lower fasting glucose (β = -0.27 ± 0.12, P = 0.02). In the those with untreated T2D, avocado intake was additionally associated with HOMA-%β (β = 0.39 ± 0.19, P = 0.04), higher insulin values 2-h after an oral glucose load (β = 0.62 ± 0.23, P = 0.01), and a higher insulinogenic index (β = 0.42 ± 0.18, P = 0.02). No associations were observed in participants with prediabetes., Conclusions: We observed an association of avocado intake with better glucose/insulin homeostasis, especially in those with T2D., Competing Interests: Declaration of competing interest Dr. Wood has received funding from the National Cattleman's Beef Association and Ionis Pharmaceutical for studies unrelated to the current analyses., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Whether red meat consumption is associated with higher inflammation or confounded by increased adiposity remains unclear. Plasma metabolites capture the effects of diet after food is processed, digested, and absorbed, and correlate with markers of inflammation, so they can help clarify diet-health relationships., Objective: To identify whether any metabolites associated with red meat intake are also associated with inflammation., Methods: A cross-sectional analysis of observational data from older adults (52.84% women, mean age 63 ± 0.3 y) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Dietary intake was assessed by food-frequency questionnaire, alongside C-reactive protein (CRP), interleukin-2, interleukin-6, fibrinogen, homocysteine, and tumor necrosis factor alpha, and untargeted proton nuclear magnetic resonance ( 1 H NMR) metabolomic features. Associations between these variables were examined using linear regression models, adjusted for demographic factors, lifestyle behaviors, and body mass index (BMI)., Results: In analyses that adjust for BMI, neither processed nor unprocessed forms of red meat were associated with any markers of inflammation (all P > 0.01). However, when adjusting for BMI, unprocessed red meat was inversely associated with spectral features representing the metabolite glutamine (sentinel hit: β = -0.09 ± 0.02, P = 2.0 × 10 -5 ), an amino acid which was also inversely associated with CRP level (β = -0.11 ± 0.01, P = 3.3 × 10 -10 )., Conclusions: Our analyses were unable to support a relationship between either processed or unprocessed red meat and inflammation, over and above any confounding by BMI. Glutamine, a plasma correlate of lower unprocessed red meat intake, was associated with lower CRP levels. The differences in diet-inflammation associations, compared with diet metabolite-inflammation associations, warrant further investigation to understand the extent that these arise from the following: 1) a reduction in measurement error with metabolite measures; 2) the extent that which factors other than unprocessed red meat intake contribute to glutamine levels; and 3) the ability of plasma metabolites to capture individual differences in how food intake is metabolized., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health. Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts. Methods: Complementary study designs: 1 ) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV 1 and FVC measures in the NHLBI Pooled Cohorts Study and 2 ) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid levels were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for the most metabolically downstream omega-3 fatty acid, docosahexaenoic acid (DHA). An increase in DHA of 1% of total fatty acids was associated with attenuations of 1.4 ml/yr for FEV 1 (95% confidence interval [CI], 1.1-1.8) and 2.0 ml/yr for FVC (95% CI, 1.6-2.4) and a 7% lower incidence of spirometry-defined airway obstruction (95% CI, 0.89-0.97). DHA associations persisted across sexes and smoking histories and in Black, White, and Hispanic participants, with associations of the largest magnitude in former smokers and Hispanic participants. The MR study showed similar trends toward positive associations of genetically predicted downstream omega-3 fatty acids with FEV 1 and FVC. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher levels of downstream omega-3 fatty acids, especially DHA, on lung health.

Background: Avocado consumption is linked to better glucose homeostasis, but small associations suggest potential population heterogeneity. Metabolomic data capture the effects of food intake after digestion and metabolism, thus accounting for individual differences in these processes., Objectives: To identify metabolomic biomarkers of avocado intake and to examine their associations with glycemia., Methods: Baseline data from 6224 multi-ethnic older adults (62% female) included self-reported avocado intake, fasting glucose and insulin, and untargeted plasma proton nuclear magnetic resonance metabolomic features (metabolomic data were available for a randomly selected subset; N = 3438). Subsequently, incident type 2 diabetes (T2D) was assessed over an ∼18 y follow-up period. A metabolome-wide association study of avocado consumption status (consumer compared with nonconsumer) was conducted, and the relationship of these features with glycemia via cross-sectional associations with fasting insulin and glucose and longitudinal associations with incident T2D was examined., Results: Three highly-correlated spectral features were associated with avocado intake at metabolome-wide significance levels (P < 5.3 ∗ 10 -7 ) and combined into a single biomarker. We did not find evidence that these features were additionally associated with overall dietary quality, nor with any of 47 other food groups (all P > 0.001), supporting their suitability as a biomarker of avocado intake. Avocado intake showed a modest association only with lower fasting insulin (β = -0.07 +/- 0.03, P = 0.03), an association that was attenuated to nonsignificance when additionally controlling for body mass index (kg/m 2 ). However, our biomarker of avocado intake was strongly associated with lower fasting glucose (β = -0.22 +/- 0.02, P < 2.0 ∗ 10 -16 ), lower fasting insulin (β = -0.17 +/- 0.02, P < 2.0 ∗ 10 -16 ), and a lower incidence of T2D (hazard ratio: 0.68; 0.63-074, P < 2.0 ∗ 10 -16 ), even when adjusting for BMI., Conclusions: Highly significant associations between glycemia and avocado-related metabolomic features, which serve as biomarkers of the physiological impact of dietary intake after digestion and absorption, compared to modest relationships between glycemia and avocado consumption, highlights the importance of considering individual differences in metabolism when considering diet-health relationships., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background The relationship between alcohol consumption and ectopic fat distribution, both known factors for cardiovascular disease, remains understudied. Therefore, we aimed to examine the association between alcohol consumption and ectopic adiposity in adults at risk for cardiovascular disease. Methods and Results In this cross-sectional analysis, we categorized alcohol intake among participants in MESA (Multi-Ethnic Study of Atherosclerosis) as follows (drinks/day): <1 (light drinking), 1 to 2 (moderate drinking), >2 (heavy drinking), former drinking, and lifetime abstention. Binge drinking was defined as consuming ≥5 drinks on 1 occasion in the past month. Visceral, subcutaneous, and intermuscular fat area, pericardial fat volume, and hepatic fat attenuation were measured using noncontrast computed tomography. Using multivariable linear regression, we examined the associations between categories of alcohol consumption and natural log-transformed fat in ectopic depots. We included 6756 MESA participants (62.1±10.2 years; 47.2% women), of whom 6734 and 1934 had chest computed tomography (pericardial and hepatic fat) and abdominal computed tomography (subcutaneous, intermuscular, and visceral fat), respectively. In adjusted analysis, heavy drinking, relative to lifetime abstention, was associated with a higher (relative percent difference) pericardial 15.1 [95% CI, 7.1-27.7], hepatic 3.4 [95% CI, 0.1-6.8], visceral 2.5 [95% CI, -10.4 to 17.2], and intermuscular 5.2 [95% CI, -6.6 to 18.4] fat but lower subcutaneous fat -3.5 [95% CI, -15.5 to 10.2]). The associations between alcohol consumption and ectopic adiposity exhibited a J-shaped pattern. Binge drinking, relative to light-to-moderate drinking, was also associated with higher ectopic fat. Conclusions Alcohol consumption had a J-shaped association with ectopic adiposity. Both heavy alcohol intake and binge alcohol drinking were associated with higher ectopic fat.

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10 -8 , we confirmed association of the FADS signal and found evidence of two additional signals (in DAGLA and BEST1) within 200 kb of the originally reported FADS signal. Outside of the FADS region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including TMX2, SLC29A2, ANKRD13D and POLD4, and spanning a > 9 Mb region on chromosome 11 (57.5 Mb ~ 67.1 Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a POLD4 missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations., (© 2023. Springer Nature Limited.)

Purpose: Since avocado consumption has been linked to a possible reduction in inflammation, we investigated associations between avocado consumption and markers of inflammation in a population-based multi-ethnic cohort [Multi-Ethnic Study of Atherosclerosis (MESA)]., Methods: We used a food frequency questionnaire (FFQ) at MESA exam 1 to capture avocado/guacamole consumption. To calculate daily servings of avocado/guacamole, we used both frequency and serving size data from the FFQ. We classified participants into three consumer groups: rare or never (daily serving ≤ 0.03), medium (0.03 < daily serving < 0.1), and heavy (0.1 ≤ daily serving). Inflammation was estimated by natural log-transformed inflammatory biomarkers (CRP, IL-2, IL-6, homocysteine, fibrinogen, TNF-a soluble receptors). We used multivariate general linear regression models to assess associations accounting for age, sex, race/ethnicity, educational level, income, energy intake, smoking status, physical activity, diet quality, body mass index, and diabetes type., Results: Among 5794 MESA participants, the average age and BMI were 62.25 y ± 10.26 and 28.28 ± 5.41 kg/m 2 , respectively, and 48% of the sample were men. Participants self-reported as Hispanic (22.30%), Caucasian (39.92%), African-American (25.39%), and Chinese (12.39%). Over 60% had higher than a high school education and 40% made $50,000 or more a year. Regarding avocado/guacamole consumption, 79% were categorized as rare or never, 12% as medium, and 9% as heavy. When adjusted for relevant confounders, there were no significant differences among the three consumer groups for any inflammatory marker., Conclusion: In this cross-sectional study, we did not find that consumption of avocado/guacamole was associated with levels of inflammatory markers., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Poor diet quality is a risk factor for type 2 diabetes and cardiovascular disease. However, knowledge of metabolites marking adherence to Dietary Guidelines for Americans (2015 version) are limited., Objectives: The goal was to determine a pattern of metabolites associated with the Healthy Eating Index (HEI)-2015, which measures adherence to the Dietary Guidelines for Americans., Methods: The analysis examined 3557 adult men and women from the longitudinal cohort Multiethnic Study of Atherosclerosis (MESA), without known cardiovascular disease and with complete dietary data. Fasting serum specimens and diet and demographic questionnaires were assessed at baseline. Untargeted 1 H 1-dimensional nuclei magnetic resonance spectroscopy (600 MHz) was used to generate metabolomics and lipidomics. A metabolome-wide association study specified each spectral feature as outcomes, HEI-2015 score as predictor, adjusting for age, sex, race, and study site in linear regression analyses. Subsequently, hierarchical clustering defined the discrete groups of correlated nuclei magnetic resonance features associated with named metabolites, and the linear regression analysis assessed for associations with HEI-2015 total and component scores., Results: The sample included 50% women with an mean age of 63 years, with 40% identifying as White, 23% as Black, 24% as Hispanic, and 13% as Chinese American. The mean HEI-2015 score was 66. The metabolome-wide association study identified 179 spectral features significantly associated with HEI-2015 score. The cluster analysis identified 7 clusters representing 4 metabolites; HEI-2015 score was significantly associated with all. HEI-2015 score was associated with proline betaine [β = 0.12 (SE = 0.02); P = 4.70 × 10 -13 ] and was inversely related to proline [β = -0.13 (SE = 0.02); P = 4.45 × 10 -14 ], 1,5 anhydrosorbitol [β = -0.08 (SE = 0.02); P = 4.37 × 10 -7 ] and unsaturated fatty acyl chains [β = 0.08 (SE = 0.02); P = 8.98 × 10 -7 ]. Intake of total fruit, whole grains, and seafood and plant proteins was associated with proline betaine., Conclusions: Diet quality is significantly associated with unsaturated fatty acyl chains, proline betaine, and proline. Further analysis may clarify the link between diet quality, metabolites, and pathogenesis of cardiometabolic disease., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Linoleic acid (LA) is a primary n -6 polyunsaturated fatty acid (PUFA), which is of interest to nutritional professionals as it has been associated with health outcomes. However, as some LA-rich foods offer protection against chronic diseases such as CVD (e.g., fatty fish), while others increase risk (e.g., red meat), the individual foods contributing to LA intake may be an important factor to consider. Therefore, this analysis sought to examine whether there are racial/ethnic differences in the proportion of overall LA intake accounted for by individual food groups, via a cross-sectional analysis of 3815 adults participating in the National Health and Nutrition Examination Survey (NHANES; 2017-2018 cycle). Separate multivariable linear regressions models specified the proportion of overall LA intake attributable to each of the nine food groups (dairy, eggs, fat, fish, fruits and vegetables, grains, meat, nuts, and sweets) as the outcome, and race/ethnicity as the predictor, with age, gender, and socioeconomic status (SES) as covariates, in order to estimate whether there were mean differences by race/ethnicity in the proportion of overall LA intake attributable to each of these foods seperately. After a Bonferroni correction for multiple testing, eggs, grains, fruits and vegetables, meat, and fish each accounted for a different proportion of overall LA intake according to racial/ethnic grouping (all p < 0.006 after a Bonferroni correction). These findings indicate the food sources of LA in the diet differ by race/ethnicity, and warrant future investigations into whether this plays a role in health disparities.

Objective: The current study examined school-summer differences in children's sleep patterns and sleep hygiene. Cross-sectional relationships with children's sleep, sleep hygiene, and weight status were explored during the school year and summer., Methods: Children (5-8 years) and their parents (n = 197 dyads) were recruited from 4 schools in southeastern Texas and via Facebook. Parents reported children's school year and summer sleep, sleep hygiene, and screen media use. Children's body mass index (BMI) was objectively assessed at the beginning and end of the summer. Associations between children's sleep hygiene and screen media use, sleep duration, and weight status were explored., Results: Children's sleep midpoint was earlier during the school year (1:54 AM ± 0.03) than in the summer (2:06 AM ± 0.03; t = 4.07, p < .0001). During summer, children increased their screen media use by 38 minutes (t = 2.32, p = .023) and decreased their caffeine intake from 7.43 to 7.0 (with scores ranging from 3 to 15; t = 2.83, p = .006). Greater sleep-inhibiting (β = 0.40, p = .011) and fewer sleep-promoting (β = -0.28, p = .049) behaviors during the school year were associated with having a higher BMI. There were no associations among sleep patterns, sleep hygiene and BMI during summer., Conclusions: More positive school year sleep hygiene behaviors were supportive of having a healthier weight status. Changes in these behaviors during the summer did not portend worse weight outcomes. Supporting families in the establishment of sleep-promoting behaviors, particularly during the school year may help address the child obesity epidemic., (Copyright © 2023 National Sleep Foundation. All rights reserved.)

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like mesenchymal cell state and a more differentiated sympathetic adrenergic cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional cofactor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism, G/T, that affects a GATA motif in the first intron of LMO1. Here, we showed that WT zebrafish with the GATA genotype developed adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduced the penetrance of MYCN-driven tumors, which were restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrated that TATA/TATA tumors also exhibited a mesenchymal cell state and were low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduced the neuroblastoma-initiation rate by preventing formation of the adrenergic cell state. This mechanism was conserved over 400 million years of evolution, separating zebrafish and humans.

Purpose: This study aimed to understand the experience of families caring for a child with cancer in New Zealand (NZ) who received nutrition and dietetic support during cancer treatment and their preferences for the delivery, format, and timing of nutrition information., Methods: Childhood cancer patients and their families (N = 21) participated in a mixed-methods study at a specialist paediatric oncology centre in Auckland, NZ. Before the semi-structured interview, participants completed a questionnaire capturing demographic, disease, and treatment characteristics of their child, their nutrition concerns, and their information needs. Quantitative data were described, and qualitative thematic analysis of the semi-structured interviews was performed using NVivo data analysis software., Results: Eighty-six percent of participants indicated they had concerns about their child's nutrition during treatment. The most common concerns were anorexia, vomiting, and weight loss. While many were happy with the quality of the nutrition support received, one-third of the patients wanted more support. Four key themes emerged from the interviews: (1) patients experience significant and distressing nutrition challenges; (2) patients and families have mixed perceptions of EN; (3) there are gaps in the current nutrition support system for inpatients; and (4) a desire for more accessible nutrition support., Conclusion: Childhood cancer patients and families experience significant and distressing nutrition challenges during treatment. Standardising information given to patients and their families may optimise nutrition support for paediatric oncology patients and reduce the discordance between families and health professionals. Future implementation of a nutrition decision aid in this population is warranted., (© 2023. The Author(s).)

Background/purpose: Hispanic/Latinos in the US are at increased risk for type 2 diabetes (T2D). Data suggest that avocado intake is associated with better glycemic control, but whether this translates to protection from T2D has not been studied. The goal of the current analyses was to examine whether consuming avocados at baseline is associated with lower incident T2D over a six-year period, compared to not consuming avocados at baseline., Subjects/methods: Using data from a large population of US adults with Hispanic ancestry, without known or unknown T2D at baseline (N=6,159), participants were classified as avocado consumers (N=983) or non-consumers (N=5,176) based on the mean of two 24-hour dietary recalls. Cox proportional hazard models estimated the association of avocado consumption with incident T2D (N=656 cases) over a six-year follow-up period, in the population as a whole, and separately in those with normoglycemia vs. prediabetes at baseline. A set of three sequential models were run: the first controlling only for sociodemographic factors ("minimally adjusted" models), the second for these and health behaviors ("fully adjusted" models), and a third for both sets of covariates and also body mass index (BMI; "fully adjusted + BMI" models)., Results: In the population as a whole, avocado intake at baseline was associated with reduced incident T2D in both the minimally adjusted (hazard ratio [HR] (+/- 95% confidence intervals [CIs]): 0.70 (0.52 - 0.94), P=.04) and the fully adjusted models (HR: 0.72 (0.54-0.97), P=.03). This association was observed in both those with prediabetes and with normoglycemia at baseline, but only reached significance in those with prediabetes (minimally adjusted model: HR: 0.68 (0.48-0.97), P=.03; fully adjusted model: HR: 0.69 (0.48-0.98), P=.04), not in those with normoglycemia (minimally adjusted model: HR: 0.86 (0.45-1.65), P=.65; fully adjusted model: HR: 0.80 (0.41-1.55), P=.50). In models which additionally controlled for BMI ("fully adjusted + BMI model"), the associations were slightly attenuated (overall population: HR: 0.79 (0.59-1.06), P=.60; normoglycemia: HR: 0.83 (0.42-1.64), P=.60; prediabetes: HR= 0.75 (0.54 - 1.05), P=0.09)., Conclusions: In our longitudinal analyses, adults with Hispanic / Latino ancestry who consumed avocado were less likely to develop T2D than those who did not consume avocado at baseline, especially if they had prediabetes at baseline.

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry., Article Highlights: We aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions., (© 2023 by the American Diabetes Association.)

Objective: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD)., Design: Pooled analysis., Data Sources: A consortium of 19 studies from 12 countries identified up to May 2020., Study Selection: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate., Data Extraction and Synthesis: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis., Main Outcome Measures: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m 2 . In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m 2 and <75% of baseline rate., Results: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I 2 =9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I 2 =0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I 2 =5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v <60 years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m 2 ), hypertension, diabetes, and coronary heart disease at baseline., Conclusions: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest and declare: support from Australian National Health and Medical Research Council Career Development Fellowship and the University of New South Wales Safety Net Fellowship for the submitted work; MM reports research funding from Resolve to Save Lives, World Health Organisation and North western University, and support as invited speaker in the Nordic Dairy Congress 2022. CMR and LMS report research funding from the US National Institute of Health (NIH). CMR reports participation on the Data Safety Monitoring Boards of the SUPER and ADEPT trials and leadership role as associate editor of Diabetes Care. ACvW reports research funding from Jaap Schouten Foundation. JMG reports research funding from Jaap Schouten Foundation, EU Horizon 2020, and Ministry of Health, Welfare and Sports, The Netherlands, and leadership role as the Vice President of the Dutch Health Council. EKH reports research funding from Dutch Kidney Foundation. FI and NGF receive the MRC Epidemiology Unit core support. NGF reports research fundings from the NIHR Cambridge Biomedical Research Centre Theme on Nutrition, Diet and Lifestyle. JT declares conference support from the University of Antioquia, Colombia and possession of stocks from Orion Pharma. MU declares possession of stocks from Orion Pharma. WSH declares possession of stock in OmegaQuant Analytics, LLC (a laboratory that offers blood fatty acid testing to healthcare providers, researchers and consumers). PSS reports research funding from the National Health and Medical Research Council of Australia and honoraria from Biogen Australia and Roche Australia. ACW reports research funding from the US Department of Agriculture/Agricultural Research Service, NIH, National Cattlemen’s Beef Association and Hass Avocado Board Avocado Nutrition Research Center. JA has received research honoraria for lectures from AstraZeneca and Novartis, and has participated in the advisory board for AstraZeneca and Boerhinger Ingelheim, unrelated to the present study. UR reports research funding from Swedish Research Council Forma and Swedish Diabetes Foundation. RM reports research funding from the US NIH, Gates Foundation, Nestle and Danone, and consulting fees from Development Initiatives with leadership role as chair of the Independent Expert Group, Global Nutrition Report. AT declares as co-chair of ClinGen Gout Genetic Curation Panel and reports research funding from the US National Institute of Health; AK reports research funding from the German Research Foundation. DM reports research funding from the US NIH, the Gates Foundation, The Rockefeller Foundation, Vail Innovative Global Research, and the Kaiser Permanente Fund at East Bay Community Foundation; personal fees from Acasti Pharma and Barilla; scientific advisory board, Beren Therapeutics, Brightseed, Calibrate, Elysium Health, Filtricine, HumanCo, Instacart, January Inc., Perfect Day, Tiny Organics, and (ended) Day Two, Discern Dx, and Season Health; stock ownership in Calibrate and HumanCo; and chapter royalties from UpToDate. No other relationships or activities that could appear to have influenced the submitted work were reported., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with renal impairment (RI) are typically excluded from trials evaluating chimeric antigen receptor (CAR) T cell therapies. We evaluated the outcomes of patients with RI receiving standard of care (SOC) CAR T cell therapy for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this retrospective, single-center cohort study of patients with R/R DLBCL treated with SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after 2 or more prior lines of therapy, renal and survival outcomes were compared based on RI and fludarabine dose reduction (DR) status. RI was defined by an estimated glomerular filtration rate <60 mL/min/1.73 m 2 as determined by the Modification of Diet in Renal Disease equation using day -5 creatinine (Cr) values. Acute kidney injury (AKI) was identified and graded using standard Kidney Disease: Improving Global Outcomes criteria. Renal recovery was considered to occur if Cr was within .2 mg/mL of baseline by day +30. Fludarabine was considered DR if given at <90% of the recommended Food and Drug Administration label dose. Among 166 patients treated with CAR T cell therapy were 17 patients (10.2%) with baseline RI and 149 (89.8%) without RI. After CAR T cell infusion, the incidence of any grade AKI was not significantly different between patients with baseline RI and those without RI (42% versus 21%; P = .08). Similarly, severe grade 2/3 AKI was seen in 1 of 17 patients (5.8%) with baseline RI and in 11 of 149 patients (7.3%) without RI (P = 1). Decreased renal perfusion (28 of 39; 72%) was the most common cause of AKI, with cytokine release syndrome (CRS) contributing to 17 of 39 AKIs (44%). Progression-free survival (PFS) and overall survival (OS) did not differ between patients with RI and those without RI or between those who received standard-dose fludarabine and those who received reduced-dose fludarabine. In contrast, patients with AKI had worse clinical outcomes than those without AKI (multivariable PFS: hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2 to 3.7; OS: HR, 3.9; 95% CI, 2.1 to 7.4). Notably, peak inflammatory cytokine levels were higher in patients who experienced AKI. Finally, we describe 2 patients with end-stage renal disease (ESRD) on dialysis who received lymphodepletion and CAR T cell therapy. Baseline renal function did not affect renal or efficacy outcomes after CAR T cell therapy in DLBCL. On the other hand, patients with AKI went on to experience worse clinical outcomes. AKI was commonly related to CRS and high peak inflammatory cytokine levels. CAR T cell therapy is feasible in patients with ESRD and requires careful planning of lymphodepletion., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Gut microbiome studies have documented depletion of butyrate-producing taxa in type 2 diabetes. We analyzed associations between butyrate-producing taxa and detailed measures of insulin homeostasis, whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans, all of whom completed an oral glucose tolerance test. Stool microbiome was assessed by whole-metagenome shotgun sequencing with taxonomic profiling. We examined associations among 36 butyrate-producing taxa (n = 7 genera and 29 species) and insulin sensitivity, insulin secretion, disposition index, insulin clearance, and prevalence of dysglycemia (prediabetes plus diabetes, 46% of cohort), adjusting for age, sex, BMI, and race. The genus Coprococcus was associated with higher insulin sensitivity (β = 0.14; P = 0.002) and disposition index (β = 0.12; P = 0.012) and a lower rate of dysglycemia (odds ratio [OR] 0.91; 95% CI 0.85-0.97; P = 0.0025). In contrast, Flavonifractor was associated with lower insulin sensitivity (β = -0.13; P = 0.004) and disposition index (β = -0.11; P = 0.04) and higher prevalence of dysglycemia (OR 1.22; 95% CI 1.08-1.38; P = 0.0013). Species-level analyses found 10 bacteria associated with beneficial directions of effects and two bacteria with adverse associations on insulin homeostasis and dysglycemia. Although most butyrate producers analyzed appear to be metabolically beneficial, this is not the case for all such bacteria, suggesting that microbiome-directed therapeutic measures to prevent or treat diabetes should be targeted to specific butyrate-producing taxa rather than all butyrate producers., (© 2022 by the American Diabetes Association.)

Importance: Evidence linking low-carbohydrate diets (LCDs) to mortality is limited among multiethnic populations., Objective: To evaluate the association between LCDs and mortality by race and ethnicity., Design, Setting, and Participants: The Multi-Ethnic Study of Atherosclerosis is a large, population-based prospective cohort study of adults aged 45 to 84 years recruited from 6 US communities. A total of 6109 participants without baseline cardiovascular disease were included in this analysis. Baseline data were collected from July 2000 to August 2002, with follow-up completed by December 2017. The data were analyzed between May 2021 and April 2022., Exposures: Food frequency questionnaires were used to assess dietary intake. From these data, overall LCD scores were calculated from the percentages of energy intake from carbohydrates, fats, and proteins. Animal-based (emphasizing saturated fat and animal protein) and vegetable-based (emphasizing monounsaturated fat and vegetable protein) LCD scores were also calculated., Main Outcomes and Measures: All-cause and cause-specific mortality over a median follow-up of 15.9 years (IQR, 14.3-16.6 years)., Results: Among the 6109 participants (mean [SD] age, 62.3 [10.3] years; 3190 women [52.2%]; 1623 African American [26.6%], 701 Chinese American [11.5%], 1350 Hispanic [22.1%], and 2435 non-Hispanic White [39.8%]), there were 1391 deaths. Overall, LCD scores were not associated with mortality, but when analyses were stratified by race and ethnicity, a lower risk of all-cause and non-CV mortality was observed among Hispanic participants with moderate carbohydrate intake. Specifically, the hazard ratios for total mortality for overall LCD scores were 0.58 (95% CI, 0.40-0.84) for quintile 2, 0.67 (95% CI, 0.45-0.98) for quintile 3, 0.60 (95% CI, 0.41-0.87) for quintile 4, and 0.83 (95% CI, 0.57-1.21) for quintile 5, with quintile 1 as the reference group. A similar association was observed for animal-based (but not vegetable-based) LCD scores. In contrast, no significant associations were found between LCD scores and mortality risk in the other racial and ethnic groups., Conclusions and Relevance: In this cohort study of multiethnic US adults, LCD score was not associated with mortality in the whole population. However, moderate carbohydrate intake was associated with a lower risk of mortality among Hispanic participants. These findings suggest that the association between carbohydrate intake and mortality may differ according to race and ethnicity. Dietary guidelines considering these differences may be necessary.

Hypertension (HTN) is a well-established risk factor for cardiovascular diseases (CVDs), including ischemic heart disease, stroke, heart failure, and atrial fibrillation. The prevalence of HTN, as well as mortality rates attributable to HTN, continue to increase, particularly in the United States and among Black populations. The risk of HTN involves a complex interaction of genetics and modifiable risk factors, including dietary patterns. In this regard, there is accumulating evidence that links dietary intake of red meat with a higher risk of poorly controlled blood pressure and HTN. However, research on this topic contains significant methodological limitations, which are described in the review. The report provided below also summarizes the available research reports, with an emphasis on processed red meat consumption and how different dietary patterns among certain populations may contribute to HTN-related health disparities. Finally, this review outlines potential mechanisms and provides recommendations for providers to counsel patients with evidence-based nutritional approaches regarding red meat and the risk of HTN, as well as CVD morbidity and mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies have suggested that infants high in negative affect have higher levels of adiposity, arising in part via changes in nutrition (e.g., “feeding to soothe”). Few studies have examined whether positive affect shows similar or inverse associations with adiposity. The current study examined cross-sectional and longitudinal relationships between adiposity and observations of positive affect in both a social and a non-social context, using data from infants at four (n = 125) and 12 (n = 80) months of age. Our analyses did not find any cross-sectional associations between positive affect and adiposity (all p > 0.05). However, in the longitudinal analyses, positive affect in a non-social context, when observed at four months of age, was positively associated with weight-for-length at 12 months of age (zWFL; ß = 1.49, SE = 0.67, p = 0.03), while positive affect observed at four months of age in a social context was inversely associated with body fat percentage at 12 months of age (ß = −11.41, SE = 5.44, p = 0.04). These findings provide preliminary evidence that the p positive affect is related to adiposity in infancy and suggest that the direction of association (i.e., direct or inverse) may be specific to the context in which positive affect is measured. Future research should examine the role of nutritional status in any relationships between adiposity and emotion at this early stage.

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses., (© 2022 Bastard et al.)

Background: Recommendations for postoperative surveillance and adjuvant therapy following curative-intent resection for biliary tract cancers-including intrahepatic and extrahepatic cholangiocarcinoma (IHCCA and EHCCA) and primary gallbladder cancer (GBC)-are uniform across primary tumor site. However, these tumors may have distinct patterns of recurrence., Methods: A retrospective observational cohort study was performed at a specialty cancer center. Patients undergoing resection of IHCCA, EHCCA, and GBC were identified (2005-2020). Recurrence-free survival (RFS) was estimated using Kaplan-Meier and Cox proportional hazard methods. Anatomic patterns of initial site of recurrence were described and compared., Results: There were 142 patients included; 50 IHCCA, 32 EHCCA, and 60 GBC. Median RFS was 30.8 months, which was not significantly different between IHCCA, EHCCA, or GBC in univariate analysis or after adjustment. Nodal positivity was significantly associated with poor RFS (HR 3.92, P≤0.001). The most common initial site of recurrence overall was intrahepatic (n=49/64, 77%), in isolation (n=32) or synchronous with other site of recurrence (n=17). Significant differences in anatomic pattern of recurrence were observed (P=0.049) with IHCCAs more commonly recurring with simultaneous hepatic-pulmonary disease (n=5/22, 23%; EHCCA n=2/19, 10%; GBC n=1/23, 4%), GBC more commonly recurring within the porta (n=7/23, 30%; IHCCA n=0; EHCCA n=1/19, 5%), and EHCCA more commonly recurring within the peritoneum (n=5/19, 26%; IHCCA n=2/22, 9%, GBC n=2/23, 9%)., Conclusions: Patterns of initial recurrence appear to differ between primary tumor site, likely reflecting underlying differences in anatomy and biology. These data could help inform future studies for adjuvant therapy as well as timing and anatomic focus for surveillance imaging., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-868/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Background and Aims: The DASH diet conveys protection against type 2 diabetes mellitus (T2D) Via plant-based and non-plant-based recommendations. Research has not identified which glucose homeostasis pathways are improved. We examined associations between adherence to a DASH diet and six glucose homeostasis traits, probing whether associations could be attributed to the plant-based (DASH-P) and/or non-plant based (DASH-NP) components., Methods and Results: We included data from 295 adults without T2D (age 59.3 ± 9.00 years; 63.46% non-Hispanic White and 36.54% African American, self-reported race ancestry) participating in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). An oral glucose tolerance test (OGTT) yielded fasting plasma glucose, insulin, C-peptide, and insulin secretion, sensitivity, and disposition index. Habitual dietary intake was assessed by food frequency questionnaire (FFQ). Associations between DASH components and glucose homeostasis traits were examined, controlling for demographics, body mass index (BMI), physical activity, and energy intake. For significant associations, the models were repeated with scores for DASH-P and DASH-NP as predictors in the same model. DASH and DASH-P scores were inversely associated with fasting plasma glucose (DASH:β = -0.036 ± 0.012,P = 0.005; DASH-P: β = -0.04 ± 0.017,P = 0.002), and positively associated with insulin sensitivity (DASH:β = 0.022 ± 0.012,P = 0.042; DASH-P: = 0.036 ± 0.015,P = 0.014). The DASH score was also associated with disposition index (β = 0.026 ± 0.013,P = 0.038), but this association did not reach significance with DASH-P (β = 0.035 ± 0.018,P = 0.051). No associations were observed with DASH-NP score (all P > 0.05)., Conclusions: DASH diet is associated with improvement in specific glucose homeostasis traits, likely arising from increased plant-based foods. Such research may help tailor future dietary advice to specific metabolic risk, and to food groups most effective at improving these., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: Identify factors contributing to time a family spends in a Multidisciplinary Craniofacial Team Clinic (MDCT) and implement an intervention to reduce this time., Design: Interventional: a restructuring of clinics to serve those patients requiring fewer provider encounters separately., Setting: An American Cleft Palate-Craniofacial Association-accredited MDCT in an academic children's hospital., Patients/participants: One hundred sixty-seven patients with craniofacial diagnoses., Interventions: Time data were tabulated over ∼2 years. Following 9 months of data collection, patients requiring fewer provider encounters were scheduled to a separate clinic serving children with craniosynostosis, and data were collected in the same fashion for another 14 months., Main Outcome Measures: Principal outcome measures included total visit time and proportion of the visit spent without a provider in the room before and after clinic restructuring., Results: The average time spent by family in a clinic session was 161.53 minutes, of which 64.3% was spent without a provider in the room. Prior to clinic restructuring, a greater number of provider encounters was inversely associated with percentage of time spent without a provider ( P < .001). Upon identifying this predictor, scheduling patients who needed fewer provider encounters to a Craniosynostosis Clinic session resulted in reduction in absolute and percentage of time spent without a provider ( P < .001)., Conclusions: The number of provider encounters is a significant predictor of the proportion of a clinic visit spent without a provider. Clinic restructuring to remove patient visits that comprise fewer provider encounters resulted in a greater percentage of time spent with a provider in an MDCT.

Background & Aims: A genome-wide significant association between anti-Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus., Methods: The dichotomous GWAS (25% individuals exhibiting highest anti-H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori-eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants., Results: The association of the TLR1/6/10 locus with anti-H pylori IgG titers (rs12233670; β = -0.267 ± SE 0.034; P = 4.42 × 10 -15 ) presented with high heterogeneity and failed replication. Anti-H pylori IgG titers declined within 2-4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels., Conclusions: The association between anti-H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti-H pylori IgG titers on therapy, clearance, and antibody decay. H pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

A man in his 60s presented with a worsening headache, confusion and expressive dysphasia which, on admission, progressed to a falling Glasgow Coma Score and seizures. He was subsequently admitted to the intensive care unit. The clinical diagnosis was antibody-negative autoimmune encephalitis. Despite immunotherapy, the patient died 5 months after initial presentation and postmortem examination revealed he had CD8 encephalitis. This case demonstrates that CD8 encephalitis can present similarly to autoimmune encephalitis both clinically and on imaging. A brain biopsy would have revealed the diagnosis in life, although this would not have altered his treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ) are molecularly diverse. TP53 is the most frequently altered gene with approximately 50% of patients harboring mutations. This qualitative study describes the distinct genomic alterations in GCs and GEJs stratified by TP53 mutation status., Patients and Methods: Tumor DNA sequencing results of 324 genes from 3741 patients with GC and GEJ were obtained from Foundation Medicine. Association between gene mutation frequency and TP53 mutation status was examined using Fisher's exact test. Functional gene groupings representing molecular pathways suggested to be differentially mutated in TP53 wild-type (TP53WT) and TP53 mutant (TP53MUT) tumors were identified. The association of the frequency of tumors containing a gene mutation in the molecular pathways of interest and TP53 mutation status was assessed using Fisher's exact test with a P-value of <.01 deemed statistically significant for all analyses., Results: TP53 mutations were noted in 61.6% of 2946 GCs and 81.4% of 795 GEJs (P < .001). Forty-nine genes had statistically different mutation frequencies in TP53WT vs. TP53MUT patients. TP53WT tumors more likely had mutations related to DNA mismatch repair, homologous recombination repair, DNA and histone methylation, Wnt/B-catenin, PI3K/Akt/mTOR, and chromatin remodeling complexes. TP53MUT tumors more likely had mutations related to fibroblast growth factor, epidermal growth factor receptor, other receptor tyrosine kinases, and cyclin and cyclin-dependent kinases., Conclusion: The mutational profiles of GCs and GEJs varied according to TP53 mutation status. These mutational differences can be used when designing future studies assessing the predictive ability of TP53 mutation status when targeting differentially affected molecular pathways., (© The Author(s) 2022. Published by Oxford University Press.)