Association between BMI, RFM and mortality and potential mediators: Prospective findings from the Moli-sani study.

BACKGROUND: Body mass index (BMI) is the most frequently used adiposity measure, yet it is unable to differentiate fat mass from lean mass. Relative fat mass (RFM) has been proposed as an alternative. This paper aims to study RFM and BMI association with mortality in a general Italian population and potential mediators of such association. METHODS: 20,587 individuals from the Moli-sani cohort were analysed (mean age = 54 ± 11, women = 52%, median follow up = 11.2 years, interquartile range = 1.96 years). Cox regressions were used to assess BMI, RFM, and their interactive association with mortality. Dose-response relationships were computed with spline regression, mediation analysis was performed. All analyses were separated for men and women. RESULTS: Men and women with BMI > 35 kg/m2 and men in the 4th quartile of RFM showed an independent association with mortality (HR = 1.71, 95% CI = 1.30-2.26 BMI in men, HR = 1.37, 95%CI = 1.01-1.85 BMI in women, HR = 1.37 CI 95% = 1.11-1.68 RFM in men), that was lost once adjusted for potential mediators. Cubic splines showed a U-shaped association for BMI in men and women, and for RFM in men. Mediation analysis showed that 46.5% of the association of BMI with mortality in men was mediated by glucose, C reactive protein, forced expiratory volume in 1 s (FEV1), and cystatin C; 82.9% of the association of BMI in women was mediated by HOMA index, cystatin C and FEV1; lastly, 55% of RFM association with mortality was mediated by glucose, FEV1 and cystatin C. Regression models including BMI and RFM showed that RFM drives most of the risk in men, but is not predictive in women. CONCLUSIONS: The association between anthropometric measures and mortality was U shaped and it was largely dependent on sex. Associations were mediated by glucose metabolism, renal and lung function. Public health interventions should mainly focus on people with severe obesity or impaired metabolic, renal, or respiratory function.

Ultra-processed food intake and all-cause and cause-specific mortality in individuals with cardiovascular disease: the Moli-sani Study.

AIMS: To evaluate the association of ultra-processed food (UPF) intake and mortality among individuals with history of cardiovascular disease (CVD) and analyse some biological pathways possibly relating UPF intake to death. METHODS AND RESULTS: Longitudinal analysis on 1171 men and women (mean age: 67 ± 10 years) with history of CVD, recruited in the Moli-sani Study (2005-10, Italy) and followed for 10.6 years (median). Food intake was assessed using a food frequency questionnaire. UPF was defined using the NOVA classification according to degree of processing and categorized as quartiles of the ratio (%) between UPF (g/day) and total food consumed (g/day). The mediating effects of 18 inflammatory, metabolic, cardiovascular, and renal biomarkers were evaluated using a logistic regression model within a counterfactual framework. In multivariable-adjusted Cox analyses, higher intake of UPF (Q4, ≥11.3% of total food), as opposed to the lowest (Q1, UPF <4.7%), was associated with higher hazards of all-cause (hazard ratio [HR]: 1.38; 95% confidence interval (CI): 1.00-1.91) and CVD mortality (HR: 1.65; 95% CI: 1.07-2.55). A linear dose-response relationship of 1% increment in UPF intake with all-cause and CVD mortality was also observed. Altered levels of cystatin C explained 18.3% and 16.6% of the relation between UPF (1% increment in the diet) with all-cause and CVD mortality, respectively. CONCLUSION: A diet rich in UPF is associated with increased hazards of all-cause and CVD mortality among individuals with prior cardiovascular events, possibly through an altered renal function. Elevated UPF intake represents a major public health concern in secondary CVD prevention.

Habitual adherence to a traditional Mediterranean diet and risk of SARS-CoV-2 infection and Coronavirus disease 2019 (COVID-19): a longitudinal analysis.

Evidence on habitual Mediterranean diet (MD) and risk of SARS-CoV-2 infection, and COVID-19 is limited. 1,520 participants from the Moli-sani Study (2017-2020) were tested during January-September 2021 and adherence to MD was ascertained through the Mediterranean Diet Score (MDS). SARS-CoV-2 infection cases were determined through serology, and previous clinical diagnosis of COVID-19 disease was self-reported. Results were presented as odd ratios (OR) with 95% confidence intervals (CI). The MDS was not associated with the likelihood of SARS-CoV-2 infection (OR= 0.94; 95% CI: 0.83-1.06) and COVID-19 (OR= 0.82; 95% CI: 0.62-1.10) diagnosis. High consumption of cereals was associated with lower odds of SARS-CoV-2 infection (OR = 0.91; 95% CI: 0.83-1.00; for each 25 g/d increase). Likelihood of having being diagnosed with COVID-19 disease decreased in association with increasing olive oil intake (OR= 0.10; 95% CI: 0.01-0.79; for each additional 10 g/d), moderate alcohol consumption (OR= 0.18; 95% CI: 0.04-0.82) and higher intakes of fruits and nuts (OR = 0.89; 95% CI: 0.79-0.99). Our findings emphasise the adoption and maintenance of a balanced MD as a key strategy to reduce the risk of future SARS-CoV-2 infections and COVID-19.

Exploring domains, clinical implications and environmental associations of a deep learning marker of biological ageing.

Deep Neural Networks (DNN) have been recently developed for the estimation of Biological Age (BA), the hypothetical underlying age of an organism, which can differ from its chronological age (CA). Although promising, these population-specific algorithms warrant further characterization and validation, since their biological, clinical and environmental correlates remain largely unexplored. Here, an accurate DNN was trained to compute BA based on 36 circulating biomarkers in an Italian population (N = 23,858; age ≥ 35 years; 51.7% women). This estimate was heavily influenced by markers of metabolic, heart, kidney and liver function. The resulting Δage (BA-CA) significantly predicted mortality and hospitalization risk for all and specific causes. Slowed biological aging (Δage < 0) was associated with higher physical and mental wellbeing, healthy lifestyles (e.g. adherence to Mediterranean diet) and higher socioeconomic status (educational attainment, household income and occupational status), while accelerated aging (Δage > 0) was associated with smoking and obesity. Together, lifestyles and socioeconomic variables explained ~48% of the total variance in Δage, potentially suggesting the existence of a genetic basis. These findings validate blood-based biological aging as a marker of public health in adult Italians and provide a robust body of knowledge on its biological architecture, clinical implications and potential environmental influences.

Fine-grained investigation of the relationship between human nutrition and global DNA methylation patterns.

PURPOSE: Nutrition is an important, modifiable, environmental factor affecting human health by modulating epigenetic processes, including DNA methylation (5mC). Numerous studies investigated the association of nutrition with global and gene-specific DNA methylation and evidences on animal models highlighted a role in DNA hydroxymethylation (5hmC) regulation. However, a more comprehensive analysis of different layers of nutrition in association with global levels of 5mC and 5hmC is lacking. We investigated the association between global levels of 5mC and 5hmC and human nutrition, through the stratification and analysis of dietary patterns into different nutritional layers: adherence to Mediterranean diet (MD), main food groups, macronutrients and micronutrients intake. METHODS: ELISA technique was used to measure global 5mC and 5hmC levels in 1080 subjects from the Moli-sani cohort. Food intake during the 12 months before enrolment was assessed using the semi-quantitative EPIC food frequency questionnaire. Complementary approaches involving both classical statistics and supervised machine learning analyses were used to investigate the associations between global 5mC and 5hmC levels and adherence to Mediterranean diet, main food groups, macronutrients and micronutrients intake. RESULTS: We found that global DNA methylation, but not hydroxymethylation, was associated with daily intake of zinc and vitamin B3. Random Forests algorithms predicting 5mC and 5hmC through intakes of food groups, macronutrients and micronutrients revealed a significant contribution of zinc, while vitamin B3 was reported among the most influential features. CONCLUSION: We found that nutrition may affect global DNA methylation, suggesting a contribution of micronutrients previously implicated as cofactors in methylation pathways.

Life Course Socioeconomic Status and Risk of Hospitalization for Heart Failure or Atrial Fibrillation in The Moli-Sani Study Cohort.

We investigated the association of cumulative socioeconomic disadvantage (CSD) and socioeconomic (SES) trajectories across life course with the risk of first hospitalization for heart failure (HF) or atrial fibrillation (AF) and tested some biological mechanisms in explaining such associations. Longitudinal analysis on 21,756 HF- and AF-free subjects recruited in the Moli-sani Study (2005-2010; Italy) and followed up for 8.2 years. CSD was computed using childhood SES, education and adulthood SES indicators, and the same were used to define overall trajectories. High disadvantage across life course (CSD≥8) posed subjects at increased risk of HF (Hazard ratio [HR]=2.58; 95%CI 1.78, 3.74) or AF (HR=1.57;1.05,2.33), as compared to low CSD. All explanatory factors accounted for 18.5% and 24% of the excess of HF and AF risks, respectively, associated with CSD. For subjects with low childhood SES, advancements in education lowered risk of HF (HR=0.70;0.48, 1.02) or AF (HR=0.50;0.28, 0.89), whereas achievements of adulthood SES were unlikely to contribute to disease reduction. In conclusion, a life-course disadvantaged SES is an important predictor of first hospitalization for HF and AF; known risk factors partially explained the SES-disease gradient. Upwardly mobile groups are likely to mitigate the effect of poor childhood circumstances especially through educational advancement.

Daily Coffee Drinking Is Associated with Lower Risks of Cardiovascular and Total Mortality in a General Italian Population: Results from the Moli-sani Study.

BACKGROUND: An inverse relationship between coffee intake and mortality has been observed in several population cohorts, but rarely within Mediterranean countries. Moreover, the biological pathways mediating such an association remain unclear. OBJECTIVES: We assessed the associations between coffee consumption and total and cause-specific mortality and examined the mediating roles of N-terminal pro B-type natriuretic peptide (NTproBNP), high-sensitivity Troponin I, blood glucose, lipid metabolism, and selected biomarkers of inflammation and renal function. METHODS: We longitudinally analyzed data on 20,487 men and women (35-94 years old at baseline) in the Moli-sani Study, a prospective cohort established in 2005-2010. Individuals were free from cardiovascular disease (CVD) and cancer and were followed-up for a median of 8.3 years. Dietary data were collected by a 188-item semi-quantitative FFQ. Coffee intake was standardized to a 30-mL Italian espresso cup size. HRs with 95% CIs were calculated by multivariable Cox regression. RESULTS: In comparison with no/rare coffee consumption (up to 1 cup/d), HRs for all-cause mortality across categories of coffee consumption (>1 to ≤2, >2 to ≤3, >3 to ≤4 and >4 cups/d) were 0.79 (95% CI, 0.65-0.95), 0.84 (95% CI, 0.69-1.03), 0.72 (95% CI, 0.57-0.92), and 0.85 (95% CI, 0.62-1.12), respectively. For CVD mortality, a nonlinear (P for non-linearity = 0.021) J-shaped association was found (magnitude of the relative reduction = 37%; nadir at 3-4 cups/d). Circulating levels of NTproBNP explained up to 26.4% of the association between coffee and all-cause mortality, while systolic blood pressure was likely to be on the pathway between coffee and CVD mortality, although to a lesser extent. CONCLUSIONS: In this large cohort of Italian adults, moderate consumption (3-4 cups/d) of Italian-style coffee was associated with lower risks of all-cause and, specifically, of CVD mortality. Among the known biomarkers investigated here, NTproBNP likely mediates the relationship between coffee intake and all-cause mortality.

Association of a traditional Mediterranean diet and non-Mediterranean dietary scores with all-cause and cause-specific mortality: prospective findings from the Moli-sani Study.

PURPOSE: To evaluate in an Italian general population, the association with mortality of a traditional Mediterranean diet (MD) and non-Mediterranean dietary (non-MD) patterns, and their combined effect, and to test some biomarkers of cardiovascular (CVD) risk as potential mediators of such associations. METHODS: Longitudinal analysis on 22,849 men and women aged ≥ 35 years, recruited in the Moli-sani Study (2005-2010), followed up for 8.2 years (median). The MD was assessed by the Mediterranean diet score (MDS). The Dietary  Approaches to Stop Hypertension (DASH), the Palaeolithic diet, and the Nordic diet were chosen as reportedly healthy non-MD patterns. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated by multivariable Cox regression. RESULTS: Participants reaching higher MDS or DASH diet score experienced lower risk of both all-cause (HR 0.77; 95% CI 0.66-0.90 and 0.81; 0.69-0.96, respectively, highest vs lowest quartile) and CVD (0.77; 0.59-1.00 and 0.81; 0.69-0.96, respectively) death risk; risk reduction associated with the Palaeolithic diet was limited to total and other cause death, whereas the Nordic diet did not alter risk of mortality. Increasing adherence to MD was associated with higher survival in each stratum of non-MD diets. Biomarkers of glucose metabolism accounted for 7% and 21.6% of the association between either MDS or DASH diet, respectively, with total mortality risk. CONCLUSIONS: Both the traditional MD and DASH diet may reduce risk of all-cause mortality among Italians, as well as risk of dying from cardiovascular causes. The Palaeolithic diet did not appear to reduce cardiovascular risk, while the Nordic eating pattern was unlikely to be associated with any substantial health advantage.

Egg consumption and risk of all-cause and cause-specific mortality in an Italian adult population.

PURPOSE: Dietary guidelines recommend to limit egg consumption to 4 servings per week but the relation between egg intake and health outcomes is still controversial. To evaluate the association of egg consumption and mortality risk in Italian adults and to investigate nutritional factors and serum lipids as potentially explaining such associations. METHODS: Longitudinal analysis on 20,562 men and women aged ≥ 35y, free from cardiovascular disease (CVD) and cancer belonging to the Moli-sani Study cohort (enrolled 2005-2010) followed up for a median of 8.2 years. RESULTS: In multivariable-adjusted analysis as compared to low intake (> 0 ≤ 1 egg/week), eating > 4 eggs/week led to an increased risk of all-cause (Hazard ratio [HR] = 1.50; 95%CI 1.13-1.99), CVD (HR = 1.75; 1.07-2.87) and cancer mortality (HR = 1.52; 0.99-2.33). Similarly, an intake of 2-4 eggs/week was associated with higher all-cause (HR = 1.22; 1.01-1.46) and CVD mortality risk (HR = 1.43; 1.03-1.97). An increase of 1 egg per week was associated with higher mortality risk among high-risk individuals, such as those with hypertension and hyperlipidaemia. Dietary cholesterol explained about 43.0% and 39.3% (p values < 0.0001) of the association of eggs with all-cause and CVD mortality, respectively, while serum lipids (e.g., total cholesterol) accounted for a small proportion of egg-mortality relation. CONCLUSIONS: Among Italian adults, high egg consumption leads to an increased risk of all-cause and CVD mortality, with the risk being evident even at the recommended intake of 2-4 eggs per week. A substantial part of this association was likely due to the egg contribution to dietary cholesterol. Our findings suggest limiting the consumption of eggs in the diet and these results should be considered in the development of dietary guidelines and updates.

The CASSIOPEA Study (Economic Crisis and Adherence to the Mediterranean diet: poSSIble impact on biOmarkers of inflammation and metabolic PhEnotypes in the cohort of the Moli-sAni Study): Rationale, design and characteristics of participants.

BACKGROUND AND AIMS: The CASSIOPEA Study was designed to evaluate whether the economic downturn during the late 2000s was a contributing factor to the observed decrease in adherence to Mediterranean diet (MD). METHODS AND RESULTS: The study protocol consists of two steps: A) recall of 7406 men and women who, between 2005 and 2006, had been randomly recruited in the Moli-sani Study from the general population of Molise, to assess possible economic hardship (EH) related to the economic crisis initiated in 2007; B) re-examination, between 2017 and 2020, of available subjects identified in Step 1 as poorly or harder hit by EH to test the hypothesis that EH is associated with a decrease in MD adherence, possibly resulting in increased inflammation. The results of Step 1 are reported here. From the initial sample of individuals re-examined after 12.6 years (median; IQR = 12.1-13.0 y), 3646 were finally analysed. An Economic Hardship Score (EHS; range 0-14) was obtained by scoring three domains: 1) change in employment status; 2) financial hardship and 3) financial hardship for health expenditures. Overall, 37.8% of the sample reported high EHS (≥3), whilst 32% scored 0 (no EH). Those with high EHS were prevalently women and younger, with low socioeconomic status. CONCLUSIONS: High economic hardship was prevalently reported by weaker socioeconomic groups. Longitudinal analysis (step 2) will examine whether the economic crisis had an effect on adherence to Mediterranean diet with consequent potential impact on inflammation, one of the main biological pathways linking MD to health outcomes. CLINICALTRIALS. GOV IDENTIFIER: NCT03119142.

Associations between systemic inflammation and somatic depressive symptoms: Findings from the Moli-sani study.

BACKGROUND: The link between systemic inflammation and depression has been deeply investigated, but relatively few studies explored symptom-specific associations, mostly focusing on common inflammatory biomarkers like C-reactive protein (CRP) levels. METHODS: We investigated associations of low-grade inflammation with depressive symptoms assessed through a reduced version of Patient Health Questionnaire 9 (PHQ-9) in a large population-based cohort of adult Italians (N = 13 301). We built logistic regressions between each depressive symptom and composite index of systemic inflammation based on four circulating biomarkers, namely CRP, Plt, WBC, and GLR (INFLA)-score, a composite blood-based inflammation index, and with its component biomarkers, namely CRP, platelets count (Plt), white blood cells count (WBC), and granulocyte-to-lymphocyte ratio (GLR). RESULTS: We observed a strong association of the altered appetite/eating symptom with standardized INFLA-score (OR [95% CI] = 1.19 [1.12-1.26]; corrected p = 3.0 × 10-7 ), CRP (1.28 [1.20-1.36]; p = 1.9 × 10-13 ), and WBC (1.13 [1.06-1.20]; p = 2.3 × 10-3 ), and of tiredness/low energy with GLR (1.11 [1.05-1.17]; p = 9.4 × 10-3 ). These associations remained stable within nondepressed participants (PHQ-9 < 10), and after adjustment for the use of antidepressants, main chronic conditions, and lifestyle factors; while they were notably attenuated within depressed participants (PHQ-9 ≥ 10) and-for altered appetite only-by adjustment for obesity. CONCLUSIONS: This study provides a robust replication of the association previously reported between CRP and altered appetite in a large US population cohort, and supports a link between systemic inflammation, altered appetite, and tiredness. Moreover, it extends this evidence to inflammatory markers other than CRP and suggests new targets for the treatment of atypical depression.

NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) and the Risk of Stroke.

Background and Purpose- NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a risk factor for atrial fibrillation and a marker of cardiac function used in the detection of heart failure. Given the link between cardiac dysfunction and stroke, NT-proBNP is a candidate marker of stroke risk. Our aim was to evaluate the association of NT-proBNP with stroke and to determine the predictive value beyond a panel of established risk factors. Methods- Based on the Biomarkers for Cardiovascular Risk Assessment in Europe-Consortium, we analyzed data of 58 173 participants (50% men; mean age 52 y) free of stroke from 6 community-based cohorts. NT-proBNP measurements were performed in the central Biomarkers for Cardiovascular Risk Assessment in Europe laboratory. The outcomes considered were total stroke and subtypes of stroke (ischemic/hemorrhagic). Results- During a median follow-up time of 7.9 years, we observed 1550 stroke events (1176 ischemic). Increasing quarters of the NT-proBNP distribution were associated with increasing risk of stroke ( P for trend <0.0001; multivariable Cox regression analysis adjusted for risk factors and cardiac diseases). Individuals in the highest NT-proBNP quarter (NT-proBNP >82.2 pg/mL) had 2-fold (95% CI, 75%-151%) greater risk of stroke than individuals in the lowest quarter (NT-proBNP <20.4 pg/mL). The association remained unchanged when adjusted for interim coronary events during follow-up, and though it was somewhat heterogeneous across cohorts, it was highly homogenous according to cardiovascular risk profile or subtypes of stroke. The addition of NT-proBNP to a reference model increased the C-index discrimination measure by 0.006 ( P=0.0005), yielded a categorical net reclassification improvement of 2.0% in events and 1.4% in nonevents and an integrated discrimination improvement of 0.007. Conclusions- In European individuals free of stroke, levels of NT-proBNP are positively associated with risk of ischemic and hemorrhagic stroke, independently from several other risk factors and conditions. The addition of NT-proBNP to variables of established risk scores improves prediction of stroke, with a medium effect size.

Body Mass Index and Mortality in Elderly Subjects from the Moli-Sani Study: A Possible Mediation by Low-Grade Inflammation?

The association between obesity and mortality in the elderly remains controversial. To test the association between BMI and mortality, with the hypothesis of a mediation by low-grade inflammation (LGI), a prospective study design (median follow-up 7.8 years) was used on a sample of 4,970 elderly subjects (age ≥ 65 years) from the Moli-sani Study cohort. The association between BMI categories and overall or cause-specific mortality (hazard ratio, HR) was calculated by multivariable Cox regression. Dose-response relationship was tested using restricted cubic splines. Interaction between BMI and LGI, assessed through high-sensitivity C-reactive protein (hs-CRP) and INFLA-score, was also tested. In comparison with normal-weight, overweight was significantly associated with a 20% (adjusted HR = 0.80; 95%CI 0.67-0.95) reduced risk of total mortality, while severe obesity (BMI > 40) with an increased risk (HR = 1.81; 95%CI 1.13-2.93). Cubic spline curves showed a U-shaped relationship between BMI and total mortality (p value for nonlinear relationship = 0.001). Similar results were found for cardio-cerebrovascular and other causes mortality. Hs-CRP and INFLA-score were associated with an increased risk of total mortality in adjusted analyses. Mediation analysis did not show any effect of LGI on the association between BMI and mortality. However, after stratification for LGI under or below the population median, greater LGI increased the risk of mortality in obese elderly more than expected (p for interaction = 0.04). A U-shaped association between BMI and mortality was observed in Italian elderly subjects. While the association was independent of LGI levels, there was a significant interaction between BMI and LGI in increasing mortality risk in obese elderly individuals.

Age- and sex-based ranges of platelet count and cause-specific mortality risk in an adult general population: prospective findings from the Moli-sani study.

Platelet count varies by age, sex and ethnicity. However, previous studies have adopted standard ranges to identify subjects with thrombocytopenia or thrombocytosis. The aim of this study was to test the predictive role of age-sex-based cut-offs of platelet count proposed by an Italian collaborative study, towards the risk of cause-specific death. We conducted a prospective analysis on 21,563 adult subjects (mean age 55.6 ± 11.8) randomised from the general population of the Moli-sani study. Hazard ratios (HR) were calculated by multivariable Cox-proportional hazard models with 95% confidence intervals. Over a median follow-up of 8.2 years (interquartile range: 7.3 to 9.2 years; 175,972 person-years), we ascertained and validated 1,130 deaths, 415 of which are from cardiovascular disease, 439 from cancer and 276 from non-vascular/non-cancer causes. As opposed to the normal ranges defined by age and sex (extreme values from 122 to 405 x109/L), lower platelet number (87.7% of values being higher than 100x109/L) was associated with increased risk of total (HR = 1.92; 95%CI 1.38-2.67), cancer (HR = 1.77; 95%CI 1.03-3.05), and non-cardiovascular/non-cancer mortality (HR = 3.16; 95%CI 1.84-5.42) but was unrelated to cardiovascular mortality. Higher platelet count was not associated with any death risk. In conclusion, age-sex-based low platelet count, well above the traditional lower normal range of <100 x109/L, is associated with increased total and specific mortality risk in a general population.

Dietary anthocyanins and health: data from FLORA and ATHENA EU projects.

Adherence to a 'Mediterranean diet' has been shown to be beneficial to human health. Fruit and vegetables represent some of the main components of the Mediterranean diet and their role has been increasingly considered in the process of preventing or reducing the risk of chronic degenerative diseases, such as cerebrovascular or coronary heart disorders, cancer and neurodegenerative diseases. To investigate the beneficial effect of these dietary compounds, two EU-funded projects were conducted during the last 10 years. Their results from experimental models suggest that dietary anthocyanin enrichment is beneficial against a number of ischemic and degenerative conditions. On the other hand, human studies demonstrated that anthocyanin supplementation can counteract the inflammatory response to stress conditions, such as a fatty meal. Moreover, an intervention trial in patients with breast cancer undergoing radiotherapy is presently testing the possible beneficial effect of the administration of a product enriched in anthocyanins on the inflammatory response to radiation and on its consequent skin toxicity, as well as on systemic low-grade inflammation reaction.

Adherence to the Mediterranean diet is associated with lower platelet and leukocyte counts: results from the Moli-sani study.

Platelet (PLT) and white blood cell (WBC) counts are 2 markers of inflammation and have been linked to the risk for cerebrovascular and coronary heart disease. A Mediterranean diet (MD) has been associated with reduced inflammation and mortality for major chronic diseases. We aimed at evaluating the association between the MD and both PLT and WBC counts. This cross-sectional analysis in a population-based cohort study included 14,586 healthy Italian citizens enrolled within the Moli-sani study. Adherence to MD was appraised by either the MD Score (MDS) or the Italian Mediterranean Index (IMI). PLT and WBC counts were both inversely related to MD adherence (MDS: P < .0001 and P = .008, respectively). As compared with those with poorer MD adherence, subjects with greater adherence had both reduced odds of being in the highest PLT-count group (MDS: odds ratio = 0.50; 95% confidence interval, 0.31-0.80) and increased odds of being in the lowest WBC-count group (IMI: odds ratio = 1.41; 95% confidence interval, 1.07-1.86). The association between WBC count and MDS disappeared when further adjusted for PLT count, whereas the association between PLT count and the MD was not affected by adjustment for WBCs. Food antioxidant and dietary fiber content modified the inverse association between MDS and WBC count and partially accounted for the association with PLTs.

A score of low-grade inflammation and risk of mortality: prospective findings from the Moli-sani study.

Low-grade inflammation is associated with an increased risk of chronic degenerative disease, but its relationship with mortality is less well explored. We aimed at evaluating, at a large epidemiological level, the possible association of low-grade inflammation, as measured by a composite score, with overall mortality risk. We conducted a population-based prospective investigation on 20,337 adult subjects free from major hematological disease and acute inflammatory status, randomly recruited from the general population of the Moli-sani study. A low-grade inflammation score was obtained from the sum of 10-tiles of plasmatic (C-reactive protein) and cellular (leukocyte and platelet counts, granulocyte/lymphocyte ratio) biomarkers of low-grade inflammation; higher levels indicated increased low-grade inflammation. Hazard ratios were calculated using multivariable Cox proportional hazard models with 95% confidence intervals. At the end of follow-up (median 7.6 years), 837 all-cause deaths were recorded. As compared to subjects in the lowest quartile of the low-grade inflammation score, those in the highest category had a significantly increased risk in overall mortality (HR=1.44; 1.17-1.77), independently of possible confounders, including the presence of chronic diseases and a number of health-related behaviors. The magnitude of the association of low-grade inflammation with mortality was relatively higher in type 2 diabetic patients (HR=2.90; 1.74-4.84) and in individuals with a history of cardiovascular disease (HR=2.48; 1.50-4.11) as compared to their counterparts who were free from the disease. In conclusion, an elevated degree of low-grade inflammation, as measured by a composite score of inflammatory biomarkers, is an independent risk factor for total mortality in an apparently healthy adult general population.

Circulating Tissue Factor Levels and Risk of Stroke: Findings From the EPICOR Study.

BACKGROUND AND PURPOSE: Tissue factor (TF) expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. Blood-borne TF has been also demonstrated to contribute to thrombogenesis. However, few studies have evaluated the association of circulating levels of TF with stroke. We investigated the association of baseline circulating levels of TF with stroke events occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort. METHODS: Using a nested case-cohort design, a center-stratified random sample of 839 subjects (66% women; age range, 35-71 years) was selected as subcohort and compared with 292 strokes in a mean follow-up of 9 years. Blood samples were collected at baseline in citrate, plasma was stored in liquid nitrogen and TF was measured by ELISA (IMUBIND, TF ELISA, Instrumentation Laboratory, Milan, Italy). The odd ratios and 95% confidence intervals, adjusted by relevant confounders (covariates of TF) and stratified by center, were estimated by a Cox regression model using Prentice method. RESULTS: Individuals in the highest compared with the lowest quartile of TF plasma levels had significantly increased risk of stroke (odds ratioIVvsI quartile, 2.01; 95% confidence interval, 1.25-3.23). The association was independent from several potential confounders (odds ratioIVvsI quartile, 1.91; 95% confidence interval, 1.15-3.19). No differences were observed between men and women. The increase in risk was restricted to ischemic strokes (odds ratioIVvsI quartile, 2.13; 95% confidence interval, 1.10-4.12; fully adjusted model), whereas high levels of TF were not associated with the risk of hemorrhagic stroke (odds ratioIVvsI quartile, 1.12; 95% confidence interval, 0.49-2.55; fully adjusted model). CONCLUSIONS: Our data provide evidence that elevated levels of circulating TF are potential risk factors for ischemic strokes.

Prevalence and cardiovascular risk profile of chronic kidney disease in Italy: results of the 2008-12 National Health Examination Survey.

BACKGROUND: National surveys in countries outside Europe have reported a high prevalence (11-13%) of chronic kidney disease (CKD). Studies in Europe have provided a variable prevalence likely due to differences in study design, including age and extent of geographic areas, equation used to evaluate estimated glomerular filtration rate (eGFR) and CKD stages examined. METHODS: The 2008-12 National Health Examination Survey in Italy randomly extracted samples from the general population aged 35-79 years, stratified by age and gender, from the resident list of each Italian region (440 persons/1.5 million of residents). We estimated the prevalence of CKD by means of urinary albumin : creatinine ratio and eGFR (CKD-EPI equation-enzymatic assay of serum creatinine). Cardiovascular (CV) risk profile was also evaluated. RESULTS: Three thousand eight hundred and forty-eight men and 3704 women were examined. In the whole population, mean age was 57 ± 12 and 56 ± 12 years in men and women, respectively; hypertension was prevalent in men and women, respectively (56 and 43%) and the same held true for overweight (48 and 33%), obesity (26 and 27%), diabetes (14 and 9%) and smoking (21 and 18%), whereas CV disease was less frequent (9 and 6%). Overall, the prevalence of CKD (95% confidence interval) was 7.05% (6.48-7.65). Early stages constituted 59% of the CKD population [Stage G1-2 A2-3: 4.16% (3.71-4.61) and Stage G3-5: 2.89% (2.51-3.26)]. At multivariate regression analysis, age, obesity, hypertension, diabetes, CV disease and smoking were all independent correlates of CKD. CONCLUSIONS: CKD has a relatively lower prevalence in Italy, in particular for advanced stages, when compared with similar national surveys outside Europe. This occurs despite older age and unfavourable CV risk profile of the whole population.

Nut consumption is inversely associated with both cancer and total mortality in a Mediterranean population: prospective results from the Moli-sani study.

Nut intake has been associated with reduced inflammatory status and lower risk of CVD and mortality. The aim of this study was to examine the relationship between nut consumption and mortality and the role of inflammation. We conducted a population-based prospective investigation on 19 386 subjects enrolled in the Moli-sani study. Food intake was recorded by the Italian version of the European Project Investigation into Cancer and Nutrition FFQ. C-reactive protein, leucocyte and platelet counts and the neutrophil:lymphocyte ratio were used as biomarkers of low-grade inflammation. Hazard ratios (HR) were calculated using multivariable Cox proportional hazard models. During a median follow-up of 4·3 years, 334 all-cause deaths occurred. As compared with subjects who never ate nuts, rare intake (≤2 times/month) was inversely associated with mortality (multivariable HR=0·68; 95 % CI 0·54, 0·87). At intake ≥8 times/month, a greater protection was observed (HR=0·53; 0·32, 0·90). Nut intake (v. no intake) conveyed a higher protection to individuals poorly adhering to the Mediterranean diet (MD). A significant reduction in cancer deaths (HR=0·64; 95 % CI 0·44, 0·94) was also observed, whereas the impact on CVD deaths was limited to an inverse, but not significant, trend. Biomarkers of low-grade inflammation were reduced in nut consumers but did not account for the association with mortality. In conclusion, nut intake was associated with reduced cancer and total mortality. The protection was stronger in individuals with lower adherence to MD, whereas it was similar in high-risk groups (diabetics, obese, smokers or those with the metabolic syndrome), as compared with low-risk subjects. Inflammation did not explain the observed relationship.