Olive oil consumption is associated with lower cancer, cardiovascular and all-cause mortality among Italian adults: prospective results from the Moli-sani Study and analysis of potential biological mechanisms.

BACKGROUND: Olive oil consumption has been reportedly associated with lower mortality rates, mostly from cardiovascular diseases, but its potential impact on cancer death remains controversial. Moreover, biological mechanisms possibly linking olive oil consumption to mortality outcomes remain unexplored. METHODS: We longitudinally analysed data on 22,892 men and women from the Moli-sani Study in Italy (follow-up 13.1 y), to examine the association of olive oil consumption with mortality. Dietary data were collected at baseline (2005-2010) through a 188-item FFQ, and olive oil consumption was standardised to a 10 g tablespoon (tbsp) size. Diet quality was assessed through a Mediterranean diet score. Multivariable-adjusted Cox proportional hazard models, also including diet quality, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The potential mediating role of inflammatory, metabolic, cardiovascular and renal biomarkers on the association between olive oil intake and mortality was evaluated on the basis of change-in-estimate and associated p values. RESULTS: Multivariable HRs for all-cause, cancer, cardiovascular and other cause mortality associated with high (>3 tbsp/d) versus low (≤1.5 tbsp/d) olive oil consumption were 0.80 (0.69-0.94), 0.77 (0.59-0.99), 0.75 (0.58-0.97) and 0.97 (0.73-1.29), respectively. Taken together, the investigated biomarkers attenuated the association of olive oil consumption with all-cause and cancer mortality by 21.2% and 13.7%, respectively. CONCLUSIONS: Higher olive oil consumption was associated with lower cancer, cardiovascular and all-cause mortality rates, independent of overall diet quality. Known risk factors for chronic diseases only in part mediated such associations suggesting that other biological pathways are potentially involved in this relationship.

Blood-based biological ageing and red cell distribution width are associated with prevalent Parkinson's disease: findings from a large Italian population cohort.

Background: Aging clocks tag the actual underlying age of an organism and its discrepancy with chronological age and have been reported to predict incident disease risk in the general population. However, the relationship with neurodegenerative risk and in particular with Parkinson's Disease (PD) remains unclear, with few discordant findings reporting associations with both incident and prevalent PD risk. Objective: To clarify this relationship, we computed a common aging clock based on blood markers and tested the resulting discrepancy with chronological age (ΔPhenoAge) for association with both incident and prevalent PD risk. Methods: In a large Italian population cohort - the Moli-sani study (N=23,437; age ≥ 35 years; 52% women) - we carried out both Cox Proportional Hazards regressions modelling ΔPhenoAge as exposure and incident PD as outcome, and linear models testing prevalent PD as exposure and ΔPhenoAge as outcome. All models were incrementally adjusted for age, sex, education level completed and other risk/protective factors previously associated with PD risk in the same cohort (prevalent dysthyroidism, hypertension, diabetes, use of oral contraceptives, exposure to paints, daily coffee intake and cigarette smoking). Results: No significant association between incident PD risk (209 cases, median (IQR) follow-up time 11.19 (2.03) years) and PhenoAging was observed (Hazard Ratio [95% Confidence Interval] = 0.98 [0.71; 1.37]). However, a small but significant increase of ΔPhenoAge was observed in prevalent PD cases vs healthy subjects (ß (Standard Error) = 1.39 (0.70)). An analysis of each component biomarker of PhenoAge revealed a significant positive association of prevalent PD status with red cell distribution width (RDW; ß (SE) = 0.46 (0.18)). All the remaining markers did not show any significant evidence of association. Conclusion: The reported evidence highlights systemic effects of prevalent PD status on biological aging and red cell distribution width. Further cohort and functional studies may help shedding a light on the related pathways altered at the organism level in prevalent PD, like red cells variability, inflammatory and oxidative stress mechanisms.

Endogenous thrombin potential and time-dependent thrombin generation parameters are independent risk factors for mortality in the general population.

BACKGROUND: Thrombin generation (TG) is used as a global test of coagulation and is an indicator of thrombosis and bleeding risk. Until now, data on the association of TG and mortality are inconclusive. OBJECTIVES: We investigated the association between TG and mortality in the prospective Moli-sani cohort (n = 21 920). METHODS: TG was measured using calibrated automated thrombinography using PPP-Reagent Low. Lag time (LT), endogenous thrombin potential (ETP), peak height, time-to-peak (TTP), and velocity index were quantified. The association of TG and mortality was studied by Cox regression and adjusted for sex, age, body mass index, smoking, contraceptives, and medical history (cardiovascular diseases, hypertension, hypercholesterolemia, diabetes, and cancer). RESULTS: LT and TTP were 4.1 ± 1.0 minutes and 6.6 ± 1.5 minutes, on average. The peak height was 364 ± 88 nM, velocity index was 163 ± 63 nM/min, and ETP was 1721 ± 411 nM·min. ETP was negatively associated with all-cause mortality (hazard ratio [HR], 0.86; 95% CI, 0.81-0.92; P < .001). Subjects in the lowest quintile of the ETP (ETPQ1) had a 1.3-fold higher mortality rate. Additionally, a high TTP/LT ratio was negatively associated with mortality (HR, 0.71; 95% CI, 0.57-0.89; P = .003). Individuals in quintile 1 of the TTP/LT ratio had a 1.4-fold higher mortality rate compared with the remainder of the cohort. Subjects that were both in ETPQ1 and TTP/LTQ1 had a 1.8-fold higher mortality rate, regardless of whether they reported history of cardiovascular disease at baseline (HR, 1.61 [CI: 1.07-2.42]) or not (HR, 1.89 [CI: 1.51-2.36]). CONCLUSION: Low ETP and TTP/LT ratios are independent risk factors for all-cause mortality in the general population.

High alpha-2-macroglobulin levels are a risk factor for cardiovascular disease events: A Moli-sani cohort study.

BACKGROUND: α2-macroglobulin (α2M) is a versatile endopeptidase inhibitor that plays a role in cell growth, inflammation and coagulation. α2M is an inhibitor of key coagulation enzyme thrombin. Hypercoagulability due to an excess of thrombin production can cause thrombotic events. Therefore, we investigated the association of α2M levels and cardiovascular events in a subset of the general Italian population. METHODS: We determined α2M levels in the baseline samples of a prospective cohort (n = 19,688; age: 55 ± 12 years; 47.8 % men) of the Moli-sani study and investigated the association with the cardiovascular events (n = 432, 2.2 %) in the median follow-up period of 4.3 years. Hazard ratios (HR) with 95 % confidence intervals (CI) were calculated by multivariable Cox regression and adjusted for a large panel of confounding factors. RESULTS: α2M levels above the 90th percentile were significantly associated with cardiovascular disease (CVD) events after full adjustment for age, sex, current smoking, BMI, oral contraceptive use, cardiovascular diseases, hypertension, hypercholesterolemia, diabetes and history of cancer (HR: 1.36; CI: 1.06-1.74). Moreover, high α2M was associated with coronary heart disease (CHD; HR: 1.47; CI: 1.12-1.91), but not stroke. Stratification for CVD at baseline showed that high α2M levels are associated with CHD events in subjects without CVD at baseline (HR: 1.40; CI: 1.00-1.95) and subjects with CVD at baseline (HR: 1.58; CI: 1.02-2.44). CONCLUSION: We show in a prospective cohort that high levels of α2M could be a risk factor for cardiovascular events, especially coronary heart disease events.

The Moli-sani risk score, a new algorithm for measuring the global impact of modifiable cardiovascular risk factors.

BACKGROUND: Cardiovascular (CV) disease is preventable through interventions targeting modifiable factors. Most algorithms based on modifiable CV risk factors (CV-rf) have been developed in US populations and do not account for the role of diet. We aimed to assess an algorithm based on modifiable CV-rf including diet, using data from an Italian population. METHODS: To derive the Moli-sani Risk Score (MRS), we used data on 16,656 men and women (age ≥ 35 y) from the population of the Moli-sani Study. The Risk-and-Prevention-Study, Italy (N = 8606) acted as external validation cohort and the Life's-Simple-7 score was used as benchmark. The MRS targeted at fatal or non-fatal CV events and included 9 common modifiable CV-rf. RESULTS: After 8.1 years (median) of follow-up, 816 events occurred in the derivation cohort. The MRS was calculated as a weighted sum of its 9 components, with weights reflecting the strength of the association. In comparison with individuals in the first, those in the fourth quartile of the score had hazard ratio (HR) for CV events equal to 3.18 (95%CI: 2.54-3.97). One more point in the score was associated with 7% (6%-8%) and 4% (3%-5%) higher hazard of events in the derivation and validation cohort, respectively. The MRS performed better than the Life's Simple-7 for discrimination. CONCLUSION: We propose the Moli-sani Risk Score, a validated, performing algorithm able to measure the combined impact that modifiable CV-rf have on CV risk. The score can be used to design preventive interventions, quantify the effectiveness of interventions, and compare different preventive strategies.

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.

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.

Association between the Inflammatory Potential of the Diet and Biological Aging: A Cross-Sectional Analysis of 4510 Adults from the Moli-Sani Study Cohort.

Chronological age (CA) may not accurately reflect the health status of an individual. Rather, biological age (BA) or hypothetical underlying "functional" age has been proposed as a relevant indicator of healthy aging. Observational studies have found that decelerated biological aging or Δage (BA-CA) is associated with a lower risk of disease and mortality. In general, CA is associated with low-grade inflammation, a condition linked to the risk of the incidence of disease and overall cause-specific mortality, and is modulated by diet. To address the hypothesis that diet-related inflammation is associated with Δage, a cross-sectional analysis of data from a sub-cohort from the Moli-sani Study (2005-2010, Italy) was performed. The inflammatory potential of the diet was measured using the Energy-adjusted Dietary Inflammatory Index (E-DIITM) and a novel literature-based dietary inflammation score (DIS). A deep neural network approach based on circulating biomarkers was used to compute BA, and the resulting Δage was fit as the dependent variable. In 4510 participants (men 52.0%), the mean of CA (SD) was 55.6 y (±11.6), BA 54.8 y (±8.6), and Δage -0.77 (±7.7). In a multivariable-adjusted analysis, an increase in E-DIITM and DIS scores led to an increase in Δage (ß = 0.22; 95%CI 0.05, 0.38; ß = 0.27; 95%CI 0.10, 0.44, respectively). We found interaction for DIS by sex and for E-DIITM by BMI. In conclusion, a pro-inflammatory diet is associated with accelerated biological aging, which likely leads to an increased long-term risk of inflammation-related diseases and mortality.

Increased Adherence to a Mediterranean Diet Is Associated With Reduced Low-Grade Inflammation after a 12.7-Year Period: Results From the Moli-sani Study.

BACKGROUND: There is little knowledge on the association of changes over time in adherence to a Mediterranean diet (MD) with changes in modifiable cardiovascular disease (CVD) risk factors and of markers of low-grade inflammation. OBJECTIVE: To evaluate the association between long-term changes in MD adherence and concurrent changes in established CVD risk factors and in markers of low-grade inflammation among adult Italians. DESIGN: A prospective cohort study was conducted. Dietary and health data were obtained both at baseline (2005-2010) and at follow-up (2017-2020). Adherence to the MD was estimated by a Mediterranean Diet Score ranging from zero to nine points, and the exposure was change in this score measured after a median 12.7-year period. PARTICIPANTS/SETTING: This study included a subgroup of 897 men and 1,126 women aged ≥35 years at enrolment in the Moli-sani Study (n = 24,325). MAIN OUTCOME MEASURES: Changes in two composite z scores, including nine established CVD risk factors (eg, serum lipid levels and blood pressure) and four inflammatory markers (including C-reactive protein), respectively, were measured both at enrolment and after the same 12.7-year period. STATISTICAL ANALYSES PERFORMED: Multivariable-adjusted linear regression models were used. RESULTS: In a multivariable-adjusted analysis, an increased Mediterranean Diet Score over time was associated with decreased levels in the Inflammatory score (ß = -0.372, 95% CI -0.720 to -0.025), but had little or no influence on the CVD risk score (ß = -0.200, 95% CI -0.752 to 0.351), compared with individuals who had decreased their MD adherence. Among individual food groups/nutrients included in the Mediterranean Diet Score, an increased intake of monounsaturated over saturated fats over time was associated with lower CVD Risk Score, whereas increased consumption of cereals was inversely linked to the Inflammatory Score, compared with the reduced consumption group. CONCLUSIONS: An increased adherence to a traditional MD over time was associated with reduced low-grade inflammation. These findings suggest the potential of a traditional Mediterranean eating pattern to help reduce the long-term risk of inflammation-related chronic diseases in an ageing population.

Association of nutritional glycaemic indices with global DNA methylation patterns: results from the Moli-sani cohort.

BACKGROUND: High dietary glycaemic index (GI) and load (GL) have been associated with increased risk of various cardiometabolic conditions. Among the molecular potential mechanisms underlying this relationship, DNA methylation has been studied, but a direct link between high GI and/or GL of diet and global DNA methylation levels has not been proved yet. We analyzed the associations between GI and GL and global DNA methylation patterns within an Italian population. RESULTS: Genomic DNA methylation (5mC) and hydroxymethylation (5hmC) levels were measured in 1080 buffy coat samples from participants of the Moli-sani study (mean(SD) = 54.9(11.5) years; 52% women) via ELISA. A 188-item Food Frequency Questionnaire was used to assess food intake and dietary GI and GL for each participant were calculated. Multiple linear regressions were used to investigate the associations between dietary GI and GL and global 5mC and 5hmC levels, as well as the proportion of effect explained by metabolic and inflammatory markers. We found negative associations of GI with both 5mC (ß (SE) = - 0.073 (0.027), p = 0.007) and 5hmC (- 0.084 (0.030), p = 0.006), and of GL with 5mC (- 0.14 (0.060), p = 0.014). Circulating biomarkers did not explain the above-mentioned associations. Gender interaction analyses revealed a significant association of the gender-x-GL interaction with 5mC levels, with men showing an inverse association three times as negative as in women (interaction ß (SE) = - 0.16 (0.06), p = 0.005). CONCLUSIONS: Our findings suggest that global DNA methylation and hydroxymethylation patterns represent a biomarker of carbohydrate intake. Based on the differential association of GL with 5mC between men and women, further gender-based separate approaches are warranted.

Joint association of food nutritional profile by Nutri-Score front-of-pack label and ultra-processed food intake with mortality: Moli-sani prospective cohort study.

OBJECTIVE: To jointly analyse two food dimensions, the Food Standards Agency Nutrient Profiling System (FSAm-NPS), used to derive the Nutri-Score front-of-pack label, and the NOVA classification in relation to mortality. DESIGN: Prospective cohort study. SETTING: Moli-sani Study, Italy 2005-10. PARTICIPANTS: 22 895 participants (mean age 55 (SD 12) years; 48% men). MAIN OUTCOMES MEASURES: Associations between dietary exposures and mortality risk, assessed using multivariable cause specific Cox proportional hazard models controlled for known risk factors. RESULTS: A total of 2205 deaths occurred during 272 960 person years of follow-up. In the highest quarter of the FSAm-NPS index compared with the lowest quarter, multivariable adjusted hazard ratios for all cause and cardiovascular mortality were 1.19 (95% confidence interval 1.04 to 1.35; absolute risk difference 4.3%, 95% confidence interval 1.4% to 7.2%) and 1.32 (1.06 to 1.64; 2.6%, 0.3% to 4.9%), respectively. The hazard ratios were 1.19 (1.05 to 1.36; absolute risk difference 9.7%, 5.0% to 14.3%) and 1.27 (1.02 to 1.58; 5.0%, 1.2% to 8.8%), respectively, for all cause and cardiovascular mortality when the two extreme categories of ultra-processed food intake were compared. When these two indices were analysed jointly, the magnitude of the association of the FSAm-NPS dietary index with all cause and cardiovascular mortality was attenuated by 22.3% and 15.4%, respectively, whereas mortality risks associated with high ultra-processed food intake were not altered. CONCLUSIONS: Adults with the lowest quality diet, as measured using the FSAm-NPS dietary index (underpinning the Nutri-Score), and the highest ultra-processed food consumption (NOVA classification) were at the highest risk for all cause and cardiovascular mortality. A significant proportion of the higher mortality risk associated with an elevated intake of nutrient poor foods was explained by a high degree of food processing. In contrast, the relation between a high ultra-processed food intake and mortality was not explained by the poor quality of these foods.

Role of leukocytes, gender, and symptom domains in the influence of depression on hospitalization and mortality risk: Findings from the Moli-sani study.

Background: Major depressive disorder is a mental illness associated with chronic conditions like cardiovascular disease (CVD). Circulating inflammation has been proposed as a potential mechanism underlying this link, although the role of specific biomarkers, gender, and symptom domains is not well elucidated. Methods: We performed multivariable Cox regressions of first hospitalization/all-cause mortality and CVD, ischemic heart (IHD), and cerebrovascular disease (CeVD) causes vs. depression severity in an Italian population cohort (N = 13,191; age ≥ 35 years; 49.3% men; 4,856 hospitalizations and 471 deaths, median follow-up 7.28 and 8.24 years, respectively). In models adjusted for age, sex, and socioeconomic status, we estimated the proportion of association explained by C-reactive protein (CRP), platelet count, granulocyte-to-lymphocyte ratio (GLR), and white blood cell count (WBC). Gender-by-depression interaction and gender-stratified analyses were performed. Associations of polychoric factors tagging somatic and cognitive symptoms with incident clinical risks were also tested, as well as the proportion explained by a composite index of circulating inflammation (INFLA score). Results: Significant proportions of the influence of depression on clinical risks were explained by CRP (4.8% on IHD hospitalizations), GLR (11% on all-cause mortality), and WBC (24% on IHD/CeVD hospitalizations). Gender-by-depression interaction was significantly associated only with all-cause mortality (p = 0.03), with moderate depression showing a + 60% increased risk in women, but not in men. Stable associations of somatic, but not of cognitive, symptoms with increased hospitalization risk were observed (+ 16% for all causes, + 14% for CVD causes), with INFLA score explaining small but significant proportions of these associations (2.5% for all causes, 8.6% for IHD causes). Conclusions: These findings highlight the importance of cellular components of inflammation, gender, and somatic depressive symptoms in the link between depression and clinical (especially CVD) risks, pointing to the existence of additional pathways through which depression may play a detrimental effect on the cardiovascular system.

Fibrinogen levels in relation to colorectal cancer onset: A nested case-cohort study from the Moli-sani cohort.

Background: Patients with cancer are commonly characterized by abnormalities in laboratory coagulation tests, underlying a subclinical hypercoagulable condition. Due to the involvement of the hemostatic system in cancer patients, some of its biomarkers, such as fibrinogen, could be a useful tool in predicting cancer risk. We performed a case-cohort study to evaluate the relationship among fibrinogen levels and colorectal cancer (CRC). Methods: In the framework of Moli-sani Study (N = 24,325, enrolled 2005-2010) a subcohort of 1,290 individuals (55.0% women; mean age 55.0 ± 12.0 years) was selected and compared with 126 CRC cases identified during a follow-up of 4.3 years. Incident cases of colorectal cancer were ascertained by direct linkage with hospital discharge forms according to the International Classification of Disease (ICD-9-CM) codes: 153-154. Events were validated through medical records and confirmed by histological reports. Fibrinogen levels were measured in frozen citrated plasma samples. Hazard Ratio (HR) and 95% confidence interval (CI), adjusted by relevant covariates were estimated by a Cox regression model using Prentice method. Results: Individuals with levels of fibrinogen ≥400 mg/dL had a higher hazard to develop colorectal cancer when compared to those with lower levels after adjustment for sex and age (HR: 1.81; 95% CI 1.12-2.92). Additional adjustment for CRC family history, income, physical activity, diabetes medication and hypercholesterolemia did not modify the result (HR: 1.91; 95% CI 1.15-3.17). Analyses stratified by age and sex showed a most evident association in elderly (HR: 2.30; 95% CI: 1.10-4.81) and in women (HR: 2.28; 95% CI: 1.08-4.81). Sensitivity analyses confirmed the main findings, showing independence from a potential role of confounding by a large panel of biomarkers, including inflammation and hemostasis factors. Conclusion: Our results, based on a case-cohort study from a general adult population apparently free from any cancer during the recruitment, showed that fibrinogen levels ≥400 mg/dL were positively and independently associated with CRC, suggesting that this glycoprotein could be a potential biomarker for this type of cancer and supporting the "common soil hypothesis" in the pathophysiology of cardiovascular disease and tumors.

The inflammatory potential of the diet as a link between food processing and low-grade inflammation: An analysis on 21,315 participants to the Moli-sani study.

BACKGROUND & AIMS: Food processing may adversely affect human health through a variety of mechanisms, including the development of a chronic pro-inflammatory state. In this study we aimed to test the hypothesis that an increasing degree of food processing is directly associated with low-grade inflammation, and evaluate to what extent this association is mediated by the inflammatory potential of highly processed foods. METHODS: Cross-sectional analysis on 21,315 subjects (mean age 55 ± 3 y) from the Moli-sani Study with complete dietary data collected by a validated 188-item food frequency questionnaire. The NOVA classification was used to categorize foods on the basis of industrial processing as: 1) unprocessed/minimally processed foods; 2) processed culinary ingredients; 3) processed foods; 4) ultra-processed foods (UPF). The inflammatory potential of the diet was evaluated through the Energy-adjusted Dietary Inflammatory Index (E-DII™). Low-grade inflammation was assessed by a composite INFLA-score including C-reactive protein, leukocyte and platelet counts and the granulocyte to lymphocyte ratio. RESULTS: In multivariable-adjusted linear regression models, the INFLA-score was positively associated with E-DII (ß = 0.15; 0.10, 0.19), processed foods (ß = 0.04; 0.01, 0.08) and UPF (ß = 0.13; 0.07, 0.19), but inversely associated with minimally processed foods (ß = -0.09; -0.13, -0.06). The E-DII score was inversely associated with minimally processed food (ß = -0.40; 95%CI -0.41, -0.39 for 5% increment in the weight ratio) but directly with either processed culinary ingredients (ß = 0.18; 0.15, 0.21 for 1% increment), processed food (ß = 0.28; 0.27, 0.29 for 5% increment) or UPF (ß = 0.34; 0.32, 0.36 for 5% increment). The inclusion of the E-DII into the multivariable model explained 88.5% of the association of processed food with the INFLA-score (p < 0.0001) and mitigated by 32.6% (p < 0.0001) the association with UPF. CONCLUSIONS: The association of UPF with low-grade inflammation is only partially explained by the high pro-inflammatory potential of these foods. Further studies are warranted to test whether the observed adverse relationship of UPF with low-grade inflammation could be triggered by mechanisms that are not directly related to the pro-inflammatory potential of highly processed food products.

Low antithrombin levels are associated with low risk of cardiovascular death but are a risk factor for cancer mortality.

BACKGROUND: Thrombosis is common in subjects suffering from cardiovascular diseases (CVD) and cancer. Hypercoagulation plays a pivotal role in the pathophysiology of thrombosis. Therefore, the inactivation of thrombin, the key enzyme in coagulation, is tightly regulated via antithrombin (AT). AT deficiency is related to thrombosis and cardiovascular death. In this study we investigated the association between AT levels and mortality, in particularly cardiovascular-related and cancer-related death in the general population. METHODS: We studied the association of AT levels and mortality in a prospective cohort sampled from the general Italian population (n = 19,676). AT levels were measured in the baseline samples, and mortality was recorded during a median follow-up period of 8.2 years. Cox regression was performed to investigate the association of all-cause, CVD-related and cancer-related mortality with variations in AT levels. RESULTS: In total, 989 subjects died during follow-up, of which 373 subjects of CVD and 353 of cancer-related causes. Cox analysis revealed that, after adjustment for age, sex, current smoking, BMI, diabetes, hypertension, hypercholesterolemia, history of cardiovascular disease, history of cancer, vitamin K antagonists, antiplatelet medication, heparin and oral contraceptives AT levels were not associated with all-cause mortality (HRQ1vsQ5: 0.92, 95% CI:0.74-1.15). Interestingly, the risk of CVD-related mortality was reduced in subjects with low AT levels compared to subjects with higher AT levels, after adjustment for age and sex and other confounders did not change the association (HRQ1vsQ5: 0.64, 95% CI:0.44-0.91). Moreover, low AT levels were associated with increased cancer mortality in a fully adjusted model (HRQ1vsQ2-5: 1.26, 95% CI:0.88-1.81). CONCLUSIONS: Low AT levels are associated to a lower risk of fatal cardiovascular events in the general population, regardless of age, sex and medication use. In contrast, low AT levels are associated with lower cancer survival. For the first time we show that AT levels lower than the normal range in the general population, even before the development or diagnosis of cancer, are associated with an elevated risk of cancer death.

Increased BMI and Blood Lipids Are Associated With a Hypercoagulable State in the Moli-sani Cohort.

The coagulation system can be assessed by the thrombin generation (TG) assay, and increased TG peak height, endogenous thrombin potential (ETP), and velocity index are associated with an increased risk of thrombosis. Obesity had been reported to increase TG and is associated with dyslipidemia, which also predisposes to atherosclerotic cardiovascular disease (CVD). However, the effect of the blood lipid profile on TG has not been studied extensively. To gain more insight into the associations of TG, body mass index (BMI) and lipid profile, we studied TG in relation to these parameters in a large Italian population cohort, the Moli-sani study (N = 22,546; age ≥ 35 years; 48% men). TG was measured in plasma samples collected at the enrollment of subjects in the Moli-sani study. TG was triggered with 1 or 5 pM tissue factor, and TG parameters lag time, peak, ETP, time-to-peak (TTP) and velocity index (VI). Additionally, thrombomodulin was added to assess the function of the activated protein C system during TG. In both women and men, overweight (BMI 25-30 kg/m2) and obesity (BMI > 30 kg/m2) were significantly associated with higher ETP, peak and VI (all p < 0.001). High total cholesterol, triglycerides and LDL-cholesterol levels were significantly associated with increased ETP and peak (all p < 0.001). Linear regression analysis revealed that the ETP is positively associated with both plasma LDL and HDL cholesterol levels, whereas the velocity index is positively associated with HDL cholesterol. Additionally, ETP, peak and VI were significantly associated with the plasma triglycerides content. In conclusion, our study shows significant associations of high BMI and blood lipid levels with increased TG parameters, and this hypercoagulability may partly explain the increased risk of CVD in individuals with obesity and/or dyslipidemia.

Incremental monounsaturated to saturated fat ratio and fibre consumption is associated with a reduction in a composite score of modifiable cardiovascular risk factors: Prospective results from the Moli-sani study.

BACKGROUND/OBJECTIVES: Unsaturated fats, fibre-rich foods and polyphenols are distinctive features of a traditional Mediterranean diet and have pleiotropic properties possibly contributing to reduce the long-term risk of non-communicable diseases and mortality associated with this diet. We aimed to evaluate whether changes over time in dietary fats, fibre and polyphenols consumption are associated with modifications in cardiovascular disease (CVD) risk factors. METHODS: The analytic sample consists of a sub-cohort of 2023 men and women enrolled in the Moli-sani Study (n = 24,325). Dietary and health data were obtained both at baseline (2005-2010) and at re-examination (2017-2020). The exposures were changes in dietary fats, fibre and polyphenols consumption measured after 12.7 years (median), and the outcome was change in a composite score including 13 modifiable CVD risk factors (e.g., blood lipids, C-reactive protein), measured both at enrolment and after the 12.7 years period. RESULTS: In multivariable-adjusted analysis including lifestyles, sociodemographic and clinical factors, an incremental intake of the ratio of monounsaturated to saturated fats or of fibre was associated with a reduction in the composite score of CVD risk factors (ß = -0.086; 95%CI -0.150, -0.021 and ß = -0.051; 95%CI -0.091, -0.012, respectively). Change in polyphenol intake was not associated with a substantial variation in the CVD risk score (p = 0.15). CONCLUSIONS: An incremental consumption over time of monounsaturated versus saturated fats and of fibre was associated with an improvement in modifiable CVD risk factors as reflected by a composite score.

Clinical Network for Big Data and Personalized Health: Study Protocol and Preliminary Results.

The use of secondary hospital-based clinical data and electronical health records (EHR) represent a cost-efficient alternative to investigate chronic conditions. We present the Clinical Network Big Data and Personalised Health project, which collects EHRs for patients accessing hospitals in Central-Southern Italy, through an integrated digital platform to create a digital hub for the collection, management and analysis of personal, clinical and environmental information for patients, associated with a biobank to perform multi-omic analyses. A total of 12,864 participants (61.7% women, mean age 52.6 ± 17.6 years) signed a written informed consent to allow access to their EHRs. The majority of hospital access was in obstetrics and gynaecology (36.3%), while the main reason for hospitalization was represented by diseases of the circulatory system (21.2%). Participants had a secondary education (63.5%), were mostly retired (25.45%), reported low levels of physical activity (59.6%), had low adherence to the Mediterranean diet and were smokers (30.2%). A large percentage (35.8%) were overweight and the prevalence of hypertension, diabetes and hyperlipidemia was 36.4%, 11.1% and 19.6%, respectively. Blood samples were retrieved for 8686 patients (67.5%). This project is aimed at creating a digital hub for the collection, management and analysis of personal, clinical, diagnostic and environmental information for patients, and is associated with a biobank to perform multi-omic analyses.

Mediterranean diet and other dietary patterns in association with biological aging in the Moli-sani Study cohort.

BACKGROUND & AIMS: Biological age (BA) is the hypothetical underlying age of an organism and has been proposed as a more powerful predictor of health than chronological age (CA). The difference between BA and CA (Δage) reflects the rate of biological aging, with lower values indicating slowed-down aging. We sought to compare the relationship of four a priori-defined dietary patterns, including a traditional Mediterranean diet (MD) and three non-Mediterranean diets, with biological aging (Δage) among Italian adults. We also examined distinctive nutritional traits of these diets as potential mediators of such associations. METHODS: Cross-sectional analysis on a sub-cohort of 4510 subjects (aged ≥35 y; 52.0% women) from the Moli-sani Study (enrolment, 2005-2010). Food intake was recorded by a 188-item semi-quantitative food-frequency questionnaire. A Mediterranean diet score (MDS) was used as exposure and compared with non-Mediterranean dietary patterns, i.e. DASH (Dietary Approaches to Stop Hypertension), Palaeolithic and the Nordic diets. A Deep Neural Network based on 36 blood biomarkers was used to compute BA and the resulting Δage (BA-CA), which was tested as outcome in multivariable linear regressions adjusted for clinical factors, lifestyles and sociodemographic factors. RESULTS: In a multivariable-adjusted model, 1 standard deviation increase in the MDS was inversely associated with Δage (ß = -0.23; 95%CI -0.40, -0.07), and similar findings were observed with the DASH diet (ß = -0.17; 95%CI -0.33, -0.01). High dietary polyphenol content explained 29.8% (p = 0.04) and 65.8% (p = 0.02) of these associations, respectively, while other nutritional factors analysed (e.g. dietary fibre) were unlikely to be on the pathway. No significant associations were found with either the Palaeolithic or the Nordic diets. CONCLUSIONS: Increasing adherence to either the traditional MD or the DASH diet was associated with delayed biological aging, possibly through their high polyphenol content.

Correlates of Calcidiol Deficiency in Adults-Cross-Sectional, Observational, Population-Based Study.

The prevalence, determinants, and clinical significance of vitamin D deficiency in the population are debated. The population-based study investigated the cross-sectional associations of several variables with serum 25-hydroxyvitamin D (calcidiol) measured using standardized calibrators. The study cohort consisted of 979 persons of the Moli-sani study, both sexes, ages ≥35 years. The correlates in the analyses were sex, age, education, local solar irradiance in the month preceding the visit, physical activity, anthropometry, diabetes, kidney function, albuminuria, blood pressure, serum cholesterol, smoking, alcohol intake, calorie intake, dietary vitamin D intake, and vitamin D supplement. The serum calcidiol was log transformed for linear regression because it was positively skewed (skewness = 1.16). The prevalence of calcidiol deficiency defined as serum calcidiol ≤12 ng/mL was 24.5%. In multi-variable regression, older age, lower solar irradiance, lower leisure physical activity, higher waist/hip ratio, higher systolic pressure, higher serum cholesterol, smoking, lower alcohol intake, and no vitamin D supplement were independent correlates of lower serum calcidiol (95% confidence interval of standardized regression coefficient ≠ 0) and of calcidiol deficiency (95% confidence interval of odds ratio > 1). The data indicate that low serum calcidiol in the population could reflect not only sun exposure, age, and vitamin D supplementation but also leisure physical activity, abdominal obesity, systolic hypertension, hypercholesterolemia, smoking, and alcohol intake.