Discrimination and net-reclassification of cardiovascular disease risk with Lipoprotein(a) levels: The ATTICA study (2002-2022).

BACKGROUND: Lipoprotein(a) [Lp(a)] is a recognized as risk factor for atherosclerotic cardiovascular disease (ASCVD). However, its influence on clinical risk evaluations remains unclear. OBJECTIVE: This study aimed to determine whether Lp(a) improves CVD risk prediction among apparently healthy adults from the general population. METHODS: In 2002, n = 3,042 adults free of CVD, residing in Athens metropolitan area, in Greece, were recruited. A 20-year follow-up was conducted in 2022, comprising n = 2,169 participants, of which n = 1,988 had complete data for CVD incidence. RESULTS: Lp(a) levels were significantly associated with 20-year ASCVD incidence in the crude model (Hazard Ratio per 1 mg/dL: 1.004, p = 0.048), but not in multi-adjusted models considering demographic, lifestyle, and clinical factors. Adding Lp(a) to the Reynolds Risk Score (RRS) and Framingham Risk Score (FRS) variables resulted in positive Net Reclassification Improvement (NRI) values (0.159 and 0.160 respectively), indicating improved risk classification. Mediation analysis suggested that C-reactive protein, Interleukin-6, and Fibrinogen mediate the relationship between Lp(a) and ASCVD. No significant interaction was observed between Lp(a) and potential moderators. CONCLUSION: Lp(a) levels can predict 20-year CVD outcomes and improve CVD risk prediction within the general population, possibly via the intricate relationship between Lp(a), systemic inflammation, atherothrombosis.

The burden of cardiovascular disease and related risk factors, in Greece; the ATTICA epidemiological study (2002-2022).

AIM: The aim of this study was to present the burden of cardiovascular disease (CVD) and its related risk factors based on a 20-year observation period (2002-2022). METHODS: In 2002, 3,042 Greek adults (aged: 45 (12) years) free of CVD, cancer, or any other chronic infections were enrolled. In 2022, the 20-year follow-up was performed on 2,169 participants (1,988 had complete data for CVD). Lifetime risk for CVDs and Disability-Adjusted-Life-Years (DALYs) lost were also calculated. RESULTS: The 20-year CVD incidence was 3,600 cases/10,000 individuals (man-to-woman ratio 5:4). At the index age of 40 years, the lifetime risk for developing CVD was 68% for men and 63% for women; as the participants were getting older, the lifetime risk declined by approximately 19% and 13% for men and women, respectively, but remained at high levels, reaching 55% for both sexes. Participants between 45-55 years exhibited the highest CVD burden concerning aggregated DALYs. The burden was greater in men than in women, at ages below 35 years; beyond this age threshold, this trend shifted, and women exhibited a higher CVD burden. CONCLUSION: The burden of CVD in Greece has shown increasing trends over the past 20 years as a result of the accumulative growth of the prevalence of modifiable CVD risk factors. The disability-adjusted life-years lost are the most observed ever before, urging for efficient public health strategies and measures.

Adherence to the Mediterranean diet and 20-year incidence of hypertension: the ATTICA prospective epidemiological study (2002-2022).

BACKGROUND/OBJECTIVES: Dietary habits are a significant predictor of hypertension (HTN). We aimed to evaluate the long-term association between adherence to the Mediterranean diet and HTN incidence. SUBJECTS/METHODS: This was a prospective study among 1415 non-hypertensive adults (44% men, age: 41 ± 13 years) followed up for 20 years. Anthropometric, lifestyle, and clinical parameters were evaluated at baseline. Adherence to the Mediterranean diet was evaluated both at baseline and 10 years through the MedDietScore (range: 0-55, higher values indicate greater adherence). RESULTS: At the 20-year follow-up, 314 new HTN cases were recorded. HTN incidence was 35.5%, 22.5%, and 8.7% in the lowest, middle, and upper tertile of baseline MedDietScore, respectively (p < 0.001). For each 1-point increase in baseline MedDietScore, the 20-year HTN risk decreased by 7% [relative risk (RR): 0.925, 95% confidence interval (CI): 0.906, 0.943], and this effect remained significant after adjustment for age, sex, and baseline lifestyle and clinical confounders, i.e., body mass index, physical activity, smoking, systolic and diastolic blood pressure, family history of HTN, and presence of hypercholesterolemia and diabetes mellitus (RR: 0.973, 95%CI: 0.949, 0.997). In a similar multiadjusted model, compared to subjects who were consistently away from the Mediterranean diet (in the lowest MedDietScore tertile both at baseline and 10 years), only those who were consistently close (in the middle and upper MedDietScore tertiles both at baseline and 10 years) exhibited a 47% lower 20-year HTN risk. CONCLUSION: A high adherence to the Mediterranean diet, particularly when longitudinally sustained, is associated with lower incidence of HTN.

Mediterranean-Type Diet Adherence and Body Mass Index through 20 Years of Follow-Up: Results from the ATTICA Cohort Study (2002-2022).

Evidence of the association between dietary habits and long-term body weight status is scarce. This study aimed to evaluate changes in Mediterranean-type diet (MTD) adherence in relation to body weight during 20 years of follow-up. Data from n = 1582 participants from the ATTICA cohort study (2002-2022) were used. MTD adherence was assessed via MedDietScore, and body weight status via body mass index (BMI) by 3 different measurements. We found that MTD adherence and changes in this adherence were inversely related to BMI at 20 years and the mean BMI during the 20-year follow-up. In multi-adjusted linear regression models, a 1/55 increase in baseline, 10-year, and 20-year MedDietScore was associated with a decrease of 0.05-0.13 kg/m2 in BMI at 20 years and of 0.08-0.09 kg/m2 in the mean BMI. Being consistently close to the MTD for 20 years was associated with a >90% decreased risk of maintaining overweight/obesity during the 20-year period. Strong, protective, long-lasting effects of the MTD were observed, even in those who deviated from the MTD in the follow-up (41% of the sample). Our results highlight the need to focus on the overall diet quality to minimize the risk of maintaining an excessive body weight during the life-course.

Long-Term Adherence to the Mediterranean Diet Reduces 20-Year Diabetes Incidence: The ATTICA Cohort Study (2002-2022).

This study aimed to evaluate the association between adherence to the Mediterranean diet and the 20-year incidence of type II diabetes mellitus (T2DM) among adults from the ATTICA study. This study involved a prospective cohort of 3042 men and women recruited at baseline from the Attica region in Greece. Sociodemographic, anthropometric, lifestyle, and clinical characteristics were evaluated at baseline and follow-up examinations; adherence to the Mediterranean diet was assessed through the MedDietScore (range 0-55); four Mediterranean diet trajectories were identified (i.e., increasing, decreasing, and sustained high and sustained low adherence levels). For the present analysis, data from 2000 individuals with complete information were used (age 43 ± 13 years; 49% men). Over the 20-year period, 26.3% (95%CI 24.4%, 28.3%) of participants developed T2DM; men exhibited a 1.5-times higher incidence compared to women (p < 0.001). Individuals consistently close to the Mediterranean diet throughout the studied period had an improved glycemic and lipidemic profile (at baseline and at 10-y follow-up) (all p-values < 0.001) and showed a 21% reduction in their 20-year risk of developing T2DM compared to those who were consistently away (RR = 0.79, 95%CI 0.47, 0.86). A long-term adherence to the Mediterranean diet is protective against the onset of T2DM and, therefore, could be incorporated in public health actions for the prevention of the disease.

Outcomes of COVID-19 re-infections: a single-center cohort of 167 patients with systemic rheumatic diseases.

Data on COVID-19 re-infections in patients with systemic rheumatic diseases (SRDs) are lacking. We aimed to describe the course and outcomes of COVID-19 re-infections in these patients versus controls. In this single-center retrospective study, we included 167 consecutive SRD patients with at least one COVID-19 re-infection (mean age 47.3 years, females 70.7%). SRD patients were compared in terms of patient-perceived COVID-19 re-infection severity and hospitalizations/deaths with 167 age/sex-matched non-SRD controls. Logistic regression analysis was performed to assess potential milder re-infection versus primary infection severity, adjusting for study group, demographics (age, sex), vaccination status, body mass index, smoking, and comorbidities. 23 and 7 out of 167 re-infected SRD patients experienced two and three re-infections, respectively, which were comparable to the re-infection rates in controls (two: 32; and three: 2) who also had comparable COVID-19 vaccination history (89% and 95% vaccinated, respectively). In the initial infection, patients with SRDs were hospitalized (7.2% versus 1.8%, p = 0.017), and had received antiviral treatment (16.1% versus 4.7%, p < 0.001) more frequently than controls. However, hospitalizations (1.8% vs 0.6%) and antiviral treatment (7.8% vs 3.5%) did not differ (p > 0.05) between patients and controls at the first re-infection, as well as during the second and third re-infection; no deaths were recorded. Perceived severity of re-infections was also comparable between patients and controls (p = 0.847) and among those on biologic DMARDs or not (p = 0.482). In multivariable analysis, neither SRDs presence nor demographics or comorbidities were associated with COVID-19 re-infection severity. COVID-19 re-infection severity (patient-perceived/hospitalizations/deaths) did not differ between SRDs and controls.

Non-invasive tools for liver steatosis and steatohepatitis predict incidence of diabetes, cardiovascular disease and mortality 20 years later: The ATTICA cohort study (2002-2022).

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) or, as recently renamed, metabolic dysfunction-associated steatotic liver disease (MASLD), has common metabolic pathways with diabetes and cardiovascular disease (CVD). Non-invasive tools (NITs) for liver steatosis and steatohepatitis (MASH) were studied as potential predictors of diabetes, cardiovascular disease (CVD) and mortality over a 20-year period. METHODS: In 2001-02, 3042 individuals from the Attica region of Greece were recruited randomly, and were stratified by subgroups of sex, age and region to reflect the general urban population in Athens, Greece. Validated NITs for hepatic steatosis (Hepatic Steatosis Index (HIS), Fatty Liver Index (FLI), Lipid Accumulation Product (LAP), NAFLD liver fat score (NAFLD-LFS)) and steatohepatitis (Index of non-alcoholic steatohepatitis (ION), aminotransferase-creatinine-clearance non-alcoholic steatohepatitis (acNASH)) were calculated. Incidence of diabetes, CVD and mortality were recorded 5, 10 and 20 years later. RESULTS: Within a 20-year observation period, the diabetes and CVD incidence was 26.3% and 36.1%, respectively. All hepatic steatosis and steatohepatitis NITs were independently associated with diabetes incidence. ION and acNASH presented independent association with CVD incidence [(Hazard Ratio (HR)per 1 standard deviation (SD) = 1.33, 95% Confidence Interval (95% CI) (1.07, 1.99)) and (HRper 1 SD = 1.77, 95% CI (1.05, 2.59)), respectively]. NAFLD-LFS which is a steatosis NIT indicating features of steatohepatitis, was linked with increased CVD mortality (HRper 1 SD = 1.35, 95% CI (1.00, 2.30)) and all-cause mortality (HRper 1 SD = 1.43, 95% CI (1.08, 2.01)). Overall, steatohepatitis NITs (i.e., ION and acNASH) presented stronger associations with the outcomes of interest compared with steatosis NITs. Clinically important trends were observed in relation to diabetes and CVD incidence progressively over time, i.e. 5, 10 and 20 years after baseline. CONCLUSIONS: Easily applicable and low-cost NITs representing steatohepatitis may be early predictors of diabetes and CVD onset. More importantly, these NITs increased the attributable risk conveyed by conventional CVD risk factors by 10%. Thus, their potential inclusion in clinical practice and guidelines should be studied further.

Increased body weight and central adiposity markers are positively associated with the 20-year incidence of cardiovascular disease: The ATTICA epidemiological study (2002-2022).

Increased adiposity predisposes to cardiovascular disease (CVD). We hypothesized that the presence of obesity would be positively associated with CVD risk, and that the co-presence of central obesity would modify/enhance this association. This was a prospective study (2002-2022) among 1845 Greek adults (mean age, 44.8 ± 13.5 years; men, 49.8%). At baseline, the presence of overweight/obesity was assessed via body mass index (BMI), whereas central obesity was defined as waist circumference ≥102/88 cm, waist-to-hip-ratio ≥0.95/0.80, or waist-to-height-ratio ≥0.50 in men/women. BMI was reevaluated at 10 years and longitudinal BMI trajectories (2002-2012) were identified. CVD incidence was recorded at 20 years (ratio of new cases to the number of participants assessed). Compared with participants with normal weight at baseline, those with obesity exhibited a 27% higher 20-year CVD risk after adjustment for age, sex, lifestyle habits, and medical status (hazard ratio, 1.271; 95% confidence interval, 1.012-1.597). In similar multiadjusted models, compared with participants who were always non-overweight/obese, those who were always overweight/obese exhibited a 40% higher 20-year CVD risk (hazard ratio, 1.403; 95% confidence interval, 1.018-1.936). Additional control for high-sensitivity C-reactive protein attenuated the associations. In the combined baseline body weight classification analysis, CVD incidence was the lowest in participants with normal weight without central obesity, moderate in those with overweight/obesity without central obesity, and highest in those with normal weight and central obesity and overweight/obesity and central obesity (P < .001). Obesity leads to increased CVD risk, partly mediated by inflammation. The combination of BMI with simple measures of abdominal adiposity is superior for CVD risk screening.

The impact of traditional cardiovascular risk factor control on 7-year follow-up atherosclerosis progression in systemic lupus erythematosus.

OBJECTIVES: The 2022 EULAR recommendations for cardiovascular risk management in patients with rheumatic disorders, including SLE, call for rigorous management of cardiovascular risk factors (CVRF). The impact of CVRF target attainment on atherosclerotic plaque progression hasn't been previously evaluated in prospective ultrasound studies. METHODS: A total of 115 patients with SLE and 1:1 age and sex-matched healthy controls who had a baseline carotid and femoral ultrasound examination in our cardiovascular research unit were invited for a 7-year follow-up assessment of new plaque development. We aimed to compare the incidence of plaque progression between SLE patients and controls and reveal the extent to which it is affected by the attainment of European Society of Cardiology (ESC) targets for modifiable CVRFs (blood pressure, smoking status, body weight, lipids and physical activity), and disease-related features (disease duration, disease activity, autoantibodies, treatments). RESULTS: Eighty-six SLE patients and 42 controls had a 7-year follow-up carotid and femoral plaque examination. New plaque development was observed in 32/86 patients vs 8/42 controls (P = 0.037). Patients with SLE had a 4-fold higher risk for plaque progression than controls (OR: 4.16, CI: 1.22, 14.19, P = 0.023), adjusting for potential confounders. Multivariate regression analyses showed a 50% decrease in plaque progression for every modifiable CVRF fulfilling ESC targets (OR: 0.56, CI: 0.34, 0.93, P = 0.026). CONCLUSION: Patients with SLE develop a rapid progression of atherosclerotic plaques which may be drastically reduced by CVRF target attainment according to ESC guidelines.

Nocebo-associated treatment discontinuation with subcutaneous anti-osteoporotic drugs. A systematic review and meta-analysis of placebo-arm dropouts in randomized-controlled trials.

OBJECTIVE: Nocebo is a concept of therapeutics referring to unpleasant symptoms attributed by a patient to a drug, due to negative anticipation. Patients receiving oral anti-osteoporotic drugs in randomized controlled trials (RCT) can experience adverse events leading to dropout, implying that nocebo contributes to treatment discontinuation for these drugs. In this study we aim to investigate the nocebo effect of subcutaneous anti-osteoporotic drugs with a higher compliance rate than orally administered drugs. STUDY DESIGN: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for double-blind trials investigating subcutaneous anti-osteoporotic drugs for osteoporosis (namely, denosumab, teriparatide, abaloparatide and romosozumab) published up to May 2023. MAIN OUTCOME MEASURE: Dropouts due to reported adverse events in the placebo arms ("nocebo dropouts"). RESULTS: Data from 17 trials were extracted. Among 10,529 placebo-treated patients the pooled nocebo-dropout percentage was 3 % for denosumab (average: 0.03; 95 % CI: 0.01-0.05), 1 % for romosozumab (average: 0.01; 95 % CI: 0.00-0.03) and 6 % for teriparatide and abaloparatide (average: 0.06; 95 % CI: 0.05-0.07). Nocebo-dropouts were significantly higher in men than women (6 % vs. 3 %, respectively, p = 0.012), in older (mean age >68 years) than in younger patients (5 % vs. 1 %, respectively, p = 0.017) and in those with more severe osteoporosis (based on the percentage of participants with prior fragility-related fractures in the study cohort) compared with patients with no prior fracture history (4 % vs. 1 %, respectively, p = 0.046). CONCLUSION: Nocebo responses may contribute to treatment discontinuation with subcutaneous anti-osteoporotic drugs in clinical practice. Higher nocebo-related dropout rates in the higher-risk RCT population (older patients, males, those with prior fractures) show that nocebo mechanisms have the potential to hinder therapeutic efforts to specific populations who would benefit most. Prospero registration number CRD42020212843.

Diet Quality and Consumption of Healthy and Unhealthy Foods Measured via the Global Diet Quality Score in Relation to Cardiometabolic Outcomes in Apparently Healthy Adults from the Mediterranean Region: The ATTICA Epidemiological Cohort Study (2002-2022).

The Global Diet Quality Score (GDQS) is a novel food-based score that assesses both nutrient adequacy and chronic disease risk, by evaluating healthy (GDQS+) and unhealthy foods (GDQS-). The aim of this study was to evaluate the association among GDQS, GDQS+, and GDQS- against the 20-year risk of cardiometabolic outcomes in a Mediterranean population. The sample was n = 2169 initially free of cardiovascular disease (CVD) participants of the ATTICA study (2002-2022) that participated in the 20-year follow-up. The incidence of CVD, hypertension, hypercholesterolemia, and type 2 diabetes mellitus (T2DM) was defined according to WHO-ICD-10 criteria. The GDQS was computed based on previously published instructions. In multivariate analyses, a higher diet quality, per 1/49 of the GDQS, was associated with an 8% [95% Confidence Interval-CI: 6-9%] and 2% [95% CI: 1-3%] lower CVD and T2DM risk, respectively. A higher consumption of healthy foods, per 1/32 of GDQS+, was associated with a 9% [95% CI: 7-11%] and 2% [95% CI: 1-3%] lower CVD and T2DM risk, respectively. Contrarily, a lower consumption of unhealthy foods (GDQS-) was not associated with cardiometabolic events in the adjusted models (all p value< 0.05). In clinical practice or future public health actions to ameliorate dietary habits and prevent CVD and T2DM, more attention should be focused on healthy foods that should be included in our diets.

Omicron variant dominance and anti-SARS-CoV-2 vaccination are key determinants for a milder course of COVID-19 in patients with systemic autoimmune rheumatic diseases.

INTRODUCTION: This study aimed to determine whether the introduction of anti-SARS-CoV-2 vaccines and the dominance of the omicron variant had a significant impact on the outcome of COVID-19 in patients with systemic autoimmune rheumatic diseases (SAIRDs). METHODS: Using data entered to the Greek Rheumatology Society COVID-19 registry, we investigated the incidence of hospitalization and death due to COVID-19, during the successive periods of the pandemic according to the prevalent strain (wild-type, Alpha, Delta, Omicron) in vaccinated and unvaccinated patients. Variables independently associated with hospitalization and death were explored using multivariate regression analyses, while Kaplan-Meier curves were used to depict survival data. RESULTS: From August 2020 until June 30, 2022, 456 cases (70.2% females) of COVID-19 with a mean age (± SD) of 51.4 ± 14.0 years were reported. In unvaccinated patients, the proportions of hospitalization and death were 24.5% and 4%, compared to 12.5% and 0.8% in the vaccinated group (p < 0.001 for both comparisons). The rates of hospitalization for the wild-type, Alpha, Delta, and Omicron periods were 24.7%, 31.3%, 25.9%, and 8.1% respectively (p < 0.0001), while the case fatality rates were 2.7%, 4%, 7%, and 0%, respectively (p = 0.001). Using multivariable regression analysis, factors independently associated with hospitalization were infection by a non-Omicron variant, being non-vaccinated, exposure to rituximab, older age, and respiratory and cardiovascular disease. Independent predictors for death were contracting COVID-19 during the Alpha or Delta period, pulmonary disease, and older age, while being vaccinated was protective. CONCLUSIONS: In this 2-year analysis, the rates of hospitalization and death among patients with SAIRDs have declined significantly. Vaccination and the dominance of the Omicron variant appear to be the major determinants for this shift. Key points • During the late phase of the pandemic, the proportion of severe COVID-19 cases, defined as requiring hospitalization or resulting in death, in patients with systemic autoimmune rheumatic diseases has declined. • Anti-SARS-CoV-2 vaccination and the dominance of the Omicron strain are the key factors that have independently contributed to this shift.

Associations between meat type consumption pattern and incident cardiovascular disease: The ATTICA epidemiological cohort study (2002-2022).

BACKGROUND: Meat consumption has shown from detrimental to beneficial effects against cardiovascular disease (CVD) incidence, mainly depending on the type of meat studied (i.e., red/white, processed/unprocessed) and quantity consumed. OBJECTIVE: To examine the associations between meat type consumption patterns and incident CVD among apparently healthy adults. DESIGN: ATTICA study was conducted in the greater metropolitan Athens area, Greece, during 2001-2002 studying adults free-of-CVD at baseline. Twenty-year follow-up was performed in n = 1988 participants (n = 718 incident cases). Meat consumption during the follow-up period was categorized as: never/rare meat consumption (i.e., <1 time/week), mostly red meat (i.e., compared to other types of meat or processed meat), mostly white meat, and mostly processed meat products (e.g., bacon, sausage). RESULTS: Approximately 38% of the participants reported rare or no consumption of any type of meat, 31% consumed mostly red meat, 19% mostly white meat and the remainder 12% mostly processed meat. In multivariate analysis, compared to never/rarely consuming any type of meat, consuming mostly processed meat [HR: 2.89, 95%CI: 1.05, 7.89], but not red meat [HR: 1.22, 95%CI: 0.81, 1.82], was positively associated with incident CVD during 20 years of follow-up, while consuming mostly white meat was inversely associated with incident CVD [HR: 0.35, 95%CI: 0.17, 0.71]. CONCLUSIONS: The findings of this study suggest that the type of meat, irrespective of the frequency of consumption, plays a role in the risk of developing CVD. In clinical practice, emphasis should be placed on avoiding processed meat and replacing it with white unprocessed meat.

Inappropriate prescribing in geriatric rural primary care: impact on adverse outcomes and relevant risk factors in a prospective observational cohort study.

BACKGROUND: Several tools have revealed an association between potentially inappropriate medications (PIM) and adverse outcomes, but the one most fitted for the rural population has not been determined. AIMS: We investigated the performance of the Screening Tool of Older Persons' Prescriptions (STOPP) and Screening Tool to Alert doctors to the Right Treatment (START) in identifying inappropriate prescribing and its association with adverse outcomes among older rural primary health care users. METHODS: A cohort of consenting outpatients aged ≥ 65 years in a rural Greek primary care center was assessed for PIM and potential prescribing omissions (PPO) using the START/STOPP version 2 criteria. Medications, comorbidities, functional status, and laboratory data were recorded along with 6-month incidence of emergency department visits, hospitalization, and death prospectively. RESULTS: Among 104 participants (median age 78 years, 49.1% women, receiving a median of 6 drugs), PPO was found in 78% and PIMs in 61%. PIM was multivariately correlated with multimorbidity (p = 0.029) and polypharmacy (p < 0,001), while drug-PPO was only associated with multimorbidity (p = 0.039). The number of PIM predicted emergency department visits and hospitalizations at 6-month follow-up (p value 0.011), independent of age, sex, frailty, comorbidities, and total medication number. DISCUSSION: The START/STOPP tool is useful in identifying inappropriate prescribing patterns leading to increased utilization of acute care services in older adults followed at a rural primary care setting. CONCLUSION: Inappropriate prescribing as identified by the START/STOPP criteria is prevalent among older adults with multimorbidity in rural primary care, and independently associated with future acute care visits.

Lifestyle Trajectories Are Associated with Incidence of Cardiovascular Disease: Highlights from the ATTICA Epidemiological Cohort Study (2002-2022).

The study aimed to assess the trajectories of lifestyle characteristics and their association with 20-year cardiovascular disease (CVD) incidence. In 2002, 3042 Greek adults (aged: 45 (12) years) free of CVD were enrolled. In 2022, the 20-year follow-up was performed on 2169 participants; of those, 1988 had complete data for CVD. The 20-year CVD incidence was 3600 cases/10,000 individuals; the man-to-woman ratio was 1.25, with the peak difference in the 35-45 age group (i.e., 2.1); however, a reversal of the trend was observed in the age-groups 55-65 and 65-75, with a resumption of an almost equal incidence in those >75 years. In multi-adjusted analysis, age, sex, abnormal waist circumference, hypercholesterolemia, hypertension, and diabetes were positively associated with 20-year CVD risk, explaining 56% of the excess CVD risk, whereas an additional 30% was attributed to lifestyle trajectories; being physically active throughout life-course and being close to the Mediterranean diet were protective, while continuous smoking was detrimental against CVD risk. Mediterranean diet adherence protected against CVD development even if not sustained, while quitting smoking or engaging in physical activities during the 20-year observation did not offer any significant protection. A life-course personalized approach that is cost-effective and long-term sustained is needed to prevent CVD burden.

Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age.

Aging is characterized by the progressive deregulation of homeostatic mechanisms causing the accumulation of macromolecular damage, including DNA damage, progressive decline in organ function and chronic diseases. Since several features of the aging phenotype are closely related to defects in the DNA damage response (DDR) network, we have herein investigated the relationship between chronological age and DDR signals in peripheral blood mononuclear cells (PBMCs) from healthy individuals. DDR-associated parameters, including endogenous DNA damage (single-strand breaks and double-strand breaks (DSBs) measured by the alkaline comet assay (Olive Tail Moment (OTM); DSBs-only by γH2AX immunofluorescence staining), DSBs repair capacity, oxidative stress, and apurinic/apyrimidinic sites were evaluated in PBMCs of 243 individuals aged 18-75 years, free of any major comorbidity. While OTM values showed marginal correlation with age until 50 years (rs = 0.41, p = 0.11), a linear relationship was observed after 50 years (r = 0.95, p < 0.001). Moreover, individuals older than 50 years showed increased endogenous DSBs levels (γH2Ax), higher oxidative stress, augmented apurinic/apyrimidinic sites and decreased DSBs repair capacity than those with age lower than 50 years (all p < 0.001). Results were reproduced when we examined men and women separately. Prospective studies confirming the value of DNA damage accumulation as a biomarker of aging, as well as the presence of a relevant agethreshold, are warranted.

Meta-analysis of placebo-arm dropouts in osteoporosis randomized-controlled trials and implications for nocebo-associated discontinuation of anti-osteoporotic drugs in clinical practice.

Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients' negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice. PURPOSE: Osteoporosis is a common disease requiring long-term treatment. Despite the availability of effective anti-osteoporotic drugs, adherence to treatment is low. Nocebo, a behavior mostly related to the negative expectations to a certain treatment, decreases adherence and negatively affects treatment outcomes and health-related care costs in chronic diseases. Since in double-blind placebo-controlled randomized trials any unfavorable outcome leading to discontinuation in placebo arms is considered as nocebo, we aimed to investigate the size of nocebo response in patients participating in osteoporosis trials. METHODS: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for dropouts due to reported adverse events in the placebo arms (nocebo dropouts) in all double-blind trials investigating anti-osteoporotic drugs published between January 1993 and March 2022. Only data on bisphosphonates and selective estrogen receptor modulators (SERMs) were analyzed (Prospero registration number CRD42020212843). RESULTS: Data from 44 trials were extracted. In 16,460 placebo-treated patients, the pooled nocebo-dropout was 8% both for bisphosphonates (average: 0.08; range 0.01-0.27; 95%CI 0.06-0.10) and SERMs (average: 0.08; range 0.03-0.15; 95%CI 0.05-0.13). Nocebo-dropouts were higher in bisphosphonate trials enrolling individuals ≥ 65 years (11%) (n = 18) compared to trials enrolling younger individuals (6%) (n = 18) (average: 0.11; 95%CI 0.08-0.13 vs. average: 0.06; 95%CI 0.05-0.08, respectively, p = 0.001). Participants' sex, dosing-intervals, publication year, or severity of osteoporosis had no impact on the nocebo-dropouts. CONCLUSION: Almost 1 in 10 osteoporosis patients receiving placebo in trials of bisphosphonates and SERMs experiences AEs leading to dropout, implying that nocebo contributes to treatment-discontinuation in clinical practice. Efforts to identify and minimize nocebo, especially in older patients, are warranted.

Geriatric Frailty Is Associated With Oxidative Stress, Accumulation, and Defective Repair of DNA Double-Strand Breaks Independently of Age and Comorbidities.

Defects in the DNA damage response and repair (DDR/R) network accumulate during the aging process. Physical frailty, a state of reduced physiological function and decreased resilience to biological stressors, is also exacerbated by aging, but its link with DDR/R aberrations beyond the effect of age and comorbidities is unclear. Fifty-three community-dwelling older adults, aged 65-102 years, who underwent frailty classification according to the Rockwood Clinical Frailty Scale (CFS), and 51 healthy adults younger than 45 years were examined in parallel. The following DDR/R parameters were determined in their peripheral blood mononuclear cells (PBMCs): (a) oxidative stress and abasic (apurinic/apyrimidinic; AP) sites, (b) endogenous DNA damage (alkaline comet assay olive tail moment [OTM] indicative of DNA single-strand breaks [SSBs] and double-strand breaks [DSBs] and γH2AX levels by immunofluorescence [DSBs only]), (c) capacity of the 2 main DNA repair mechanisms (DSB repair and nucleotide excision repair). Older individual-derived PBMCs displayed reduced-to-oxidized glutathione ratios indicative of increased levels of oxidative stress and increased AP sites, as well as increased accumulation of endogenous DNA damage (OTM and γH2AX) and defective DSB-repair capacity, compared with younger controls. These DDR/R aberrations were more pronounced in frail versus nonfrail older adults. Notably, oxidative stress, AP sites, DSBs, and DSB-repair capacity were associated with individual CFS levels after adjusting for chronological age, sex, Charlson Comorbidity Index, and polypharmacy. Geriatric frailty is independently associated with increased DNA damage formation and reduced DSB-R capacity, supporting further research into these measures as potential frailty biomarkers.

Mediterranean Diet and Cardiovascular Disease: The Moderating Role of Adequate Sleep-Results from the ATTICA Cohort Study (2002-2022).

The relationship between diet, sleep duration and cardiovascular disease (CVD) has not been well understood. The aim of the present study was to test the potential modifying role of sleep duration in the association between adherence to the Mediterranean-type diet (MD) and CVD risk. The study consisted of n = 313 initially free-of-CVD adults, from the ATTICA cohort study (2002-2022), with available information on sleep habits. Sleep habits were categorized as inadequate and adequate sleep duration (< or ≥7 h/day, respectively). In multi-adjusted analysis, MD adherence was inversely associated with CVD risk [Hazard Ratio-HR per 1/55 in MedDietScore: 0.80, 95% Confidence Interval-CI: 0.65, 0.98]. A significant interaction between sleep duration and MedDietScore was observed (p < 0.001). In subgroup analysis, the protective association between MD adherence and CVD risk was found only in participants who slept adequately, i.e., >7 h/day [HR:0.80, 95%CI: 0.65, 0.98]. Those who had a high adherence to the MD along with adequate sleep habits, had a 70% reduced 20-year CVD risk [HR:0.30, 95%CI: 0.11, 0.80], compared to those who had a low MD adherence and inadequate sleep habits. Sleep duration should be a part of an individual's lifestyle, together with dietary and other habits, to effectively evaluate CVD risk for future events.