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Background: Coronavirus disease 2019 (COVID-19) pandemic continues to escalate intensively worldwide. Massive studies on general populations with SARS-CoV-2 infection have revealed that pre-existing comorbidities were a major risk factor for the poor prognosis of COVID-19. Notably, 49–75% of COVID-19 patients had no comorbidities, but this cohort would also progress to severe COVID-19 or even death. However, risk factors contributing to disease progression and death in patients without chronic comorbidities are largely unknown; thus, specific clinical interventions for those patients are challenging. Methods: A multicenter, retrospective study based on 4806 COVID-19 patients without chronic comorbidities was performed to identify potential risk factors contributing to COVID-19 progression and death using LASSO and a stepwise logistic regression model. Results: Among 4806 patients without pre-existing comorbidities, the proportions with severe progression and mortality were 34.29% and 2.10%, respectively. The median age was 47.00 years [interquartile range, 36.00–56.00], and 2162 (44.99%) were men. Among 51 clinical parameters on admission, age ≥ 47, oxygen saturation < 95%, increased lactate dehydrogenase, neutrophil count, direct bilirubin, creatine phosphokinase, blood urea nitrogen levels, dyspnea, increased blood glucose and prothrombin time levels were associated with COVID-19 mortality in the entire cohort. Of the 3647 patients diagnosed with non-severe COVID-19 on admission, 489(13.41%) progressed to severe disease. The risk factors associated with COVID-19 progression from non-severe to severe illness were increased procalcitonin levels, SpO2 < 95%, age ≥ 47, increased LDH, activated partial thromboplastin time levels, decreased high-density lipoprotein cholesterol levels, dyspnea and increased D-dimer levels. Conclusions: COVID-19 patients without pre-existing chronic comorbidities have specific traits and disease patterns. COVID-19 accompanied by severe bacterial infections, as indicated by increased procalcitonin levels, was highly associated with disease progression from non-severe to severe. Aging, impaired respiratory function, coagulation dysfunction, tissue injury, and lipid metabolism dysregulation were also associated with disease progression. Once factors for multi-organ damage were elevated and glucose increased at admission, these findings indicated a higher risk for mortality. This study provides information that helps to predict COVID-19 prognosis specifically in patients without chronic comorbidities.

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is activated constitutively in a wide array of human cancers. It is an appealing molecular target for novel therapy as it directly regulates expression of genes involved in cell proliferation, survival, angiogenesis, chemoresistance and immune responsiveness. In addition to these well-established oncogenic roles, STAT3 has also been found to mediate a wide array of functions in modulating cellular behavior. The transcriptional function of STAT3 is canonically regulated through tyrosine phosphorylation. However, STAT3 phosphorylated at a single serine residue can allow incorporation of this protein into the inner mitochondrial membrane to support oxidative phosphorylation (OXPHOS) and maximize the utility of glucose sources. Conflictingly, its canonical transcriptional activity suppresses OXPHOS and favors aerobic glycolysis to promote oncogenic behavior. Apart from mediating the energy metabolism and controversial effects on ATP production, STAT3 signaling modulates lipid metabolism of cancer cells. By mediating fatty acid synthesis and beta oxidation, STAT3 promotes employment of available resources and supports survival in the conditions of metabolic stress. Thus, the functions of STAT3 extend beyond regulation of oncogenic genes expression to pleiotropic effects on a spectrum of essential cellular processes. In this review, we dissect the current knowledge on activity and mechanisms of STAT3 involvement in transcriptional regulation, mitochondrial function, energy production and lipid metabolism of malignant cells, and its implications to cancer pathogenesis and therapy.

Objective To examine whether 5 years of high-intensity interval training (HIIT) increases high-density lipoprotein cholesterol (HDL-C) concentration more than moderate-intensity continuous training (MICT) and control (CON) in older men and women. Methods A total of 1567 older adults (790 [50.4%] women) were randomized (2:1:1) to either CON (n=780; asked to follow the national recommendations for physical activity) or 2 weekly sessions of HIIT (10-minute warm-up followed by 4×4-minute intervals at ∼90% of peak heart rate) or MICT (50 minutes of continuous work at ∼70% of peak heart rate). Serum HDL-C concentration was measured by standard procedures at baseline and at 1 year, 3 years, and 5 years. The study took place between August 21, 2012, and June 31, 2018. Linear mixed models were used to determine between-group differences during 5 years using the per protocol approach. Results Men in HIIT had a smaller reduction in HDL-C (−1.2%) than men in CON (−6.9%) and MICT (−7.8%) after 5 years (P=.01 and P=.03 for CON vs HIIT and MICT vs HIIT, respectively). No effect of exercise intensity on HDL-C was seen in women. Changes in peak oxygen uptake were associated with changes in HDL-C in both men and women, whereas changes in body weight and fat mass were not. Conclusion In men, HIIT seems to be the best strategy to prevent a decline in HDL-C during a 5-year period. No effect of exercise intensity was seen for older women. Trial registration ClinicalTrials.gov identifier: NCT01666340.

Graphical abstract, Highlights • MetS occurs in a 1 out of 4 obese children and increases the future risk of serious health complications. • The serum level of adiponectin decreases while leptin increases as body weight increases, in the understudy children group. • The serum level of the inflammatory marker CRP increases significantly as body weight increases in the understudy population. • Adipokines and CRP can distinguish the children with Metabolic Syndrome as compared to children with no Metabolic Syndrome., Background Metabolic syndrome (MetS) occurs in a proportion of overweight and obese children and increases their future risk of serious health complications, even in adolescence and young adulthood. We aimed to explore the role of certain adipokines and inflammatory markers in identifying children with MetS. Methods This study is a secondary analysis of data coming from the Healthy Growth Study, a cross-sectional study conducted with schoolchildren in Greece. The present study included data from a representative sample of 1376 schoolchildren (mean age: 11.19 ± 0.66 years), recruited from 77 primary schools in four large regions in Greece. Anthropometric, clinical and biochemical data were recorded. Children’s body weight status and the presence of MetS were determined and their correlation with the serum levels of leptin, adiponectin and C-reactive protein (CRP) was explored. Results The prevalence of the MetS was 21.7 % and 3.7 % in obese and overweight children, respectively. The balance of adipokines was disturbed in obesity, as the serum level of adiponectin decreased as body weight increased, while the serum level of leptin increased. The serum level of the inflammatory marker CRP increased significantly as body weight increased. Discriminant analysis showed that these factors could distinguish the children with MetS as compared to children with no MetS. Conclusions In the under study Mediterranean childhood population, monitoring of the levels of adipokines and CRP could identify the overweight and obese children with MetS. Appropriate individualized dietary and lifestyle interventions can be applied in these children to prevent health complications associated with MetS.

Background Even when low-density lipoprotein-cholesterol (LDL-C) levels are lower than guideline thresholds, a residual risk of atherosclerosis remains. It is unknown whether triglyceride (TG) levels are associated with subclinical atherosclerosis and vascular inflammation regardless of LDL-C. Objectives This study sought to assess the association between serum TG levels and early atherosclerosis and vascular inflammation in apparently healthy individuals. Methods An observational, longitudinal, and prospective cohort study, including 3,754 middle-aged individuals with low to moderate cardiovascular risk from the PESA (Progression of Early Subclinical Atherosclerosis) study who were consecutively recruited between June 2010 and February 2014, was conducted. Peripheral atherosclerotic plaques were assessed by 2-dimensional vascular ultrasound, and coronary artery calcification (CAC) was assessed by noncontrast computed tomography, whereas vascular inflammation was assessed by fluorine-18 fluorodeoxyglucose uptake on positron emission tomography. Results Atherosclerotic plaques and CAC were observed in 58.0% and 16.8% of participants, respectively, whereas vascular inflammation was evident in 46.7% of evaluated participants. After multivariate adjustment, TG levels ≥150 mg/dl showed an association with subclinical noncoronary atherosclerosis (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.08 to 1.68; p = 0.008). This association was significant for groups with high LDL-C (OR: 1.42; 95% CI: 1.11 to 1.80; p = 0.005) and normal LDL-C (OR: 1.85; 95% CI: 1.08 to 3.18; p = 0.008). No association was found between TG level and CAC score. TG levels ≥150 mg/dl were significantly associated with the presence of arterial inflammation (OR: 2.09; 95% CI: 1.29 to 3.40; p = 0.003). Conclusions In individuals with low to moderate cardiovascular risk, hypertriglyceridemia was associated with subclinical atherosclerosis and vascular inflammation, even in participants with normal LDL-C levels. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318), Central Illustration

Background Exposure to particulate matter (PM) emitted from vehicle exhaust might disrupt systemic function and elevate the risk of cardiovascular disease. In this study, we examined the changes of cardiometabolic biomarkers among vehicle inspectors exposed daily to PM0.25 and components. Methods This cross-sectional study was conducted at two vehicle inspection centers, Pulogadung and Ujung Menteng, located in East Jakarta, Indonesia. The exposed respondents were 43 workers from vehicle inspection centers, and the unexposed group consisted of 22 staff officers working in the same locations. Vehicle exhaust particulate matter was measured for eight hours using a Leland Legacy personal pump attached to a Sioutas Cascade Impactor. The used filters were 25 and 37-mm quartz filters. The particulate matter concentration was analyzed using a gravimetric method, whereas trace elements were analyzed using energy dispersive X-ray fluorescence. An EEL Smoke Stain Reflectometer analyzed black carbon. Results The personal exposure concentrations of PM0.25 were 10.4-fold higher than those in unexposed groups. Calcium and sulfur were the major components in the obtained dust, and their levels were 3.3- and 7.2-fold higher, respectively, in the exposed group. Based on an independent-samples t-test, high-density lipoprotein, triglyceride, HbA1c, total immunoglobulin E, high-sensitivity C-reactive protein, tumor necrosis factor–alpha, and nitric oxide levels were significantly different between the groups. Conclusions In summary, it was suggested that PM0.25 exposure from vehicle exhaust might affect cardiometabolic biomarkers change.

Cardiovascular disease (CVD) risk factors cluster in an individual. Exercise is universally recommended to prevent and treat CVD. Yet, clinicians lack guidance on how to design an exercise prescription (ExRx) for patients with multiple CVD risk factors. To address this unmet need, we developed a novel clinical decision support system to prescribe exercise (prioritize personalize prescribe exercise [P3-EX]) for patients with multiple CVD risk factors founded upon the evidenced-based recommendations of the American College of Sports Medicine (ACSM) and American Heart Association. To develop P3-EX, we integrated (1) the ACSM exercise preparticipation health screening recommendations; (2) an adapted American Heart Association Life’s Simple 7 cardiovascular health scoring system; (3) adapted ACSM strategies for designing an ExRx for people with multiple CVD risk factors; and (4) the ACSM frequency, intensity, time, and time principle of ExRx. We have tested the clinical utility of P3-EX within a university-based online graduate program in ExRx among students that includes physicians, physical therapists, registered dietitians, exercise physiologists, kinesiologists, fitness industry professionals, and kinesiology educators in higher education. The support system P3-EX has proven to be an easy-to-use, guided, and time-efficient evidence-based approach to ExRx for patients with multiple CVD risk factors that has applicability to other chronic diseases and health conditions. Further evaluation is needed to better establish its feasibility, acceptability, and clinical utility as an ExRx tool.

Objective To investigate the effect of replacing sitting with standing on cardiovascular risk factors tested in clinical trials. Methods We searched databases from inception up to August 28, 2019, for studies examining the effect of replacing sitting with standing on fasting blood glucose, fasting insulin, and lipid levels; blood pressure; body fat mass; weight; and waist circumference in healthy adults. Differences in mean ± SD values were used for pooling the data and calculating the mean differences and CIs. Results The search found 3507 abstracts. Nine clinical trials (8 randomized and 1 nonrandomized) with 877 (64.4% [n=565] women) participants met all inclusion criteria. The mean ± SD age was 45.34±5.41 years; mean follow-up was 3.81 months, and mean difference in standing time between the intervention and control groups was 1.33 hours per day. The follow-up fasting blood glucose and body fat mass values were slightly but significantly lower than baseline records in the intervention groups compared with control groups (−2.53; 95% CI, −4.27 to −0.79 mg/dL; and −0.75; 95% CI, −0.91 to −0.59 kg). The analysis for fasting insulin levels, lipid levels, blood pressure, weight, and waist circumference revealed no significant differences. Conclusion Replacing sitting with standing can result in very small but statistically significant decreases in fasting blood glucose levels and body fat mass with no significant effect on lipid levels, blood pressure, weight, and waist circumference. Replacing sitting with standing can be used as an adjunctive intervention to decrease the burden of cardiovascular risk factors but cannot be used as an alternative to physical activity to decrease sedentary time.

Background and aims: We tested the hypothesis that on-treatment HbA1c levels independently associate with coronary atheroma progression and major adverse cardiovascular events (MACE: death, myocardial infarction, cerebrovascular accident, coronary revascularization, or hospitalization for unstable angina) rates. Methods: We performed a post-hoc pooled analysis of data from seven prospective, randomized trials involving serial coronary intravascular ultrasonography (IVUS). The percent atheroma volume (PAV) was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque. Using multivariable mixed modeling, we determined the association of on-treatment HbA1c with annualized change in PAV. Cox proportional hazard models were used to assess the association of HbA1c with incidence of MACE. Results: Among 3,312 patients (mean age 58.6±9years, 28.4%women) average on-treatment HbA1c was 6.2±1.1%. Overall, there was no net significant annualized change in PAV (0.12±0.19%, p = 0.52). In a fully adjusted multivariable analysis (following adjustment of age, sex, body mass index, systolic blood pressure, smoking, low- and high-density lipoprotein cholesterol, triglyceride levels, peripheral vascular disease, trial, region, and baseline PAV), higher on-treatment HbA1c levels were independently associated with annualized changes in PAV [beta-estimate (95% confidence interval): 0.13(0.08, 0.19), p

International audience; Background and AimsApolipoprotein A1 (A1) and haptoglobin (HP) serum levels are associated with the spread and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We have constructed and validated a multivariable risk calculator (A1HPV6) integrating A1, HP, alpha2-macroglobulin, and gamma glutamyl transferase to improve the performances of virological biomarkers.MethodsIn a prospective observational study of hospitalized patients with nonsevere SARS-CoV-2 infection, A1HPV6 was constructed in 127 patients and validated in 116. The specificity was assessed in 7482 controls representing the general population. The primary diagnostic endpoint was the area under the receiver operating characteristic curve in patients with positive SARS-CoV-2 PCR. The primary prognostic endpoint was the age-and-sex adjusted risk of A1HPV6 to predict patients with WHO-stage > 4 (W > 4) severity. We assessed the kinetics of the A1HPV6 components in a nonhuman primate model (NHP), from baseline to 7 days (D7) after SARS-CoV-2 infection.ResultsThe area under the receiver operating characteristic curve for A1HPV6 was 0.99 (95% CI 0.97–0.99) in the validation subset, which was not significantly different from that in the construction subset, 0.99 (0.99–0.99; P = .80), like for sensitivity 92% (85–96) vs 94% (88–97; P = .29). A1HPV6 was associated with W > 4, with a significant odds ratio of 1.3 (1.1–1.5; 0.002). In NHP, A1 levels decreased (P < .01) at D2 and normalized at D4; HP levels increased at D2 and peaked at D4. In patients, A1 concentration was very low at D2 vs controls (P < .01) and increased at D14 (P < .01) but was still lower than controls; HP increased at D2 and remained elevated at D14.ConclusionThese results validate the diagnostic and prognostic performances of A1HPV6. Similar kinetics of apolipoprotein A1, HP, and alpha-2-macroglobulin were observed in the NHP model. ClinicalTrials.gov number, NCT01927133.

Persons with underlying noncommunicable diseases (NCDs) are more likely to acquire severe coronavirus disease 2019 disease and to die from coronavirus disease 2019. An urgent need for potential therapy to prevent and control NCDs is critical. We hypothesized that higher intakes of multiple individual nutrients, fruits, or vegetables would be linked with a low risk of NCDs in the Korean population. Thus, we aim to explore the association between NCDs, including cardiovascular diseases, type 2 diabetes mellitus (T2DM), arthritis, depression, and dietary factors. A total of 56,462 adults aged 18 years (2009-2019) were included. Dietary factors, including intakes of multiple individual nutrients, fruits, and vegetables, were assessed. Multivariable-adjusted logistic regression models were used to explore the associations between dietary factors and NCDs. Interactions were found between intakes of multiple individual nutrients and sex for T2DM, hypertension, stroke, myocardial infarction, arthritis, and osteoarthritis. Only in women was a 2-fold increase in daily multiple individual nutrient intake (vitamins A, B1, B2, B3, C; potassium, protein; phosphorus; calcium; iron; monounsaturated fatty acid and polyunsaturated fatty acid; n-3 fatty acid and n-6 fatty acid; and water) associated with a lower prevalence of T2DM, hypertension, stroke, myocardial infarction, arthritis, and osteoarthritis. In both women and men, high fruit or vegetable consumption was linked with a lower risk of T2DM, hypertension, dyslipidemia, osteoarthritis, and depression than low consumption. Our findings found higher intakes of fruits, vegetables, and multiple individual nutrients are linked with a lower risk of NCDs in the Korean adult population. Further work is needed to identify whether interactions between intake of multiple individual nutrients, vegetables, and fruits affect the presence of NCDs., Graphical Abstract Image, graphical abstract

BACKGROUND Dyslipidemia induces platelet hyperactivation and hyper-aggregation, which are linked to thrombosis. Anthocyanins could inhibit platelet function in vitro and in mice fed high-fat diets with their effects on platelet function in subjects with dyslipidemia remained unknown. This study aimed to investigate the effects of different doses of anthocyanins on platelet function in individuals with dyslipidemia. METHODS A double-blind, randomized, controlled trial was conducted. Ninety-three individuals who were initially diagnosed with dyslipidemia were randomly assigned to placebo or 40, 80, 160 or 320 mg/day anthocyanin groups. The supplementations were anthocyanin capsules (Medox, Norway). Platelet aggregation by light aggregometry of platelet-rich plasma, P-selectin, activated GPⅡbⅢa, reactive oxygen species (ROS), and mitochondrial membrane potential were tested at baseline, 6 weeks and 12 weeks. FINDINGS Compared to placebo group, anthocyanins at 80 mg/day for 12 weeks reduced collagen-induced platelet aggregation (-3.39±2.36%) and activated GPⅡbⅢa (-8.25±2.45%) (P

The fish paste product, fish balls ‘tsumire’, is a traditional type of Japanese food made from minced fish as well as imitation crab, kamaboko and hanpen. Although tsumire is known as a high-protein and low-fat food, there is a lack of scientific evidence on its health benefits. Hence, we aimed to investigate the effects of tsumire intake on organ weight and biomarker levels in Sprague–Dawley rats for 84 d as a preliminary study. Six-week-old male Sprague–Dawley rats were divided into two groups: group I, fed normal diets, and group II, fed normal diets with 5 % dried tsumire. Throughout the administration period, we monitored their body weight and food intake; at the end of this period, we measured their organ weight and analysed their blood biochemistry. No significant differences were observed with respect to body weight, food intake, organ weight and many biochemical parameters between the two groups. It was found that inorganic phosphorus and glucose levels were higher in group II rats than in group I rats. On the other hand, sodium, calcium, amylase and cholinesterase levels were significantly lower in group II than in group I. Interestingly, we found that the levels of aspartate aminotransferase, alanine transaminase, lactate dehydrogenase and leucine aminopeptidase in group II were significantly lower than in group I, and that other liver function parameters of group II tended to be lower than in group I. In conclusion, we consider that the Japanese traditional food, ‘tsumire,’ may be effective as a functional food for human health management worldwide.

Highlights • Individuals with ANGPTL3 loss-of-function mutations have reduced cholesterol levels, triglyceride levels, and risk of coronary heart disease, making ANGPTL3 a potential therapeutic target. • An antisense oligonucleotide inhibitor of ANGPTL3 and a monoclonal antibody against ANGPTL3 have been advanced into clinical trials, with encouraging results to date. • A distinct approach to targeting ANGPTL3 would be therapeutic gene editing in patients to induce permanent loss of function mutations mimicking those in individuals with naturally occurring cardioprotective mutations., Summary Hyperlipidemia is a major causal risk factor for atherosclerosis and coronary heart disease (CHD). Angiopoietin-like 3 (ANGPTL3) has emerged as a promising molecular target to reduce CHD risk due to its regulation of all 3 major lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Here, the authors review the discovery of ANGPTL3, the role of ANGPTL3 in lipoprotein metabolism, and the genetic association between naturally occurring ANGPTL3 loss-of-function mutations and CHD. In light of the favorable consequences of ANGPTL3 deficiency, various therapeutic strategies to target ANGPTL3 are currently in development, including a monoclonal antibody, an antisense oligonucleotide, and gene editing., Central Illustration

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) levels by facilitating the degradation of the LDL receptor (LDLR) and is an attractive therapeutic target for hypercholesterolemia intervention. Herein, we generated a novel fully human antibody with favourable druggability by utilizing phage display-based strategy. Methods A potent single-chain variable fragment (scFv) named AP2M21 was obtained by screening a fully human scFv phage display library with hPCSK9, and performing two in vitro affinity maturation processes including CDR-targeted tailored mutagenesis and cross-cloning. Thereafter, it was transformed to a full-length Fc-silenced anti-PCSK9 antibody FAP2M21 by fusing to a modified human IgG1 Fc fragment with L234A/L235A/N297G mutations and C-terminal lysine deletion, thus eliminating its immune effector functions and mitigating mAb heterogeneity. Findings Our data showed that the generated full-length anti-PCSK9 antibody FAP2M21 binds to hPCSK9 with a KD as low as 1.42 nM, and a dramatically slow dissociation rate (koff, 4.68 × 10−6 s−1), which could be attributed to its lower binding energy (-47.51 kcal/mol) than its parent counterpart FAP2 (-30.39 kcal/mol). We verified that FAP2M21 potently inhibited PCSK9-induced reduction of LDL-C uptake in HepG2 cells, with an EC50 of 43.56 nM. Further, in hPCSK9 overexpressed C57BL/6 mice, a single tail i.v. injection of FAP2M21 at 1, 3 and 10 mg/kg, dose-dependently up-regulated hepatic LDLR levels, and concomitantly reduced serum LDL-C by 3.3% (P = 0.658, unpaired Student's t-test), 30.2% (P = 0.002, Mann-Whitney U-test) and 37.2% (P = 0.002, Mann-Whitney U-test), respectively. Interpretation FAP2M21 with potent inhibitory effect on PCSK9 may serve as a promising therapeutic agent for treating hypercholesterolemia and associated cardiovascular diseases.

Aims: Inflammation has been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN) as suggested in various cross-sectional studies. However, more convincing prospective studies in diabetes patients are scarce. Therefore, we aimed to evaluate whether proinflammatory cytokines could predict the incidence of DPN through a prospective study with a five-year follow-up. Methods: We followed up 315 patients with diabetes who did not have DPN, recruited from five community health centers in Shanghai in 2014, for an average of 5.06 years. Based on the integrity of blood samples, 106 patients were selected to obtain the proinflammatory cytokines. Plasma markers of proinflammatory cytokines at baseline included interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and intercellular adhesion molecule 1 (ICAM-1). Neuropathy was assessed by MSNI at baseline and during follow-up. Results: Among the 106 randomly chosen patients, 63 developed DPN after 5.06±1.14 years of follow-up. The baseline plasma levels of TNF-α, IL-6, and ICAM-1 were higher in the neuropathic group (P

Visual Abstract, Highlights • Aortic stenosis was less prevalent in carriers of the PCSK9 R46L variant. • Variation at the PCSK9 locus influences LDL-C levels, but not Lp(a). • PCSK9 is produced and secreted by aortic valves. • In vitro, PCSK9 inhibition might lower calcification in aortic valve cells. • PCSK9 inhibition could represent a therapeutic strategy for aortic stenosis., Summary The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.

Concerns about the external validity of traditional randomized clinical trials (RCTs), together with the widespread availability of real-world data and advanced data analytic tools, have led to claims that common sense and clinical observation, rather than RCTs, should be the preferred method to generate evidence to support clinical decision-making. However, over the past 4 decades, results from well-done RCTs have repeatedly contradicted practices supported by common sense and clinical observation. Common sense and clinical observation fail for several reasons: incomplete understanding of pathophysiology, biases and unmeasured confounding in observational research, and failure to understand risks and benefits of treatments within complex systems. Concerns about traditional RCT models are legitimate, but randomization remains a critical tool to understand the causal relationship between treatments and outcomes. Instead, development and promulgation of tools to apply randomization to real-world data are needed to build the best evidence base in cardiovascular medicine., Central Illustration, Highlights • Well-conducted RCTs have repeatedly contradicted practices supported by common sense and clinical observation. • Common sense and clinical observation fail because of the inability to fully understand complex biopsychosocial systems. • RCTs must be integrated into clinical practice to improve the evidence base in cardiology.

Highlights • We examined links between medical claims and health check-up data for older adults. • Patients receiving pharmacotherapies were more likely to participate in health checkups. • Patients with intensive disease control were more likely to be aged ≥ 90 years. • Linking these databases can improve evaluations of diseases control in older adults., The Japanese government encourages older adults to participate in annual health checkups designed to detect lifestyle diseases such as hypertension, diabetes, and dyslipidemia. However, individuals who are already being treated for these diseases are unlikely to benefit from health checkup participation. This retrospective cohort study of older adults evaluated the associations of pharmacological treatments for these diseases with health checkup participation and identified the disease control factors among patients receiving treatments. Using medical claims data and health checkup data between September 2013 and August 2014 from 820,215 older adults aged ≥ 75 years residing in Tokyo, Japan, we examined the associations between pharmacological treatments and health checkup participation using binary logistic regression analysis. Next, patients receiving pharmacological treatments were categorized into intensive, moderate, or limited disease control based on their blood pressure, hemoglobin A1c levels, and lipid levels; multinomial logistic regression analyses were used to identify the disease control factors. The results showed that patients receiving pharmacological treatments were more likely (odds ratio: 1.374; P

Table olives, a product of olive tree (Olea europaeaL.), is an important fermented product of the Mediterranean Diet. Agronomical factors, particularly the cultivar, the ripening stage and the processing method employed are the main factors influencing the nutritional and non-nutritional composition of table olives and their organoleptic properties. The important nutritional value of this product is due to its richness in monounsaturated fat (MUFA), mainly oleic acid, fibre and vitamin E together with the presence of several phytochemicals. Among these, hydroxytyrosol (HT) is the major phenolic compound present in all types of table olives. There is a scarcity ofin vitro,in vivoand human studies of table olives. This review focused comprehensively on the nutrients and bioactive compound content as well as the health benefits assigned to table olives. The possible health benefits associated with their consumption are thought to be primarily related to effects of MUFA on cardiovascular health, the antioxidant (AO) capacity of vitamin E and its role in protecting the body from oxidative damage and the anti-inflammatory and AO activities of HT. The influence of multiple factors on composition of the end product and the potential innovation in the production of table olives through the reduction of its final salt content was also discussed.

Background Anthocyanins, one of the major plant bioactive substances, possess anti-oxidative and anti-inflammatory capacity. However, their dose–response relationship has remained unclear. The present study investigated the dose–response relationship of anthocyanins with oxidative stress and inflammation in subjects with dyslipidemia. Design and Participants: A total of 169 participants with dyslipidemia were randomly assigned to placebo (n = 43), anthocyanins 40 mg/day (n = 44), 80 mg/day (n = 40), or 320 mg/day (n = 42) groups. Urine 8-iso-prostaglandin F2α (8-iso-PGF2α), 8-hydroxy-2′-deoxyguanosine (8-OHdG) and serum malonaldehyde (MDA), total superoxide dismutase (T-SOD), UA (uric acid), interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured at baseline, at 6 weeks, and at 12 weeks. Results Anthocyanin supplementation (320 mg/day) for 6 weeks significantly improved T-SOD versus baseline (P, Graphical abstract Image 1, Highlights • Anthocyanins improve oxidative stress in a dose-response manner. • Anthocyanins improve anti-inflammatory capacity in a dose-response manner. • 80 mg/day anthocyanin could reach the threshold level for producing beneficial functions after 12-week intervention. • Anthocyanins prevent the progression of metabolic diseases in subjects with dyslipidemia.

Background: Elevated homocysteine (Hcy) is associated with several pathologies. Gene–diet interactions related to Hcy might be used to customize dietary advice to reduce disease incidence. To explore this possibility, we investigated interactions between anthropometry, biochemical markers and diet and single-nucleotide polymorphisms (SNPs) in relation to Hcy concentrations. Five SNPs of Hcy-metabolizing enzymes were analyzed in 2010 black South Africans. Results: Hcy was higher with each additional methylenetetrahydrofolate reductase (MTHFR) C677T minor allele copy, but was lower in methionine synthase (MTR) 2756AA homozygotes than heterozygotes. Individuals harboring cystathionine β synthase (CBS) 833 T/844ins68 had lower Hcy concentrations than others. No interactive effects were observed with any of the anthropometrical markers. MTHFR C677T and CBS T833C/844ins68 homozygote minor allele carriers presented with lower Hcy as high density lipoprotein cholesterol (HDL-c) increased. Hcy concentrations were negatively associated with dietary protein and animal protein intake in the TT and TC genotypes, but positively in the CC genotype of CBS T833C/844ins68. Hcy was markedly higher in TT homozygotes of MTHFR C677T as added sugar intake increased. In CBS T833C/844ins68 major allele carriers, biotin intake was negatively associated with Hcy; but positively in those harboring the homozygous minor allele. Conclusions: The Hcy–SNP associations are modulated by diet and open up the possibility of invoking dietary interventions to treat hyperhomocysteinemia. Future intervention trials should further explore the observed gene–diet and gene–blood lipid interactions. Keywords: Biotin, Blood lipid–gene interactions, Gene–diet interactions, Hyperhomocysteinemia, Nutrient–gene interactions, Nutrigenetics, Precision nutrition, Protein, Sugar, Total homocysteine

Background: Sex is one of the most powerful modifiers of disease development. Clear sexual dimorphism exists in cardiometabolic health susceptibility, likely due to differences in sex steroid hormones. Changes in the gut microbiome have been linked with the development of obesity, type 2 diabetes, and atherosclerosis; however, the impact of microbes in sex-biased cardiometabolic disorders remains unclear. The gut microbiome is critical for maintaining a normal estrous cycle, testosterone levels, and reproductive function. Gut microbes modulate the enterohepatic recirculation of estrogens and androgens, affecting local and systemic levels of sex steroid hormones. Gut bacteria can also generate androgens from glucocorticoids. Scope of review: This review summarizes current knowledge of the complex interplay between sexual dimorphism in cardiometabolic disease and the gut microbiome. Major conclusions: Emerging evidence suggests the role of gut microbiome as a modifier of disease susceptibility due to sex; however, the impact on cardiometabolic disease in this complex interplay is lacking. Elucidating the role of gut microbiome on sex-biased susceptibility in cardiometabolic disease is of high relevance to public health given its high prevalence and significant financial burden. Keywords: Sex differences, Steroids, Gut microbiota, Metabolic disease, Cardiovascular disease

Data presented in this article are supplementary data to our primary article ‘Association of Alcohol Consumption and Aortic Calcification in Healthy Men Aged 40–49 Years for the ERA JUMP Study’ [1]. In this article, we have presented supplementary tables showing the independent association of alcohol consumption with coronary artery calcification using Tobit conditional regression and ordinal logistic regression. Keywords: Alcohol, Coronary, Atherosclerosis, Calcification, Men

Objective Metabolic syndrome (MetS) refers to a cluster of risk factors for cardiovascular disease, including obesity, hypertension, dyslipidemia, and hyperglycemia. While sizable prior literature has examined associations between individual risk factors and quantitative measures of cortical thickness (CT), only very limited research has investigated such measures in MetS. Furthermore, the relative contributions of these risk factors to MetS-related effects on brain morphology have not yet been studied. The primary goal of this investigation was to examine how MetS may affect CT. A secondary goal was to explore the relative contributions of individual risk factors to regional alterations in CT, with the potential to identify risk factor combinations that may underlie structural changes. Methods Eighteen participants with MetS (mean age = 59.78 years) were age-matched with 18 healthy control participants (mean age = 60.50 years). CT measures were generated from T1-weighted images and groups were contrasted using whole-brain general linear modeling. A follow-up multivariate partial least squares correlation (PLS) analysis, including the full study sample with complete risk factor measurements (N = 53), was employed to examine which risk factors account for variance in group structural differences. Results Participants with MetS demonstrated significantly reduced CT in left hemisphere inferior parietal, rostral middle frontal, and lateral occipital clusters and in a right hemisphere precentral cluster. The PLS analysis revealed that waist circumference, high-density lipoprotein cholesterol (HDL-C), triglycerides, and glucose were significant contributors to reduced CT in these clusters. In contrast, diastolic blood pressure showed a significantly positive association with CT while systolic blood pressure did not emerge as a significant contributor. Age was not associated with CT. Conclusion These results indicate that MetS can be associated with regionally specific reductions in CT. Importantly, a novel link between a risk factor profile comprising indices of obesity, hyperglycemia, dyslipidemia and diastolic BP and localized alterations in CT emerged. While the pathophysiological mechanisms underlying these associations remain incompletely understood, these findings may be relevant for future investigations of MetS and might have implications for treatment approaches that focus on specific risk factor profiles with the aim to reduce negative consequences on the structural integrity of the brain., Highlights • Cortical thickness is reduced bilaterally in metabolic syndrome. • Five out of six risk factor components contribute to altered cortical thickness. • Particular risk factor combination may be an important target for intervention.

Background Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes. Objectives This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH). Methods In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker. Results Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. Conclusions Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non–lipid-related metabolites associated with all 3 diseases., Central Illustration

Objective: Increased left ventricular (LV) mass is an important precursor to heart failure. Inflammation plays an important role in increasing LV mass. However, the contribution of subclinical coronary artery disease (CAD) to the inflammation-LV mass relationship is unknown. In subjects with psoriasis, a chronic inflammatory skin disease, we evaluated if systemic inflammation assessed by plasma glycoprotein A (GlycA) associated with LV mass measured on coronary CT angiography (CCTA). Additionally, we analyzed whether this relationship was mediated by early CAD assessed as noncalcified coronary burden (NCB). Methods: We performed an observational longitudinal study of 213 subjects with psoriasis free of known cardiovascular disease, 189 of whom were followed over one year. All participants had GlycA measurements by nuclear magnetic resonance spectroscopy and LV mass and NCB quantified by CCTA. Results: The cohort had a mean age of 50.3 (±12.9) years and 59% were male. There was moderate psoriasis severity and low cardiovascular risk. LV mass increased by GlycA tertiles [1st tertile:24.6 g/m2.7(3.8), 2nd tertile:25.5 g/m2.7(3.8), 3rd tertile:27.7 g/m2.7(5.5), p

Highlights • We compared the effects of volunteer- and expert-led weight-loss intervention. • Participants were instructed to maintain a well-balanced, low-energy diet. • The completion proportions was significantly higher in the expert-led group. • The degree of body weight change was similar for both groups. • Such programs could be an alternative strategy for low-cost obesity management., This study compared the effect of volunteer- and expert-led versions of a community-based weight-loss intervention in a non-randomized comparative trial conducted in Ibaraki, Japan from 2016 to 2017. Participants were 145 Japanese adults with overweightness or obesity, aged 20–69 years, with 77 in a volunteer-led group and 68 in an expert-led group. Both groups received the same program content and intervention period. Community volunteers were trained in four or five 3-hour training sessions while experts were highly trained and experienced professionals in the fields of exercise and nutrition prescription. Participants were also instructed to maintain a well-balanced, low-energy diet. The primary outcome measure was body weight change. In the volunteer- and expert-led groups, 58 of 77 (75%) and 61 of 68 (95%) participants completed the 12-week intervention, respectively. The mean (95% confidence interval, CI) weight loss of the volunteer-led group was 6.4 (95% CI: 5.6–7.2) kg, corresponding to 8.9% of initial body weight, while that of the expert-led group was 6.3 (95% CI: 5.5–7.1) kg, corresponding to 8.2% of the initial body weight. The proportion of participants who completed the course was significantly higher in the expert-led group (P

Summary The importance of inflammation and inflammatory pathways in atherosclerotic disease and acute coronary syndromes (ACS) is well established. The success of statin therapy rests not only on potently reducing levels of low-density lipoprotein cholesterol, but also on the many beneficial, pleiotropic effects statin therapy has on various inflammatory mechanisms in atherosclerotic disease, from reducing endothelial dysfunction to attenuating levels of serum C-reactive protein. Due to the growing awareness of the importance of inflammation in ACS, investigators have attempted to develop novel therapies against known markers of inflammation for several decades. Targeted pathways have ranged from inhibiting C5 cleavage with a high-affinity monoclonal antibody against C5 to inhibiting the activation of the p38 mitogen-activated protein kinase signaling cascades. In each of these instances, despite promising early preclinical and mechanistic studies and phase 2 trials suggesting a potential benefit in reducing post-MI complications or restenosis, these novel therapies have failed to show benefits during large, phase 3 clinical outcomes trials. This review discusses several examples of novel anti-inflammatory therapies that failed to show significant improvement on clinical outcomes when tested in large, randomized trials and highlights potential explanations for why targeted therapies against known markers of inflammation in ACS have failed to launch., Central Illustration

Visual Abstract, Highlights • The enzyme PCSK9 binds to the hepatic LDL receptor and targets it for a intracellular degradation, leading to decreased number of LDL receptor on cells and reduced removal of circulating LDL cholesterol. • The usefulness of circulating PCSK9 as a marker for risk of coronary heart disease in the general population remains unclear. • In this large prospective population study, serum levels of PCSK9 were modestly associated with increased risk of myocardial infarction in age- and sex-adjusted analysis. However, after adjustment for LDL-C and other lipids, the strength of the association was largely attenuated. • Our findings suggest that serum levels of PCSK9 do not contribute additional useful information in cardiovascular risk assessment beyond the information provided by lipid measurements. • Moreover, our results are consistent with the biological understanding of PCSK9 and of its effect on atherosclerosis being mainly mediated by changes in LDL- receptor function., Summary The usefulness of circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) as a risk marker of coronary heart disease in the general population remains unclear. In a nested case-control study in Norway, 1,488 incident myocardial infarctions were registered during 11.3 years of follow-up and compared with 3,819 controls. Compared with participants in the lowest quartile of PCSK9, myocardial infarction risk was 47% higher in the highest quartile after adjustment for age and sex. After additional adjustment for low-density lipoprotein cholesterol, the association was strongly attenuated. Thus, circulating PCSK9 does not contribute useful information in the assessment of myocardial infarction risk in the general population beyond the information provided by lipid measurements.

Despite continued advances in health care, the cardiovascular disease (CVD) mortality rate has plateaued in recent years and appears to be trending upward. Poor diet is a leading cause of obesity and type 2 diabetes mellitus, which are leading contributors to CVD morbidity and mortality. Although dietary modification is a cornerstone of CVD prevention, implementation in clinical practice is limited by inadequate formal training in nutrition science. In this report, we review the individual components of a heart-healthy diet, evidence-based dietary recommendations, and the impact of diet on CVD risk factor prevention and management. Furthermore, we examine the unique difficulties of dietary counseling in low-socioeconomic-status environments and provide an evidence-based approach to better serve these populations. We utilized PubMed searches in adults with no date restriction with the following search terms: “carbohydrate,” “fat,” protein,” “DASH,” “Mediterranean,” “plant-based,” “vegetarian,” “cardiovascular disease,” “obesity,” “weight loss,” “diabetes,” “socioeconomic status,” and “race.” In this review, we demonstrate that patients should focus on implementing a general diet plan that is high in fruits, whole grains, legumes, and nonstarchy vegetables while low in trans-fats, saturated fats, sodium, red meat, refined carbohydrates, and sugar-sweetened beverages. The Dietary Approaches to Stop Hypertension, Mediterranean, and vegetarian diets have the most evidence for CVD prevention. Clinicians should understand the barriers that patients may face in terms of access to healthy dietary choices. Further research is needed to determine the dietary changes that are most economically, socioculturally, and logistically feasible to reduce these barriers. Improvement in diet is a public health priority that can lead to a significant population-level reduction in CVD morbidity and mortality. It is imperative that clinicians understand current dietary practice guidelines and implement evidence-based dietary counseling in those at high risk for CVD.

We report on a case of very rare autosomal recessive cholesteryl ester storage disease due to lysosomal acid lipase deficiency (LALD). LALD is caused by mutations in the lysosomal acid lipase A (LIPA) gene resulting in cholesteryl ester accumulation in liver, spleen, and macrophages. It can lead to liver failure, accelerated atherosclerosis and premature death. Until recently, treatment options were limited to lipid-lowering medications to control dyslipidemia. Presently, a long-term enzyme replacement therapy with Sebelipase alfa, a recombinant human lysosomal acid lipase, is available for patients with LALD.Our patient's condition became conspicuous at the age of two due to a xanthogranuloma of the chin together with increased lipid levels, elevated liver enzymes and hepatomegaly. It took another five years until our patient was diagnosed with LALD after genetic testing. A bi-weekly therapy with intravenous Sebelipase alfa was started at the age of 26 years. It led to normalization of lipid levels, reduction of liver enzymes and beginning regression of hepatomegaly in the absence of adverse drug reactions after 46 infusions.Since LALD can take a fatal course even in patients with a long-term stable condition, it is essential to identify affected patients early and to treat them appropriately by enzyme replacement therapy. LALD should be suspected in patients with low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) in conjunction with elevated liver enzymes or hepatomegaly.A registry for LALD patients shall help to advance our understanding of the disease as well as improve patient care (NCT01633489). Keywords: Lysosomal acid lipase deficiency (LALD), Cholesteryl ester storage disease, Sebelipase alfa (Kanuma™), LALD registry

Classification of the category of diabetes is extremely important for clinicians to diagnose and select the correct treatment plan. Glycosylation, oxidation and other post-translational modifications of membrane and transmembrane proteins, as well as impairment in cholesterol homeostasis, can alter lipid density, packing, and interactions of Red blood cells (RBC) plasma membranes in type 1 and type 2 diabetes, thus varying their membrane micropolarity. This can be estimated, at a submicrometric scale, by determining the membrane relative permittivity, which is the factor by which the electric field between the charges is decreased relative to vacuum. Here, we employed a membrane micropolarity sensitive probe to monitor variations in red blood cells of healthy subjects (n=16) and patients affected by type 1 (T1DM, n=10) and type 2 diabetes mellitus (T2DM, n=24) to provide a cost-effective and supplementary indicator for diabetes classification. We find a less polar membrane microenvironment in T2DM patients, and a more polar membrane microenvironment in T1DM patients compared to control healthy patients. The differences in micropolarity are statistically significant among the three groups (p, Graphical abstract Image 1, Highlights • Dynamic flux of cholesterol is differentially altered in T1DM and T2DM. • Red blood cell senses the dynamic flux of lipids by changing its micropolarity. • Laurdan can measure micropolarity in red blood cells membranes. • Differences in micropolarity between the three groups are statistically significant. • Red blood cell Micropolarity is an innovative assay for diabetes classification.