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Risk assessment of nutrients: There must be a threshold for their effects.
Löwik, MR, Astrup, A, Boobis, AR, Calder, PC, Daniel, H, Rietjens, IM, Sievenpiper, JL, Verhagen, H
Regulatory toxicology and pharmacology : RTP. 2024;:105539
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Abstract
Nutrients serve physiological functions in a dose-dependent manner and that needs to be recognized in risk assessment. An example of the consequences of not properly considering this can be seen in a recent assessment by the European Food Safety Authority (EFSA). EFSA concluded in 2022 that the intake of added and free sugars should be "as low as possible in the context of a nutritionally adequate diet". That conclusion of EFSA is based on the effects on two surrogate endpoints for an adverse effect found in randomized controlled trials with high sugars intake levels: fasting glucose and fasting triglycerides. The lowest intake levels in these trials were around 10 energy% and at this intake level there were no adverse effects on the two outcomes. This indicates that the adverse effects of sugars have an observable threshold value for these two endpoints. The most appropriate interpretation from the vast amount of data is that currently no definitive conclusion can be drawn on the tolerable upper intake level for dietary sugars. Therefore, EFSA's own guidance would lead to the conclusion that the available data do not allow the setting of an upper limit for added sugars and hence, that more robust data are required to identify the threshold value for intake of sugars.
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ADHD medication discontinuation and persistence across the lifespan: a retrospective observational study using population-based databases.
Brikell, I, Yao, H, Li, L, Astrup, A, Gao, L, Gillies, MB, Xie, T, Zhang-James, Y, Dalsgaard, S, Engeland, A, et al
The lancet. Psychiatry. 2024;(1):16-26
Abstract
BACKGROUND Although often intended for long-term treatment, discontinuation of medication for ADHD is common. However, cross-national estimates of discontinuation are missing due to the absence of standardised measures. The aim of this study was to determine the rate of ADHD treatment discontinuation across the lifespan and to describe similarities and differences across countries to guide clinical practice. METHODS We did a retrospective, observational study using population-based databases from eight countries and one Special Administrative Region (Australia, Denmark, Hong Kong, Iceland, the Netherlands, Norway, Sweden, the UK, and the USA). We used a common analytical protocol approach and extracted prescription data to identify new users of ADHD medication. Eligible individuals were aged 3 years or older who had initiated ADHD medication between 2010 and 2020. We estimated treatment discontinuation and persistence in the 5 years after treatment initiation, stratified by age at initiation (children [age 4-11 years], adolescents [age 12-17 years], young adults [age 18-24 years], and adults [age ≥25 years]) and sex. Ethnicity data were not available. FINDINGS 1 229 972 individuals (735 503 [60%] males, 494 469 females [40%]; median age 8-21 years) were included in the study. Across countries, treatment discontinuation 1-5 years after initiation was lowest in children, and highest in young adults and adolescents. Within 1 year of initiation, 65% (95% CI 60-70) of children, 47% (43-51) of adolescents, 39% (36-42) of young adults, and 48% (44-52) of adults remained on treatment. The proportion of patients discontinuing was highest between age 18 and 19 years. Treatment persistence for up to 5 years was higher across countries when accounting for reinitiation of medication; at 5 years of follow-up, 50-60% of children and 30-40% of adolescents and adults were covered by treatment in most countries. Patterns were similar across sex. INTERPRETATION Early medication discontinuation is prevalent in ADHD treatment, particularly among young adults. Although reinitiation of medication is common, treatment persistence in adolescents and young adults is lower than expected based on previous estimates of ADHD symptom persistence in these age groups. This study highlights the scope of medication treatment discontinuation and persistence in ADHD across the lifespan and provides new knowledge about long-term ADHD medication use. FUNDING European Union Horizon 2020 Research and Innovation Programme.
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Predicting weight loss success on a new Nordic diet: an untargeted multi-platform metabolomics and machine learning approach.
Pigsborg, K, Stentoft-Larsen, V, Demharter, S, Aldubayan, MA, Trimigno, A, Khakimov, B, Engelsen, SB, Astrup, A, Hjorth, MF, Dragsted, LO, et al
Frontiers in nutrition. 2023;:1191944
Abstract
BACKGROUND AND AIM Results from randomized controlled trials indicate that no single diet performs better than other for all people living with obesity. Regardless of the diet plan, there is always large inter-individual variability in weight changes, with some individuals losing weight and some not losing or even gaining weight. This raises the possibility that, for different individuals, the optimal diet for successful weight loss may differ. The current study utilized machine learning to build a predictive model for successful weight loss in subjects with overweight or obesity on a New Nordic Diet (NND). METHODS Ninety-one subjects consumed an NND ad libitum for 26 weeks. Based on their weight loss, individuals were classified as responders (weight loss ≥5%, n = 46) or non-responders (weight loss <2%, n = 24). We used clinical baseline data combined with baseline urine and plasma untargeted metabolomics data from two different analytical platforms, resulting in a data set including 2,766 features, and employed symbolic regression (QLattice) to develop a predictive model for weight loss success. RESULTS There were no differences in clinical parameters at baseline between responders and non-responders, except age (47 ± 13 vs. 39 ± 11 years, respectively, p = 0.009). The final predictive model for weight loss contained adipic acid and argininic acid from urine (both metabolites were found at lower levels in responders) and generalized from the training (AUC 0.88) to the test set (AUC 0.81). Responders were also able to maintain a weight loss of 4.3% in a 12 month follow-up period. CONCLUSION We identified a model containing two metabolites that were able to predict the likelihood of achieving a clinically significant weight loss on an ad libitum NND. This work demonstrates that models based on an untargeted multi-platform metabolomics approach can be used to optimize precision dietary treatment for obesity.
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The New Nordic Renal Diet Induces a Pronounced Reduction of Urine Acid Excretion and Uremic Toxins in Chronic Kidney Disease Patients (Stage 3 and 4).
Hansen, NM, Berg, P, Rix, M, Pareek, M, Leipziger, J, Kamper, AL, Astrup, A, Vaarby Sorensen, M, Salomo, L
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2023;(3):412-419
Abstract
OBJECTIVE Metabolic acidosis and the uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with increased risks of kidney disease progression, muscle catabolism, cardiovascular disease, and mortality in patients with chronic kidney disease (CKD). The New Nordic Renal Diet (NNRD) is a plant-focused meal pattern, with reduced phosphorus and protein content compared to an average Danish diet. Due to a higher amount of plant-based products, we hypothesized that NNRD would reduce renal excretion of acids and uremic toxins. Thus, we evaluated the effects of NNRD on metabolic acidosis and uremic toxins in patients with moderate CKD, stages 3-4. DESIGN AND METHODS This post hoc analysis is based on a randomized controlled crossover trial comparing 1 week of the NNRD to a control 1-week period of an average Danish diet, in patients with CKD stages 3 and 4. Urine pH and urine excretion of bicarbonate, ammonium, titratable acids, IS, and PCS alongside plasma total CO2 (tCO2) were measured at days 1, 4, and 7 in 18 patients. RESULTS After 7 days on NNRD 24-hour urine net acid excretion was decreased by 80% (P < .001), 24-hour urine excretion of ammonium and bicarbonate decreased by 34% (P < .001), and increased by 678% (P < .001), respectively, compared with the control period. Plasma tCO2 was increased by 8% (P = .005). Moreover, 24-hour urine excretion of PCS and IS were reduced by 31% (P = .018) and 29% (P < .001), respectively. CONCLUSION One week of NNRD in patients suffering from moderate CKD effectively improved metabolic acidosis with a marked reduction in urine net acid excretion that included a large increase in urine bicarbonate excretion. In addition, NNRD reduced urinary excretion of the uremic toxins PCS and IS. These results encourage further investigations of the long-term effects of NNRD on renal protection in patients with CKD.
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Harnessing the Magic of the Dairy Matrix for Next-Level Health Solutions: A Summary of a Symposium Presented at Nutrition 2022.
Unger, AL, Astrup, A, Feeney, EL, Holscher, HD, Gerstein, DE, Torres-Gonzalez, M, Brown, K
Current developments in nutrition. 2023;(7):100105
Abstract
An emerging body of scientific evidence demonstrates that the food matrix-the interaction among nutrients, bioactive components, and physical structure of a food-can affect health in significant, unexpected ways beyond its individual nutrients. In particular, research suggests that consumption of dairy foods such as milk, yogurt, and cheese may affect human health in a matrix-dependent fashion. To disseminate and discuss the growing body of evidence surrounding the role of the dairy food matrix on cardiometabolic health, 3 expert researchers on the topic of the food matrix shared the latest science in a session entitled "Next-Level Health Solutions: The Magic of the Matrix" at the American Society for Nutrition's 2022 LIVE ONLINE Conference. This article is a summary of the literature presented and discussed during that session. A substantial body of literature demonstrates that full-fat dairy foods, particularly fermented dairy foods, may beneficially modulate cardiometabolic outcomes depending on an individual's health status. These findings have important implications for current authoritative dietary guidance that recommends the consumption of low-fat or fat-free dairy foods. Furthermore, this evidence may inform practical applications of harnessing dairy's unique profile of bioactives for health promotion and disease prevention at the individual and community levels.
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An integrated single cell and spatial transcriptomic map of human white adipose tissue.
Massier, L, Jalkanen, J, Elmastas, M, Zhong, J, Wang, T, Nono Nankam, PA, Frendo-Cumbo, S, Bäckdahl, J, Subramanian, N, Sekine, T, et al
Nature communications. 2023;(1):1438
Abstract
To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states.
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Health effects of the New Nordic Renal Diet in patients with stage 3 and 4 chronic kidney disease, compared with habitual diet: a randomized trial.
Misella Hansen, N, Kamper, AL, Rix, M, Feldt-Rasmussen, B, Leipziger, J, Sørensen, MV, Berg, P, Astrup, A, Salomo, L
The American journal of clinical nutrition. 2023;(5):1042-1054
Abstract
BACKGROUND Chronic kidney disease (CKD) leads to an accumulation of waste products and causes adverse cardiometabolic effects. OBJECTIVES We investigated the health effects of the New Nordic Renal Diet (NNRD), a novel meal pattern reduced in phosphorus, protein, and sodium. METHODS A 26-wk randomized trial compared the NNRD with a habitual diet. The NNRD group received weekly home deliveries of food and recipes. Monthly study visits included fasting blood samples, 24-h urine samples, blood pressure, and anthropometric measurements. Intention-to-treat analysis used linear mixed-effects models. RESULTS Sixty patients, mean estimated glomerular filtration rate (eGFR) 34 mL/min/1.73 m2 and body mass index of 25-27 kg/m2, were included and 58 completed. Metabolic syndrome was present in 53% (NNRD group) and 57% (control group). The NNRD group (n = 30) reduced their 24-h urine phosphorus excretion by 19% (-153 mg; 95% confidence interval [CI]: -210, -95), control group (n = 30) (no change), between-group difference -171 mg (95% CI: -233, -109; P < 0.001). Proteinuria was reduced by 39% in the NNRD group (-0.33 g/d; 95% CI: -0.47, -0.18), control group (no change), between-group difference -0.34 g/d (95% CI: -0.52, -0.17; P < 0.001). Plasma urea was reduced by -1.5 mmol/L in the NNRD group (95% CI: -2.1, -0.9), control group (no change), between-group difference -1.4 mmol/L (95% CI: -2.0, -0.7; P < 0.001). Systolic blood pressure fell by -5.2 mmHg in the NNRD group (95% CI: -8.4, -2.1), control group (no change), between-group difference -3.9 mmHg (95% CI; -7.6, -0.2; P = 0.04). The NNRD group lost -1.7 kg (95% CI: -2.6, -0.8), control group (no change), between-group difference -2.0 kg (95% CI: -3.0, -1.0; P < 0.001). There were no effects on eGFR during the 26-wk intervention. CONCLUSION NNRD in moderate CKD reduces phosphorus excretion, proteinuria, systolic blood pressure, and weight, mainly by reducing abdominal fat. This trial was registered at clinicaltrials.gov as NCT04579315.
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Prevention and management of obesity in a lifetime perspective.
Hjorth, MF, Helbo, AS, Astrup, A
Danish medical journal. 2023;(7)
Abstract
The prevalence of obesity is increasing across all geographies. Obesity develops due to a disruption of the energy balance regulation. However, the cause is not well understood. Identification of causal factors that may be modified is crucial to reduce the prevalence of obesity. However, the interventions needed will likely differ between life stages. Hence, obesity research should span from pre-conception to adulthood. In this review, we point to gaps and limitations in existing research, highlight recently initiated studies from which we are awaiting results and point to future directions.
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Gestational weight gain in women with pre-pregnancy overweight or obesity and anthropometry of infants at birth.
Mogensen, CS, Zingenberg, H, Svare, J, Astrup, A, Magkos, F, Geiker, NRW
Frontiers in pediatrics. 2023;:1142920
Abstract
OBJECTIVE To examine the association of gestational weight gain (GWG) among women with pre-pregnancy overweight or obesity with infant weight and BMI z-score at birth. METHODS This study is a secondary analysis of a randomized controlled trial including data from 208 infants at birth born by mothers with pre-pregnancy BMI between 28 and 45 kg/m2 who completed the APPROACH study (randomized to a high-protein low-glycemic index diet or a moderate-protein moderate-glycemic index diet). This analysis pooled the two diet treatment groups together and data were analyzed using a linear mixed model. RESULTS Limiting GWG by 1 kg was associated with lower birthweight (-16 g, P = 0.003), BMI z-score (-0.03SD, P = 0.019), weight z-score (-0.03SD, P = 0.004), and infant abdominal circumference (-0.06 cm, P = 0.039). Infants born by mothers whose GWG was ≤9 kg weighed less (122 g, 95% CI: 6-249, P = 0.040), had similar BMI z-score (0.2SD, 95% CI: -0.06 to 0.55, P = 0.120), and lower incidence of emergency cesarean deliveries (11.5% vs. 23.1%, P = 0.044) compared to infants born by mothers whose GWG was >9 kg. When women were classified into GWG quartiles, women in Q1 (GWG range: -7.0 to 3.2 kg) gave birth to smaller infants (3,420 g, P = 0.015) with lower BMI z-score (-0.5SD, P = 0.041) than women in Q2 (3.3-7.1 kg), Q3 (7.2-10.9 kg) and Q4 (11.1-30.2 kg). CONCLUSIONS Limiting GWG among women with pre-pregnancy overweight or obesity was associated with lower infant weight, BMI z-score, weight z-score, and abdominal circumference at birth. Moreover, GWG below the Institute of Medicine guideline of a maximum of 9 kg was associated with lower birthweight and fewer emergency cesarean deliveries.
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A high-protein low-glycemic index diet attenuates gestational weight gain in pregnant women with obesity: the "An optimized programming of healthy children" (APPROACH) randomized controlled trial.
Geiker, NRW, Magkos, F, Zingenberg, H, Svare, J, Chabanova, E, Thomsen, HS, Ritz, C, Astrup, A
The American journal of clinical nutrition. 2022;(3):970-979
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Abstract
BACKGROUND Prepregnancy overweight and excessive gestational weight gain (GWG) increase the risk of complications and offspring obesity. OBJECTIVES We aimed to investigate the effect of a high-protein low-glycemic index (HPLGI) diet on GWG, birth weight, and risk of gestational complications in pregnant women with obesity. METHODS A total of 279 women with prepregnancy overweight or obesity (BMI: 28-45 kg/m2), between 18 and 45 y old, and in their late first trimester with singleton pregnancies, were randomly assigned to 1 of 2 ad libitum diets: a high-protein low-glycemic index diet (HPLGI 25%-28% of energy from protein and glycemic index ≤ 55) and a moderate-protein moderate-glycemic index diet (MPMGI 15%-18% of energy from protein and glycemic index ∼60). Diets were consumed from gestational week 15 and throughout pregnancy. Participants received dietary guidance by a clinical dietician 9 times to facilitate adherence. RESULTS Out of 141 and 138 women randomly assigned to the HPLGI and MPMGI diets, 105 and 104 completed the intervention, respectively (75%). In the available case analyses, GWG was 6.8 ± 1.3 kg among women assigned the HPLGI diet and this was significantly lower, by -1.7 kg (95% CI: -2.8, -0.5 kg; P = 0.004), than the GWG of 8.5 ± 1.3 kg among women assigned the MPMGI diet. There were no significant differences between diets on major neonatal outcomes (birth weight and other anthropometric measures). The incidence of composite pregnancy complications was lower for the HPLGI than for the MPMGI diet (35.4% compared with 53.7%, respectively; P = 0.009), including cesarean delivery (15.4% compared with 28.8%, respectively; P = 0.03). There were no reported maternal, fetal, or neonatal deaths. Incidence of miscarriages (1%-2%) did not differ between groups. CONCLUSIONS A moderate increase in dietary protein in conjunction with a reduction in glycemic index during the last 2 trimesters of pregnancy reduced GWG and limited complications and cesarean deliveries among women with overweight or obesity.