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Background The consumption of 2 g/d plant sterols (PS) reduces circulating low-density lipoprotein cholesterol (LDL-C) up to 10%. The degree of LDL-C lowering was associated with specific apolipoprotein E (APOE, rs429358) and cholesterol 7α-hydroxylase (CYP7A1, rs3808607) genosets in previous post hoc analyses of randomized controlled trials. However, since post-hoc analyses do not conform to the randomization model, there is a greater potential that the findings may be due to type I error, thus warranting validation through an a priori-designed intervention trial. Objective The GenePredict Plant Sterol study (GPS) was designed to validate associations of LDL-C lowering with specific APOE and CYP7A1 genosets through a priori recruitment of individuals carrying pre-specified genosets. Methods A two center, double-blind, placebo-controlled, randomized two-period crossover dietary intervention with 2 g/d of PS for 28 days with a minimum 28 day washout was undertaken from July 2017 to December 2019. A priori recruitment of individuals with slightly elevated LDL-C was based on genosets of APOE isoforms and CYP7A1 rs3808607. Randomization was performed with stratification by sex and genoset. Results The recruitment target of 64 participants with pre-specified genosets could not be reached, despite the screening of 477 individuals; 42 participants completed the intervention trial. Reductions in LDL-C were similar across all three genosets (-0.298 ±0.164, -0.357 ±0.115, -0.293 ±0.109 mmol/L, P = 0.0002 overall, P = 0.9126 for treatment*genoset), providing evidence that the shortfall in recruitment may not have stopped the trial from meeting the objective. Conclusions APOE and CYP7A1 genotypes did not influence the efficacy of LDL-C reductions upon dietary intervention with PS. Findings of previous post-hoc analyses could not be validated in a trial using a priori genotype-based recruitment. Obtaining adequate numbers of participants is challenging in trials using genoset-based recruitment, even for common variants.Trial Registration: Clinical Trials #NCT02765516 https://clinicaltrials.gov/ct2/show/NCT02765516.

Background Chronic kidney disease (CKD) is associated with a reduced quality of life and an increased risk of kidney failure, cardiovascular events, and all-cause mortality. Accumulation of nitrogen-based uremic toxins leads to worsening of symptoms in individuals with CKD. Many uremic toxins, such as indoxyl and p-cresol sulphate, are produced exclusively by the gut microbiome through the proteolytic digestion of aromatic amino acids. Strategies to reduce the production of these toxins by the gut microbiome in individuals with CKD may lessen symptom burden and delay the onset of dialysis. One such strategy is to change the overall metabolism of the gut microbiome so that less uremic toxins are produced. This can be accomplished by manipulating the energy source available to the microbiome. Fermentable carbohydrates which reach the gut microbiome, like resistant starch (RS), have been shown to inhibit or reduce bacterial amino acid metabolism. This study aims to investigate the effects of resistant potato starch (RPS) as a prebiotic in individuals with CKD before the onset of dialysis. Methods This is a double-blind, randomized two-period crossover trial. Thirty-six eligible participants will consent to follow a 26-week study regimen. Participants will receive 2 sachets per day containing either 15 g of RPS (MSPrebiotic, resistant potato starch treatment) or 15 g cornstarch (Amioca TF, digestible starch control). Changes in blood uremic toxins will be investigated as the primary outcome. Secondary outcomes include the effect of RPS consumption on symptoms, quality of life and abundance, and diversity and functionality of the gut microbiome. Discussion This randomized trial will provide further insight into whether the consumption of RPS as a prebiotic will reduce uremic toxins and symptoms in individuals who have CKD. Trial registration ClinicalTrials.govNCT04961164. Registered on 14 July 2021

This study aimed to determine the effect of pure forms of sucralose and aspartame, in doses reflective of common consumption, on glucose metabolism. Healthy participants consumed pure forms of a non-nutritive sweetener (NNS) that were mixed with water and standardized to doses of 14% (0.425 g) of the acceptable daily intake (ADI) for aspartame and 20% (0.136 g) of the ADI for sucralose every day for 2 weeks. Blood samples were collected and analyzed for glucose, insulin, active glucagon-like peptide-1 (GLP-1), and leptin. Seventeen participants (10 females and 7 males; age, 24 ± 6.8 years; body mass index, 22.9 ± 2.5 kg/m2) participated in the study. The total area under the curve values of glucose, insulin, active GLP-1 and leptin were similar for the aspartame and sucralose treatment groups compared with the baseline values in healthy participants. There was no change in insulin sensitivity after NNS treatment compared with the baseline values. These findings suggest that daily repeated consumption of pure sucralose or aspartame for 2 weeks had no effect on glucose metabolism among normoglycaemic adults. However, these results need to be tested in studies with longer durations. Novelty Daily consumption of pure aspartame or sucralose for 2 weeks had no effect on glucose metabolism. Daily consumption of pure aspartame or sucralose for 2 weeks had no effect on insulin sensitivity among healthy adults.

Background Functional food ingredients and natural health products have been demonstrated to reduce disease risk and thereby help to lower health care costs across populations at risk for chronic or degenerative diseases. However, typically a wide range of interindividual variability exists in response across individuals to nutritional and natural health product bioactives, such as plant sterols (PS). This study aims to determine and utilize information on the associations between genosets and the degree of responsiveness to dietary PS intervention, with a long-term objective of developing genetic tests to predict responses to PS. Methods This clinical trial is designed as a double-blind, placebo controlled, randomized two-period crossover study. Sixty-four eligible participants with the specific a priori-determined single nucleotide polymorphisms (SNPs) associated with a responsiveness to PS will consume PS or a placebo treatment for two 4-week periods. The PS treatment consists of two daily single portions of margarine, each providing 1 g PS during the PS period (2.0 g/day of PS in total). The placebo will be an identical margarine containing no added PS. Low-density lipoprotein cholesterol (LDL-C) responsiveness to the controlled administration of PS will be investigated as the primary outcome, and the associations between interindividual genoset variabilities and response to PS consumption will be determined. Discussion This research will provide further insight into whether the associations between previously identified SNPs and the response of LDL-C to PS consumption can be used in a predictive manner. It will also provide insight into the complexities of undertaking a nutrigenetic trial with prospective recruitment based on genotype. Trial registration ClinicalTrials.gov: Identifier: NCT02765516. Registered on 6 May 2016.

Background Primary hypertension accounts for almost 95% of all cases of high blood pressure and is a major modifiable risk factor for cardiovascular diseases. Lifestyle interventions have been shown to prevent hypertension. One of the prominent potential therapeutic lifestyle strategies to prevent or manage hypertension is increasing dietary protein as a macronutrient or as bioactive peptides. An emerging plant-based protein source that may have anti-hypertensive properties is hemp seed. Methods/design A randomized, double-blind, crossover clinical trial will be conducted on 35 hypertensive participants aged 18–75 years, with a BMI between 18.5 and 40 kg/m2, systolic blood pressure (SBP) between 130 and 160 mmHg and diastolic blood pressure (DBP) ≤ 110 mmHg. The trial will be conducted for a period of 22 weeks and will consist of three treatment periods of 6 weeks, separated by 2-week washout periods. The treatments will be consumed twice a day and consist of 25 g casein, hemp seed protein (HSP), or HSP plus HSP hydrolysate (HSP+). The primary outcome of this trial is 24-h SBP, measured on the first day of first phase and the last day of each phase. Office-measured blood pressure, pulse-wave velocity and augmentation index and anthropometrics will be determined at the first and last days of each period. Also, body composition will be assessed by dual x-ray absorptiometry (DXA) scan on the first day of the first phase and within the last 2 days of each treatment period. Blood samples will be collected on the first and last 2 days of each treatment phase whereas urine samples will be collected on the first day of the first phase plus the last day of each phase to be analyzed for specific biomarkers. Discussion This trial protocol is designed to evaluate the hypotensive potential of consuming whole HSP, and HSP+, in comparison to casein protein. This study will be the first trial investigating the potential anti-hypertensive benefit of dietary hemp protein plus bioactive peptide consumption in humans. Trial registration National Clinical Trial (NCT), ID: NCT03508895. Registered on 28 June 2018. Retrospectively registered on the publicly accessible Registry Databank at ClinicalTrials.gov (http://ClinicalTrials.gov).

By replacing sugar, nonnutritive sweeteners (NNSs) are thought to aid in weight management and decrease insulin resistance. We reviewed the latest randomized clinical trials (RCTs) investigating the effects NNSs on glycaemic control.Six RCTs addressed this topic between 2017 and 2018; the majority tested artificial NNS (sucralose or aspartame), with only one testing natural NNS (stevia and monk fruit extract). Most found no effect of NNS on blood glucose, insulin, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels; however, two trials showed an effect of sucralose on the acute insulin response.We are still incapable of reaching a definite judgement on which types of NNS, if any, impact glycaemic control. There is a need for more research to overcome the limitations of recent RCTs, related to sample size, intervention duration, dose, form of NNSs used, and inclusion of males or female participants only. Future studies should also compare different NNS types with each other, and include the increasingly popular 'natural' NNS.

Background Obesity has become a major driver in the burden of chronic diseases. The Canadian Clinical Practice Guidelines recommend a lifestyle intervention for the management and prevention of obesity. This includes behavior modification, dietary counseling, and physical activity. With the market overwhelmed with weight loss programs, the majority are focused on low-calorie diets and general recommendations for exercise. Most are not personalized and are not administered by healthcare professionals. An interdisciplinary team of highly trained healthcare professionals has the ability to provide medically sound and safe advice in all aspects of an individuals’ life, such as lifestyle, sleep, mental health, and behaviors. A clinically managed weight loss program is defined as a team including a dietitian, exercise professional, psychologist, and/or physician or nurse practitioner oversight. With limiting results in the literature regarding clinically managed weight loss programs, it is difficult to conclude whether it may be effective. Therefore, the objective of this systematic review is to assess clinically managed weight loss programs, with a physician or nurse practitioner oversight in comparison with non-clinically managed weight loss programs with no physician oversight or nurse practitioner oversight in adults who are living with overweight or obesity. Methods A literature search will be executed by a knowledge synthesis librarian on MEDLINE, Cochrane Central, Embase, PsycINFO, and CINAHL. The data collected will be extracted, stored, and managed in MS Excel 2016. The extraction of the data will include study details, study population details, health team details, intervention details, and outcome details. Discussion The prevalence of obesity has been increasing throughout the decades. The results from this systematic review may aid in recommending a more clinically safe weight loss program for those who struggle with overweight or obesity. Systematic review registration PROSPERO CRD42020170014

Benefits of pulse consumption on glycemic control are well established; however, research examining the effects of pulse fractions incorporated into extruded products is limited. In a randomized, repeated-measures crossover study, adults (n = 26) consumed cereals made with oat flour (control), oat flour and pea starch (starch), oat flour and pea protein (protein), oat flour, pea starch and pea protein (starch+protein), oat flour, pea fibre and pea protein (fibre+protein), and pea fibre, pea starch and pea protein (fibre+starch+protein). Blood glucose (BG) and insulin concentrations, and appetite incremental area under the curve (iAUC) were calculated before (0–120 min) and after (120–200 min) the ad libitum meal for measurement of food intake. Pre-meal, overall mean BG and iAUC were lower following the protein, starch+protein, protein+fibre, and the fibre+starch+protein cereals compared with the starch and control. For pre-meal overall mean insulin concentrations, fibre+protein led to a lower response compared with control, starch+protein, and protein cereals. Fibre+starch+protein also led to lower insulin compared with protein cereal. Pre-meal insulin iAUC was lower following fibre+protein compared with control and protein cereals. The inclusion of yellow pea protein and fibre in oat-based breakfast cereal reduces postprandial glycemia; however this effect is dependent on fraction type. ClinicalTrials.gov: NCT02366572. Novelty: Inclusion of pulse protein and fibre in oat flour-based breakfast cereal reduces postprandial glucose response. The glycemic benefits of whole pulses are at least somewhat retained in some pulse fractions.

Research investigating hemp protein consumption on glycemic response is limited. The effects of hemp protein consumption on blood glucose (BG), insulin, and satiety compared with soybean protein and a carbohydrate control were examined. Two acute randomized repeated-measures crossover experiments were conducted. In both, participants consumed the following isocaloric treatments: 40 g of hemp protein (hemp40), 20 g of hemp protein (hemp20), 40 g of soybean protein (soy40), 20 g of soybean protein (soy20), and a carbohydrate control. In experiments 1 (n = 27) and 2 (n = 16), appetite and BG were measured before (0–60 min, pre-pizza) and after a pizza meal (80–200 min, post-pizza). In experiment 1, food intake was measured at 60 min by ad libitum meal; in experiment 2 a fixed meal was provided (based on body weight) and insulin was measured pre-pizza and post-pizza. In both experiments, BG response was affected by treatment (p < 0.01), time (p < 0.001) and time-by-treatment (p < 0.001) from 0–200 min. Protein treatments lowered 0–60-min BG overall mean and area under the curve compared with control (p < 0.05) dose-dependently. In experiment 2, hemp40 and soy40 lowered (p < 0.05) overall mean insulin concentrations compared with hemp20, soy20, and control pre-meal. Results suggest that hemp protein, like soybean, dose-dependently lowers postprandial BG and insulin concentrations compared with a carbohydrate control. Clinical trial registry: NCT02366598 (experiment 1) and NCT02458027 (experiment 2). Novelty: Hemp protein concentrate dose-dependently leads to lower postprandial BG response compared with a carbohydrate control. No differences were seen between hemp and soy protein.

Research indicates that the post-prandial glycemic benefits of consuming whole pulses are retained when consumed in a mixed meal, pureed, and ground into flours. The glycemic benefits of pulse flours when incorporated into extruded products are unknown. In a randomized, repeated-measures crossover study, adults (n = 26) consumed extruded corn snacks made with the addition of 40% pulse flour from either: whole yellow pea, split yellow pea, green lentil, chickpea, or pinto bean. The control snack was 100% corn. Food intake was measured with an ad libitum meal consumed at 120 min. Blood glucose (BG), insulin and appetite were measured regularly before (pre-meal, 0-120 min) and after (post-meal, 140-200 min) the meal. Pinto bean and chickpea snacks led to lower (p

Non-nutritive artificial sweeteners (NNSs) may have the ability to change the gut microbiota, which could potentially alter glucose metabolism. This study aimed to determine the effect of sucralose and aspartame consumption on gut microbiota composition using realistic doses of NNSs. Seventeen healthy participants between the ages of 18 and 45 years who had a body mass index (BMI) of 20&ndash, 25 were selected. They undertook two 14-day treatment periods separated by a four-week washout period. The sweeteners consumed by each participant consisted of a standardized dose of 14% (0.425 g) of the acceptable daily intake (ADI) for aspartame and 20% (0.136 g) of the ADI for sucralose. Faecal samples collected before and after treatments were analysed for microbiome and short-chain fatty acids (SCFAs). There were no differences in the median relative proportions of the most abundant bacterial taxa (family and genus) before and after treatments with both NNSs. The microbiota community structure also did not show any obvious differences. There were no differences in faecal SCFAs following the consumption of the NNSs. These findings suggest that daily repeated consumption of pure aspartame or sucralose in doses reflective of typical high consumption have minimal effect on gut microbiota composition or SCFA production.

Current evidence indicates that foods with added plant sterols or stanols can lower serum levels of low-density lipoprotein cholesterol. This review summarizes the recent findings and deliberations of 31 experts in the field who participated in a scientific meeting in Winnipeg, Canada, on the health effects of plant sterols and stanols. Participants discussed issues including, but not limited to, the health benefits of plant sterols and stanols beyond cholesterol lowering, the role of plant sterols and stanols as adjuncts to diet and drugs, and the challenges involved in measuring plant sterols and stanols in biological samples. Variations in interindividual responses to plant sterols and stanols, as well as the personalization of lipid-lowering therapies, were addressed. Finally, the clinical aspects and treatment of sitosterolemia were reviewed. Although plant sterols and stanols continue to offer an efficacious and convenient dietary approach to cholesterol management, long-term clinical trials investigating the endpoints of cardiovascular disease are still lacking. International Plant Sterol and Stanol Association (IPSSA); National Center for Complementary and Integrative Health (NCCIH); National Center for Advancing Translational Sciences [IR13AT009270-01]

Many functional foods have been developed which propose to lower circulating cholesterol concentrations, such as plant sterols or β-glucan. However, response to these foods is often highly variable between individuals, with some benefiting from cholesterol lowering and while others do not. One of the potential causes of this inter-individual variability in response could be genetics. This review looks at the associations between the single nucleotide polymorphism rs3808607 in the Cytochrome P450 Family 7 Subfamily A Member 1 ( CYP7A1 ) gene, and variability in the response of circulation cholesterol concentrations following the consumption of various functional foods.

Background: Obesity is a worldwide problem. With the prevalence of obesity increasing, many weight loss programs have been created to aid in the epidemic. Based on the Canadian Clinical Practice Guidelines for obesity management, a weight loss program should involve nutrition, exercise, and psychological components. The Wellness Institute (WI) is a non-profit organization that operates as a medical fitness facility and created the Weight Loss Clinic (WLC) to provide personalized support for individuals based on diet, exercise, and lifestyle, targeting all the core components required for a weight loss program. Since the weight loss industry is dominated by non-evidence-based programs with majority focused on calorie-reduced diets, there is a gap in research on weight loss programs with an exercise and psychological component. Thus, the aim of this pilot study is to collect data on the effectiveness of the comprehensive evidence-based clinically managed weight loss program offered at the WI for future research applications.Materials and Methods: The WLC is a 17-week program during which each participant will progress depending on their personal goals. Population: Inclusion criteria are individuals over the age of 18 years old, are overweight or obese (BMI > 25 kg/m2), have been told by a physician or primary care provider to lose weight, who are concerned with weight and may have other health problems, and have tried to lose weight in the past but have been unsuccessful at maintaining weight loss. Outcome Measures: Outcome measures include: anthropometric measurements, body composition, cardiovascular assessment, clinical chemistry, physical activity assessment, nutrition assessment, behaviour change assessment, and health screenings. Ethics Approval: This evaluation received approval from the University of Manitoba Health Research Ethics Board (Ethics # HS22267 (H2018:401)). Clinicaltrials.gov ID: NCT04290910

Non-nutritive sweeteners are thought to be useful replacements for caloric sweeteners in sweet food and beverages, since the reduction in energy and carbohydrate intake may lead to health benefits stemming from weight management and glycemic control. However, the potential effects of non-nutritive sweeteners on glucose metabolism and gut hormones have not been determined definitively. Here, the available evidence of the effects of aspartame and sucralose consumption on glucose metabolism and gut hormones is reviewed. A majority of studies have found that consumption of aspartame or sucralose has no effect on concentrations of blood glucose, insulin, or gut hormones; however, 2 trials have shown that aspartame consumption affects glucose, insulin, and glucagon-like peptide 1 concentrations, while only a few trials have shown that sucralose consumption affects glucose, insulin, and glucagon-like peptide 1 concentrations. One study found higher glucose concentrations after sucralose consumption, while 3 studies found lower concentrations and 33 studies found no change in glucose concentrations. Moreover, only 4 studies reported increased concentrations of glucagon-like peptide 1. Three studies reported decreased insulin sensitivity following sucralose consumption, while 1 trial reported an increase in insulin sensitivity. In summary, the evidence from the clinical trials conducted to date is contradictory because of the different protocols used.

The objective of the present exploratory study was to investigate how the fatty acid (FA) composition of different food sources for preterm infants including breast milk (BM), formula (F), human milk fortifiers (HMFs), and total parenteral nutrition (TPN) impacted preterm infant's plasma FA. The associations between FA content of plasma with antioxidant enzyme activity and cognition were also evaluated.Thirty-two premature infants were included in the present study. Five different feeds (BM, F, BM + F, BM + HMF, and TPN) were provided. Foods and preterm infant plasma samples were collected at the same time on the same day biweekly where possible. Separation and identification of the plasma and food FA methyl esters were performed by gas-liquid chromatography. Antioxidant enzymes were measured. The Bayley Scale of Infant Development version III was used to evaluate cognition.In food sources, BM contained significantly lower stearic acid (C18:0) (P 0.05), oleic acid (C18:1n9) (P 0.01), linoleic acid (C18:2n6) (P 0.01), α-linoleic acid (C18:3n3) (P 0.01), and arachidonic acid (C20:4n6) (P 0.05) compared with the F. Palmitic acid (C16:0) was significantly higher (P 0.05) in the BM + HMF compared with the BM. Stearic acid (C18:0) was significantly higher (P 0.05) in the BM + F and BM + HMF compared with the BM. In the plasma lauric acid (C12:0) (P 0.05) and myristic acid (C14:0) (P 0.001) were higher in the BM-fed babies compared with the F-fed or TPN-recipient groups. Antioxidant enzymes, activities and cognition scores did not differ by feeding groups, however the study may not have been powered to detect these differences.The type, and therefore quality, of fatty acids is an important consideration when selecting what is fed to premature infants because differences in feed fatty acids were seen in some plasma fatty acids in the study.

International audience; Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5alpha-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5alpha-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs.

Recent work suggests that plant sterol (PS) consumption may lower triglyceride (TG) concentrations; however, human clinical trial evidence is inconsistent. We associated SNP r5882 in cholesteryl ester transfer protein with changes in TG concentrations following PS consumption (2 g/day for 4 weeks) in a dual-centre, single-blind, randomized, crossover trial. TG concentrations were lowered in homozygotes for the minor G-allele of rs5882 (–0.46 ± 0.13 mmol/L, p = 0.002, n = 10); there was no effect in the A-allele carriers.

Background: Benefits of plant sterols (PS) for cholesterol loweringare compromised by large variability in efficacy across individuals.High fractional cholesterol synthesis measured by deuterium incor-poration has been associated with nonresponse to PS consumption;however, prospective studies that show this association have yet tobe conducted.Objective: Thegoalwastotestwhetherthelathosterol-to-cholesterolratio (L:C), a surrogate marker of endogenous cholesterol synthesis,serves as an a priori predictor of cholesterol lowering in response toPS consumption.Design: Sixty-three mildly hypercholesterolemic adults who werepreselected as possessing either high endogenous cholesterol synthe-sis [HS;n = 24;L:C = 2.036 0.39mmol/mmol(mean 6 SD)]orlowendogenous cholesterol synthesis [LS; n = 39; L:C = 0.99 6 0.28mmol/mmol (mean 6 SD)] on the basis of baseline L:C consumed2 g PS/d or a placebo for 28 d with the use of a dual-center, single-blind, randomized crossover design. Plasma lipid and noncholesterolsterol concentrations were measured at the end of each phase.Results: PS consumption lowered total cholesterol (TC; 20.25 60.05 mmol/L; P , 0.0001) and LDL cholesterol (20.17 6 0.04mmol/L; P , 0.0001) overall. Specifically, LS individuals respondedto PS treatment with a reduction in TC (20.40 6 0.07 mmol/L; P ,0.0001) and LDL cholesterol (20.29 6 0.05 mmol/L; P = 0.0002),whereas HS individuals failed to show cholesterol lowering (TC:20.09 6 0.09 mmol/L; P = 0.2843; LDL cholesterol: 20.05 60.07 mmol/L; P = 0.4917). The odds of LS participants respondingwith cholesterol lowering better thanthe mean cholesterol lowering inall participants to PS consumption were 4.25 (95% CI: 1.242, 14.556;P = 0.0211) for TC and 3.36 (95% CI: 1.112, 10.161; P = 0.0317) forLDL cholesterol, which was higher than for HS participants.Conclusions: The L:C ratio predicts the extent of reduction incirculating TC and LDL cholesterol in response to PS consumption.Cholesterol synthesis assessment may thus have a use in identifyingresponders and nonresponders to PS therapy. This trial was regis-tered at clinicaltrials.govas NCT01131832. Am J Clin Nutr doi:10.3945/ajcn.114.095356.Keywords cholesterol lowering, interindividual variability, non-cholesterol sterols, plant sterols, randomized controlled trialINTRODUCTIONPlant sterols (PS)

IntroductionLifestyle factors, such as diet, physical activity and sleep, are associated with the development of many chronic diseases. The objective of The Manitoba Personalized Lifestyle Research study is to understand how these lifestyle factors interact with each other and with other factors, such as an individual’s genetics and gut microbiome, to influence health.MethodsAn observational study of adults, with extensive phenotyping by objective health and lifestyle assessments, and retrospective assessment of early life experiences, with retrospective and prospective utilisation of secondary data from administrative health records.Study populationA planned non-random convenience sample of 840 Manitobans aged 30–46 recruited from the general population, stratified by sex (equal men and women), body mass index (BMI; 60% of participants with a BMI>25 kg/m2) and geography (25% from rural areas). These stratifications were selected based on Manitoba demographics.MeasurementsLifestyle factors assessed will include dietary pattern, physical activity, cardiovascular fitness, and sleep. Factors such as medical history, socioeconomic status, alcohol and tobacco consumption, cognition, stress, anxiety, and early life experiences will also be documented. A maternal survey will be performed. Body composition and bone density will be measured by dual energy X-ray absorptiometry. Blood pressure, pulse wave velocity, and augmentation index will be measured on two consecutive days. Chronic disease risk biomarkers will be measured in blood and urine samples. DNA will be extracted for genetic analysis. A faecal sample will be collected for microbiome analysis. Participants may provide their Manitoba personal health information number to link their study data with administrative health records.Ethics and disseminationEthics approval has been obtained from the University of Manitoba Health Research Ethics Board (protocol # HS18951; 05/01/2016). Data analysis, release of results and publication of manuscripts are scheduled to start in early 2019. Additional information atwww.TMPLR.ca.Trial registration numberNCT03674957; Pre-results.

BACKGROUND Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference −0.37 kg/m 2 ; 95% confidence interval [CI] −1.10 to 0.36; I 2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I 2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749

Dietary oils are a significant contributor to overall energy and fatty acid intakes. Changes in the amount and/or type of dietary oils consumed have the potential to impact human health. Clinical trials represent the gold standard for testing the health impacts of such changes in dietary oils. The objective of this review is to explore best practices for clinical trials examining impacts of dietary oils including 1) pre-clinical topics such as research question generation, study design, participant population, outcome measures and intervention product selection and/or preparation; 2) clinical trial implementation topics such as recruitment, trial management, record keeping and compliance monitoring; and 3) post-clinical trial topics dealing with sample analysis and storage as well as management, publication and data access. The use of digital case report forms, and the best practices in reporting and publishing results are also addressed. In summary, properly designed and implemented clinical trials studying dietary oils produce strong scientific evidence-guiding their use.

Reducing intestinal cholesterol absorption with plant sterol consumption is a well-characterized strategy to lower LDL-C and potentially reduce cardiovascular disease risk. However, over 50 years of clinical research demonstrate that there is significant heterogeneity in the individual LDL-C lowering response to plant sterol therapy. A clear understanding of why plant sterols work effectively in some individuals but not in others will ensure optimal integration of plant sterols in future personalized nutritional lipid-lowering strategies. This review will examine the current knowledge base surrounding the metabolic and genetic determinants of LDL-C lowering in response to plant sterol consumption.

Epidemiological studies have linked small birth weight and lack of breastfeeding to type 2 diabetes mellitus. This study aimed to determine if (i) small birth weight promotes and (ii) suckling prevents the development of adiposity and diabetes biomarkers in a Yucatan miniature pig model. At 3 days of age, the intrauterine growth-restricted (IUGR) piglet (n = 6) was paired with a normal weight (NW), same-sex littermate (n = 6) and fed milk replacer for 4 weeks. A sow-fed normal weight littermate (n = 6) was also compared with the NW littermate to assess the effects of suckling. All pigs were fed a standard diet ad libitum for 5 h·day–1from week 4. At 9.5 months, pigs underwent intravenous glucose tolerance (IVGTT) and insulin sensitivity tests (IST). At 10 months, tissues were harvested for fat analysis and pancreas histology. IUGR pigs demonstrated compensatory growth before sexual maturity and had greater subcutaneous fat depth; birth weight also negatively correlated with visceral fat content. Visceral and subcutaneous adiposity were greater in females than males. IVGTT and IST outcomes were not different due to birth weight or suckling. However, visceral adiposity was associated with several glucose tolerance outcomes and females were more glucose intolerant due to their greater adiposity. Pancreas insulin content or histology outcomes were not different. This model did not develop markers of type 2 diabetes mellitus because of small birth weight or formula feeding. However, visceral adiposity and sex were associated with glucose intolerance, which is consistent with data in humans.

Phytosterols are a family of compounds similar to cholesterol which have been shown to lower cholesterol levels when supplemented in the diet. A daily dose of 2–3 g of phytosterols has been shown to reduce LDL-cholesterol levels by 5–15%. Phytosterol supplementation can be undertaken using phytosterol enriched functional foods or nutraceutical preparations. The type of phytosterol supplemented, such as plant sterol or saturated plant stanol appear to be equally effective in lowering cholesterol levels. Phytosterols, whether in esterified or free form have both been shown to lower cholesterol levels, with esterified phytosterol formulations having a greater number of clinical trials demonstrating efficacy. The functional food or nutraceutical matrix which is used to deliver supplemental phytosterols can significantly affect cholesterol lowering efficacy. Effective cholesterol lowering by phytosterols depends on delivery of phytosterols to the intestine in a form which can compete with cholesterol for absorption. New phytosterol functional food and nutraceuticals products should always be tested to demonstrate adequate delivery of phytosterol dose and effective total and LDL-cholesterol lowering. Phytosterol products which do not effectively lower cholesterol will negatively impact the perception and use of phytosterols, and must not be allowed on the marketplace.

Cardiovascular disease risk and its associated complications correlate positively with circulating cholesterol levels. Plasma cholesterol levels are maintained by reciprocally related endogenous cholesterol synthesis and cholesterol absorption from dietary and biliary sources. Numerous in vivo clinical methods exist to quantify the absorption and synthesis of cholesterol in humans. This review summarizes these different methods available to study cholesterol absorption and synthesis, highlighting each method's strengths and weaknesses, as well as their applicability in different types of trials.

CONTEXT: Nonnutritive sweetener (NNS) consumption is increasing among children, yet its long-term health impact is unclear, particularly when exposure occurs during early life. OBJECTIVE: To synthesize evidence from prospective studies evaluating the association of early-life NNS exposure and long-term metabolic health. DATA SOURCES: Medline, Embase, and Cochrane Library (inception to July 2015). STUDY SELECTION: We aimed to include randomized controlled trials (RCTs) evaluating NNS-based interventions and prospective cohort studies reporting NNS exposure among pregnant women, infants, or children ( DATA EXTRACTION: The primary outcome was BMI; secondary outcomes included growth velocity, overweight/obesity, adiposity, and adverse metabolic effects. Study quality and risk of bias were evaluated using validated assessment tools. RESULTS: We identified 6 eligible cohort studies and 2 RCTs (n = 15 641 children). Half of the cohorts reported increasing weight gain or fat mass accumulation with increasing NNS intake, and pooled data from 2 cohorts showed a significant correlation with BMI gain (weighted mean correlation 0.023, 95% confidence interval 0.006 to 0.041). RCTs reported contradictory effects on weight change in children receiving NNSs. No eligible studies evaluated prenatal or infant NNS exposure. LIMITATIONS: Meta-analysis was limited because of the small number of eligible studies and heterogeneity of populations and outcomes. CONCLUSIONS: There is limited and inconsistent evidence of the long-term metabolic effects of NNS exposure during gestation, infancy, and childhood. Further research is needed to inform recommendations for the use of NNSs in this sensitive population.

BACKGROUND The benefits of plant sterols (PSs) for cholesterol lowering are hampered by large heterogeneity across individuals, potentially because of genetic polymorphisms. OBJECTIVE We investigated the impact of candidate genetic variations on cholesterol response to PSs in a trial that recruited individuals with high or low endogenous cholesterol synthesis, estimated by lathosterol to cholesterol (L:C) ratio. DESIGN Mildly hypercholesterolemic adults preselected as possessing either high endogenous cholesterol synthesis (n = 24; mean ± SEM: L:C ratio = 2.03 ± 0.39 μmol/mmol) or low endogenous cholesterol synthesis (n = 39; mean ± SEM: L:C ratio = 0.99 ± 0.28 μmol/mmol) consumed 2 g PS/d or a placebo for 28 d by using a dual-center, single-blind, randomized crossover design. Cholesterol synthesis and change in cholesterol absorption were measured with stable isotopic tracers. Candidate single-nucleotide polymorphisms and apolipoprotein E (APOE) isoform were assessed by TaqMan genotyping assay. RESULTS The cholesterol fractional synthesis rate was higher (P < 0.001) in participants with high endogenous cholesterol synthesis (mean ± SEM: placebo: 9.16% ± 0.47%; PSs: 9.74% ± 0.47%) than in participants with low endogenous cholesterol synthesis (mean ± SEM placebo: 5.72% ± 0.43%; PS: 7.10% ± 0.43%). Low-density lipoprotein (LDL) cholesterol lowering in response to PSs was associated with individuals' genotypes. Cholesterol 7 alpha-hydroxylase (CYP7A1-rs3808607) T/T homozygotes showed no LDL cholesterol lowering (mean ± SEM: -0.05 ± 0.07 mmol/L, P = 0.9999, n = 20), whereas the presence of the G-allele associated with LDL cholesterol response in a dose-dependent fashion (mean ± SEM G/T: -0.22 ± 0.06 mmol/L, P = 0.0006, n = 35; G/G: -0.46 ± 0.12 mmol/L, P = 0.0009, n = 8). Similarly, APOE ɛ3 carriers (mean ± SEM: -0.13 ± 0.05 mmol/L, P = 0.0370, n = 40) responded less than APOE ɛ4 carriers (mean ± SEM: -0.31 ± 0.07 mmol/L, P < 0.0001, n = 23). Moreover, genoset CYP7A1-rs3808607 T/T/APOE ɛ3 was associated with nonresponsiveness (mean ± SEM: +0.09 ± 0.08 mmol/L, P = 0.9999, n = 14). rs5882 in cholesteryl ester transfer protein (CETP) and rs4148217 in ATP-binding cassette subfamily G member 8 (ABCG8) did not associate with LDL cholesterol lowering. Cholesterol absorption decreased as a result of PS consumption, but this decrease was not related to circulating LDL cholesterol concentrations, cholesterol synthesis phenotype, or genotypes. CONCLUSION CYP7A1-rs3808607 and APOE isoform are associated with the extent of reduction in circulating LDL cholesterol in response to PS consumption and could serve as potential predictive genetic markers to identify individuals who would derive maximum LDL cholesterol lowering with PS consumption. The trial was registered at clinicaltrials.gov as NCT01131832.

We thank Sievenpiper and colleagues[1][1] for their interest in our work.[2][2] Although we agree that study design must be considered when evaluating evidence to inform health decision making, it is often necessary to look beyond randomized controlled trials (RCTs) for additional (and sometimes

Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non-random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, cross-over trial design. Three of the treatment oil diets: 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL-proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p = 0.0005 and p = 0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p = 0.0243) and DHA-enriched high oleic canola oil (p = 0.0249), although high-oleic canola oil had the lowest binding at baseline (p = 0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding.

Plant sterol (PS) consumption may lower triglyceride (TG) concentrations. However, human clinical trial evidence is inconsistent, with only some trials showing TG reductions. This heterogeneity in responsiveness of TG concentrations to PS consumption could have a genetic basis. Our objective was to investigate whether SNPs in genes related to TG metabolism could be associated with changes in TG concentrations following PS consumption. 63 mildly hypercholesterolemic adults, pre-assessed for cholesterol synthesis using lathosterol to cholesterol ratio (L/C) (High, n=24, L/C = 2.03 ± 0.39 umol/mmol; Low, n=39, L/C =0.99±0.28 umol/mmol) consumed either 2g/d (free sterol) of PS ester or placebo in margarine for 28 d in a dual-center, single-blind, randomized, crossover design. Serum TG concentrations were measured at the end of each phase. Candidate SNPs and ApoE variant were accessed by TaqMan assay. PS consumption did not lower TG overall (p=0.0506), but had an interaction with rs5882 in CETP (p=0.0080). Hom...

Non-cholesterol sterols (NCS) are used as surrogate markers of cholesterol metabolism which can be measured from a single blood sample. Cholesterol precursors are used as markers of endogenous cholesterol synthesis and plant sterols are used as markers of cholesterol absorption. However, most aspects of NCS analysis show wide variability among researchers within the area of biomedical research. This variability in methodology is a significant contributor to variation between reported NCS values and hampers the confidence in comparing NCS values across different research groups, as well as the ability to conduct meta-analyses. This paper summarizes the considerations and conclusions of a workshop where academic and industrial experts met to discuss NCS measurement. Highlighted is why each step in the analysis of NCS merits critical consideration, with the hopes of moving toward more standardized and comparable NCS analysis methodologies. Alkaline hydrolysis and liquid-liquid extraction of NCS followed by parallel detection on GC-FID and GC-MS is proposed as an ideal methodology for the bio-analysis of NCS. Furthermore the importance of cross-comparison or round robin testing between various groups who measure NCS is critical to the standardization of NCS measurement.

PURPOSE OF REVIEW Noncholesterol sterols (NCSs) in plasma encompass endogenous cholesterol precursors and exogenous phytosterols and cholesterol metabolites, which are used as surrogate measures of cholesterol synthesis and cholesterol absorption, respectively. The ratios of cholesterol synthesis to cholesterol absorption surrogates are also utilized to assess the overall balance of cholesterol metabolism, with higher values representing more synthesis and lower values more absorption. The objective of this review is to focus on recent findings using plasma NCSs and their potential in customizing dietary and pharmacological hypolipidemic therapies. RECENT FINDINGS NCSs are often used to assess the impact of pharmacological and dietary interventions on cholesterol metabolism. Various forms of dyslipidemia have been characterized using NCSs, and NCSs may be a valuable tool in selecting appropriate treatment therapies. NCSs levels are affected by genetic, dietary and physiological factors and have been related to cardiovascular disease risk. SUMMARY The expanded use of plasma NCSs is currently limited by the lack of standardized methodology. However, noncholesterol sterols are still a valuable research tool for the overall assessment of cholesterol metabolism and may have clinical potential in the personalization of diet and medicine.

Reducing intestinal cholesterol absorption with plant sterol consumption is a well-characterized strategy to lower LDL-C and potentially reduce cardiovascular disease risk. However, over 50 years of clinical research demonstrate that there is significant heterogeneity in the individual LDL-C lowering response to plant sterol therapy. A clear understanding of why plant sterols work effectively in some individuals but not in others will ensure optimal integration of plant sterols in future personalized nutritional lipid-lowering strategies. This review will examine the current knowledge base surrounding the metabolic and genetic determinants of LDL-C lowering in response to plant sterol consumption.

We previously demonstrated that intra-uterine growth-restricted (IUGR) Yucatan miniature pigs develop modestly elevated blood pressure (BP) as young adults. The present study evaluated the effects of a post-weaning Western-style, high-salt-fat-sugar (HSFS) diet on early programming of BP. IUGR piglets (3 d old, 0·77 (sem0·04) kg,n6) were paired with normal weight (NW) same-sex littermates (1·14 (sem0·03) kg,n6) and fed milk replacer for 4 weeks. A third littermate was left with the sow (SF; 1·01 (sem0·05) kg,n6). When 4 weeks old, all pigs were placed on a HSFS dietad libitumfor 5 h/d. When 11 months old, telemeters were implanted to measure BP in pigs before (4·5 % NaCl) and after (0·5 % NaCl) a 7 d reduced salt challenge. At necropsy, nephron numbers were determined. Before sexual maturity, IUGR pigs had greater relative feed intake (P P sem4·9) mmHg,P = 0·044) than NW (97·2 (sem1·8) mmHg) and SF (98·9 (sem5·3) mmHg) pigs. Systolic BP was similar among the three groups, but was significantly elevated compared with levels previously reported for a control diet. Salt restriction reduced BP in all groups (P P>0·05) in the degree of salt sensitivity among groups. In conclusion, a post-weaning Western-style diet exacerbates early programming of diastolic BP in Yucatan miniature swine, whereas systolic BP is more sensitive to postnatal diet.

Intrauterine growth restriction (IUGR), in both animals and humans, has been linked to metabolic syndrome later in life. There has been recent evidence that perturbations in sulfur amino acid metabolism may be involved in this early programming phenomenon. Methionine is the precursor for cellular methylation reactions and for the synthesis of cysteine. It has been suggested that the mechanism behind the "fetal origins" of adult diseases may be epigenetic, involving DNA methylation. Because we have recently demonstrated the fetal origins phenomenon in Yucatan miniature swine, we hypothesized that sulfur amino acid metabolism is altered in IUGR piglets. In this study, metabolites and the activities of sulfur amino acid cycle enzymes were analyzed in liver samples of 3- to 5-day-old runt (IUGR: 0.85±0.13 kg) and large (1.36±0.21 kg) Yucatan miniature pig littermates (n=6 pairs). The IUGR piglets had significantly lower specific and total activities of betaine-homocysteine methyltransferase (BHMT) and cystathionine γ-lyase (CGL) than larger littermates (P

Background: The cholesterol-lowering effectiveness of plant sterol (PS) therapy is hindered by wide-ranging variability in LDLcholesterol responsiveness across individuals. To capitalize on the LDL-cholesterol-lowering potential of PS in the clinical setting, it is paramount to characterize the metabolic factors that underlie this heterogeneity of responsiveness. Objective: The objective was to investigate the relation between cholesterol synthesis and plasma LDL-cholesterol reductions in response to PS consumption. Design: We evaluated previously conducted clinical PS interventions incorporating stable-isotope measures of cholesterol synthesis and conducted feeding studies in animal models of response (Syrian Golden hamsters) and nonresponse (C57BL/6J mice) to PS consumption. Results: From our clinical study population (n = 113), we identified 47 nonresponders (3.73 6 1.10% change in LDL cholesterol) and 66 responders (215.16 6 1.04% change in LDL cholesterol) to PS therapy. The basal cholesterol fractional synthesis rate (FSR) as measured by direct deuterium incorporation was 23% higher (P = 0.003) in the nonresponder subgroup than in responders to PS therapy. The basal cholesterol FSR correlated (r = 0.22, P = 0.02) with the percentage change in LDL cholesterol after PS intervention. In support of our clinical observations, nonresponding mice showed a 77% higher (P = 0.001) basal cholesterol FSR than that of responding hamsters. Compared with control mice, PS-fed mice showed an increase in hepatic nuclear sterol regulatory element binding protein 2 abundance (1.3-fold of control, P = 0.04) and b-hydroxy-b-methylglutaryl coenzyme A reductase‐mRNA expression (2.4-fold of control, P = 0.00). Conclusion: The results suggest that subjects with high basal cholesterol synthesis are less responsive to PS treatment than are subjects with low basal cholesterol synthesis. Am J Clin Nutr 2010; 92:41‐6.

Publisher Summary Human diets and physical activity patterns have changed substantially over the past several millennia. Prior to the advent of the agricultural technologies that emerged 10,000 years ago, human ancestors were primarily hunter-gatherers. While their patterns of intake differed depending on geographic location, climate, and season, it is clear that ancestral diets overall were substantially different from modern-day North-American diets, particularly in terms of energy density and overall food availability. Concurrently, our ancestors had profoundly different activity patterns. The energy required to forage and hunt for food imposed substantial demands on energy expenditure and thus represented a vastly different energy balance model than that typical of modern North Americans. This chapter aims to compare modern-day energy intake and expenditure patterns to those of the Paleolithic era, gleaning insight into tackling the current obesity pandemic.