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Background: Few studies have examined the associations of trimethylamine-N-oxide (TMAO) and its precursors (choline, betaine, dimethylglycine, and L-carnitine) with the risk of atrial fibrillation (AF) and heart failure (HF). This study sought to investigate these associations., Methods: Prospective associations of these metabolites with incident AF and HF were examined among participants at high cardiovascular risk in the PREDIMED study (PREvención con DIeta MEDiterránea) after follow-up for about 10 years. Two nested case-control studies were conducted, including 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma levels of TMAO and its precursors were semi-quantitatively profiled with liquid chromatography tandem mass spectrometry. Odds ratios were estimated with multivariable conditional logistic regression models., Results: After adjustment for classical risk factors and accounting for multiple testing, participants in the highest quartile vs. the lowest quartile of baseline choline and betaine levels had a higher risk of AF [OR (95% CI): 1.85 (1.30-2.63) and 1.57 (1.09-2.24), respectively]. The corresponding OR for AF for extreme quartiles of dimethylglycine was 1.39 (0.99-1.96). One SD increase in log-transformed dimethylglycine was positively associated with AF risk (OR, 1.17; 1.03-1.33). The corresponding ORs for HF for extreme quartiles of choline, betaine, and dimethylglycine were 2.51 (1.57-4.03), 1.65 (1.00-2.71) and 1.65 (1.04-2.61), respectively. TMAO and L-carnitine levels were not associated with AF or HF., Conclusions: Our findings support the role of the choline metabolic pathway in the pathogenesis of AF and HF., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: The potential associations between acylcarnitine profiles and incidence of type 2 diabetes (T2D) and whether acylcarnitines can be used to improve diabetes prediction remain unclear., Objective: To evaluate the associations between baseline and 1-year changes in acylcarnitines and their diabetes predictive ability beyond traditional risk factors., Design, Setting, and Participants: We designed a case-cohort study within the PREDIMED Study including all incident cases of T2D (n = 251) and 694 randomly selected participants at baseline (follow-up, 3.8 years). Plasma acylcarnitines were measured using a targeted approach by liquid chromatography-tandem mass spectrometry. We tested the associations between baseline and 1-year changes in individual acylcarnitines and T2D risk using weighted Cox regression models. We used elastic net regressions to select acylcarnitines for T2D prediction and compute a weighted score using a cross-validation approach., Results: An acylcarnitine profile, especially including short- and long-chain acylcarnitines, was significantly associated with a higher risk of T2D independent of traditional risk factors. The relative risks of T2D per SD increment of the predictive model scores were 4.03 (95% CI, 3.00 to 5.42; P < 0.001) for the conventional model and 4.85 (95% CI, 3.65 to 6.45; P < 0.001) for the model including acylcarnitines, with a hazard ratio of 1.33 (95% CI, 1.08 to 1.63; P < 0.001) attributed to the acylcarnitines. Including the acylcarnitines into the model did not significantly improve the area under the receiver operator characteristic curve (0.86 to 0.88, P = 0.61). A 1-year increase in C4OH-carnitine was associated with higher risk of T2D [per SD increment, 1.44 (1.03 to 2.01)]., Conclusions: An acylcarnitine profile, mainly including short- and long-chain acylcarnitines, was significantly associated with higher T2D risk in participants at high cardiovascular risk. The inclusion of acylcarnitines into the model did not significantly improve the T2D prediction C-statistics beyond traditional risk factors, including fasting glucose., (Copyright © 2019 Endocrine Society.)

Study Objectives: To investigate the associations of circulating metabolites with sleep duration and sleep variability. We also assessed the ability of metabolites to discriminate between sleep duration and sleep variability categories., Methods: Cross-sectional analyses were performed on baseline data from 205 participants with overweight/obesity in the "Satiety Innovation" (SATIN) study. A targeted metabolite profiling (n = 159 metabolites) approach was applied using three different platforms (nuclear magnetic resonance, liquid chromatography coupled to mass spectrometry, and gas chromatography coupled to mass spectrometry). Associations between circulating metabolite concentrations and accelerometer-derived sleep duration and variability in sleep duration were assessed using elastic-net regression analysis. Ten-fold cross-validation was used to estimate the discriminative accuracy of metabolites for sleep duration and sleep variability categories., Results: A metabolite profile, including acyl-carnitines (C11:0/C5:1-DC/iso-C11:0, 2-M-C4:1/3-M-C4:1, C4:0), sphingomyelins (42:1, 33:1), glycerol, stearic acid, 2- and 3- hydroxyl-butyric acid, docosahexaenoic acid, serotonin, and phosphatidylcholine (34:2), was significantly associated with high sleep duration (4th plus 5th quintile). Ten metabolites, including acyl-carnitines (C18:1, C7:0, C6-OH), phosphatidylcholine (40:6, 37:4, 42:5), lyso-phosphatidylcholine (20:1), sucrose, glutamic acid, and triacylglycerol (52:4), were significantly associated with high sleep variability (4th plus 5th quintile). The area under the curve was 0.69 (95% CI: 0.62-0.75) and 0.63 (95% CI: 0.53-0.72) in the multimetabolite score for high sleep duration and sleep variability, respectively. The variance in sleep duration explained by metabolites was 7%. No metabolites were selected for prediction of sleep variability (continuous)., Conclusions: A small set of metabolites within distinct biochemical pathways were associated with high sleep duration and sleep variability. These metabolites appeared to moderately discriminate sleep duration and sleep variability categories., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Study Objectives: To examine independent and combined associations of sleep duration and sleep variability with body composition, obesity and type 2 diabetes (T2D) in elders at high cardiovascular risk., Methods: Cross-sectional analysis of 1986 community-dwelling elders with overweight/obesity and metabolic syndrome from PREDIMED-Plus trial. Associations of accelerometry-derived sleep duration and sleep variability with body mass index (BMI), waist circumference (WC) and body composition were assessed fitting multivariable-adjusted linear regression models. Prevalence ratios (PR) and 95% confidence intervals (CI) for obesity and T2D were obtained using multivariable-adjusted Cox regression with constant time. "Bad sleepers" (age-specific non-recommended sleep duration plus sleep variability above the median) and "good sleepers" (age-specific recommended sleep duration plus sleep variability below the median) were characterized by combining sleep duration and sleep variability, and their associations with these outcomes were examined., Results: One hour/night increment in sleep duration was inversely associated with BMI (β -0.38 kg/m2 [95% CI -0.54, -0.23]), WC (β -0.86 cm [95% CI -1.25, -0.47]), obesity (PR 0.96 [95% CI 0.93, 0.98]), T2D (PR 0.93 [95% CI 0.88, 0.98]) and other DXA-derived adiposity-related measurements (android fat and trunk fat, all p < .05). Each 1-hour increment in sleep variability was positively associated with T2D (PR 1.14 [95% CI 1.01, 1.28]). Compared with "good sleepers," "bad sleepers" were positively associated with obesity (PR 1.12 [95% CI 1.01, 1.24]) and T2D (PR 1.62 [95% CI 1.28, 2.06])., Conclusions: This study revealed cross-sectional associations of sleep duration with adiposity parameters and obesity. Sleep duration and sleep variability were associated with T2D. Considering simultaneously sleep duration and sleep variability could have additional value, particularly for T2D, as they may act synergistically.

Background: Metabolites of the tryptophan-kynurenine pathway (i.e., tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxyanthranilic) may be associated with diabetes development. Using a case-cohort design nested in the Prevención con Dieta Mediterránea (PREDIMED) study, we studied the associations of baseline and 1-year changes of these metabolites with incident type 2 diabetes (T2D)., Methods: Plasma metabolite concentrations were quantified via LC-MS for n = 641 in a randomly selected subcohort and 251 incident cases diagnosed during 3.8 years of median follow-up. Weighted Cox models adjusted for age, sex, body mass index, and other T2D risk factors were used., Results: Baseline tryptophan was associated with higher risk of incident T2D (hazard ratio = 1.29; 95% CI, 1.04-1.61 per SD). Positive changes in quinolinic acid from baseline to 1 year were associated with a higher risk of T2D (hazard ratio = 1.39; 95% CI, 1.09-1.77 per SD). Baseline tryptophan and kynurenic acid were directly associated with changes in homeostatic model assessment for insulin resistance (HOMA-IR) from baseline to 1 year. Concurrent changes in kynurenine, quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine/tryptophan ratio were associated with baseline-to-1-year changes in HOMA-IR., Conclusions: Baseline tryptophan and 1-year increases in quinolinic acid were positively associated with incident T2D. Baseline and 1-year changes in tryptophan metabolites predicted changes in HOMA-IR. Tryptophan levels may initially increase and then deplete as diabetes progresses in severity., (© 2018 American Association for Clinical Chemistry.)

Methotrexate (MTX) is a dihydrofolate reductase inhibitor that is used for the treatment of tumors and autoimmune diseases. Several automated binding assays are used in clinical practice and numerous chromatographic methods have been developed toward higher specificity and sensitivity. In the present study, phenyl cartridges were used for the solid-phase extraction (SPE) of MTX from human serum samples; subsequently, extracts were analyzed by reversed-phase high-performance liquid chromatography. Isocratic separation was implemented on a Kromasil-C18 column with a mobile phase consisting of 50 mM sodium acetate buffer (pH 3.6)-acetonitrile (89:11, v/v) and ultraviolet detection at 307 nm. MTX eluted in less than 12 min with no interference from impurities or 24 examined drugs. Detector response was linear in the range of 0.025-5.00 µΜ (coefficient of correlation > 0.99). Recovery from the serum was 93.1-98.2% and bias was < 8.3%. Intra-day and inter-day precision were <7.8 and 12.6%, respectively (n = 6). The limit of quantitation was 0.01 µM and the limit of detection was 0.003 µΜ. The method was validated by using serum samples from osteosarcoma patients treated with high-dose MTX (8-12 g/m(2)). In conclusion, the combined use of a phenyl-functionalized sorbent for SPE and a Kromasil-C18 column, and specific detection at 307 nm, assured a selective, fast, robust and cost-effective method for the monitoring of MTX in osteosarcoma patients under high-dose MTX treatment, thus contributing to more efficient treatment., (© The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In Palestine, there is a little information about nutrition of adolescents compared to other age groups. This study was designed to assess the nutritional status of Palestinian school-aged children (11-16 years) in East Jerusalem during 2002-03. A school-based cross-sectional study targeted randomly 313 adolescents from public and private schools. A previously validated and reliable questionnaire was administered through interviews that included anthropometric and hemoglobin measurements, 24-h dietary intake recall and physical activity questionnaire. It was found that being overweight (24.3%) or obese (9.9%) coexisted with being underweight (4.8%) and/or anemic (23.3%). Only 22.4% of the study subject had physical activity for ≥5 days a week with boys being more physically active than girls (p < 0.01). Inadequate energy intake had 55.66% of boys and 64.81% of girls; inadequate protein intake was reported by 15.07% of boys and 43.08% of girls. The majority of them met <80% of the recommended daily allowances for most micronutrients. The whole sample and especially boys consumed more total, saturated fat, less monounsaturated fat and carbohydrates than what is advised. Obese and overweight adolescents had lower energy intake (p < 0.05) and a lower trend in being physically active than normal weight counterparts. School health education programs targeted at adolescents and parents need to be developed as part of overweight-obesity, malnutrition and anemia prevention.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the burden of this devastating cancer is expected to increase further in coming years. The collection and analysis of epidemiologic HCC data will play a critical role in guiding future disease prevention strategies and optimizing patient management. Previous epidemiologic studies have highlighted striking global variations in the incidence of HCC, which is particularly high in much of east Asia and sub-Saharan Africa, and lower, but on the increase, in North America and most of Europe. This variation appears to be related to the complex etiology of HCC, with different risk factors, primarily infection with hepatitis B or hepatitis C virus, responsible for driving HCC incidence rates in different regions. Although previous studies have contributed considerably to the knowledge of HCC epidemiology, there are limitations associated with the currently available data, which arise from studies performed at different times in the past, using varying methodologies, and with diverse patient populations. A new and global approach to the study of HCC epidemiology is required if HCC disease prevention and treatment strategies are to be adequately directed and supported in coming years.