Benefits and Harms of Edible Vegetable Oils and Fats Fortified with Vitamins A and D as a Public Health Intervention in the General Population: A Systematic Review of Interventions.

This systematic review aims to assess whether edible vegetable oils and fats fortified with vitamin A and/or D are effective and safe in improving vitamin intake and ameliorating deficiency states in the general population. In November 2022, we systematically searched MEDLINE, Cochrane CENTRAL, Scopus, Global Index Medicus, ClinicalTrials.gov, and WHO ICTRP (International Clinical Trials Registry Platform) for randomized controlled trials (RCT) and non-randomized studies of interventions (NRSI) investigating the fortification of edible vegetable oils and fats with either vitamin A or vitamin D or both as compared to the same vegetable oils and/or fats without vitamin A and D fortification or no interventions, in the general population, without age restriction. We assessed the methodological quality of included RCTs using Cochrane's risk of bias tool 2.0 and of NRSIs using ROBINS-I tool. We performed random-effects meta-analysis and assessed certainty of evidence using GRADE. We included eight studies. Available evidence showed no significant effect of fortification with vitamin A on serum retinol levels (RCTs: MD 0.35 µmol/L, 95% CI -0.43 to 1.12; two trials; 514 participants; low-certainty evidence; CCTs: MD 0.31 µmol/L, 95% CI -0.18 to 0.80; two trials; 205 participants; very low-certainty evidence) and on subclinical vitamin A deficiency. Low-certainty evidence showed no effect of vitamin D fortification on serum 25-hydroxy vitamin D concentration (MD 6.59 nmol/L, 95% CI -6.89 to 20.07; one trial; 62 participants). In conclusion, vitamin A-fortified vegetable oils and fats may result in little to no difference in serum retinol levels in general populations. The dose of vitamin A used in the trials may be safe but may not be sufficient to reduce subclinical vitamin A deficiency. Further, the evidence suggests that vitamin D fortification results in little to no difference in serum 25-hydroxy vitamin D concentration. Several aspects of providing fortified oils and fats to the general population as a public health intervention should be further investigated, including optimal fortification dose, effects on vitamin D deficiency and its clinical symptoms and potential adverse effects.

Effects of a gluten-reduced or gluten-free diet for the primary prevention of cardiovascular disease.

BACKGROUND: Cardiovascular diseases (CVD) are a major cause of disability and the leading cause of death worldwide. To reduce mortality and morbidity, prevention strategies such as following an optimal diet are crucial. In recent years, low-gluten and gluten-free diets have gained strong popularity in the general population. However, study results on the benefits of a gluten-reduced or gluten-free diet are conflicting, and it is unclear whether a gluten-reduced diet has an effect on the primary prevention of CVD. OBJECTIVES: To determine the effects of a gluten-reduced or gluten-free diet for the primary prevention of CVD in the general population. SEARCH METHODS: We systematically searched CENTRAL, MEDLINE, Embase, CINAHL and Web of Science up to June 2021 without language restrictions or restrictions regarding publication status. Additionally, we searched ClinicalTrials.gov for ongoing or unpublished trials and checked reference lists of included studies as well as relevant systematic reviews for additional studies. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs), such as prospective cohort studies, comparing a low-gluten or gluten-free diet or providing advice to decrease gluten consumption with no intervention, diet as usual, or a reference gluten-intake category. The population of interest comprised adults from the general population, including those at increased risk for CVD (primary prevention). We excluded cluster-RCTs, case-control studies, studies focusing on participants with a previous myocardial infarction and/or stroke, participants who have undergone a revascularisation procedure as well as participants with angina or angiographically-defined coronary heart disease, with a confirmed diagnosis of coeliac disease or with type 1 diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility of studies in a two-step procedure following Cochrane methods. Risk of bias (RoB) was assessed using the Cochrane risk of bias tool (RoB2) and the 'Risk Of Bias In Non-randomised Studies - of Interventions' (ROBINS-I) tool, and the certainty of evidence was rated using the GRADE approach. MAIN RESULTS: One RCT and three NRSIs (with an observational design reporting data on four cohorts: Health Professionals Follow-up Study (HPFS), Nurses' Health Study (NHS-I), NHS-II, UK Biobank) met the inclusion criteria. The RCT was conducted in Italy (60 participants, mean age 41 ± 12.1 years), two NRSIs (three cohorts, HPFS, NHS-I, NHS II) were conducted across the USA (269,282 health professionals aged 24 to 75 years) and one NRSI (Biobank cohort) was conducted across the UK (159,265 participants aged 49 to 62 years). Two NRSIs reported that the lowest gluten intake ranged between 0.0 g/day and 3.4 g/day and the highest gluten intake between 6.2 g/day and 38.4 g/day. The NRSI reporting data from the UK Biobank referred to a median gluten intake of 8.5 g/day with an interquartile range from 5.1 g/day to 12.4 g/day without providing low- and high-intake categories. Cardiovascular mortality From a total of 269,282 participants, 3364 (1.3%) died due to cardiovascular events during 26 years of follow-up. Low-certainty evidence may show no association between gluten intake and cardiovascular mortality (adjusted hazard ratio (HR) for low- versus high-gluten intake 1.00, 95% confidence interval (CI) 0.95 to 1.06; 2 NRSIs (3 cohorts)). All-cause mortality From a total of 159,265 participants, 6259 (3.9%) died during 11.1 years of follow-up. Very low-certainty evidence suggested that it is unclear whether gluten intake is associated with all-cause mortality (adjusted HR for low vs high gluten intake 1.00, 95% CI 0.99 to 1.01; 1 NRSI (1 cohort)). Myocardial infarction  From a total of 110,017 participants, 4243 (3.9%) participants developed non-fatal myocardial infarction within 26 years. Low-certainty evidence suggested that gluten intake may not be associated with the development of non-fatal myocardial infarction (adjusted HR for low versus high gluten intake 0.99, 95% CI 0.89 to 1.10; 1 NRSI (2 cohorts)). Lowering gluten intake by 5 g/day also showed no association on the primary prevention of non-fatal and fatal myocardial infarction (composite endpoint) in linear dose-response meta-analyses (adjusted HR 1.02, 95% CI 0.98 to 1.06; 1 NRSI (2 cohorts)). Coronary risk factors  Type 2 diabetes From a total of 202,114 participants, 15,947 (8.0%) developed type 2 diabetes after a follow-up between 22 and 28 years. There was low-certainty evidence that a lower compared with a higher gluten intake may be associated with a slightly increased risk to develop type 2 diabetes (adjusted HR 1.14, 95% CI 1.07 to 1.22; 1 NRSI (3 cohorts)). Furthermore, lowering gluten intake by 5 g/day may be associated with a slightly increased risk to develop type 2 diabetes in linear dose-response meta-analyses (adjusted HR 1.12, 95% CI 1.08 to 1.16; 1 NRSI (3 cohorts)). Blood pressure, low-density lipoprotein level, body mass index (BMI) After six months of follow-up, very low-certainty evidence suggested that it is unclear whether gluten intake affects systolic blood pressure (mean difference (MD) -6.9, 95% CI -17.1 to 3.3 mmHg). There was also no difference between the interventions for diastolic blood pressure (MD -0.8, 95% CI -5.9 to 4.3 mmHg), low-density lipoprotein levels (MD -0.1, 95% CI -0.5 to 0.3 mmol/L) and BMI (MD -0.1, 95% CI -3.3 to 3.1 kg/m²).  No study reported data on adverse events or on other outcomes. Funding sources did not appear to have distorted the results in any of the studies. AUTHORS' CONCLUSIONS: Very low-certainty evidence suggested that it is unclear whether gluten intake is associated with all-cause mortality. Our findings also indicate that low-certainty evidence may show little or no association between gluten intake and cardiovascular mortality and non-fatal myocardial infarction. Low-certainty evidence suggested that a lower compared with a higher gluten intake may be associated with a slightly increased risk to develop type 2 diabetes - a major cardiovascular risk factor. For other cardiovascular risk factors it is unclear whether there is a difference between a gluten-free and normal diet. Given the limited findings from this review predominantly based on observational studies, no recommendations for practice can be made.

A1- and A2 beta-casein on health-related outcomes: a scoping review of animal studies.

PURPOSE: Food-derived bioactive peptides may influence important physiological functions. An important example is beta-casomorphins, which are opioid peptides derived from A1 beta-casein in bovine milk and have been associated to be risk factors for non-communicable diseases in humans. A1 and A2 beta-casein are different with respect to the release of bioactive peptides, in particular BCM-7. However, evidence from human studies is limited and could be complemented with evidence derived from animal studies. We conducted a scoping review to identify animal studies investigating the effects of A1 beta-casein or BCM-7 compared to A2 beta-casein or any other intervention on health-related outcomes. METHODS: We systematically searched for relevant studies in two electronic databases (Medline, Embase; last search performed March 2020). Two reviewers independently undertook study selection and data extraction of included references. Results were summarized tabularly and narratively. RESULTS: We included 42 studies investigating various animal models, including rats, mice, rabbits, and dogs. Six studies investigated health-related outcomes of A1- vs. A2 milk, while most studies (n = 36) reported on physiological properties (e.g., analgesic effect) of BCM-7 as an opioid peptide. Included studies were extremely heterogeneous in terms of the study population, type of intervention and dose, and type of outcome measures. CONCLUSIONS: Only a few studies comparing the effects of A1- and A2 milk were identified. More studies addressing this research question in animal models are needed to provide essential information to inform research gaps. Results from future studies could eventually complement research for humans, particularly when the body of evidence remains uncertain as is the case in the A1- and A2 milk debate.

Predicting negative health outcomes in older general practice patients with chronic illness: Rationale and development of the PROPERmed harmonized individual participant data database.

The prevalence of multimorbidity and polypharmacy increases significantly with age and are associated with negative health consequences. However, most current interventions to optimize medication have failed to show significant effects on patient-relevant outcomes. This may be due to ineffectiveness of interventions themselves but may also reflect other factors: insufficient sample sizes, heterogeneity of population. To address this issue, the international PROPERmed collaboration was set up to obtain/synthesize individual participant data (IPD) from five cluster-randomized trials. The trials took place in Germany and The Netherlands and aimed to optimize medication in older general practice patients with chronic illness. PROPERmed is the first database of IPD to be drawn from multiple trials in this patient population and setting. It offers the opportunity to derive prognostic models with increased statistical power for prediction of patient-relevant outcomes resulting from the interplay of multimorbidity and polypharmacy. This may help patients from this heterogeneous group to be stratified according to risk and enable clinicians to identify patients that are likely to benefit most from resource/time-intensive interventions. The aim of this manuscript is to describe the rationale behind PROPERmed collaboration, characteristics of the included studies/participants, development of the harmonized IPD database and challenges faced during this process.

Non-nutritive sweeteners for diabetes mellitus.

BACKGROUND: Products sweetened with non-nutritive sweeteners (NNS) are widely available. Many people with type 1 or type 2 diabetes use NNS as a replacement for nutritive sweeteners to control their carbohydrate and energy intake. Health outcomes associated with NNS use in diabetes are unknown. OBJECTIVES: To assess the effects of non-nutritive sweeteners in people with diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Scopus, the WHO ICTRP, and ClinicalTrials.gov. The date of the last search of all databases (except for Scopus) was May 2019. We last searched Scopus in January 2019. We did not apply any language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of four weeks or more comparing any type of NNS with usual diet, no intervention, placebo, water, a different NNS, or a nutritive sweetener in individuals with type 1 or type 2 diabetes. Trials with concomitant behaviour-changing interventions, such as diet, exercise, or both, were eligible for inclusion, given that the concomitant interventions were the same in the intervention and comparator groups. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts, full texts, and records retrieved from trials registries, assessed the certainty of the evidence, and extracted data. We used a random-effects model to perform meta-analysis, and calculated effect estimates as risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs). We assessed risk of bias using the Cochrane 'Risk of bias' tool and the certainty of evidence using the GRADE approach. MAIN RESULTS: We included nine RCTs that randomised a total of 979 people with type 1 or type 2 diabetes. The intervention duration ranged from 4 to 10 months. We judged none of these trials as at low risk of bias for all 'Risk of bias' domains; most of the included trials did not report the method of randomisation. Three trials compared the effects of a dietary supplement containing NNS with sugar: glycosylated haemoglobin A1c (HbA1c) was 0.4% higher in the NNS group (95% CI -0.5 to 1.2; P = 0.44; 3 trials; 72 participants; very low-certainty evidence). The MD in weight change was -0.1 kg (95% CI -2.7 to 2.6; P = 0.96; 3 trials; 72 participants; very low-certainty evidence). None of the trials with sugar as comparator reported on adverse events. Five trials compared NNS with placebo. The MD for HbA1c was 0%, 95% CI -0.1 to 0.1; P = 0.99; 4 trials; 360 participants; very low-certainty evidence. The 95% prediction interval ranged between -0.3% and 0.3%. The comparison of NNS versus placebo showed a MD in body weight of -0.2 kg, 95% CI -1 to 0.6; P = 0.64; 2 trials; 184 participants; very low-certainty evidence. Three trials reported the numbers of participants experiencing at least one non-serious adverse event: 36/113 participants (31.9%) in the NNS group versus 42/118 participants (35.6%) in the placebo group (RR 0.78, 95% CI 0.39 to 1.56; P = 0.48; 3 trials; 231 participants; very low-certainty evidence). One trial compared NNS with a nutritive low-calorie sweetener (tagatose). HbA1c was 0.3% higher in the NNS group (95% CI 0.1 to 0.4; P = 0.01; 1 trial; 354 participants; very low-certainty evidence). This trial did not report body weight data and adverse events. The included trials did not report data on health-related quality of life, diabetes complications, all-cause mortality, or socioeconomic effects. AUTHORS' CONCLUSIONS: There is inconclusive evidence of very low certainty regarding the effects of NNS consumption compared with either sugar, placebo, or nutritive low-calorie sweetener consumption on clinically relevant benefit or harm for HbA1c, body weight, and adverse events in people with type 1 or type 2 diabetes. Data on health-related quality of life, diabetes complications, all-cause mortality, and socioeconomic effects are lacking.