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2008;87:323-331. BACKGROUND: Berries are a particularly rich source of polyphenols. They also contain other bioactive substances, such as vitamin C. Previous studies indicated that the consumption of polyphenol-rich foods (eg, [...]

PURPOSE: Bilberries are abundant in polyphenols. Dietary polyphenols have been associated with strategies for prevention and treatment of chronic inflammatory diseases. We investigated the effect of bilberry juice on serum and plasma biomarkers of inflammation and antioxidant status in subjects with elevated levels of at least one risk factor for cardiovascular disease (CVD). METHODS: In a randomized controlled trial, participants consumed either bilberry juice (n = 31) or water (n = 31) for 4 weeks. RESULTS: Supplementation with bilberry juice resulted in significant decreases in plasma concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-15, and monokine induced by INF-gamma (MIG). Unexpectedly, an increase in the plasma concentration of tumor nuclear factor-alpha (TNF-alpha) was observed in the bilberry group. CRP, IL-6, IL15, MIG, and TNF-alpha are all target genes of nuclear factor- kappa B (NF-kappaB), -a transcription factor that is crucial in orchestrating inflammatory responses. Plasma quercetin and p-coumaric acid increased in the bilberry group, otherwise no differences were observed for clinical parameters, oxidative stress or antioxidant status. Furthermore, we studied the effect of polyphenols from bilberries on lipopolysaccharide (LPS)-induced NF-kappaB activation in a monocytic cell line. We observed that quercetin, epicatechin, and resveratrol inhibited NF-kappaB activation. CONCLUSIONS: These findings suggest that supplementation with bilberry polyphenols may modulate the inflammation processes. Further testing of bilberry supplementation as a potential strategy in prevention and treatment of chronic inflammatory diseases is warranted. [ABSTRACT FROM AUTHOR]

Berries are a rich source of various polyphenols, including the flavonoid quercetin. In this article, the results of three intervention studies investigating the bioavailability of quercetin from berries are reviewed. In the first study, we investigated the short-term kinetics of quercetin after consumption of black currant juice and showed that quercetin is rapidly absorbed from it. In the second study, we showed that plasma quercetin levels increase up to 50% in subjects consuming 100 g/day of bilberries, black currants, and lingonberries as a part of their normal diets for 2 mo. In the third study, healthy subjects consumed a diet high or low in vegetables, berries, and other fruit for 6 wk. Quercetin concentrations nearly doubled in the high-vegetable, -berry, and -other fruit group and decreased by 30% in subjects consuming less of these foods than normally. The results showed that plasma quercetin is bioavailable from a diet containing berries and indicate that it may be a good biomarker of fruit and vegetable intake in general. [ABSTRACT FROM AUTHOR]

The flavanones naringenin and hesperetin exhibit estrogenic, anticarcinogenic and antioxidative properties. Orange juice and grapefruit juice contain high amounts of these compounds, and therefore their intake from the diet can be relatively high. No data are available regarding plasma concentrations or plasma kinetics of flavanones. The objectives of this study were to develop methods allowing the analysis of naringenin and hesperetin from plasma and urine and to study their plasma kinetics and urinary excretion. We also wanted to assess whether plasma or urine flavanone concentrations can be used as biomarkers of intake. Healthy volunteers ingested orange juice (five women and three men) or grapefruit juice (two women and three men) once (8 mL/kg). Eleven blood samples and urine were collected between 0 and 24 h after juice administration. Flavanones were analyzed by HPLC with electrochemical detection. Naringenin and hesperetin were bioavailable from the studied juices, but interindividual variation in bioavailability was remarkable. The resulting plasma concentrations were comparatively high, and the peak plasma concentrations (C(max)) were 0.6 +/- 0.4 micromol/L (means +/- SD) for naringenin from orange juice and 6.0 +/- 5.4 micromol/L for naringenin from grapefruit juice. The corresponding value for hesperetin from orange juice was 2.2 +/- 1.6 micromol/L. The elimination half-lives were between 1.3 and 2.2 h, and therefore plasma concentrations reflect short-term intake. The relative urinary excretion varied depending on the flavanone source and dose and was 30.2 +/- 25.5% and 1.1 +/- 0.8% for naringenin from grapefruit juice and orange juice, respectively, and 5.3 +/- 3.1% for hesperetin from orange juice. The considerable difference in the relative urinary excretion of naringenin from the two juices was most likely caused by dose-dependent renal clearance rather than differences in bioavailability (as indicated by the similar C(max)-to-dose ratios). The results indicate that urine flavanone concentrations are not good biomarkers of dietary intake. We conclude that because of the relatively high concentrations of flavanones in plasma after ingestion of orange juice or grapefruit juice, considerable health effects could ensue in individuals consuming them regularly. [ABSTRACT FROM AUTHOR]

Background and Aims: INTERASPIRE is an international study of coronary heart disease (CHD) patients, designed to measure if guideline standards for secondary prevention and cardiac rehabilitation are being achieved in a timely manner., Methods: Between 2020 and 2023, adults hospitalized in the preceding 6-24 months with incident or recurrent CHD were sampled in 14 countries from all 6 World Health Organization regions and invited for a standardized interview and examination. Direct age and sex standardization was used for country-level prevalence estimation., Results: Overall, 4548 (21.1% female) CHD patients were interviewed a median of 1.05 (interquartile range .76-1.45) years after index hospitalization. Among all participants, 24.6% were obese (40.7% centrally). Only 38.6% achieved a blood pressure (BP) < 130/80 mmHg and 16.6% a LDL cholesterol (LDL-C) of <1.4 mmol/L. Of those smoking at hospitalization, 48% persisted at interview. Of those with known diabetes, 55.2% achieved glycated haemoglobin (HbA1c) of <7.0%. A further 9.8% had undetected diabetes and 26.9% impaired glucose tolerance. Females were less likely to achieve the targets: BP (females 36.8%, males 38.9%), LDL-C (females 12.0%, males 17.9%), and HbA1c in diabetes (females 47.7%, males 57.5%). Overall, just 9.0% (inter-country range 3.8%-20.0%) reported attending cardiac rehabilitation and 1.0% (inter-country range .0%-2.4%) achieved the study definition of optimal guideline adherence., Conclusions: INTERASPIRE demonstrates inadequate and heterogeneous international implementation of guideline standards for secondary prevention in the first year after CHD hospitalization, with geographic and sex disparity. Investment aimed at reducing between-country and between-individual variability in secondary prevention will promote equity in global efforts to reduce the burden of CHD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Circulating dietary biomarkers are not direct proxies for intake, as the biomarkers reflect not only food and supplement consumption but also nutrient absorption, metabolism, and tissue distribution. Therefore, along with nutrient intake, several other upstream factors can impact dietary biomarker concentrations, including demographic, medical history, and genetic factors., Objectives: The aim of this study was to explore the dietary and nondietary determinants of circulating levels of vitamins A, C, D, and E among children aged 6 mo-4 y., Methods: Plasma retinol, β-carotene, ascorbic acid, 25(OH)D, α-tocopherol, and γ-tocopherol were measured in 2887 samples from 1490 children enrolled in The Environmental Determinants of Diabetes in the Young study. Dietary intake was assessed with 3-d food records. Associations of genetic and environmental factors with biomarker concentrations were examined using multivariable linear regression models with random intercepts., Results: All biomarkers except retinol were positively associated with intake of the same nutrient. Inverse associations were identified between recent gastrointestinal infection and β-carotene, ascorbic acid, and α-tocopherol, whereas recent respiratory infection was associated inversely with plasma retinol. Several genetic determinants of biomarker status were identified, validating previously reported findings. For some genetic and environmental exposures, we found evidence of statistical interaction with same-nutrient intake, indicating that the association between intake and biomarker concentration is dependent on the level or status of these other exposures. For example, the association between β-carotene intake and concentration is weaker among children with a recent respiratory infection., Conclusions: Our findings suggest that nondietary exposures including childhood infections can alter micronutrient metabolism. This summary of micronutrient determinants will facilitate improved design of future analyses exploring the role of diet in childhood chronic disease etiology through a better understanding of relevant potential confounders and mediators of the diet-outcome relationships., Competing Interests: Conflict of interest All authors report no conflict of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years., Methods: We followed 8500 T1D-susceptible children born in the U.S., Finland, Sweden, and Germany in 2004 -2010 from the Environmental Determinants of Diabetes in the Young (TEDDY) study, which is a prospective observational birth cohort. Dietary intake of seven B vitamins was calculated from foods and dietary supplements based on 24-h recall at 3 months and 3-day food records collected regularly from 6 months to 10 years of age. Cox proportional hazard models were adjusted for energy, HLA-genotype, first-degree relative with T1D, sex, and country., Results: A total of 778 (9.2) children developed at least one autoantibody (any IA), and 335 (3.9%) developed multiple autoantibodies. 280 (3.3%) children had IAA and 319 (3.8%) GADA as the first autoantibody. 344 (44%) children with IA progressed to T1D. We observed that higher intake of niacin was associated with a decreased risk of developing multiple autoantibodies (HR 0.95; 95% CI 0.92, 0.98) per 1 mg/1000 kcal in niacin intake. Higher intake of pyridoxine (HR 0.66; 95% CI 0.46, 0.96) and vitamin B12 (HR 0.87; 95% CI 0.77, 0.97) was associated with a decreased risk of IAA-first autoimmunity. Higher intake of riboflavin (HR 1.38; 95% CI 1.05, 1.80) was associated with an increased risk of GADA-first autoimmunity. There were no associations between any of the B vitamins and the outcomes "any IA" and progression from IA to T1D.  CONCLUSION: In this multinational, prospective birth cohort of children with genetic susceptibility to T1D, we observed some direct and inverse associations between different B vitamins and risk of IA., (© 2024. The Author(s).)

Context: Use of levonorgestrel-releasing intrauterine device (LNG-IUD) has become common irrespective of age and parity. To date, only a few studies have examined its possible metabolic changes and large-scale biomarker profiles in detail and in a longitudinal design., Objective: To apply the metabolomics technique to examine the metabolic profile associated with the use of LNG-IUD both in a cross-sectional and in a longitudinal design., Design: The study consists of cross-sectional and longitudinal analyses of a population-based survey (Health 2000) and its 11-year follow-up (Health 2011). All participants aged 18-49 years with available information on hormonal contraceptive use and metabolomics data (n=1767) were included. Altogether 212 metabolic measures in LNG-IUD users (n=341) were compared to those in non-users of hormonal contraception (n=1426) via multivariable linear regression models. Participants with complete longitudinal information (n=240) were divided into continuers, stoppers, starters, and never-user groups, and 11-year changes in levels of each metabolite were compared., Results: After adjustment for covariates, levels of 102 metabolites differed in LNG-IUD current users compared to non-users of hormonal contraception (median difference in biomarker concentration: -0.12 SD): lower levels of fatty acids concentrations and ratios, cholesterol, triglycerides and other lipids, as well as particle concentration, cholesterol, total lipids and phospholipids in lipoproteins. The 11-year metabolic changes did not differ in relation to changes in LNG-IUD use., Conclusions: The use of LNG-IUD was associated with several moderate metabolic changes, mostly suggestive of a reduced arterial cardiometabolic risk. Changes in LNG-IUD use were not related to long-term metabolic changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background & Aims: Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene., Methods: The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m 2 ). The effects of HFE variants on these associations were also evaluated., Results: Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes ( n  = 92) and severe liver-related outcomes ( n  = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02-1.21]; p  = 0.012 and HR 1.11 [95% CI 1.02-1.21]; p  = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes., Conclusion: Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia.

Background and Aims: Effective and feasible population screening strategies are needed for the early detection of individuals at high risk of future severe liver-related outcomes. We evaluated the predictive performance of the combination of liver fibrosis assessment, phenotype profile, and genetic risk., Methods: Data from 5795 adults attending the Finnish Health 2000 Survey were linked with healthcare registers for liver-related outcomes (hospitalization, hepatocellular cancer, and death). Fibrosis was assessed using the enhanced liver fibrosis (ELF) test, phenotype profile by the chronic liver disease (CLivD) risk score, and genetic risk by a validated Polygenic Risk Score (PRS-5). Predictive performance was assessed by competing-risk analyses., Results: During a median 13-year follow-up, 64 liver-related outcome events were recorded. ELF, CLivD score, and PRS-5 were independently associated with liver-related outcomes. The absolute 10-year risk of liver-related outcomes at an ELF value of 11.3 ranged from 0.3% to 33% depending on the CLivD score. The CLivD score added 51% of new predictive information to the ELF test and improved areas under the curve (AUCs) from 0.91, 0.81, and 0.71 for ELF alone to 0.95, 0.85, and 0.80, respectively, for ELF combined with the CLivD score at 1, 5, and 10 years. The greatest improvement was for 10-year predictions (delta-AUC 0.097, p < .0001). Adding PRS-5 did not significantly increase predictive performance. Findings were consistent in individuals with obesity, diabetes, or alcohol risk use, and regardless of whether gamma-glutamyltransferase was used in the CLivD score., Conclusion: A combination of ELF and CLivD score predicts liver-related outcomes significantly better than the ELF test alone., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Introduction: Type 1 diabetes (T1D) is an autoimmune disease in which pro-inflammatory and cytotoxic signaling drive the death of the insulin-producing β cells. This complex signaling is regulated in part by fatty acids and their bioproducts, making them excellent therapeutic targets., Areas Covered: We provide an overview of the fatty acid actions on β cells by discussing how they can cause lipotoxicity or regulate inflammatory response during insulitis. We also discuss how diet can affect the availability of fatty acids and disease development. Finally, we discuss development avenues that need further exploration., Expert Opinion: Fatty acids, such as hydroxyl fatty acids, ω-3 fatty acids, and their downstream products, are druggable candidates that promote protective signaling. Inhibitors and antagonists of enzymes and receptors of arachidonic acid and free fatty acids, along with their derived metabolites, which cause pro-inflammatory and cytotoxic responses, have the potential to be developed as therapeutic targets also. Further, because diet is the main source of fatty acid intake in humans, balancing protective and pro-inflammatory/cytotoxic fatty acid levels through dietary therapy may have beneficial effects, delaying T1D progression. Therefore, therapeutic interventions targeting fatty acid signaling hold potential as avenues to treat T1D.

Background & Aims: The Enhanced Liver Fibrosis® (ELF) test exhibits good discriminative performance in detecting advanced liver fibrosis and in predicting liver-related outcomes in patients with specific liver diseases, but large population-based studies are missing. We analysed the predictive performance of the ELF test in a general population cohort., Methods: Data were sourced from the Health 2000 study, a Finnish population-based health examination survey conducted in 2000-2001. Subjects with baseline liver disease were excluded. The ELF test was performed on blood samples collected at baseline. Data were linked with national healthcare registers for liver-related outcomes (hospitalisation, cancer, and death)., Results: The cohort comprised 6,040 individuals (mean age 52.7. 45.6% men) with 67 liver-related outcomes during a median 13.1-year follow-up. ELF predicted liver outcomes (unadjusted hazards ratio 2.70, 95% CI 2.16-3.38). with 5- and 10-year AUCs of 0.81 (95% CI 0.71-0.91) and 0.71 (95% CI 0.63-0.79) by competing-risk methodology. The 10-year risks for liver outcomes increased from 0.5% at ELF <9.8 to 7.1% at ELF ≥11.3, being higher among men than women at any given ELF level. Among individuals with body mass index ≥30 kg/m 2 , diabetes, or alanine aminotransferase >40 U/L. Five-year AUCs for ELF were 0.85, 0.87, and 0.88, respectively. The predictive ability of the ELF test decreased with time: the 10-year AUCs were 0.78, 0.69, and 0.82, respectively., Conclusions: The ELF test shows good discriminative performance in predicting liver-related outcomes in a large general population cohort and appears particularly useful for predicting 5-year outcomes in persons with risk factors., Impact and Implications: The Enhanced Liver Fibrosis test exhibits good performance for predicting liver-related outcomes (hospitalisation, liver cancer, or liver-related death) in the general population, especially in those with risk factors., Competing Interests: The authors declare that they have no conflicts of interest regarding the content of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

High sodium concentration alters leukocyte activation, and in particular T-helper (Th) lymphocyte polarization, and drives the development of autoimmune diseases in mouse studies. Similar results have been obtained with human leukocytes under in vitro settings and in few observational studies. Therefore, salt has been implicated as a risk factor for autoimmune diseases. Here, we examined whether physiologically relevant changes in salt intake or diet alter cytokine concentrations. In a 20-wk double-blinded, placebo-controlled study 106 participants were randomized to Habitual and Healthy Nordic diets, and further to Usual Sodium and Reduced Sodium intake groups using a cross-over setup. Plasma concentrations of 45 cytokines were measured at three different time-points using a multiplex assay. Repeated analyses of covariance revealed that high salt ingestion (or changes in the diet) did not induce significant changes in any of the signature cytokines controlling Th1, Th2 or Th17 polarization. Several other pro-inflammatory interleukins, chemokines and growth factors were also unaffected by the level of salt intake or changes in the diet. We conclude that in humans clinically relevant changes in salt intake or diet do not have reflections on the systemic concentrations of pro-inflammatory cytokines in vivo., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Background: A high consumption of ultra-processed foods (UPFs) is often associated with low nutritional quality, but data on associations with biomarkers are scarce. We aimed to explore associations between UPF intake, diet quality, and concentrations of biomarkers of nutrition and inflammation measured in mid-pregnancy., Methods: This cross-sectional study included n = 2,984 pregnant women recruited during 2002-2008 in the Norwegian Mother, Father, and Child Cohort Study (MoBa). Concentrations of C-reactive protein (CRP) and 21 nutritional biomarkers including carotenes (α-carotene, β-carotene, γ-carotene, α-cryptoxanthin, β-cryptoxanthin, lutein, lycopene), vitamins [α-tocopherol, γ-tocopherol, 25-hydroxyvitamin D (25-OH-D), retinol], creatinine, elements (K, Na, Co, Cu, Mn, Mo, Se, Zn), and ferritin (Fe) were measured in blood and urine collected in mid-pregnancy. Habitual diet in pregnancy was assessed using a validated semi-quantitative food frequency questionnaire. We calculated the relative (%) energy contribution of UPF to overall intake according to the NOVA classification. We also applied a diet quality index (DQI) adapted to assess adherence to Norwegian dietary guidelines (DQI; min-max: 0-110, higher score meaning higher adherence). We present summary statistics for biomarker concentrations and explored associations between UPF intake or the DQI and measured biomarkers using adjusted linear, logistic, and generalized additive regression models., Results: Ultra-processed food intake was positively associated with biomarker concentrations of vitamin E (γ-tocopherol), creatinine, K, and Na [βs: 5.6 to 17% increase in biomarker concentration per interquartile range (IQR) increase in UPF intake] and negatively associated with carotenoids (α-carotene, β-carotene, γ-carotene, α-cryptoxanthin, β-cryptoxanthin, lutein, lycopene), vitamin A, Mo, and Se (βs: -2.1 to -18%). Inversely, high diet quality (i.e., the DQI) was positively associated with concentrations of carotenoids, vitamins [vitamin A (retinol) and D (25-OH-D)], and Se (β: 1.5 to 25%) and negatively associated with vitamin E (γ-tocopherol), creatinine, and Na (β: -4.8 to -8.3%). A weak, positive association was found between UPF and CRP (β: 5.4%, 95% CI 0.12-11%)., Conclusion: High UPF intake was associated with reduced concentrations of nutrition biomarkers in mid-pregnancy. Associations in the opposite direction were found with high adherence to the Norwegian dietary guidelines, suggesting that the two dietary scoring systems capture diet quality in a mirrored manner in this population., 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 © 2022 Kelsey, Papadopoulou, Borge, Dahl, Brantsæter, Erlund, Meltzer, Haug and Caspersen.)

Background & Aims: Nutrient status may affect the risk of microbial infections and play a role in modulating the immune response against such infections. The aim of this study was to determine whether serum 25-hydroxyvitamin D [25(OH)D] and serum fatty acids in infancy are associated with microbial infections by the age of 18 months., Methods: Altogether 576 newborn infants from Trial to Reduce IDDM in the Genetically at Risk (TRIGR) born between 2002 and 2007 were included. The concentration of 25(OH)D vitamin and proportions of 26 fatty acids (presented as % of total fatty acids) were analyzed in cord blood serum and in sera taken at 6, 12, and 18 months of age. The cord blood samples and mean of 6-18-month values were used as exposures. Infections were detected by screening IgG antibodies against 10 microbes using enzyme immunoassay and antibodies against 6 coxsackievirus B serotypes by plaque neutralization assay in serum samples taken at 18 months of age., Results: A higher proportion of n-3 polyunsaturated fatty acids (PUFAs) and especially long-chain n-3 PUFAs at birth and at the age of 6-18 months was associated with decreased risk of coxsackievirus B2 infection unadjusted and adjusted for region, case-control status, and maternal type 1 diabetes. Higher proportion of docosapentaenoic acid (DPA, 22:5 n-3) at birth was associated with a decreased risk of respiratory syncytial virus infection. 25(OH)D vitamin concentration was not consistently associated with the risk of infections. When only infected children were included docosahexaenoic acid (DHA, 22:6 n-3) and arachidonic acid (20:4 n-6) proportions were positively associated with IgG antibody levels against influenza A virus. 25(OH)D vitamin concentration showed an inverse association with rotavirus IgG levels among children with rotavirus seropositivity., Conclusions: In young children with increased susceptibility to type 1 diabetes, long-chain n-3 PUFAs may influence the risk of viral infections and immune response against the infections. However, this association may depend on the type of virus suggesting virus-specific effects., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Liver fibrosis screening is recommended in high-risk populations, but the optimal definition of "high risk" remains to be established. We compared the performance of several risk-stratification strategies in a population-based setting., Methods: Data were obtained from the Finnish population-based health examination surveys Health 2000 and FINRISK 2002-2012. The Chronic Liver Disease Risk Score (CLivD) was compared to previously published risk-stratification strategies based on elevated liver enzymes, alcohol use, diabetes, fatty liver index, body mass index, and/or metabolic risk factors for their ability to detect either advanced liver fibrosis or incident severe liver events. Advanced fibrosis was defined as an Enhanced Liver Fibrosis (ELF TM ) score >9.8 in the Health 2000 study (n = 6084), and incident liver events were ascertained from registry linkage in the combined FINRISK 2002-2012 and Health 2000 cohort (n = 26,957)., Results: Depending on the cohort, 53%-60% of the population was considered at risk using the CLivD strategy (low-intermediate-high risk, excluding the minimal-risk category), compared to 30%-32% according to the other risk-stratification strategies. The CLivD captured 85%-91% of cases in the population with advanced liver fibrosis and 90% of incident severe liver events within 10 years from baseline. This compares to 33%-44% and 56%-67% captured by the other risk-stratification strategies, respectively. The 10-year cumulative incidence of liver events varied by risk-stratification strategy (1.0%-1.4%)., Conclusions: Compared to previously reported traditional risk factor-based strategies, use of the CLivD captured substantially more cases with advanced liver disease in the population and may be superior for targeting further fibrosis screening., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Use of hormonal intrauterine devices has grown during the last decades. Although hormonal intrauterine devices act mostly via local effects on the uterus, measurable concentrations of levonorgestrel are absorbed into the systemic circulation. The possible metabolic changes and large-scale biomarker profiles associated with hormonal intrauterine devices have not yet been studied in detail., Objective: To examine through the metabolomics approach the metabolic profile of patients using hormonal intrauterine devices and how this metabolic profile is affected by duration and discontinuation of use., Study Design: The study consisted of cross-sectional analyses of 5 population-based surveys (FINRISK and FinHealth studies), spanning from 1997 to 2017. All fertile-aged participants (18-49 years) in the surveys with available information on hormonal contraceptive use and metabolomics data (n=5649) were included in the study. Altogether, 211 metabolic measures of users of hormonal intrauterine devices (n=1006) were compared with those of nonusers of hormonal contraception (n=4643) via multivariable linear regression models. To allow comparison across multiple measures, association magnitudes were reported in standard deviation units of difference in biomarker concentration compared with the reference group., Results: After adjustment for covariates, levels of 141 metabolites differed in current users of hormonal intrauterine devices compared with nonusers of hormonal contraception (median difference in biomarker concentration, 0.09 standard deviation): lower levels of particle concentration of larger lipoprotein subclasses, triglycerides, cholesterol and derivatives, apolipoproteins A and B, fatty acids, glycoprotein acetyls, and aromatic amino acids. The metabolic pattern of hormonal intrauterine device use did not change according to duration of use. When comparing previous users and never-users of hormonal intrauterine devices, no significant metabolic differences were observed., Conclusion: The use of hormonal intrauterine devices was associated with several moderate metabolic changes previously associated with reduced arterial cardiometabolic risk. The metabolic effects were independent of duration of use of the hormonal intrauterine devices. Moreover, the metabolic profiles were similar after discontinuation of hormonal intrauterine device use and in never-users., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The optimal screening strategy for dysglycemia (including type 2 diabetes and impaired glucose tolerance) in patients with coronary artery disease (CAD) is debated. We tested the hypothesis that measures of insulin resistance by HOMA indexes may constitute good screening methods., Research Design and Methods: Insulin, C-peptide, glycated hemoglobin A1c, and an oral glucose tolerance test (OGTT) were centrally assessed in 3,534 patients with CAD without known dysglycemia from the fifth European Survey of Cardiovascular Disease Prevention and Diabetes (EUROASPIRE V). Three different HOMA indexes were calculated: HOMA of insulin resistance (HOMA-IR), HOMA2 based on insulin (HOMA2-ins), and HOMA2 based on C-peptide (HOMA2-Cpep). Dysglycemia was diagnosed based on the 2-h postload glucose value obtained from the OGTT. Information on study participants was obtained by standardized interviews. The optimal thresholds of the three HOMA indexes for dysglycemia diagnosis were obtained by the maximum value of Youden's J statistic on receiver operator characteristic curves. Their correlation with clinical parameters was assessed by Spearman coefficients., Results: Of 3,534 patients with CAD (mean age 63 years; 25% women), 41% had dysglycemia. Mean insulin, C-peptide, and HOMA indexes were significantly higher in patients with versus without newly detected dysglycemia (all P < 0.0001). Sensitivity and specificity of the three HOMA indexes for the diagnosis of dysglycemia were low, but their correlation with BMI and waist circumference was strong., Conclusions: Screening for dysglycemia in patients with CAD by HOMA-IR, HOMA2-ins, and HOMA2-Cpep had insufficient diagnostic performance to detect dysglycemia with reference to the yield of an OGTT, which should still be prioritized despite its practical drawbacks., (© 2022 by the American Diabetes Association.)

Objective: Iodine is an essential part of the thyroid hormones thyroxine and triiodothyronine. Therefore, it is essential to monitor iodine supply in a population. The biochemical marker for assessing and controlling iodine is urinary iodine concentration (UIC)., Materials and Methods: This cross-sectional study included 180 pregnant women and 308 women of reproductive age. Urine specimens from 185 of the 488 volunteers were used. The urine specimens were measured using 2 methods: (1) ammonium persulfate digestion (APD), followed by the Sandell-Kolthoff (S-K) reaction modified on microplate for spectrophotometric detection; and (2) the reference method, inductively coupled plasma mass spectrometry (ICP-MS)., Results: The regression equation between the methods was ICP-MS method = 1.137*(APD S-K)-5.57. A Passing-Bablok regression showed no deviation from linearity (P = .17). A Bland-Altman plot showed a negative mean bias of -2.7%., Conclusion: The APD S-K reaction modified on microplate for spectrophotometric detection of UIC can be implemented into routine work. Its results are comparable to those of laboratories worldwide and to ICP-MS., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Maternal diabetes is a well-known risk factor for pregnancy complications. Possible links between long-term maternal blood sugar in the normal range and pregnancy complications are less well described., Methods: We assayed glycated haemoglobin (HbA1c) in blood samples collected around the 18th week of pregnancy for 2937 singleton pregnancies in the Norwegian Mother, Father and Child Cohort Study (2000-09). Perinatal outcomes (gestational length, birthweight, birth length and head circumference, large-for-gestational age, small-for-gestational age, congenital malformations, preterm delivery and preeclampsia) were obtained from medical records. We tested associations using linear and log-binomial regression, adjusting for maternal age, body mass index (BMI) and smoking., Results: Size at birth increased modestly but linearly with HbA1c. Birthweight rose 0.10 standard deviations [95% confidence interval (CI): 0.03, 0.16], for each 5-mmol/mol unit increase in HbA1c, corresponding to about 40 g at 40 weeks of gestation. Large-for-gestational age rose 23% (95% CI: 1%, 50%) per five-unit increase. Other pregnancy complications increased in non-linear fashion, with strongest associations within the top quartile of HbA1c (>35 mmol/mol or >5.4%). Per unit HbA1c within the top quartile, preterm delivery increased by 14% (95% CI: 1%, 31%), preeclampsia increased by 20% (95% CI: 5%, 37%) and gestational duration decreased by 0.7 days (95% CI: -1.0, -0.3)., Conclusions: Among women with no recorded diabetes, higher HbA1c levels at 18 gestational weeks were associated with important perinatal outcomes independent of mother's age, smoking or BMI., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Aims: Altered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity., Methods: Serum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children ( n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth ( n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers., Results: Correlations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations., Conclusions: In cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored., Trial Registry Number: NCT00179777., 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 © 2022 Niinistö, Miettinen, Cuthbertson, Honkanen, Hakola, Autio, Erlund, Arohonka, Vuorela, Härkönen, Hyöty, Krischer, Vaarala, Knip, Virtanen and TRIGR Investigators.)

Objective: Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs., Design: Register-based cross-sectional study., Methods: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated., Results: Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs., Conclusions: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.

Background: Few randomized clinical trials have explored the health effects of bilberries in humans. The aim was to test the effect of bilberry and red grape-juice consumption on visual memory, motor speed and dexterity as well as inflammatory and tissue damage biomarkers of plasma in aged men with subjective memory impairment., Methods: Nine-week double-blind, placebo-controlled, dietary intervention study of aged men (n = 60, age ≥ 67 years) with subjective memory impairment randomized to consume a 50/50 mix of bilberry/red grape-juice or an iso-caloric placebo juice. A selection of Cambridge Cognition Test Battery (CANTAB), Grooved Pegboard tests and blood-sampling for biomarker analysis were performed before and after the intervention., Results: Compared to placebo the selected memory and motor test scores were un-affected by the bilberry/red grape intervention. However, the plasma levels of tissue damage biomarkers decreased significantly more in the bilberry/red grape group. In particular lactate dehydrogenase (LDH) decreased from 362 U/L (median, baseline) to 346 U/L (median, post intervention) in the bilberry/red grape group. Also, several biomarkers of inflammation (EGF, IL6, IL9, IL10 and TNFα) decreased significantly more in the bilberry/red grape group. Furthermore, several plasma polyphenols; p-coumaric acid, hippuric acid, protocatechuic acid, 3HPAA and vanillic acid, increased significantly more in the bilberry/red grape group compared to placebo with the largest increase in p-coumaric acid with 116%; from 2.2 [1.0,5.5] to 4.7 [2.8,8.1] μM/L (median [95% CL])., Conclusions: The results indicate that a nine-week bilberry/red grape juice intervention has no measurable effects on the selected memory scores in aged men experiencing memory problems but decreases the level of biomarkers of inflammation and tissue damage. Whether the dampening effects on inflammation and tissue damage biomarkers have relevance for neuroinflammatory brain pathology remains to be established., Trial Registration: Registration number ( ClinicalTrials.gov : NCT00972972 ), September 9, 2009., (© 2021. The Author(s).)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) increases morbidity and mortality. However, patients in biopsy-based cohorts are highly selected and the absolute risks of liver- and non-liver outcomes in NAFLD in population remains undefined. We analysed both liver-related and non-liver-related outcomes in Finnish population cohorts of NAFLD., Methods: We included 10 993 individuals (6707 men, mean age 53.3 ± 12.6 years) with NAFLD (fatty liver index ≥60) from the Finnish population-based FINRISK and Health 2000 studies. Liver fibrosis was assessed by the dAAR score, and genetic risk by a recent polygenic risk score (PRS-5). Incident liver-related outcomes, cardiovascular disease (CVD), cancer and chronic kidney disease (CKD) were identified through linkage with national registries., Results: Mean follow-up was 12.1 years (1128 069 person-years). The crude incidence rate of liver-related outcomes in NAFLD was 0.97/1000 person-years. The cumulative incidence increased with age, being respectively 2.4% and 1.5% at 20 years in men and women aged 60 years at baseline, while the relative risks for CVD and cancer were 9-16 times higher. The risk of CKD exceeded that of liver outcomes at a baseline age around 50 years. 20-year cumulative incidence of liver-related outcomes was 4.3% in the high, and 1.5% in the low PRS-5 group. The dAAR score associated with liver outcomes, but not with extra-hepatic outcomes., Conclusion: The absolute risk of liver-related outcomes in NAFLD is low, with much higher risk of CVD and cancer, emphasizing the need for more individualized and holistic risk-stratification in NAFLD., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)

Adequate iron supply in pregnancy is important for both the woman and the fetus, but iron status is often assessed late in first trimester, if assessed at all. Therefore, identification of factors associated with iron status is important to target vulnerable groups with increased risk of deficiency. Our objectives were to (1) describe iron status in mid-pregnancy and (2) identify sociodemographic and lifestyle predictors of pregnancy iron status. This cross-sectional study uses data from The Norwegian Mother, Father and Child Cohort Study (collected 2002-2008) and The Medical Birth Registry of Norway. Iron status was measured as non-fasting plasma ferritin (P-Fe) and transferrin in gestational week (GW) 18 (n 2990), and by lowest reported Hb in GW 0-30 (n 39 322). We explored predictors of iron status with elastic net, linear and log-binomial regression models. Median P-Fe was 33 μg/l, and 14 % had depleted iron stores (P-Fe <15 μg/l). P-Fe below 30 μg/l was associated with reduced Hb. We identified eleven predictors, with interpregnancy interval (IPI) and parity among the most important. Depleted iron stores was more common among women with IPI < 6 months (56 %) and 6-11 months (33 %) than among those with IPI 24-59 months (19 %) and among nulliparous women (5 %). Positively associated factors with iron status included hormonal contraceptives, age, BMI, smoking, meat consumption and multi-supplement use. Our results highlight the importance of ferritin measurements in women of childbearing age, especially among women not using hormonal contraceptives and women with previous and recent childbirths.

Purpose of Review: To describe the INTERASPIRE scientific protocol-an international survey of secondary prevention of coronary heart disease (CHD)., Recent Findings: This international survey is being conducted through National Societies of Cardiology in selected countries from each of the six WHO regions and has the following overall aims: (i) describe prevalence of cardiometabolic and renal risk factors together with biomarkers in CHD patients; (ii) describe current risk factor management through lifestyle changes and cardioprotective drug therapies; (iii) provide an objective assessment of clinical implementation of preventive care by comparison with the lifestyle and risk factor targets defined in international and national guidelines; (iv) investigate the reasons for variation in preventive cardiology practice between regions and countries; and (v) promote the principles of best preventive cardiology practice. This international survey will provide a unique picture of CHD patients; their cardiometabolic, renal and biomarker status; lifestyle and therapeutic management; and the quality of preventive care provided in all WHO regions., (© 2021. The Author(s).)

Objectives: An observed variation in the risk of celiac disease, according to the season of birth, suggests that vitamin D may affect the development of the disease. The aim of this study was to investigate if vitamin D concentration is associated with the risk of celiac disease autoimmunity (CDA) in genetically at-risk children. Study Design: Children prospectively followed in the multinational The Environmental Determinants of Diabetes in the Young study, conducted at six centers in Europe and the US, were selected for a 1-to-3 nested case-control study. In total, 281 case-control sets were identified. CDA was defined as positivity for tissue transglutaminase autoantibodies (tTGA) on two or more consecutive visits. Vitamin D was measured as 25-hydroxyvitamin D [25(OH)D] concentrations in all plasma samples prior to, and including, the first tTGA positive visit. Conditional logistic regression was used to examine the association between 25(OH)D and risk of CDA. Results: No significant association was seen between 25(OH)D concentrations (per 5 nmol/L increase) and risk for CDA development during early infancy (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.95-1.04) or childhood (OR 1.02, 95% CI 0.97-1.07). When categorizing 25(OH)D concentrations, there was an increased risk of CDA with 25(OH)D concentrations <30 nmol/L (OR 2.23, 95% CI 1.29, 3.84) and >75 nmol/L (OR 2.10, 95% CI 1.28-3.44) in early infancy, as compared with 50-75 nmol/L. Conclusion: This study indicates that 25(OH)D concentrations <30 nmol/L and >75 nmol/L during early infancy were associated with an increased risk of developing CDA in genetically at-risk children. The non-linear relationship raises the need for more studies on the possible role of 25(OH)D in the relation to celiac disease onset., 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 © 2021 Andrén Aronsson, Liu, Norris, Uusitalo, Butterworth, Koletzko, Virtanen, Erlund, Kurppa, Hagopian, Rewers, She, Toppari, Ziegler, Akolkar, Krischer and Agardh.)

Background: Circulating fatty acids have been linked to development of type 1 diabetes., Objectives: To study the prospective associations of serum fatty acids with the risk of islet autoimmunity in high-risk children., Methods: A nested case-control selection was carried out within the TRIGR cohort, which included infants with HLA (DQB1 or DQA1)-conferred disease susceptibility and a first-degree relative with type 1 diabetes, born between 2002 and 2007 in 15 countries and followed-up until 2017. The present study included 244 case children positive for at least two islet autoantibodies (ICA, IAA, GADA, and IA-2A) and two control children were matched for country and age. Proportions of 26 serum fatty acids at cord blood and at 6, 12, and 18 months of age were assessed using gas-chromatography., Results: The average proportions of the following fatty acids were associated with an increased risk of islet autoimmunity, adjusted for sex, HLA risk, and maternal type 1 diabetes: pentadecanoic acid (15:0) (OR 3.41: 95% CI 1.70, 6.85), heptadecanoic acid (iso 17:0) (2.64: 1.62, 4.28) and (anteiso 17:0) (2.27: 1.39, 3.70), stearic acid (18:0) (23.8: 2.32, 244.6), and conjugated linoleic acid (18:2n-7) (2.60: 1.47, 4.59). Breastfeeding and not having maternal type 1 diabetes were positively associated with levels of the above-mentioned fatty acids. N-3 fatty acids were not consistently associated with islet autoimmunity., Conclusions: We found direct associations of pentadecanoic acid, heptadecanoic acid, stearic acid, and conjugated linoleic acid with the risk of islet autoimmunity. Further studies are needed to understand the complex role of fatty acids in the development of type 1 diabetes., (© 2021 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n - 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity.