•The vitamin D endocrine system have a variety of actions on cells and tissues involved in COVID-19 progression.•Early calcifediol (25-hydroxyvitamin D) treatment to hospitalized COVID-19 patients ...significantly reduced intensive care unit admissions-Calcifediol seems to be able to reduce severity of the COVID-19.•Calcifediol seems to be able to reduce severity of the disease.
The vitamin D endocrine system may have a variety of actions on cells and tissues involved in COVID-19 progression especially by decreasing the Acute Respiratory Distress Syndrome. Calcifediol can rapidly increase serum 25OHD concentration. We therefore evaluated the effect of calcifediol treatment, on Intensive Care Unit Admission and Mortality rate among Spanish patients hospitalized for COVID-19.
Parallel pilot randomized open label, double-masked clinical trial.
University hospital setting (Reina Sofia University Hospital, Córdoba Spain.)
76 consecutive patients hospitalized with COVID-19 infection, clinical picture of acute respiratory infection, confirmed by a radiographic pattern of viral pneumonia and by a positive SARS-CoV-2 PCR with CURB65 severity scale (recommending hospital admission in case of total score > 1).
All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 h on the first day, and 200 mg every 12 h for the following 5 days), azithromycin (500 mg orally for 5 days. Eligible patients were allocated at a 2 calcifediol:1 no calcifediol ratio through electronic randomization on the day of admission to take oral calcifediol (0.532 mg), or not. Patients in the calcifediol treatment group continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly until discharge or ICU admission. Outcomes of effectiveness included rate of ICU admission and deaths.
Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50 %) p value X2 Fischer test p < 0.001. Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95 %CI 0.002−0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95 %CI: 0.003-0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged.
Our pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer.
Intestinal microbiota changes are associated with the development of obesity. However, studies in humans have generated conflicting results due to high inter-individual heterogeneity in terms of ...diet, age, and hormonal factors, and the largely unexplored influence of gender. In this work, we aimed to identify differential gut microbiota signatures associated with obesity, as a function of gender and changes in body mass index (BMI). Differences in the bacterial community structure were analyzed by 16S sequencing in 39 men and 36 post-menopausal women, who had similar dietary background, matched by age and stratified according to the BMI. We observed that the abundance of the Bacteroides genus was lower in men than in women (P<0.001, Q = 0.002) when BMI was > 33. In fact, the abundance of this genus decreased in men with an increase in BMI (P<0.001, Q<0.001). However, in women, it remained unchanged within the different ranges of BMI. We observed a higher presence of Veillonella (84.6% vs. 47.2%; X2 test P = 0.001, Q = 0.019) and Methanobrevibacter genera (84.6% vs. 47.2%; X2 test P = 0.002, Q = 0.026) in fecal samples in men compared to women. We also observed that the abundance of Bilophila was lower in men compared to women regardless of BMI (P = 0.002, Q = 0.041). Additionally, after correcting for age and sex, 66 bacterial taxa at the genus level were found to be associated with BMI and plasma lipids. Microbiota explained at P = 0.001, 31.17% variation in BMI, 29.04% in triglycerides, 33.70% in high-density lipoproteins, 46.86% in low-density lipoproteins, and 28.55% in total cholesterol. Our results suggest that gut microbiota may differ between men and women, and that these differences may be influenced by the grade of obesity. The divergence in gut microbiota observed between men and women might have a dominant role in the definition of gender differences in the prevalence of metabolic and intestinal inflammatory diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Scope
The consumption of two healthy diets (Mediterranean (MED) and low‐fat (LF) diets) may restore the gut microbiome dysbiosis in obese patients depending on the degree of metabolic dysfunction.
...Methods and results
The differences in bacterial community at baseline and after 2 years of dietary intervention of 106 subjects from the CORDIOPREV study were analyzed, 33 of whom were obese patients with severe metabolic disease (5 criteria for metabolic syndrome) (MetS‐OB), 32 obese patients without metabolic dysfunction (2 or less criteria for metabolic syndrome) (NonMetS‐OB) and 41 non‐obese subjects (NonMetS‐NonOB). Our study showed a marked dysbiosis in people with severe metabolic disease (Met‐OB), compared with obese people without MetS (NonMetS‐OB) and non‐obese people (NonMetS‐NonOB). This disbiotic pattern was reversed by consumption of both MED (35% of calories as fat (22% MUFA fat, 6% PUFA fat and <10% saturated fat) or LF (<30% total fat (<10% saturated fat, 12%–14% MUFA fat and 6–8% PUFA fat) diets, whereas no significant microbiota changes were observed in NonMetS‐NonOB and NonMetS‐OB groups.
Conclusion
Our results suggest that the chronic intake of two healthy dietary patterns partially restores the gut microbiome dysbiosis in obese patients with coronary heart disease, depending on the degree of metabolic dysfunction.
A dysbiotic pattern in gut microbiota is found in obese people with metabolic dysfunction whereas the gut microbiota of obese people without metabolic disease is only partially altered as compared with non‐obese people. This dysbiosis is reversed by the chronic consumption of both Mediterranean or low‐fat diets, shaping microbiota to the pattern found in metabolically healthy people. However, no relevant microbiota changes were observed after the dietary intervention in non‐obese and obese people without metabolic dysfunction.
Background and objectives
A Mediterranean lifestyle may prevent and mitigate cardiometabolic disorders. We explored whether adherence to a Mediterranean lifestyle was prospectively associated with ...the risk of metabolic syndrome (MetS) among coronary heart disease (CHD) patients.
Methods
The Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention (CORDIOPREV) study was an interventional diet study to compare a Mediterranean diet with a low‐fat diet, in 1002 CHD patients. The Mediterranean lifestyle (MEDLIFE) index was used to assess adherence to a MEDLIFE at baseline, and after 5 years, in 851 participants from the CORDIOPREV study. Subjects were classified as having high (>13 points), moderate (12–13 points), and low (<12 points) adherence to the MEDLIFE. Multivariable logistic regression models were used to determine the association between MEDLIFE adherence and the risk of MetS development or reversal.
Results
During the 5‐year follow‐up, CORDIOPREV participants with high adherence to MEDLIFE had a lower risk of MetS development (odds ratio OR 0.37, 95% confidence interval CI 0.19–0.75, p < 0.01) and a higher likelihood of reversing preexisting MetS (OR 2.08 CI 95% 1.11–3.91, p = 0.02) compared with participants in the low MEDLIFE adherence group. Each additional one‐point increment in the MEDLIFE index was associated with a 24% lower risk of MetS development (OR 0.76, 95% CI 0.64–0.90, p < 0.01) and a 21% higher likelihood of reversing preexisting MetS (OR 1.21 CI 95% 1.04–1.41, p = 0.01).
Conclusions
Our results showed that greater adherence to a MEDLIFE reduced the risk of subsequent MetS development and increased the likelihood of reversing preexisting MetS among patients with CHD at baseline.
Abstract
Aims
Familial hypercholesterolaemia (FH) and elevated lipoprotein(a) Lp(a) are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Aortic valve ...stenosis (AVS) is the most prevalent valvular heart disease and low-density lipoprotein cholesterol (LDL-C) and Lp(a) may be involved in its pathobiology. We investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH.
Methods and results
SAFEHEART is a long-term prospective cohort study of a population with FH and non-affected relatives (NAR). We analysed the frequency and predictors of the need for AVR due to AVS in this cohort. Five thousand and twenty-two subjects were enrolled (3712 with FH; 1310 NAR). Fifty patients with FH (1.48%) and 3 NAR (0.27%) required AVR odds ratio 5.71; 95% confidence interval (CI): 1.78–18.4; P = 0.003 after a mean follow-up of 7.48 (3.75) years. The incidence of AVR was significantly higher in patients with FH (log-rank 5.93; P = 0.015). Cox regression analysis demonstrated an association between FH and AVR (hazard ratio: 3.89; 95% CI: 1.20–12.63; P = 0.024), with older age, previous ASCVD, hypertension, increased LDL-CLp(a)-years, and elevated Lp(a) being independently predictive of an event.
Conclusion
The need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, increased LDL-CLp(a)-years and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials.
ClinicalTrials.gov number NCT02693548.
Graphical abstract
Summary
Background
Obesity can influence hepatic mitochondrial function, and cause non‐alcoholic steatohepatitis (NASH). Diagnosis and follow‐up rely on invasive liver biopsy so blood‐based markers ...are urgently required.
Aim
To investigate whether values of circulating metabolites from energy and one‐carbon (1‐C) metabolism may: (a) reflect hepatic mitochondrial flexibility failure and (b) act as NASH biomarkers.
Methods
Patients with severe obesity undergoing bariatric surgery (n = 270) were investigated using quantitative targeted plasma metabolomics. Comparisons were with non‐obese controls without liver disease (n = 50). Obese patients with NASH (n = 53) and without NASH (n = 130) representing extreme groups of liver disease were assessed to test the diagnostic ability of the measured circulating metabolites. Paired liver biopsy and plasma samples from NASH patients were available 1 year post‐surgery and were evaluated to monitor metabolomic changes with liver damage resolution.
Results
We identified correlations between human liver metabolism and obesity. High‐plasma α‐ketoglutarate (α‐KG) and lactate concentrations in NASH patients indicating citric acid cycle replenishment via glutaminolysis might also be a crucial point in NASH onset. Plasma measurements of α‐KG, β‐hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH area under receiver operating characteristic curve (AUC) of 0.826 and predicted NASH resolution without ambiguity (AUC of 0.999).
Conclusion
Changes in plasma mitochondrial metabolites appear to be associated with NASH. These metabolic responses may be dynamically remodelled following resolution of liver damage through massive weight loss.
Adipose tissue dysregulation in obesity strongly influences systemic metabolic homeostasis and is often linked to insulin resistance (IR). However, the molecular mechanisms underlying adipose tissue ...dysfunction in obesity are not fully understood. Herein, a proteomic analysis of subcutaneous (SC) and omental (OM) fat from lean subjects and obese individuals with different degrees of insulin sensitivity was performed to identify adipose tissue biomarkers related to obesity‐associated metabolic disease. Our results suggest that dysregulation of both adipose tissue extracellular matrix (ECM) organization and intracellular trafficking processes may be associated with IR in obesity. Thus, abnormal accumulation of the small leucine‐rich proteoglycan, lumican, as observed in SC fat of IR obese individuals, modifies collagen I organization, impairs adipogenesis and activates stress processes endoplasmic reticulum and oxidative stress in adipocytes. In OM fat, IR is associated with increased levels of the negative regulator of the Rab family of small GTPases, GDI2, which alters lipid storage in adipocytes by inhibiting insulin‐stimulated binding of the Rab protein, Rab18, to lipid droplets. Together, these results indicate that lumican and GDI2 might play depot‐dependent, pathogenic roles in obesity‐associated IR. Our findings provide novel insights into the differential maladaptive responses of SC and OM adipose tissue linking obesity to IR.
Circulating microRNAs (miRNAs) have been proposed as biomarkers for type 2 diabetes (T2D). Adipose tissue (AT), for which dysfunction is widely associated with T2D development, has been reported as a ...major source of circulating miRNAs. However, the role of dysfunctional AT in the altered pattern of circulating miRNAs associated with T2D onset remains unexplored. Herein, we investigated the relationship between T2D-associated circulating miRNAs and AT function, as well as the role of preadipocytes and adipocytes as secreting cells of candidate circulating miRNAs. Among the plasma miRNAs related to T2D onset in the CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) cohort, baseline miR-223-3p levels (diminished in patients who next developed T2D incident-T2D) were significantly related to AT insulin resistance (IR). Baseline serum from incident-T2D participants induced inflammation and IR in 3T3-L1 adipocytes. We demonstrated that tumor necrosis factor (TNF)-α inhibited miR-223-3p secretion while enhancing miR-223-3p intracellular accumulation in 3T3-L1 (pre)adipocytes. Overexpression studies showed that an intracellular increase of miR-223-3p impaired glucose and lipid metabolism in these cells. Our findings provide mechanistic insights into the alteration of circulating miRNAs preceding T2D, unveiling both preadipocytes and adipocytes as miR-223-3p-secreting cells and suggesting that inflammation promotes miR-223-3p intracellular accumulation, which might contribute to (pre)adipocyte dysfunction and body metabolic dysregulation.
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The relationship between adipose dysfunction and circulating miRNAs associated with T2D onset was investigated. Low circulating miR-223-3p related to adipose tissue insulin resistance index (ATIRI) in incident-T2D subjects. Both preadipocytes and adipocytes secrete miR-223-3p, and inflammation-induced intracellular miR-223-3p accumulation leads to cell dysfunction, which might contribute to body metabolic dysregulation.
Background Although familial hypercholesterolemia (FH) confers a high risk of coronary artery disease, most patients are undiagnosed, and little is known about the efficiency of genetic cascade ...screening programs at national level. Objective The aim of the study was to estimate the cost-effectiveness of a national genetic cascade screening program in Spain. Methods An economic evaluation was performed using a decision tree analysis. The choice in the decision tree was between implementation of the national program for FH (NPFH) or keeping the usual clinical care. The NPFH detects FH patients through total cholesterol measurement at primary care level and use of genetic testing in index cases and relatives. The payer (National Health System) and social (including the productivity lost) perspectives were considered. The outcome variables were coronary events avoided, deaths avoided, and quality-adjusted life years (QALYs) gained. Results From the payer perspective, the application of the NPFH during 1 year prevents 847 coronary events and 203 deaths in the 9000 FH patients cohort during a 10-year follow-up, yielding an extra 767 QALYs, at a cost of €29,608 per QALY gained. From the social perspective, the NPFH is dominant over the control (the cost decreases and the effectiveness increases). The sensitivity analysis confirms the robustness of the findings. Conclusion The NPFH based on molecular testing is a cost-effective diagnostic and management strategy that supports government expenditure aimed at preventing coronary artery disease in FH patients in Spain. Implementation of such a strategy is likely to be also cost-effective in countries with similar developed healthcare systems.
Metabolic syndrome (MetS) results in postprandial metabolic alterations that predisposes one to a state of chronic low-grade inflammation and increased oxidative stress. We aimed to assess the effect ...of the consumption of the quantity and quality of dietary fat on fasting and postprandial plasma lipopolysaccharides (LPS). A subgroup of 75 subjects with metabolic syndrome was randomized to receive 1 of 4 diets: HSFA, rich in saturated fat; HMUFA, rich in monounsaturated fat; LFHCC n-3, low-fat, rich in complex carbohydrate diet supplemented with n-3 polyunsaturated fatty acids; LFHCC low-fat, rich in complex carbohydrate diet supplemented with placebo, for 12 weeks each. We administered a fat challenge reflecting the fatty acid composition of the diets at postintervention. We determined the plasma lipoproteins and glucose and gene expression in peripheral blood mononuclear cells (PBMC) and adipose tissue. LPS and LPS binding protein (LBP) plasma levels were determined by ELISA, at fasting and postprandial (4 h after a fat challenge) states. We observed a postprandial increase in LPS levels after the intake of the HSFA meal, whereas we did not find any postprandial changes after the intake of the other three diets. Moreover, we found a positive relationship between the LPS plasma levels and the gene expression of IkBa and MIF1 in PBMC. No statistically significant differences in the LBP plasma levels at fasting or postprandial states were observed. Our results suggest that the consumption of HSFA diet increases the intestinal absorption of LPS which, in turn, increases postprandial endotoxemia levels and the postprandial inflammatory response.
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