Effects of boron citrate supplementation on cardiometabolic factors, inflammatory biomarkers and anthropometric measures in obese patients: study protocol for a randomised, double-blind clinical trial.

INTRODUCTION: Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. The efficacy and safety of boron citrate (BC), a novel therapeutic approach, in patients with obesity are not known. The current trial will take place to determine the effects of BC supplementation on cardiometabolic factors, inflammatory biomarkers, anthropometric measures and body composition in obese patients. METHODS AND ANALYSIS: This double-blind, placebo-controlled, randomised clinical trial will involve 60 eligible obese participants aged 18-60 years. Participants will randomly be allocated to receive either BC capsules (containing 10 mg of boron) in the intervention group or placebo capsules (containing 10 mg of maltodextrin) in the placebo group for 12 weeks. Moreover, physical activity and dietary recommendations will be provided for both groups. To assess the dietary intakes of participants, a 3-day food record (2 days of the week and 1 day of the weekend) will be filled. Cardiometabolic factors, inflammatory biomarkers including tumour necrosis factor α, C reactive protein, interleukin-6 and interleukin-10 levels, anthropometric measures and body composition will be assessed at the baseline and end of the intervention. The findings of this study will provide evidence for the effectiveness of BC in the management of obesity. ETHICS AND DISSEMINATION: There are so far no reported adverse effects associated with the use of boron. This trial was approved by the Ethics Committee of Tabriz University of Medical Sciences (approval number: IR.TBZMED.REC.1401.350). Positive as well as negative findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: IRCT20220806055624N1.

Yogurt consumption and risk of mortality from all causes, CVD and cancer: a comprehensive systematic review and dose-response meta-analysis of cohort studies.

OBJECTIVES: To quantify the dose-response relation between yogurt consumption and risk of mortality from all causes, CVD and cancer. DESIGN: Systematic review and meta-analysis. SETTING: We conducted a comprehensive search of PubMed/Medline, ISI Web of Science and Scopus databases through August 2022 for cohort studies reporting the association of yogurt consumption with mortality from all causes, CVD and cancer. Summary relative risks (RR) and 95 % CI were calculated with a random-effects model. PARTICIPANTS: Seventeen cohort studies (eighteen publications) of 896 871 participants with 75 791 deaths (14 623 from CVD and 20 554 from cancer). RESULTS: High intake of yogurt compared with low intake was significantly associated with a lower risk of deaths from all causes (pooled RR 0·93; 95 % CI: 0·89, 0·98, I2 = 47·3 %, n 12 studies) and CVD (0·89; 95 % CI: 0·81, 0·98, I2 = 33·2 %, n 11), but not with cancer (0·96; 95 % CI: 0·89, 1·03, I2 = 26·5 %, n 12). Each additional serving of yogurt consumption per d was significantly associated with a reduced risk of all-cause (0·93; 95 % CI: 0·86, 0·99, I2 = 63·3 %, n 11) and CVD mortality (0·86; 95 % CI: 0·77, 0·99, I2 = 36·6 %, n 10). There was evidence of non-linearity between yogurt consumption and risk of all-cause and CVD mortality, and there was no further reduction in risk above 0·5 serving/d. CONCLUSION: Summarising earlier cohort studies, we found an inverse association between yogurt consumption and risk of all-cause and CVD mortality; however, there was no significant association between yogurt consumption and risk of cancer mortality.

Sodium selenite and Se-enriched yeast supplementation in atherosclerotic patients: Effects on the expression of pyroptosis-related genes and oxidative stress status.

BACKGROUND AND AIMS: Atherosclerosis as a chronic inflammatory disorder of the arterial wall is the main leading cause of the cardiovascular disease (CVD). Caspase-dependent pyroptosis plays a pivotal role in the pathogenesis of CVD. Selenium (Se) is an important component of the antioxidant defense and plays a crucial role in cardiovascular health. This study aimed to investigate the effects of daily consumption of sodium selenite and Se-enriched yeast on the expression of pyroptosis-related genes, and biomarkers of oxidative stress in patients with atherosclerosis. METHODS AND RESULTS: In this randomized, double-blinded, placebo-controlled clinical trial, 60 patients with atherosclerosis were recruited. Participants received 200 µg/day of sodium selenite, Se-enriched yeast, or placebo for 8 following weeks. The pyroptosis-related genes' mRNA expression in peripheral blood mononuclear cells (PBMCs) was assessed before and after the intervention. Also, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and glutathione peroxidases (GPX) were measured at baseline and following the intervention. Following sodium selenite and Se-enriched yeast supplementation, the relative expression levels of TLR4, ASC, NLRP3, and NF-κB1 were significantly downregulated (p < 0.05). Furthermore, the changes in GPX were significantly increased after selenite and yeast supplementation (p < 0.05). Also, selenite and yeast consumption caused a statistically significant decrease in the change of MDA level (p < 0.05). CONCLUSION: In summary, these findings showed that Se supplementation may reduce inflammation through down-regulation of some pro-inflammatory genes, improving antioxidant defenses in atherosclerosis patients. Further research is required to come to a definite conclusion of selenium supplementation on the CVD risk. This study was registered on the Iranian Registry of Clinical Trials website (identifier: RCT20110123005670N28; https://www.irct.ir/).

Total, dietary, and supplemental calcium intake and risk of all-cause cardiovascular, and cancer mortality: a systematic review and dose-response meta-analysis of prospective cohort studies.

Considerable controversy exists regarding the association between calcium intake and mortality risk. Therefore, this study aimed to summarize available findings on the associations of total, dietary and supplemental calcium intake with all-cause, CVD, and cancer mortality. We searched PubMed, Scopus, Embase, and ISI Web of Knowledge until February 2020 to identify eligible publications. Random-effects models were used to calculate pooled effect sizes (ESs) and 95% confidence intervals (CIs) for highest versus lowest categories of calcium intake and to incorporate variation between studies. Linear and non-linear dose-response analyses were done to evaluate the dose-response relations between calcium intake and mortality. 36 publications were included in this systematic review and 35 in the meta-analysis. During the follow-up periods ranging from 4.2 to 28 years, the total number of deaths from all causes was 163,657 (83703 from CVD and 83929 from cancer). Total calcium intake was associated with a lower risk of CVD mortality (Pooled ES for highest v lowest category: 0.91; 95% CI: 0.83-0.99, I2=68.1%, P < 0.001). Dietary calcium intake was associated with a lower risk of all-cause mortality (Pooled ES for highest v lowest category: 0.95; 95% CI: 0.92-0.99, I2=62.1%, P < 0.001). Supplemental calcium intake was not significantly associated with risk of all-cause, CVD and cancer mortality. In the dose-response analysis, there was evidence of nonlinear association between calcium intake and risk of all-cause, CVD, and cancer mortality. In conclusion, a non-linear association between calcium intake with all-cause, CVD, and cancer mortality risk was observed in this meta-analysis. Moderate intake of total (1000-1800), dietary (600-1200), and supplemental calcium (600-1200) was inversely significantly associated with mortality risk but higher calcium intake was not associated with a lower risk of mortality.

The relationship between Dietary Inflammatory Index and disease severity and inflammatory status: a case-control study of COVID-19 patients.

Numerous studies have revealed strong relationships between COVID-19 and inflammation. However, the imminent link between diet-related inflammation and the COVID-19 risk has not been addressed before. So, we explored the capability of the Energy-Adjusted Dietary Inflammatory Index (E-DII) to predict the inflammatory markers, incidence and severity of COVID-19. We conducted a case-control study consisting of 120 adults; they had been admitted for COVID-19 at hospital during June and July, 2020. The E-DII score was calculated based on the dietary intake, which was evaluated by a 138-item semi-quantitative food frequency questionnaire. Serum levels of inflammatory markers including the Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and White blood cells (WBCs) differential were measured. Severity of disease was assessed by chest radiology criteria. Patients with the maximum pro-inflammatory energy adjusted E-DII score had 7·26 times greater odds of developing COVID-19, as compared to those in tertiles 1 (E-DII T3v. E-DII T1: OR = 7·26; 95 % CI 2·64 to 9·94, P < 0·001). Also, a positive association between E-DII and C-reactive protein (CRP) was observed (BE-DII = 1·37, 95 % CI 0·72, 2·02), such that with each unit increase in E-E-DII, the CRP levels were increased by 1·37 units. Furthermore, a significant association was found between E-DII and the severity of disease (BE-DII = 0·03, 95 % CI 0·01, 0·06. 0·024). Patients consuming a diet with a higher pro-inflammatory potential were at a greater risk of COVID-19 occurrence; also, the severity of disease was elevated with a high score inflammatory diet.

A novel inflammatory signaling pathway in patients with slow coronary flow: NF-κB/IL-1ß/nitric oxide.

PURPOSE: The slow coronary flow (SCF) was identified as delayed opacification of epicardial coronary arteries in the absence of stenotic lesion. Metabolic syndrome (MetS), oxidative stress, and inflammation may be possible known insulting factors for the pathogenesis of SCF. This investigation aimed to assess the relationship between some inflammatory markers, oxidative stress parameters and MetS components with SCF phenomenon. METHODS: A total of 35 patients with SCF and 35 subjects with normal coronary flow (NCF) were included in the study. We assessed some inflammatory markers (IL-1ß, IL-18, TNF-α, and NF-κB mRNA expression in peripheral blood mononuclear cells (PBMCs)). Moreover, blood samples of the participants were tested for total antioxidant capacity (TAC), glutathione peroxidase (GPX) and nitric oxide (NO) levels using enzyme-linked immunosorbent assay (ELISA). Diagnosis of MetS was based on the National Cholesterol Education Program's Adult Treatment Panel III report (ATPIII) criteria, 2005. Diagnostic criteria for coronary flow rates of all subjects were documented by thrombolysis in myocardial infarction (TIMI) frame count method. RESULTS: SCF patients had significantly higher prevalence of MetS (46%, p = 0.048).We found that the level of TAC was significantly higher in the NCF group (p = 0.006). Furthermore, the NO concentration was significantly lower in SCF groups (p = 0.001). A significant incremental difference was detected in IL-1ß (fold change 2.82 ± 0.31, p < 0.05) and NF-κB (fold change 4.62 ± 0.32, p < 0.05) mRNA expression in the SCF group when compared with its level in the NCF group. Furthermore, according to logistic regression analysis, there were significant associations between IL-1ß, NF-κB expression levels and the incidence of SCF (p < 0.05). CONCLUSION: Based on the findings of this study, the pathogenesis of the SCF phenomenon may be closely associated with metabolic syndrome and inflammation. The NF-κB/IL-1ß/nitric oxide & MetS signaling pathway might be considered as potential therapeutic targets in the management of SCF patients but further researches is required to guarantee these findings.

Effects of sodium selenite and selenium-enriched yeast on cardiometabolic indices of patients with atherosclerosis: A double-blind randomized clinical trial study.

Introduction: Atherosclerosis and related cardiovascular diseases (CVDs) are the major causes of mortality worldwide. The available reports regarding the effects of selenium (Se) supplementation in the realm of atherosclerosis have been equivocal. The present investigation is aimed to assess the effects of sodium selenite and Se-enriched yeast supplementation on metabolic parameters among atherosclerotic patients. Methods: In this double-blind placebo-controlled randomized clinical trial, 60 patients diagnosed with atherosclerosis were randomly allocated into either 200 µg/day selenite, yeast, or placebo groups for eight consecutive weeks. Serum levels of lipid profile and glycemic indices were measured at the baseline and end of the intervention. Results: There were no significant within-or between-group changes in levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-c), fasting blood sugar, insulin, and homeostatic model assessment for IR throughout the study (P ≥0.05). Only the low density lipoprotein cholesterol (LDL-c) levels were significantly lower in the yeast group in comparison with the placebo group (P = 0.015). Conclusion: The administration of Se-enriched yeast is significantly effective in decreasing LDL-c levels in patients with atherosclerosis. Additional clinical trial studies investigating the effect of Se administration on glucose homeostasis parameters and lipid profiles in atherosclerotic patients are suggested for a more definitive conclusion.

Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: Effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes.

The effects of oleoylethanolamide (OEA) on NAFLD are yet to be examined in human. The objective of the present study was to examine the effects of OEA supplementation along with weight loss intervention on the expression of PPAR-α, uncoupling proteins 1and 2 (UCP1 and UCP2) genes in the peripheral blood mononuclear cells (PBMCs), metabolic parameters, and anthropometric indices among obese patients with NAFLD. In this triple-blind placebo-controlled randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group along with calorie-restricted diets for 12 weeks. At pre-and post-intervention phase, mRNA expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, serum levels of metabolic parameters as well as diet and appetite sensations were assessed. There was a significant increase in the expression levels of PPAR-α, UCP1, and UCP2 genes in the PBMCs, compared to the placebo at the endpoint. A significant decrease in the anthropometric indices, energy and carbohydrate intakes, glycemic parameters, except for hemoglobin A1c concentration was also observed in the OEA group, compared to the placebo group. OEA treatment significantly resulted in decreased serum levels of triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, increased serum levels of high-density lipoprotein cholesterol (HDL-C), and improved appetite sensations. Importantly, a significant improvement in TG, ALT, AST, ALT/AST, HDL-C levels as well as appetite sensations by OEA were under the influence of body mass index (BMI). Although liver steatosis severity was significantly reduced in both groups, the between-group differences did not reach statistical significance (P = 0.061). In conclusion, the present study, for the first time, revealed that OEA supplementation significantly improved anthropometric and metabolic risk factors related to NAFLD.

Reinforcement learning-based control of tumor growth under anti-angiogenic therapy.

BACKGROUND AND OBJECTIVES: In recent decades, cancer has become one of the most fatal and destructive diseases which is threatening humans life. Accordingly, different types of cancer treatment are studied with the main aim to have the best treatment with minimum side effects. Anti-angiogenic is a molecular targeted therapy which can be coupled with chemotherapy and radiotherapy. Although this method does not eliminate the whole tumor, but it can keep the tumor size in a given state by preventing the formation of new blood vessels. In this paper, a novel model-free method based on reinforcement learning (RL) framework is used to design a closed-loop control of anti-angiogenic drug dosing administration. METHODS: A Q-learning algorithm is developed for the drug dosing closed-loop control. This controller is designed using two different values of the maximum drug dosage to reduce the tumor volume up to a desired value. The mathematical model of tumor growth under anti-angiogenic inhibitor is used to simulate a real patient. RESULTS: The effectiveness of the proposed method is shown through in silico simulation and its robustness to patient parameters variation is demonstrated. It is demonstrated that the tumor reaches its minimal volume in 84 days with maximum drug inlet of 30 mg/kg/day. Also, it is shown that the designed controller is robust with respect to  ±â€¯20% of tumor growth parameters changes. CONCLUSION: The proposed closed-loop reinforcement learning-based controller for cancer treatment using anti-angiogenic inhibitor provides an effective and novel result such that with a clinically valid and safe dosage of drug, the volume reduces up to 1mm3 in a reasonable short period compared to the literature.

Polypill for the prevention of cardiovascular disease (PolyIran): study design and rationale for a pragmatic cluster randomized controlled trial.

BACKGROUND: The complexity of treatment regimens, costs and pill burden decrease the medication adherence and contribute to shortfall in cardiovascular preventive drug coverage. The polypill, a fixed dose combination pill of established drugs, is expected to increase adherence and reduce the costs whilst preventing major cardiovascular events (MCVE). DESIGN AND METHODS: The PolyIran trial is a pragmatic cluster randomized trial nested within the Golestan Cohort Study (GCS). Subjects were randomized to either non-pharmacological preventive interventions alone (minimal care arm) or together with a polypill (polypill arm) comprising hydrochlorothiazide, aspirin, atorvastatin and either enalapril or valsartan. This study benefits from the infrastructure of the primary health care system in Iran and the interventions are delivered by the local auxiliary health workers (Behvarz) to the participants. The primary outcome of the study is the occurrence of first MCVE within five years defined as non-fatal and fatal myocardial infarction, unstable angina, sudden death, heart failure, coronary artery revascularization procedures, and non-fatal and fatal stroke. TRIAL STATUS: From February 2011 to April 2013, 8410 individuals (236 clusters) attended the eligibility assessment. Of those, 3421 in the polypill arm and 3417 in the minimal care arm were eligible. The study is ongoing. CONCLUSION: The infrastructure of GCS and the primary health care system in Iran enabled the conduct of this pragmatic large-scale trial. If the polypill strategy proves effective, it may be implemented to prevent cardiovascular disease in developing countries.

Prevalence, awareness and risk factors of hypertension in a large cohort of Iranian adult population.

BACKGROUND: There is considerable variation in hypertension prevalence and awareness, and their correlates, across different geographic locations and ethnic groups. We performed this cross-sectional analysis on data from the Golestan Cohort Study (GCS). METHODS: Enrollment in this study occurred in 2004-2008, and included 50,045 healthy individuals from Golestan Province in northeastern Iran. Hypertension was defined as a SBP at least 140 mmHg, a DBP at least 90 mmHg, a prior diagnosis of hypertension, or the use of antihypertensive drugs. Potential correlates of hypertension and its awareness were analyzed by logistic regression adjusted for sex, age, BMI, place of residence, literacy, ethnicity, physical activity, smoking, black and green tea consumption and wealth score. RESULTS: Of the total cohort participants, 21,350 (42.7%) were hypertensive. Age-standardized prevalence of hypertension, using the 2001 WHO standard world population, was 41.8% (95% confidence interval: 38.3-45.2%). Hypertension was directly associated with female sex, increased BMI, Turkmen ethnicity, and lack of physical activity, and inversely associated with drinking black tea and wealth score. Among hypertensive patients, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated patients had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese patients, and those with a higher wealth score. CONCLUSION: Hypertension is highly prevalent in rural Iran, many of the affected individuals are unaware of their disease, and the rate of control by antihypertensive medications is low. Increasing hypertension awareness and access to health services, especially among less privileged residents are recommended.