Effects of magnesium supplementation on carotid intima-media thickness and metabolic profiles in diabetic haemodialysis patients: a randomised, double-blind, placebo-controlled trial.

This study evaluated the effects of Mg administration on carotid intima-media thickness (CIMT), glycaemic control and markers of cardio-metabolic risk in diabetic haemodialysis (HD) patients. This randomised, double-blind, placebo-controlled clinical trial was conducted in fifty-four diabetic HD patients. Participants were randomly divided into two groups to take either 250 mg/d Mg as magnesium oxide (n 27) or placebo (n 27) for 24 weeks. Mg supplementation resulted in a significant reduction in mean (P<0·001) and maximum levels of left CIMT (P=0·02) and mean levels of right CIMT (P=0·004) compared with the placebo. In addition, taking Mg supplements significantly reduced serum insulin levels (ß=-9·42 pmol/l; 95% CI -14·94, -3·90; P=0·001), homoeostasis model of assessment-insulin resistance (ß=-0·56; 95 % CI -0·89, -0·24; P=0·001) and HbA1c (ß=-0·74 %; 95 % CI -1·10, -0·39; P<0·001) and significantly increased the quantitative insulin sensitivity check index (ß=0·008; 95 % CI 0·002, 0·01; P=0·002) compared with the placebo. In addition, Mg administration led to a significant reduction in serum total cholesterol (ß=-0·30 mmol/l; 95% CI -0·56, -0·04; P=0·02), LDL-cholesterol (ß=-0·29 mmol/l; 95% CI -0·52, -0·05; P=0·01), high-sensitivity C-reactive protein (hs-CRP) (P<0·001) and plasma malondialdehyde (MDA) (P=0·04) and a significant rise in plasma total antioxidant capacity (TAC) levels (P<0·001) compared with the placebo. Overall, we found that taking Mg for 24 weeks by diabetic HD patients significantly improved mean and maximum levels of left and mean levels of right CIMT, insulin metabolism, HbA1c, total cholesterol and LDL-cholesterol, hs-CRP, TAC and MDA levels.

Substituting brown rice for white rice on diabetes risk factors in India: a randomised controlled trial.

India has the second largest number of people with type 2 diabetes (T2D) globally. Epidemiological evidence indicates that consumption of white rice is positively associated with T2D risk, while intake of brown rice is inversely associated. Thus, we explored the effect of substituting brown rice for white rice on T2D risk factors among adults in urban South India. A total of 166 overweight (BMI ≥ 23 kg/m2) adults aged 25-65 years were enrolled in a randomised cross-over trial in Chennai, India. Interventions were a parboiled brown rice or white rice regimen providing two ad libitum meals/d, 6 d/week for 3 months with a 2-week washout period. Primary outcomes were blood glucose, insulin, glycosylated Hb (HbA1c), insulin resistance (homeostasis model assessment of insulin resistance) and lipids. High-sensitivity C-reactive protein (hs-CRP) was a secondary outcome. We did not observe significant between-group differences for primary outcomes among all participants. However, a significant reduction in HbA1c was observed in the brown rice group among participants with the metabolic syndrome (-0·18 (se 0·08) %) relative to those without the metabolic syndrome (0·05 (se 0·05) %) (P-for-heterogeneity = 0·02). Improvements in HbA1c, total and LDL-cholesterol were observed in the brown rice group among participants with a BMI ≥ 25 kg/m2 compared with those with a BMI < 25 kg/m2 (P-for-heterogeneity < 0·05). We observed a smaller increase in hs-CRP in the brown (0·03 (sd 2·12) mg/l) compared with white rice group (0·63 (sd 2·35) mg/l) (P = 0·04). In conclusion, substituting brown rice for white rice showed a potential benefit on HbA1c among participants with the metabolic syndrome and an elevated BMI. A small benefit on inflammation was also observed.

Vitamin D supplementation and inflammatory and metabolic biomarkers in patients with knee osteoarthritis: post hoc analysis of a randomised controlled trial.

The aim of this study was to determine whether vitamin D supplementation and maintaining vitamin D sufficiency are associated with changes in inflammatory and metabolic biomarkers in patients with knee osteoarthritis (OA) and vitamin D deficiency. A total of 413 participants with symptomatic knee OA and vitamin D deficiency were enrolled in a randomised, placebo-controlled trial and received 1·25 mg vitamin D3 or placebo monthly for 24 months across two sites. In this post hoc analysis, 200 participants from one site (ninety-four from the placebo group and 106 from the vitamin D group; mean age 63·1 (sd 7·3) years, 53·3 % women) were randomly selected for measurement of serum levels of inflammatory and metabolic biomarkers at baseline and 24 months using immunoassays. In addition, participants were classified into two groups according to serum 25-hydroxyvitamin D (25(OH)D) levels at months 3 and 24: (1) not consistently sufficient (25(OH)D≤50 nmol/l at either month 3 or 24, n 61), and (2) consistently sufficient (25(OH)D>50 nmol/l at both months 3 and 24, n 139). Compared with placebo, vitamin D supplementation had no significant effect on change in serum high-sensitive C-reactive protein, IL-6, IL-8, IL-10, leptin, adiponectin, resistin, adipsin and apelin. Being consistently vitamin D sufficient over 2 years was also not associated with changes in these biomarkers compared with not being consistently sufficient. Vitamin D supplementation and maintaining vitamin D sufficiency did not alter serum levels of inflammatory and metabolic biomarkers over 2 years in knee OA patients who were vitamin D insufficient, suggesting that they may not affect systemic inflammation in knee OA patients.

Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women of reproductive age. Insulin resistance is a main pathophysiologic feature in these patients. According to some studies, the intake of probiotic bacteria may improve glucose homoeostasis. The aim of this study was to investigate the effect of synbiotics on metabolic parameters and apelin in PCOS patients. This randomised double-blind placebo-controlled trial was conducted on eighty-eight PCOS women aged 19-37 years old. The participants were randomly assigned to two groups receiving (1) synbiotic supplement (n 44), and (2) placebo (n 44) for 12 weeks. Fasting blood samples were taken at baseline and after 12 weeks. The two groups showed no difference in fasting blood sugar (adjusted mean difference: 0·60; 95 % CI -3·80, 5·00, P=0·727), plasma glucose fasting 2-h (adjusted mean difference 2·09; 95 % CI -9·96, 14·15, P=0·134), HbA1c (adjusted mean difference 0·06; 95 % CI -0·09, 0·22, P=0·959), homoeostatic model assessment-insulin resistance (HOMA-IR) (adjusted mean difference: 0·02; 95 % CI -0·99, 1·03, P=0·837), quantitative insulin sensitivity check index (QUICKI) (adjusted mean difference: -0·02; 95 % CI -0·33, 0·29, P=0·940) and C-reactive protein (CRP) (adjusted mean difference: 0·24; 95 % CI -1·61, 2·08, P=0·141) by the end of the intervention. A significant difference was observed in the mean apelin 36 before and after the intervention between synbiotic and placebo groups (adjusted mean difference: -4·05; 95 % CI -7·15, -0·96, P=0·004). A 12-week synbiotic supplementation has no significant beneficial effects on HOMA-IR and CRP in PCOS patients, whereas the level of apelin 36 significantly decreased.

Selenium supplementation lowers insulin resistance and markers of cardio-metabolic risk in patients with congestive heart failure: a randomised, double-blind, placebo-controlled trial.

This study was carried out to evaluate the effects of Se supplementation on metabolic profiles in patients with congestive heart failure (CHF). This randomised double-blind, placebo-controlled trial was performed among fifty-three subjects with CHF, aged 45-85 years old. Subjects were randomly allocated into two groups to take either 200 µg/d of Se as Se yeast (n 26) or placebo (n 27) for 12 weeks. Metabolic profiles were assessed at baseline and at the end of trial. Compared with the placebo, Se supplementation led to significant reductions in serum insulin (-18·41 (sd 27·53) v. +13·73 (sd 23·63) pmol/l, P<0·001), homoeostatic model of assessment for insulin resistance (-1·01 (sd 1·61) v. +0·55 (sd 1·20), P<0·001) and a significant increase in quantitative insulin sensitivity check index (QUICKI) (+0·007 (sd 0·03) v. -0·01 (sd 0·01), P=0·007). In addition, Se supplementation significantly decreased LDL-cholesterol (-0·23 (sd 0·29) v. -0·04 (sd 0·28) mmol/l, P=0·03) and total-:HDL-cholesterol ratio (-0·47 (sd 0·31) v. -0·06 (sd 0·42), P<0·001), and significantly increased HDL-cholesterol levels (+0·18 (sd 0·19) v. +0·02 (sd 0·13) mmol/l, P=0·001) compared with the placebo. In addition, taking Se supplements was associated with a significant reduction in high-sensitivity C-reactive protein (hs-CRP) (-1880·8 (sd 3437·5) v. +415·3 (sd 2116·5) ng/ml, P=0·01), and a significant elevation in plasma total antioxidant capacity (TAC) (+30·9 (sd 118·0) v. -187·9 (sd 412·7) mmol/l, P=0·004) and total glutathione levels (+33·7 (sd 130·4) v. -39·2 (sd 132·8) µmol/l, P=0·003) compared with the placebo. When we applied Bonferroni correction for multiple outcome testing, QUICKI (P=0·11), LDL-cholesterol (P=0·51), hs-CRP (P=0·17), TAC (P=0·06) and GSH (P=0·05) became non-significant, and other metabolic profiles did not alter. Overall, our study supported that Se supplementation for 12 weeks to patients with CHF had beneficial effects on insulin metabolism and few markers of cardio-metabolic risk.

Effects of pomegranate supplementation on exercise performance and post-exercise recovery in healthy adults: a systematic review.

The functional significance of pomegranate (POM) supplementation on physiological responses during and following exercise is currently unclear. This systematic review aimed (i) to evaluate the existing literature assessing the effects of POM supplementation on exercise performance and recovery; exercise-induced muscle damage, oxidative stress, inflammation; and cardiovascular function in healthy adults and (ii) to outline the experimental conditions in which POM supplementation is more or less likely to benefit exercise performance and/or recovery. Multiple electronic databases were used to search for studies examining the effects of POM intake on physiological responses during and/or following exercise in healthy adult. Articles were included in the review if they investigated the effects of an acute or chronic POM supplementation on exercise performance, recovery and/or physiological responses during or following exercise. The existing evidence suggests that POM supplementation has the potential to confer antioxidant and anti-inflammatory effects during and following exercise, to improve cardiovascular responses during exercise, and to enhance endurance and strength performance and post-exercise recovery. However, the beneficial effects of POM supplementation appeared to be less likely when (i) unilateral eccentric exercise was employed, (ii) the POM administered was not rich in polyphenols (<1·69 g/l) and (iii) insufficient time was provided between POM-ingestion and the assessment of physiological responses/performance (≤1 h). The review indicates that POM has the potential to enhance exercise performance and to expedite recovery from intensive exercise. The findings and recommendations from this review may help to optimise POM-supplementation practice in athletes and coaches to potentially improve exercise-performance and post-exercise recovery.

Associations between dietary patterns and serum lipids, apo and C-reactive protein in an adult population: evidence from a multi-city cohort in South America.

Several previous epidemiological studies from developed countries have shown that an unhealthy dietary pattern affects plasma lipid levels and inflammation biomarkers. We assessed the cross-sectional associations between dietary patterns and cardiovascular risk factors among 961 adults from a multi-city cohort in South America. We conducted a principal component analysis to derive dietary patterns. As outcomes, we examined plasma levels of apo A-I, apo B, high-sensitivity C-reactive protein (hs-CRP), LDL-, HDL- and serum total cholesterol and TAG. The crude and adjusted changes in each outcome were estimated for quartiles of dietary patterns using multivariable linear regression models. The prudent pattern (PP) characterised by higher intake of fruits, vegetables, fish, seafood, whole cereal and low-fat dairy products was associated with reduced plasma concentrations of apo B (-8·5 mg/l), total cholesterol (-18·8 mg/dl) and LDL-cholesterol (-16·5 mg/dl) and hs-CRP (-1·6 mg/l) in men. In women also reduced plasma concentrations of apo B (-6·6 mg/l), total (-12·0 mg/dl) and LDL (-9·3 mg/dl). The 'Western-like' pattern characterised by higher intake of eggs, pastry and cakes, pizza, snacks, refined grains, red meat, vegetable oils and poultry was not significantly associated with any of the selected serum lipid or inflammatory biomarkers. The explained variances were 10·3 and 7·4 %, respectively. The PP was associated with better lipid profile, mainly lower atherogenic particles (apo B) and LDL-cholesterol and serum total cholesterol. This study provides possible evidence of a prudent diet in South American populations to help reduce the burden of CVD.

The metabolic effects of a commercially available chicken peri-peri (African bird's eye chilli) meal in overweight individuals.

A growing body of evidence suggests that capsaicin ingestion may lead to desirable metabolic outcomes; however, the results in humans are equivocal. Whether or not benefits may be gained from ingestion of capsaicin via a commercially available meal has not been determined. The objectives of this randomised, cross-over intervention study were to compare the 2 h postprandial effects of a standard commercially prepared meal containing chilli (HOT, 5·82 mg total capsaicinoids) with a similar meal with no chilli (CON, 25 kg/m2 and a waist circumference >94 cm (men) or 80 cm (women), were studied. Participants had normal glucose tolerance and were accustomed, but were not regular chilli eaters. A paired t test indicated that insulin AUC was smaller following the HOT meal (P=0·002). Similarly, there was a tendency for glucose AUC to be reduced following the HOT meal (P=0·056). No discernable effects of the HOT meal were observed on metabolic rate, core temperature, hs-CRP concentrations and endothelial-dependent microvascular reactivity. The results from this study indicate that a standard restaurant meal containing a relatively small dose of capsaicin delivered via African bird's eye chilli, which is currently available to the public, results in lower postprandial insulin concentrations in overweight individuals, compared with the same meal without chilli.

Effect of high-protein meal replacement on weight and cardiometabolic profile in overweight/obese Asian Indians in North India.

The aim of the present study was to evaluate the impact of a high-protein meal replacement (HPMR) on weight and metabolic, lipid and inflammatory parameters in overweight/obese Asian Indians. In this 12-week open-label, parallel-arm randomised controlled trial, 122 overweight/obese men and women were administered either a HPMR or a control diet after 2 weeks of diet and exercise run-in. Body weight, waist circumference (WC), percentage body fat (%BF), fasting blood glucose, post-oral glucose tolerance test (post-OGTT) blood glucose, fasting and post-OGTT serum insulin, lipid profile, high-sensitivity C-reactive protein (hs-CRP), kidney function and hepatic aminotransferases were assessed before and after the intervention. Additional improvement in mean values for the following parameters in the HPMR group compared with the control group was observed: body weight, 4·9 % (95 % CI 3·8, 6·1; P<0·001); WC, 3·8 % (95 % CI 2·5, 5·1; P<0·001); %BF, 6·3 % (95 % CI 4·3, 8·2; P<0·001); systolic blood pressure, 2·8 % (95 % CI 0·4, 5·1; P=0·002); diastolic blood pressure, 3·5 % (95 % CI 0·7, 6·3; P= 0·01); post-OGTT blood glucose, 7·3 % (95 % CI 1·4, 13·1; P=0·02); total cholesterol, 2·5 % (95 % CI 1·6, 3·5; P<0·001); LDL-cholesterol, 7·3 % (95 % CI 1·7, 12·9; P<0·01); alanine aminotransferase, 22·0 % (95 % CI 2·1, 42; P=0·03) and aspartate aminotransferase, 15·2 % (95 % CI 0·9, 29·5; P=0·04). The absolute reduction in BMI was 0·9 units in the intervention arm compared with the control arm (-0·9 %, 95 % CI -1·4, -0·5; P<0·001) and in serum TAG was 11·9 mg/dl (-11·9 mg/dl, 95 % CI -21·1, -2·7; P<0·01). The reduction in fasting serum insulin in the intervention v. the control arm was 3·8 v. 0 % (P=0·002); post-OGTT serum insulin was 50·3 v. 77·3 mU/l (P=0·005); and hs-CRP, 16·7 % v. 0 % (P=0·002). These findings show that intervention with HPMR may lead to significant weight loss and improvement in obesity measures, metabolic, lipid and inflammatory parameters and hepatic transaminases in overweight/obese Asian Indians.

Dietary intake of fat and fibre according to reference values relates to higher gut microbiota richness in overweight pregnant women.

The diet-microbiota-metabolism relationships during pregnancy are mostly unknown. We explored the effect of the habitual diet and adherence to the dietary reference values on gut microbiota composition and diversity. Further, the association of gut microbiota with serum lipidomics and low-grade inflammation was evaluated. Overweight and obese women (BMI 30·7 (sd 4·4) kg/m2, n 100) were studied at early pregnancy (≤17 weeks). Intakes of nutrients were calculated from 3-d food diaries. Faecal microbiota composition was analysed using 16S rRNA gene sequencing. Fasting serum lipidomic profiles were determined by NMR. High-sensitivity C-reactive protein, glycoprotein acetylation (GlycA) and lipopolysaccharide activity were used as markers for low-grade inflammation. The recommended dietary intake of fibre and fat was related to higher gut microbiota richness and lower abundance of Bacteroidaceae. Correlations were observed between gut microbiota richness and GlycA and between a few microbiota genera and serum lipoprotein particles. As a conclusion, adherence to the dietary reference intake of fat and fibre was associated with beneficial gut microbiota composition, which again contributed to lipidomic profile. Higher gut microbiota richness and nutrient intakes were linked to a lower level of low-grade inflammation marker GlycA. This finding offers novel insights and opportunities for dietary modification during pregnancy with potential of improving the health of the mother and the child.

Transferrin saturation concentrations associated with telomeric ageing: a population-based study.

There are limited data on the association between Fe overload and leucocyte telomere length (LTL), known as a useful biomarker of the replicative ageing of cells. The aim of the study was to evaluate associations between Fe-status biomarkers and LTL. A cross-sectional study included 1174 men and women aged 50-79 years who provided blood samples for assays of Fe-status biomarkers including ferritin, transferrin saturation (TSAT), total Fe-binding capacity (TIBC) and relative LTL. They were free of hepatitis, potential infection or Fe deficiency. In multiple linear regression analysis adjusted for potential confounding variables, log-transformed LTL was positively associated with TIBC (adjusted coefficient estimate for its highest quartile: 0·17 (se 0·03), P45 %) but also with high-normal concentrations (35-45 %) of TSAT had shorter LTL compared with those with low-normal concentrations (<30 %) (P<0·05). We also observed that less-active or obese persons with high TSAT concentrations had shorter LTL than others. Our findings that cellular ageing is influenced not only by Fe overload but also by high-normal concentrations of TSAT support the hypothesis regarding the detrimental effects of labile Fe, which has a potent pro-oxidant activity in the body.

Synbiotic supplementation and the effects on clinical and metabolic responses in patients with rheumatoid arthritis: a randomised, double-blind, placebo-controlled trial.

Synbiotic intake may be associated with reduced inflammation in patients with rheumatoid arthritis (RA) due to optimised inflammatory markers, oxidative stress and insulin resistance. This research was conducted to assess the effects of synbiotic supplementation on the clinical and metabolic parameters of patients with RA. A total of fifty-four patients with RA were allocated into two groups to receive either a synbiotic capsule (n 27) or a placebo (n 27) for 8 weeks in this randomised, double-blind, placebo-controlled trial. Fasting blood samples were taken at baseline and week 8 of the study to quantify related markers. After the 8-week intervention, compared with the placebo, synbiotic supplementation resulted in a significant reduction in serum high-sensitivity C-reactive protein (hs-CRP) levels (-1427·8 (sd 3267·2) v. +2833·4 (sd 5639·7) ng/ml, P=0·001). In addition, compared with the placebo, synbiotic supplementation improved disease activity score-28 joints (DAS-28) (-1·6 (sd 0·8) v. -0·3 (sd 0·5), P<0·001) and visual analogue scales (VAS) pain (-30·4 (sd 18·7) v. -11·5 (sd 15·9), P<0·001). In addition, a significant elevation in plasma nitric oxide (NO) (+0·8 (sd 4·4) v. -2·6 (sd 4·5) µmol/l, P=0·008), and significant reductions in insulin values (-13·8 (sd 26·4) v. +4·2 (sd 28·2) pmol/l, P=0·01), homoeostasis model of assessment-estimated insulin resistance (HOMA-IR) (-0·5 (sd 1·0) v.+0·1 (sd 1·1), P=0·03) and homoeostatic model assessment-ß-cell function (HOMA-B) (-9·4 (sd 17·9) v. +3·3 (sd 18·9), P=0·01) following supplementation with the synbiotic compared with the placebo. Compared with the placebo, synbiotic supplementation also resulted in a significant increase in plasma GSH (+36·6 (sd 63·5) v. -58·5 (sd 154·4) µmol/l, P=0·005). Overall, our study demonstrated that synbiotic supplementation for 8 weeks among patients with RA had beneficial effects on hs-CRP, DAS-28, VAS, NO, insulin levels, HOMA-IR, HOMA-B and GSH levels.

The effects of selenium supplementation on biomarkers of inflammation and oxidative stress in patients with diabetic nephropathy: a randomised, double-blind, placebo-controlled trial.

This study was carried out to assess the effects of Se supplementation on biomarkers of inflammation and oxidative stress in patients with diabetic nephropathy (DN). This randomised, double-blind, placebo-controlled clinical trial was conducted among sixty patients with DN. Patients were randomly divided into two groups to take either 200 µg/d Se supplements as Se yeast (n 30) or placebo (n 30) for 12 weeks. In unadjusted analyses, compared with the placebo, Se supplementation led to a significant reduction in high-sensitivity C-reactive protein (hs-CRP) (-1069·2 (sd 1752·2) v. -135·3 (sd 1258·9) ng/ml, P=0·02), matrix metalloproteinase-2 (MMP-2) (-612·3 (sd 679·6) v. +76·0 (sd 309·1) ng/ml, P<0·001) and plasma malondialdehyde (MDA) concentrations (-0·1 (sd 0·7) v. +0·4 (sd 0·9) µmol/l, P=0·01). In addition, a significant increase in plasma total antioxidant capacity (TAC) (+174·9 (sd 203·9) v. +15·8 (sd 382·2) mmol/l, P=0·04) was observed following supplementation with Se compared with the placebo. Subjects who received Se supplements experienced a borderline statistically significant decrease in serum protein carbonyl (PCO) levels (P=0·06) compared with the placebo. When we adjusted the analysis for baseline values of biochemical parameters, age and BMI, serum hs-CRP (P=0·14) and MDA levels (P=0·16) became non-significant, whereas plasma nitric oxide (NO) (P=0·04) and glutathione (GSH) (P<0·001) became statistically significant, and other findings did not change. Supplementation with Se had no significant effect on NO, transforming growth factor ß (TGF-ß), advanced glycation end products (AGE), PCO and GSH compared with the placebo. Overall, our study demonstrated that Se supplementation among DN patients had favourable effects on serum MMP-2, plasma NO, TAC and GSH, but did not affect hs-CRP, TGF-ß, AGE, PCO and MDA.

The effects of vitamin D, K and calcium co-supplementation on carotid intima-media thickness and metabolic status in overweight type 2 diabetic patients with CHD.

This study was conducted to examine the effects of vitamin D, K and Ca co-supplementation on carotid intima-media thickness (CIMT) and metabolic status in overweight diabetic patients with CHD. This randomised, double-blind, placebo-controlled trial was conducted among sixty-six diabetic patients with CHD. Participants were randomly allocated into two groups to take either 5µg vitamin D, 90 µg vitamin K plus 500 mg Ca supplements (n 33) or placebo (n 33) twice a day for 12 weeks. Fasting blood samples were obtained at the beginning of the study and after the 12-week intervention period to determine related markers. Vitamin D, K and Ca co-supplementation resulted in a significant reduction in maximum levels of left CIMT (-0·04 (sd 0·22) v. +0·04 (sd 0·09) mm, P=0·02). Changes in serum vitamin D (+6·5 (sd 7·8) v. +0·4 (sd 2·2) ng/ml, P<0·001), Ca (+0·6 (sd 0·3) v. +0·1 (sd 0·1) mg/dl, P<0·001) and insulin concentrations (-0·9 (sd 3·1) v. +2·6 (sd 7·2) µIU/ml, P=0·01), homoeostasis model for assessment of estimated insulin resistance (-0·4 (sd 1·2) v. +0·7 (sd 2·3), P=0·01), ß-cell function (-2·1 (sd 9·0) v. +8·9 (sd 23·7), P=0·01) and quantitative insulin sensitivity check index (+0·007 (sd 0·01) v. -0·006 (sd 0·02), P=0·01) in supplemented patients were significantly different from those in patients in the placebo group. Supplementation resulted in significant changes in HDL-cholesterol (+2·7 (sd 7·0) v. -2·5 (sd 5·7) mg/dl, P=0·002), high-sensitivity C-reactive protein (-1320·1 (sd 3758·3) v. +464·0 (sd 3053·3) ng/ml, P=0·03) and plasma malondialdehyde concentrations (-0·4 (sd 0·5) v. -1·0 (sd 1·1) µmol/l, P=0·007) compared with placebo. Overall, vitamin D, K and Ca co-supplementation for 12 weeks among diabetic patients with CHD had beneficial effects on maximum levels of left CIMT and metabolic status. The effect of vitamin D, K and Ca co-supplementation on maximum levels of left CIMT could be a chance finding.

Oxidative stress and nitric oxide are increased in obese children and correlate with cardiometabolic risk and renal function.

Oxidative stress and nitric oxide (NO) appear to represent important links between obesity and cardiovascular, metabolic and/or renal disease. We investigated whether oxidative stress and NO production/metabolism are increased in overweight and obese prepubertal children and correlate with cardiometabolic risk and renal function. We performed a cross-sectional evaluation of 313 children aged 8-9 years. Anthropometrics, 24-h ambulatory blood pressure, pulse wave velocity (PWV), insulin resistance (homoeostasis model assessment index (HOMA-IR)), inflammatory/metabolic biomarkers, estimated glomerular filtration rate (eGFR), plasma total antioxidant status (TAS), plasma and urinary isoprostanes (P-Isop, U-Isop), urinary hydrogen peroxide (U-H2O2), and plasma and urinary nitrates and nitrites (P-NOx, U-NOx) were compared among normal weight, overweight and obese groups, according to WHO BMI z-score reference. U-Isop were increased in the obese group, whereas U-NOx were increased in both overweight and obese children. U-Isop were positively correlated with U-H2O2, myeloperoxidase (MPO), high-sensitivity C-reactive protein, HOMA-IR and TAG. TAS correlated negatively with U-Isop and MPO and positively with PWV. HOMA-IR and U-H2O2 were associated with higher U-Isop, independently of BMI and eGFR, and total cholesterol and U-H2O2 were associated with U-NOx, independently of BMI, eGFR values and P-NOx concentration. In overweight and obese children, eGFR decreased across P-NOx tertiles (median: 139·3 (25th, 75th percentile 128·0, 146·5), 128·0 (25th, 75th percentile 121·5, 140·4), 129·5 (25th, 75th percentile 119·4, 138·3), P for linear trend=0·003). We conclude that oxidant status and NO are increased in relation to fat accumulation and, even in young children, they translate into higher values of cardiometabolic risk markers and affect renal function.

The effects of moderate energy restriction on apnoea severity and CVD risk factors in obese patients with obstructive sleep apnoea.

Nutritional intervention for weight loss is one of the treatment options for obstructive sleep apnoea (OSA) in patients with overweight or obesity. However, the effects of moderate energy restriction on OSA severity are not yet known. The present study aimed to evaluate the effects of moderate energy restriction on OSA severity and CVD risk factors in obese patients with OSA. In this 16-week randomised clinical trial, twenty-one obese subjects aged 20-55 years and presenting an apnoea/hypopnoea index (AHI)≥5 events/h were randomised into two groups: the energy restriction group (ERG) and the control group (CG). The ERG was instructed to follow an energy-restricted diet -3347·2 kJ/d (-800 kcal/d) and the CG was advised not to change their food intake. At the beginning and at the end of the study, participants underwent evaluation of the following: OSA (Watch-PAT200®), nutritional parameters, blood pressure, sympathetic activity, inflammatory biomarkers, metabolic profile and endothelial function. The ERG (n 11), compared with the CG (n 10), had a significantly greater reduction in body weight (Cohen's d=-1·19; P<0·001), in AHI (Cohen's d=-0·95; P=0·04) and in plasma concentrations of adrenaline (Cohen's d=-1·02; P=0·04) as well as a significantly greater increase in minimum O2 saturation (Cohen's d=1·08; P=0·03). Although energy restriction was not associated with significant improvements in CVD risk factors, medium-to-large effect sizes were observed, suggesting that the statistically non-significant difference between groups may be due to the small sample size. This study suggests that in obese patients with OSA, moderate energy restriction is able to reduce the parameters of OSA severity and sympathetic activity.

A tryptophan metabolite prevents depletion of circulating endothelial progenitor cells in systemic low-grade inflammation.

Background: Chronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated. Methods: In this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation. Results: Repeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity. Interpretation: Overall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation.

HS-CRP Modifies the Prognostic Value of Platelet Count for Clinical Outcomes After Ischemic Stroke.

Background We examined whether the relationship between baseline platelet count and clinical outcomes is modulated by HS-CRP (high-sensitivity C-reactive protein) in patients with ischemic stroke. Methods and Results A total of 3267 patients with ischemic stroke were included in the analysis. The primary outcome was a combination of death and major disability at 1 year after ischemic stroke. Secondary outcomes included major disability, death, vascular events, composite outcome of vascular events or death, and an ordered 7-level categorical score of the modified Rankin Scale at 1 year. Multivariate logistic regression and Cox proportional hazards regression models were used to assess the association between the baseline platelet count and clinical outcomes stratified by HS-CRP levels when appropriate. There was an interaction effect of platelet count and HS-CRP on the adverse clinical outcomes after ischemic stroke (all Pinteraction<0.05). The elevated platelet count was significantly associated with the primary outcome (odds ratio [OR], 3.14 [95% CI, 1.77-5.58]), major disability (OR, 2.07 [95% CI, 1.15-3.71]), death (hazard ratio [HR], 2.75 [95% CI, 1.31-5.79]), and composite outcome of vascular events or death (HR, 2.57 [95% CI, 1.38-4.87]) among patients with high HS-CRP levels (all Ptrend<0.05). Conclusions The HS-CRP levels had a modifying effect on the association between platelet count and clinical outcomes in patients with ischemic stroke. Elevated platelet count was significantly associated with adverse clinical outcomes in patients with ischemic stroke with high HS-CRP levels, but not in those with low HS-CRP levels. These findings suggest that strategies for anti-inflammatory and antiplatelet therapy should be developed according to the results of both platelet and HS-CRP testing.

Effects of the Dietary Approaches to Stop Hypertension Diet on Change in Cardiac Biomarkers Over Time: Results From the DASH-Sodium Trial.

Background The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to reduce biomarkers of cardiovascular disease. We aimed to characterize the time course of change in biomarkers of cardiac injury (high-sensitivity cardiac troponin I), cardiac strain (NT-proBNP [N-terminal pro-B-type natriuretic peptide]), and inflammation (hs-CRP [high-sensitivity C-reactive protein]) while consuming the DASH diet. Methods and Results The DASH-Sodium trial was a randomized controlled trial of 412 adults with elevated blood pressure or hypertension. Participants were randomly assigned to 12 weeks of the DASH diet or a typical American diet. Energy intake was adjusted to maintain body weight. Measurements of high-sensitivity cardiac troponin I, NT-proBNP, and hs-CRP were performed in stored serum specimens, collected at baseline and ≈4, 8, and 12 weeks after randomization. In both the control diet and DASH diet, levels of NT-proBNP decreased; however, there was no difference between diets (P-trend compared with control=0.22). On the DASH diet versus control, levels of high-sensitivity cardiac troponin I decreased progressively during follow-up (P-trend compared with control=0.025), but a statistically significant between-diet difference in change from baseline levels was not observed until week 12 (% difference, 17.78% [95% CI, -29.51% to -4.09%]). A similar pattern was evident for hs-CRP (P-trend compared with control=0.01; % difference at week 12, 19.97% [95% CI, -31.94% to -5.89%]). Conclusions In comparison with a typical American diet, the DASH diet reduced high-sensitivity cardiac troponin I and hs-CRP progressively over 12 weeks. These results suggest that the DASH diet has cumulative benefits over time on biomarkers of subclinical cardiac injury and inflammation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000608.

A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis.

Background & Aims: Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Methods: Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Results: Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] -9 µg/L efruxifermin vs. -3.4 µg/L placebo; p = 0.0130) and ELF score (-0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB -5.7 kPa efruxifermin vs. -1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Conclusions: Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Lay summary: Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. Clinical Trial Number: NCT03976401.