Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Supplementation with Seabuckthorn Oil Augmented in 16:1n-7t Increases Serum Trans-Palmitoleic Acid in Metabolically Healthy Adults: A Randomized Crossover Dose-Escalation Study.

BACKGROUND: In animal models cis-palmitoleic acid (9-hexadecenoic acid; 16:1n-7c), a lipokine, improves insulin sensitivity, inflammation, and lipoprotein profiles; in humans trans-palmitoleic acid (16:1n-7t) has been associated with lower incidence of type 2 diabetes. The response to dose-escalation of supplements containing cis- and trans-palmitoleic acid has not been evaluated. OBJECTIVES: We examined dose-escalation effects of oral supplementation with seabuckthorn oil and seabuckthorn oil augmented in 16:1n-7t on serum phospholipid fatty acids (PLFAs). METHODS: Thirteen participants (7 women and 6 men; age 48 ± 16 y, BMI 30.4 ± 3.7 kg/m2) participated in a randomized, double-blind, crossover, dose-escalation trial of unmodified seabuckthorn oils relatively high in 16:1n-7c (380, 760, and 1520 mg 16:1n-7c/d) and seabuckthorn oils augmented in 16:1n-7t (120, 240, and 480 mg 16:1n-7t/d). Each of the 3 escalation doses was provided for 3 wk, with a 4-wk washout period between the 2 supplements. At the end of each dose period, fasting blood samples were used to determine the primary outcomes (serum concentrations of the PLFAs 16:1n-7t and 16:1n-7c) and the secondary outcomes (glucose homeostasis, serum lipids, and clinical measures). Trends across doses were evaluated using linear regression. RESULTS: Compared with baseline, supplementation with seabuckthorn oil augmented in 16:1n-7t increased phospholipid 16:1n-7t by 26.6% at the highest dose (P = 0.0343). Supplementation with unmodified seabuckthorn oil resulted in a positive trend across the dose-escalations (P-trend = 0.0199). No significant effects of either supplement were identified on blood glucose, insulin, lipids, or other clinical measures, although this dosing study was not powered to detect such effects. No carryover or adverse effects were observed. CONCLUSIONS: Supplementation with seabuckthorn oil augmented in 16:1n-7t and unmodified seabuckthorn oil moderately increased concentrations of their corresponding PLFAs in metabolically healthy adults, supporting the use of supplementation with these fatty acids to test potential clinical effects in humans.This trial was registered at clinicaltrials.gov as NCT02311790.

Circulating Biomarkers of Dairy Fat and Risk of Incident Diabetes Mellitus Among Men and Women in the United States in Two Large Prospective Cohorts.

BACKGROUND: In prospective studies, the relationship of self-reported consumption of dairy foods with risk of diabetes mellitus is inconsistent. Few studies have assessed dairy fat, using circulating biomarkers, and incident diabetes mellitus. We tested the hypothesis that circulating fatty acid biomarkers of dairy fat, 15:0, 17:0, and t-16:1n-7, are associated with lower incident diabetes mellitus. METHODS AND RESULTS: Among 3333 adults aged 30 to 75 years and free of prevalent diabetes mellitus at baseline, total plasma and erythrocyte fatty acids were measured in blood collected in 1989 to 1990 (Nurses' Health Study) and 1993 to 1994 (Health Professionals Follow-Up Study). Incident diabetes mellitus through 2010 was confirmed by a validated supplementary questionnaire based on symptoms, diagnostic tests, and medications. Risk was assessed by using Cox proportional hazards, with cohort findings combined by meta-analysis. During mean±standard deviation follow-up of 15.2±5.6 years, 277 new cases of diabetes mellitus were diagnosed. In pooled multivariate analyses adjusting for demographics, metabolic risk factors, lifestyle, diet, and other circulating fatty acids, individuals with higher plasma 15:0 had a 44% lower risk of diabetes mellitus (quartiles 4 versus 1, hazard ratio, 0.56; 95% confidence interval, 0.37-0.86; P-trend=0.01); higher plasma 17:0, 43% lower risk (hazard ratio, 0.57; 95% confidence interval, 0.39-0.83; P-trend=0.01); and higher t-16:1n-7, 52% lower risk (hazard ratio, 0.48; 95% confidence interval, 0.33-0.70; P-trend <0.001). Findings were similar for erythrocyte 15:0, 17:0, and t-16:1n-7, although with broader confidence intervals that only achieved statistical significance for 17:0. CONCLUSIONS: In 2 prospective cohorts, higher plasma dairy fatty acid concentrations were associated with lower incident diabetes mellitus. Results were similar for erythrocyte 17:0. Our findings highlight the need to better understand the potential health effects of dairy fat, and the dietary and metabolic determinants of these fatty acids.

Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts.

BACKGROUND AND PURPOSE: The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke. METHODS: We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses' Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis. RESULTS: A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results. CONCLUSIONS: In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.

Impact of Dietary and Metabolic Risk Factors on Cardiovascular and Diabetes Mortality in South Asia: Analysis From the 2010 Global Burden of Disease Study.

OBJECTIVES: To quantify cardiovascular disease and diabetes deaths attributable to dietary and metabolic risks by country, age, sex, and time in South Asian countries. METHODS: We used the 2010 Global Burden of Disease national surveys to characterize risk factor levels by age and sex. We derived etiological effects of risk factors-disease endpoints, by age, from meta-analyses. We defined optimal levels. We combined these inputs with cause-specific mortality rates to compute population-attributable fractions as a percentage of total cardiometabolic deaths. RESULTS: Suboptimal diet was the leading cause of cardiometabolic mortality in 4 of 5 countries, with population-attributable fractions from 40.7% (95% uncertainty interval = 37.4, 44.1) in Bangladesh to 56.9% (95% uncertainty interval = 52.4, 61.5) in Pakistan. High systolic blood pressure was the second leading cause, except in Bangladesh, where it superseded suboptimal diet. This was followed in all nations by high fasting plasma glucose, low fruit intake, and low whole grain intake. Other prominent burdens were more variable, such as low intake of vegetables, low omega-3 fats, and high sodium intake in India, Nepal, and Pakistan. CONCLUSIONS: Important similarities and differences are evident in cardiometabolic mortality burdens of modifiable dietary and metabolic risks across these countries, informing health policy and program priorities.

Mercury exposure and risk of cardiovascular disease in two U.S. cohorts.

BACKGROUND: Exposure to methylmercury from fish consumption has been linked to a potentially increased risk of cardiovascular disease, but evidence from prior studies is equivocal. Beneficial effects of the ingestion of fish and selenium may also modify such effects. METHODS: Among subjects from two U.S. cohorts (a total of 51,529 men and 121,700 women) whose toenail clippings had been stored, we prospectively identified incident cases of cardiovascular disease (coronary heart disease and stroke) in 3427 participants and matched them to risk-set-sampled controls according to age, sex, race, and smoking status. Toenail mercury and selenium concentrations were assessed with the use of neutron-activation analysis. Other demographic characteristics, cardiovascular risk factors, fish consumption, and lifestyle habits were assessed by means of validated questionnaires. Associations between mercury exposure and incident cardiovascular disease were evaluated with the use of conditional logistic regression. RESULTS: Median toenail mercury concentrations were 0.23 µg per gram (interdecile range, 0.06 to 0.94) in the case participants and 0.25 µg per gram (interdecile range, 0.07 to 0.97) in the controls. In multivariate analyses, participants with higher mercury exposures did not have a higher risk of cardiovascular disease. For comparisons of the fifth quintile of mercury exposure with the first quintile, the relative risks were as follows: coronary heart disease, 0.85 (95% confidence interval [CI], 0.69 to 1.04; P=0.10 for trend); stroke, 0.84 (95% CI, 0.62 to 1.14; P=0.27 for trend); and total cardiovascular disease, 0.85 (95% CI, 0.72 to 1.01; P=0.06 for trend). Findings were similar in analyses of participants with low selenium concentrations or low overall fish consumption and in several additional sensitivity analyses. CONCLUSIONS: We found no evidence of any clinically relevant adverse effects of mercury exposure on coronary heart disease, stroke, or total cardiovascular disease in U.S. adults at the exposure levels seen in this study. (Funded by the National Institutes of Health.).

Dynamics of a stochastic modified Leslie-Gower predator-prey system with hunting cooperation.

In this paper, we consider a stochastic two-species predator-prey system with modified Leslie-Gower. Meanwhile, we assume that hunting cooperation occurs in the predators. By using Itô formula and constructing a proper Lyapunov function, we first show that there is a unique global positive solution for any given positive initial value. Furthermore, based on Chebyshev inequality, the stochastic ultimate boundedness and stochastic permanence are discussed. Then, under some conditions, we prove the persistence in mean and extinction of system. Finally, we verify our results by numerical simulations.

How prices and income influence global patterns in saturated fat intake by age, sex and world region: a cross-sectional analysis of 160 countries.

OBJECTIVE: When considering proposals to improve diets, it is important to understand how factors like price and income can affect saturated fat (SF) intake and demand. In this study, we examine and estimate the influence of price and income on intake across 160 countries, by age and sex, and derive sensitivity measures (price elasticities) that vary by age, sex and world region. DESIGN: We econometrically estimate intake responsiveness to income and prices across countries, accounting for differences by world region, age and sex. Intake data by age, sex and country were obtained from the 2018 Global Dietary Database. These data were then linked to global price data for select food groups from the World Bank International Comparison Programme and income data from the World Development Indicators Databank (World Bank). RESULTS: Intake differences due to price were highly significant, with a 1% increase in price associated with a lower SF intake (% energy/d) of about 4.3 percentage points. We also find significant differences across regions. In high-income countries, median (age 40) intake reductions were 1.4, 0.8 and 0.2 percentage points, given a 1% increase in the price of meat, dairy, and oils and fats, respectively. Price elasticities varied with age but not sex. Intake differences due to income were insignificant when regional binary variables were included in the analysis. CONCLUSION: The results of this study show heterogeneous associations among prices and intake within and across countries. Policymakers should consider these heterogeneous effects as they address global nutrition and health challenges.

Dual-Targeting Nanovesicles Carrying CSF1/CD47 Identified from Single-Cell Transcriptomics of Innate Immune Cells in Heart Transplant for Alleviating Acute Rejection.

Although immunosuppressive drugs for targeting T cells are the standard of care in acute transplantation rejection, the role of innate immune cells should not be ignored. Here, single-cell RNA sequencing (scRNA-seq) and flow cytometry are performed to reveal the dynamic changes of innate immune cells within the acute rejection time and find a significantly-increased presence of Ly6G- Ly6C+ inflammatory macrophages and decreased presence of neutrophils among all types of immune cells. Next, to further explore potential targets regulating Ly6G- Ly6C+ inflammatory macrophages, scRNA-seq is used to analyze the reciprocal signaling of both neutrophils and macrophages, along with the surface genes of macrophages. It is found that activating colony-stimulating factor 1/ colony-stimulating factor 1 receptor (CSF1/CSF1R) andcluster of differentiation 47/signal regulatory protein α (CD47/SIRPα) signaling may serve as a strategy to relieve Ly6G- Ly6C+ inflammatory macrophage-mediated early graft rejection. To investigate this hypothesis, CSF1/CD47 dual-targeting nanovesicles (NVs) derived from IFN-γ-stimulated induced pluripotent stem cell-derived mesenchymal stem cells ( iPSC-MSCs )are designed and constructed. It is confirmed that CSF1/CD47 NVs synergistically induce the differentiation of Ly6G- Ly6C- M2 inhibitory macrophages by the CSF1/CSF1R pathway, and inhibit the phagocytosis of inflammatory macrophages and inflammatory response by the CD47/SIRPα pathway, ultimately relieving immune rejection. This study highlights the power of dual-targeting CSF1/CD47 NVs as an immunosuppressant against early innate immune responses with the potential for broad clinical applications.

Reactive Oxygen Species Responsive Multifunctional Fusion Extracellular Nanovesicles: Prospective Treatments for Acute Heart Transplant Rejection.

Heart transplantation offers life-saving treatment for patients with end-stage heart failure; however, ischemia-reperfusion injury (IRI) and subsequent immune responses remain significant challenges. Current therapies primarily target adaptive immunity, with limited options available for addressing IRI and innate immune activation. Although plant-derived vesicle-like nanoparticles show promise in managing diseases, their application in organ transplantation complications is unexplored. Here, this work develops a novel reactive oxygen species (ROS)-responsive multifunctional fusion extracellular nanovesicles carrying rapamycin (FNVs@RAPA) to address early IRI and Ly6C+Ly6G- inflammatory macrophage-mediated rejection in heart transplantation. The FNVs comprise Exocarpium Citri grandis-derived extracellular nanovesicles with anti-inflammatory and antioxidant properties, and mesenchymal stem cell membrane-derived nanovesicles expressing calreticulin with macrophage-targeting ability. A novel ROS-responsive bio-orthogonal chemistry approach facilitates the active targeting delivery of FNVs@RAPA to the heart graft site, effectively alleviating IRI and promoting the polarization of Ly6C+Ly6G- inflammatory macrophages toward an anti-inflammatory phenotype. Hence, FNVs@RAPA represents a promising therapeutic approach for mitigating early transplantation complications and immune rejection. The fusion-targeted delivery strategy offers superior heart graft site enrichment and macrophage-specific targeting, promising improved transplant outcomes.

Impact of Produce Prescriptions on Diet, Food Security, and Cardiometabolic Health Outcomes: A Multisite Evaluation of 9 Produce Prescription Programs in the United States.

BACKGROUND: Produce prescriptions may improve cardiometabolic health by increasing fruit and vegetable (F&V) consumption and food insecurity yet impacts on clinical outcomes and health status have not been evaluated in large, multisite evaluations. METHODS: This multisite, pre- and post-evaluation used individual-level data from 22 produce prescription locations in 12 US states from 2014 to 2020. No programs were previously evaluated. The study included 3881 individuals (2064 adults aged 18+ years and 1817 children aged 2-17 years) with, or at risk for, poor cardiometabolic health recruited from clinics serving low-income neighborhoods. Programs provided financial incentives to purchase F&V at grocery stores or farmers markets (median, $63/months; duration, 4-10 months). Surveys assessed F&V intake, food security, and self-reported health; glycated hemoglobin, blood pressure, body mass index (BMI), and BMI z-score were measured at clinics. Adjusted, multilevel mixed models accounted for clustering by program. RESULTS: After a median participation of 6.0 months, F&V intake increased by 0.85 (95% CI, 0.68-1.02) and 0.26 (95% CI, 0.06-0.45) cups per day among adults and children, respectively. The odds of being food insecure dropped by one-third (odds ratio, 0.63 [0.52-0.76]) and odds of improving 1 level in self-reported health status increased for adults (odds ratio, 1.62 [1.30-2.02]) and children (odds ratio, 2.37 [1.70-3.31]). Among adults with glycated hemoglobin ≥6.5%, glycated hemoglobin declined by -0.29% age points (-0.42 to -0.16); among adults with hypertension, systolic and diastolic blood pressures declined by -8.38 mm Hg (-10.13 to -6.62) and -4.94 mm Hg (-5.96 to -3.92); and among adults with overweight or obesity, BMI decreased by -0.36 kg/m2 (-0.64 to -0.09). Child BMI z-score did not change -0.01 (-0.06 to 0.04). CONCLUSIONS: In this large, multisite evaluation, produce prescriptions were associated with significant improvements in F&V intake, food security, and health status for adults and children, and clinically relevant improvements in glycated hemoglobin, blood pressure, and BMI for adults with poor cardiometabolic health.

Sugar-sweetened beverage intakes among adults between 1990 and 2018 in 185 countries.

Sugar-sweetened beverages (SSBs) are associated with cardiometabolic diseases and social inequities. For most nations, recent estimates and trends of intake are not available; nor variation by education or urbanicity. We investigated SSB intakes among adults between 1990 and 2018 in 185 countries, stratified subnationally by age, sex, education, and rural/urban residence, using data from the Global Dietary Database. In 2018, mean global SSB intake was 2.7 (8 oz = 248 grams) servings/week (95% UI 2.5-2.9) (range: 0.7 (0.5-1.1) in South Asia to 7.8 (7.1-8.6) in Latin America/Caribbean). Intakes were higher in male vs. female, younger vs. older, more vs. less educated, and urban vs. rural adults. Variations by education and urbanicity were largest in Sub-Saharan Africa. Between 1990 and 2018, SSB intakes increased by +0.37 (+0.29, +0.47), with the largest increase in Sub-Saharan Africa. These findings inform intervention, surveillance, and policy actions worldwide, highlighting the growing problem of SSBs for public health in Sub-Saharan Africa.

Children's and adolescents' rising animal-source food intakes in 1990-2018 were impacted by age, region, parental education and urbanicity.

Animal-source foods (ASF) provide nutrition for children and adolescents' physical and cognitive development. Here, we use data from the Global Dietary Database and Bayesian hierarchical models to quantify global, regional and national ASF intakes between 1990 and 2018 by age group across 185 countries, representing 93% of the world's child population. Mean ASF intake was 1.9 servings per day, representing 16% of children consuming at least three daily servings. Intake was similar between boys and girls, but higher among urban children with educated parents. Consumption varied by age from 0.6 at <1 year to 2.5 servings per day at 15-19 years. Between 1990 and 2018, mean ASF intake increased by 0.5 servings per week, with increases in all regions except sub-Saharan Africa. In 2018, total ASF consumption was highest in Russia, Brazil, Mexico and Turkey, and lowest in Uganda, India, Kenya and Bangladesh. These findings can inform policy to address malnutrition through targeted ASF consumption programmes.

Evaluation of a Produce Prescription Program for Patients With Diabetes: A Longitudinal Analysis of Glycemic Control.

OBJECTIVE: Produce prescriptions have shown promise in improving diabetes care, although most studies have used small samples or lacked controls. Our objective was to evaluate the impacts of a produce prescription program on glycemic control for patients with diabetes. RESEARCH DESIGN AND METHODS: Participants included a nonrandom enrollment of 252 patients with diabetes who received a produce prescription and 534 similar control participants from two clinics in Hartford, Connecticut. The start of the COVID-19 pandemic in March 2020 coincided with program implementation. Produce prescription enrollees received vouchers ($60 per month) for 6 months to purchase produce at grocery retail. Controls received usual care. The primary outcome was change in glycated hemoglobin (HbA1c) between treatment and control at 6 months. Secondary outcomes included 6-month changes in systolic (SBP) and diastolic blood pressure (DBP), BMI, hospitalizations, and emergency department admissions. Longitudinal generalized estimating equation models, weighted with propensity score overlap weights, assessed changes in outcomes over time. RESULTS: At 6 months, there was no significant difference in change in HbA1c between treatment and control groups, with a difference of 0.13 percentage points (95% CI -0.05, 0.32). No significant difference was observed for change in SBP (3.85 mmHg; -0.12, 7.82), DBP (-0.82 mmHg; -2.42, 0.79), or BMI (-0.22 kg/m2; -1.83, 1.38). Incidence rate ratios for hospitalizations and emergency department visits were 0.54 (0.14, 1.95) and 0.53 (0.06, 4.72), respectively. CONCLUSIONS: A 6-month produce prescription program for patients with diabetes, implemented during the onset of the COVID-19 pandemic, was not associated with improved glycemic control.

Incident type 2 diabetes attributable to suboptimal diet in 184 countries.

The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.8-14.4 million) incident T2D cases, representing 70.3% (68.8-71.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.0-27.1%)), excess refined rice and wheat intake (24.6% (22.3-27.2%)) and excess processed meat intake (20.3% (18.3-23.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.4-87.7%)) and Latin America and the Caribbean (81.8% (80.1-83.4%)); and lowest proportional burdens were in South Asia (55.4% (52.1-60.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally.

Global, regional, and national consumption of animal-source foods between 1990 and 2018: findings from the Global Dietary Database.

BACKGROUND: Diet is a major modifiable risk factor for human health and overall consumption patterns affect planetary health. We aimed to quantify global, regional, and national consumption levels of animal-source foods (ASF) to inform intervention, surveillance, and policy priorities. METHODS: Individual-level dietary surveys across 185 countries conducted between 1990 and 2018 were identified, obtained, standardised, and assessed among children and adults, jointly stratified by age, sex, education level, and rural versus urban residence. We included 499 discrete surveys (91·2% nationally or subnationally representative) with data for ASF (unprocessed red meat, processed meat, eggs, seafood, milk, cheese, and yoghurt), comprising 3·8 million individuals from 134 countries representing 95·2% of the world population in 2018. We used Bayesian hierarchical models to account for differences in survey methods and representativeness, time trends, and input data and modelling uncertainty, with five-fold cross-validation. FINDINGS: In 2018, mean global intake per person of unprocessed red meat was 51 g/day (95% uncertainty interval [UI] 48-54; region-specific range 7-114 g/day); 17 countries (23·9% of the world's population) had mean intakes of at least one serving (100 g) per day. Global mean intake of processed meat was 17 g/day (95% UI 15-21 g/day; region-specific range 3-54 g/day); seafood, 28 g/day (27-30 g/day; 12-44 g/day); eggs, 21 g/day (18-24 g/day; 6-35 g/day); milk 88 g/day (84-93 g/day; 45-185 g/day); cheese, 8 g/day (8-10 g/day; 1-34 g/day); and yoghurt, 20 g/day (17-23 g/day; 7-84 g/day). Mean national intakes were at least one serving per day for processed meat (≥50 g/day) in countries representing 6·9% of the global population; for cheese (≥42 g/day) in 2·3%; for eggs (≥55 g/day) in 0·7%; for milk (≥245 g/day) in 0·3%; for seafood (≥100 g/day) in 0·8%; and for yoghurt (≥245 g/day) in less than 0·1%. Among the 25 most populous countries in 2018, total ASF intake was highest in Russia (5·8 servings per day), Germany (3·8 servings per day), and the UK (3·7 servings per day), and lowest in Tanzania (0·9 servings per day) and India (0·7 servings per day). Global and regional intakes of ASF were generally similar by sex. Compared with children, adults generally consumed more unprocessed red meat, seafood and cheese, and less milk; energy-adjusted intakes of other ASF were more similar. Globally, ASF intakes (servings per week) were higher among more-educated versus less-educated adults, with greatest global differences for milk (0·79), eggs (0·47), unprocessed red meat (0·42), cheese (0·28), seafood (0·28), yoghurt (0·22), and processed meat (0·21). This was also true for urban compared to rural areas, with largest global differences (servings per week) for unprocessed red meat (0·47), milk (0·38), and eggs (0·20). Between 1990 and 2018, global intakes (servings per week) increased for unprocessed red meat (1·20), eggs (1·18), milk (0·63), processed meat (0·50), seafood (0·44), and cheese (0·14). INTERPRETATION: Our estimates of ASF consumption identify populations with both lower and higher than optimal intakes. These estimates can inform the targeting of intervention, surveillance, and policy priorities relevant to both human and planetary health. FUNDING: Bill & Melinda Gates Foundation and American Heart Association.

PD-1 Cellular Nanovesicles Carrying Gemcitabine to Inhibit the Proliferation of Triple Negative Breast Cancer Cell.

PD-1 inhibitor Keytruda combined with chemotherapy for Triple-negative breast cancer (TNBC) has been approved for FDA, successfully representing the combination therapy of immunotherapy and chemotherapy for the first time in 2020. However, PD-L1 inhibitor Tecentriq combined with albumin paclitaxel using the similar strategy failed to achieve the expected effect. Therefore, it is still necessary to explore new effective immunotherapy and chemotherapy-based combined strategies. We developed a cell membrane-derived programmed death-ligand 1(PD-1) nanovesicle to encapsulate low-dose gemcitabine (PD-1&GEM NVs) to study the effect on breast cancer in vitro and in vivo. We found that engineered PD-1&GEM NVs could synergistically inhibit the proliferation of triple-negative breast cancer, which interacted with PD-L1 in triple-negative breast cancer to disrupt the PD-L1/PD-1 immune inhibitory axis and promoted cancer cell apoptosis. Moreover, PD-1&GEM NVs had better tumor targeting ability for PD-L1 highly-expressed TNBC cells, contributing to increasing the drug effectiveness and reducing toxicity. Importantly, gemcitabine-encapsulated PD-1 NVs exerted stronger effects on promoting apoptosis of tumor cells, increasing infiltrated CD8+ T cell activation, delaying the tumor growth and prolonging the survival of tumor-bearing mice than PD-1 NVs or gemcitabine alone. Thus, our study highlighted the power of combined low-dose gemcitabine and PD-1 in the nanovesicles as treatment to treat triple-negative breast cancer.

Small Extracellular Vesicles Derived From MSCs Have Immunomodulatory Effects to Enhance Delivery of ASO-210 for Psoriasis Treatment.

Mesenchymal stem cells (MSCs) have been increasingly used for treating autoimmune diseases due to their immune modulation functions, but inefficient homing to the target tissue and safety issues limits their wide application. Recently, increasing studies demonstrate small extracellular vesicles (sEVs) as key mediators of MSCs to exert their immunomodulatory effects. In this study, we found that sEVs derived from human umbilical cord MSCs stimulated by IFN-γ (IFNγ-sEVs) inhibited proliferation and activation of peripheral blood mononuclear cells and T cells in vitro. Furthermore, we confirmed that IFNγ-sEVs reduced psoriasis symptoms including thickness, erythema, and scales of skin lesions; exhausted Th17 cells, increased Th2 cells; and reduced enrichment of inflammatory cytokines such as IL-17A, IFN-γ, IL-6, and TNF-α in both spleen and skin lesions in vivo. Importantly, IFNγ-sEVs significantly improved the delivery efficiency and stability of ASO-210, the antisense oligonucleotides of miR-210 block the immune imbalance and subsequent psoriasis development. Our results reveal MSC-sEVs as promising cell-free therapeutic agents and ideal delivery vehicles of antisense oligonucleotides for psoriasis treatment.

Global dietary quality in 185 countries from 1990 to 2018 show wide differences by nation, age, education, and urbanicity.

Evidence on what people eat globally is limited in scope and rigour, especially as it relates to children and adolescents. This impairs target setting and investment in evidence-based actions to support healthy sustainable diets. Here we quantified global, regional and national dietary patterns among children and adults, by age group, sex, education and urbanicity, across 185 countries between 1990 and 2018, on the basis of data from the Global Dietary Database project. Our primary measure was the Alternative Healthy Eating Index, a validated score of diet quality; Dietary Approaches to Stop Hypertension and Mediterranean Diet Score patterns were secondarily assessed. Dietary quality is generally modest worldwide. In 2018, the mean global Alternative Healthy Eating Index score was 40.3, ranging from 0 (least healthy) to 100 (most healthy), with regional means ranging from 30.3 in Latin America and the Caribbean to 45.7 in South Asia. Scores among children versus adults were generally similar across regions, except in Central/Eastern Europe and Central Asia, high-income countries, and the Middle East and Northern Africa, where children had lower diet quality. Globally, diet quality scores were higher among women versus men, and more versus less educated individuals. Diet quality increased modestly between 1990 and 2018 globally and in all world regions except in South Asia and Sub-Saharan Africa, where it did not improve.

Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia: A Randomized Clinical Trial.

Importance: Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels. Objective: To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA [CaPre]), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia. Design, Setting, and Participants: This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate. Interventions: Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks. Main Outcomes and Measures: The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups. Results: A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men [65.2%]), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, TG levels were reduced by 26.0% (95% CI, 20.5%-31.5%) in the ω-3-PL/FFA group and 15.1% (95% CI, 6.6%-23.5%) in the placebo group at 12 weeks (mean treatment difference, -10.9% [95% CI, -20.4% to -1.5%]; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% [95% CI, -23.1% to -2.4%]; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% [95% CI, -8.0% to 1.6%]; P = .18), VLDL-C (-3.8% [95% CI, -12.2% to 4.7%]; P = .38), HDL-C (0.7% [95% CI, -3.7% to 5.1%]; P = .77), or LDL-C (4.5% [95% CI, -5.9% to 14.8%]; P = .40) levels; corresponding differences at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%; P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%; P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%; P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5% [95% CI, -34.5% to -4.6%]; P = .08 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% [95% CI, -33.8% to -5.3%]; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo. Conclusions and Relevance: This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.