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.

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.

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.

The association between hypoalbuminemia and risk of death due to cancer and vascular disease in individuals aged 65 years and older: findings from the prospective Moli-sani cohort study.

Background: Serum albumin is inversely associated with overall mortality, but its association with specific causes of death remains uncertain. This study aims to investigate whether hypoalbuminemia, defined as serum albumin levels ≤35 g/L, is associated with mortality specifically attributed to cancer and/or vascular diseases. Methods: Serum albumin levels were measured in the population-based, prospective cohort of the Moli-sani study, established between 2005 and 2010. Hypoalbuminemia was defined as serum albumin levels ≤35 g/L. Cause-specific mortality was assessed using the validated Italian mortality registry and coded according to the International Classification of Diseases, Revision 9. Over a median follow-up period of 13.1 years, the relationship between serum albumin and mortality, adjusted for covariates, was investigated using competing-risk survival analysis. Findings: The analysed cohort comprised 17,930 individuals aged ≥35 years, of whom 8445 were men (47.1%). The mean age was 54 years (standard deviation (SD) = 11 years), with 3299 individuals (18.4%) aged older than 65 years. All participants had C-reactive protein levels <10 mg/L and no history of liver, renal, cardiovascular, or cancer disease. Hypoalbuminemia was found in 406 individuals (2.3%). The study documented a total of 1428 deaths, with 574 attributed to cancer and 464 to vascular causes. Hypoalbuminemia was independently associated with mortality when compared to serum albumin >40 g/L (Hazard Ratio (HR) = 1.61, 95% Confidence Interval: 1.21-2.13). A decrease of 1-SD in serum albumin levels corresponded to HR of 1.16 (1.09-1.22), 1.16 (1.05-1.28), and 1.13 (1.03-1.23) for total, vascular and cancer mortality, respectively. Upon stratifying by age, hypoalbuminemia was associated with total mortality solely in those aged ≥65 years (HR = 1.83; 1.33-2.50) but not in the <65 years group (HR = 1.03; 0.53-2.00; P < 0.0001 for difference). Similar age-related patterns emerged for vascular death (per 1-SD decrease HR = 1.19; 1.07-1.33 in individuals ≥65 years and HR = 1.05; 0.86-1.29 in individuals <65 years) and cancer mortality (HR = 1.15; 1.02-1.30; ≥65 years and HR = 1.08; 0.96-1.23; <65 years). Interpretation: Individuals ≥65 years old with serum albumin levels ≤35 g/L are at higher risk of total, cancer, and vascular mortality. Funding: This paper was developed within the project funded by Next Generation EU-"Age-It - Ageing well in an ageing society" project (PE0000015), National Recovery and Resilience Plan (NRRP)-PE8-Mission 4, C2, Intervention 1.3.

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.

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.

Determinants of serum uric acid levels in an adult general population: results from the Moli-sani Study.

OBJECTIVES: High levels of serum uric acid (UA) are associated with cerebro-cardiovascular disease risk factors. This study aimed at evaluating the main determinants of serum UA levels in relation to biochemical, lifestyle, and clinical variables. METHODS: The study population included 15,594 participants (48% men, age ≥ 35 years) to the Moli-sani Study, for whom data on serum UA levels were available. Association of UA with dependent variables was investigated by multivariable linear regression analysis separately for men and women. RESULTS: Average serum UA levels were higher in men than in women (6.1 ± 1.3 vs 4.6 ± 1.2 mg/dL, respectively). Cystatin C, creatinine, albumin, triglycerides, body mass index (BMI), and diuretic therapy were the major determinants of the heterogeneity of UA levels. In women, the final model, resulting from the stepwise analysis, explained 41.6% of the UA variability. In particular, cystatin C explained 22.5% of UA variance, followed by BMI (7.2%), albumin (4.0%), and creatinine (1.9%). The final model in men fitted the data less than in women (total R2 = 29.1%), and creatinine was found to be the main determinant of UA levels (10.1%), followed by triglycerides (7.6%), BMI (3.7%), and albumin (2.0%). CONCLUSIONS: In a general adult population, the major determinants of serum UA levels are cystatin C, creatinine, BMI, triglycerides, albumin, and the use of diuretics. Knowledge of its main determinants will be useful to better evaluate the relationship between UA levels and detrimental health outcomes and to clarify if an increase in uricemia is a marker or an independent risk factor. Key Points • Increased serum uric acid (UA) levels are reportedly associated with cardiovascular disease risk factors. • The major determinants of heterogeneity of UA levels are cystatin C, creatinine, BMI, triglycerides, albumin, and the use of diuretics, in a general adult population. • Studying the main determinants associated with high levels of serum uric acid would help better understanding if uric acid is a marker or an independent cardiovascular risk factor.

Sodium Intake and Proteinuria/Albuminuria in the Population-Observational, Cross-Sectional Study.

Sodium effects on proteinuria are debated. This observational, cross-sectional, population-based study investigated relationships to proteinuria and albuminuria of sodium intake assessed as urinary sodium/creatinine ratio (NaCR). In 482 men and 454 women aged 35-94 years from the Moli-sani study, data were collected for the following: urinary NaCR (independent variable); urinary total proteins/creatinine ratio (PCR, mg/g), urinary albumin/creatinine ratio (ACR, mg/g), and urinary non-albumin-proteins/creatinine ratio (calculated as PCR minus ACR) (dependent variables). High values were defined as PCR ≥ 150 mg/g, ACR ≥ 30 mg/g, and urinary non-albumin-proteins/creatinine ratio ≥ 120 mg/g. Urinary variables were measured in first-void morning urine. Skewed variables were log-transformed in analyses. The covariates list included sex, age, energy intake, body mass index, waist/hip ratio, estimated urinary creatinine excretion, smoking, systolic pressure, diastolic pressure, diabetes, history of cardiovascular disease, reported treatment with antihypertensive drug, inhibitor or blocker of the renin-angiotensin system, diuretic, and log-transformed data of total physical activity, leisure physical activity, alcohol intake, and urinary ratios of urea nitrogen, potassium, and phosphorus to creatinine. In multivariable linear regression, standardized beta coefficients of urinary NaCR were positive with PCR (women and men = 0.280 and 0.242, 95% confidence interval = 0.17/0.39 and 0.13/0.35, p < 0.001), ACR (0.310 and 0.265, 0.20/0.42 and 0.16/0.38, p < 0.001), and urinary non-albumin-proteins/creatinine ratio (0.247 and 0.209, 0.14/0.36 and 0.09/0.33, p < 0.001). In multivariable logistic regression, higher quintile of urinary NaCR associated with odds ratio of 1.81 for high PCR (1.55/2.12, p < 0.001), 0.51 of 1.62 for high ACR (1.35/1.95, p < 0.001), and of 1.84 for high urinary non-albumin proteins/creatinine ratio (1.58/2.16, p < 0.001). Findings were consistent in subgroups. Data indicate independent positive associations of an index of sodium intake with proteinuria and albuminuria in the population.

Reduced pulmonary function, low-grade inflammation and increased risk of total and cardiovascular mortality in a general adult population: Prospective results from the Moli-sani study.

AIM: to investigate the relation of pulmonary function impairment with mortality and the possible mediation by low-grade inflammation in a general adult population. METHODS: A prospective investigation was conducted on 14,503 individuals from the Moli-sani study (apparently free from lung disease and acute inflammatory status at baseline; 2005-2010). The 2012 Global Lung Function Initiative percent predicted (% pred) value of forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF25-75) and FEV1 quotient (FEV1Q) index were used. C-reactive protein and blood cell counts were measured and a score of subclinical inflammation (INFLA-score) was calculated. RESULTS: Over a median follow-up of 8.6y, 503 deaths (28.9% cardiovascular) were ascertained. Total mortality increased by 19% for each decrease in 1 standard deviation of FEV1% pred or FVC% pred (Hazard Ratio:1.19; 95% CI:1.11-1.28 and 1.19; 1.10-1.28, respectively). Comparable findings for FEV1Q (1.30; 1.15-1.47) were observed. A statistically significant increased risk in cardiovascular mortality of 23%, 32% and 49% was observed for 1 standard deviation decrease of FEV1% pred, FVC% pred and FEV1Q, respectively. INFLA-score mediated the association of FEV1% pred and FEV1Q with cardiovascular mortality by 22.3% and 20.1%, respectively. Subjects with FEV1, FVC lower than normal limit showed increased risk both in total and cardiovascular mortality. Abnormal FEF25-75 values were associated with 33% (1.33; 1.02-1.74) total mortality risk. CONCLUSIONS: Obstructive lung function impairment was associated with decreased survival. Low-grade inflammation mainly mediated the association of FEV1 with cardiovascular mortality.

Platelet Distribution Width Is Associated with P-Selectin Dependent Platelet Function: Results from the Moli-Family Cohort Study.

Defined as an index of platelet size heterogeneity, the platelet distribution width (PDW) is still a poorly characterized marker of platelet function in (sub)clinical disease. We presently validated PDW as a marker of P-selectin dependent platelet activation in the Moli-family cohort. Platelet-bound P-selectin and platelet/leukocyte mixed aggregates were measured by flow cytometry in freshly collected venous blood, both before and after in vitro platelet activation, and coagulation time was assessed in unstimulated and LPS- or TNFα-stimulated whole blood. Closure Times (CT) were measured in a Platelet Function Analyzer (PFA)-100. Multivariable linear mixed effect regression models (with age, sex and platelet count as fixed and family structure as random effect) revealed PDW to be negatively associated with platelet P-selectin, platelet/leukocyte aggregates and von Willebrand factor (VWF), and positively with PFA-100 CT, and LPS- and TNF-α-stimulated coagulation times. With the exception of VWF, all relationships were sex-independent. In contrast, no association was found between mean platelet volume (MPV) and these variables. PDW seems a simple, useful marker of ex vivo and in vitro P-selectin dependent platelet activation. Investigations of larger cohorts will define the usefulness of PDW as a risk predictor of thrombo-inflammatory conditions where activated platelets play a contributing role.

Combined influence of depression severity and low-grade inflammation on incident hospitalization and mortality risk in Italian adults.

BACKGROUND: Depression and low-grade systemic inflammation are associated risk factors for hospitalizations and mortality, although the nature of this relationship is under-investigated. METHODS: We performed multivariable Cox regressions of first hospitalization/mortality for all and specific causes vs depression severity, in an Italian population cohort (N=13,176; age≥35 years; 49.4% men), incrementally adjusting for sociodemographic, health and lifestyle factors. We tested potential mediation, additive and interactive effects of INFLA-score, a composite circulating inflammation index, and potential concurrent mediations of main lifestyles and chronic conditions. RESULTS: Over 4,856 hospitalizations (median follow-up 7.28 years), we observed an increased incident risk of events by 24% (CI=17-32%) and 59% (30-90%) for moderate and severe depression, which also showed a 125% (33-281%) increased risk of all-cause mortality (over 471 deaths, 8.24 years). These remained stable after adjustment for lifestyles, health conditions and INFLA-score, which explained 2.1%, 7.6%, 16.3% and 8%, 14.9% and 12% of depression influence on hospitalizations and mortality risk, respectively. These proportions remained substantially stable after reciprocal adjustments. INFLA-score showed significant additive (but not interactive) effects on both hospitalizations and mortality risk. LIMITATIONS: Depression severity was defined using a sub-version of Patient Health Questionnaire 9, which was validated here. Directionality links among exposures could not be established since they were collected simultaneously. CONCLUSIONS: These findings suggest a combined influence of depression and low-grade inflammation on health, which is partly intertwined and dependent on lifestyles and chronic conditions. This suggests the existence of pathways other than inflammation through which depression may play its detrimental effect.

Relation between pulmonary function and 10-year risk for cardiovascular disease among healthy men and women in Italy: the Moli-sani Project.

BACKGROUND: Pulmonary dysfunction could influence the onset and the evolution of cardiovascular disorders. This study evaluated whether pulmonary dysfunction based on spirometry, plethysmography and carbon monoxide diffusion test is associated with the estimated risk of cardiovascular disease in 10 years. DESIGN: We performed a cross-sectional general population-based cohort study. METHODS: The Moli-sani Project is a population-based cohort study of subjects aged ≥35 years, randomly recruited from the general population in Italy. Cardiovascular risk in 10 years was predicted by the CUORE score which provides an estimate of the probability of a first coronary or cerebrovascular event in the next 10 years, based on a risk equation derived from Italian cohorts. Out of 12,933 subjects with high-quality flow/volume manoeuvre, 8,132 subjects had suitable plethysmography and 3,422 carbon monoxide diffusion (carbon monoxide alveolar diffusion test [DLCO]). RESULTS: In multivariate analyses, reduced pulmonary function expressed by forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and total lung capacity (TLC) were inversely associated with CUORE score both in men and in women, independently of other risk factors such as age, height, smoking habits, total cigarettes exposure (pack-years), pulmonary disease, body mass index, social status and physical activity. In contrast, there was no association between FEV1/FVC ratio, residual volume, DLCO and CUORE risk score. CONCLUSIONS: In both genders from an adult general Italian population, pulmonary function decline is associated with increased cardiovascular risk. These results suggest that pulmonary monitoring could be useful to more accurately predict cardiovascular risk.

Pandemic and seasonal vaccine coverage and effectiveness during the 2009-2010 pandemic influenza in an Italian adult population.

OBJECTIVES: To evaluate the response to pandemic vaccination and seasonal and pandemic vaccine effectiveness (VE) in an Italian adult population, during the 2009-2010 influenza season. METHODS: Data were recorded by interviewing 19,275 subjects (≥35 years), randomly recruited from the general population of the Moli-sani project. Events [influenza-like illness (ILI), hospitalization and death], which had occurred between 1 November 2009 and 31 January 2010 were considered. VE was analyzed by multivariable Poisson regression analysis. RESULTS: Pandemic vaccine coverage was very low (2.4%) in subjects at high-flu risk, aged 35-65 years (N = 8,048); there was no significant preventive effect of vaccine against ILI. Seasonal vaccine coverage was 26.6% in the whole population (63% in elderly and 21.9% in middle-aged subjects at high-flu risk). There was a higher risk to develop ILI in middle-age [VE: -17% (95% CI: -35,-1)] or at high flu-risk [VE: -17% (95% CI: -39, 2)] vaccinated groups. CONCLUSIONS: Coverage of pandemic vaccine was very low in a Southern Italy population, with no protective effect against ILI.