Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies

Diabetes Care

OBJECTIVE Breastfeeding duration is inversely associated with risks of cardiovascular disease (CVD) and type 2 diabetes in parous women. However, the association among women at high risk, including women with type 2 diabetes or gestational diabetes (GDM) is unclear. RESEARCH DESIGN AND METHODS We included 15,146 parous women with type 2 diabetes from the Nurses’ Health Study I and II (NHS, NHS II) and 4,537 women with a history of GDM from NHS II. Participants reported history of breastfeeding via follow-up questionnaires. Incident CVD by 2017 comprised stroke or coronary heart disease (CHD: myocardial infarction, coronary revascularization). Adjusted hazard ratios (aHRs) and 95% CIs were estimated using Cox models. RESULTS We documented 1,159 incident CVD cases among women with type 2 diabetes in both cohorts during …

Metabolism

BackgroundMetabolic Syndrome (MetS) is a progressive pathophysiological state defined by a cluster of cardiometabolic traits. However, little is known about metabolites that may be predictors of MetS incidence or reversion. Our objective was to identify plasma metabolites associated with MetS incidence or MetS reversion.MethodsThe study included 1468 participants without cardiovascular disease (CVD) but at high CVD risk at enrollment from two case-cohort studies nested within the PREvención con DIeta MEDiterránea (PREDIMED) study with baseline metabolomics data. MetS was defined in accordance with the harmonized International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria, which include meeting 3 or more thresholds for waist circumference, triglyceride, HDL cholesterol, blood pressure, and fasting blood glucose. MetS incidence was …

Clinical Pediatrics

Dr. Lester F. Soyka: E. M., a 13-year-old girl, was referred to the Massachusetts General Hospital because of uncontrolled hyper-tension. She was in apparent good health until four years ago when she had an episode of dysuria and pyuria diagnosed as cystitis and treated with Furadantin. She had two subsequent attacks three years ago and one year ago similarly treated. She seemed well until six weeks prior to admission when gross hematuria developed with no associated symptoms and no previous history of recent upper respiratory infection. Penicillin was started. In the next few days she developed headache, abdominal cramps, and anorexia. On admission to another hospital it was found that her blood pressure was 270/190, there was marked arteriolar spasm on funduscopy, and her urine was loaded with red and white blood cells with no casts. Intravenous and retrograde pyelography showed a shrunken …

Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization of the ischemic neuroretina. Here we show that metabolic shifts in the neurovascular niche define angiogenic fate. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Hence, strategies to change the metabolic environment of vessels could promote a regenerative phenotype in vascular diseases.

American Journal of Epidemiology

Animal studies have shown that exposure to cigarette smoke during pregnancy can induce neurobehavioral anomalies in multiple subsequent generations. However, little work has examined such effects in humans. We examined the risk of grandchild autism spectrum disorder (ASD) in association with grandmother smoking during pregnancy, using data from 53,562 mothers and grandmothers, and 120,267 grandchildren in the Nurses’ Health Study II using nurse reporting in 1999 of her mother’s smoking. Grandchildren’s ASD diagnoses were reported by the mothers in 2005 and 2009. Among grandmothers, 13,383 (25.0%) smoked during pregnancy, and 509 (0.4%) grandchildren were diagnosed with ASD. The adjusted odds ratio (aOR) of ASD for grandmother smoking during pregnancy was 1.52 (95% confidence limit [CI]: 1.06, 2.20). Results were similar with direct grandmother reporting in 2001 of her …

EBioMedicine

BackgroundLung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants.MethodsWe utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and …

Food Chemistry

This study introduces a multidisciplinary approach to investigate bioactive food metabolites often overlooked due to their low concentrations. We integrated an in-house food metabolite library (n = 494), a human metabolite library (n = 891) from epidemiological studies, and metabolite pharmacological databases to screen for food metabolites with potential bioactivity. We identified six potential metabolites, including meglutol (3-hydroxy-3-methylglutarate), an understudied low-density lipoprotein (LDL)-lowering compound. We further focused on meglutol as a case study to showcase the range of characterizations achievable with this approach. Green pea tempe was identified to contain the highest meglutol concentration (21.8 ± 4.6 mg/100 g). Furthermore, we identified a significant cross-sectional association between plasma meglutol and lower LDL cholesterol in two Hispanic adult cohorts (n = 1,628) (β …

Journal of the American Geriatrics Society

Background Caregiving is commonly undertaken by older women. Research is mixed, however, about the impact of prolonged caregiving on their health, well‐being, and mortality risk. Using a prospective study design, we examined the association of caregiving with mortality in a cohort of older women. Methods Participants were 158,987 postmenopausal women aged 50–79 years at enrollment into the Women's Health Initiative (WHI) who provided information on current caregiving status and caregiving frequency at baseline (1993–1998) and follow‐up (2004–2005). Mortality was ascertained from baseline through March of 2019. Cox regression with caregiving status defined as a time‐varying exposure was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality, adjusting for sociodemographic factors, smoking, and history of diabetes, hypertension, cardiovascular disease (CVD …

Journal of Allergy and Clinical Immunology

BackgroundThere are increasing numbers of metabolomic studies in food allergy (FA) and asthma, which, however, are predominantly limited by cross-sectional designs, small sample size, and being conducted in European populations.ObjectiveWe sought to identify metabolites unique to and shared by children with FA and/or asthma in a racially diverse prospective birth cohort, the Boston Birth Cohort.MethodsMass spectrometry–based untargeted metabolomic profiling was performed using venous plasma collected in early childhood (n = 811). FA was diagnosed according to clinical symptoms consistent with an acute hypersensitivity reaction at food ingestion and food specific-IgE > 0.35 kU/L. Asthma was defined on the basis of physician diagnosis. Generalized estimating equations were applied to analyze metabolomic associations with FA and asthma, adjusting for potential confounders.ResultsDuring a …

Diabetes/Metabolism Research and Reviews

Background Several metabolites are individually related to incident type 2 diabetes (T2D) risk. We prospectively evaluated a novel T2D‐metabolite pattern with a risk of progression to T2D among high‐risk women with a history of gestational diabetes mellitus (GDM). Methods The longitudinal Nurses' Health Study II cohort enroled 116,429 women in 1989 and collected blood samples from 1996 to 1999. We profiled plasma metabolites in 175 incident T2D cases and 175 age‐matched controls, all with a history of GDM before the blood draw. We derived a metabolomics score from 21 metabolites previously associated with incident T2D in the published literature by scoring according to the participants' quintile (1–5 points) of each metabolite. We modelled the T2D metabolomics score categorically in quartiles and continuously per 1 standard deviation (SD) with the risk of incident T2D using conditional logistic …

EClinicalMedicine

BackgroundUltra-processed foods (UPFs) are emerging as a risk factor for colorectal cancer (CRC), yet how post-diagnostic UPF intake may impact CRC prognosis remains unexplored.MethodsData collected from food frequency questionnaires were used to estimate intakes of total UPFs and UPF subgroups (serving/d) at least 6 months but less than 4 years post-diagnosis among 2498 patients diagnosed with stages I–III CRC within the Nurses' Health Study and Health Professionals Follow-up Study during 1980–2016. Hazard ratios (HR) and 95% confidence intervals (CIs) of all-cause, CRC- and cardiovascular disease (CVD)-specific mortality in association with UPF consumption were estimated using an inverse probability weighted multivariable Cox proportional hazards regression model, adjusted for confounders.FindingsThe mean (SD) age of patients at diagnosis was 68.5 (9.4) years. A total of 1661 deaths …

The American Journal of Clinical Nutrition

BackgroundThe health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood.ObjectivesOur goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors.MethodsA total of 400 participants (200 from each study group), aged 55–75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry …

International Urogynecology Journal

MethodsThis was an analysis within the Nurses’ Health Study (NHS) I and II. The main exposure was the cumulative daily intake for each choline-containing compound obtained from a detailed daily food frequency questionnaire. The primary outcome was UUI, defined as urine loss with a sudden feeling of bladder fullness or when a toilet is inaccessible, occurring> 1/month. Cox proportional hazards regression models were used to calculate multivariate-adjusted relative risks and 95% confidence intervals (CIs) for the association between total choline and choline derivatives and risk of UUI. Fixed effects meta-analyses of results from NHSI and NHSII were performed for postmenopausal women only to obtain a pooled estimate of the impact of choline consumption on UUI.ResultsThere were 33,273 participants in NHSI and 38,732 in NHSII who met all the criteria for inclusion in the analysis. The incidence of UUI …

Journal of Allergy and Clinical Immunology

MethodsUntargeted metabolomic profiling was conducted on plasma samples from 4 timepoints during a longitudinal peanut OIT interventional trial in children ages 7-18. After OIT, participants were challenged before and after a 4-week avoidance period and categorized as either having persistent protection (sustained unresponsiveness (SU)) or loss of protection (transient desensitization (TD)). Using linear and logistic regression and time series analyses, we identified changes in metabolites and pathways associated with (1) OIT over time, and (2) differences between SU and TD participants.ResultsWe identified decreases in arachidonic acid (p= 1.3 e-23) and linoleic acid (p= 1.0 e-04) pathways during OIT. Comparing SU versus TD revealed differing concentrations of bile acid (p= 3.7 e-08), arachidonic acid (p= 3.2 e-09), and histidine pathways. Notably, the bile acid metabolite, lithocholate (3.48 [1.53, 9.24], p …

Communications Biology

Type 2 diabetes (T2D) is known as one of the important risk factors for the severity and mortality of COVID-19. Here, we evaluate the impact of T2D and its genetic susceptibility on the severity and mortality of COVID-19, using 459,119 individuals in UK Biobank. Utilizing the polygenic risk scores (PRS) for T2D, we identified a significant association between T2D or T2D PRS, and COVID-19 severity. We further discovered the efficacy of vaccination and the pivotal role of T2D-related genetics in the pathogenesis of severe COVID-19. Moreover, we found that individuals with T2D or those in the high T2D PRS group had a significantly increased mortality rate. We also observed that the mortality rate for SARS-CoV-2-infected patients was approximately 2 to 7 times higher than for those not infected, depending on the time of infection. These findings emphasize the potential of T2D PRS in estimating the severity and …

Cell Metabolism

Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and …

PLOS Global Public Health

The impact of the humanitarian crisis in Venezuela on care for noncommunicable diseases (NCDs) such as diabetes is unknown. This study aims to document health system performance for diabetes management in Venezuela during the humanitarian crisis. This longitudinal study on NCDs is nationally representative at baseline (2014–2017) and has follow-up (2018–2020) data on 35% of participants. Separate analyses of the baseline population with diabetes (n = 585) and the longitudinal population with diabetes (n = 210) were conducted. Baseline analyses constructed a weighted care continuum: all diabetes; diagnosed; treated; achieved glycaemic control; achieved blood pressure, cholesterol, and glycaemic control; and achieved aforementioned control plus non-smoking. Weighted multinomial regression models controlling for region were used to estimate the association between socio-demographic characteristics and care continuum stage. Longitudinal analyses constructed an unweighted care continuum: all diabetes; diagnosed; treated; and achieved glycaemic control. Unweighted multinomial regression models controlling for region were used to estimate the association between socio-demographic characteristics and changes in care continuum stage. Among 585 participants with diabetes at baseline, 71% were diagnosed, 51% were on treatment, and 32% had achieved glycaemic control. Among 210 participants with diabetes in the longitudinal population, 50 (24%) participants’ diabetes management worsened, while 40 (19%) participants improved. Specifically, the proportion of those treated decreased (60% in 2014–2017 to 51 …

Cancer Research

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancer types. A key — yet poorly understood — facet in the disease state is cachexia, a multi-organ pathological state characterized by physical wasting and tissue catabolism. It occurs in 80% of PDAC patients, and to date there are no preventative or early detection methods. Cachexia leads to limited tolerance to anti-cancer therapy and contributes to disease lethality. Here, we present the first-of-its-kind systemic metabolomic analysis across cachectic stages to better understand disease progression. We used the well-established mutant KRASG12D(LSL/+) mutant p53 inducible mouse model of PDAC. Model physiology faithfully recaptures human cachexia: we observe progressive overall weight loss as well as loss of skeletal muscle and adipose tissue. As with human disease, weight loss occurs prior to loss of appetite in the animals …

Journal of the Endocrine Society

Context The association between women's stress and pregnancy glucose levels remain unclear, specifically when considering the preconception period as a sensitive window of exposure. Objective We investigated whether preconception perceived stress was associated with glucose levels during pregnancy among women attending a fertility center (2004-2019). Methods Before conception, women completed a psychological stress survey using the short version of the validated Perceived Stress Scale 4 (PSS-4), and blood glucose was measured using a 50-gram glucose load test during late pregnancy as a part of screening for gestational diabetes. Linear and log-binomial regression models were used to assess associations of total PSS-4 scores with mean glucose levels and abnormal glucose levels ( ≥ 140 mg/dL), adjusting for age, body mass index …

Med

BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts.MethodsA group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management …

Med

BackgroundImmune checkpoint inhibitor (ICI)-related liver injury is a growing concern as ICIs are increasingly used in cancer treatment regimens. Interestingly, ICIs have exhibited antiviral effects among patients with chronic hepatitis B virus (HBV). However, the underlying mechanisms remain unclear, and clinical data on patients with previous HBV infection/exposure and isolated anti-HBV core antibodies (IAHBcs) are lacking.MethodsWe report a case illustrating the dual effects of ICIs in a patient experiencing panlobular hepatitis and concurrent HBV reactivation.FindingsA 68-year-old male patient positive for IAHBcs was admitted with panlobular hepatitis and HBV reactivation after receiving systemic chemotherapy (several months before admission) and ICI treatment (4 weeks before admission) subsequent to metastatic primary lung cancer (NSCLC stage IV). This was followed by a rapid and significant …

Med

BackgroundCrohn's disease complicated by perianal fistulae is more prevalent and severe in patients of African ancestry.MethodsWe profiled single cells from diverse patients with Crohn's disease with perianal fistula from colorectal mucosa and fistulous tracts. Immunofluorescence was performed to validate predicted cell-cell interactions. Unstimulated monocytes were chronically cultured in diverse cohorts. A subset was analyzed by single-nucleus RNA + ATAC sequencing.FindingsFistulous tract cells from complete proctectomies demonstrated enrichment of myeloid cells compared to paired rectal tissues. Ligand-receptor analysis highlights myeloid-stromal cross-talk and cellular senescence, with cellular co-localization validated by immunofluorescence. Chitinase-3 like-protein-1 (CHI3L1) is a top upregulated gene in stromal cells from fistulae expressing both destructive and fibrotic gene signatures. Monocyte …

Med

BackgroundGenome-wide association studies (GWASs) associate phenotypes and genetic variants across a study cohort. GWASs require large-scale cohorts with both phenotype and genetic sequencing data, limiting studied phenotypes. The Human Phenotype Project is a longitudinal study that has measured a wide range of clinical and biomolecular features from a self-assignment cohort over 5 years. The phenotypes collected are quantitative traits, providing higher-resolution insights into the genetics of complex phenotypes.MethodsWe present the results of GWASs and polygenic risk score phenome-wide association studies with 729 clinical phenotypes and 4,043 molecular features from the Human Phenotype Project. This includes clinical traits that have not been previously associated with genetics, including measures from continuous sleep monitoring, continuous glucose monitoring, liver ultrasound …

Med

BackgroundA healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity.MethodsIn four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity.FindingsThe identified healthy lifestyle metabolomic signature was reflective of lipid …

Med

BackgroundGenome-wide association studies (GWASs) associate phenotypes and genetic variants across a study cohort. GWASs require large-scale cohorts with both phenotype and genetic sequencing data, limiting studied phenotypes. The Human Phenotype Project is a longitudinal study that has measured a wide range of clinical and biomolecular features from a self-assignment cohort over 5 years. The phenotypes collected are quantitative traits, providing higher-resolution insights into the genetics of complex phenotypes.MethodsWe present the results of GWASs and polygenic risk score phenome-wide association studies with 729 clinical phenotypes and 4,043 molecular features from the Human Phenotype Project. This includes clinical traits that have not been previously associated with genetics, including measures from continuous sleep monitoring, continuous glucose monitoring, liver ultrasound …

Med

BackgroundAddiction is a chronic and relapsing brain disorder. Despite numerous neuroimaging and neurophysiological studies on individuals with substance use disorder (SUD) or behavioral addiction (BEA), currently a clear neural activity signature for the addicted brain is lacking.MethodsWe first performed systemic coordinate-based meta-analysis and partial least-squares regression to identify shared or distinct brain regions across multiple addictive disorders, with abnormal resting-state activity in SUD and BEA based on 46 studies (55 contrasts), including regional homogeneity (ReHo) and low-frequency fluctuation amplitude (ALFF) or fractional ALFF. We then combined Neurosynth, postmortem gene expression, and receptor/transporter distribution data to uncover the potential molecular mechanisms underlying these neural activity signatures.FindingsThe overall comparison between addiction cohorts and …

Med

BackgroundHuman subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives.MethodsWe measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio …

Med

BackgroundEvidence on the associations of fine particulate matter (PM2.5) with cardiopulmonary mortality in the oldest-old (aged 80+ years) people remains limited.MethodsWe conducted a time-stratified case-crossover study of 1,475,459 deaths from cardiopulmonary diseases in China to estimate the associations between short-term exposure to ambient PM2.5 and cardiopulmonary mortality among the oldest-old people.FindingsEach 10 μg/m3 increase in PM2.5 concentration (6-day moving average [lag05]) was associated with higher mortality from cardiopulmonary diseases (excess risks [ERs] = 1.69%, 95% confidence interval [CI]: 1.54%, 1.84%), cardiovascular diseases (ER = 1.72%, 95% CI: 1.54%, 1.90%), and respiratory diseases (ER = 1.62%, 95% CI: 1.33%, 1.91%). Compared to the other groups, females (ER = 1.94%, 95% CI: 1.73%, 2.15%) (p for difference test = 0.043) and those aged 95–99 years …

Med

BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts.MethodsA group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management …

Med

BackgroundA healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity.MethodsIn four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity.FindingsThe identified healthy lifestyle metabolomic signature was reflective of lipid …

Med

BackgroundREDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) showed that icosapent ethyl (IPE) reduced major adverse cardiovascular events by 25%. Since the underlying mechanisms for these benefits are not fully understood, the IPE-PREVENTION CardioLink-14 trial (ClinicalTrials.gov: NCT04562467) sought to determine if IPE regulates vascular regenerative (VR) cell content in people with mild to moderate hypertriglyceridemia.MethodsSeventy statin-treated individuals with triglycerides ≥1.50 and <5.6 mmol/L and either atherosclerotic cardiovascular disease or type 2 diabetes with additional cardiovascular risk factors were randomized to IPE (4 g/day) or usual care. VR cells with high aldehyde dehydrogenase activity (ALDHhi) were isolated from blood collected at the baseline and 3-month visits and characterized with lineage-specific cell surface markers. The …

Med

BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts.MethodsA group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management …

Med

BackgroundPerineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). This prompted an investigation into how nerves within the tumor microenvironment affect the adaptive immune system and tumor growth.MethodsWe used RNA sequencing analysis of human tumor tissue from a recent HNSCC clinical trial, proteomics of human nerves from HNSCC patients, and syngeneic orthotopic murine models of HPV-unrelated HNSCC to investigate how sensory nerves modulate the adaptive immune system.FindingsCalcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking sensory nerve function surgically, pharmacologically, or genetically increased CD8 and CD4 T cell activity in vivo.ConclusionsOur data support sensory nerves playing a role in …

Med

BackgroundThe treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms.MethodsWe performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III–IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed.FindingsCPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8+ T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and …

Med

BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts.MethodsA group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management …

Med

BackgroundA healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity.MethodsIn four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity.FindingsThe identified healthy lifestyle metabolomic signature was reflective of lipid …

Med

BackgroundDosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients.MethodsWe designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK).FindingsWe demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that …

Med

BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts.MethodsA group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management …

Med

BackgroundThe extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD.MethodsParticipants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors.FindingsA total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range …