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Abstract Purpose Economic downturns may have detrimental effects on mental health. We investigated the association of economic hardship resulting from the late 2000s Great Recession with long-term changes in mental health. Methods We analysed data from 1,647 participants to the larger Moli-sani cohort (2005–2010, Italy), who were re-examined between 2017 and 2020. To evaluate economic hardship, we performed a Latent Class Analysis on nine items linked to change in employment status and financial hardship. Depression symptoms were measured by the Patients’ Health Questionnaire (PHQ-2; higher values indicate more depressive symptoms; data available in N = 941 individuals) and health perception as assessed by the 36-Item Short Form Health Survey (decreased values indicate worsening of health perception). Results Economic hardship was categorized into three classes: “None”, “Average” and “High”, the latter reflecting increasing economic hardship. Mean (standard deviation) changes in PHQ-2, SF-36 mental and physical after 12.8 years (median) were − 0.1 (1.3), 0.5 (9.9) and − 2.2 (6.2) units, respectively. Changes in SF-36 mental score decreased by 1.0 unit (0.3) monotonically across “none” to “average” to “high” category in a multivariable-adjusted model analysis; the SF-36 physical score decreased by 0.4 (0.2) unit and PHQ-2 increased by 0.1 (0.1). In comparison with participants in the “none”, those in the “high” class had 84% (95%CI: 26%–170%) higher odds to report an increment in PHQ-2 values from baseline to re-examination. Conclusions Economic hardship resulting from the Great Recession in late 2000s was associated with deterioration of mental health, as reflected by increased depression symptoms and reduced perceived mental health.

Abstract Background Breakfast quality, together with regularity of breakfast, has been suggested to be associated with cardiometabolic health advantages. We aimed to evaluate the quality of breakfast and its socioeconomic and psychosocial correlates in a large sample of the Italian population. Methods Cross-sectional analyses on 7,673 adult and 505 children/adolescent regular breakfast eaters from the Italian Nutrition & Health Survey (INHES; 2010-2013). Dietary data were collected through a single 24-h dietary recall. Breakfast quality was assessed through the Breakfast Quality Index (BQI) combining intake of ten food groups, energy, and nutrients of public health concern, and potentially ranging from 0 to 10. The association of sociodemographic and psychosocial factors with BQI were analyzed by multivariable-adjusted linear regression models. Results The average BQI was 4.65 (SD ± 1.13) and 4.97 (SD ± 1.00) in adults and children/adolescents, respectively. Amongst adults, older age (β = 0.19; 95%CI 0.06 to 0.31 for > 65 vs. 20–40 years) and having a high educational level (β = 0.13; 0.03 to 0.23; for postsecondary vs. up to elementary) were independent predictors of better breakfast quality, while men reported lower BQI (β = -0.08; -0.14 to -0.02 vs. women). Perceived stress levels at home and work and financial stress were inversely associated with BQI. Children/adolescents living in Central and Southern Italian regions had lower BQI compared to residents in Northern Italy (β = -0.55; -0.91 to -0.19 and β = -0.24; -0.47 to -0.01, respectively). Conclusions In adults, breakfast quality was associated with age, sex, and educational level. Perceived stress levels were inversely associated with the quality of breakfast. In children/adolescents, a north-south gradient in breakfast quality was observed.

Background/Objectives: Studies investigating the associations between life-course socioeconomic status (SES) and biological aging (the difference between biological and chronological age, Δage) have mostly been focused on epigenetic clocks and on a limited number of mediators. The aim of this study was to investigate this relationship using a blood-based aging clock, as well as the potential mediation of different factors including lifestyles or their proxies and physical and mental wellbeing. Methods: A deep-learning aging clock based on 36 blood markers was deployed, in a large Italian population cohort: the Moli-sani study (N = 4772; ≥35 years; 48% men). SES was defined as an eight-level trajectory over the life course, which was tested with Δage in linear models incrementally adjusted for age, sex, and prevalent health conditions. Moreover, the proportion of associations explained by diverse potential mediators, including diet, smoking, physical activity, alcohol, body mass index (BMI), and physical and mental quality of life (QoL) was estimated. Results: Compared to participants with a stably high SES, those showing an educational and financial downward trajectory were older than their CA (β (95%CI) = 1.28 (0.73–1.83) years), as were those with a stably low SES (0.75 (0.25–01.25) years). These associations were largely explained by the tested mediators (overall proportion: 36.2% and 66.3%, respectively), prominently by physical QoL (20.7% and 41.0%), BMI (16.8% and 34.3%), lifestyle (10.6% and 24.6%), and dietary inflammatory score (5.3% and 9.2%). Conclusions: These findings indicate that life-course socioeconomic inequalities are associated with accelerated biological aging, suggesting physical wellbeing and pro-inflammatory lifestyles as potential public health targets to slow down this process in susceptible socioeconomic strata of the population.

The KALRN gene (encoding kalirin) has been implicated in several neuropsychiatric and neurodegenerative disorders. However, genetic evidence supporting this implication is limited and targeted epigenetic analyses are lacking. Here, we tested associations between epigenetic variation in KALRN and interindividual variation in depressive symptoms (PHQ9) and cognitive (MoCA) performance, in an Italian population cohort (N = 2409; mean (SD) age: 67 (9) years; 55% women). First, we analyzed the candidate region chr3:124584826–124584886 (hg38), within the KALRN promoter, through pyrosequencing of 1385 samples. Then, we widened the investigated region by analyzing 137 CpGs annotated to the whole gene, rescued from epigenome-wide (Illumina EPIC) data from 1024 independent samples from the same cohort. These were tested through stepwise regression models adjusted for age, sex, circulating leukocytes fractions, education, prevalent health conditions and lifestyles. We observed no statistically significant associations with methylation levels in the three CpGs tested through pyrosequencing, or in the gene-wide association analysis with MoCA score. However, we observed a statistically significant association between PHQ9 and cg13549966 (chr3:124106738; β (Standard Error) = 0.28 (0.08), Bonferroni-corrected p = 0.025), located close to the transcription start site of the gene. This association was driven by a polychoric factor tagging somatic depressive symptoms (β (SE) = 0.127 (0.064), p = 0.048). This evidence underscores the importance of studying epigenetic variation within the KALRN gene and the role that it may play in brain diseases, particularly in atypical depression, which is often characterized by somatic symptoms.

BackgroundAging 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.ObjectiveTo 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.MethodsIn 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).ResultsNo 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 (β (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; β (SE) = 0.46 (0.18)). All the remaining markers did not show any significant evidence of association.ConclusionThe 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.

This historical and personal review mainly focuses on the contribution of our research group and other Italian Colleagues to the development of aspirin pharmacology and its clinical use as an antithrombotic drug, in the Sixties, Seventies and Eighties. The main lines of research that have been developed over the last three decades, both at the experimental and clinical level, are not the subject of the present review.

Analizamos “los cantos para dormir al bebé”, un “antiguo” género musical de las mujeres indígenas toba-qom del Chaco argentino, que no había sido estudiado hasta el presente. Examinamos las transformaciones de este canto, según sus diferentes contextos performativos: desde el ámbito doméstico en las comunidades indígenas hasta las grabaciones en CDs y los espectáculos para audiencias interculturales. Para esto último, nos centramos en el análisis comparativo de las versiones en vivo realizadas por Zunilda Méndez, una anciana cantante qom, y Charo Bogarin, una joven cantante mestiza vinculada a la música electrónica y pop. A través de este análisis, mostramos cómo un mismo canto, en tanto mantiene su estructura melódica y lírica distintiva, es objeto de diferentes procesos de hibridación cultural que abarcan tanto los aspectos sonoro-musicales como los visuales y corporales de las performances. Así, apreciamos la continuidad de algunos rasgos de la música qom a la vez que la exotización y la exclusión de otros, para de ese modo adaptarse a las sensibilidades estéticas hegemónicas en los mercados culturales globalizados. La diversidad de versiones muestra que, a pesar de la violencia de los procesos de colonización y también de aquellos de dominación masculina, los cantos de las mujeres qom siguen operando como complejos y dinámicos signos de identidades étnicas y de género, en diversos contextos y audiencias.

IntroductionCentral nervous system (CNS) tumors are severe health conditions with increasing incidence in the last years. Different biological, environmental and clinical factors are thought to have an important role in their epidemiology, which however remains unclear.ObjectiveThe aim of this pilot study was to identify CNS tumor patients’ subtypes based on this information and to test associations with tumor malignancy.Methods90 patients with suspected diagnosis of CNS tumor were recruited by the Neurosurgery Unit of IRCCS Neuromed. Patients underwent anamnestic and clinical assessment, to ascertain known or suspected risk factors including lifestyle, socioeconomic, clinical and psychometric characteristics. We applied a hierarchical clustering analysis to these exposures to identify potential groups of patients with a similar risk pattern and tested whether these clusters associated with brain tumor malignancy.ResultsOut of 67 patients with a confirmed CNS tumor diagnosis, we identified 28 non-malignant and 39 malignant tumor cases. These subtypes showed significant differences in terms of gender (with men more frequently presenting a diagnosis of cancer; p = 6.0 ×10−3) and yearly household income (with non-malignant tumor patients more frequently earning ≥25k Euros/year; p = 3.4×10−3). Cluster analysis revealed the presence of two clusters of patients: one (N=41) with more professionally active, educated, wealthier and healthier patients, and the other one with mostly retired and less healthy men, with a higher frequency of smokers, personal history of cardiovascular disease and cancer familiarity, a mostly sedentary lifestyle and generally lower income, education and cognitive performance. The former cluster showed a protective association with the malignancy of the disease, with a 74 (14-93) % reduction in the prevalent risk of CNS malignant tumors, compared to the other cluster (p=0.026).DiscussionThese preliminary data suggest that patients’ profiling through unsupervised machine learning approaches may somehow help predicting the risk of being affected by a malignant form. If confirmed by further analyses in larger independent cohorts, these findings may be useful to create potential intelligent ranking systems for treatment priority, overcoming the lack of histopathological information and molecular diagnosis of the tumor, which are typically not available until the time of surgery.

Platelet distribution width (PDW), a marker of platelet size heterogeneity used as a readout of processes leading to platelet production and destruction, was recently reported to tag platelet activation variability. As platelets participate in the pathogenesis of many acute and chronic diseases, we evaluated PDW as a predictor of all-cause and cause-specific mortality. Longitudinal analysis was performed on 17,334 participants (52% women, mean age 55.6±12 years) in the Moli-sani study cohort, without a history of hematological diseases. Baseline PDW measurements were categorized in tertiles, the lowest acting as the reference. A multivariable Cox-proportional hazard model was used to estimate the association between PDW and mortality. Over a median follow-up of 11.6 years (interquartile range 10.7-12.5), 1,535 deaths [37.7% cardiovascular disease (CVD) and 36.5% cancer] were ascertained. As compared to those in the first PDW tertile (14.6-16.0 fL), individuals within the highest tertile (16.6-20.4 fL) had an increased risk of all-cause [hazard ratios (HR):1.20; 95% CI: 1.04-1.37] and CVD mortality (HR:1.29; 1.03-1.62). No association between PDW and cancer mortality was found in the whole sample. Subgroup analyses by two age classes (35-65y, ≥65y) showed that the association of PDW with both all-cause and cancer mortality was more apparent in the elderly (HR:1.34; 1.14-1.58, P for interaction =0.028 and HR:1.37; 1.01-1.85, P for interaction =0.020, respectively). We conclude that PDW-associated increase in CVD mortality risk could be related to accelerated/altered activation, production, or destruction of platelets, leading to several clinical conditions and death. In the elderly, PDW involvement in all-cause and cancer mortality should be further investigated. *Moli-sani investigators Steering committee: Licia Iacoviello, Giovanni de Gaetano, Maria Benedetta Donati. Scientific secretariat: Marialaura Bonaccio, Americo Bonanni, Chiara Cerletti, Simona Costanzo, Amalia De Curtis, Augusto Di Castelnuovo, Alessandro Gialluisi, Francesco Gianfagna, Mariarosaria Persichillo, Teresa Di Prospero. Safety and ethical committee: Jos Vermylen, Renzo Pegoraro, Antonio Spagnolo. External event adjudicating committee: Deodato Assanelli, Livia Rago. Baseline and follow-up data management: Simona Costanzo, Marco Olivieri, Teresa Panzera. Data analysis: Augusto Di Castelnuovo, Marialaura Bonaccio, Simona Costanzo, Simona Esposito, Alessandro Gialluisi, Francesco Gianfagna, Sabatino Orlandi, Emilia Ruggiero, Alfonsina Tirozzi. Biobank, molecular and genetic laboratory: Amalia De Curtis, Sara Magnacca, Fabrizia Noro, Alfonsina Tirozzi. Recruitment staff: Mariarosaria Persichillo, Francesca Bracone, Teresa Panzera. Communication and press office: Americo Bonanni. Regional institutions: Direzione Generale per la Salute - Regione Molise; Azienda Sanitaria Regionale del Molise; Agenzia Regionale per la Protezione Ambientale del Molise; Molise Dati Spa; Offices of vital statistics of the Molise region. Hospitals: Presidi Ospedalieri ASReM: Ospedale A. Cardarelli, Campobasso; Ospedale F. Veneziale, Isernia; Ospedale San Timoteo, Termoli (CB); Ospedale Ss. Rosario, Venafro (IS); Ospedale Vietri, Larino (CB); Ospedale San Francesco Caracciolo, Agnone (IS); Casa di Cura Villa Maria, Campobasso; Ospedale Gemelli Molise, Campobasso; IRCCS Neuromed, Pozzilli (IS), Italy.

Inducible promoters are one of cellular and molecular biology’s most important technical tools. The ability to deplete, replete, and overexpress genes on demand is the foundation of most functional studies. Here, we developed and characterized a new xylose-responsive promoter (Pxyl), the second inducible promoter system for the model haloarcheon Haloferax volcanii. Generating RNA-seq datasets from cultures in the presence of four historically used inducers (arabinose, xylose, maltose, and IPTG), we mapped upregulated genomic regions primarily repressed in the absence of the above inducers. We found a highly upregulated promoter that controls the expression of the xacEA (HVO_B0027-28) operon in the pHV3 chromosome. To characterize this promoter region, we cloned msfGFP (monomeric superfold green fluorescent protein) under the control of two upstream regions into a modified pTA962 vector: the first 250 bp (P250) and the whole 750 bp intergenic fragments (P750). The P250 sequence drove the expression of msfGFP constitutively, and its expression did not respond to the presence or absence of xylose. However, the P750 promoter showed not only to be repressed in the absence of xylose but also expressed higher levels of msfGFP than the previously described inducible promoter PtnaA in the presence of the inducer. Finally, we validated the inducible Pxyl promoter by reproducing morphological phenotypes already described in the literature. By overexpressing the tubulin-like FtsZ1 and FtsZ2, we observed similar but slightly more pronounced morphological defects than the tryptophan-inducible promoter PtnaA. FtsZ1 overexpression created larger, deformed cells, whereas cells overexpressing FtsZ2 were smaller but mostly retained their shape. In summary, this work contributes a new xylose-inducible promoter that could be used simultaneously with the well-established PtnaA in functional studies in H. volcanii in the future.

Introduction Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking.Methods and analysis The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners’ offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed.Ethics and dissemination This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study’s course and findings through regular meetings.Trial registration number NCT05339841.

Besides the Mediterranean diet, there is a paucity of studies examining plant-based diets in relation to cancer outcomes in Mediterranean populations. We analyzed 22,081 apparently cancer-free participants (mean age 55 ± 12 year) from the Moli-sani study (enrollment period 2005–2010; Italy). A general pro-vegetarian food pattern was computed by assigning positive or negative scores to plant- or animal-derived foods, respectively from a 188-item FFQ. A priori healthful or unhealthful pro-vegetarian food patterns distinguished between healthy plant foods (e.g., fruits, vegetables) and less-healthy plant foods (e.g., fruit juices, refined grains). Cancer incidence was defined as the earliest diagnosis of cancer from hospital discharge records over a median follow-up of 12.9 years. In multivariable-adjusted analyses, a general pro-vegetarian food pattern was associated with a lower rate of cancer incidence (HR = 0.85; 95%CI 0.75–0.97 for Q5 vs. Q1); no association was observed between the healthful or unhealthful pro-vegetarian food patterns and overall cancer incidence. A healthful pro-vegetarian pattern, however, was inversely associated with digestive cancer (HR = 0.76; 95%CI 0.58–0.99 for Q5 vs. Q1), while the unhealthful pro-vegetarian pattern was directly linked to respiratory cancer (HR = 1.68; 95%CI 1.06–2.68 for Q5 vs. Q1). Our findings in a Mediterranean population support the hypothesis that some, but not all pro-vegetarian diets, might prevent some cancers.

Epidemiological data on the association between fibrinogen levels and mortality are scarse and controversial. Longitudinal analyses were performed, separately by sex, on 17,689 individuals from the Moli-sani study [53% women, ≥35 years, free from cardiovascular disease (CVD) or cancer at enrolment], to evaluate the association between plasma fibrinogen and all-cause and cause-specific mortality. Over a median follow-up of 11.2 years, 1,058 deaths (34.7% CVD, 36.3% cancer) were ascertained. Both in the lowest (1.12-2.64 g/L) and highest (≥3.62 g/L) fibrinogen quintiles, women had an increased all-cause mortality hazard, when compared with third quintile (2.97-3.23 g/L). Dose-response analyses showed a U-shaped relationship in women (P overall

PurposeRadiation-induced skin toxicity is a common and distressing side effect of breast radiation therapy (RT). We investigated the use of quantitative spectrophotometric markers as input parameters in supervised machine learning models to develop a predictive model for acute radiation toxicity.Methods and materialsOne hundred twenty-nine patients treated for adjuvant whole-breast radiotherapy were evaluated. Two spectrophotometer variables, i.e. the melanin (IM) and erythema (IE) indices, were used to quantitatively assess the skin physical changes. Measurements were performed at 4-time intervals: before RT, at the end of RT and 1 and 6 months after the end of RT. Together with clinical covariates, melanin and erythema indices were correlated with skin toxicity, evaluated using the Radiation Therapy Oncology Group (RTOG) guidelines. Binary group classes were labeled according to a RTOG cut-off score of ≥ 2. The patient’s dataset was randomly split into a training and testing set used for model development/validation and testing (75%/25% split). A 5-times repeated holdout cross-validation was performed. Three supervised machine learning models, including support vector machine (SVM), classification and regression tree analysis (CART) and logistic regression (LR), were employed for modeling and skin toxicity prediction purposes.ResultsThirty-four (26.4%) patients presented with adverse skin effects (RTOG ≥2) at the end of treatment. The two spectrophotometric variables at the beginning of RT (IM,T0 and IE,T0), together with the volumes of breast (PTV2) and boost surgical cavity (PTV1), the body mass index (BMI) and the dose fractionation scheme (FRAC) were found significantly associated with the RTOG score groups (p

Neuromedin U (NMU) is a neuropeptide involved in gut-brain axis, energy balance and immune response. We aimed at analysing the association between NMU epigenetic variability and metabolic indices and the potential mediating role of low-grade inflammation in a general population of Italian adults. NMU Blood DNA methylation levels at two CpG islands (NMU76 and NMU32) were analysed using pyrosequencing in a randomly selected sub-cohort of 1,160 subjects from the Moli-sani study (≥35years; 49.20% men). Multivariable regressions adjusted for age, sex, smoking, alcohol and vegetable consumption were performed to estimate the associations between methylation and metabolic phenotypes (BMI, waist-to-hip ratio, blood pressure, glucose, HOMA-IR, lipids, lipoprotein(a) and apolipoproteins). Mediation analysis was performed to identify the influence of low-grade inflammation in the association using a composite index based on C reactive protein, granulocyte-to-lymphocyte ratio (GLR), platelet and white blood cell counts (INFLA-score). Using principal component analysis four methylation factors were identified: NMU76-F1, NMU76-F2, NMU32-F1 and NMU32-F2. NMU76-F1 was FDR significantly associated with total cholesterol (for 1 SD increase: β = 4.5 ± 1.4 mg/dL of, R2 = 10.8%, p = 0.001), ApoB (0.03 ± 0.01 g/L, 12.2%, p = 0.0004), with INFLA-score (1.05 ± 0.22, p = 2.7E-6) and GLR (-0.27 ± 0.03, 30.4%, p = 1.3E-20). GLR and lymphocyte numbers mediate the association of NMU76-F1 with cholesterol (24.0% of total effect, Sobel p = 0.013) and ApoB (42.6%, p = 9E-7), respectively. These findings suggest that NMU promoter methylation patterns could mark a pathway linking lipids with haematopoiesis and systemic inflammation.

Alessandro Gialluisi,1 Federica Santonastaso,2 Marialaura Bonaccio,1 Francesca Bracone,1 Nitin Shivappa,3,4 James R Hebert,3,4 Chiara Cerletti,1 Maria Benedetta Donati,1 Giovanni de Gaetano,1 Licia Iacoviello1,2 On behalf of the Moli-sani Investigators1Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy; 2Department of Medicine and Surgery, University of Insubria, Varese, Italy; 3Cancer Prevention and Control Program and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA; 4Department of Nutrition, Connecting Health Innovations LLC, Columbia, SC, USACorrespondence: Alessandro GialluisiDepartment of Epidemiology and Prevention, IRCCS Neuromed, Via dell´Elettronica, 86077, Pozzilli, ItalyTel +390865915244Email alessandro.gialluisi@gmail.comBackground: Depression is a mood disorder characterized by a high rate of resistance to pharmacological treatments, which has often been linked to chronic inflammation. This can be influenced by different environmental factors, in particular pro-inflammatory diets. However, a mediating role of circulating inflammation has never been observed.Aim: To test the association between a dietary inflammatory index (DII®) and continuous depressive symptoms (adapted version of PHQ9) in an Italian population cohort (N=13,301), along with potential explanatory effect of a composite index (INFLA-score) based on four circulating inflammatory biomarkers: C-reactive protein, granulocyte-to-lymphocyte ratio, platelet and white blood cell counts.Results: Significant positive associations were observed between DII and total depressive symptoms (standardized β (SE) = 0.038 (0.005), p < 0.001), and with two factors tagging somatic (0.012 (0.003), p < 0.001) and cognitive symptoms (0.012 (0.003), p < 0.001), after adjustment for different potential confounders (socioeconomic status, chronic health conditions and lifestyles). These associations were about twice as strong in women than in men. INFLA-score explained a small but significant proportion of the association with total depressive symptoms (0.90– 2.30%, p < 0.05), which was mainly driven by granulocyte-to-lymphocyte ratio (1.18– 1.65%). This effect was even stronger for the somatic (2.66– 4.66%) but not for the cognitive factor (0%).Conclusion: These findings support a strong link between inflammatory diet and depression, especially with somatic symptoms and within women. Moreover, they provide novel evidence for a potential explanatory role of circulating inflammation in this association, suggesting new paths for prevention and treatment of major and atypical depression.Keywords: dietary inflammatory index, depressive symptoms, atypical depression, circulating inflammation, granulocyte-to-lymphocyte ratio, white blood cells

BackgroundPatients 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).MethodsIn 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.ResultsIndividuals 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.ConclusionOur 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.

BackgroundMajor 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.MethodsWe 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).ResultsSignificant 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).ConclusionsThese 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.

Proteolysis plays a fundamental role in many processes that occur within the cellular membrane including protein quality control, protein export, cell signaling, biogenesis of the cell envelope among others. Archaea are a distinct and physiologically diverse group of prokaryotes found in all kinds of habitats, from the human and plant microbiomes to those with extreme salt concentration, pH and/or temperatures. Thus, these organisms provide an excellent opportunity to extend our current understanding on the biological functions that proteases exert in cell physiology including the adaptation to hostile environments. This revision describes the advances that were made on archaeal membrane proteases with regard to their biological function and potential natural targets focusing on the model haloarchaeon Haloferax volcanii.

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.

Immune cells are known to aggravate the inflammatory impact of Duchene muscular dystrophy. Here, the authors describe impaired thymic development and suggest thymic involution in this model of disease is linked to disease acceleration due to impaired immunological tolerance.

Late eating is reportedly associated with adverse metabolic health, possibly through poor diet quality. We tested the hypothesis that meal timing could also be linked to food processing, an independent predictor of health outcomes. We analysed data on 8688 Italians (aged > 19years) from the Italian Nutrition & HEalth Survey (INHES) established in 2010–2013 throughout Italy. Dietary data were collected through a single 24 h dietary recall, and the NOVA classification was used to categorize foods according to increasing levels of processing: (1) minimally processed foods (e.g., fruits); (2) culinary ingredients (e.g., butter); (3) processed foods (e.g., canned fish); (4) ultra-processed foods (UPFs; e.g., carbonated drinks, processed meat). We then calculated the proportion (%) of each NOVA group on the total weight of food eaten (g/d) by creating a weight ratio. Subjects were classified as early or late eaters based on the population’s median timing for breakfast, lunch and dinner. In multivariable-adjusted regression models, late eaters reported a lower intake of minimally processed food (β = −1.23; 95% CI −1.75 to −0.71), a higher intake of UPF (β = 0.93; 0.60 to 1.25) and reduced adherence to a Mediterranean Diet (β = −0.07; −0.12 to −0.03) as compared to early eaters. Future studies are warranted to examine whether increased UPF consumption may underpin the associations of late eating with adverse metabolic health reported in prior cohorts.

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 (β = 0.22; 95%CI 0.05, 0.38; β = 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.

In the Sixties, the few anti-thrombotic drugs available were administered following several criteria including tradition of the “School”, preference of the doctor in charge, pressure of pharmaceutical companies [...]

Abstract Background Single cardio-metabolic risk factors are each known modifiable risk factors for adverse health and quality of life outcomes. Yet, evidence on the clustered effect of these parameters and the metabolic syndrome (MetS) on health-related quality of life (HRQoL) is still limited and mostly cross-sectional. The objectives of this study were to identify clusters of cardio-metabolic physiological functioning, to assess their associations with HRQoL in comparison with the MetS, to elucidate the modifying role of physical activity, and to assess differences in health service utilization. Methods This study is based on longitudinal data from two time points (2010/11 & 2017/18) of the Swiss Study on Air Pollution and Lung and Heart Diseases (SAPALDIA). Latent class analysis (LCA) grouped participants based on a priori selected cardio-metabolic and MetS related physiological functioning variables (Body mass index, body fat, glycated hemoglobin, blood triglycerides, blood pressure). The 36-item Short-Form Health Survey (SF-36) was used to assess HRQoL. Quantile regressions were performed with and without adjustment for physical activity, to detect independent associations of the latent classes, MetS and physical activity with HRQoL. To assess the modifying role of physical activity, we additionally grouped participants based on the combination of physical activity and latent classes or MetS, respectively. Logistic regressions were used to investigate health service utilization as outcome. Results The LCA resulted in three classes labeled “Healthy” (30% of participants in 2017/18), “At risk” and “Unhealthy” (29%). The Unhealthy class scored lowest in all physical component scores of HRQoL. Compared to healthy and active participants, inactive participants in the “Unhealthy” class showed lower scores in the physical functioning domain both cross-sectionally (− 9.10 (− 12.02; − 6.18)) and longitudinally. This group had an odds ratio of 2.69 (1.52; 4.74) for being hospitalized in the previous 12 months. Conclusions These results point to subjects with adverse cardio-metabolic physiological functioning and low activity levels as an important target group for health promotion and maintenance of well-being. The promotion of physical activity at the early stages of aging seems pivotal to mitigate the impact of the MetS on HRQoL at higher age.

Excess antigenic exposure, such as in cancers or chronic viral infection, can lead to T cell exhaustion. Here the authors show that despite high exposure to antigen in the context of chronic LCMV infection in mice, exhausted CD8+ T cells have low levels of TCR signalling that can be reactivated by PD-L1 blockade.

While archaeal proteomics advanced rapidly, a comprehensive proteome database for archaea is lacking. Therefore, the authors here launch the Archaeal Proteome Project, a community-effort providing insights into archaeal cell biology via the combined reanalysis of Haloferax volcanii proteomics data.

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.

Objectives: To estimate psychological distress experienced during the Italian lockdown (March-May 2020) by assessing, in the transition period of the pandemic (June-September 2020), participants’ recalling of their psychological state.Methods: Cross-sectional analysis on 1,880 adults (mean age 48.9 ± 14.5 years) from the web-based ALT RISCOVID-19 survey. Participants were asked to retrospectively recall their psychological state during lockdown concerning symptoms of depression (Patients’ Health Questionnaire), anxiety (General Anxiety Disorder), stress (Perceived Stress Scale) and post-traumatic stress (Screening Questionnaire for Disaster Mental Health).Results: Experienced symptoms of depression, anxiety and post-traumatic stress was recalled by 15.8, 15.3 and 13.1% of respondents, respectively. These psychometric scales tended to decrease during the 4-month period of assessment (p < 0.05), while perceived stress levels did not (p = 0.13). Men and older individuals reported lower symptoms of depression (β = −0.42 and β = −0.42; p < 0.0001, respectively), anxiety (β = −0.41 and β = −0.45; p < 0.0001, respectively), stress (β = −0.36 and β = 0.50; p < 0.0001, respectively) and post-traumatic stress (β = −0.42; p < 0.0001, men vs women).Conclusion: Recalled psychological distress experienced during COVID-19 lockdown tended to decrease during the transition period of the pandemic, except for stress. Women and younger people were at higher risk to recall psychological distress.

Among candidate neurodegenerative/neuropsychiatric risk-predictive biomarkers, platelet count, mean platelet volume and platelet distribution width have been associated with the risk of major depressive disorder (MDD), Alzheimer’s disease (AD) and Parkinson’s disease (PD) through epidemiological and genomic studies, suggesting partial co-heritability. We exploited these relationships for a multi-trait association analysis, using publicly available summary statistics of genome-wide association studies (GWASs) of all traits reported above. Gene-based enrichment tests were carried out, as well as a network analysis of significantly enriched genes. We analyzed 4,540,326 single nucleotide polymorphisms shared among the analyzed GWASs, observing 149 genome-wide significant multi-trait LD-independent associations (p < 5 × 10−8) for AD, 70 for PD and 139 for MDD. Among these, 27 novel associations were detected for AD, 34 for PD and 40 for MDD. Out of 18,781 genes with annotated variants within ±10 kb, 62 genes were enriched for associations with AD, 70 with PD and 125 with MDD (p < 2.7 × 10−6). Of these, seven genes were novel susceptibility loci for AD (EPPK1, TTLL1, PACSIN2, TPM4, PIF1, ZNF689, AZGP1P1), two for PD (SLC26A1, EFNA3) and two for MDD (HSPH1, TRMT61A). The resulting network showed a significant excess of interactions (enrichment p = 1.0 × 10−16). The novel genes that were identified are involved in the organization of cytoskeletal architecture (EPPK1, TTLL1, PACSIN2, TPM4), telomere shortening (PIF1), the regulation of cellular aging (ZNF689, AZGP1P1) and neurodevelopment (EFNA3), thus, providing novel insights into the shared underlying biology of brain disorders and platelet parameters.

Polyphenols are naturally occurring compounds endowed with antioxidant and anti-inflammatory properties. We sought to examine the association of dietary polyphenols with the risk of severe lumbar spinal stenosis (LSS), a condition possibly characterized by a high inflammatory component. A case-control study included 156 patients with LSS and indication to surgery and 312 controls, matched (1:2) for sex, age (±6 months), and physical activity. The polyphenol intake was calculated by matching food consumption data from a 188-item food frequency questionnaire with the Phenol-Explorer database regarding the polyphenol content of each reported food. In a multivariable-adjusted logistic regression analysis including lifestyles, sociodemographic factors, and the Mediterranean Diet Score, a 1-standard deviation (SD) increase in dietary polyphenols intake was associated with lower odds of LSS (Odds ratio [OR] = 0.65; 95% CI: 0.47–0.89). Analyses of different polyphenol classes showed that a per 1-SD in the consumption of flavonoids and stilbenes was related to lower LSS risk (OR = 0.57; 95% CI: 0.42–0.78; OR = 0.40; 95% CI: 0.27–0.61, respectively). Further adjustment for the total dietary antioxidant capacity did not modify the strength of these associations. A diet rich in polyphenols is independently associated with a lower risk of severe LSS, possibly through mechanisms that include the anti-inflammatory potential of these bioactive compounds.

Previous research has shown that the built environment plays a crucial role for health-related quality of life (HRQoL) and health care utilization. But, there is limited evidence on the independence of this association from lifestyle and social environment. The objective of this cross-sectional study was to investigate these associations, independent of the social environment, physical activity and body mass index (BMI). We used data from the third follow-up of the Swiss study on Air Pollution and Lung and Heart diseases In Adults (SAPALDIA), a population based cohort with associated biobank. Covariate adjusted multiple quantile and polytomous logistic regressions were performed to test associations of variables describing the perceived built environment with HRQoL and health care utilization. Higher HRQoL and less health care utilization were associated with less reported transportation noise annoyance. Higher HRQoL was also associated with greater satisfaction with the living environment and more perceived access to greenspaces. These results were independent of the social environment (living alone and social engagement) and lifestyle (physical activity level and BMI). This study provides further evidence that the built environment should be designed to integrate living and green spaces but separate living and traffic spaces in order to improve health and wellbeing and potentially save health care costs.

Neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) suffer from the lack of risk-predictive circulating biomarkers, and clinical diagnosis occurs only when symptoms are evident. Among potential biomarkers, platelet parameters have been associated with both disorders. However, these associations have been scarcely investigated at the genetic level. Here, we tested genome-wide coheritability based on common genetic variants between platelet parameters and PD/AD risk, through Linkage Disequilibrium Score Regression. This revealed a significant genetic correlation between platelet distribution width (PDW), an index of platelet size variability, and PD risk (rg [SE] = 0.080 [0.034]; p = 0.019), which was confirmed by a summary-summary polygenic score analysis, where PDW explained a small but significant proportion PD risk (